 
# The Fast Track to Fertility

## Sherif G. Awadalla, M.D.

## Michael D. Scheiber, M.D.

## Thomas H. Burwinkel, M.D.

### Institute for Reproductive Health

### Cincinnati, Ohio
This book is intended as a guide and not a prescription for your infertility treatment. The book stresses that medical consultation sooner rather than later will give the best outcome. This book is not a substitute for treatment by a qualified health care professional. The authors and publisher are not responsible for any adverse outcomes or consequences which are experienced by any individual utilizing the information contained in this book. Use this book to help you understand medical treatment and not as a substitute for professional health care.

Clomid,Serophene, Gonal-F, Follistim, Bravelle, Repronex

Menopur Femara Letrozole, Arimidex (anastazole), metformin

(Glucophage), Avandia, Actos, Pergonal, Lupron, Depo-Provera,

Danazol, Provera, and Aygestin are all registered trademarks.

Copyright 2008, 2011 Sherif G. Awadalla, M.D. and Michael D. Scheiber, M.D.

All Rights Reserved.

Smashwords Edition

No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording or by any information storage and retrieval system, without permission in writing from the publisher. Inquiries should be addressed to:

Institute for Reproductive Health  
3805 Edwards Avenue  
Suite 450  
Cincinnati, Ohio 45209  
513-924-5550  
www.cincinnatifertility.com

Printed in the United States of America

111011

First Edition - ISBN: 1-929733-59-3 (9781929-733590)

Second Edition - ISBN: 1-929733-70-4 (9781929-733705)

### MicroPress

Custom Publisher

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# Table of Contents

#### Acknowledgements

#### Introduction
#### Chapter 1: The Big Picture

#### Chapter 2: Normal Human Reproduction and Maximizing Natural Conception
#### Chapter 3: Common Causes of Infertility

#### Chapter 4: Finding the Cause (Diagnostic Work Ups)
#### Chapter 5: Treatment Options (An Overview)

#### Chapter 6: Ovulation Drugs and Insemination Therapy
#### Chapter 7: Surgical Treatment of Infertility

#### Chapter 8: In Vitro Fertilization and Preimplantation Genetic Diagnosis
#### Chapter 9: Post-Sterilization Fertility (What to Do after Tubal Ligation or Vasectomy)

#### Chapter 10: The Male Factor
#### Chapter 11: Endometriosis

#### Chapter 12: Polycystic Ovary Syndrome

Chapter 13: Hormones and Reproduction

#### Chapter 14: Miscarriage and Recurrent Pregnancy Loss
#### Chapter 15: Third Party Reproduction: Donor Eggs, Donor Sperm, Donor Embryos, Surrogacy and Gestational Carriers

#### Chapter 16: Gender Selection and Family Balancing
#### Chapter 17: The Fertility Lifestyle

#### Chapter 18: Emotional Balance (contributed by Joyce Sutkamp Friedeman, PhD, APRN, LPCC)
#### Chapter 19: Dealing with Insurance (contributed by Sheila Lilze)

#### Summary

# Acknowledgements

Writing this book was a two year initial effort. We knew that the time was right because so much has changed in our field. We knew that couples were constantly searching for information. Because the field is rapidly changing many of the available books are outdated. To give you an idea of the rapidity of change, several chapters had to be modified while the book was in preparation in order to make their content timely and relevant. What we did not know at the beginning was what a mammoth undertaking this book would be.

We want to thank several individuals for contributing a chapter each. Dr. Shane Russell contributed an excellent chapter on the male factor. Dr. Jason St Pierre contributed a section of male reproductive physiology. Dr Joyce Friedman wrote the chapter on emotional concerns. Two of our expert billing specialists wrote the chapter on dealing with insurance. Sheila Lilze and Karen Hauser contributed this chapter which addresses one of the most pressing concerns of our patients. We also were fortunate enough to have two excellent contributors to the graphic content of the book. Our graphics illustrator was Tori Ratcliffe. Also Shannon Kolatz who was a student at the University of Michigan contributed several excellent diagrams for the book.

We would like to thank our wives for supporting us through this project. They assumed many of our duties at home so we would have time to work on the book. Susan Awadalla contributed the title of the book. Jayne Scheiber from the Department of Chemistry at Berkley contributed greatly to the editorial process. Our dedicated office staff made many suggestions for improvement during manuscript preparation. Several of our patients read early versions of the manuscript and made helpful suggestions. They encouraged us to continue the effort.

We have tried to make the information in this book as accurate and comprehensive as possible. It is intended as a guide and not a prescription for your infertility treatment. We have stressed in the book that medical consultation sooner rather than later will give you the best outcome. We want to emphasize that this book is not a substitute for treatment by a qualified health care professional. We therefore are not responsible for any adverse outcomes or consequences which are experienced by any individual utilizing the information contained in this book. Please use this book to help you understand medical treatment. It is certainly not a substitute for professional health care.

# Introduction

This work is a contemporary guide to the efficient diagnosis and treatment of infertility. It is written for the millions of couples all over the world who suffer from this common condition. Because of the stigma associated with the inability to conceive, couples with this disorder suffered silently for decades. Fortunately, there is more and more discussion about infertility today. Unfortunately, much of this discussion comes in the form of tabloid covers, sensational TV talk shows, TV drama series, and advice from helpful but misinformed family members and friends. Much of the readily available information about infertility is outdated, extremely fragmented, or comes from random and inaccurate web site postings. The resultant discussion of infertility is, therefore, often full of myths and misconceptions.

Few people who don't suffer from infertility understand the emotional pain associated with this condition. As physicians who have decades of combined experience with infertility treatment, we see couples constantly searching for accurate information. Couples want to know what causes infertility and what treatment is best for them. They worry about the cost of treatment, the possibility of failure, and the risk of multiple births. It is for these couples that we have written _The Fast Track to Fertility_.

The field of infertility treatment has undergone revolutionary changes with the advent of _In Vitro_ Fertilization (IVF) and the associated reproductive technologies. New effective treatments and medications become available every year. Now, more than ever, there is a true need for an accurate, timely book that clearly explains the truth and dispels the myths and misconceptions surrounding fertility diagnosis and therapy.

This book discusses in clear, concise, and medically accurate lay terms the basics of normal human reproduction. It discusses the causes of infertility. Most important, we outline the steps in diagnosing and treating this medical condition efficiently. It is towards this goal that we have designated the emphasis of this book as the "Fast Track to Fertility." While this term is often used in the fertility community to refer specifically to a strategy of skipping certain steps in treatment and going immediately to IVF, we use the term more broadly to refer to an individualized strategy for each couple. We attempt to stress the importance for each couple of quickly identifying the cause of infertility and moving very quickly to a specific treatment plan to maximize their fertility potential with a minimum of cost and suffering. For many couples the Fast Track may mean moving quickly to IVF. For other couples the Fast Track may be as simple as lifestyle changes. But for all couples, the point remains that the sooner a problem is identified and treated appropriately by a professional, the better the chances are for a healthy conception and pregnancy outcome.

Infertility treatment does not have to take forever! In fact, using the Fast Track approach outlined here, the majority of cases can be resolved within six to seven months and many cases even sooner. We offer advice on how to deal with the emotional trauma associated with infertility, as well as practical guidance on lifestyle issues that impact fertility. This book offers a sobering warning to those who attempt to defy the biologic clock. It also offers hope for those who seek out the facts and have the courage to pursue their dream of parenthood.

We have been privileged to have worked with thousands of couples over the years and have obtained a successful outcome for the majority of those couples. We have learned that infertility treatment is more of a journey than a destination. This book is intended as a tribute to the perseverance and endurance of those who have journeyed with us. It is also intended to offer hope and guidance to those of you who are just beginning your own journey and to ensure that your journey takes the Fast Track!

# Chapter 1  
The Big Picture

## Why this book is written just for you...

If you're reading this book, most likely you or someone you love is suffering from infertility. You already know the heartbreak of facing a menstrual period month after month and possibly year after year. The average couple suffers through two to four years of this ordeal before seeking help. We regularly see couples who have suffered with infertility for more than ten years.

Infertility is painful enough to deal with in and of itself. But none of us lives in a vacuum. While you're not getting pregnant, you take note of the fact that everyone else around you seems to be! Your friends and family are constant reminders of your ordeal. Baby showers, pregnant women, strollers at the mall, and holidays are all powerful reminders that everyone else has what you don't have! Many couples rate infertility as the most emotionally stressful experience of their lives. It can damage your self-esteem as a man or a woman. It can cause depression and extreme anxiety. And infertility can be traumatic for your relationship as a couple. While it is true that hardship can bring you closer together as a couple, it can also tear you apart.

Adding stress to the couple's relationship is the fact that men and women often see the same picture from different angles. In our experience, women often view infertility as an urgent problem in need of immediate resolution. Men are more willing to take a "let's keep trying and maybe it will happen" approach. Be careful. This latter approach can throw you right off the Fast Track to fertility and severely limit your treatment options and odds of success.

There can also be a great deal of denial associated with infertility. The majority of naturally conceived pregnancies will occur within six to nine months of unprotected intercourse. The couple who says, "We've only been trying for a year" but hasn't used any form of contraception for five years, has really experienced at least five years of infertility. They have already wasted precious time with the diagnosis and treatment of their condition.

Even one month of trying to get pregnant unsuccessfully can be an ordeal. The month starts and you wonder when you will ovulate. Maybe you're using an ovulation prediction kit or a temperature graph. You get up every day to test your temperature, urine or both. You may be worried that you are not having sex at the right time of the month. Should you have sex every day, every other day, or several times a day? Can having sex too frequently also be a problem? The most intimate part of your lives can become a burdensome chore under these circumstances, driving a wedge between you.

During this ordeal, everyone you know seems to be telling you to relax and you'll get pregnant. What could be more annoying! How can you relax when you're going through all this? You get through the ovulation time and you wait day after day, hoping and praying that your menstrual period won't start. It does start. How depressing! No one needs to face failure in addition to cramping and bleeding every month. Your friends and family have already offered unsolicited, well-meaning, and probably useless advice. Every month you must decide anew if you should go to see your family physician, your Ob/Gyn or a specialist. Or should you wait and just keep trying?

If this scenario sounds all too familiar, you have come to the right place. This book is about one thing: helping you to get pregnant as quickly as possible. In most cases pregnancy should be possible within six to seven months or even sooner when handled appropriately by a qualified and caring physician! When doctors treat a medical condition, their goal is to obtain a cure as soon as possible. Why then is the treatment of infertility usually so dragged out? It is because doctors and patients have been taught to view it as a non urgent condition. We beg to differ! If you can't get pregnant, then it is an urgent issue for you! The biologic clock, as you will come to see, never stops ticking.

You may have understandably already waited a little too long to start thinking about getting pregnant. You wanted to finish your education, get established at work and maybe buy a house. But don't delay any further. It is important to consider that you may want to have more than one child. If treatment for the first pregnancy takes forever, the second chance may be gone. All of these issues make staying on the Fast Track urgent! If you feel this sense of urgency, then this book is written just for you.

This book can be your starting point on the Fast Track to fertility. It will provide you with the basic facts about normal and abnormal reproduction and guidelines for the efficient diagnosis and treatment of infertility. In our combined experience of treating infertility seven days a week for over three decades, we have learned most of the pearls and potholes that you may encounter. This book will let us help you take advantage of the pearls and avoid the potholes so that you can stay on the Fast Track to fertility.

### Infertility: Fact vs. Fiction

Infertility is defined as the failure to conceive after one year of intercourse without any form of protection. Infertility is a global problem that affects 15 to 18 percent of couples of childbearing age worldwide. The Center for Disease Control (CDC) estimates that 7 million U.S. couples have difficulty with fertility.

Although knowledge in the field of infertility has expanded dramatically, there have been barriers to the delivery of healthcare in this area. Infertility can cause a couple to experience both physical and emotional stress. Patients with infertility should receive the same quality of care and the same kind of insurance coverage as patients with other medical conditions. Most developed countries, including England, France, Australia, Japan, and many others, offer much better infertility benefits than the United States. In order to improve the delivery of these services, we must educate patients, physicians, nurses, and hospital administrators as well as Congress and health insurers. Today, more than ever, we are able to treat successfully most conditions that cause infertility. Evaluation and treatment of infertility should not be delayed because of myths and misconceptions held by both healthcare professionals and the general public.

For instance, it is widely believed that stress causes infertility. In truth, physical and emotional stress is more likely the result rather than the cause of infertility. Perhaps because infertility is an issue that generally affects women, it has unfortunately been trivialized for decades. It is often easier to tell women to "relax and you will get pregnant" than to deal with the underlying disease process that is causing the infertility. It is both frustrating and annoying for someone going through infertility treatment to hear that if they just relaxed they would get pregnant. Relaxing has never been shown to unblock damaged tubes or change a sperm count of zero!

One common misconception is that if you are patient and just keep trying, pregnancy will eventually occur. The unfortunate fact is that if one year has passed without conception, it is relatively unlikely that pregnancy will ever occur without medical assistance. After the first year of infertility, the yearly conception rate will not exceed 4 to 5 percent for most couples.

Another misconception is that having intercourse at the wrong time within the menstrual cycle can lead to infertility. It is highly unlikely that a couple having intercourse as little as twice a week on average will experience infertility of any significant duration due to poor coital timing. In addition, studies have shown that, even in couples who are not trying to conceive, the frequency of intercourse tends to be greatest around the time of ovulation, perhaps related to hormonal effects on human behavior.

One thing that is crystal clear is that the age of the woman (and to a lesser extent the man) does dramatically affect her odds of ever conceiving. This is commonly known as the "biologic clock." It is now understood that the egg supply undergoes constant attrition during human life and that this attrition starts prior to birth in the fetal stage. It is therefore ideal that evaluation and treatment of infertility occur as early as possible to obtain the best possible outcome. Sperm quality in men will also decrease with age somewhat, but the change in pregnancy potential is much less significant that that with women. Delaying evaluation and treatment may leave patients with fewer options and lower success rates.

Don't let any of these myths bump you off the Fast Track to fertility. Remember, the sooner you get help, the sooner you're likely to get pregnant.

### When should you look for help?

Couples often wonder when they should seek evaluation and treatment. In young, healthy couples without fertility concerns, the conception rate per menstrual cycle is approximately 22 percent. At six months of attempting conception, roughly 80 percent of all couples have been successful. At one year, roughly 85 percent have conceived. In couples that have not conceived after one year, the monthly conception rate decreases dramatically with each subsequent cycle. **Therefore, it has been traditional to recommend that couples seek treatment after approximately one year of unprotected intercourse. If the wife is thirty-five or more years of age, it is now recommended that they seek treatment after six months due to the effect of the biologic clock on the ovary.**

Women in their mid-twenties are at their peak fertility potential. Following the age of thirty-two, there is a significant decrease in monthly fertility rate. Following the age of thirty-eight, there is further dramatic decrease in monthly fertility. Another reason to seek therapy early is that the incidence of miscarriage rises significantly after the age of thirty-five and dramatically after the age of forty. For women in their mid-twenties, the miscarriage rate is roughly 20 percent. Women who are greater than forty years of age have miscarriage rates that approach 40 to 50 percent. In patients in their late thirties and early forties, the incidence of chromosomal errors such as Down syndrome also increases dramatically, making early treatment not only more successful but safer as well.

In addition to age, other factors should prompt couples to seek help sooner. If there is a history of gynecologic surgery such as removal of a tube or ovary, you should be evaluated earlier. If you have had a pelvic infection in the past such as Chlamydia or gonorrhea, then earlier evaluation is better. If your menstrual cycles are irregular, then you should seek help immediately. Similarly, a history of infertility in a previous relationship should prompt you to seek help quickly.

Waiting too long will frequently lead to poorer results with treatment. People tend to delay evaluation because of hope and fear. They hope that they will get pregnant if they just keep trying. They are afraid that treatment will be difficult and expensive. Ironically, waiting too long is the best way to make treatment more difficult and more expensive. Early diagnosis and treatment is your ticket to success with the least amount of pain!

### What type of specialist should you see?

In most communities the obstetrician/gynecologist (Ob/Gyn) will be the first contact point. He or she is a doctor trained specifically in all aspects of care of the woman's reproductive system. The Ob/Gyn treats pregnant and non pregnant women, delivers babies, performs hysterectomies, and provides other gynecological services. He/she is also involved in annual screening exams that include Pap smears and mammography. To some extent he/she will also be involved in the care of the infertile patient. During residency training, the Ob/Gyn will have had some brief but specific training in infertility. If your Ob/Gyn has time, he/she can certainly be involved in the initial diagnosis and treatment process. If you are thirty-five years or older or, if after working with the Ob/Gyn for four to six months you have still not conceived, then referral to an infertility specialist is critical. Once you conceive, your Ob/Gyn or nurse midwife can then take care of you again and will be the one to deliver your baby.

A family practice physician treats adult men and women as well as children. This primary care physician has had some training in obstetrics and gynecology. He or she will usually do very little infertility diagnosis and treatment. Your family physician can be an excellent source of referral to a qualified specialist. Some family physicians still do deliveries and will resume your care once you are pregnant.

For a variety of reasons, you may choose to see an "infertility specialist." Perhaps your doctor has referred you, or you as a couple have made the decision to seek expert care because too much time has passed without conception. Reproductive Endocrinology and Infertility ( **REI)** is a formal subspecialty of Obstetrics and Gynecology, and a true infertility specialist is called a **Reproductive Endocrinologist (RE).** A Board Certified RE has been trained twice: once for four years of residency as an Ob/Gyn, and then a second time for three years of fellowship as an RE. He or she has had to pass four separate board certification examinations, two for general OB/GYN and then two more for REI, to become a board certified infertility specialist. Typically an RE only treats infertility and female hormonal disorders. He or she will not do deliveries or general gynecologic services. Focusing only on infertility treatment allows the RE to dedicate sufficient time and resources to treat the more complex cases of infertility in the community.

It is important to distinguish between someone specializing in infertility and an infertility specialist. Any physician can advertise to specialize in infertility treatment. However, only a Board Certified Reproductive Endocrinologist has been specifically trained and certified to be an infertility specialist.

For the male member of an infertile couple, a family physician, Ob/Gyn, internist or urologist can order the initial semen analysis. If the semen parameters are abnormal or if there is some physical difficulty such as with a prostate infection, then a urologist will be consulted. He or she is a specialist in the male reproductive tract. All urologists have been trained in male infertility. They can do basic evaluation and testing. Some urologists have been subspecialty trained in male infertility and routinely perform vasectomy reversals or testicular sperm aspirations. These techniques are discussed in detail in later chapters. Your Ob/Gyn or RE can refer you if necessary to a urologist who specializes in infertility treatment.

### How Do You Choose a Specific Doctor or Practice?

Once you have made the important decision to seek help from either an Ob/Gyn or a specialist like an RE, you have the task of selecting a particular physician or group. This choice is extremely important, as these professionals will be the conductors on your Fast Track to Fertility. You want to work with a doctor who is competent, communicative, and understands how you feel about the situation. If you have been trying for a long time or are over thirty-five, then you will probably want to see an RE right away. If you are just beginning the investigation or are younger, then an Ob/Gyn will be able to help you with the initial diagnosis and treatment of infertility. You can often get a recommendation of a specific doctor or group of doctors from friends and family. Your primary care doctor can also suggest a physician or group for you to see. Some local or national infertility organizations also maintain referral lists. If seeing pregnant women in the waiting room of your Ob/Gyn's office upsets you, then choose an RE where most of the other patients will not be visibly pregnant and will understand what you're going through.

Once you have narrowed down your search, call the office and talk to a nurse about the doctors in the group and the type of patients whom they care for. Ask a few questions about infertility to see if the staff is familiar with this condition. Often the attitude of the staff will mirror that of the doctors. Look at the group's web site. It should give you a lot of information about the staff, their credentials, and the range of services that they offer.

Many prospective patients also stop by and make an appointment in person. This gives you the opportunity to see what the office looks like. While the appearance of a practice is certainly not everything, it does give you some clues as to how busy it is and what kinds of patients the practice is caring for. Ask if the practice offers _in vitro_ fertilization (IVF) if you feel that you might need this service. That way if you end up needing IVF, you will not have to start a whole new relationship with a whole new practice before receiving the treatment you need.

If you are definitely interested in IVF or think that it may be your best treatment option, find out how many cycles are done each year by the practice. More experienced centers may be better equipped to deal with difficult or unusual cases. Do they see patients Monday through Friday only? If you need ovulation medications or IVF, you may likely need to be seen on Saturdays or Sundays. Ask if the doctors are board certified in Ob/Gyn and Reproductive Endocrinology. Remember that it takes a few years after training to be board certified. A doctor in his or her thirties can still be board eligible. By the early forties, most physicians have had time to complete board certification.

### What can you do to help?

Besides seeking help early and finding the right doctors, there are certain other things you can do while trying to get pregnant to help start out on the Fast Track to fertility. You should take a prenatal or multivitamin containing folic acid. Don't wait until you are actually pregnant, as being on these supplements before conception may help reduce birth defects. Avoid vaginal douching as it can change the acidity as well as the normal bacterial environment of the vagina. Most commercial personal lubricants can be destructive to sperm, and their use during intercourse should be discouraged.

Try to maintain a normal body weight. Being too thin or too heavy will affect ovulation and sperm production adversely. Excess weight is an extremely common cause of ovulation problems in women. Remember you don't have to bring your weight down to normal to make a big difference. Often a 10 percent weight loss can return women to normal ovulatory menstrual cycles. Men need to avoid hot tub or whirlpool use, as the heat can damage or kill their sperm. Once pregnant, women will need to avoid hot tub use also.

Other environmental factors such as smoking tobacco or marijuana can also have a negative impact on fertility. Smoking lowers pregnancy rates and increases miscarriage rates. It is not enough to say, "I will quit once I am pregnant." Smoking itself will reduce the chance of getting pregnant and having a healthy outcome. For men, smoking causes lower sperm counts and abnormalities in sperm structure and movement. Smoking cessation is very difficult. You should talk to your family doctor about medications or smoking cessation programs if you are having a hard time quitting. Acupuncture and hypnosis may also provide help in kicking the habit. Contact the American Lung Association about local programs. Smoking cessation is a huge challenge for most individuals. Try starting with some small steps. If you can cut down smoking by 50 percent, think of how much healthier you will be and how much money you can save!

Talk to your doctor honestly about alcohol or other substance intake. Remember, all conversations with your physician are bound by ethical rules to be completely confidential. If you drink regularly, meaning almost every day, that can be a problem for both men and women trying to conceive. Once pregnant, women should not drink alcohol at all. If you occasionally drink heavily or go on binges, that can also be a problem. Try not to get angry or defensive if your spouse brings this up at the appointment with your physician. All concerns should be freely aired.

Try not to let intercourse become a burden. Remember, you were physically attracted to each other before you were trying to have a baby! Intercourse should generally be two to three times per week around the mid-cycle for women with regular menstrual cycles. Obviously this is more difficult to time if your cycles are irregular, which is why it is important to seek help sooner in this situation. Tell your doctors if there are problems with intercourse. If there is a difficulty with erection or ejaculation, your doctor can recommend specific treatments.

Try to be supportive of each other. The last thing you need is to beat up on each other emotionally. It is common for one person or the other to feel that the infertility is their fault. But remember, couples are trying to get pregnant! Try not to play the blame game. It is simply a problem that you both have to overcome.

If you are a man reading this book with your partner, you should understand that women might feel differently about infertility than you do. Typically, once they have decided to conceive, women want to get pregnant as quickly as possible. Men often think, "What's the rush? Give it time. If it happens, it happens." Your wife may already be frustrated that every one she knows is either already pregnant or has children. She may also feel the burden of infertility more than you do, since she knows that only she can actually be the one to get pregnant and successfully carry the pregnancy. Women may also be more in tune with the issue of the biologic clock. They often feel that the odds are declining with each passing month, and they may be right!

Try to find a quiet time without distraction when you are both relaxed to discuss your feelings about infertility. Try to listen carefully to what your partner is saying. Not feeling understood is a common source of frustration among couples. On the other hand, being supportive of each other during such a difficult time can strengthen your relationship. Women often accuse men of not listening, the truth is that everyone is typically better at talking than listening. It takes a lot of effort to be attentive and recognize your partner's concerns.

### Causes of Infertility

Infertility can be caused by a variety of factors. Some of these may be predominantly a female factor (such as blocked tubes or poor ovulation) or a male factor (such as low sperm counts). Many, if not most, of our patients have subtle combinations of both male and female factors contributing to their fertility problem. While the many causes of infertility will be discussed in subsequent chapters, we would like to stress that the most successful approach to dealing with infertility is to understand that it is a couple's issue, not one specific to the husband or wife. By approaching the problem this way, we help to avoid one member of the couple feeling guilty or wholly to blame.

### What basic tests are usually done?

An entire chapter in this book is devoted to Finding the Cause of Infertility, but we thought a brief summary would be helpful here. Investigation for the male begins with a semen analysis. This is ideally conducted in a specialized (andrology) laboratory that can perform a detailed analysis of semen. Generally abstinence of two days prior to sperm collection is recommended. If the semen analysis and history of sexual function are completely normal, then in most cases the investigation of the male is complete. If the semen analysis is abnormal, then a urologic exam may be appropriate. During this exam, your doctor will seek a more detailed history about potential toxin exposures, drug use and lifestyle. On physical examination, the size of the testes will be assessed. The presence or absence of a varicocele (a collection of swollen veins in the testes that can overheat and damage the sperm) will be determined. Also, your doctor may examine the prostate to rule out a prostate infection or problems.

General physical examination with the female focuses on the endocrine (hormonal) system. Your physician will carefully inspect the thyroid gland and the neck. The chin, upper lip, axilla and abdominal areas are inspected for evidence of excessive hair growth. A pelvic examination is performed to check for any deformity of the uterus or cervix or cysts on the ovaries. The remainder of the diagnostic work-up for the female is basically an outpatient evaluation of ovulation, tubal, uterine and cervical factors. Ovulation can be confirmed most simply and efficiently with a single blood test (a progesterone level) in the second half of the menstrual cycle. A hysterosalpingogram (HSG) is usually performed. This is an x-ray test that evaluates the uterine cavity and checks for tubal blockage. It is also known to "flush the tubes," which may help improve pregnancy rates for a short time afterwards. A transvaginal ultrasound exam allows the physician to assess the muscle layer of the uterus and the health of the ovaries. One final step for patients with symptoms suspicious for endometriosis or at high risk for pelvic scarring may include a laparoscopic examination. This is a surgical procedure involving small incisions in the umbilicus and lower abdomen through which a miniature camera can be placed inside the abdomen and pelvic cavity for direct observation. The physician can also correct any pathology that may be found.

Once an appropriate evaluation has been completed on _both_ members of the couple, then your physician can determine the best treatment course for you. Remember that half of infertility can be attributed to predominantly male factors. Do not get bumped off the Fast Track by undergoing months of simple therapy before your husband has had a semen analysis!

### What treatments are available?

Tremendous progress has occurred in the therapy for the infertile patient. At the present time, about 85 percent of couples completing the full range of therapeutic options can expect a successful outcome. We devote several chapters to detailing the available treatment options later in the book. Once again, as part of providing the "Big Picture," we will touch briefly upon them here as an overview.

When lack of regular ovulation (anovulation) is identified as the primary problem, a workup will be completed to determine any underlying treatable causes. Once this has been accomplished, we usually start improving ovulation with simple oral medications. The first line agent in these cases is clomiphene citrate, more commonly known by the brand name Clomid. About two-thirds of anovulatory patients will respond to treatment with Clomid. At the time of ovulation, either intercourse or intrauterine insemination may be performed. Unfortunately, the cumulative pregnancy rate is only between 35 and 40 percent after several rounds of clomiphene. This medication is usually effective- if it is to be effective at all in your case- within three to six months of administration. You should definitely see an RE if you haven't conceived within this time frame.

The second line of therapy both for anovulation but also for cases of unexplained infertility or mild cases of endometriosis or mild male factor infertility is gonadotropin therapy. These are the so-called "injectable fertility drugs." These drugs typically contain either pure follicle-stimulating hormone (FSH) or a mixture of follicle-stimulating hormone and luteinizing hormone (LH) to stimulate the ovaries to produce several eggs at once. Pergonal was the original brand of gonadotropins, but it is no longer manufactured. It has been replaced by purer formulations that go by brand names such as Gonal-F, Follistim, Menopur, Repronex, and Bravelle in the United States. Utilizing these agents, we can expect ovulation rates of approximately 90 percent. Conception rates after several cycles may be as high as 50 to 70 percent.

When tubal disease is the primary problem, therapy generally begins with a laparoscopic surgery to correct anatomical problems. Removal of scar tissue and endometriosis can be helpful in mild cases, and some completely blocked tubes can be opened with minimally invasive outpatient procedures such as tubal canalization. When tubal disease is more advanced, a microsurgical reconstruction can be done at the time of open incision (laparotomy). However, _in vitro_ fertilization (IVF) has advanced so significantly in the last ten years that many patients with severe tubal disease will be better served by the much less invasive IVF procedure than by surgery.

Treatment of the male factor is somewhat more controversial. Treatment of significant anatomic problems (such as swollen veins called varicoceles, or prostate infections) may be undertaken to see if semen parameters improve. But the most direct treatment for the couple in such cases appears to be intrauterine insemination or in vitro fertilization. Intrauterine insemination is an office-based technology to deliver sperm into the uterus at the time of ovulation. It is important to realize that this is more effective in cases where there is a mild abnormality. In more severe abnormalities, IVF is dramatically more effective and usually the best way to get on the Fast Track to fertility.

When basic conventional treatment is unsuccessful, then the option of assisted reproductive technologies may be utilized. These are direct techniques that involve isolation and direct fertilization of the eggs and sperm. The most commonly used technique is IVF. This technique involves administration of fertility medicines to the woman that results in the development of multiple follicles. Each follicle contains a single egg. The eggs are then retrieved nonsurgically by a technique known as transvaginal ultrasound-guided oocyte retrieval. This procedure is typically completed within twenty to thirty minutes. Following egg retrieval, the sperm is processed and each egg is incubated with sperm. In cases where the sperm count is very low, then the sperm can be injected directly into the egg with a technique called ICSI. Two to five days following the egg retrieval, the best 1-3 embryos are generally placed in the upper uterus. Close to 50 percent of patients who are thirty-five years or younger can achieve conception in a single IVF cycle. Since only one or two embryos are usually replaced in this age group, the risk of anything more than twins is minimal. Remember that appropriate diagnosis and early treatment with a knowledgeable health care provider will be your best bet to achieve success quickly and safely.

# Chapter 2  
Normal Human Reproduction and  
Maximizing Natural Conception

In this chapter we will discuss the structure and function of the normal male and female reproductive tract. This will help you to understand how things work and why problems arise. After a discussion of what is normal, you will see how abnormalities of each stage of the reproductive tract may contribute to infertility.

### The Normal Female Reproductive Tract

The diagram above shows a basic outline of the female reproductive tract. The vagina is the channel that connects the external genitalia to the cervix (the mouth of the womb). It also serves as the lower birth canal. The cervix serves several purposes. Chief among these is its ability produce watery mucus around the time of ovulation that helps sperm enter the upper reproductive tract. It also acts as a barrier to keep bacteria out of the normally sterile uterus and upper tract. It is the cervix that dilates during labor and allows the baby to come out of the uterus and into the birth canal.

The uterus (or womb) is a small thick muscular organ. Before pregnancy it is the size of a small pear, but it will grow to the size of a watermelon near term in pregnancy. The uterus has to be able to expand to allow for the growth of a seven to nine pound baby plus the amniotic fluid and placenta. It does this by enlarging the cells within it. No new cells are produced within the uterine wall. The uterine muscle wall must stay strong. Eventually its contractions will expel the fetus down the vaginal canal to allow for birth. Two months after delivery its size is nearly back to normal again. It is a truly remarkable organ!

The muscle wall of the uterus is called the myometrium and its lining is called the endometrium. The embryo eventually implants into the thick, spongy, glandular endometrium that will provide it with nutrition and eventually allow the placenta to implant. During the normal menstrual cycle, the endometrium responds to hormones secreted by the ovary. During the early part of the cycle, the endometrium thickens in response to estrogen secretion by the ovary as a preparatory step to implantation. After ovulation, the lining responds to progesterone hormone from the ovary and begins to become mature and secrete substances that the embryo needs to live.

In a cycle during which conception occurs, the ovary continues to make progesterone and support the endometrial lining until the placenta takes over. In a cycle during which conception does not occur, the lining will break down in response to falling hormone levels and be shed as menstrual flow. The first day of true bleeding is referred to as cycle day one. A normal menstrual cycle is usually between twenty-seven and thirty-two days and is counted as being from the first day of full flow in one cycle until the next day of full flow begins.

Opening into the uterus and connecting the uterus to the rest of the pelvis where the eggs are released by the ovaries are the fallopian tubes. Usually seven to ten centimeters in length, these delicate structures play a vital role in initiating a pregnancy. The far end of the fallopian tube is like the end of a trumpet. It is large and wide open. There are finger-like projections at the end called fimbriae. The function of these exquisitely delicate projections is to sweep up the microscopic egg from the ovary when ovulation occurs. The egg is then transported into the tube by two processes. First are muscle contractions of the tube itself. The second mechanism is the sweeping action of the tubal cilia, fine hair-like projections from specialized tubal cells that help sweep the egg towards the uterus.

### The Ovary

The ovaries are almond shaped structures that are on the right and left side of the pelvis hanging immediately under the opening of the fallopian tubes and attached to the pelvis by ligaments and blood vessels. The ovary has two primary functions: to mature and release eggs on a monthly basis and to secrete hormones. A thin layer of tissue covers the ovary. Immediately underneath this layer are the follicles, fluid filled structures each of which contains a single egg (called an oocyte). A woman is born with all the follicles she will ever have. The ovary cannot make any new follicles. It can only use the supply within it until it is exhausted and menopause sets in.

During the first half of the menstrual cycle, in response to signals coming from high up in the brain, the ovary recruits hundreds of dormant follicles to begin the final maturation processes. As time passes by, one follicle becomes dominant and continues to grow while the others fall back and essentially die out. The dominant follicle then goes on to release its egg at ovulation while the other follicles undergo a process called atresia. It seems wasteful that hundreds of follicles die for one to go on and ovulate, but that is the way the human body works!

During the process of ovulation, the follicle wall thins out and then eventually ruptures. The egg then pops out of the follicle, washed out by the eruption of the follicular fluid. Although this process sounds like a mini volcano, the actual release of the egg occurs over several hours. Once the egg is released, it may or may not be picked up by the fallopian tube. It also may or may not get fertilized in the tube. Occasionally more than one egg naturally releases. This results in natural fraternal twinning. Natural twins happen about 3 percent of the time.

What controls the function of the ovary? A small gland in the brain called the hypothalamus stimulates another gland called the pituitary to secrete hormones that control the ovary. The most important of these are follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These two hormones stimulate the ovarian cycle and then at midcycle a big pulse of LH stimulates ovulation itself. Ovulation detection kits are designed to pick up the LH surge, which generally precedes ovulation by approximately 36 hours.

After ovulation, the follicle turns into the corpus luteum, the portion of the ovary that secretes progesterone. Progesterone will keep the lining of the uterus from shedding and allow the embryo to implant. If no embryo implants after approximately 14 days, the lining will shed and a new cycle will begin. As you can imagine, it is a delicate balance between the brain, the ovary, the tubes, and the uterus that allows conception to occur.

### The Normal Male Reproductive Tract

The penis is the male sexual organ that serves two functions: passage of urine from the body and the transfer of sperm into the female reproductive tract. The penis is covered by loose skin that allows for expansion and erection during sexual excitement. Erection is accomplished by blood filling the spongy channels within the penis. During sexual excitement, the arteries feeding the penis dilate and fill with blood. The bulbous end of the penis is called the glans. In the uncircumcised male this is covered by foreskin. The practice of circumcision varies from culture to culture. It is performed primarily either for religious reasons or to reduce infections between the glans and the foreskin. There are good data to suggest that circumcision can reduce the spread of the HIV virus. Circumcision does not specifically affect reproductive function.

The two testicles are suspended below the body in the scrotum. The reason the testes are outside the body is that it allows the testicular temperature to be maintained about 2 degrees Fahrenheit cooler than body temperature. This lower temperature is ideal for sperm production and is the reason that men who are trying to impregnate their partners should avoid hot tubs, steam rooms, etc. The muscles in the scrotum lift and lower the testicles in low and high temperatures to maintain the testicular temperature at the ideal point.

The testes are the male equivalent to the ovaries in the female. They produce sperm just like the ovary produces eggs. The testes on a microscopic level are composed of long curvy channels called seminiferous tubules. Along the walls of the channels are two cells. The Leydig cells make testosterone, a hormone that is critical for sperm development. Testosterone circulates in the body as the primary male hormone, causing the male voice to deepen and stimulating facial hair growth and muscle development. The physical characteristics that we typically think of as male result from the action of testosterone or its derivatives at various target sites in the body.

A second type of cells, the Sertoli cells, takes the immature sperm and nurtures them as they develop into fully formed adult sperm. This process takes about seventy-two days. Unlike the ovary that matures only existing eggs, the testes constantly make new sperm from existing germ cells. When the sperm are mature they are released by the Sertoli cells into the seminiferous tubules. The tubules then transport the sperm into the epididymis, which is a collection site on top of the testes. The epididymis is highly coiled. If straightened out it would measure approximately twenty feet. During their journey through the epididymis, the immature sperm mature and gain the ability to fertilize an egg. From there they travel into the vas deferens, which is the final channel out of the testes.

The vas then travels out of the testes and into the abdomen where it joins the seminal vesicles to form the ejaculatory ducts which transfer the sperm and seminal fluid into the urethra during sexual excitement. The urethra is the channel inside the penis through which both urine and sperm pass. It travels from the urinary bladder through the prostate gland and ends at the tip of the penis. The prostate is a chestnut-sized gland that surrounds the urethra. The prostate and seminal vesicles secrete milky alkaline fluid that mixes in with the sperm during the process of ejaculation. The ejaculated fluid helps to neutralize the vaginal acidic fluid so the sperm can survive in the vagina long enough to travel into the cervical mucus where they can be safely stored. Approximately 90 percent of the ejaculate by volume is the secretions of the prostate and seminal vesicles. The remainder is the actual sperm that is transferred by the vas deferens.

The brain controls the testes in the same way that it controls the ovary through the secretion of FSH and LH. Prior to puberty, the body suppresses the production of these two hormones. At puberty, rising levels of LH and FSH stimulate respectively the Leydig cells to make testosterone and the Sertoli cells to start producing sperm. The Sertoli cells need high concentrations of local testosterone to make sperm. Think of the Leydig cells as the testosterone factory next door to the Sertoli cells. The testosterone levels are highest in the testes, and the Sertoli cells need this high local level to function.

### Normal Reproduction

Now that you have a good understanding of both the female and male anatomy, we can discuss the intricacies of normal reproduction. It's amazing how many things have to go exactly right in order to achieve a healthy conception. After that, we can discuss more of the specifics about what may go wrong. When you look at the details, it's easy to understand why, even under ideal circumstances, natural conception rates are only 20-22 percent per month. Anything that breaks down in this highly delicate system can lead to fertility concerns.

Statistics show that 80% of couples attempting conception will succeed within 6 months and 85% within one year. The remaining 15% are considered infertile because the yearly conception rates from here on are extremely low. This contradicts the classic myth that if you keep trying it will happen. The monthly chance of conception is also known to decrease as age of the female increases. Women in the 30s will conceive at 50% of the monthly rate when compared to women in the 20s.

For pregnancy to occur, ovulation needs to be intact. That means that the ovaries developed normally, are healthy, and have sufficient numbers of healthy eggs. The hypothalamus and the pituitary regions of the brain need to be functioning normally and sending the appropriate signals to the ovaries. The ovaries have to respond to these signals and release an egg at the time of optimal maturity for fertilization. Once released, the egg has about twenty-four hours to be fertilized, although fertilization may occur as much as forty-eight hours after ovulation in rare cases.

Once the egg has been released from the ovary, the fallopian tube needs to be freely mobile and the fimbriae must sweep along the surface of the ovary to "grab " the egg. The delicate fimbriae have to be in excellent shape, and there cannot be any tubal blockage. Tubal disease is the leading cause of infertility worldwide.

During intercourse, sperm is released into the vagina at the time of male ejaculation. This means that erectile and ejaculatory function have to be normal. Sperm production in the testes and the hormonal environment accompanying sperm production has to be normal. There have to be enough sperm and they have to be able to swim. They also have to be structurally normal enough to bind, penetrate, and fertilize the egg once they meet up together in the fallopian tube.

After ejaculation, a fair bit of semen leaks out from the vagina. This is normal and should not be a cause for concern. Within just a few minutes of ejaculation, most of the healthy sperm will swim to the opening of the cervix and enter into the cervical canal. So everything in the environment of the cervix must be normal and the mucus nice and healthy. From the repository of sperm in the cervix, waves of sperm will be released periodically to start the very long journey to meet the egg. The sperm must swim through the uterus and the fallopian tube to reach the egg, which, at that time in the cycle, is still located in the far end of the tube. So everything has to be normal in the uterine environment for the sperm, and there cannot be any scarring of the tubal openings that allow the sperm to enter.

Many people do not realize that fertilization and early embryo development actually occur in the tube and not in the uterus. The egg and sperm both have to be receptive to each other, and the entire biochemical process of the actual fertilization itself needs to be intact to for an embryo to form. Once fertilized, the zygote or early embryo then lives in the tube for five to seven days, continuing to divide until it reaches an advanced embryo stage called blastocyst, made up of hundreds of small cells. It is the blastocyst that is then deposited into the uterus, where it has an opportunity to establish a pregnancy. So, in order for pregnancy to be established, the tubal transport system that is responsible for moving the egg and the sperm together and eventually the embryo back to the uterus has to be functional. The environment for blastocyst development in the tube has to be ideal, the embryo has to be genetically strong enough and healthy enough to continue to divide and grow, and the uterine cavity has to be receptive at exactly the right time for implantation to occur.

With everything that has to happen in precisely the right way, it is no wonder we refer to the miracle of life! The next chapter will be devoted to discussing what may go wrong during each of these processes, resulting in infertility. But before leaving normal reproduction, we'd like to discuss some of the things we think are helpful to promote natural conception.

### Promoting Natural Conception

Some basic things can help you to conceive more quickly. First, a balanced diet for both partners is important. Avoid smoking and also reduce drinking alcohol. Recent studies suggest that a little bit of caffeine when trying to get pregnant is not a problem. That would amount to no more than 2 servings of a caffeinated beverage per day. Try to maintain a normal body weight and exercise at least twice per week.

Now that you can see what an incredibly intricate process normal reproduction is, what are some of things you can do to help this process along? As far as general recommendations for timing of intercourse, take the length of your menstrual cycle and subtract approximately 16 days. Try to have intercourse from that point on every other day for approximately three attempts. Therefore, for a woman with a typical 28-day cycle, intercourse should be on days 12, 14, and 16. If the cycle is 30 days in length, the ideal days would be 14, 16, and 18. If the cycle is approximately 32 days, it would be days 16, 18, and 20.

For couples in which the man has normal sperm counts, intercourse every day or every other day will yield the same results. Therefore, it is certainly not necessary to attempt intercourse every day during your fertile time, but waiting more than two days may miss ovulation. Daily timed intercourse solely for the purpose of attempting pregnancy can sometimes turn an otherwise great experience into a daily chore. It is important to know that some variation is not a problem. Occasionally couples choose to have sex multiple times in one day. Again, this will not cause infertility for most couples, but it may rapidly deplete the supply of sperm in men with lower sperm counts.

Many couples wonder if certain sexual intercourse positions may improve their chances of conception. There is no position that has been clearly established to be superior. It is thought that the standard missionary position allows more pooling of sperm around the cervix, although this recommendation has little clear scientific basis. After intercourse, when the penis is withdrawn, some sperm will immediately come out from the vagina. The remaining sperm will stay attached by surface tension to the vaginal wall as well as to the cervical secretions. Because of this, prolonged bed rest is not necessary. You may want to rest for approximately five minutes after intercourse and then resume activity without concern about any discharge of seminal fluid.

You should definitely avoid using most commercial lubricants, as many contain substances that kill sperm. Also avoid douching unless prescribed by your doctor, as it may cause the vaginal environment to be inhospitable to sperm. If a lubricant is required, then a small amount of pure mineral or canola oil, which does not mix with the physiologic fluids, could be utilized.

### What about ovulation prediction kits?

These urine test kits look for a hormone called Luteinizing Hormone (LH) in the urine. There is a surge in the blood LH level about 24-36 hours prior to ovulation. This surge will eventually be reflected in the urine. In theory, ovulation can be predicted by recognizing this surge. To really accurately detect this surge, blood needs to be tested two to three times daily in a laboratory. Testing the urine at home once or twice daily is expensive and provides only a vague (about twelve to forty hours) window for ovulation. We recommend the timing approach to intercourse outlined above rather than the use of ovulation prediction kits.

For couples that choose to use the predictor kits, the best time to have intercourse is the day after the LH surge is detected. The day of the LH surge is also viable. In many cases our patients can make neither heads nor tails of the kits. They can also be falsely positive in some women with high LH levels or never positive in women who have a small LH surge. There is no advantage to using a prediction kit over timing intercourse based on cycle length. If you have irregular cycles, you are probably not ovulating regularly, and using these kits will be expensive and frustrating as well as unhelpful.

### Are temperature graphs accurate?

Basal body temperature graphing (BBT) is an old tried and true, but not highly accurate, method of evaluating ovulation. After ovulation there is an increase in the production of progesterone, which causes a slight temperature increase in the human body. In theory, these temperature changes can be used to gain information about ovulation. If you are interested in charting your temperatures, you need a basal body temperature (BBT) thermometer, available at many drug stores. They have a limited temperature range and expanded markings between 98 and 100 degrees, and they are more accurate than an ordinary thermometer because they indicate very small changes in this range. A mercury thermometer is more accurate than an electronic one for this purpose. You can then print off the internet a graph or track your temperatures on line at a multitude of web sites. Your doctor can also give you a graph on which to chart your temperatures if you don't have internet access.

Graphing for a given cycle begins on day one, which is defined as the first day of full menstrual flow. It continues until the next day one. A completely flat temperature graph indicates lack of ovulation. In almost all cases when ovulation does not occur, the cycles are long (more than 35 days in length) or short (less than 25 days in length). Also, ovulation after day 16 is considered delayed. Theoretically, ovulation occurs the day of lowest temperature prior to the temperature rise plus or minus two days. In other words, temperature graphing is unlikely to pinpoint ovulation more accurately than a 3-4 day window. By the time your temperature goes up, you have probably already missed the window of fertilization for the egg, so this is a highly unreliable method for timing intercourse. Below are some example graphs.

## Graph showing normal ovulatory temperature shift

## Graph showing lack of ovulation

While BBT's may be of some limited use, more often than not they waste a great deal of time and cause a great deal of anxiety every morning before getting out of bed! Remember that it is very rare that improper timing of intercourse is the cause of infertility! A single blood progesterone level drawn about one week before the expected onset of menses and a good medical history will offer significantly more information than either urine LH kits or BBT's. Don't fall off the Fast Track by spending months on temperature charts and urine kits. If you are not getting pregnant, see your doctor!

# Chapter 3  
Common Causes of Infertility

Now that we have discussed the delicate and intricate process of conception, it is easy to understand why infertility is such a common problem. Any subtle imbalance in the system can lead to infertility. This chapter is devoted to a discussion of some of the more common fertility issues that we see and treat every day. Remember that the sooner you seek qualified care, the sooner you can have these problems diagnosed and efficiently treated. Early diagnosis and treatment increases your chances of a successful pregnancy with minimally invasive and less expensive options.

### Problems with Ovulation

Irregular ovulation or complete lack of ovulation (called oligo-ovulation and anovulation, respectively) are some of the most common causes of infertility. There are several reasons why the ovary may not work properly, and the best clue that you may not be ovulating is usually that the menstrual cycle falls outside the normal 27-32 day range.

Frequently the LH and FSH signals from the pituitary gland in the brain are not arriving at the ovary in the right way, resulting in irregular cycles and problems with fertility. This condition is commonly associated with increased body weight, excess hair growth or acne, and other findings consistent with the polycystic ovary syndrome (PCOS). This is such a common disorder that we have devoted an entire chapter to its discussion later in the book. PCOS is a highly treatable condition.

Women who are either too thin or exercise too much, or are too heavy can have a disruption of the signals between the brain and the ovaries that causes anovulation. In these cases, there is usually nothing wrong with the ovaries themselves, they are merely not getting the right signals from the brain. This condition is termed hypothalamic anovulation because it is the signals from the hypothalamus that are the problem. In other words, the car is fine, but the ignition switch is malfunctioning.

Less commonly, however, the problem resides within the ovary itself. In about 1 percent of women of childbearing age, the ovary runs out of eggs prematurely. In this case the ignition switch (the hypothalamus) and the gas pedal (the pituitary) are both working, but the engine itself (the ovaries) is broken. This can happen at any age, including the teens. This is known as premature ovarian failure, and it is probably the most difficult type of infertility to treat. This problem is diagnosed by testing FSH levels in the blood which will be elevated in cases where the egg supply is diminished or absent. Issues involving the quality of the eggs increase dramatically as women enter their mid-to-late thirties and early forties.

Other hormonal imbalances, such as with the thyroid or adrenal glands, can also cause ovulation problems. Such problems can usually be detected by simple blood tests, but only if you seek help to have the evaluation! If your cycles are irregular, you are probably not ovulating properly and should seek help right away.

### Tubal Problems

As we discussed above, the tube plays a critical role in egg pick-up, sperm transport, fertilization, early embryo development, and subsequent transport of the early embryo back to the uterus. It should, therefore come as no surprise that tubal problems can be a major cause of infertility. Unfortunately, the fallopian tube is very vulnerable to infection, and infection frequently scars the tube and renders it nonfunctional. In fact, tubal scarring (pelvic adhesions) is the leading cause of infertility in the world! In developing countries, tubal infection from systemic tuberculosis is the most common cause. In the United States and Europe, sexually transmitted infections with Chlamydia and gonorrhea are the most common causes of tubal disease. Sexually transmitted diseases can be prevented through the use of barrier contraception such as condoms or abstinence. Endometriosis is also a common cause of tubal scarring.

When the tubes scar near the ends, the fimbriae can get stuck together (called agglutination), making it unlikely for them to function properly in picking up the egg. Severe scarring can even cause the tube to close over entirely and dilate and fill with fluid, a condition called hydrosalpinx. Less severe scarring can close the tube close to the uterus, causing proximal obstruction, preventing the sperm from reaching the egg or preventing the embryo from returning to the uterus.

Normal reproductive tract

Pelvic adhesions

A tube that works a little bit but not ideally may result in a tubal pregnancy. A tubal pregnancy occurs when a damaged tube is able to pick up an egg and allow fertilization but is unable to transport the embryo back to the uterus. The embryo may therefore implant in the tube itself instead of the uterus. The medical term for a tubal pregnancy is an ectopic pregnancy, meaning a pregnancy that it is in the wrong place. A tubal pregnancy unfortunately cannot be moved back into the uterus. It is important to recognize tubal pregnancies and treat them early, because they can rupture and cause severe internal bleeding. Tubal pregnancies can sometimes be treated with medication to dissolve the tissue if detected very early, or they may require surgery.

Women with infertility problems are at higher risk than the general population for tubal pregnancy. That is why most fertility centers will perform a blood test as soon as the menstrual period is missed. These blood pregnancy levels are then followed closely to see how they are rising. If rising abnormally, there may be suspicion for an ectopic pregnancy. Early ultrasound will also be performed to confirm that the pregnancy has been established in the uterus where it belongs. Approximately 1.5 percent of all pregnancies in the general population are ectopic. In an infertility population, 3-5 percent of all pregnancies are likely to be ectopic. Women with a history of previous tubal pregnancy have an increased chance of both infertility and repeat ectopic pregnancy in the future.

By now you can see what a problem tubal scarring is! Tubal scarring is often detected by an x-ray dye test called a hysterosalpingogram (HSG) or by diagnostic laparoscopy (a small outpatient surgery). If you have tubal scarring, the best option is to have it surgically repaired to improve the function of the tube. If the tube is severely damaged, it may be necessary to remove the tube. It takes a great deal of surgical experience to decide which tube needs to be removed and which needs to be repaired. Do not despair if the tubes cannot be fixed! _In Vitro_ Fertilization works beautifully to bypass damaged tubes. Just don't wait too long to give IVF a chance, since it works best when you are younger.

### Cervical Problems

As we discussed previously, the cervix acts as an internal sperm bank. Sperm are normally deposited in the vagina but cannot survive there for long because the vagina is acidic. The semen has properties that help the sperm live longer in the vagina. After intercourse some of the sperm will stay attached to the vaginal walls and the rest will come out. Many couples are concerned that some semen escapes from the woman's vagina after intercourse. This is normal and is not a significant cause of infertility. The sperm remaining in the vagina have an opportunity to migrate into the cervical mucus where they can live for 24-48 hours. From the cervix, sperm travels into the upper reproductive tract in waves so whenever the egg appears, it will be met by a wave of sperm capable of fertilizing it. A second important function of the cervix is to hold the pregnancy in place prior to the time of birth.

If you have had surgery on the cervix such as a freezing or burning, a cone, or a "LEEP" biopsy, the cervix may have problems performing either of these two important functions. It may lose its capacity to produce mucus, making it hard for the sperm to travel into the reproductive tract. It also may be weakened, making it hard to retain the pregnancy for full term delivery. The human papilloma virus (HPV) is the most frequent cause of abnormal Pap smears that may require surgery on the cervix. The negative effects on fertility of an abnormal cervical environment can largely be bypassed with the simple treatment known as intrauterine insemination (or IUI). With IUI a tiny tube is used to bypass the cervix during ovulation and place the sperm higher up into the uterus near the openings of the fallopian tubes. Diagnosis of cervical infertility is usually made by the medical history, because testing (such as post-coital tests) is very unreliable.

### Endometriosis

Endometriosis is a common disorder that is associated with infertility. It occurs when the glands that normally line the cavity of the uterus grow elsewhere in the pelvis. It can be associated with painful periods, painful intercourse, and often painful bowel movements during the menstrual cycle. The resulting inflammation in the pelvic cavity causes a less-than-ideal environment for development and release of the egg, and it is also associated with scarring around the tubes and the ovaries that may result in mechanical infertility issues. We have devoted an entire subsequent chapter to endometriosis because this is such a common disorder. Sometimes the only symptom of endometriosis is infertility. The absence of pelvic pain or bad menstrual cramps does not rule out this condition!

Unfortunately, endometriosis does not usually show up on x-ray testing or ultrasound, so a small incision surgical technique called laparoscopy may be required to diagnoses endometriosis. Fortunately, we can usually treat the endometriosis during the same procedure.

### Uterine Problems

As the home of the developing fetus from about day six after ovulation until delivery, the uterus plays a crucial role in normal fertility. Abnormalities of the lining of the uterus (called the endometrium) can certainly cause infertility. If ovulation is not just right, then the hormones from the ovaries that cause normal development of the endometrium will be disordered, and the endometrium will not be favorable for implantation. A history of D&C's from previous miscarriages or abortions or a history of infection following a previous delivery (either vaginal or cesarean) can cause scarring of the endometrium, rendering it incapable of implantation. Newer procedure for heavy menstrual periods called endometrial ablation can cause scarring inside the uterus. In its most severe form, called Asherman's syndrome, the lining is so scarred that there is no normal lining to shed and a woman's menstrual periods will stop altogether. Most uterine problems are diagnosed by ultrasound, x-ray dye testing, or hysteroscopy an outpatient procedure requiring no incisions during which a small fiber optic camera is placed through the cervix and into the uterine cavity).

An overgrowth of glandular tissue anywhere in the body can form polyps. These are very common in the nasal passages, vocal cords, and often the colon. Uterine polyps can also form in the endometrial cavity and cause inflammation or take up space that makes implantation more difficult for the embryo. Fortunately, uterine polyps are usually benign and can be easily removed during a small outpatient procedure.

Abnormalities of the muscle wall called the myometrium can also cause fertility concerns. Fibroids are the most common cause of myometrial abnormalities. These are usually benign, non-cancerous tumors which can grow to be quite large and distort the uterus. They can be superficial or extremely deep within the wall of the uterus. Common symptoms from fibroids include heavy menstrual cramping and excessive bleeding. If the fibroids are too large, distort the cavity of the uterus, or are actually arising from within the uterine cavity, then they may need to be removed surgically. Such a procedure is called a myomectomy.

### Fibroid uterus

While fibroids are extremely common, abnormalities in the way the uterus develops can also cause reproductive problems. While many of these may take the form of recurrent miscarriages rather than trouble conceiving, they are worth evaluating. Some developmental abnormalities of the uterus include a double uterus, a half a uterus or a wall in the middle of the uterus (a uterine septum). Of these, the septum (shown below) is the easiest to repair surgically, and is covered in the chapter on surgery.

### A uterine septum

### Male Factor Problems

Almost half of all fertility is caused by male factor, or problems with the numbers of sperm, their ability to swim, or their ability to bind and penetrate the egg. Unfortunately, a clear cause of poor sperm function cannot usually be pinpointed and corrected. Fortunately, recent advances in IVF mean that some men with even no normal sperm in their ejaculate can still biologically father their own children!

Hormonal imbalances in men can cause low sperm counts. Paradoxically, we frequently see men who have been prescribed testosterone supplementation for low sperm counts! Testosterone supplementation is a huge mistake as it will interrupt the normal signals between the brain and the testes that control sperm production and reduce sperm counts even further. In fact, testosterone supplements have often been experimented with as a form of male birth control pill!

Many different factors can affect male fertility. Prescription drugs can interfere with the production or function of sperm. Some antibiotics, blood pressure medications, ulcer medications, and steroids are potential causes for sperm dysfunction. In addition, recreational drugs, such as alcohol, cocaine, marijuana and tobacco, are responsible for deleterious effects on sperm function. Therefore, it is extremely important that the patient is honest with the physician about drug use during the history portion of the consultation. Physical illness such as diabetes or high blood pressure can also frequently affect sperm production. Occasionally a hernia repair or other groin surgery can lead to male factor infertility as well.

Some men may have had brain surgery or suffer from pituitary problems that cause disordered production of LH and FSH. This can result in testicular shut down. Replacement of the proper hormones can allow sperm production to return to normal, but this process may take six months to one year. If the LH and FSH are just a little bit low, some men will respond to therapy with clomiphene citrate (Clomid), which is the same medication we often use to stimulate the ovaries to ovulate.

Undescended testes can also be a cause of male factor infertility. During embryologic development the testes begin inside the abdomen and then drop down into the scrotum. Occasionally this does not occur normally, and a boy is born with undescended testes that are still in the abdomen or groin rather than the scrotum. If a child is discovered to have an undescended testis, surgery is generally performed. Sometimes the affected testis can be pulled back down into the scrotum. Sometimes it is too damaged or cannot be pulled down. In that case it is removed because testes left in the abdomen can become cancerous. In many cases one testis can be brought down and the other needs to be removed. If the testes were once undescended, their production of normal sperm is often significantly impaired.

In some cases, a man's testis can twist, an extremely painful condition called testicular torsion. Although the affected testis can often be saved with surgery if treated promptly, torsion may subsequently be associated with lower overall function. Therefore, men with a history of any of these problems should have a semen analysis performed very early in the infertility diagnosis.

Another developmental abnormality in the male reproductive tract can occur when the tube that transports sperm from the testes to the urethra never develops. This condition is referred to as congenital absence of the vas deferens. This condition is commonly seen in individuals who either have cystic fibrosis or carry one gene for this disease. In such cases the sperm count will be 0. Fortunately, the sperm are still there in the testes and can be extracted easily in the office and successfully used for IVF.

The prostate can also cause its share of problems. Inflammation or infection of the prostate gland is called prostatitis and is fairly common. This is usually associated with pain in the bladder and with painful urination. It can also cause the urinary stream to be weaker. Prostatitis can introduce inflammatory white blood cells into the ejaculate and cause problems with sperm function. The prostate can also enlarge in men in the forties and fifties, causing problems with urination and ejaculation. Drugs given to reduce the size of the prostate may affect sperm production, so check with your doctor before starting on these prescriptions.

Difficulties with sexual function are also extremely common causes of male factor infertility. Inability to obtain an erection sufficient for intercourse is an obvious problem. Fortunately, therapy for erectile dysfunction is readily available and highly effective today. Some men simply cannot ejaculate during intercourse. In such cases a semen specimen can be obtained by masturbation and used for artificial insemination. Note that premature ejaculation will not cause infertility. While this problem can cause sexual dissatisfaction or frustration, the sperm is still being deposited into the vagina, just more quickly than you or your partner may ideally prefer.

Finally, a collection of swollen veins in the testes called a varicocele may impair fertility, probably by causing an overheating of the testicular temperature. Surgical correction of a varicocele is controversial. Correction of a very large clinically obvious varicocele may improve sperm function within 6-12 months of repair. Surgical intervention on smaller varicoceles has been very disappointing to date, and couples will probably be better served by moving to IVF.

# Chapter 4  
Finding the Cause of Infertility

Now that we have discussed some of the more common causes of infertility, we can move forward with a detailed discussion of diagnosing these problems. For younger women under 35 years of age, if pregnancy has not occurred after one year of unprotected intercourse, it is unlikely that it will occur spontaneously within any reasonable future period of time. Therefore, if you are under 35 and have been having intercourse without any form of protection for one year and have not conceived, you should definitely begin the infertility evaluation. However, **if you are over 35 years of age and have not conceived after 6 months of unprotected intercourse, then an evaluation is critical!** This is particularly important because so many women today are waiting until their mid- to late-30s to attempt conception. We have found that fear of the unknown is one big barrier to obtaining a fertility evaluation. Therefore, we think you will find the following discussion of a typical workup useful in knowing what to expect when you do see your doctor.

### The Medical History

The best place to start the infertility evaluation is with a detailed medical history by a qualified professional. Infertility experts can make about 80 percent of their diagnoses just by interviewing a couple with infertility and asking the right questions. A good medical history will focus on all the factors above that we have already discussed. Often, the major problem is discovered with the first question to be asked: the age of the female partner! The duration of infertility, a history of infertility in previous relationships, a detailed sexual history, a menstrual cycle history, a history of previous surgeries or pregnancy complications, and a careful review of systems often identifies the likely cause and allows us to target our further evaluation.

If a woman has become pregnant in the recent past, then there may not be a severe infertility problem. On the other hand, a patient in her mid-30s with a prolonged duration of infertility suggests that there is likely a major abnormality to be dealt with.

The menstrual history is then examined in detail. If menstrual periods occur other than 27-32 days apart, it generally indicates ovulation difficulties. The length of the menstrual cycle is determined by measuring the time from the first day of full flow one month until the next first day of full flow. Patients who know when to expect their menses but have cycles shorter than 26 days or longer than 32 days may still have ovulatory dysfunction. This is frequently confusing to patients. For example, if a woman tests basal body temperatures or urine ovulation predictors and determines that she is ovulating on day 9 or on day 20, she could conclude that she is ovulating normally and regularly. However these ovulations may not be normal since egg quality may diminish if the time to develop egg maturity is either too short or too long.

Next is a discussion of any history of prior marriages. Naturally, if a woman has a history of infertility in a prior marriage, this will suggest a primary female factor. On the other hand, if in prior relationships the woman has conceived, it may be the current male partner that has a deficiency in sperm production. Any history of sterilization with or without a subsequent reversal would naturally be extremely important. For the woman, any history of sexually transmitted diseases (STDs) such as Chlamydia or gonorrhea would suggest the possibility of tubal scarring. Unfortunately many sexually transmitted diseases are difficult to diagnose and originally may have produced only mild symptoms, much like the flu. The number of sexual partners in the past correlates with the risk of STDs, with more than four lifetime partners significantly increasing the risk.

Next, we turn our attention to the medical condition of the patient. If there is an underlying medical condition, such as diabetes or high blood pressure, then this needs to be treated prior to conception. If the patient has had abdominal surgery, there may be an increased risk of scarring of the fallopian tubes. If there is a history of intra-abdominal infections, such as a ruptured appendix, that can be a common cause of scarring of the fallopian tubes. All medications which the woman has or is taking should be reviewed. For instance, a history of chemotherapy or radiation may result in a decrease in the egg supply. Current treatment for medical conditions such as arthritis, inflammatory bowel disease, or acne can sometimes be problematic and should be addressed before initiating fertility therapy.

### The Physical Examination

Once the history is completed, the physician will conduct a thorough physical examination, including a pelvic examination. Any abnormal increased growth of hair on the face or abdomen or an enlargement of the thyroid gland at the base of the neck may suggest hormonal problems. Weight and blood pressure should be recorded. Abnormal body weight is a frequent cause of ovulation difficulties and can cause difficulties with pregnancy once it is established. Abnormal blood pressure should also be managed prior to conception.

On pelvic examination we look for any suggestion of endometriosis. Frequently this can be noted as scarring behind the uterus. Endometriosis may be suggested on exam by a retroverted or tilted uterus that feels scarred into place. Uterine and ovarian structures are also evaluated during a careful pelvic exam, checking for fibroids or cysts. The cervix is also examined for evidence of narrowing or blockage as well as the quality or presence of mucus.

### Ovulation

Blood tests are another important diagnostic tool. Irregular menstrual cycles are a good indicator of disordered ovulation. While, temperature charts or urine ovulation predictor kits may be of limited utility, a single properly timed blood test will provide significantly more information. A serum progesterone level drawn about seven days prior to the expected onset of menses is the best way to determine the adequacy of ovulation. A serum level greater than 3 ng/ml (the scientific units used to measure progesterone) in most modern laboratories is consistent with ovulation. However, women are probably more likely to conceive in cycles with a progesterone level of greater than 10 ng/ml. In women with irregular cycles, other hormone levels such as thyroid and prolactin as well as some adrenal hormones should be checked. These can be associated with anovulation if they are out of balance and can usually be easily corrected.

### Egg Quality and Ovarian Reserve

Just because a woman is ovulating does not mean that she is releasing high quality eggs with good potential for fertilization and normal embryo development. Unfortunately, the effects of the **biologic clock** mean that egg quality is decreasing almost yearly even in normal women. Age affects both the number and quality of the eggs available, and there is rapid decline in both during normal reproductive life. A woman actually has the greatest number of eggs in her ovaries that she will ever have while she is still a fetus! Prior to birth during fetal life, the ovaries have an average of two million eggs. At birth, the egg supply is depleted to one million eggs. Between birth and age 13 at which time most women begin ovulating and menstruating, another 500,000 eggs are depleted. This depletion occurs by a process known as atresia, in which the eggs dissolve in the ovary. By the time a woman has reached the age of ovulation and menstruation, she has already lost 1.5 million eggs and now has about 500,000 remaining eggs in her ovaries. Typically one thousand eggs are lost per month until the age of menopause is reached. This holds true whether the woman is on birth control pills or not, whether she has menstrual periods or not, whether she is pregnant or not, and whether she is breastfeeding or not.

Unfortunately, there is no way to prevent or slow down the process of atresia. So, if a woman is 25, it is felt that she is still has "plenty of time" to conceive. Egg quality is also thought to be relatively good. In her mid-30s, there is less time but clearly an opportunity for conception to occur. In her late 30s and early 40s, we are in a situation that we commonly refer to as "the ninth inning." This really means that we have very little time to achieve optimal results for the patient. Furthermore, many of our patients have no children and would like to have more than one child. We therefore would like to achieve the first pregnancy as quickly as possible so they still have a reasonable opportunity to achieve another pregnancy later.

A woman's age gives us an indication as to how many eggs are left in her ovaries. Of course not everyone at 35 has an identical egg supply. There are excellent techniques to screen for the status of the biologic clock, referred to as **ovarian reserve testing**. Because more and more women are becoming educated and entering the workplace and delaying childbearing, the issue of the status of the "biological clock" has become increasingly important. Testing for the number and quality of the eggs left in the ovaries is the goal of ovarian reserve testing.

There are several different tests to assess ovarian reserve. One technique which we often use is referred to as the antral follicle count, during which a small ultrasound wand is placed in the vagina sometime in the first four days of the menstrual cycle. Here we count all of the small follicles up to 10 millimeters in diameter that are seen in each ovary. There is not an agreed upon number of normal antral follicles, but antral follicle counts of greater than five to ten per ovary are considered excellent. Two to four are considered good. One to two is considered poor. This test should be performed by an experienced individual. Most routine office gynecologic ultrasounds done outside of a fertility center will not contain this information.

Another important test of ovarian reserve is the day 3 FSH level. Remember that the first day of full menstrual flow is referred to as day 1 (spotting before full flow doesn't count). The day following that is day 2 and the next day is day 3. Follicle-stimulating hormone (FSH) should be measured ideally on day 3. Laboratory standards will again vary slightly, but, in general, a value less than 10 IU/L (again, another scientific unit used to measure hormones) is felt to be ideal. Values exceeding 15 IU/L, especially in women over 35 years of age, are associated with a poor prognosis.

The newest and most accurate test for assessing ovarian reserve is the anti-mullerian hormone test (AMH). AMH is produced by small follicles in the ovary and can be used to estimate their number. An AMH level of greater than 1.2 is considered normal in most labs. Values less than 1.0 are suggestive of reduced ovarian reserve. Values less than 0.4 are suggestive of extreme reduction of ovarian reserve. Values greater than 4 are suggestive of polycystic ovaries. It's important to note that women on birth control pills will have reduced AMH levels. This is an artifact from the birth control pills. Also women with rare conditions such as hypothalamic amenorrhea will have low AMH levels but have normal ovarian reserve.

AMH is measure in nanograms per milliliter (ng/ml)

Normal AMH

Increased (freq PCOD)

Low normal

Low

Extremely low | **>** 1.2

>4

0.7-0.9

0.2-0.6

<0.2

---|---

 |

---|---

While debate exists as to which of these is the most predictive test, some form of ovarian testing is probably appropriate in all women 35 years of age or older who are having trouble conceiving. It may also be appropriate for any patient who has had an ovary or a portion of an ovary removed for cysts or endometriosis. Ovarian reserve testing should also be performed immediately for women who have undergone chemotherapy. For any patient 39 years of age or above, it is absolutely critical. As ovarian reserve declines, so do the chances of having a healthy delivery. There is preliminary data that suggests that low AMH levels are associated with a higher miscarriage rate.

### The HSG

In order to assess the fallopian tubes and also examine the uterine cavity, a hysterosalpingogram (HSG) is often performed. This test is an x-ray of the uterus and tubes and is best performed in the early phase of the menstrual cycle between days five and twelve. The timing of the test is important because it should be completed prior to ovulation and any possibility of pregnancy. The study is usually done in the x-ray department of the hospital and is usually performed by your gynecologist or reproductive endocrinologist. Sometimes a radiologist may perform this exam. Because this test uses iodinated contrast material, it should not be done if the patient has a history of iodine allergy. This test should also not be done if the person could be pregnant or has an active infection. If the menstrual period before the HSG is not completely normal, then the physician should be notified and a pregnancy test should be performed prior to the x-ray. The dose of radiation during the study which is typically done fluoroscopically (with an image intensification screen) is very, very small. The fear of radiation exposure is therefore unwarranted.

During an HSG, a speculum is placed in the vagina to visualize the cervix, which is then cleansed and stabilized with a small instrument. A cervical cannula (a hollow tube) is then placed within the cervix and an iodine-containing contrast that shows up on x-ray is gently pushed into the uterus and through the fallopian tubes. Most patients report that the HSG is not as painful as they had feared, but there is no denying that this test can be uncomfortable for some patients. We routinely perform 8-10 HSGs per week and, in experienced hands, the whole procedure should take less than 5-10 minutes. The discomfort can be minimized by taking 400-800mg of ibuprofen approximately one hour before the procedure.

### Typical normal HSG

### Abnormal HSG with tubal blockage

After the test, the physician will discuss the results with you, indicating if there are any abnormalities in the structure of the uterus such as a division or septum. Also, any abnormalities in the fallopian tubes such as blockage or scarring are noted. This test does provide valuable information, but it is probably more accurate for the uterus than it is for the fallopian tubes.

Sometimes HSG results can be misleading. There are cases in which the test indicates an obstruction but the tubes are really just in spasm as a reaction to the dye going through them. There are also cases in which the test indicates the tubes are open when really they are scarred or obstructed. This test is therefore ideally reserved for cases in which the doctor has relatively low suspicion that there may be a problem with the tubes. In cases where we strongly suspect fallopian tubes scarring, then laparoscopy (described below) provides superior information.

The HSG test may have a therapeutic value also, as pregnancy rates for two to three months following the test may improve. This suggests that "flushing the tubes" may have dislodged mucous plugging.

### Ultrasound

A transvaginal ultrasound examination is often very helpful as this allows us to examine the structure of the uterus, looking for fibroids, septums, etc. It can also help evaluate the ovaries for cysts or other abnormalities or find pelvic masses that may indicate other problems such as endometriosis. This type of internal ultrasound examination is not usually painful for women and actually hurts less than the abdominal ultrasound exam that must be done with a full bladder.

Ultrasound view of the normal uterus

### The Post Coital Test

An old test that you may have heard of is the post-coital test. This test is designed to assess the appropriate entry of sperm into the female reproductive system. Typically this test would be scheduled mid-cycle between days 12 and 14, around the time of ovulation. The couple is instructed to have intercourse two to six hours prior to the office visit. A small swab of cervical mucous is then removed from the cervix with a q-tip and examined under a microscope for the presence of live sperm. Although this test is of historic interest, it has been abandoned in modern day practice since it does not reliably predict fertility or infertility.

### The Semen Analysis

A semen analysis "sperm count" should be one of the very first steps in the infertility evaluation. This test is noninvasive and relatively inexpensive. One or two semen analyses spaced one to two weeks apart are suggested early in the infertility investigation. Abstinence for two to five days is recommended prior to the semen analysis. It is easier to work with a specialized andrology lab than a standard hospital laboratory. Most general laboratories do not have any private areas for sperm collection and often it becomes awkward for the patient to arrange for his analysis and to drop the specimen off. The specimen is collected in a sterile container either at home or in the laboratory. If collected at home, 45 minutes is allowed for transport without any effect on the results. Once the specimen is obtained, then a full semen analysis is performed.

The semen analysis is divided into several components. The ejaculate is analyzed for its volume and its consistency, its acidity, and whether it liquefies. The ejaculate is initially a gel and then turns into liquid after it is allowed to stand for 30 to 40 minutes. Many people are surprised to learn that a normal volume of ejaculate is only one-half to one teaspoonful.

The sperm count is extremely important and is reported as a concentration of millions of sperm per milliliter. Normal values are usually considered to be greater than 20 million sperm per milliliter. Motility (the percentage of sperm that are swimming or moving) is another important parameter to evaluate. Typically it is healthy to have 50 percent or more of the sperm motile. Progression, or how well the sperm are able to move forward in a straight direction, is measured and graded (usually on a scale of 0 to 4). A grade of 2 or 3 is considered excellent. The semen is also analyzed for the presence of white blood cells, which may indicate an infection (often in the prostate gland). In cases where sperm is absent altogether (azoospermia), analysis of the ejaculate fluid may reveal the presence of mechanical blockage in the sperm outflow tract.

Perhaps one of the most important factors looked at in the semen analysis is the Kruger strict morphology, a study of the sperm's structure. This is a microscopic examination of specially stained sperm that details the shape of the sperm, evaluates the normalcy of the sperm head and tail pieces, and their relationship to one another. Most laboratories in a hospital setting are not able to provide this kind of analysis. It should be done in an andrology laboratory at a reproductive center. Experience with the assisted reproductive technologies such as _in vitro_ fertilization has allowed us to use Kruger strict morphology results to help predict how likely a sperm is to bind, penetrate, and fertilize the egg. This gives us an important clue as to sperm function. In our laboratory, 4 percent or more completely normal sperm correlates with good fertility potential. Fourteen percent or more normal sperm is considered excellent. Less than 4% normal is associated with infertility.

There are other measures of sperm viability and function like the post-coital test, the sperm penetration essay, the osmotic swelling test, or the hemizona binding assay, but these tests are becoming less clinically relevant as the advanced reproductive technologies have vastly improved in the last decade. At this point in time, if there are any motile sperm, it is possible for us to perform IVF with intracytoplasmic sperm injection (ICSI) and obtain excellent results **. ICSI has without question revolutionized the treatment of male factor infertility!**

The table below shows some normal parameters of semen analysis

Volume (amount) 0.5 – 5.0 milliliters (ml)

Count (concentration)20 – 150 million per ml

Motility ( % moving) 45% or more

Mobility (speed) 2 or more (graded 1 – 3)

Kruger morphology4% or more normal

(% structurally perfect)

It is important to recognize that there is a lot of variation in semen parameters. The only real way to obtain an accurate picture is to analyze several specimens over a period of time. One should not be alarmed by an individual abnormal specimen because of this biologic variation. Generally, if one or two semen analyses are normal and there appears to be no difficulty with intercourse, then further male testing will not be necessary.

However, if the sperm count is abnormal, then further evaluation of the male is necessary. There are many specific causes of male factor infertility, but most commonly, there is no clear cause. This uncertainty is very common in other medical conditions as well. A careful examination by a urologist can rule out any structural or hormonal problems contributing to male infertility.

### Laparoscopy

The final step in the investigation of infertility if suggested by symptoms or other findings may be a laparoscopic examination. This is a surgical procedure done through small incisions, typically one in the umbilicus and one or two in the lower abdomen. This test is typically reserved as a final test because it is more invasive and more expensive than the other forms of testing. It also frequently requires general anesthesia. However, pathology encountered at the time of laparoscopy (such as tubal scarring or endometriosis) can often be corrected at the same time. Usually a hysteroscopy is performed at the same time which allows the interior cavity of the uterus to be examined for abnormalities. A more detailed discussion of these procedures is included in the surgery chapter.

Preconception Carrier Genetic Screening

Genetic carrier screening involves testing your DNA before you become pregnant to help predict your chances of having a child with a genetic disorder. This does not test your baby or chances of having a child with a chromosome disorder such as Down's syndrome where there is an extra chromosome 21. A carrier is a person who has no symptoms (or only minor symptoms) of a disorder but can pass the gene for that disorder onto his or her child. You can have a sample of blood or saliva sent to a laboratory for testing. You can have carrier testing done before pregnancy or during pregnancy. If you have the testing before pregnancy you have a broader range of options and more time to make decisions than when you are pregnant.

Testing for more and more genetic conditions are becoming available at a very reasonable price. As such, the recommendations for which diseases you should be offered screening for will likely change in the near future. Currently the testing recommended based on the following:

You are a member of an ethnic group that has a high rate of carriers for certain genetic disorders

You or your spouse has a genetic disorder

You already have a child with a genetic disorder.

There is a family history of a genetic disorder

Carrier screening is currently recommended for the following ethnic groups for (a) specific disorder(s).

Non-Hispanic whites should be offered cystic fibrosis carrier screening

People of African, Mediterranean, and Southeast Asian heritage should be offered screening for thalassemias and sickle cell disease.

People of Eastern European Jewish descent (Ashkenazi Jews) should be offered screening for Tay-Sachs disease, Canavan disease, familial dysautonomia, and cystic fibrosis. Carrier screening is available for mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia group C, Bloom syndrome, and Gaucher disease.

An example for genetic carrier screening: If you and your spouse are both white and there is no family history of anyone in your family of having cystic fibrosis, your chances of being a carrier are on the order of 1 out of 27. Therefore the risk of having a child with cystic fibrosis is 1/27 (carrier rate female patient) x 1/27 (carrier rate male patient) x ¼ (risk from recessive gene)= 2,916 or about a 1 out of 3,000 chance of having a child with cystic fibrosis when you do not know if you carry a defective gene for the disease.

However, if you have a relative such as a sister with CF of the female partner the risk that female partner carries the abnormal gene is now 1 out of 2. There for the chance of having a child with CF is now ½ (carrier rate female patient) x 1/30 (carrier rate male patient) x ¼ (risk from recessive gene) = 1/240. This is more than 10 times higher risk of having a child with CF than the general population. This couple should strongly consider genetic testing.

An example when not to do genetic carrier screening: You have a brother who has a child with Down's syndrome or Trisomy 21. The affected child has had a chromosome test which shows that the child has an extra chromosome 21. In this situation there is no increase risk that you would have a child with Down's syndrome. Also since Down's syndrome is not caused by a silently carried recessive trait there is no screen for this prior to pregnancy. In this case you could be tested when you are pregnant to see if your fetus has Down's syndrome. Another option would be to do IVF with genetic testing on the embryos before they are placed into the uterus-preimplantation genetic screening.

There is also much discussion for including testing for Fragile X and Spinal Muscular Atrophy (SMA) although these are not formally recommended at the present time. There is also testing for these disease and for more than 100 other genetic diseases. If your insurance does not cover the costs of the screening, there will be some cost to you. The testing involves a simple blood test and the results are known within 2-4 weeks. Better genetic testing labs will have a genetic counselor contact you with your results.

These tests can be used to calculate the chance that your child will have a specific genetic disorder. For most of the disorders for which carrier screening is available (recessive traits), if both parents carry the abnormal gene, there is a 25% chance the child will get the abnormal gene from each parent and will have the disorder. There is a 50% chance the child will be a carrier of the disorder just like the parents and a 25% chance they will not be a carrier at all. If only one parent carries the disorder, there is a 50% chance the child will be a carrier and a near 0% chance that the child will have the disorder.

A normal test result does not mean that your child will be free of any genetic diseases. There are 30,000 to 40,000 genes in humans and the current technology can only detect mutations for just over 100 genetic diseases. The current technology does not know all the mutations for each genetic disease either. There are spontaneous mutations that occur and therefore cannot be detected before conception. There are birth defects that occur that are not genetic in nature and thus cannot be detected with genetic carrier screening.

If you and your partner learn that both of you are carriers of a genetic condition, you have several options. You may choose to proceed with becoming pregnant, with the option of considering prenatal genetic diagnosis with chorionic villus sampling or amniocentesis. You may choose to utilize donor eggs or donor sperm to avoid the chances of having the child with the disorder. You can also do IVF with preimplantation genetic diagnosis (PGD) to replace embryos that are unaffected (non carrier) or carriers for the disorder. You would not transfer the embryos that have the disease (affected). If you choose to do PGD the embryos can also be screened for chromosome abnormalities such as Down syndrome at the same time you are testing the embryos for a specific recessive genetic disease.

It is possible to screen one partner only and then screen the other partner if something is found. This is called sequential screening. It is possible to screen both partners at the same time (simultaneous screening) or not to screen either partner.

What do we do with the results?

The fact that you as a couple decide to have an evaluation does not mean that you are compelled to begin treatment immediately. But knowledge is power, and the results of the workup will allow you to discuss treatment options with your doctor. Then you can partner in an informed decision-making process to decide when to start treatment and which treatment options you may be interested in. In most cases, a thorough evaluation can be completed within 2 months.

Remember that identification of the cause of infertility is the single most important step in treating this disorder. It is not advisable to begin treatment without a diagnosis, as this can greatly delay appropriate targeted therapy. For example, a woman might ask her doctor for a "fertility pill." He/she obliges her with a prescription for Clomid, which is continued for 6 months without success. After that she may take a break for a few months. She then takes a few months to get an appointment with the doctor again. Then some testing may be done to identify the true cause of the infertility. Using this approach, at least one year may have been wasted and you have already fallen off the Fast Track! Early diagnosis and treatment will always obtain the highest pregnancy rates with the lowest risk of miscarriage.

# Chapter 5  
Treatment Options

Now that you have a basic understanding of the most common causes of infertility and how we identify them, we can turn our attention to the various treatment options. Most treatments for infertility can be divided into four general categories, some of which are often combined in the treatment process:

1. Ovulation Induction

2. Intrauterine Insemination (artificial insemination)

3. Surgical treatments

**4.** _In Vitro_ **Fertilization (Assisted Reproductive Technnologies)**

After the diagnostic testing is completed, choosing the proper fertility therapy is the single most important decision to be made. Undertreatment will ultimately waste time and achieve poor results. Overtreatment will incur unnecessary expense and risk. Here the experience of your doctor, coupled with your understanding of what each therapy can accomplish, will form an effective partnership for decision-making. The purpose of this chapter is to outline the most common treatments in enough detail so you can understand what they can accomplish and how they differ. A clear understanding of the risks and benefits of each therapy is important. At the end of the chapter we present some typical cases to help illustrate the course of therapy. After reviewing this chapter, you can then turn to the subsequent chapters in which these treatments are fully detailed to learn even more about those options that may be specific to keeping you on the Fast Track!

### Ovulation Induction

If abnormal or disordered ovulation appears to be the primary problem, routine hormonal blood work is performed to determine if there is an easily treatable underlying cause such as thyroid dysfunction. In most cases, a specific abnormality accounting for ovulation problems cannot be determined.

The first line agent in these cases is clomiphene citrate, more commonly known by the brand names Clomid or Serophene. Newer medications that are not specifically approved for ovulation induction but are widely used with good safety profiles may also include letrozole (Femara) and Tamoxifen. Due to less side effects and a reduced incidence of multiple pregnancy Femara use is increasing both nationally and internationally. At some point in the future Femara use may become more common than Clomid use. At the time of ovulation with these medications, either intercourse or intrauterine insemination may be performed.

The expected ovulation rate with Clomid is very high for most women with anovulation and a relatively normal body weight. Ovulation rates are lower in heavier women or women significantly below their ideal body weight. Unfortunately, the cumulative pregnancy rate is only between 35 and 40 percent for most patients after three to four months of treatment. Almost all conceptions that result from taking oral ovulation agents occur within three to four months of administration. If you have been on Clomid for longer than this without successful conception, then you should see a fertility specialist.

The second line of therapy for ovulation induction is the injection of drugs known as gonadotropins. These drugs typically contain either pure follicle-stimulating hormone (FSH) or a mixture of follicle-stimulating hormone and luteinizing hormone (LH). Examples of these agents include such drugs as Gonal-F, Follistim, Bravelle, Repronex, and Menopur. These drugs are given in a series of subcutaneous injections (just like someone might take an allergy shot at home or a diabetic might take an insulin shot at home) from about the third day of the menstrual cycle until the eggs reach maturity (usually about 7-10 days later). We can typically achieve ovulation rates of approximately 90 percent using these agents. Cumulative conception rates are 50 to 70 percent after three to four cycles. Because these medications require careful ultrasound and serum hormone testing, they should be administered only by a physician with specialized training and experience in their use.

Multiple pregnancies are an issue with either oral or injectable ovulation agents. With clomiphene citrate, multiples occur 7 to 10 percent of the time, with the vast majority of multiple pregnancies being twin gestations. With Femara the estimated multiple pregnancy rate is 3-4%. With gonadotropin therapy, multiple pregnancy rates are approximately 25 percent. Twins still account for the majority of these multiple births, but triplets can occur in about 3 to 4 percent of cases and more than triplets in less than 1 percent of cases with injectable drugs. Careful monitoring and dosage adjustment can reduce multiple pregnancy rates to these levels. However, at the present time, there is no technique that can completely eliminate the chances of multiple births.

### Intrauterine Insemination (Artificial Insemination) Treatments

Treatment of the male factor is somewhat more controversial. A varicocele is a collection of dilated veins in the scrotum. If a large varicocele is identified, then there is some agreement that surgical repair should be performed. However, in most cases, either a small varicocele or none is identified. Surgery to remove a small varicocele is controversial and is often not associated with any consistent improvement in sperm parameters. If there is evidence of a prostate infection, then antibiotics may be used. If there is evidence of decreased hormone levels or decreased serum testosterone levels, then Clomid can be used by men in an attempt to improve semen parameters. This approach has demonstrated mixed results.

The most direct treatment to deal with mild male factor disease appears to be intrauterine insemination. This is often combined with the use of ovulation drugs for the female partner to improve the chances that more eggs and more sperm may be able to meet up together at just the right time. Intrauterine insemination is an office-based technology to deliver sperm into the uterus very near the openings of the fallopian tubes at the time of ovulation. It is important to realize that this is more effective in cases where the fertility abnormality is mild. In more severe abnormalities, _in vitro_ fertilization is much more effective.

### Intrauterine insemination

The term intrauterine means "in the uterus" and refers to placement of the sperm within the uterine cavity. Rather than sperm being deposited in the vagina during intercourse, intrauterine insemination (IUI) allows your doctor to deliver high numbers of sperm into the upper reproductive tract just when the egg is ready for fertilization. Not only are more healthy sperm placed closer to the egg, but this technique allows us to bypass any problems associated with the vaginal or cervical environments as well. Insemination is typically scheduled based on an ovulation triggering injection that has been administered to the woman. About one to two hours prior to the insemination, the male collects the sperm specimen, usually by masturbation. It is also possible to use a special collection condom. Remember that a standard condom should never be used since it is coated with chemicals that will destroy sperm.

After the sperm is collected, it is allowed to liquefy for 30 to 45 minutes and then undergoes sperm washing. This is a process of centrifugation that separates the live moving sperm from dead sperm and other cells in the ejaculate. A skilled andrology (sperm) lab is essential in the preparation of the sperm specimen. Most labs will evaluate the sperm before and after washing. This information is helpful to track any trends in sperm numbers.

The insemination process involves placing a speculum (instrument used to see the cervix, as used for a Pap smear) in the vagina. A small, soft, flexible catheter (tube) is then used to transfer the sperm into the upper uterus. The patient is then asked to rest for five to ten minutes before resuming daily activities. Insemination can cause mild cramping, but most women describe it as feeling like a Pap smear when performed by an experienced physician. A small amount of watery discharge from the cervical mucus and the speculum is common after insemination. There is no reason to fear that the sperm will come out when the patient gets up and leaves because the sperm is retained within the uterus by surface tension. A small amount of spotting may also occur after insemination. This is no cause for alarm. Having intercourse the night of the insemination may improve pregnancy rates as even more sperm will be available for fertilization.

Most studies have shown that combining ovulation induction for the female with intrauterine insemination gives higher pregnancy rates than timed intercourse alone. Insemination performed for male factor infertility with a woman's natural cycle is associated with poor pregnancy rates and almost no improvement over intercourse alone. Because of these data, insemination is typically combined with an ovulation-inducing agent for the woman. Ovulation induction and intrauterine insemination are therefore commonly used to treat not only male factor cases but infertility resulting from ovulation problems, cervical factor, unexplained infertility, and endometriosis-associated infertility. Because insemination is less expensive than IVF it is more widely utilized, but it is much less effective in most cases.

### Surgical Treatments

Ovulation medication and insemination rely on healthy fallopian tubes to pick up the eggs and to deliver the sperm to the eggs as well as return the fertilized embryo to the uterus. For cases of infertility related to tubal disease or endometriosis, surgery still plays an important role in the treatment process.

Therapy for tubal disease generally begins with laparoscopic surgery to remove scar tissue and endometriosis. In some cases, fallopian tube blockage can also be relieved with a combination of hysteroscopy and laparoscopy. If the disease is more advanced, a microsurgical reconstruction can be done at the time of open incision (laparotomy). Surgery to reverse tubal ligation is also usually performed this way at the present.

Fallopian tube repair is associated with pregnancy rates as high as 60 to 80 percent in younger patients following tubal reversal or as low as 20 percent with operations to create a new opening in the end of a tube that has scarred completely shut. In some cases, if the tubal blockage is close to the uterus, a catheter (similar to those used to open blocked blood vessels near the heart) can be used to open the fallopian tube without any incisions. Pregnancy rates following fallopian tube catheterization are in the range of 40 to 60 percent. For badly scarred tubes, _in vitro_ fertilization usually represents a much less invasive and more successful alternative to surgery.

The subsequent chapter on surgery discusses these operations in more detail, but we will provide an introduction here. **Laparoscopy** is the most commonly used surgical fertility procedure. Usually performed under general anesthesia in an outpatient surgery setting, laparoscopy involves making between one and four small incisions (2 to 10 millimeters in size) in and around the belly button and lower abdomen. The surgeon then inserts the laparoscope (a lighted instrument that visualizes the reproductive tract) and accompanying lasers and instruments through these incisions. Laparoscopy can be used _diagnostically_ to gather information about the reproductive tract as well as _therapeutically_ to repair damage to the reproductive tract. In an ideal situation the procedure is both diagnostic and therapeutic, meaning that the physician can make the diagnosis and institute treatment at the same time.

During a laparoscopic procedure, the surgeon visually inspects the uterus, fallopian tubes and ovaries. The fallopian tubes are also checked for blockage and flushed clean by a process called chromotubation, during which colored dye is injected into the uterus and observed as it spills out the end of the tubes. Using lasers and other instruments, the surgeon can remove scarring and destroy endometriosis. If the fallopian tubes are obstructed, they can sometimes be repaired. The feasibility of repair depends on how severely damaged the tubes are and the skill and experience of the surgeon.

**Hysteroscopy** is a procedure performed through the cervix (mouth of the womb). This procedure does not require any incisions and can sometimes be performed in the office setting without general anesthesia. During hysteroscopy, the surgeon slightly dilates the cervix and places a small fiber optic camera into the cavity of the uterus to directly inspect the interior. Hysteroscopy can be used to repair any pathology found there such as endometrial scarring, polyps or fibroids.

**Laparotomy** is a surgery performed through an open incision that is usually four to six inches long. The incision is usually a "bikini" or lower abdominal transverse incision (known medically as a Pfanenstiel incision). This incision heals quickly and is cosmetically ideal because it is low on the abdomen and will not be seen even when the woman is wearing a bathing suit. Sometimes the incision has to be vertical due to the level of disease process or a previous incision. Most vertical incisions extend from below the belly button to the pubic area. Laparotomy is performed to remove large fibroids, extensive scarring or severe endometriosis. It is also frequently utilized to perform a tubal ligation reversal. Full details of surgical procedures are found in the chapter specifically dedicated to this topic.

### Assisted Reproductive Technologies (ART)

If basic conventional treatment is unsuccessful, then the assisted reproductive technologies may be utilized. These are office-based techniques that involve isolation and direct manipulation of the actual eggs and sperm to create embryos that can then be transferred to the woman's uterus.

The most commonly used technique is _in vitro_ fertilization (IVF). This technique involves administration of ovulation inducing drugs to the woman. These drugs result in the development of multiple follicles. Each follicle contains a single egg. The eggs are then retrieved nonsurgically by a technique known as transvaginal ultrasound- guided retrieval, typically completed within twenty to thirty minutes and without general anesthesia. Following egg retrieval, the sperm is processed and each egg is incubated with sperm. In cases in which the sperm count is very low, sperm can be injected directly into the egg (a technique called intracytoplasmic sperm injection, or ICSI). Two to five days following the egg retrieval, the best two or three embryos are generally placed in the upper uterus. About 50% of patients who are thirty-five years or younger can achieve conception from their first IVF cycle.

### 3 day old human embryos from IVF

**Without question, in vitro fertilization is the best treatment that your doctor has to offer you!** This is because it provides the highest pregnancy rate (more than twice the rate of natural conception of even young healthy couples without fertility concerns) in a given cycle and offers patients the most control over multiple births. Although twins are still common with IVF (around 30 percent of successful births), most responsible centers are transferring only two embryos at a time in the majority of their patients under 35 years of age. This means that the chance of anything more than twins resulting from IVF is much lower than with any of the ovulation inducing medications. In fact, single embryo transfers (which reduce the risk of even twins to less than 2 percent) are becoming more and more common.

Due to the increasing success of IVF in achieving pregnancy and limiting multiples, its use has become more common in the last 10 years. It represents the best treatment option for many infertility patients. Unfortunately, insurance often does not cover IVF procedures. _In vitro_ fertilization is perhaps the most feared and misunderstood of all the therapies for infertility. Misconceptions abound based on what friends and family say, random Internet postings, and also media coverage of glamorous cases. In many cases, _in vitro_ fertilization is the most rapid and effective method for staying on the Fast Track and, more often than not, will result in the birth of a singleton. IVF is discussed in detail in a subsequent chapter.

### Choice of Treatment

Choosing the right treatment involves collaboration between you and your doctor. Your choice of therapy will depend on the nature of your fertility problem and how aggressive you want to be with treatment. The best way for you to learn which level is appropriate for which type of case is to show some examples. The following are some typical cases:

**Case #1:** Tara is a 28-year-old woman who has been married for two years. She has used no contraception for six months and is concerned that her menstrual periods are, and always have been, quite irregular. She menstruates every three months or so. She called her doctor's office and was told to wait another 6 months and then evaluation would begin. She is tired of waiting and all of her friends and coworkers are pregnant. There is no need for her to wait since she is obviously not ovulating properly with such irregular cycles! The situation will likely be the same if she waits another six months, and she will have wasted valuable time. If there are no other problems and her examination is normal, some basic hormonal blood work can be initiated and her husband's sperm count can be checked. She can then be quickly started on Clomid or Femara with a reasonable expectation of pregnancy. If she does not conceive within three cycles, further testing and more aggressive therapy is needed.

**Case #2:** Susan is a 38-year-old woman who has been infertile for two years. The x-ray of the uterus (HSG) shows one tube is blocked. Her doctor performs laparoscopy and removes a severely scarred tube and performs a laser repair on the other tube that turns out well. Because at 38 she is reproductively older, she should not then expend more time with natural attempts after surgery. Her treatment of choice would reasonably include ovulation induction and intrauterine insemination. The choice of ovulation drugs with this patient would depend on how aggressive she wishes to be. There is a case to be made for brief administration of Clomid and insemination if she chooses, but, if this is not rapidly effective, she should move to injectable drugs or IVF. If the repair of the remaining tube at the time of surgery were marginal or suboptimal, then she would be better off proceeding directly to _in vitro_ fertilization without further delay.

**Case #3:** Rebecca is a 36-year-old woman who had no trouble conceiving her first child, but she has had virtually no menstrual periods following childbirth. Heavy bleeding after her first delivery required the manual removal of the placenta and then a D&C (scraping of the inside of the uterus). An x-ray for this patient has shown severe scarring of her uterus, which is the cause of her infertility. A hysteroscopic repair best treats this condition. Since her irregular periods are due to a damaged uterus and not irregular ovulation, surgery is the preferred treatment rather than ovulation drugs.

**Case #4:** Laurie is a 30-year-old woman who has not had a child before and has been married for three years. Her husband is 30 years of age and in good health and has fathered a child previously. Her work-up shows normal ovulatory function. He has a normal sperm count. The patient has a history of a LEEP procedure, where part of the cervix is removed because of abnormal or precancerous cells detected at the time of an abnormal Pap smear. Physical examination shows that the cervix is markedly narrowed or stenosed. Her cervix will not naturally transport sperm well. This patient would do well with intrauterine insemination. Because intrauterine insemination is not effective in the natural cycle, an ovulation-inducing drug would also be used. Since Laurie is young, therapy will begin with Clomid and move on to injectables only if she does not conceive.

**Case #5:** Kathy is a 33-year-old woman who has been married for three years and has not used contraception for two years. Her past history shows no medical problems. Her husband is 34 years of age and in good health. He has been married previously but has never fathered a child. A work-up shows her to be ovulating and an x-ray shows no abnormalities of the uterus. His sperm count is lower than normal, 10 million per milliliter (normal would be 20 million or more). His motility is 30 percent (normal would be 50 percent or more). This is a typical case of male factor infertility with a combination of low sperm count and low motility. Frequently a low percentage of the sperm that are present may also be structurally abnormal (a low critical morphology). The initial approach with this patient would be ovulation drugs and intrauterine insemination. During this process her doctor would continue to evaluate the sperm. If this process does not work within three to six cycles, then this couple would be excellent candidates for _in vitro_ fertilization. He would also be a candidate for a urological evaluation including a physical examination.

**Case #6:** Michelle is 36 years old, has been married for five years, and has used no birth control for two years. She appears to be ovulating. Her husband has a normal sperm count. She had a laparoscopic exam one year ago that was normal. This couple suffers from unexplained infertility. Generally patients are very unhappy to have this as their diagnosis. This unhappiness is due to the misconception that if their infertility is unexplained, there is no definite treatment to utilize. Unexplained infertility is probably a result of several variables combined together, including possibly poor sperm delivery into the reproductive tract and inefficient ovulatory function. Excellent results can be obtained in a case like this with ovulation drugs and intrauterine insemination. An alternative option would be _in vitro_ fertilization immediately if the couple wishes to be more aggressive. The choice of ovulation-inducing agent depends on the preference of the couple. In order to reduce the cost of therapy and the risk of multiple pregnancies, Clomid would be initially used. If not effective after a few cycles, Michelle can advance to injectable drugs or IVF.

**Case #7:** Beth is 35 years old, has been married for five years, and is known to have endometriosis. She has used no birth control for three years. Her gynecologist has given her Clomid previously. Her husband has normal sperm counts and she appears to be ovulating. This is what is typically referred to as endometriosis-associated infertility. In a case like this the two options available are ovulation drugs combined with intrauterine insemination or _in vitro_ fertilization. Excellent results can be obtained using either approach. Generally, _in vitro_ fertilization gives superior results with a lower risk of high order multiple pregnancies. This couple should have a consultation with their doctor to jointly decide which treatment makes the most sense for them.

**Case #8:** Lisa is 38 years old, has been married for ten years and has not used contraception for that period of time. She is known to have endometriosis and her husband has a sperm count of 2 million per milliliter with 20 percent motility. Given the patient's age and severity of her disease process as well as the abnormality of the sperm, _in vitro_ fertilization is the technology that would most likely succeed. Any lesser technology is unlikely to succeed and would probably waste valuable time. The merits of an aggressive approach should be discussed with this patient. She clearly has little time to lose.

### Summary of Treatment Options

Today, more than ever, we have effective tools to successfully treat most cases of infertility. Choosing effective therapy is the single most important decision once proper diagnosis has been made. Undertreatment of infertility is probably the single most common error that throws couples off the Fast Track. Because of limited insurance coverage, couples commonly dwell on ineffective treatments, hoping that success will come at some point and that more expensive treatments will not be necessary. It is important to remember that any given treatment is most likely to work within three or four cycles. If a specific treatment has not worked within that time frame, it is unlikely to ever work at all. Implementing therapy quickly is critical. Time lost on the biologic clock can never be regained. This becomes increasingly important when the woman is in her mid thirties! Remember, rapid diagnosis and treatment are your key to success.

# Chapter 6  
Ovulation Drugs and Insemination Therapy

Ovulation medications are commonly known as ovulation inducing agents. These medications can be used in one of two kinds of patients. The first kind of patient is one who does not ovulate. Normal ovulatory cycles have a length of 27 to 35 days. Most women who do not ovulate have few and irregular menses, with cycles occurring at intervals of greater than 35 days or shorter than 25 days apart. For patients with ovulatory dysfunction, ovulation drugs are used to promote ovulation of a single mature egg, just as the system is naturally designed to do. We are trying to recreate a normal cycle in this setting. This treatment approach is referred to as **ovulation induction**.

The second kind of patient in whom we use ovulation inducing agents is the patient who is already ovulating but suffers from infertility for other reasons, including unexplained infertility, mild male factor infertility, or endometriosis-related infertility. For these patients, we are using the ovulation drugs for **superovulation** , a process in which we are trying to stimulate the ovaries to produce several mature eggs at a time to improve fertility rates. Superovulation by itself for these conditions does not dramatically increase pregnancy rates, but will do so effectively when combined with intrauterine insemination.

There are two classes of ovulation medications:

1. Oral medications

2. Injectable drugs

### Oral Ovulation Inducing Agents

The only FDA approved oral medications for ovulation induction contain the drug **clomiphene citrate,** sold under the brand names **Serophene** or **Clomid**. Serophene and Clomid are equivalent. Clomid was the first ovulation-inducing agent available in the United States. It was introduced in the 1950s and is the most widely known "fertility drug" on the market. Clomid was initially investigated as a medication for the treatment of breast cancer and abnormally thickened uterine linings, but it was rapidly noted to improve ovulation in test subjects with these conditions. The term "fertility drug" is truly a misnomer, since Clomid is actually an ovulation drug. If given alone to someone who is ovulating, it can actually decrease fertility. Clomid is not a "wonder drug" and should not be used indiscriminately in all cases of infertility. Inappropriate use of Clomid can result in ovarian enlargement, cysts, and poor pregnancy rates. It is really to be used in cases in which the individual is not ovulating, or coupled with careful monitoring and intrauterine insemination as a treatment for conditions such as unexplained infertility, mild male factor infertility, or endometriosis-associated infertility.

Clomiphene citrate is an antiestrogen (hence its initial development as a breast cancer drug) and functions by "fooling" the pituitary gland into thinking that there is not enough estrogen in the body. This gland then stimulates the ovary to make follicles (egg producing structures) which mature, secrete estrogen and eventually release the eggs. The cost for one cycle of Clomid will depend on the dosage but typically ranges from $10 to $50 per month. Clomid is initially prescribed in doses of one to two tablets, starting either the third or the fifth day of the menstrual cycle for a total of five days. Remember that day one of the cycle is defined as the first day of full menstrual flow. Ovulation typically occurs seven days after the last Clomid tablet is taken. For couples with anovulation and normal semen parameters, timed intercourse can then be attempted based on this knowledge.

Clomid should be monitored with either blood progesterone levels or with ultrasound to confirm ovulation. Blood progesterone levels should be drawn about a week after predicted ovulation. If Clomid is given on days three through seven, and ovulation predicted on day fourteen, the ideal time to draw a progesterone level would be around day twenty one. A level greater than 3 (nanograms per milliliter) is suggestive of ovulation. Most clinics would like to see higher levels. A value of 7-10 ng/mL or greater is ideal. If the value is low, one can increase the dose of Clomid in the subsequent cycle. If the value is normal, then the dose of Clomid should not be increased simply because pregnancy did not occur at that dose. Inappropriate increases can give poor results.

More accurate than blood progesterone levels are ultrasound follicle measurements. A follicle study performed by an experienced examiner can be very informative. The follicle is the egg sac that enlarges and eventually ruptures to release an egg. There is a single egg within each follicle. Eggs cannot be seen by ultrasound since they are microscopic. The follicle, however, is large enough to be visualized and measured by ultrasound. By performing an ultrasound between days 10 and 14 of the menstrual cycle, your doctor can evaluate the level of stimulation from Clomid and determine the number and size of the follicles. Below is an ultrasound showing an ovary containing follicles:

Ovary containing follicles

The ideal time to trigger ovulation is also determined. In most cases hCG (human Chronic Gonadotropin) will be administered by injection in order to trigger ovulation. Without hCG, ovulation will still occur if the follicles are mature, but the exact time of ovulation will be unknown. hCG is available either as a generic form or by several brand names (Ovidrel, Pregnyl, Novarel). hCG will trigger ovulation in the presence of a mature follicle approximately 32 – 44 hours after the shot is administered. Knowing this window of time is helpful so we can either instruct the couple to time intercourse or perform insemination based on a very narrow window of ovulation.

At the time of ultrasound monitoring, the thickness of the lining of the uterus is also assessed. It is thought that a lining thickness of six millimeters or more is ideal for implantation. Unfortunately, one of the side effects of Clomid is a thinning of the lining of the uterus. Clomid can also decrease the production of cervical mucus, thus creating a barrier to sperm entry into the reproductive tract. These undesireable side effects from Clomid help explain why, despite excellent ovulation rates, pregnancy rates are still limited to 35-45 percent after three to six cycles.

The duration of Clomid therapy should not exceed three to six months. Almost all pregnancies will occur by cycle four. If you are not working with a reproductive endocrinologist and you are not pregnant after three to four cycles of Clomid, you should seek expert help.

The multiple pregnancy rate in the general population is currently 3% without fertility medications. With Clomid, multiple pregnancy rates of 5-9% percent are expected, with twins representing the vast majority of multiples. Triplets resulting from clomiphene therapy represent less than 1 percent of pregnancies conceived during treatment. Most of the side effects from Clomid are due to its antiestrogen actions. Many patients have no side effects at all, but some patients complain of hot flushes or night sweats and occasionally mild headaches. Some abdominal bloating or cramping is very common. Much more rarely, women may develop a follicle in the ovary that persists for one or two months before spontaneously resolving. True overstimulation (ovarian hyperstimulation) from Clomid requiring treatment is extremely rare.

Some women (or their husbands) may also complain that they feel "hormonal" while taking Clomid. Generally this means that they may react in a more emotional, more "moody" fashion to various situations. Many patients say that their friends or coworkers may be put off by sensitive behavior or that they have cried in reaction to trivial things like a TV commercial. It is important for your support network to understand this so they are not confused by the way you may act on Clomid. Infertility in and of itself is associated with feelings of depression, anxiety and frustration. Surging hormones thrown into the formula do not help!

### New Oral Ovulation Drugs

Since Clomid is not as highly effective as we would like, there is a great deal of interest in developing other oral ovulation drugs. The most promising new class of medications is called **aromatase inhibitors**. Aromatase is an enzyme that converts precursor hormones into estrogens. These drugs work by reducing the production of estrogens for the first few days of the menstrual cycle. The pituitary gland reacts by releasing a surge of follicle-stimulating hormone (FSH). FSH stimulates the ovaries to produce follicles, which in turn will secrete estrogen.

Because these drugs if given constantly will reduce estrogen levels, they are useful as ancillary treatment for certain hormone-dependent cancers such as breast and prostate cancer. Aromatase inhibitors were developed to treat these types of cancers by lowering estrogen levels. These medications are not yet FDA-approved for ovulation induction, and some manufacturers have even issued notices to doctors saying that they should not be used for ovulation induction. However, several large studies have suggested that Femara is as safe as Clomid for ovulation induction.

The two most common aromatase inhibitors used in ovulation are **Femara (Letrozole)** and **Arimidex (anastazole)**. Most of the available information on aromatase inhibitors and ovulation is for Femara. Since we are always concerned with the effects of ovulation drugs on the fetus, it is reassuring to know that these medications are not given during pregnancy itself and that, due to a short half-life, they are almost completely out of the blood stream before conception even occurs.

Almost all studies done to date comparing Femara and Clomid indicate that the two drugs are equally effective in terms of ovulation rates and pregnancy rates. However, it is speculated that the multiple pregnancy rate with Femara may be slightly lower than that with Clomid because it causes fewer follicles to mature and release. Femara also appears to be associated with better development of the lining of the uterus than Clomid. At the time of this writing, use of Femara is expanding both nationaly and internationally. Femara is also associated with a lower incidence of side effects including hot flashes and irritability. Typical dosing for Femara is 5 mg days 3 through 7 of the menstrual cycle. Ovulations expected to occur around day 14 of the menstrual cycle. Some individuals who do not conceived with Clomid will conceive with Femara. Most pregnancies that occur with Femara will occur during the first 4 months of use.

One final class of oral medications that can be used for ovulation induction is known as selective estrogen receptor modulators (SERMs). These drugs stimulate the pituitary into releasing FSH by binding to its estrogen receptors. The most common medication in this category is tamoxifen, which is another breast cancer drug. Tamoxifen works about as well as Clomid and has similar side effects to Clomid, but it does not thin out the uterine lining as much as Clomid can. It has been used on and off for twenty years for ovulation induction by a few practitioners, but there is little information about its overall safety.

### Drugs that Reduce Insulin Resistance

For individuals with polycystic ovaries (PCOS), some benefit can be achieved with medications that reduce insulin resistance. PCOS, described in detail in Chapter 12, is a syndrome that includes increased body weight, irregular menstrual periods and slight increases in male hormones. At least 80 percent of individuals with PCOS have increased body weight. The remainder have normal or decreased body weight. It is our current belief that most cases of PCOS are due to insulin resistance. This means that the woman's body has to produce large quantities of insulin in order to maintain blood sugar in the normal range. High levels of insulin result in weight gain and irregular menstruation. It makes sense that making the body more sensitive to insulin will restore normal function.

There are many insulin sensitizers that are commonly used to treat adult diabetes. Examples of these drugs include **metformin (Glucophage)** , **Avandia** and **Actos**. The greatest amount of information for the treatment of PCOS, especially in those women who wish to conceive, is with metformin. We will therefore focus on metformin.

Some studies have shown that metformin will work whether body weight is normal or increased. It has been our experience that the best results are in overweight patients. Metformin works best in combination with a low-carbohydrate, high-lean protein, low-fat diet. The combination of metformin and dietary change can result in a weight loss of 10% or more. That in and of itself may result in a 35% pregnancy rate! Weight reduction will also dramatically improve the outcome of pregnancy. Starting pregnancy with increased body weight will increase pregnancy complications such as high blood pressure and diabetes.

There is no increase in the multiple pregnancy rates from conception on metformin therapy. The dose of metformin varies by body weight, but a typical dose may be 1500 milligrams per day. This can either be given as 500 milligrams three times per day or as an extended release dose of 1500 milligrams with dinner daily once daily. Metformin can cause gastrointestinal side effects such as diarrhea, nausea, or bloating. It is important to gradually work up to the ideal dose to reduce the chance of side effects.

If you have PCOS and conceive with metformin therapy, your doctor may recommend continuing or stopping the medication. There are pros and cons of each approach. Metformin is a class B drug which is considered as safe as many medications routinely used in pregnancy. If metformin is not enough to achieve pregnancy, it can be continued and another agent such as Clomid or the injectable medications can be added. As initial treatment for PCOS, metformin is almost as effective as Clomid. Either can be tried initially and then the second added as needed. In cases of PCOS where there is increased body weight, we prefer to begin with metformin and then add Clomid as needed later.

### Injectable Ovulation-Inducing Medications

If oral medications such as Clomid are ineffective, then your doctor may recommend the stronger, more effective injectable ovulation-inducing medications called gonadotropins. In general, they are much more effective than Clomid and produce more eggs with fewer side effects in a given cycle. The first such agent available was **Pergonal** , which has been replaced by newer formulations. Pergonal became available more than thirty years ago and was an extract of the urine of menopausal women. The urine of menopausal women contains high levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). By concentrating these hormones from the urine, it was possible to obtain results for patients who did not respond to Clomid.

Gonadotropins can be used in a variety of situations. One common use is for patients who did not conceive on Clomid therapy. There are two possibilities as to why a patient would not have success with Clomid treatment. The first is that she did not ovulate with Clomid, and the second is that she did ovulate but did not conceive with Clomid. The second is much more common than the first.

Because injectable drugs are expensive and somewhat involved, it is important to obtain a sperm count and some evidence that the fallopian tubes are open prior to initiating treatment. A semen analysis as well as either a HSG (x-ray of the tubes and uterus) or laparoscopy will provide this information. These procedures are discussed in detail in the previous chapter.

FSH is the main active ingredient in most of the injectable medications. Some of the available injectable ovulation-inducing agents containing FSH alone are **Gonal-F, Follistim,** and **Bravelle**. Another medication, Menopur, contains both FSH and LH. In most cases, these drugs can be used interchangeably, although some patients may have a specific indication for one medication over another. So you may want to ask your doctor about using the agent that is most cost-effective, given your specific insurance coverage or individual financial status. These medications can be used alone or combined with oral agents such as Clomid or Femara. In our practice we frequently combine injectable agents with Femara in order to reduce the number of injections and the cost of the treatment.

At any given time, one drug may be less expensive than the others, and the drug companies will from time-to-time have "specials" when they reduce the cost of these medications. For one ovulation cycle the medication costs will typically range from $600 to $1,000. You will probably also have some costs associated with your office visits and blood work that are required for monitoring the ovarian response to the medications. For most patients, three cycles will be an average time frame to achieve conception. Younger patients and thinner patients tend to require less medication than older patients or patients with increased body weight.

In rare cases a patient must use an agent containing both FSH and LH. Such patients account for less than 5 percent of all cases and are typically women with a condition known as "hypothalamic amenorrhea." These patients have no menstrual periods, and when progesterone is administered in the form of Provera or Prometrium, have no withdrawal bleeding. Their reproductive systems are completely shut down and they will require both FSH and LH to ovulate properly. However, in most cases, any of the above agents can be used relatively interchangeably.

All of the gonadotropins can be injected subcutaneously with a tiny needle under the skin, much like an allergy shot or an insulin shot. Treatment begins early in the cycle after checking a baseline ultrasound to make sure the reproductive tract is in an ideal state to start the treatment. Dosages are usually measured in units and will vary in most cases from 75 to 300 units administered once daily. Because the dose varies from individual to individual and from cycle to cycle, it is critical that the patient be carefully monitored. Also, the physician should be expert and have experience in the administration of these potent drugs. In most communities, only Reproductive Endocrinologists will administer these drugs.

After the first three to five days of injections, the patient returns to the fertility center for follow up. An ultrasound exam is used to look at the number and the size of the developing follicles on the ovaries, and an estrogen blood test is taken to measure the hormonal secretion of the follicles. The combination of these tests will be used to fine tune further dosing of the gonadotropins for another two to three days. Ovulation induction is as much an art as it is a science, and the experience of the physician is critical to obtain the best possible response. The goal of treatment is to produce enough follicles to get good pregnancy rates while at the same time minimizing the occurrence of multiple pregnancies.

Typically between days 9 and 14 of the cycle, one to three follicles have reached a mature size. When this occurs, hCG will be administered to ensure release of the eggs from the follicles and help to time the ovulation. In contrast to Clomid therapy in which ovulation can occur without hCG triggering, this trigger is an essential part of the gonadotropin therapy.

Once the hCG is administered, ovulation will occur in 36 to 44 hours. The couple can then have timed intercourse or use intrauterine insemination. If timed intercourse is utilized, we recommend intercourse on the night of the hCG shot and then 36 to 44 hours following the hCG shot at the time of predicted ovulation. If intrauterine insemination is recommended, we suggest intercourse the night of the hCG shot and then insemination would be performed 36 to 44 hours after the hCG shot at the time of predicted ovulation.

Some Reproductive Endocrinologists recommend two inseminations, one on the day before ovulation and a second one on the actual day of ovulation. Recent research suggests that the results with one and two inseminations are similar if couples are also having intercourse as described above. Insemination significantly increases pregnancy rates over timed intercourse in cases in which the injectable drugs are given to treat unexplained infertility, endometriosis-associated infertility, or male factor infertility. If the problem appears to be an ovulation disorder, then timed intercourse can be used and insemination would be considered optional. However insemination may be superior to timed intercourse even in these cases, and many couples will just choose insemination in the hope that they will conceive more rapidly since treatment is expensive.

Pregnancy rates per cycle with gonadotropins and insemination are approximately 18 to 25 percent depending on the type of infertility case. Cumulative pregnancy rates are in the range of 40 to 60 percent after 3 to 4 cycles. These success rates are roughly twice those achieved with Clomid. Side effects of injectable ovulation medications include abdominal bloating and cramping and ovarian cyst formation. Hyperstimulation is a complication in which the ovaries are enlarged and painful. This condition can be associated with fluid build up within the abdomen and, in rare cases, severe abdominal distention. Sometimes the abdominal fluid needs to be removed so the patient can feel better. In most cases bed rest and pain medication will help. Careful monitoring by an experienced doctor can reduce the risk of this side effect. In some cycles where too many follicles have formed, hCG triggering may be cancelled to avoid severe hyperstimulation.

The multiple pregnancy rate associated with injectable drugs is approximately 20 to 25 percent, depending on the type of case. The most common type of multiple birth is twins, but the incidence of triplets is 3-5 percent. Higher order pregnancies are rare but, unfortunately, do occur. Any multiple pregnancy is at higher risk due to the increased chance of premature birth. Premature babies can have multiple medical problems, some of which may be permanent. Therefore, it is important to keep the multiple pregnancy rates as low as possible. Because your physician cannot control the exact number of eggs fertilized and implanted with gonadotropin therapy, it is impossible, even in the best of hands and with careful monitoring, to eliminate entirely the risk of high order multiple pregnancies (triplets and greater). Only _in vitro_ fertilization gives us that type of control over multiple pregnancies, because we are controlling and limiting the exact number of embryos that are being replaced into the uterus. If couples wish to avoid the risk of triplets or more associated with gonadotropin therapy, they can skip this level of treatment and go directly to IVF. _In vitro_ fertilization not only helps eliminate high order multiple pregnancies, but is also significantly more effective in achieving pregnancy for most couples and, therefore, keeps them on the Fast Track. Therefore, many of our patients choose to go right to IVF. The most common reason not to choose IVF is the cost associated with this procedure.

### Do ovulation drugs increase the risk of ovarian cancer?

In 1987, Ron _et al_ published an article in the _American Journal of Epidemiology_ regarding the risk of ovarian cancer related to the use of ovulation-inducing agents, commonly known as fertility drugs. In this particular study, which was very well done, no risk was associated with the use of ovulation-inducing agents. Several years passed without any further major articles addressing this topic. Then in 1992, Whittmore _et al_ published an article, also in the _American Journal of Epidemiology_ examining the association of ovarian cancer with the use of ovulation-inducing agents. The study itself did not contain any new information but was a reanalysis of twelve earlier studies published between 1956 and 1986 in the United States. There are many problems with Whittmore's study, including the fact that many patients were enrolled during a period of time when fertility drugs were not widely utilized. There is also no clear definition of what a fertility drug is. However, the study did show a slightly increased risk of developing ovarian cancer in individuals who had used fertility drugs compared to controls. The risk was focused primarily in the group who failed to conceive regardless of treatment.  
In October 1996, a critical review of published data regarding the proposed association of ovulation-inducing drugs and increased risk of ovarian cancer appeared in _Fertility and Sterility_. The authors of this review, who did a computerized search for all articles and case reports regarding this issue, concluded that an association between ovulation-inducing agents and ovarian cancer does not necessarily indicate a cause and effect relationship. The study showed that infertility alone is an independent risk factor for the development of ovarian cancer. It also indicated that women who never conceived are probably in a high risk category regardless of the use of fertility agents. According to the authors of this article from the UCLA School of Medicine, the apparent association between fertility drug use and ovarian cancer may arise because these women are the most likely to have used ovulation-inducing agents as part of their infertility treatment.

In the November1999 issue of _Lancet_ , Vann _et al_ reported a study from Australia. They studied nearly 30,000 women referred for IVF. They found that the incidence of breast and ovarian cancer was not increased over that expected in the general population. They found no association between the number of IVF cycles and the incidence of uterine or ovarian cancer. They did find that unexplained infertility was a risk factor for ovarian cancer, irrespective of drug use. This data search has confirmed that infertility is a risk factor for ovarian cancer in and of itself. The risk does not seem to be due to drug therapy.  
In February of 2002, Dr. Ness and colleagues published an article in the _American Journal of Epidemiology_ analyzing data from 8 studies including 13,000 women. Their analysis showed that use of fertility drugs did not increase the risk of ovarian cancer. They noted that women who never became pregnant were twice as likely to develop ovarian cancer. They suggest that infertility alone, not the use of ovulation drugs, increases the risk of ovarian cancer.  
In summary, a significant quantity of data suggests that infertility, in and of itself, is associated with a higher risk of ovarian cancer. This risk appears to be unrelated to the use of any ovulation-inducing medications. It is also important to know that ovarian cancer is the sixth most common malignancy in women. It represents approximately 4 percent of all female cancers. Many factors protect against the risk of ovarian cancer. Birth control pill use is protective. Pregnancy and delivery are also protective. It is hoped that through the use of ovulation-inducing agents, many pregnancies will occur which will offset the risk of ovarian cancer. For women who do not conceive, future use of birth control pills may offer some protection against this cancer.

### What are the risks of multiple births?

Multiple pregnancies pose a risk primarily to the fetus, but they can also place the mother at higher risk for pregnancy-related complications. The following table compares multiple pregnancy risks for the various treatments:

The uterus was designed to carry one fetus, and on occasion two, to term. Some fetal risks are inherent to multiple pregnancy, but most result from premature delivery, which is much more common with multiple births. If the baby is born prematurely (before 36 to 40 weeks of pregnancy), it will not be fully developed and may have health problems. The risk of preterm birth is directly related to the number of babies in the uterus. The average gestational age of delivery for a single baby is 40 weeks, twins 36 weeks, and triplets 32 weeks, even with advanced obstetric care. Babies born prior to 32 weeks are more likely to encounter serious long-term health problems. The risk of delivery prior to 32 weeks for single, twin and triplet pregnancy is approximately 5, 15, and 30 percent, respectively.

Premature birth can affect all organ systems, but it has the largest impact on the lungs, the digestive tract, and neurological development. One of the most dreaded complications of prematurity can be cerebral palsy. The incidence of birth defects in single baby pregnancies is about 3-5 percent in the United States. In twin births, this risk increases to 8-9 percent, and even further to 13 percent for triplet births.

Because pregnancy will last a short period of time, the risks to the mother are more limited but may include increased tendencies toward high blood pressure in pregnancy (called preeclampsia or toxemia) as well as diabetes of pregnancy. Multiple pregnancies often require an extended period of maternal bed rest as well as medications to stop preterm labor that may have significant side effects. Multiple gestations also increase the chances of needing a Cesarean delivery.

After the above discussion, it is easy to see why one of the main movements in Reproductive Endocrinology is to reduce the risk of multiple pregnancies resulting from fertility treatment, and why it is so important to have an experienced specialist managing your medications. It is also easy to see some of the obvious advantages of _in vitro_ fertilization in helping to reduce the risk of multiple births. In summary, ovulation-inducing drugs are commonly used in the treatment of infertility. They are highly effective agents but should be used in the proper setting at the lowest effective dose for the shortest period of time. The major risk in using them is the increased incidence of multiple births. Extended or indiscriminate use of these drugs should be discouraged as it may delay your progress on the Fast Track to fertility!

# Chapter 7  
Surgical Techniques to Treat Infertility

We always hope that a couple trying to conceive can do so with the least amount of intervention possible. However, sometimes there is a definite role for surgical therapy in the workup or treatment of infertility. Prior to the advent of _in vitro_ fertilization (IVF), surgery played a much larger role in the treatment of infertile couples. Before IVF allowed us to effectively bypass damaged tubes or severe pelvic adhesions, surgery represented the only option for many infertile couples with tubal disease or pelvic scarring. Today, IVF requires no incisions, no sutures, no scars, and no general anesthesia. Complications related to the procedures are minimal, and pregnancy rates for younger couples going through IVF are routinely almost double those of natural conception rates. Significant strides have also been taken to reduce the risk of multiple pregnancies resulting from IVF. In this environment, surgery has taken on a diminished but still important place in the fertility hierarchy.

Surgery performed for women struggling with infertility can essentially be divided into two categories: diagnostic and therapeutic. Diagnostic surgeries are performed to evaluate and find problems that may explain the infertility. Therapeutic surgeries are performed to treat known, existing problems (such as ovarian cysts or fibroids). Many times, however, a diagnostic surgery turns into a therapeutic surgery because we are often able to treat what we find during the same surgery.

### Laparoscopy

The most common type of fertility surgery is laparoscopy. This is a minimally invasive type of procedure usually performed on an outpatient basis. Most patients go home two to three hours after surgery and back to work after one to three days. During a laparoscopy, a small incision is made in or just below the belly button so that a fiber optic camera can be placed inside the abdominal-pelvic cavity, allowing the physician to directly visualize the uterus, tubes, ovaries, and remainder of the pelvis. Usually gas or air is placed inside the belly to allow the surgeon more room to work. Often a second or third tiny puncture site (about half the size of your fingertip) may be made just above the pubic bone or on either side of the abdomen to allow the entry of more specialized equipment, such as graspers or lasers, to be used.

Laparoscopy

For patients with painful periods, irregular bleeding, and infertility, the most common things we diagnose at the time of laparoscopy are endometriosis (see Chapter 11) and scar tissue (also called pelvic adhesions). When we find these things, we usually treat the endometriosis with laser therapy. At the time of laparoscopy in a patient who is trying to conceive, we will usually "flush the tubes" with a liquid dye as well. This is called chromotubation and allows us to check for tubal blockage. Below is a diagram of enodmetriosis

Endometriosis

Treating significant endometriosis will certainly improve pregnancy rates (both spontaneous and following certain fertility therapies). While there is controversy as to whether or not treating mild endometriosis will improve pregnancy rates, the only large randomized clinical trial to date suggests that it probably does improve conception slightly over the first two years following surgery. For infertility patients who also have painful periods, pelvic pain, or deep pain with intercourse, treating the endometriosis can help relieve those symptoms as well.

Scar tissue (or adhesions) can "bind down" the tubes or ovaries and prevent the tubal fimbriae (the fingerlike projections on the end of the tube that sweep along the surface of the ovary to grab up the eggs) from interacting properly with the ovary, thus preventing egg pickup. Scarring most often results from a previous (often undiagnosed) infection such as Chlamydia or gonorrhea, a ruptured appendix, endometriosis, or previous abdominal surgeries. Scar tissue can often be treated effectively through the laparoscope, although more serious cases may require an open incision (laparotomy) and more extensive therapy. During these operations, meticulous care is taken to try to restore normal anatomy and fertility potential. However, if the tubes are badly scarred on the outside, there is a good chance that they may have damage on the inside as well. Even if the ends of the tube are nicely opened, the tube itself still may not function well. IVF allows us to bypass this situation completely, making it a preferable procedure in many cases.

Sometimes, if the tubes are very dilated with abnormal fluid and swollen completely shut (called a "hydrosalpinx"), patients are better off having these badly damaged tubes removed. While removal of the hydrosalpinges will make IVF the only way possible to conceive, pregnancy rates for IVF will improve and miscarriage rates decrease after removal of the damaged tubal tissue.

There are significant advantages to having a highly trained fertility specialist perform even your initial diagnostic procedures. As a specialist, he or she may be more qualified than another surgeon to proceed with the appropriate treatment at the time of the initial diagnostic procedure if something is encountered. This may potentially save you from a repeat general anesthesia and another surgical recovery. In addition, the reproductive endocrinologist has IVF among his or her treatment options and can therefore decide when IVF will be more effective than further surgery. A surgeon who is not able to perform IVF may have a tendency to pursue repeat operations, even if the first attempt failed to correct infertility.

Following surgery, your doctor may then recommend natural attempts at pregnancy if a major problem was fully corrected. More likely, however, after the correction of endometriosis or scarring, your doctor will recommend pursuing other fertility therapies to maximize the chance of conception before any corrected problem recurs. This is especially true of endometriosis and scar tissue, which often return after a period of time. Likely therapy in these cases may include ovulation medication with intrauterine insemination, as discussed in the previous chapter.

### Hysteroscopy

Often during a diagnostic laparoscopy we will also perform a hysteroscopy. This involves dilating the cervix slightly and placing a very small (5-6 mm) fiber optic camera into the uterine cavity. This allows us to examine the cavity itself and look for problems like polyps or fibroids that may be preventing implantation. It also allows us to examine the internal opening of the fallopian tubes called the tubal ostia. If there is scarring or filmy "cobweb" tissue partially blocking the opening to the fallopian tubes, we can place a small catheter into the tube to help clear the opening.

Hysteroscope inserted into uterine cavity

The catheter can be advanced further into the tube to help unblock tubes that are plugged further out but still relatively close to the opening of the uterus. This is called a **tubal recanalization** procedure. This technology is very similar to that used during angioplasty to help unblock clogged heart vessels.

If fibroids or polyps (called intracavitary or submucous fibroids or endometrial polyps) are encountered in the cavity of the uterus, we can remove them at the time of diagnostic hysteroscopy. This can also be done as a planned procedure in patients in whom fibroids or polyps had been previously diagnosed by ultrasound or x-ray dye testing. We often use shaving or cutting instruments to perform these procedures, although electrocautery or lasers may also be used.

Many types of uterine abnormalities can also be addressed through the operative hysterocope. Asherman's syndrome is a condition in which the uterine cavity has completely scarred shut following an infection after a D&C or retained placental products after delivery. This condition can be effectively treated by removing the scar tissue through the hysteroscope. Also, women at high risk for recurrent pregnancy loss due to malformations of the uterus such as a septum (or divided uterus) may be good candidates for a hysteroscopic repair.

Hysteroscopy is performed in an outpatient setting and may even be done right in the doctor's office with a mild sedative if laparoscopy is not concurrently being performed. Most patients require only a nonsteroidal anti-inflammatory like ibuprofen to control pain for one to two days after the procedure. There are no incisions or visible scars from hysteroscopy.

### Fibroids

Fibroids in the uterus

Fibroids are extremely common benign muscle growths of the uterus. In addition to the submucous fibroids just mentioned, fibroids can grow in the muscle wall (intramural) or on the outer surface of the uterus (subserosal). Subserosal fibroids are usually the least important. These fibroids are not deep and usually do not impact the uterus's ability to carry a pregnancy. Submucosal fibroids are usually the most consequential because they are inside the uterus. Intramural fibroids depending on their size can be a significant factor as well. Sometimes fibroid should be removed and sometimes they should be left alone. This is where experience truly matters. If fibroids get so large that they may impair fertility or reduce a woman's chances of carrying to term, we may elect to operate in order to remove the fibroids. Common symptoms of fibroids are pelvic pressure, urinary frequency, and heavy, painful, prolonged menstrual periods. Fibroids inside the uterus (submucosal) can cause infertility and miscarriage. Some smaller fibroids may be removed through the laparoscope, occasionally with the help of robotic surgery. Larger fibroids may require an open procedure to completely remove the fibroids (laprotomy with myomectomy). The incision can be a lower abdominal Pfanenstiel ("bikini") incision or a vertical incision stretching from the belly button downward. The choice of incision depends on the size of the fibroids and other factors such as the presence of a previous incision and body weight.

Because the uterus must heal after a myomectomy procedure, this surgery may delay pregnancy attempts by three to four months until the muscle tissue heals back strongly enough to support a pregnancy. If a very deep uterine incision is required to completely remove the fibroids, it may not be safe to labor later with pregnancy, and an elective cesarean delivery may be recommended.

### Tubal Surgery

Some tubal surgery is performed to reverse tubal ligation, and because of its importance, we dedicated an entire subsequent chapter of this book to procedures aimed at reversing sterilization. But other reasons for tubal surgery may include the correction of scarring or endometriosis. Much of this surgery can be done through the laparoscope, as mentioned above. But if damaged segments of tube need to be removed and the tubes reconnected, your surgeon may elect to do this through an open incision with microscopic guidance. There may be an increased risk of ectopic or tubal pregnancy following tubal surgery.

### Ovarian Surgery

The most common reason to operate on the ovaries is the presence of a cyst or tumor. Simple cysts can often be removed through the laparoscope, although larger or more complex cysts may require a laparotomy. It is important not just to drain an ovarian cyst but actually to remove the cyst wall to avoid a high rate of recurrence. For women with polycystic ovarian syndrome (see Chapter 12) who have not responded to medical therapy or ovulation induction therapy, ovarian "drilling" may be performed to attempt improved ovulation. In this procedure, small holes are drilled in the ovary with either a hot needle with electrical current or a laser to reduce the amount of abnormal hormone producing tissue present. Ovulation rates can be reasonably good following drilling, but scar tissue from the procedure itself may still limit the pregnancies resulting from drilling. The use of drilling remains controversial. In our practice ovarian drilling is reserved for women with markedly enlarged ovaries or in cases where large doses of ovulation drugs have been utilized with limited success.

### Conclusion

Surgery still plays an important part in the diagnosis and treatment of infertility in this country. More procedures are possible now with small or no incisions. However in some cases an incision will be needed to obtain the best results. Stay on the Fast Track to fertility by making sure that your surgeon is a highly qualified expert in the field, and by deciding with that expert if surgery or IVF really represents your best treatment option!

# Chapter 8  
_In Vitro_ Fertilization

The world's first baby conceived from _in vitro_ fertilization was born on July 25, 1978. The birth of Louise Brown shocked the entire world. Never before had conception occurred outside the human body! This extraordinary achievement revolutionized the treatment of infertile patients and changed our understanding of reproductive physiology. Today, just three decades later, _in vitro_ fertilization (IVF) has become the most effective treatment available for producing high pregnancy rates while offering the best control over multiple births.

This progress in IVF has been the result of painstaking research and considerable trial and error. The birth of the first IVF baby was the culmination of a decade of work by Drs. Robert Edwards and Patrick Steptoe. Dr. Edwards was a Ph.D. who focused his work on the laboratory aspects of egg-sperm interaction and embryo development. Dr. Steptoe was a gynecologist and a pioneer in laparoscopy, which was then the only way to collect eggs. This ground-breaking work occurred in a small clinic near Manchester, England. Dr Edwards was awarded the Nobel prize in 2010 for his work with IVF.

Their team endured many failed attempts prior to this first successful birth. They were not at a prestigious academic institution and had no research funding. In fact, they had their patients monitor their own natural menstrual cycles (no ovulation drugs were used) and then drove together to the patient's town when ovulation was imminent. Dr. Steptoe then performed laparoscopy under general anesthesia in order to collect the one egg that was about to ovulate naturally.

The woman who underwent the first successful IVF procedure had badly damaged fallopian tubes, a condition that had resulted in ectopic (tubal) pregnancies. Both tubes eventually had to be removed, but her ovaries and uterus were saved. Without tubes, the only way for her to conceive was by fertilizing her egg outside the body and then transferring the resulting embryo into the uterus. Today IVF is routinely used for this purpose. Currently in the United States, more than 60,000 babies are born every year through _in vitro_ technologies. More than 5 million babies have been born to date in the world from IVF.

In 1978, however, IVF was greeted with a great deal of wonder and also of controversy. The technique did not catch on quickly, in part because IVF was very difficult to perform successfully. Even Drs. Steptoe and Edwards had difficulty generating more births. The original procedure utilized the natural cycle where only one egg was available. In subsequent efforts the doctors were not always able to collect the egg, and many times it would be missed. Also, not all eggs fertilize or develop normally. No one was sure exactly when to collect the egg. The natural menstrual cycle is notoriously inefficient, and that is why modern IVF uses the superovulated cycle in which multiple eggs are collected.

Another barrier to early success with IVF was the fact that human embryos are exquisitely fragile and difficult to culture in the lab. Early pioneers did not know exactly which culture medium would allow the embryos to grow successfully. It was also uncertain how long embryos should be maintained in the laboratory before transferring the embryos to the woman's uterus. Extensive research in these areas as well as the superovulation process has allowed IVF to become tremendously more effective in the last decade.

Initial attempts at IVF resulted in a barrage of public concerns. These concerns were aired by clergy, government officials, and medical ethicists, as well as the public. IVF was touted as intrusive and unnatural, and there were fears about the misuse of the technology for genetic engineering. Government funding for IVF was halted because of ethical concerns, so early work with IVF had to rely on private funding.

However, for many infertile couples, IVF was a ray of hope where once there was none. _Prior to IVF at least half of patients with infertility never conceived_ **.** These were typically women with severe tubal disease or men with low sperm counts. IVF was rapidly accepted by these infertile couples as being a miracle cure for their condition.

It took four years after the initial success in England before the first IVF baby was born in the United States in 1982 at the Jones Institute in Norfolk, Virginia. This success resulted from the collaboration of Drs. Howard and Georgiana Jones, a husband and wife team. By then, only about twenty IVF births had occurred in the entire world, illustrating the difficulty in implementing this new technology. The U.S. contribution to this procedure was to pioneer the use of "superovulation," the process in which normally ovulating women are given ovulation drugs to produce more than one egg at a time. This technology dramatically improved the efficiency of IVF by allowing physicians to collect many eggs at once. Prior to the work at the Jones Institute, ovulation medications had been given only to women who did not ovulate. Doctors simply did not know how to administer these drugs to ovulating women. In the 1980s, pregnancy rates for the best candidates were about 15 percent. The community of IVF programs worldwide was small. Yearly meetings were held to discuss these technologies. Dr. Steptoe and Edwards were always there to graciously answer questions and offer encouragement.

These early successes made it clear that IVF would prevail. It is a technology that needs only an egg, a sperm and a uterus to work. These are the three basic, necessary elements of human conception. The only real disadvantage of early IVF was the need for laparoscopy to harvest the egg. Although this is a relatively minor procedure, it still requires a general anesthetic and incisions. The development of ultrasound guided egg retrieval, which does not require surgery or general anesthesia, further propelled IVF into the forefront of infertility therapies.

Research efforts to improve IVF have also had a major impact on other fertility treatments. First, we learned how to wash sperm properly so it would fertilize the egg. Prior to IVF, it was thought that sperm had to be in the female reproductive tract for a period of hours to undergo capacitation, an important step in the sperm's ability to fertilize an egg. With IVF we learned that if sperm is washed with protein-containing culture media, it can capacitate in culture and still fertilize the egg without ever having been in the woman's reproductive tract at all. This information gave birth to intrauterine insemination technology, which is a mainstay of fertility treatment today.

The second major advance in reproductive treatment was the increased understanding of superovulation. IVF gave doctors experience and insight into the process of superovulation. We quickly learned that superovulation and insemination could be an effective treatment for many infertile couples. Today more cycles of superovulation and insemination are performed than IVF because of their lower cost and simplicity.

However, superior pregnancy rates and more precise control over multiple pregnancies means that, in most cases, _in vitro_ **fertilization is the best treatment that is available!** _In vitro_ fertilization is perhaps the most feared and misunderstood of all the infertility treatments. Misconceptions abound based on what friends and family say, what is seen on the internet, and media coverage of glamorous cases. In the vast majority of cases, _in vitro_ fertilization is the most rapid and effective method for you to get pregnant and provides the best opportunity to control the risk of multiple births.

### The Four Steps of IVF

In brief, IVF involves four steps. The first step is referred to as "superovulation." This involves stimulating the ovaries with medications that allow them to develop multiple eggs each month. The availability of multiple eggs greatly improves the efficiency of IVF. The second step in IVF is egg retrieval, a simple office-based procedure that is usually performed through the vagina with ultrasound guidance and allows isolation of the mature eggs for fertilization. The third step involves fertilizing the eggs and the sperm together in the laboratory to generate embryos ("in vitro" literally means "in glass" in Latin). The final step is embryo transfer, which involves placing the embryos through the cervix into the uterus. Most women say that embryo transfer feels about the same as a Pap smear. We shall discuss each of these steps below.

### Superovulation

A woman's ovaries are naturally programmed to produce one egg per month. If a natural cycle were used to collect and fertilize one egg with IVF, the pregnancy rates would be unacceptably low. The use of ovulation drugs in women who are already ovulating in an effort to produce many eggs is referred to as superovulation. Superovulation dramatically improves the success rate of IVF.

Preparation for superovulation involves a shut down phase and a stimulation phase. Ovarian shut down has two purposes. The first is to synchronize all the follicles so they develop about the same time and your doctor can collect eggs of the same maturity at retrieval. This procedure avoids the collection of many immature and postmature eggs that do not produce good quality embryos. The second purpose is to prevent ovulation prior to egg retrieval. If the eggs have already been released from the ovary before egg retrieval is attempted, it is almost impossible to still retrieve them. As a general rule, the younger a woman is and the more responsive her ovaries are, the more shut down and less stimulation she will need. Women over the age of 35 need less shut down and more stimulation. Some examples of the medications used for shut down are birth control pills combined with the medication Lupron (which temporarily turns off the signals between the pituitary gland and the ovary to prevent ovulation), Lupron alone, birth control pills alone, and, finally, no shut down at all. Stimulation protocols for these same patients may include a combination of oral and injectable fertility medications, injectable medications alone, and no medications at all (i.e., the natural cycle).

All treatment regimens that do not include Lupron shut down will require another type of drug near the end of the stimulation to prevent premature ovulation. These drugs belong to a class of medicines called GnRH antagonists (currently available as Cetrotide and Ganirelix) that are given as a subcutaneous injection. The choice of medication for superovulation is extremely important, and this is where the experience of the physician can come into play.

Sometimes the medication schedules can be daunting, so you should take time to ask the nurses any questions about how to handle the medication and what dose is required. Taking the wrong dose accidentally may cause poor results from your IVF cycle.

The ovarian stimulation phase will include higher dosages of the injectable ovulation medications discussed in Chapter 6. These medications include: Gonal F, Follistim, Menopur and Bravelle. Duration of these subcutaneous injections will be between 7 and 11 days. _In vitro_ fertilization will require monitoring equivalent to that performed with the injectable ovulation-inducing agents. Three or four ultrasounds and blood tests will be used to monitor the development of the follicles (or egg sacs) as well as the woman's hormonal environment. When the majority of eggs have reached a mature stage, the patient receives an injection of human chorionic gonadotropin (hCG). There are two forms of this: Ovidrel which we favor because it is a smaller subcutaneous shot and hCG (Novarel and Pregnyl) intramuscular preparations. The hCG will prepare and mature the eggs so that they will fertilize in the laboratory. The timing of the hCG injection is critically tied to the timing of the retrieval procedure. In most cases, the hCG is given 34 to 36 hours prior to the actual egg retrieval. If hCG is not given or given at the wrong time no eggs may be retrieved!!

The goal of the stimulation phase is to mature approximately five to fifteen eggs at once. If we retrieve fewer than five eggs, we simply have fewer raw materials to work with. But some women's ovaries can't produce even five eggs, and in these cases we may have to make do with one or two. About 20 percent of patients may have between 15 and 25 eggs collected at retrieval. While these patients may be a little uncomfortable for three to seven days after egg retrieval, this situation usually does not cause a significant problem. When the ovaries are stimulated to make more than 20 eggs, the patient will usually experience bloating and abdominal distention and, in rare cases, the development of ovarian hyperstimulation syndrome (OHSS). OHSS occurs when the ovaries temporarily enlarge and some fluid temporarily distends the belly. This syndrome is usually accompanied by significant pain and sometimes nausea. Occasionally patients with OHSS may have to be hospitalized to manage their symptoms and fluid balances. Preparing the ovaries for IVF is a process called "controlled ovarian hyperstimulation". To some extent everyone experiences hperstimulation it is just a question of degree. Some patients can experience considerable bloating with as little as 10 eggs collected. Other patients can have little symptoms with 25 eggs. Also women with polycystic ovaries tend to hyperstimulate or not stimulate at all. It is an almost all on or all off effect. Again this is where an experienced center can help. Hyperstimulation symptoms can be accentuated if pregnancy occurs. In cases where hyperstimulation symptoms are too much the program may recommend you freeze all the embryos and then transfer later in a frozen cycle. In a frozen embryo transfer cycle no stimulation needs to be utilized and therefore there will be no hyperstimulation symptoms

IVF is a classic case of not wanting too little or too much! We want just the right number of eggs, and then we want neither too few nor too many babies to result. There is no perfect way to predict ovarian response to the medications, and some cases are extremely difficult to manage. If the stimulation is not just right, your doctor may want to cancel the cycle and start all over. He or she is doing this in your best interest. Remember that egg retrieval begins the most expensive phase of IVF. Prior to retrieval, you will have incurred the costs of some medications, ultrasound and blood tests, but not the biggest part of the cycle. Cancellation of a suboptimal cycle occurs about 10-15 percent of the time and may avoid throwing good money and effort after bad. It is better to wait for the perfect cycle than to rush into one hampered by poor ovarian stimulation.

Now that we have discussed shut down and stimulation in some detail, let's look at some examples of how these different protocols may be applied:

Megan is 33 years of age and has had both her tubes removed because of tubal pregnancies. Ultrasound reveals that her ovaries are normal with good antral (basal) follicle counts. She would do well with a standard birth control pill / antagonist protocol. Birth control pills would be given for 2 weeks, and we would follow with moderate doses of injectable drugs (225 units per day). After a few days of stimulation we would begin a drug that prevents premature ovulation called a GnRH antagonist. This is the most common stimulation protocol used in the United States today.

Sarah is a 25-year-old with polycystic ovaries. She has irregular periods and has not conceived with Clomid. She chose IVF to reduce her chance of multiple births with injectable medications. She is 5 foot, 6 inches tall and weighs only 110 pounds. Sarah is expected to overstimulate. We would suggest a birth control pill and followed by a low dose of injected gonadotropins (about 150 units per day). Near the end of the stimulation she would receive Ganirelix or Cetrotide to prevent premature ovulation. It is important to tailor the drug doses to the type of case to avoid over or under stimulation.

Joan is 37 years of age and has had two laparoscopies for endometriosis. On prior stimulations for insemination, she has had a modest response. She probably would be too shut down with Lupron. We would consider birth control pills followed by moderate doses (300 to 375 units per day) of injectable medications. Near the end of the stimulation she would need Ganirelix or Cetrotide to prevent premature ovulation.

Mary Beth is 40 years of age and has had two previous IVF cycles that were cancelled because of poor ovarian response. We would look at indicators of ovarian reserve such as AMH or antral follicle counts as discussed previously to choose a treatment protocol. Mary Beth has the option of using donor eggs if her ovarian reserve is abnormal or if she wants to dramatically improve her chances of a healthy delivery. If these tests of ovarian reserve are normal or near normal we would proceed without shut down. Maximum stimulation with either injectable drugs or a combination of Clomid or Femara plus injectable medication would be used. Again, near the end of stimulation, Ganirelix or Cetrotide would be used to prevent premature ovulation.

While stimulation of the ovaries requires careful monitoring and involves taking several shots, it has a major effect on the success of the procedure. The experience of your doctor as well as your compliance with the protocol will give the best results. Going through an IVF cycle may also pose difficulties with your personal and work schedules, since we cannot predict exactly when the eggs will be ready prior to stimulation. However, with careful communication with your fertility staff, in most cases we can narrow the window of retrieval in advance to within three or four days. To obtain the best results, you must make your treatment a priority and remain flexible. Managing the unpredictability of the process also requires dedication from the entire staff at your fertility center. They usually have to be there on Saturdays, Sundays and holidays to collect eggs and transfer embryos, so choose a center that is staffed adequately.

### Egg Retrieval

After shut down and ovarian stimulation, the ovaries will, if all goes well, be ready for egg retrieval. Prior to egg retrieval, a nurse will sit down with you and give you detailed instructions. As mentioned above, in almost all cases hCG will be required 34 to 36 hours prior to the egg collection. hCG will prepare the eggs for harvest. It is very important that you receive clear instructions as to what dose of hCG to take and exactly when to take it. If an error occurs in the administration of this shot, typically no eggs or only immature eggs are collected. If you take it too early, you will ovulate before retrieval. If you take it too late, no eggs or immature eggs are recovered. _This is one of the most important steps in the whole process_ **, s** o pay attention when you are receiving your hCG instructions and make sure you understand them. This medication comes in a premixed syringe called Ovidrel or in a preparation requiring mixing such as Profasi, Pregnyl, or Novarel. If it requires mixing, get clear mixing instructions. If you mix it improperly, you may get too little medication. Don't be afraid to ask questions if you are not clear about any instructions.

Your clinic will usually ask you not to eat or drink for at least eight hours prior to the egg collection since an empty stomach is required for the safe administration of an anesthetic or sedation. For your own safety, it is imperative to notify the clinic staff if you accidentally forgot and had something to eat or drink before retrieval. They may be able to do the egg collection under local anesthesia instead.

On the day of the egg retrieval, make sure you have arranged for someone else to drive you to the center and home. When you arrive at the fertility center, the staff will ask you to change into a hospital gown. They will confirm your identity. Sometimes they will require a photo ID. It isn't that they don't know who you are. They are simply taking extra precautions to make sure you get your own eggs and sperm and embryos! An intravenous line will be inserted into your hand or arm in order to give fluids and medication. You will then be hooked up to sensors to monitor oxygen and blood pressure.

Most doctors will then administer either moderate or deep sedation. More and more programs are using moderate sedation because it avoids the risks and costs associated with general anesthesia, and it provides for an extremely comfortable and safe procedure without the long recovery period necessary for general anesthesia. During the procedure you will be very sleepy but able to understand instructions and talk. Many patients may be familiar with this type of sedation, as it is commonly used for small procedures like colonoscopy or removal of wisdom teeth.

The actual egg retrieval involves cleansing of the vagina and then collection of the eggs under ultrasound guidance through the vaginal canal. This is accomplished by passing an extremely thin needle to the right and to the left of the cervix and into each ovary to collect the eggs from the follicles, or egg sacs. The egg itself is too small to be seen on ultrasound. The mature follicle, however, is about two-thirds of an inch in size and can be seen and suctioned under ultrasound guidance. The fluid that is suctioned out is then handed to the embryology laboratory staff, who will identify the eggs under a microscope and isolate them.

Egg retrieval typically takes about 20-30 minutes. Following egg retrieval, patients are taken to a recovery room. There you will be observed for about an hour and your blood pressure and vital signs will be monitored until you are alert and able to eat and drink. While in recovery, you will be informed of the number of eggs collected once the technicians finish their examination of the follicular fluid. You will then want to go home and rest for the remainder of the morning. You will be more alert in the afternoon, but you should not plan tasks that require a high level of concentration such as driving or operating heavy machinery.

Typical apparatus for egg retrieval

Some mild to moderate cramping is normal for the first one to three days following retrieval, although this usually does not prevent patients from going back to work or daily activities the next day.

### Fertilization and the Embryo Lab

Once the eggs are collected, they are incubated in the laboratory. The male partner will provide a semen sample the day of egg retrieval, and then the laboratory and physician will decide as to the technique of fertilization. In some cases donor sperm will be utilized. There are two techniques that are commonly used to fertilize the eggs. The first is standard insemination, in which about 100,000 motile sperm are added to the egg, and then the egg and sperm are allowed to interact naturally in a Petri dish. The second is a procedure called intracytoplasmic sperm injection (ICSI), in which a single sperm is injected directly into a mature egg. ICSI is used in cases where there are few sperm, those present are not swimming well, or appear under the microscope to have characteristics associated with a poor chance of being able to bind and fertilize the egg. In many cases of significant male factor, all three of these sperm characteristics may be present. Below is a microscopic view of an egg undergoing ICSI.

The day following the egg retrieval, the eggs are examined under a microscope for evidence of fertilization as demonstrated by cellular findings (called the pronuclear structures). If an egg has no pronuclei, it is not fertilized. If it has two pronuclei, it is normally fertilized and called a zygote at that stage. If it has three or more pronuclei, it is fertilized abnormally and cannot be used.

Usually about two-thirds of the eggs collected at retrieval will be mature. Only a mature egg can be fertilized. Of the mature eggs, typically about 70 percent will fertilize either with standard insemination or ICSI. Because of this to average fertilization is 50%. Therefore, an average couple undergoing IVF may produce about three to seven embryos. This is far fewer than most individuals imagine. Probably because of sensational media coverage, most individuals interviewed prior to IVF expect that dozens of eggs are collected and dozens of embryos are generated. This is far from the truth. In fact, obtaining enough eggs is often a greater problem than having too many eggs. In the vast majority of cases, seven to fifteen eggs will be collected. In rare cases, 20-28 eggs are retrieved. It is highly unusual to obtain 30 or more eggs in a given case.

A normal zygote with 2 pronuclei at 24 hours

A 2- cell embryo 48 hours after egg retrieval

An 8 cell embryo at 72 hours

A mature embryo (blastocyst) at 5 days after egg

Twenty-four hours after egg retrieval, the IVF center will contact the patient with information about fertilization success. The embryos are then allowed to grow in the incubators in the embryology laboratory. Not every embryo will progress normally. In many cases, an embryo will simply stop dividing. This is believed to be a property of human embryos that is observed naturally (in vivo) as well as in an in vitro laboratory. Embryos that stop dividing in either environment are not typically healthy enough to generate a normal pregnancy. Those embryos that stop dividing in the laboratory environment are, therefore, not suitable for transfer. The remainder of the dividing embryos are then observed anywhere between two and six days prior to embryo transfer or cryopreservation (freezing).

The embryo lab is where all the "magic" happens. The quality of the lab will, to a great degree, determine the success of the IVF program. The lab is headed by a professional who has a doctorate (Ph.D.) in biological sciences. This lab director may be at the center full-time (on site) or part-time (off site). The laboratory technicians are scientists who have undergone a rigorous training program in IVF. Lab quality and management can be one of the hardest parts of an IVF program to evaluate, and yet it is critically important. IVF cycle volume can be a useful indicator of lab quality. A program that does 500 cycles per year probably has more experience than a program that does 75 cycles per year. How many births have been generated from that lab? Does the program do many ICSI cases? Do they have much success with freezing? What about the toughest cases, which involve ICSI with testicular sperm (TESA)? Is the laboratory accredited by national certifying agencies like CAP or JCAHO? The Society for Assisted Reproductive Technologies (SART) is a major monitoring and credentialing body. If the program is a SART member it means they care enough to comply with the highest standards and actually pay SART to report their data every year. Are the program results reported to the Center for Disease Control? This is a minimum requirement by law. While raw statistics can be misleading, you can certainly go to the CDC web site, www.cdc.gov , or the SART web site www.sart.org to get a general idea about the types of cases and success rates generated by a given IVF center. Look at the multiple pregnancy rates carefully. Better programs should have high pregnancy rates with lower multiple pregnancy rates. If you have time and interest, you can make an appointment to meet with the Ph.D. lab director and ask him/her questions about the lab.

### Embryo Transfer

The embryo transfer is the final critical step in the IVF cycle. Before the time of transfer, it is important that you and your doctor agree how many embryos to transfer. For the most favorable candidates, those women under 35 years of age with high quality embryos, one or two embryos will be transferred. If embryo quality is excellent no advantage may be gained by transferring more than one embryo. Single Embryo transfer (SET) is being more commonly utilized due to improved embryo quality and a desire to reduce the risks associated with multiple births. In many European countries, where they are more concerned about reducing multiple births than about maintaining pregnancy rates, single embryo transfer is the rule. Talk with your doctor about this. Please remember more is not always better. Multiple pregnancies are associated with more problems including miscarriage and premature delivery. For women between 35 and 39 two to three embryos can be transferred. Because the odds of pregnancy are less for women 40 or more years of age, four or even five embryos can be transferred.

8 cell human embryos for a day 3 transfer

blastocysts for transfer on day 5

Work with your doctor as a partner. Discuss your particular case as a couple with him or her until you reach a number of embryos to transfer that everyone feels is reasonable. IVF involves a delicate balancing act between the benefit of increased pregnancy rates against the risk of multiple births. Unfortunately, many programs with relatively poor lab quality will transfer more embryos to keep their pregnancy rates up near the national average. This can only come at the expense of increased rates of high order multiple pregnancies.

You should also discuss with your doctor the optimal stage of embryo development at which to transfer the embryos. The most common times for transfer are on the third day after egg harvest, when the embryos are at the 6-8 cell stage, or on day 5 or 6, at the more advanced blastocyst stage. Successful strategies can be built around each approach. More advanced blastocyst transfer is becoming more common at larger clinics.

There are a variety of reasons why the day of transfer may vary. The average day for most programs is the third day after egg retrieval. This allows enough time for the physician and laboratory staff to decide which embryos are progressing normally. On the third day after egg retrieval, embryos that have divided several times and contain six to eight cells are considered the best. Waiting until day 5 or day 6 after retrieval allows the IVF staff to determine that the embryo has developed to the final or blastocyst stage before being transferred to the uterus. However, extended _in vitro_ culture is a stress on the embryos, and there is a possibility that the embryos may stop dividing before day 5 or 6. If this happens, there may be no embryo transfer at all. Therefore, most fertility centers will not consider blastocyst transfer unless four or five excellent embryos are available on day 3. Waiting until day 5 will also typically leave fewer embryos for freezing, but those embryos will probably survive freezing better.

Blastocyst transfer is probably best for those who want to transfer a single embryo to reduce the risk of multiple births. Also, if earlier day 3 transfer has not succeeded, it may be useful to give this technique a try. In some cases the best embryos are transferred on day 3, and the remainder are allowed to go to blastocyst. If they progress to that stage, then they are frozen as blasts. There is a lot of information to suggest that blastocysts survive freezing well and provide excellent pregnancy rates. As a general rule, the fewer embryos that are available, the better an early transfer (day 2 or day 3) is.

On the day of embryo transfer, the physician discusses with the couple the status of the embryos that are available. Embryos that are dividing rapidly and with little fragmentation will be selected for transfer. It is important to know that most embryos will not be "perfect." However, excellent results are frequently obtained with embryos that do not have the best microscopic features.

The embryo transfer is much like an insemination, and most women describe it as feeling about like a Pap smear. The doctor uses a speculum to visualize the cervix which is then cleansed with cotton sponges. A pliable, thin, plastic tube (catheter) is then loaded with the embryos in a small droplet of fluid, and the physician transfers the embryos into the upper uterus either to a preset distance or using ultrasound guidance. The catheter is withdrawn and checked in the laboratory. The catheter is flushed under a microscope to make sure there are no retained embryos. If there is a retained embryo (one that sticks in the tube), the procedure is repeated. Below is a photo of a typical embryo transfer catheter:

Embryo transfer catheter

Following an embryo transfer in our fertility program, we ask the patient to rest lying down for about 5 minutes. Many of our patients like to decrease their activities for the rest of the day and take that day off from work as well. Other fertility programs recommend variable periods of rest intervals. It is widely agreed that extended rest following the embryo transfer does not add to the pregnancy rate.

Unfortunately, not all transfers can be made easy. There are some cases in which the cervix is narrowed (stenosis) or severely angulated. Your doctor will have probably done a trial or "practice" transfer earlier in the office and made detailed notes. He or she will then rely on those notes to guide the depth and direction of the transfer. Frequently, you will be asked to arrive with a partially filled bladder to help straighten the cervix and also to allow for ultrasound visualization of the uterus. Ultrasound is used by some programs to improve the accuracy of the embryo transfer.

In the diagram below, the catheter tip can clearly be seen in the upper uterus.

The ability of ultrasound to visualize the catheter depends on whether your bladder is sufficiently filled and also on your body weight. Most fertility programs will do ultrasound through the lower abdomen in order not to disturb the catheter, which is passed through the vagina. If you have had a previous difficult transfer and are doing IVF again, make sure to discuss this with your doctor. Sometimes measures can be taken prior to your next IVF cycle (such as dilating the cervix in the office) to make the transfer easier. If the transfer is expected to be difficult, you can be given medication ahead of time to help relax you. Patients rest for a few minutes after transfer and then leave the clinic. Extensive research has shown that bed rest after embryo transfer does not improve pregnancy rates. In spite of this each clinic has its own protocol of post embryo transfer activity.

Following the transfer, patients are given progesterone supplements to help support the lining of the uterus until the placenta can take over. Commonly used forms of progesterone are intramuscular injections or capsules/tablets of progesterone taken orally or vaginally. Vaginal progesterone creams are also available. Progesterone is dissolved in oil and therefore the injections are uncomfortable. We use predominately vaginal progesterone preparations for this reason. Approximately ten to fourteen days following the embryo transfer, a blood pregnancy test is obtained. If the test is positive, a follow up ultrasound within two weeks is performed to determine the status of the pregnancy.

A singleton pregnancy at 8 weeks

A twin pregnancy at 8 weeks

Pregnancy rates from IVF vary based on the difficulty of the case and the experience of the fertility center. The age of the woman is the most important factor for a positive pregnancy outcome. Women in their 20s conceive at higher rates than women in their 30s or 40s. Other factors, such as prior surgery to remove an ovary or severe endometriosis, may affect the number and quality of the eggs and embryos. Also, if there is a male factor, the severity of the male factor infertility and the quality of the sperm may affect the outcome of the case. The experience of the fertility center is also crucial.

For most women 35 years of age or younger, clinical pregnancy rates in the range of 40 to 60 percent per egg retrieval can be achieved. A clinical pregnancy is one that can be seen by ultrasound at about four weeks after embryo transfer. For individuals in their mid to late 30s, pregnancy rates range from 30 to 45 percent per retrieval. For women 40 or more years of age, pregnancy rates are highly variable because egg quality tends to be more of an issue. Pregnancy rates in the range of 10 to 25 percent are found for most women in their 40s, but, unfortunately, the miscarriage rate is as high as 40-50 percent in this population, so the healthy delivery rates are much lower than the pregnancy rates. There are some exceptions to these rates, including women who have had a tubal ligation. These individuals are really fertile rendered sterile by surgery, rather than infertile. They appear to have an improved prognosis. Also, women in their 40s using donated eggs have pregnancy rates in the range of 50-65 percent. Pregnancy rates for your clinic are posted on www.sart.org or www.cdc.gov.

Multiple pregnancy rates with IVF are higher than those occurring with spontaneous pregnancies because typically one to three embryos are transferred. It is important to remember that more than one embryo is transferred to obtain satisfactory pregnancy rates, not in an attempt to generate multiple births. The twin rate for IVF is in the range of 25 to 35 percent. However, pregnancies with more than twins (called "high order multiple pregnancies") in younger patients are becoming increasingly rare with IVF because most reproductive endocrinologists limit the number of embryos transferred to one or two in this age group. Therefore, even though twins are still common, IVF has the potential to reduce high order multiple pregnancies with much more precise control than any other fertility therapy. And, as technology improves, we are moving towards single embryo transfers for many patients, a practice that will limit even the risk of twins. Recent yearly statistics have shown a decline in high order multiple pregnancies.

Currently, high order multiple pregnancy rates in the range of 2-4 percent are the rule in most fertility programs in the United States. Better programs will have especially low high order multiple pregnancy rates in women less than 35 years of age. In Europe, national law limits embryo transfer to only two embryos regardless of the mother's age in most countries.

### Embryo Freezing (Cryopreservation)

After the best embryos are selected for embryo transfer, some couples may have a small number of additional healthy embryos. In these cases, extra embryos can be saved for future use by freezing (cryopreservation) or a new technology called vitrification (solidification). Vitrification is complicated to do but produces superior results. At the time of this writing vitrificiation of blastocysts is the best technology to "freeze" embryos with embryo survival rates exceeding 80%

Embryo cryopreservation can be useful in a variety of circumstances. It can be used to save extra embryos in case the first fresh cycle doesn't work. It can also be used to save embryos for another pregnancy in the future after a first successful IVF cycle. A frozen cycle is less expensive and much simpler to complete than a fresh cycle. Pregnancy rates are improving for frozen transfers. Many clinics now have frozen pregnancy rates that are as good as fresh transfers. In the very best case scenarios, we have actually had couples get pregnant from their fresh cycle and then conceive on more than one frozen attempt later. This represents a huge cost savings for the couple.

Frozen embryos also reduce the pressure or the temptation to transfer too many embryos in the fresh cycle because you know you will have a second chance with frozen embryos later. Not all embryos will survive the thawing process after freezing, but the majority will and, remarkably, do not suffer any ill effects from having been cryopreserved.

Embryo freezing can also be used to preserve fertility in women who need to undergo treatment for cancer (such as chemotherapy or radiation) that may destroy their ovarian function. In such cases all the embryos are frozen and will be saved for future transfer after the successful completion of treatment. Some couples who wish to wait to have children may want to prefreeze and bank embryos as an insurance policy for the future, although this does not guarantee a subsequent pregnancy.

Embryos are typically frozen in groups of 1-2 per "straw," or vial, since it is common to thaw 1-2 embryos at a time. The embryologist will add a cryoprotectant to the embryos. This substance stabilizes and protects them against cold damage. The embryos are then frozen in a computerized freezer chamber for several hours and are then stored in a tank of liquid nitrogen. Embryos can be stored successfully for many years, and healthy births have been recorded from embryos that had been stored for more than 10 years. The temperature of storage is -180 degrees C. At this temperature chemical reactions do not take place, so the embryos are temporarily suspended in time. A newer method of freezing, called vitrification, is gaining interest. This process involves adding cryoprotectant and then plunging the embryos in liquid nitrogen in an effort to eliminate ice crystal formation. Embryo vitrification has improved results and has replaced freezing in our clinic and many others.

While freezing can take hours, thawing of embryos is rapid, typically completed in minutes at room temperature. After thawing, the embryos are put through a series of washes to remove the cryoprotectant and then observed for 2-24 hours. Not all embryos will survive thawing intact, but in most cases we expect a 80% or more survival rate.

A frozen transfer cycle is much simpler than a fresh cycle because there is no need for stimulation and egg retrieval. The transfer of frozen embryos to the uterus is timed by either a woman's natural cycle or a cycle created with hormonal medications. This second type of cycle is often referred to as an "artificial endometrium cycle." Timing for embryo transfer in a frozen cycle is critical because the human endometrium has to be at the proper stage to receive the embryo. While natural cycle transfer sounds good, remember that many patients who undergo IVF do not have normal natural ovulatory cycles. Their cycles may not be ideal. Also, the natural cycle is highly variable, allowing little predictability for the couple. Our program uses a simple artificial endometrium protocol using estrogen pills and progesterone capsules. We no longer use any injectable medications for frozen embryo transfers. We can predict the date of transfer three weeks in advance for the couple and get excellent results with this protocol. Frozen cycles can offer an excellent second chance.

### The Devil Is in the Details

IVF appears to be very straightforward. You get the eggs, fertilize them and put them back into the uterus. What could go wrong? While IVF is simple in theory, it is extremely complex to run a highly successful IVF program. The devil, as they say, is in the details. IVF is stressful for your doctors, nurses, and laboratory personnel as well as for you. They know that you want a 100 percent pregnancy rate, and they want it too. Unfortunately, technology isn't perfect and probably never will be. The staff of the fertility clinic feels your stress and that of all their other patients. A good fertility center has a staff that works seven days a week. The staff frequently begins work at 5:30 or 6:00 a.m. to prepare for cases and often stays late into the evenings. They fully realize that these procedures are expensive and in many cases paid for entirely by the patient. They can't help but feel stressed and saddened when the procedure doesn't work. As fertility specialists, we get to know our patients better than many other physicians, so we have our hopes and prayers gathered into your treatment plan along with our medical expertise.

While IVF has made tremendous leaps in the last decade, many challenges remain. Some of these are technical. For example, there can be multiple pitfalls with ovarian stimulation. Some patients have a tendency to produce too few eggs, while others may produce far too many eggs. Too few eggs is the more common problem, but, as we have seen, those with too many can, on rare occasion, become quite ill with ovarian hyperstimulation syndrome.

Culturing of embryos is very complex and time-consuming. Any small change can cause the pregnancy rates to plummet. Good embryology labs have multiple systems of pressurized air quality control and expensive medical grade air filters. The laboratory staff must check the air mixtures in the incubators daily, and all of the incubators and freezers must be alarmed and monitored for changes in environment.

Embryo transfer can be difficult and decrease the odds of success if not done properly. It may be more difficult to transfer the embryos in women with a narrow cervix or a particularly tilted uterus. The experience and technique of your individual physician can make a big difference in the success rate.

Technical problems are not the only ones the patient confronts. There are a host of important decisions to make. Trying to figure out which program close to you can provide you with the best care can be a challenge. What about "guarantees" such as a shared risk package? Should you freeze extra embryos? What can you do before IVF to improve your odds? In the following sections we will tackle these questions and more in order to give you a better understanding of the pertinent issues. This section is really for the individual who has made a decision to pursue IVF and wants to know more.

### Before You Start IVF

Before an IVF cycle, there are a number of steps you can take to improve your chances of success. The first is to take a daily multivitamin or prenatal vitamin. They all contain Folic acid, which is important to begin before pregnancy to increase the odds of a healthy birth. If you are taking prescription medication, inform your doctor to see if it needs to be changed. Most clinics do not want you to take a lot of over-the-counter nonsteroidal pain medications such as ibuprofen during a cycle. If either you or your partner smokes, try to stop as soon as possible. Smoking or use of chewing tobacco damages both egg and sperm production. If your body weight is too low or too high, take time to correct this before your cycle. It is often unrealistic to try to bring your weight to normal. Remember that a 10 percent move in the proper direction can make a difference. Most clinics encourage exercise before the IVF cycle. During the cycle they will either ask you to not exercise or suggest low impact exercise, such as walking, swimming, or working out on an elliptical machine. High impact activities to be avoided because they put stress on the ovaries include jogging, volleyball, step aerobics, and kick boxing.

Medical evaluation prior to an IVF cycle is important. You and your partner will want to schedule a consultation with your doctor specifically about IVF. Your doctor will review your medical history. This is a good time to review the cause of your infertility and all prior treatment. Also ask if any other treatment options are available to you short of IVF. Your doctor will measure your uterus to determine the best method for embryo transfer. This is an important step called a trial transfer. Your doctor will determine what type of catheter to use for transfer and establish if your cervix is difficult to negotiate. If your cervix is narrowed, your doctor may dilate (widen) it prior to the procedure. You may need some updated studies such as a sperm count or x-ray of the uterus. Your doctor will also set the stimulation plan for your ovaries.

The doctor will then give you some information about the number of expected eggs and embryos. He or she will discuss with you the number of embryos to be transferred and the clinic success rate. This is a perfect opportunity for you to raise questions and concerns. Your cycle can be tailored to your needs. If you are worried about multiple births, you can discuss single embryo transfer. If you want or don't want frozen embryos, you can let your doctor know.

Next a session with the clinic nurses will be scheduled so they can instruct you on how to take the medication injections and sign your consent forms. The consents are complicated but important. You should take time to read them and ask any questions about them. They cover important contingencies such as how many eggs are to be fertilized and whether unused embryos are to be frozen. They also cover issues such as what happens to the embryos if you are divorced or separated, or one or both of you were to die unexpectedly.

These sessions with the doctor and the fertility staff are an excellent opportunity for you to learn about the clinic. You can ask how many cycles they do each year and how many pregnancies they have produced. How many embryos do they routinely transfer? Do they have much success with freezing? How do they feel about multiple births? Most responsible clinics are very concerned about anything more than twins.

It is important that you have answers to your questions before you start an IVF cycle.

### What about Egg Donation?

When is it reasonable to consider egg donation? For full details regarding this topic, please read further in Chapter 15 on third-party reproduction. The subject of egg donation commonly comes up in the process of IVF counseling. Egg donation offers the highest pregnancy rates for women 40 or more years of age. This does not mean that they cannot get pregnant using their own eggs. It means that their odds of having a healthy child are much greater using donated eggs. This increased success results from both higher pregnancy rates and lower miscarriage rates. The chance of having a baby with a chromosomal problem like Down syndrome (Mongoloidism) is also much lower with donated eggs from a younger woman. The delivery rate with egg donation will improve from an average of 10-15 percent with a 41-year-old's own eggs to 50 percent with egg donation from a younger woman. The miscarriage rate will be reduced from 50 percent to less than 20 percent. The chance of chromosomal error in a newborn will reduce from 2.5 percent to 0.25 percent. The odds are clearly better with egg donation and demonstrate what a huge impact age has on egg quality and reproductive function. Other cases appropriate for egg donation include premature menopause, reduced egg reserve at any age, or the prevention of genetically transmitted diseases.

Naturally egg donation is not most couples' first choice for reproduction. This decision needs to be considered over a fair amount of time in consultation among the couple, doctor, nurse, and psychologist. Don't rush into a decision out of frustration. On the other hand, if your doctor recommends egg donation because he or she believes it is highly unlikely you will carry a healthy pregnancy to term using your own eggs, then give the idea serious consideration. Stay on the Fast Track! Don't spend countless amounts of emotional, financial and physical energy on a process with your own eggs that has little or no chance of working. Learn as much as you can about the procedure. Try not to come to a final decision until you know all the facts.

### Egg Freezing

Egg freezing is a new technology to preserve eggs for future use. There are many reasons why this might be necessary. One reason is that an individual is about to receive chemotherapy or other treatment that will reduce the number of eggs available. For example a young patient with a new diagnosis of lymphoma or other tumor, may want to freeze eggs prior to chemotherapy. An additional reason is a person wants to delay childbearing and yet still hold onto a group of eggs that can be used at a later time to achieve conception. In other cases for ethical reasons a couple may want to inseminate a few eggs and freeze the others to avoid having a large number of embryos on hand. We have an extensive experience with sperm freezing. This is relatively simple because sperm are small in size and many number. As a general rule smaller cells are easier to freeze. Freezing eggs has been much more difficult than freezing sperm. This is due to the fact that there are fewer of them and they're extremely large relative to sperm. Also oocytes have a high water content making them more susceptible to cryoinjury.

Initial attempts at egg freezing were similar to embryo freezing. We used a process where cryoprotectants were added to the eggs. The eggs were then slowly frozen using a programmed freezer. After years of work with this process with poor results research has shown that egg vitrification is much more efficient. This process involves adding a cryoprotectant to each egg. The eggs are then placed in a very small volume of culture solution and then quickly vitrified. Because vitrification is very rapid it does not allow for ice crystalline formation. It is best described as "glassification" or solidification. Survival rates for eggs are much higher following vitrification. Oocyte vitrification is a very difficult technical process and at the time of this writing only larger clinics such as ours have had success with it. A limitation of this technique is that we cannot obtain a large number of eggs at once. A typical egg retrieval will yield 5-15 eggs. Only mature eggs can be vitrified. The yield of mature eggs may be in the range of 3-10 per case. In a situation where a patient needs to begin cancer therapy, there may not be enough time for multiple egg retrievals. We may only be able to have a few eggs that are frozen for future use. It is important to have realistic expectations from this new and promising technology. Eggs that are vitrified will not fertilize and divide like eggs that are in a fresh state. However results are continually improving and this technology is extremely promising. At the time of this writing egg vitrification is no longer considered experimental. It is now considered good enough to be used in a routine manner.

### Preimplantation Genetic Diagnosis (PGD)

PGD is a technology that allows for the biopsy of an individual embryo in order to test that embryo for genetic problems prior to transfer. The most common reason to use PGD is to avoid passing on a serious genetic condition such as cystic fibrosis or sickle cell anemia. Some couples don't learn that they are carriers for a disease until one of their children is tragically affected. In other cases, a family member is known to carry such a genetic disease or a couple may have learned they carry a trait through genetic screening. These couples can now avoid "rolling the dice" with the lives of their future children and avoid passing on lethal diseases. PGD was never intended to produce "designer" babies. It was meant to prevent the transmission of severe genetic disease.

PGD involves completing a standard IVF cycle. Three days after egg retrieval, one or more cell from each normally dividing embryo is removed under the microscope and tested for genetic disease. Once the cell is removed, it is carefully labeled and transported to a genetics lab that will perform the genetic testing. There are at present several ways of testing the genetic material. These techniques include genomic hybridization, SNIP array, and genetic sequencing. These techniques are for finding chromosomal errors such as Down syndrome. For single gene testing such as cystic fibrosis screening we have to use a different process. This technique is more complicated and is called polymerase chain reaction (PCR). PCR is used to amplify a single gene such as the gene for cystic fibrosis, Tay Sach's, or sickle cell anemia. Typically the genetic testing takes 2 days to complete.

During those two days, the embryos have, if all goes well, progressed to blastocyst so that a genetically normal, viable embryo can be selected for embryo transfer. PGD is highly complex and typically only offered in high volume IVF programs where enough cases are performed to reach an adequate level of expertise for these difficult cases.

Below is an image of an embryo biopsy of a day 3 eight cell embryo. You can see that one cell is being removed using a microscopic pipette.

Below is an image of a biopsy at the blastocyst stage. This is referred to as a trophectoderm biopsy. Here multiple cells are removed and there is more genetic material to work with.

While earlier testing allows us to perform a fresh embryo transfer, a program may also choose to do testing at the blastocyst stage and then freeze the embryos. There would then be sufficient time to obtain the results; then a frozen transfer can be performed with normal embryos. At the time of this writing blastocyst biopsy is becoming more common. This biopsy gives us more cells to work with which may increase accuracy of diagnosis.

Some scientists have suggested performing preimplantation genetic screening (PGS) in all women over 35 years undergoing IVF in order to help reduce the number of cases of Down syndrome or other chromosomal abnormalities in this age group. The problem is that PGS is extremely complex, expensive, and the biopsy step can slightly weaken the embryo. Therefore, doing PGS on everyone has definite disadvantages. PGD done for the prevention of inherited diseases is frequently performed in young women without a history of infertility, and these patients do not experience any drop in pregnancy rates with PGD.

PGD is new, however, and is far from perfect technology. The few cells tested may not represent what is happening in all the other cells of the embryo. Variation within the embryo is known as mosaicism. Also, as with any other laboratory test, the result may be misleading because of technical problems. Although the results of properly performed PGD are accurate more than 90 percent of the time, we still suggest that our patients who undergo PGD have the results confirmed through other testing in early pregnancy, such as CVS or amniocentesis or the newly available maternal cell free DNA test. These new tests can isolate and analyze fetal DNA from the mother's blood and are therefore far less invasive than older tests such as amniocentesis.

Some couples may not feel comfortable with the idea of selecting embryos based on their genetic potential, and it is certainly their prerogative to choose not to use this powerful tool. However, many others who have held their children while they suffered and then died of genetic diseases that can now be avoided feel that reducing the chance of transmitting a serious or lethal genetic disease to a newborn is both ethical and appropriate.

### Money Back "Guarantees"

Some fertility programs such as ours offer couples money back guarantees. Traditionally IVF is performed on a pay-as-you-go basis. You receive the services and pay for them as you go. You may get pregnant right away or after a few cycles. Some couples, unfortunately, may not get pregnant at all even after several rounds of treatment. Shared risk programs typically involve the payment of a larger initial sum of money before treatments begin. Depending on the center this amount is approximately $16,000 to $25,000, compared to a typical per cycle cost of $7,000 to $9,000. Couples enrolling in these shared risk programs may then undertake a certain number of fresh and frozen cycles, typically three to four of each. If at any point a live birth is achieved, then the program keeps the entire payment. If a live birth is not generated after the specified number of treatment cycles, then the couple receives most or all of their money back. In other words, participants in the program will then either have a baby or have the money back to pursue adoption or other options.

These types of programs have their appeal. You don't have to worry about paying for a series of IVF cycles and having no results. On the other hand, if you deliver from your first IVF cycle, you will have paid approximately double of what you might otherwise have paid. Shared risk does not include the medication costs, which are typically $2,000 to $3,000 per cycle. Not all patients are accepted into shared risk programs. Most programs have age limits for women and will look at other issues such as FSH or AMH levels. Also there is usually a weight limit. They want to accept as many patients as possible but cannot financially afford to have too many poor prognosis cases in a shared risk program. For the clinic, the shared risk program is designed to be financially neutral. This means that for every patient who gets pregnant in one cycle, there is another who took several cycles or received a refund. The availability of these program shows that IVF has come a long way. They also demonstrate to patients that the clinic has confidence in their own program. We have tracked several hundred patients through our money back program. Our live birth rate has been approximately 85%. It is without doubt one of our most successful programs!

### Summary of IVF

IVF today is the most rapid and most effective means of conception offering the greatest control over multiple births. In most cases it is the best treatment that we can offer patients. It is unfortunate that insurance or financial issues often sway patients to choose less effective and options over IVF. The major barrier to IVF use appears to be cost. Extensive research has shown that in states where IVF is covered by insurance, utilization of IVF is about four times greater than in areas where individuals have to pay for this therapy themselves. Remember that IVF is most effective in younger patients. Making the decision to undergo IVF is difficult. We hope that this chapter has given you the information that you need to be an informed consumer and stay on the Fast Track to fertility.

# Chapter 9  
Post-Sterilization Fertility

When you said, "I do!" for the first time, you probably fully intended to make a life-long commitment. After all, you loved the person you were marrying. You may even have had two, three or maybe four kids together and decided you were finished having children. At that point you may have decided to have your tubes "tied" or your partner may have decided to have a vasectomy so that you could continue to enjoy your intimate life without worrying about contraception and undesired pregnancy risk. However, life circumstances change for many of our patients, and many couples desire to regain their fertility after having a previous sterilization procedure performed on one or both members.

Many times this situation arises from a second marriage. Couples entering into a second marriage often have "his" and "hers" and now want "theirs" together. Another frequent scenario is a second marriage to a slightly younger person who may not have any children of his or her own. We also see in our practice a surprising number of couples still married after twelve or fifteen years who decide they want one more child after the others are in school full day and the house starts to seem quiet or empty. So-called "sterilization regret" (when a patient changes his or her mind some time after having had a tubal ligation or vasectomy) is all too common. Studies show that the younger a patient is when she has her tubal ligation performed, the more likely she is to regret that decision in the subsequent ten to twelve years.

Fortunately, couples hoping to regain their fertility following a previous sterilization procedure on one or both members have more and better choices than ever before. Many of these newer choices are performed completely in the physician's office and require no general anesthesia, no incisions, no sutures, and little recovery time. But tried and true techniques are also still available and can be highly successful as well. The important thing to remember is that many patients in this situation are already in their mid to late thirties and don't have any time to waste! As you know from previous chapters, the age of the female partner is often the biggest predictor of how well a fertility treatment will work. If any of the above scenarios is like your situation, you should get on the Fast Track to fertility and see your fertility specialist right away!

### Post-Tubal Ligation Fertility

For women who have had a tubal ligation, one option for recovering fertility may be tubal reanastomosis, or reconnection of the tube, an often highly successful surgical procedure available to many patients from specialized fertility surgeons. Alternatives to surgical reanastomosis include in vitro fertilization, a process in which the fallopian tubes are bypassed altogether and fertilization is achieved outside the body (see Chapter 8). Both of these techniques have distinct advantages and disadvantages, and the right one for you can be determined by a careful discussion with your reproductive endocrinologist.

Tubal ligation is one of the most commonly used forms of contraception for married women in the United States. There are many different ways of performing a tubal ligation. For tubal ligations performed the day of or the day after delivery, a small portion of the middle of the tube is usually removed. This procedure does relatively little damage to the remaining portions of the tube, but can be difficult to reverse if a very large segment is removed. For tubal ligations done six weeks after giving birth or at later intervals, the laparoscope is usually used (see Chapter 7 on laparoscopy). Several different methods are available using laparoscopy. Often clips or rings are used to block or close off the tube. These, again, are relatively easy to reverse because they do little collateral damage to the remaining segments and rarely damage more than one to two centimeters of tube.

However, the most common laparoscopic method of tubal ligation is electrocautery ("burning" the tubes). This is a highly effective means of sterilization but may be more difficult to reverse. Just as a burn on your arm leaves a red mark around the actual burn, the energy from electrocautery spreads beyond just the specific area of cautery and can damage quite a large segment of tube, leaving relatively little healthy tube to reconnect. Often, a "triple burn" technique is used in which 3 contiguous areas of the tube are burned to guarantee a good closure of the tube. This procedure can be especially difficult to reverse.

Two final types of tubal ligations, which may be done through open incisions, through the laparoscope, or even through the vagina, are impossible to reverse. Sometimes, the entire tube is removed (salpingectomy). Obviously, that leaves no tube to be reversed. Finally, a fimbriectomy is a kind of sterilization procedure in which the finger-like projections at the end of the tube that are responsible for picking up the egg are removed. While this is an extremely effective kind of sterilization, it is not surgically reversible, because the most crucial part of the tube has actually been removed.

Now, we never blame another surgeon for having done "too good" a sterilization procedure. After all, the procedure is intended to be permanent. Think how angry you would have been with your original doctor if your tubal ligation had failed and you conceived when you didn't want to. Most tubal ligations can be successfully reversed as discussed above, but your fertility surgeon will need to carefully study your previous surgical reports to determine how the original procedure was performed in order to counsel you about how successful reversal may be. A review of the pathology report can also be helpful if a portion of the tube was removed. If we know that four or more centimeters were removed, then we know that very little healthy tube may be left to work with. On the other hand, if the pathology report indicates that the removed tubal segments were only two or three centimeters, then the chances for successful reversal increase significantly.

Under the right circumstances, tubal reversal surgery can be very effective. Cumulative pregnancy rates over one to two years following sterilization reversal often approach 60%-70 percent. However, the range of pregnancy rates may vary from 20-95 percent. There are multiple factors influencing the outcome of the procedure. Of these, the length of healthy fallopian tube left to be repaired following sterilization reversal is one of the most important. Success rates are outstanding if more than six centimeters of tube remain after reversal. Pregnancy rates are very acceptable when four to six centimeters of tube are left. When less than four centimeters of undamaged tube remain at the end of microsurgery, success rates fall dramatically. Patients at risk for short tubal length are primarily those in whom either large segments of tube were removed or in which "multiple burn" cautery technique was utilized for sterilization.

Of course, the age of the woman undergoing the tubal reversal is also of primary importance in the outcome. Other major factors are her ovulatory status and her husband's sperm counts and function. Prior to having tubal reanastomosis performed, your surgeon may perform laboratory testing to confirm the "ovarian reserve" or ovulatory status of the female partner. In addition most surgeons will require a semen analysis on the male partner to confirm that live sperm are present prior to putting the female partner through a relatively complex operation.

Tubal anastomosis can be performed using a small incision (laparotomy) or using small laparoscopic incisions and the assistance of a robotic device (laparoscopically assisted robotic surgery). Tubal reversal by laparotomy relies on the microsurgical technique. After the incision is made, the surgeon uses a microscope to help him or her see the suture placement within the walls of the tubes. Controlled studies examining the differences between surgeons using a microscope and those using other methods of sterilization reversal have clearly identified the superiority of the microscopic approach over operating with the naked eye. Not all hospital operating rooms are equipped with appropriate microscopic instrumentation, and only a surgeon trained in microscopic technique should perform microscopic tubal reanastomosis. Most surgeons performing microsurgical tubal reanastomosis will do so through a mini-laparotomy incision. This is a "bikini cut" skin incision usually approximately two-thirds the size of a cesarean section scar. During a microsurgical tubal reanastomosis, the fallopian tubes are brought into the incision. The damaged or scarred portions of the fallopian tubes are removed. Then, using suture that can barely be seen by the naked eye, the surgeon stitches back together the healthy segments of tube under the microscope. This is usually accomplished in two layers.

Below is a diagram showing the scarred portion of the tube removed and the tube reconnected.

Removal of damaged portion of tube

Reconstruction of tube

At the completion of the operation, the "openness" (or patency) of the fallopian tubes is confirmed by injecting dye through the uterus out the fallopian tubes. Patency rates are greater than 80 percent in most instances. Unfortunately, because of previous scar tissue from the sterilization procedure or scar tissue that may result from the reanastomosis procedure itself, open tubes do not always function normally. Most patients require only a one-night hospital stay following tubal reanastomosis, but they may miss one to two weeks of work in recovery. Your surgeon may recommend up to six weeks off heavy exercise, aerobics, etc.

Tubal reversal surgeries are sometimes done through the laparoscope or, more recently, with robotic instrumentation through the laparoscope. These types of surgeries have a shorter recovery time and are highly specialized. It is difficult to perform reversals laparoscopically because of the need for accurate placement of very fine suture. The suture used for tubal reversal is thinner than human hair. The robot has allowed us to place these sutures accurately through laparoscopic incisions. Robotic surgery requires a highly skilled and experienced surgeon. The robot costs approximately $1.5 million and is not readily available in most hospitals. Where it is available, it will be used most commonly for prostate and heart surgery. Since tubal reversal is not usually covered by insurance, it will usually be much more expensive to perform the operation robotically. Below is a diagram of a robotic set up:

In the following diagram you can see the robotic hands placing the sutures in the tube:

Robotic surgery offers the advantage of faster recovery since there are not major incisions. The entire procedure can be performed through three small incisions. Recovery is a matter of days versus weeks for the surgery using an incision (laparotomy)

There are some disadvantages of any tubal reversal surgery. These include the need for an anesthetic (usually general anesthesia), and the small risk of injury to adjacent organs like bowel or bladder during the surgery. These risks increase significantly in women who have had previous cesarean deliveries and are therefore likely to have internal scar tissue from the earlier operations. Because the tube may not function 100 percent even though it is open again, the risk of tubal (ectopic) pregnancy following tubal reversal surgery may be as high as 10 percent (compared to 1-2 percent in the general population).

Tubal ligation reversal

One final consideration when thinking about a reanastomosis: when the tubes are functioning again, they usually remain functioning indefinitely. Let's say you are 36 and had your tubes "tied" after having three children. You get remarried, have a tubal reversal performed and deliver your fourth child. Now you're 37 with good tubes again and another 10-15 years of contraception to worry about! An alternative to tubal reversal may be _in_ _vitro_ fertilization. Following successful _in vitro_ fertilization, the tubes remain occluded and you are still sterilized. Many couples will conceive quickly after tubal reanastomosis, but the full benefit of the surgery may not be recognized for one to two years of attempted conception. In the event that tubal reanastomosis fails to achieve pregnancy, or for women who wish to avoid surgery, _in vitro_ fertilization is an excellent option.

In addition to maintaining permanent contraception, IVF also offers several other advantages over tubal reanastomosis. Pregnancy rates with IVF may be close to 50 percent in the very first month, thereby avoiding the long wait to conception after some tubal reversals. IVF requires no general anesthesia, no incisions, no sutures, no scars, no hospitalization, and no recovery period. Most women go back to work the same or the following day. Because embryos are placed directly into the uterus, ectopic pregnancy rates after IVF are only 2-5 percent at most, thereby reducing the risk compared to tubal reversal surgery. Also, very important, if any abnormalities exist in the sperm numbers or function, then IVF is a much better choice than tubal reversal since male factor problems can be simultaneously addressed during an IVF cycle.

The downside to IVF for most couples who already have children is the risk of multiple pregnancies associated with IVF. Since many patients with a previous tubal ligation may be over 35, often two embryos may be transferred in an IVF procedure to improve the chances of success. This may result in multiple pregnancy rates in the neighborhood of 25-35 percent. This risk may be minimized as technology improves and we shift towards transferring fewer and fewer (sometimes only a single) embryos to achieve acceptable pregnancy rates.

Whether tubal reversal surgery or IVF is the best option will become apparent after a careful discussion with your fertility specialist.

### Post-Vasectomy Fertility

For couples wanting to conceive after the male partner has had a vasectomy, very similar choices are available. Either surgery can be performed to reverse the vasectomy, or sperm can be non-surgically obtained and used for treatment of the couple with in vitro fertilization. Sperm is produced in the testes in response to stimulation by a specialized gland in the brain called the pituitary. The sperm is then stored and matures in the "tail" of the testes called the epididymis. After maturation, sperm travel through a long narrow tube called the vas deferens and are released during ejaculation by way of an ejaculatory duct which travels through the prostate and releases the sperm into the urethra which travels through the penis. The average time for a sperm to complete the maturation process is approximately 73 days.

Vasectomy, or "male sterilization," is a procedure during which the vas deferens is surgically blocked by tying and cutting it. Thus the sperm cannot escape from the testes, resulting in male sterility. Just as the tubal ligation is intended to be a permanent procedure in the woman, vasectomy is intended to be a permanent form of male sterilization.

Male reproductive tract

Vasectomy

In many cases it is possible to surgically reverse the vasectomy. If the original procedure was not too damaging and it has not been too many years, it is possible to reconnect the vas deferens on one or both sides. This procedure usually involves a general anesthetic. The urologist then makes an incision in the scrotum, and working under a microscope, reconnects the sperm outflow tract. In most cases the vas is successfully reconnected (vasovasosotomy). Operating time is usually two to three hours in the average case. During the procedure the urologist will check to make sure the portion of the vas closest to the testis contains sperm. If it does not, then the surgeon may have to reconnect the vas to the epididymis. This is a more difficult procedure called a vasoepididymostomy. Pregnancy rates following vasoepididymostomy may not be as good as those following vasovasosotomy. The more time that has elapsed from the initial vasectomy, the more likely scar tissue is to build up, making vasovasosotomy impossible. This is one reason that fertility rates decline with the length of time from the original vasectomy.

Vasectomy reversal

Following vasectomy reversal, most men will experience slight swelling, bruising, or discoloration of the scrotum. Ice packs and pain medication may be required for several days after the surgery. Sperm will reappear in the ejaculate four to six months after reversal. Peak sperm counts may take 12 to 24 months to appear. This significant delay in return to optimal fertility can bump you right off the Fast Track if the female partner is already over 35 years of age! Sometimes the sperm count will peak and then begin to decline because of scar tissue formation.

The chance of pregnancy after reversal depends on many factors. The time between vasectomy and reversal is one important factor. While isolated case reports of pregnancies following vas reversal many decades after the original vasectomy can be found in the medical literature, pregnancy rates will usually fall if the original procedure was done more than eight years prior to reversal. Another factor in success can be the presence of antisperm antibodies. After a vasectomy, the immune systems of many men produce antibodies against their own sperm. If these antibodies are secreted into the semen, they can bind to the heads of the sperm. This process can cause the sperm to clump together so that motility ("swimming") is impaired or the ability of the sperm to properly bind and fertilize the egg is impaired. Some of these antibodies can be removed with specialized "sperm washing" techniques and intrauterine insemination (see Chapter 6), but ultimately a couple may require IVF with ICSI to overcome this problem.

The nonsurgical option for a man with a previous vasectomy who wants to regain fertility involves either aspiration of sperm from before the point of vasectomy blockage or a tiny biopsy of the testes done under local anesthesia in the urologist's office. This small piece of the testes is examined for the presence of sperm and then rapidly frozen. This process is referred to as testicular sperm aspiration (TESA) or testicular sperm extraction (TESE). This frozen sperm is then used for IVF with ICSI (see Chapter 8).

This nonsurgical technique can be performed after any type of vasectomy. Significant advantages of TESA-IVF-ICSI over vas reversal include an easier procedure with minimal recovery time, and the fact that the odds of success are not influenced by the number of years since vasectomy. Elapsed time from the procedure to pregnancy is also potentially much shorter with IVF. Young women can achieve a pregnancy rate of almost 50 percent in one IVF cycle that takes one to two months to complete, compared to an average of twelve months to conceive after surgical vasectomy reversal. Disadvantages of this approach include the fact that both partners must undergo a procedure (although both are office-based) as well as the risk of multiple pregnancies resulting from IVF. About 25 – 30 percent of births resulting from IVF may be twins, whereas surgical vasectomy reversal is not associated with any increase in the multiple birth rates unless combined with fertility medications.

Just as with female sterilization reversal, we also always counsel our couples about one final consideration with surgical reversal. If you have a successful surgical repair you may need another vasectomy later if you wish to regain sterility. With IVF the vasectomy is left in place, thereby foregoing the need for future contraception.

### Conclusion

More options exist today than ever before for couples seeking post-sterilization fertility. Both surgical reversal options as well as minimally invasive IVF options are available for either male or female patients with previous sterilizations. A careful discussion with your fertility specialist will help you decide which option is best for you as a couple. The important thing to remember is to stay on the Fast Track by having that discussion sooner rather than later!

## Chapter 10

## Male Factor Infertility

with Shane Russell, MD

and Jason St Pierre, PhD

Throughout the book, we have stressed the fact that nearly half of all couples facing fertility concerns have a significant male factor contributing to their inability to conceive. While we have discussed male factor and its potential causes and treatments in several other places, we thought it would be useful to have a separate chapter addressing this issue specifically. If you know you have a male factor concern, or if you are a man who wants to focus on "my part in this whole thing," then this chapter's for you! Fortunately, the newer assisted reproductive techniques typically allow us to overcome even the most severe cases of male factor infertility.

In comparison to the 40 weeks of complex physiology and hard work that a woman goes through in order to establish, gestate, and deliver a pregnancy, the role of the male partner is fairly fleeting and involved only in the initial conception of the pregnancy. So it is perhaps natural that, when fertility problems arise, the focus often falls initially upon the woman. However, in this chapter we explain why every couple experiencing infertility should have a male fertility evaluation. We will also try to unravel the mysteries of the semen analysis so that you can have a good understanding of the results you may encounter. We thought that a brief discussion of male reproductive physiology would be helpful prior to explaining the evaluation, diagnosis, and treatment of male factor infertility.

### Male Reproductive Physiology

The male reproductive system consists of the gonads or testes, accessory glands, vas deferens and the penis. Each of these components needs to function together and normally for production, transport and the delivery of sperm. The male reproductive system also requires the appropriate hormonal signals from the hypothalamus and pituitary, the two glands in the brain that regulate reproduction. The hypothalamus produces gonadotropin-releasing hormone (GnRH) which acts on the pituitary gland to produce follicle-stimulating hormone (FSH) and leutinizing hormone (LH), just as in women. Both FSH and LH act on cells in the gonads and are required for sperm production. Sperm production is a continuous process that begins at puberty and occurs in the testes.

In addition to the production of sperm, the testes also produce the hormone testosterone, which is required for maintaining sperm production and typical "male" characteristics. The testis is a fascinating organ that it is maintained at 3º C below normal body temperature, which is the ideal temperature for normal sperm production or spermatogenesis. The testes are able to maintain this cooler temperature because they are outside the body in the scrotum. Exposure of the testes to extreme heat or cold can negatively affect sperm production or function.

The testes are almost entirely filled with sperm-bearing seminiferous tubules, in which the sperm is actually created. These tubules contain sperm precursor cells called spermatagonia, which undergo cell division to form immature sperm cells. As they mature, the immature sperm cells are released into the duct of the tubules and will eventually move into a structure attached to the testis called the epididymis. The final stages of sperm maturation, in which the sperm become capable of swimming (motility) and penetrating the egg, occur in the epididymis, and the sperm will be stored there until they are ejaculated. From start to finish, the sperm production process takes approximately 74 days. However, the assembly line is continuously in motion so that mature sperm are available for ejaculation each day.

Upon ejaculation, the stored sperm are forced into the vas deferens by smooth muscle contractions, and the sperm are mixed with transport fluid or semen. Semen is made up of secretions from the seminal vesicles, prostate gland and another sexual gland called the bulbourethral gland. The actual sperm and fluid from the epididymis account for a negligible amount of the total volume of semen in the ejaculate. The majority of seminal fluid, approximately 75 percent, comes from the seminal vesicles. This fluid helps to neutralize the acidic environment of the vagina. It also contains proteins that coagulate the semen after it's deposited in the vagina and fructose, which is a sugar that serves as an energy source for sperm motility. The prostate gland accounts for approximately 20 percent of semen volume and contains enzymes that allow the semen to liquefy after it's deposited in the vagina so that the sperm are able to swim out into the female reproductive tract. The bulbourethral gland contributes only 5 percent of the total semen volume and serves to lubricate the urethra just before the sperm is expelled. Each of these glands and its secretions are critical for sperm transport and proper function of the sperm once they are deposited into the vagina. If one or more of these glands is not functioning properly, the sperm may never have an opportunity to reach their target.

Sexually transmitted diseases such as gonorrhea, Chlamydia, and Mycoplasma can infect the duct system and cause infections of the epididymis and prostate as well as secrete substances that are toxic to sperm, thereby impairing sperm viability and motility. Infections may also increase the number of white blood cells present in the ejaculate. These cells produce by-products called reactive oxygen species that may damage the sperm.

### Sperm and Fertilization

At the completion of spermatogenesis, mature sperm are formed and are stored in the epididymis until they are ejaculated. The human sperm cell is an incredibly efficient cell consisting of three main parts, each of which plays a vital role in the sperm's ultimate purpose of fertilizing the egg. The sperm possesses a single flagellum (or tail) that allows the sperm to swim through the female genital tract to reach the egg. The sperm travels only an average distance of three to four inches from their deposition in the vagina to the site of fertilization in the fallopian tubes. However, for a sperm, this is the human equivalent of running more than a 26-mile marathon. "Battery cells" called mitochondria found in the midpiece of the sperm generate the energy required for this journey. The midpiece and the tail both work together to help get the sperm head to its target: the egg. The paternal chromosomes or DNA that are found in the nucleus of the sperm are located in the sperm head and must join with the DNA in the egg nucleus to make a fertilized zygote, the cell produced by the union of the sperm and the egg.

The sperm's journey to reach its target typically begins with the ejaculation of semen into the vagina and contains many roadblocks along the way. Once in the vagina, the semen must change from its gelatinous state to a liquid so the sperm are able to swim out of the semen. Following liquefaction of the semen, the sperm swim out into the cervical mucus, then into the uterus, and eventually into the fallopian tubes. While the sperm are moving through the female genital tract, they undergo a critical process called capacitation, a chemical reaction that prepares them to be able to fertilize an egg. Sperm capacitation can also be achieved in the lab by placing sperm in a culture medium with an energy source. This technique is critical for the success of IVF.

Once the sperm reach the egg, there are still several structures that must be penetrated before the egg can be fertilized. A cloud of cells from the ovary called the cumulus oophorous surrounds the egg. Sperm penetrate this layer primarily using their motile force but also with the aid of enzymes secreted by the sperm membranes. The next barrier to be encountered is the eggshell, called the zona pellucida. A chemical change, called the acrosome reaction, allows the sperm to release enzymes that digest a hole in the zona pellucida and gain access to the egg plasma membrane. The sperm is then able to fuse with the egg and its DNA is incorporated into the center of the egg, thereby achieving fertilization.

As you can see, this is a lot of work for a single cell, and it is no wonder that this system often breaks down and results in infertility! While pregnancy is the only true proof that the sperm can do their job, laboratory evaluation of the male partner in a couple trying to conceive gives us some idea of how likely this may be.

Evaluating the Male Factor

The importance of the semen analysis as an integral part of every fertility evaluation is demonstrated by some simple facts. Male factor problems play a contributing role in the infertility of fully half of couples struggling to conceive. In 25% of couples suffering from infertility, a male factor problem is the sole cause of the trouble conceiving. With so many couples having a male factor as a significant component of their infertility, it is extremely fortunate that the majority of male factor fertility problems are potentially treatable.

The Semen Analysis: The first and most important test in analyzing a man's fertility potential is the semen analysis. This is commonly known as the "sperm count," but the analysis really incorporates significantly more than just a count as we will explain below. The semen analysis is the most effective test that we have for measuring male fertility potential. Typically a sperm specimen is collected by masturbation into a small sterile container (the infamous "cup"), which is then given to a laboratory technician in an andrology laboratory. In many circumstances, a man can collect his sample at home into a sterile container that has been provided by the fertility doctor or laboratory ahead of time and bring his sample in to the laboratory. Results will still be accurate if the specimen arrives in the lab within 45 minutes or so of collection and is protected from extremes of temperature.

While many hospital or outpatient labs may perform semen analyses, there is an advantage to having it done in a certified andrology laboratory at a fertility center. In a specialized setting, the analysis will be performed by a technician who is specialized in just analyzing sperm specimens rather than a general laboratory technician. Also, the lab in a fertility center is much more likely to have a specifically designed comfortable and private area for men to collect, rather than the hallway bathroom that is often used by hospital or outpatient labs. Usually we recommend between 2 and 6 days of abstinence (no ejaculation at all) before the sample is collected to get an accurate semen analysis.

Interpreting Semen Analysis Results

While we know that the semen analysis is the best screening tool available to assess male fertility potential, we also know that the semen analysis is not a perfect assessment. Some men with low sperm counts and poor sperm quality are successful at establishing pregnancies in their partners without assistance, while others who have completely normal semen parameters are unable to do so. In general though, men with better semen parameters have an easier time initiating a pregnancy, and it is therefore beneficial to try to optimize these parameters as much as possible.

As we mentioned above, the semen analysis evaluates multiple different parameters, many of which can be important in predicting fertility potential in a male. The semen analysis can provide information regarding a man's sperm counts and quality, as well as the presence of blockages, inflammation, or infections. The 3 most important factors described by a semen analysis are:

1. Density: The number of sperm that are present

2. Motility: The percentage of sperm that are swimming and how well they are swimming

3. Morphology: The percentage of sperm that have normal shapes

For people who like clear delineations of "normal" vs. "abnormal" test results, the interpretation of a semen analysis test can be quite frustrating. In 2010, the World Health Organization (WHO) published its latest guidelines defining "normal" semen parameters. The following table shows the new 2010 criteria, as well as the previous 1999 criteria for comparison:

 | WHO 2010 Criteria | WHO 1999 Criteria

---|---|---

Semen volume | More than 1.5 cc | More than 2.0 cc

Sperm density | 15 × 106/cc or more | 20 × 106/cc or more

Sperm motility | 40% or more | 50% or more

**Sperm morphology** (strict criteria) | 4% or more | 14% or more

Sperm viability | 40% or more | 40% or more

White blood cells | Less than 1.0 × 106/cc | Less than 1.0 × 106/cc

These apparently clear cut-offs for normal values are less clear upon realizing that, in devising its guidelines, the WHO looked at 4,500 men from fourteen countries and based the "normal" values on a subset of 1,800 men whose partners were able to conceive naturally within twelve months. The bottom 5 percent of semen parameter values among these 1800 men were labeled "abnormal," with the remaining 95 percent of values being labeled "normal." To look at this another way, 95% of men whose partners conceived naturally within a year had a higher sperm count than the "normal" cutoff of 15 million/cc. Similar comparisons can be made for motility and morphology readings as well. Overall, an estimated 50 percent of infertile men have semen parameters that technically fall within the "normal" range as defined by the WHO criteria. Clearly a man's semen parameters must be evaluated with more scrutiny than just seeing if they fall within the supposed "normal" range as defined by the WHO.

Let's now look at the 3 primary semen parameters more closely and then discuss what may be the most important fertility-related parameter: the total motile count (TMC).

### Sperm Density

Sperm density refers to the average number of sperm in a given volume of semen. Most people refer to sperm density when discussing sperm counts, although the total motile count (see below) provides a more accurate picture of overall fertility. According to the 2010 WHO guidelines, a normal sperm density is 15 × 106/cc or greater. Several studies have shown that sperm counts of around 40 × 106/cc to 55 × 106/cc are associated with improved odds of establishing natural pregnancies.

A few important related terms to know:

1) _Oligospermia_ \- a sperm density that is less than what is considered normal

2) _Virtual azoospermia_ \- when only very small numbers of sperm are present (generally considered <100,000 sperm/cc)

3) _Azoospermia_ \- no sperm are present within the ejaculate

### Motility

Sperm motility refers to the percentage of sperm in a sample that are swimming. Normal sperm motility as defined by the 2010 WHO guidelines is a value of 40% or more. Decreased sperm motility is called _asthenospermia_. The total motility (percentage of all sperm that are motile) is generally denoted on the report, with most reports also describing the average "grade" of how well these sperm were swimming. The motility grade is usually described on a scale of 0 to 4 (with a normal grade generally considered to be grade 2 or 3):

0 No motility

1 Sluggish movement with absent or minimal forward progression

2 Poor to fair activity with forward progression

3 Good activity with forward progression, tail movement visualized

4 Full activity, with tail movement difficult to visualize and rapid movement across the field

### Morphology

Morphology refers to the percentage of sperm with perfectly normal shapes. An elevated percentage of sperm with abnormal shapes is termed _teratospermia_. There are multiple guidelines that are used to rate morphology, but the only criterion that we feel has useful clinical applicability is the Kruger (Strict) morphology. The original Kruger Strict guidelines developed in 1986 used a figure of 14% or greater normal forms as the cutoff for "normal" morphology. However, the strictness of the guidelines has changed over the years, and many labs now use 4 % or more as the new definition of "normal." Remember that this means the criteria are so strict that even "normal" sperm samples can have 96% of the sperm that is considered abnormal.

Many couples are worried that elevated levels of abnormally shaped sperm can lead to a higher risk of birth defects or less healthy children. The available scientific literature supports the view that there is no increased risk of these types of problems for men with decreased levels of morphologically normal sperm who conceive naturally. Those sperm with abnormal morphology are less likely to do their job, but abnormal sperm morphology should not significantly increase the risk of health problems in the child.

Various studies over the years have looked at the relationship between sperm morphology and pregnancy outcomes with natural intercourse, intrauterine insemination (IUI), and in-vitro fertilization (IVF). These studies are often contradictory and do not provide a clear picture of the impact of sperm morphology. Certainly in our practice we see pregnancies resulting from insemination therapies even if the strict morphology is 0%, as long as the total motile sperm counts are decent. However, if the Kruger strict morphology value is very low, we advise couples to move relatively more quickly towards IVF if IUI therapy is not successful. For couples considering IVF, we usually recommend intracytoplasmic sperm injection (ICSI) rather than standard IVF if the strict morphology is less than 4 percent (see the IVF chapter for a complete discussion of ICSI).

### Total Motile Count

The total motile count (TMC) is defined as the total number of swimming sperm that are present in the entire ejaculate, and can be a very important predictor of male fertility potential with natural intercourse or intrauterine insemination therapy (IUI). Sperm density itself provides less information on fertility potential, since it only reports the number of sperm present in a milliliter of ejaculate. In contrast, the TMC combines the sperm density, motility, and ejaculate volumes to provide the total number of swimming sperm that are present in the entire ejaculate. Some laboratories include the TMC on their official semen analysis report, although it may be denoted under other names such as "total motile sperm" and "motile sperm count". If the TMC is not reported, it can be easily calculated by using the following equation:

(Ejaculated Volume × Sperm Density × Total Motility) ÷ 100 = TMC

For example, if ejaculate volume is 2.0 cc, sperm density is 30 × 106/cc, and total motility is 50 percent, the TMC is (2.0 × 30 × 50) ÷ 100 = 30 million sperm.

In terms of successfully establishing a pregnancy with natural intercourse or intrauterine insemination, higher numbers of total swimming sperm are generally better. A TMC of 20 million sperm is getting into the territory of good fertility potential. There is evidence that chances of natural conception increase up to 75 million sperm, above which there is no further significant benefit. A minimum TMC of 5 million sperm is typically considered the lower cutoff for being a reasonably good candidate for intrauterine insemination (IUI). One important consideration to keep in mind when evaluating TMC is the average motility grade. If most of the swimming sperm are only twitching (grade 1), then their fertility potential is not going to be very good for natural intercourse or IUI. Therefore, a TMC is considered normal only if the average grade of motility is 2 or higher.

### Other semen parameters

1) Ejaculate volume: Many men are surprised to learn that the lower limits of a normal ejaculate volume is only 1.5 cc (about a half a teaspoon). Don't worry guys, you are not supposed to fill the cup for your semen analysis!! Decreased ejaculate volumes can be consistent with ejaculatory problems or obstruction of the ejaculatory ducts.

2) Semen pH: Fluid from the seminal vesicles (not actual sperm) make up about 70% of the ejaculate volume. The fluid from the seminal vesicles has an alkaline (basic) pH, so if the fluid from the seminal vesicles is obstructed (ejaculatory duct obstruction), then the semen will have an acidic pH (<7.5).

3) Pyospermia: The semen normally contains a small number of white blood cells (WBCs) at a concentration of <1 million/cc. Elevated levels of WBCs in the semen (called _pyospermia_ ) can be an indication of inflammation and/or infection (often in the prostate gland), that may be detrimental to sperm quality. These infections can usually be treated with a simple course of oral antibiotics.

### What To Do If An Abnormality Is Found

Because semen parameters can vary quite a bit for a number of reasons, we recommend repeating an abnormal sperm test about 10 weeks later. This 10 week time frame is the length of a spermatogenic cycle, which is the time that it takes for a spermatic precursor cell to become a fully mature sperm. Any activities that can have a negative impact on sperm quality (such as sitting in a hot tub, smoking, etc.) can damage all of the sperm in the body at that point in time. It takes approximately 10 weeks to get that damaged "batch" of sperm out of the body and replace it with a new healthier set of sperm. Therefore, any interventions designed to improve sperm numbers and quality generally take about 10 weeks to be fully effective. We know that 10 weeks can seem like a long time to wait for couples who have been trying to conceive for a year or longer, but it is generally a worthwhile investment of time. It is important to make sure that male fertility factors are optimized in an efficient and timely manner in order to keep couples on the Fast Track to Fertility.

If abnormalities are found on male fertility testing, the goal is to try to optimize the environment for sperm production to increase the man's fertility potential as much as possible. The process of improving semen parameters is not a "do-it-yourself" endeavor if done correctly. It is important to work with a qualified medical provider. One obstacle that couples often encounter is difficulty finding a qualified medical provider to work with. The vast majority of general medical doctors have had little to no training in managing male fertility problems. Unfortunately, most general urologists also have limited knowledge about the latest treatment guidelines for male infertility. The best physicians to work with are urologists who have undergone advanced fellowship training in male infertility. Finding a male infertility specialist in your area may take some research, but there are some good resources you can utilize such as the SSMR website (www.ssmr.org). If you are working with a local IVF clinic, they should also know who the local urologists are who specialize in managing male fertility problems.

### Optimizing Male Fertility Potential

The rest of this chapter will review interventions that can potentially improve the environment for producing better quality sperm. A comprehensive review of managing male fertility problems is not possible to reduce to a single book chapter, so the main focus here will be an overview of key guidelines and interventions. For a more complete discussion of male factor fertility and treatment options, we highly recommend a thorough guide written by our colleague Dr. Shane Russell called the "Male Infertility Guide for Couples" which is available in print and eBook format through Amazon.com. For couples who would like a much more in-depth discussion of male fertility evaluation and management guidelines, this book can serve as a very useful resource.

### General Recommendations for All Men Trying to Conceive

1) Regular exercise regimens can help to improve general health and decrease the risk of semen parameter abnormalities. An exception to this is excessive bicycle riding (>50 miles per week), which has been shown to decrease semen parameters in some men.

2) Dietary recommendations: A balanced diet with healthy choices can help to improve semen parameters. Dietary recommendations include:

a) 5-6 servings of fresh fruit/vegetables per day

b) Increased intake of whole grains and decreased saturated fats

c) Avoid large amounts of soy intake on a regular basis, as it is a weak estrogen

3) Healthy weight: It is recommended to maintain a normal body mass index (BMI) with a goal of 20-25.

The most beneficial way to do this from a fertility standpoint is through regular exercise and healthy dietary choices. Extreme diets that cut out whole food groups (such as carbohydrates) should be avoided. Gradual, healthy weight loss is much better than rapid weight loss which can contribute to increased stress on the body. Obesity-related surgeries can initially decrease semen parameters and sometimes result in persistent problems due to nutrient-absorption issues.

4) Antioxidants/Supplements: Reactive oxygen species (ROS) are byproducts of the normal physiologic body cell processes. These ROS can be quite damaging to surrounding cells (including sperm), but the body has effective ways of clearing ROS in normal circumstances. However, when the amount of ROS becomes more than the body's normal cleanup mechanisms can easily handle, the result is increased oxidative stress on the body. Unfortunately, sperm are especially sensitive to oxidative stress, which can result in cellular and DNA damage and lead to decreases in both sperm numbers and quality. Examples of sources of elevated levels of ROS include: varicoceles, infections/inflammation, excessive alcohol intake, and use of tobacco products or exposure to secondhand smoke.

Antioxidants are over-the-counter supplements that can help to "clean up" excess ROS and reduce oxidative damage to sperm. A wide variety of commercially available antioxidants exist, and these can cost anywhere from $20-$125 or more per month. Most of these supplements contain some combination of the following nutrients:

Vitamin A Vitamin C

Vitamin E Selenium

Zinc L-carnitine

Acetyl-L-carnitine Coenzyme Q10

Folic acid

We generally recommend that men with fertility problems start antioxidants and continue them until their partner is pregnant and through her first trimester.

### Reversible Factors That Can Improve Sperm Counts and Quality

A wide range of reversible factors can impact sperm production and quality in men. To optimize male fertility potential, the following recommendations are warranted:

1) Tobacco/drug use cessation

2) Limit alcohol intake to no more than 4 drinks per week

3) Most lubricants are detrimental to sperm quality and should be avoided (some exceptions: Preseed,

Conceive Plus)

4) Avoid hot tub, saunas, very hot showers (warms showers are OK)

5) Do not use a laptop computer directly on the lap

6) Avoid the carrying of cell phone in your front pocket

7) Do not use seat warmers

8) Stress management (relaxation techniques are encouraged)

### Medications That Can Impact Sperm Quality

Some medications can be detrimental to sperm quality. A full list cannot be given here, but most fall within the following categories:

• Antibiotics

• Antifungal/antiparasitic medications

• Antiseizure medications

• Cardiovascular medications

• Chemotherapeutic agents

• Gastrointestinal medications

• Gout medications

• Hormonally active agents

• Narcotics/opiates

• Prostate medications

• Psychiatric medications

The most important of these are hormonally active agents such as testosterone. Many men (as well as physicians) incorrectly assume that giving a man testosterone will increase their sperm production. **Actually, giving a man testosterone causes testicular function to shut down. Most men who start using testosterone supplements have little to no sperm in their ejaculate within 3-6 months.** Every week in our clinic we see couples struggling with fertility who have a severe male factor because a well-meaning but uninformed physician has prescribed the male partner testosterone in an effort to boost his fertility. This is an increasingly common problem as usage rates of testosterone supplements have increased significantly over the past decade. In a similar fashion, other androgenic compounds such as anabolic steroids, pro-hormones, testosterone boosters, and DHEA can also significantly decrease sperm production, though in most men this effect is reversible. Therefore, workout supplements should also be avoided since many of them contain these harmful precursors.

### Medical Problems That Can Impact Male Fertility

A wide range of general medical problems can impact male infertility. Some of the more common of these medical problems include:

1) Hernia repair

2) Epididymitis, prostatitis

3) Polycystic kidney disease

4) Diabetes mellitus

5) Spinal cord injury

6) Erectile dysfunction

### Hormone Problems

Hormonal influences are extremely important to normal sperm production and quality. Therefore, hormone imbalances can be an important contributor to male fertility problems. Examples of hormones that are routinely checked in men as part of a fertility evaluation include:

1) Testosterone

Normal levels of testosterone are necessary for creating a good environment for sperm production. As mentioned earlier, the worst choice of treatment for low testosterone levels in men trying to father a child is to give them testosterone replacement, as giving a man testosterone or other androgens causes a dramatic decrease in sperm production. In contrast, men with fertility problems and low testosterone levels should be treated with medications that cause the body to increase its own testosterone production. Examples of medications which can be used to increase the body's own testosterone production include: clomiphene (Clomid), anastrazole (Arimidex), and human chorionic gonadotropin (hCG). These should only be prescribed by a physician experienced in their use for male factor infertility.

2) Estrogen

All normal men make estrogen as well as testosterone. Estrogen plays an important role in maintaining good bone health. Estradiol levels that are too high or are out of balance with testosterone levels (this is a common scenario in obese men), can be potentially detrimental to sperm quality. Anastrazole (Arimidex) can be used to decrease estradiol levels when they are too high.

3) Follicle Stimulating Hormone (FSH)

FSH is the hormone from the pituitary gland that tells the testicles to make sperm. If FSH levels are very low, then this can result in decreased testicular sperm production.

Other hormone levels can be checked in some clinical circumstances, including prolactin (which if elevated can decrease testosterone production), luteinizing hormone or LH (another pituitary hormone that tells the testicles to make testosterone) and inhibin B (a testicular hormone that helps to regulate FSH release from the pituitary gland).

### Varicoceles

Varicoceles are dilated veins in the scrotum, and are analogous to varicose veins in the legs. If these scrotal veins become large enough, they can increase the temperature of the scrotum to the point that a man can experience decreased sperm production, smaller testicle size, and decreased testosterone levels. The chance that a varicocele is causing fertility problems is generally related to its size. Small (grade 0 or 1) varicoceles are felt to be clinically insignificant, while larger varicoceles (grade 2 or 3) have a higher chance of causing infertility problems. Varicoceles are generally diagnosed on physical exam by a physician, though occasionally a scrotal ultrasound may be useful when getting a good physical exam is difficult or to see if borderline sized varicoceles are of clinically significant size (generally considered to be 3.5mm or larger when evaluated in the standing position).

Clinically significant varicoceles that are associated with abnormalities of the semen analysis can be treated either surgically by tying them off (varicocelectomy) or embolization (a minimally invasive procedure in which xray guidance is used to guide a wire into the vein and material is injected to clot off the blood vessels). In general, treatment of a significant varicocele has about a 50-60% chance of significant improvements in sperm counts and quality. However, even in the best circumstances, it can take 6-12 months to see meaningful improvements in sperm quality. This delay in improvement may not be worth the wait in men whose female partners are over 32 years of age. Typically, advanced fertility treatments like IVF with ICSI can be dramatically more effective for significant male factor than surgery for the male partner.

### Developing a Global Fertility Plan

The goal of male fertility interventions is to improve the semen parameters as much as possible. In most circumstances, more conservative interventions (lifestyle modifications, hormone changes, etc.) are attempted before more aggressive options (such as varicocele repair) are undertaken. It generally takes at least 10 weeks (and sometimes up to 20 weeks) to see full improvement after any interventions. We therefore typically repeat a semen analysis about 10 weeks after the environment for sperm production has been optimized. In most circumstances, devoting 10 weeks to optimizing male fertility parameters is a good investment in staying on the Fast Track to Fertility. In some circumstances, however, the timeline for repeat testing or moving directly to female interventions (such as IUI or IVF) can be moved up, such as when the women is older than 32 years of age and/or has decreased ovarian reserve.

Typically, once the male parameters have been optimized, the focus will shift to interventions on the female side that can enhance the chances of successful conception. These treatment strategies are discussed in great detail in other chapters, but may include:

1) Medications for the woman, such as clomiphene, tamoxifen, letrozole, or anastrazole

2) Intrauterine insemination (IUI)

3) In vitro fertilization (IVF)

4) Intracytoplasmic sperm injection (ICSI)

From the male side of things, the total motile count (TMC) is usually the most predictive factor as to what types of treatments for which he is a candidate. The following are general guidelines for the number of sperm that make a couple eligible for the different treatment options that are available from the female side:

Female fertility treatment | Minimum total motile count (TMC) to be considered a candidate | Ideal TMC for this type of intervention/procedure

---|---|---

Natural intercourse combined with hormones (e.g., clomiphene, letrozole) | 10 million | 20 million or more

Intrauterine insemination | 5 million pre-wash

(1 million post-wash) | 20 million or more pre-wash

(5 million or more post-wash)

Standard IVF | 100,000 sperm/cc (regular density) | 1 million/cc or more

IVF/ICSI | 5–20 live sperm | 100,000/cc or more

The formulation of a fertility management plan that is specific for each particular couple and takes into consideration both the male and female factors is extremely important for optimizing the chances of establishing a pregnancy. Excellent communication and coordination of care between the man's and woman's fertility specialists is vital to successfully forming a treatment plan for the couple and maximizing their chances of success.

Of note, to sustain any gains in fertility that a man has made, the changes (in lifestyle, hormones, and so on) must be sustained, or else his fertility parameters may revert back to the way that they were before these changes were initiated. We generally recommend that most interventions from the male side be maintained until the woman is pregnant and through her first trimester.

### Assisted Reproductive Technologies

Despite the fact that many of the simpler treatments mentioned above can be very successful, by far the best treatment for severe male factor infertility is the use of in vitro fertilization (IVF) and associated techniques. IVF provides the most reliable way to ensure that the sperm and egg have gotten together. Conventional IVF is a technique that maximizes sperm and egg interaction to increase the likelihood of fertilization. This technique is useful for patients with mild to moderate sperm problems, but still requires a sufficient number of motile sperm with normal morphology. The eggs of the female partner are retrieved while the male partner collects a semen specimen, which is washed and processed to isolate the motile sperm. The isolated sperm and eggs are combined in a Petri dish. The dish provides a confined space so that the sperm are almost guaranteed to come in contact with the egg and increase the odds of fertilization.

The most sure-fire method for ensuring that the sperm and egg come in contact is Intracytoplasmic Sperm Injection (ICSI) (see Chapter 8). In conventional IVF, thousands of sperm are placed in a dish containing eggs, but the sperm still have some work to do, as they must penetrate the outer shell (zona pellucida) of the egg for fertilization to occur. With ICSI, a single sperm is injected with a finely drawn needle directly into the interior of the egg, thereby guaranteeing union of the sperm and egg.

Microscopic view of ICSI procedure

ICSI is useful for patients with the most severe cases of male infertility such as extremely low sperm counts, poor motility, abnormal sperm morphology, severe cases of antisperm antibodies, or no sperm in the semen. Sperm for use with ICSI can be obtained from ejaculated specimens or retrieved directly from the epididymis or testis through minor outpatient procedures. Very few sperm are required for this procedure and motility is not absolutely necessary. Since its introduction approximately 15 years ago, ICSI has revolutionized the field of assisted reproductive technology, as it has allowed men who would previously have had great difficulty conceiving an opportunity to father a child.

### Special Circumstances in Male Infertility

Azoospermia (no sperm at all in the ejaculate)

In men with no sperm in their ejaculate, there are 3 possible explanations:

a) Severe sperm production problem

b) Obstruction

c) Ejaculatory/Ductal sperm transport problem

Some reasons for sperm production problems are reversible, including hormone abnormalities and varicoceles. Stopping the use of testosterone supplements often results in the return of sperm to the ejaculate. Genetics testing is generally indicated if no reversible factors can be found. In some circumstances, small islands of sperm production can be present within the testicle that can be surgically removed and used in combination with IVF/ICSI (see TESA-ICSI chapter).

Sperm obstruction issues are sometimes able to be corrected with microsurgery. The most common reason for reversible obstruction is elective vasectomy for contraception. Modern microsurgical vasectomy reversal techniques have relatively high rates of success in the hands of fellowship-trained microsurgical experts (but generally lower rates with general urologists or doctors offering "bargain" procedures under local anesthesia in their office). Another very effective option for patients who have had a vasectomy is to surgically extract sperm from the testicle and use these sperm in combination with IVF/ICSI. The potential benefits of this approach are that it does not matter how many years have passed since the original vasectomy, and that a smaller less invasive procedure is needed for the man. Post vas reversal anti-sperm antibody problems are also not an issue when IVF/ICSI is used. Please see the chapter on post-sterilization fertility for a more complete discussion.

Ejaculatory and sperm transport problems are sometimes reversible with medical or non-surgical interventions. If these efforts fail, then surgical sperm extraction combined with IVF/ICSI is another option for patients with ejaculatory and sperm transport issues.

Recurrent Pregnancy Loss

Recurrent miscarriages are a very frustrating and emotionally distressing problem that can affect some couples. Spontaneous miscarriages are unfortunately relatively common, but couples who have had more than 2 or 3 consecutive miscarriages should consider having an evaluation for potentially reversible factors. There are a wide range of female issues that can contribute to an increased risk of miscarriage, including structural anatomical problems, clotting abnormalities, and autoimmune disease. Sperm issues can also play a role in contributing to the risk of recurrent pregnancy loss. The standard male exam includes having genetics testing (karyotype) performed. Abnormalities uncovered on karyotype testing should be followed up with formal genetics counseling, and the couple may benefit from IVF combined with preimplantation genetic diagnosis or screening (PGD or PGS), in which only embryos that do not harbor the discovered genetic abnormalities are transferred.

Male factor infertility problems are extremely common and contribute significantly to at least 50% of the fertility problems that couples in the United States experience. The good news is that most of these problems are treatable if couples are willing to invest a little time and effort to optimizing the male partner's fertility potential and keeping them on the Fast Track to Fertility. When simple treatments are not effective, IVF with ICSI can almost always be used to help overcome male factor infertility.

#  Chapter 11  
Endometriosis

Several other chapters in this book have touched on endometriosis and its impact on fertility. If you think you may have endometriosis or have already been diagnosed with endometriosis, then this chapter, which delves much more deeply into this condition, will help provide you with the knowledge you need to help stay on the Fast Track to fertility.

Endometriosis is a common cause of female infertility and pelvic pain. It is a somewhat mysterious condition that occurs when endometrial tissue (the tissue that normally lines the inside of the uterus) grows outside of the uterus, usually on the surfaces of other pelvic and abdominal organs such as the ovaries, fallopian tubes, the area behind the uterus, bowels, bladder, and lining of the pelvic cavity. Rarely, endometriosis can occur in other distant parts of the body such as the lungs, limbs, or old surgical scars.

Endometrial tissue on the ovaries and uterus

The endometrial tissue that grows outside the uterus responds to the hormonal changes of the menstrual cycle just as the lining of the uterus does. It becomes thicker during the first half of the cycle, and then it sheds to mark the beginning of the menses. While the blood from the uterus can flow out of the body naturally, the bleeding that occurs from endometriosis has no exit route. The resulting bleeding in the pelvic cavity may cause scarring and inflammation that can lead to infertility or pain or both.

The scarring can lead to mechanical problems that prevent the fallopian tubes and ovaries from interacting properly and can prevent egg pickup at the time of ovulation. The association between this type of disease and infertility is easy to understand. The association between mild cases of endometriosis or more advanced cases without a lot of mechanical scarring is more difficult to comprehend. However, the inflammation and reaction in the pelvis to the abnormal tissue causes an environment which may be less than ideal to support the egg when it is released from the ovary or which may be toxic to the sperm-egg interaction.

Because symptoms of endometriosis vary greatly from woman to woman and may mimic other medical conditions, endometriosis is often difficult to diagnose. Furthermore, the degree of symptoms does not necessarily correlate well with the degree of endometriosis that a woman may have. Some women have no symptoms at all even though their disease is extensive, while other women have severe pain even though they have a very minimal amount of endometriosis. Common symptoms of endometriosis include infertility, extremely painful menstrual cramps, chronic pelvic pain, pain during or after sex, painful bowel movements during menstruation, heavy menstrual periods, and irregular bleeding.

Endometriosis is quite common. Estimates vary, but about 5 percent of women in their reproductive years probably suffer from endometriosis. However, according to the National Institutes of Health, about 30 to 40 percent of women who do have endometriosis have fertility concerns. Additionally, 25-30 percent of women with severe disabling menstrual cramps may suffer from the disease.

The exact cause of endometriosis is unknown. One leading theory is that "retrograde menstrual flow," in which some endometrial tissue being shed from the uterus during menstruation flows backwards out the fallopian tubes and into the pelvis, causes endometriosis. Genetic factors probably play some role in the development or expression of endometriosis. Finally, endometrial tissue may spread throughout the lymph or blood system, thus potentially explaining its location at sites distant from the pelvis. Unfortunately, endometriosis can be a progressive disease and tends to recur after therapy until a woman reaches menopause.

If you've been struggling with infertility, you may be concerned that endometriosis is contributing to your trouble conceiving. This is especially true if you have friends or family members who may have had endometriosis. Unfortunately, unless very advanced disease shows up in the ovaries on ultrasound, the only way to diagnose endometriosis accurately is through a minimally invasive surgery known as laparoscopy. This procedure is described in detail in Chapter 7. During laparoscopy a specially trained gynecologist puts a small fiber optic scope into the abdominal and pelvic cavities to examine the reproductive surfaces. Endometriosis will not usually show up on ultrasound or X-ray tests and can be detected only rarely by physical examination. Fortunately, most cases of endometriosis can be treated through the laparoscope, usually with laser therapy, at the same time as the diagnosis is made. More advanced cases may require more extensive surgery. In most cases at the time of laparoscopy the endometriosis can be lasered away and scar tissue can be removed rendering the reproductive tract normal or near normal. The preceding chapter on surgical techniques discusses laparoscopy in more detail.

At the time of laparoscopy, we use standardized grading scores to rate the degree of endometriosis found. This helps with deciding on the best course of treatment and with communication between physicians. If we are all using the same scale, then we can reliably know what someone else found at the time of surgery. Endometriosis is rated as minimal, mild, moderate, or severe. It can also be graded on a scale from I-IV, with Stage IV disease being the most advanced. Standardized scoring sheets are available from the American Society for Reproductive Medicine. The physician performing the procedure will dictate an operative note that describes the endometriosis in detail. Having a copy of your operative note and laparoscopy photos available can be useful when you visit the reproductive specialist.

In addition to surgical options, many types of hormonal therapy are also available to treat endometriosis. These treatments can be highly effective, especially for treating pain associated with endometriosis. Most of these hormonal therapies rely on suppressing your body's own production of estrogen, trying to shrink the disease with high levels of progesterone or other androgen ("male sex hormones") hormones, or a combination of both. One of the most commonly used class of drugs for treating endometriosis is the gonadotropin-releasing hormone (GnRH) agonist such as leuprolide acetate (Lupron). These medications turn off the signals between the pituitary gland in the brain and the ovaries and temporarily create a menopause-like state. This lack of estrogen will help shrink the endometriosis and can be very effective therapy. Birth control pills are another common agent that can be effective in treating endometriosis and in providing pain relief. Progesterone-like hormones (or progestins) like medroxyprogesterone acetate (Depo-Provera) can also be used to treat endometriosis and can provide excellent relief from symptoms and prevent disease progression. Each of these therapies has its own trade-offs in terms of irregular bleeding patterns and side effects.

Although the majority of women using birth control pills will not experience any side effects, some may experience nausea, vomiting, bloating, breakthrough bleeding, and nipple or breast tenderness. In very few women (especially those who smoke and are over 35 years of age), there may also be a slightly higher risk for the formation of blood clots, strokes, or heart attacks. When we last counted, however, there were more than 63 different brands of birth control pills available. With this kind of variety, it is possible to find a pill that each woman can use.

The gonadotropin-releasing hormone agonists provide effective pain relief and can shrink existing endometriosis tissue with a shot administered monthly or every three months. Because the medication renders a woman temporarily "menopausal," the side effects are those that women often experience as they reach menopause: hot flushes and night sweats. Some women may have sleep disturbances, joint pain, headaches, or trouble concentrating. While these side effects can be disruptive, the side effect that we worry about medically is loss of bone density (or osteoporosis). While this loss is temporary and the bone can be regained with calcium supplementation and exercise if treatment periods are less than three to six months, it can be permanent in patients taking the GnRH agonists for longer periods of time. For this reason, small amounts of estrogen or progesterone or both are added in addition to the GnRH agonists to protect the bone if the treatment course will be prolonged.

Finally, progestin (medications similar to progesterone) therapy can be very effective in treating endometriosis. Popular courses of treatment include the "mini-pill," a daily progestin or progesterone tablet (like Provera or Aygestin), or long-acting intramuscular injections of progestins (Depo-Provera) that can be given four times per year. The most common complaint from women on progestin therapy is irregular, unpredictable bleeding. Bloating, water retention, weight gain, and depression are other less common side effects from progestin use. Again, because many different forms of therapy are available, a good reproductive endocrinologist can usually find one that's right for you.

If you're trying to get pregnant, however, medical treatment of endometriosis may not be for you. Effective medical therapy requires long-term suppression of the normal hormone cycle in order to prevent ovulation. Therefore, you will not be able to continue your conception efforts while on such therapy. You don't want to fall off the Fast Track on your fertility journey by delaying effective fertility therapy by months and months with hormonal treatment for endometriosis. For women with infertility related to endometriosis, therapy should begin very soon after surgery or after only a short term of medical therapy, because endometriosis will eventually reappear if not actively suppressed. Additionally, if scar tissue was removed or anatomic lesions corrected during surgery, your chances of conception may be greatest in the first three to six months after laparoscopy or more major surgery, before the scarring has a chance to recur.

Endometriosis can weaken the egg supply. It is helpful to obtain an AMH level to check how many eggs are left to work with. AMH levels of greater than 1 indicate the ovaries are healthy and contain an adequate level of eggs. AMH levels below 0.3 indicate decreased ovarian reserve and more aggressive management is needed.

Fortunately, great strides have been made recently in treating the infertility associated with endometriosis. Combining superovulation with intrauterine insemination can often be helpful. But the good news is that _in vitro_ fertilization (IVF) can be highly effective in helping couples conceive when endometriosis is causing fertility concerns. By removing the eggs from the inflammatory endometriosis environment of the pelvis and proceeding to IVF, we are bypassing the "evil humors" that may be impeding natural attempts at fertility. Similarly, by bypassing the fallopian tubes where fertilization normally occurs, we bypass any mechanical problems that may be caused by scarring of the tubes and ovaries from the endometriosis. Most young women with endometriosis who are willing to complete a full course of therapy with IVF will have an excellent chance of conceiving.

The first step to diagnosing and treating endometriosis starts with a call to your qualified health care professional. Patients with endometriosis should be encouraged by the progress that has been made in the research and treatment of this disease. More hope is on the way as research continues every day. In the meantime, IVF can be a highly effective and time efficient means of achieving your fertility goals.

### FAQ's

1. _I'm having trouble conceiving, but I don't have painful menstrual periods. Does that mean I can't have endometriosis?_ No. For many patients, infertility may be the only symptom of endometriosis. If we do find endometriosis in infertility patients who have no apparent symptoms, it is often only mild to moderate disease. Mild disease is often effectively treated with less invasive therapies such as superovulation with insemination or IVF. However, at least one good controlled study suggests that surgically treating even mild endometriosis can help natural conception occur in the one to two years following surgery.

2. _I had laparoscopy for endometriosis two years ago and still haven't conceived. Should I repeat the surgery?_ Probably not. If the disease was very advanced and aggressive at the time of the first surgery, then you may benefit from a second "clean up" procedure. However, if the disease was mild to moderate, you are probably better off pursuing more active fertility therapies. IVF will be less invasive and far more effective at keeping you on the Fast Track!

3. _I recently had surgery for endometriosis and now my doctor wants me to take medications for six months._ _Is this a good idea?_ It depends. If the primary indication for surgery was painful periods, pelvic pain, or pain with intercourse, then the medication can certainly be a useful addition to the surgery in terms of keeping those complaints in check. Also, if the disease was so extensive that not all of it could be safely treated surgically, then additional medical therapy may help complete the treatment process. But remember, if you're trying to get pregnant, long months of medical therapy for endometriosis can delay your attempts.

4. _Will getting pregnant help my endometriosis?_ Absolutely! Pregnancy is the best thing in the world for endometriosis. The high levels of progesterone as well as the lack of ovulation and menses serve to suppress endometriosis and shrink existing lesions. In addition, as the uterus grows from the size of a small pear to the size of a watermelon, many adhesions will be stretched away and broken up Don't worry; this happens so slowly you can't even feel it. Many of our patients with endometriosis who had trouble conceiving before their first pregnancy do much better the second time around. However, if you have a history of endometriosis and infertility and are having trouble conceiving the second time, don't delay on starting treatment again.

5. _Will endometriosis decrease the chances that IVF will be successful for me?_ Probably not. Because IVF removes the eggs from the inflammatory process in the pelvis and helps bypass any scar tissue or mechanical issues, IVF is very successful, even for patients with severe endometriosis. There is no evidence to suggest that the endometriosis will prevent implantation of healthy embryos once they are transferred back to the uterus. The only qualification to this answer is for patients with endometriomas. An endometrioma occurs when a walled off cyst of endometriosis occurs deep within the ovarian tissue. This can affect the amount of remaining healthy tissue left to make good eggs for an IVF cycle. There is considerable debate in the medical literature whether surgically removing these "chocolate cysts" (so named because the endometriosis fluids inside looks like chocolate syrup) prior to IVF is helpful or not. But by and large, IVF is very successful for patients with endometriosis.

As you have read, endometriosis can contribute to infertility as well as uncomfortable symptoms. But as with most other causes of infertility, the key to staying on the Fast Track to fertility involves the proactive recognition and treatment of this disorder.

# Chapter 12  
Polycystic Ovarian Syndrome

In previous chapters of this book, we have discussed the importance of normal ovulation in women who are trying to conceive. We also discussed how some ovulation medications may help treat women with irregular cycles. Many women suffering from infertility that is caused by the lack of ovulation really have a condition called polycystic ovarian syndrome (or PCOS). This chapter goes into considerable detail regarding this condition and the options for treating it.

### The Basics

Polycystic ovarian syndrome (PCOS) is an extremely common endocrine disorder. PCOS is conservatively estimated to occur in 5-10 percent of reproductive-aged women in the United States. This disease has been recognized since the middle 1800s. Drs. Stein and Leventhal, who published their findings of irregular cycles, infertility, and excess hair growth in women with multiple small cysts in their ovaries, finally formally described PCOS in the 1930s. For years, strict criteria were required to make the diagnosis of PCOD (polycystic ovarian _disease,_ often referred to as Stein-Leventhal Syndrome), and if a woman did not have all of the criteria then she did not meet the diagnosis. However, over the last decade or so, clinicians have realized that this endocrine disorder really encompasses several distinct subsets of patients, not all of whom manifest exactly the same symptoms or physiologic findings. Thus, PCO _disease_ has evolved into PCO _syndrome_ , recognizing that there are many women who have many but not all of the classic findings and who will still benefit from an appropriate workup and treatment of their syndrome. Despite the wide array of presentations or symptoms of PCOS, experts in the field agree that there are some common clinical and laboratory aspects that most women with PCOS share.

Most women with PCOS have ovulatory dysfunction or are not ovulating at all. This condition probably results from very complex and often subtle abnormalities in the communication between the brain (particularly the hypothalamus and the pituitary gland) and the ovary, but it is often compounded by obesity and other hormonal imbalances. If the egg is not released from the ovary each month in a normal fashion, this can obviously lead to infertility. Your physician, friends, or family may have told you to attempt unprotected intercourse for up to a year before seeking fertility care. However, if you know or suspect that you have PCOS, failure to ovulate (anovulation), or irregular menstrual cycles, you should seek care sooner. Don't get bumped off the Fast Track! Months without ovulation are wasted months for a woman trying to conceive.

In addition to infertility, anovulation and its accompanying infrequent or irregular menstrual cycles may have long-term health consequences. In the absence of ovulation, the ovary does not make the hormone progesterone in the second half of the menstrual cycle. Without progesterone, the lining of the uterus is not shed in an efficient and timely manner. After a number of years, this can place women with PCOS at risk for an abnormal buildup of the lining of the uterus (endometrial hyperplasia). If left untreated, hyperplasia can eventually lead to uterine cancer. For this reason, women with PCOS who are not trying to get pregnant should be treated with progesterone-like medications to induce a normal menstrual period at least every two to three months. Another option is a daily birth control pill, which contains progesterone and can help prevent the overgrowth of the lining. Birth control pills can help reduce the risk of ovarian cancer in some women as well.

Another common feature of PCOS is clinical or laboratory hyperandrogenism. This means that women with PCOS have either increased circulating amounts of or increased responsiveness to "male" hormones like testosterone or DHEAS. Both men and women have circulating estrogens ("female hormones") and androgens ("male hormones"), but in different ratios. The higher than average levels of androgens (especially the "free" form that is able to bind to the skin and hair cells) in women with PCOS may result in oily skin or acne and excess hair on the face, between the breasts, or on the lower abdomen, back and buttocks. In order for the diagnosis of PCOS to be made, these abnormalities must exist in the absence of other related hormonal disorders. A good reproductive endocrinologist can distinguish PCOS from other underlying disorders.

If you had been taking oral contraceptives in the past to control irregular cycles and have now stopped the pill in order to attempt pregnancy, you may have noticed that your acne and hair growth worsened after the first three or four months off the pill. This is because the hormones in the birth control pill help regulate the imbalance found with PCOS. These symptoms usually do not mean that you have a new condition or have gotten much worse, it's just that you have lost the additional benefits from being on the pill. It is likely that the irregular cycles initially prompting treatment with the pill may really have been a symptom of some form of PCOS. The unwanted hair growth and acne can be discouraging when you come off the pill, but, unfortunately, it is difficult to treat them with more than topical care or hair removal methods while you are trying to conceive.

Most women with PCOS also display changes in the ovaries that can be seen with ultrasound or laparoscopy. In fact, the name itself describes the typical anatomical findings seen in this disorder: poly (many), cystic (small collections of fluid). When the eggs in the ovaries do not develop to maturity, many small "follicles" (small fluid-filled sacs containing immature eggs) develop and can be seen on ultrasound underneath the surface of the ovaries. A typical ultrasound is shown below. Note the appearance of the small dark circles around the edge of the ovary. These circles are called the "beaded necklace" or "string of pearls" sign on ultrasound.

Ultrasound picture of polycystic ovaries

The ovaries of women with PCOS are often enlarged as well. However, most women with PCOS do not have the kind of "cysts on the ovary" that we normally think of as problematic or requiring surgery. These multiple small follicles are not the kind of "cysts" that rupture or twist.

Another common feature of PCOS is increased body weight. If you have PCOS, you may feel as though you barely eat anything and you are trying to exercise but the weight keeps piling on! This weight problem is very common with PCOS and results from higher than average circulating levels of insulin. Women with PCOS tend to be heavy and have trouble losing weight. One underlying mechanism behind the ovulatory irregularity and the obesity associated with PCOS is probably insulin resistance. The cells of women with PCOS do not respond as well to their bodies' own insulin as those of someone without PCOS. Therefore, in order to keep blood sugar levels normal, a woman with PCOS will need to secrete a lot more insulin than an average person might. Unfortunately, insulin is a hormone that stimulates fat storage, so high circulating levels will cause women with PCOS to put on weight easily, especially around the abdomen. These high insulin levels also make it harder than average to take off weight, and they perpetuate the abnormal signals in the ovary that are preventing ovulation. Insulin resistance also causes swings in blood sugar after eating. Unfortunately, higher insulin levels also put women with PCOS at higher risk for developing diabetes during pregnancy or later in life. While many women with PCOS have increased body weight approximately 30% have normal or low body weight. These individuals have little or no insulin resistance.

But don't give up! With appropriate diet and exercise and sometimes treatment of the insulin resistance, most women with PCOS can and will lose weight. Diets low in simple sugars and carbohydrates and high in fiber and lean protein can help women avoid the high insulin peaks after meals. The low carbohydrate high protein diet is also called the Atkins diet. This diet eliminated the most common forms of carbohydrates such as: sweets, rice, potatoes, pasta, breads and most snack foods. The diet focuses on protein which is present in beans, meat, chicken, fish and cheese. It also encourages, vegetables and salads. For specifics of the "Fertility Diet", please go to the chapter on Lifestyle where it is discussed in detail.

In addition to a modified diet, regular exercise will help reduce insulin resistance as well as burn calories. Forty to fifty minutes of good aerobic exercise five to six times per week will help make significant improvements. This exercise may be as simple as brisk uninterrupted walking outdoors, walking or jogging on the treadmill, working out on an elliptical machine or exercise bike, or swimming. Remember that variety in your workout helps keep it fun! Also, working with weights will help build lean muscle that will speed your metabolism and burn fat faster. If you are significantly out of shape, check with your physician before starting any exercise or diet regimen.

Some women with PCOS are significantly obese and may weigh 100-200 pounds above their ideal body weight. Obesity will impede fertility and increase pregnancy complications dramatically. But we realize that, realistically, women who are seeing us as fertility specialists often do not have the time or the resources to lose 120 or 130 pounds before conceiving. This is especially true of women in their later 30s, for whom time is so critical. However, even relatively small changes can really help. A weight loss of 10-15 percent (often 20-30 lbs) in an obese patient is often all it takes to significantly improve spontaneous ovulation or the response to ovulation-inducing drugs. So take pride in your efforts to lose even small amounts of weight and remember your fast-paced walk may be keeping you on the Fast Track to fertility!

Now, in keeping with the initial part of this chapter, remember that all women with PCOS are not the same. There is a whole subset of women with PCOS that we call "skinny PCOS" or "lean PCOS." These are women who have polycystic ovaries, anovulation, and some amount of acne or excess hair growth but tend to be very thin. Their physicians tell many women like this that they cannot have PCOS because they are not heavy. Many skinny PCOS patients will benefit from the treatment plans described below. A good reproductive endocrinologist can help determine if you might have skinny PCOS or one of its many other variants.

### Treatment Strategies

Treatment for PCOS depends largely on an individual woman's fertility desires. For those women not desiring immediate pregnancy, there are basically two options to help regulate menstrual cycles and prevent endometrial hyperplasia or thickening of the lining of the uterus. The most common option is the use of oral contraceptives or birth control pills. The pill will give most women normal bleeding patterns and prevent hyperplasia. Since ovulation can occur unpredictably in women with PCOS, the pill also provides adequate contraception for those women who do not want to conceive. The hormones in oral contraceptives will also help reduce acne and facial hair in most patients with PCOS. In women who do not require contraception or have difficult side effects from the pill, progesterone given for 10-12 days every 30-60 days will induce a reliable menstruation.

In women who are particularly bothered by unwanted hair growth, significant improvement can be obtained with a combination of medications. As already mentioned, oral contraceptives are extremely useful in this regard. Other medications may include drugs like spironolactone that reduce the secretion of androgen hormones or interfere with their action in the skin and hair cells. These medications are not safe to take while you are trying to conceive as they could potentially harm the developing fetus, so most physicians will only prescribe these medications in combination with the birth control pill or for women who have been sterilized.

Over the last decade, another therapeutic option has proven effective for women with PCOS. As already mentioned, insulin resistance may represent the underlying problem for a lot of PCOS patients. Drugs often used to treat patients with adult onset diabetes help sensitize the body's cells to the action of insulin, thereby reducing insulin resistance. These medications can help break the cycle of weight gain and anovulation in women with PCOS and are considered first line therapy by many practitioners. Some of these agents may also help women with PCOS to lose weight. Some of the more common drugs are metformin (Glucophage, Fortamet) and pioglitazone (Actos). In about 30 percent of selected PCOS patients, we can achieve reliable ovulation and pregnancy rates with nothing more than metformin, diet and exercise. The most effective diet used with Metformin is the low carb. high protein diet. This diet eliminated high carbohydrate food such as bread, rice, potatoes, pasta and sweets. It encourages protein rich foods such as meat, chicken, fish, pork and cheese. The most common complaint we get with metformin is diarrhea and nausea, but these side effects usually ease after the first month or so of therapy and can be minimized by starting at a low dose and working up to therapeutic levels. Rare severe side effects include muscle weakness, confusion, and dehydration; they may be markers of a more serious condition and should be reported to your physician. If metformin therapy alone is not enough to induce ovulation, many patients will respond well to a combination of metformin and other ovulation inducing agents such as clomiphene citrate ( Clomid).

For women with PCOS who desire pregnancy, ovulation induction is often necessary. This involves medical treatment in order to help the ovaries release an egg each month in a reliable fashion. Often this treatment involves simple and relatively inexpensive oral medications like clomiphene citrate (Clomid, Serophene), selective estrogen modulators like tamoxifen, or the aromatase inhibitors like letrozole (Femara). Other PCOS patients may require more intensive and expensive therapies with injectable medications. For many patients with other causes of infertility, we are trying to induce the development of multiple eggs to enhance fertility. However, for women with PCOS and anovulation, we are simply trying to restore normal ovulation, which means the development and release of a single egg per month. This is a crucial distinction, because women with PCOS are prone to develop multiple follicles, which could cause ovarian hyperstimulation or place a couple at risk for multiple pregnancy. These topics are more fully covered in the chapter on ovulation drugs.

Because of the tendency for women with PCOS to make high numbers of eggs in response to medications and the subsequent risk for multiple births, _in vitro_ fertilization may also be a very effective treatment strategy. Not only are success rates with IVF higher than with any other form of therapy, but also the option of transferring only one or two embryos to the uterus during an IVF cycle helps to eliminate the risk of high order multiple pregnancy (triplets and above).

### Summary

PCOS is a common and readily treatable disorder. Because of the long-term metabolic considerations with PCOS, the challenge for your doctor is to identify and meet your specific needs during your entire life span. While you are trying to conceive, that means effectively diagnosing and treating your PCOS to keep you on the Fast Track to fertility!

### Case Examples

The following are examples are provided to give you an idea of the spectrum of women we see with PCOS and how there is hope for most of these women with appropriate treatment.

1. _Maria is a 29-year-old white female who had never been pregnant before. She started her periods in seventh grade, but she never became regular and was having only three to four menstrual cycles per year in high school. She developed acne and noticed increased hair growth on her forearms, buttocks, and sideburn area and started on the birth control pill in college both because she had become sexually active and to regulate her cycles. She went off the birth control when she married three years ago, and her cycles became irregular again. She is 5'7" tall and had steadily been putting on weight. She weighed 170 pounds when she graduated high school and currently weighs 246 pounds. She had been working with her primary OB/GYN to achieve pregnancy for one-and-a-half years prior to seeing us and was still not having ovulatory cycles despite eight months of therapy with Clomid, starting at a 50mg dose and moving all the way up to 200mg (a maximal dose)._ Maria had the history, physical findings on examination, and laboratory and ultrasound results to confirm a diagnosis of PCOS. We started her on metformin therapy, and she began a program of exercise and low carbohydrate diet. Over a four month time frame she lost 23 pounds and had 2 spontaneous menstrual cycles. On her third cycle she conceived naturally!

2. _Layla is a 24-year-old white female with a history of anovulation and infertility. She suffered from irregular periods since high school and had been off the pill for eight months when she came to see us. Her history as well as her physical exam findings suggested lean PCOS. She weighed 122 pounds at her first visit and had increased hair growth, especially on the lower abdomen and buttocks region. Her ultrasound showed a classic "string of pearls."_ We started Layla on metformin therapy, which helped her energy levels, but her cycles did not improve. Nor did she respond to clomiphene therapy at doses of 50, 100, or 150 mg/day. Since simpler therapies had not worked, we moved on to gonadotropins (injectable fertility medicines) with Layla. She became pregnant with a single baby on her second round of therapy with recombinant FSH.

3. _Janice weighed 240 pounds and was 36 years old when she came to see us. She had conceived her first son on clomiphene therapy four years ago and had gone back on birth control pills after finishing breast-feeding. Her periods had become irregular again since stopping the pill to conceive. She had been started on metformin therapy by her primary OB/GYN and had lost 12 pounds but did not resume ovulation. She had also not responded to increasing doses of clomiphene (up to 200 mg/day) for the six months before being referred to our practice._ We encouraged Janice to continue her efforts at diet and exercise as well as her metformin and and added gonadotropin therapy. Despite a good ovulatory response to the medications, she still did not conceive after four cycles. We reviewed the treatment options, and Janice and her husband decided to undergo a cycle of IVF, which resulted in the birth of a healthy little girl after the first attempt.

4. _Victoria is a 34-year-old African American female who weighs 184 pounds. She had a history of PCOS that had responded relatively well to clomiphene. However, her husband's sperm counts and motility were fairly low, and she had a history of endometriosis as diagnosed by a laparoscopy performed for painful periods two years before attempting conception._ We attempted clomiphene therapy and intrauterine insemination for two rounds without success. Because of the male factor and history of endometriosis, we elected to skip gonadotropin therapy and proceed directly to IVF with Ellen at that point. She conceived on her first fresh cycle of IVF. Unfortunately, she miscarried at eight weeks. Two months later, she conceived again with her frozen embryos and delivered a healthy little boy.

As you can see, with appropriate workup, evaluation, and specialized treatment, even women with difficult PCOS can stay on the successful Fast Track to fertility!

# Chapter 13  
Hormones and Reproduction

### Endocrinology

Your fast track to fertility takes a side track with this chapter as this chapter describes the endocrine processes associated with fertility and human reproduction. We will do the best that we can to explain what happens in the human body and how different situations impact the natural process of human reproduction. We hope common language will explain the interactions and help to make learning reproductive endocrinology easier. Unfortunately a few medical terms will have to be used to help explain the process. These key medical terms will be explained so that you will appreciate the beauty of the endocrinology of human reproduction.

A hormone is a substance produced by a gland that is released in the bloodstream. The hormone then travels to a target organ where it exerts control over its function. A gland that releases substances into the bloodstream is specifically called an endocrine gland. There are many endocrine glands in the body and each can release one or more hormones. Hormones from one gland also typically control the secretion of other hormones. It is beyond the scope of this chapter to discuss all hormones and their control. Our goal here is to discuss the major hormones which are important to reproduction. The major glands involved in reproduction are the pituitary gland, the thyroid gland, the ovary, the testis and the adrenal glands.

### The Pituitary "Master" Gland

Human reproduction and physiology are controlled through the hypothalamic pituitary ovarian/testicular axis. Conveniently the higher cerebral cortex, the thinking part of the brain, is physically located above the hypothalamus. There are many nerve connections that lead from the higher brain to the hypothalamus. Thus emotions occurring in the higher brain can influence the reproductive system through nerve interactions and neurotransmitters produced by the higher brain. The hypothalamus is also located superior (above) to the pituitary. The major hormone concerned with regulating the reproductive system is the 10 amino acid protein (decapeptide) gonadotropin releasing hormone ( GnRH). The posterior pituitary is a direct extension of the hypothalamic neuron cells that make oxytocin and vasopressin. the cell bodies of these neurons are located in the hypothalamus and their axons travel through the pituitary stalk to terminate in the posterior pituitary. From these nerve endings the hormones oxytocin and vasopressin are released into the circulation. Meanwhile the anterior pituitary receives a blood supply from hypothalamus called the portal system. GnRH from the portal vessels stimulate follicle stimulating hormone (FSH) and luteinizing hormone (LH) to be produced and released. FSH and LH produced in the anterior pituitary travel through the blood stream to the testicles and ovaries where they regulate sperm and egg production as well as testosterone and estrogen production and release. The testosterone and estrogen provide negative feedback to the GnRH neurons of the hypothalamus and FSH/LH producing cells (gonadotrophs) in the anterior pituitary.

Other hormones can influence this hypothalamic-pituitaryovarian/testicular (HPO) axis. Opiates either from orally ingested pain medications or those that are released from exercise and stress can inhibit(decrease) the release of GnRH and can cause infrequent or no ovulations thus causing long, irregular or absent menstrual cycles in females and in the male low or no sperm production. High prolactin levels can decrease release of GnRH as well and cause irregular or absent menstrual cycles. Abnormal thyroid function can affect GnRH secretion and menstruation.

The hypothalamus pituitary axis has other hormone systems that are similar to the HPO axis. The thyroid regulation has thyrotropin releasing hormone(TRH) produced in the hypothalamus and gets released into the portal system and carried to the anterior pituitary where it causes TSH to be released. The TSH then travels through the bloodstream to the thyroid where it causes thyroid hormones (T3 and T4) to be secreted. T3 and T4 then have negative feedback on the release of TRH and thus lower subsequent thyroid output. In a similar fashion corticotrophin releasing hormone (CRH) travels from the hypothalamus to the anterior pituitary where it causes the release of ACTH. The ACTH causes corticosteroids to be released from the adrenal gland. The corticosteroids negatively feedback on the release of CRH and thus keep this system in check.

### Ovary

The ovary contains the follicles within which the oocytes or eggs develop. The pituitary hormones FSH and LH control this process. The steroid hormones estrogen and progesterone are produced by cells that line the inside and walls of the follicle. They then regulate the development of the endometrium or lining of the uterus. If a pregnancy occurs then the follicle produces progesterone and estrogen to maintain the pregnancy until the placental production of these two hormones takes over adequate production levels. If a pregnancy does not occur then the follicle stops making progesterone and estrogen and a menses or period starts. This is how menstrual cycles work.

The menstrual cycle usually lasts from 24 to 36 days. The ideal for teaching purposes is 28 days with day 1 being when the first day of full menses. The first part of the cycle is called the follicular phase as this is when the follicle becomes bigger and the egg develops and matures inside of it. This phase is 14 days in the ideal cycle but can vary from 12-21 days in real cycles. Follicle development is driven by FSH. LH also is needed for an adequate follicular phase as it stimulates the outer cells of the follicle, the theca cells to produce testosterone which then moves or diffuses inward to the inner cell layers of the follicle called the granulosa cells. Here under the influence of FSH the granulosa cells transform the testosterone into estrogen. The estrogen stimulates the endometrium to grow until ovulation or release of the egg occurs. The LH levels go way up or surge when the follicle is mature and causes the egg to be released from the follicle into the fallopian tube, hence ovulation. This "LH surge" is detected by ovulation monitoring kits when the LH hormone passes into the urine. The follicle is called a corpus luteum after ovulation. After ovulation LH is needed to stimulate the follicle to make progesterone which transforms the estrogen primed endometrium into the secretory endometrium. This secretory endometrium is the key component of the secretory phase of the menstrual cycle. This phase is when the embryo attaches to the endometrium to establish a pregnancy. This phase lasts 12-14 days. If there is no pregnancy, estrogen and progesterone production ceases and a menses ensues within 1-2 days after the hormone levels drop. When a pregnancy occurs the human chorionic gonadotropin (hCG) produced by the placenta of the pregnancy stimulates the follicle or corpus luteum to continue progesterone and estrogen production until the placenta can sustain production by itself. Progesterone, as mentioned earlier, negatively feedbacks to the hypothalamus and does not let another ovulation to occur. Many contraceptives contain strong progesterone-like molecules that mimic the pregnancy state to inhibit ovulation.

FSH testing deserves special mention. Frequently your fertility specialist will check your FSH levels. Normal levels of FSH during your period are in the 4-7 uIU/mL range. A standard time to check FSH is day 3 of the cycle. It is considered abnormal if your levels are less than 2 or over 11 on day 3. Levels less than 2 occur when the HPO axis is under functioning. This can be from excessive exercise, weight loss or starvation, poor nutrition, extreme emotional distress, or in rare instances a tumor of the brain. Usually an evaluation to see the cause of this is warranted. In our laboratory an FSH level above 11 indicates what is called decreased ovarian reserve. In this situation your ovaries are not developing eggs/follicles in response to the FSH as normally happens. To compensate the pituitary increases the amount and pulses of FSH to drive follicle development and is detectable in the blood stream. This situation is associated with fewer eggs and decreased success rate with fertility treatments using your own eggs.

### Testis

The male testicle is comprised of seminiferous tubules, Sertoli cell, and Leydig cells. Sertoli cells are support cells outside of the seminiferous tubules that support the spermatogonial germ cells to make sperm and protect the sperm from the immune system of the male. Leydig cells or testosterone producing cells are outside and next to the seminiferous tubules. LH stimulates the Leydig cells to make testosterone. The seminiferous tubule is comprised of a basement membrane that encircles the spermatogonia and lumen of the tubule. Spermatogonial germ cells line the inside of the seminiferous tubules and give rise to spermatocytes (immature sperm cells). The spermatocytes then work their way inward to the inside of the seminiferous tubule as they mature. Myoid or muscle type cells outside of the seminiferous tubule move the free mature sperm from the lumen toward the epididymis where long term storage takes place until mature sperm are released at ejaculation. The seminal vesicles add fluid to the sperm cells at ejaculation to form the ejaculate (sperm cells and fluid). FSH and testosterone together stimulate the Sertoli cells to support spermatogenesis. Taking androgen supplements (DHEA, androstenedione, or hCG) or testosterone to body build or to increase libido will decrease spermatogenesis to very low levels. We have seen men on androgen supplements that have zero sperm production. Stopping these supplements allow the sperm counts to return to the man's normal levels. Please tell your physician if you are on any type of supplements or hormones so they can determine if they will affect your fertility.

### Thyroid gland

The thyroid gland is responsible for metabolism of the body at the cellular level. Almost all of the body's metabolic processes or functions require thyroid hormone for metabolism but also development, steroidogenesis, and specific tissue activities. The thyroid gland is located just below the Adam's apple or cricoid cartilage and is comprised of a left and right lobe. For unknown reasons thyroid disease is 8-10 times more common in women 190 The Fast Track to Fertility: Second edition than men. This may be because women are more susceptible to autoimmune diseases possibly related to the female hormonesestrogen and progesterone. As we currently understand thyroid diseases are mainly autoimmune in nature. The goal for clinicians is to diagnose and treat thyroid disease before it becomes significant. Thyroid screening is easily done now with highly sensitive or ultra sensitive TSH testing.

Normal thyroid function as mentioned earlier involves the hypothalamic pituitary axis. Thyrotropin releasing hormone (TRH) is released from the hypothalamus to the anterior pituitary where it releases thyroid stimulating hormone (TSH). TSH in turn helps iodide to enter the thyroid gland cells in the thyroid gland. Within the thyroid gland iodide is oxidized to iodine, which is then bound to thyroxin. Combinations of thyronine with one iodine and two iodine atoms then join to form thyronineT3 (containing three iodines) and thyroxine T4 (containing four iodines). TSH also causes release of T4 and T3 from thyroid storage into the circulation. T3 is the active hormone in the body. Thirty percent of T4 is converted into T3. As you can see there are many different thyroid related hormones that can be measured by blood testing. Fortunately, testing technology has improved that we can measure very low levels of TSH. TSH is the only the only blood test that we need to screen for normal, high or low thyroid function. In the typical assays if the TSH level is high, the TSH levels are greater than 4.5 uIU/mL and this signifies low thyroid function or hypothyroidism. When thyroid function is high, the anterior pituitary release of TSH goes down and the levels drop below 0.4 uIU/mL.

### Hypothyroidism

Hypothyroidism develops commonly in women. Symptoms of hypothyroidism include fatigue, weight gain, and dry skin, irregular or absent menstrual cycles and lethargy. The etiology of hypothyroidism is not known in most cases. Most cases of hypothyroidism are thought to be autoimmune in nature. When an enlargement of the thyroid gland occurs it is called a goiter. When this happens due to autoimmune causes it is called a Hashimoto's thyroiditis. Hypothyroidism can cause miscarriages, recurrent miscarriages and has been associated with lower IQ levels in children born from pregnancies with untreated or under treated hypothyroidism. Screening for hypothyroidism is done by checking at TSH level. In almost all cases this will be elevated to above 4.5. Values can be as high as 100. A full thyroid panel will then show a low total T4 and free T4.

Subclinical hypothyroidism is the situation when the TSH levels are high but the T4 level is normal. Subclinical hypothyroidism is present in 4-8.5% of adults and the incidence increases with age. Treating these patients decreases the chances of goiter, helps the patients feel better physically and mentally, improves cognitive function and increases children's IQ scores when pregnant women are treated.

The treatment of hypothyroidism and subclinical hypothyroidism is simple with synthetic thyroxine (T4). The initial daily does is usually fifty micrograms daily. After four weeks of therapy the TSH blood test is repeated. The target range is 0.45 to 2.50 uIU/mL. Once the goal has been met the patient needs to be rechecked every six to twelve months. When patients become pregnant the TSH levels need to be monitored every trimester as the increased body weight may increase the amount of medication needed to maintain a euthyroid or normal thyroid state. Frequently your physician will automatically increase your total dose of thyroid supplement by having you take two extra doses each week when you first find out that you are pregnant and then retest your TSH levels.

### Hyperthyroidism

Hyperthyroidism is when the thyroid function is higher than normal by releasing too much thyroxine (T4). There are two primary causes of hyperthyroidism: Plummer's disease (toxic nodular goiter) and Grave's disease (toxic diffuse goiter). Plummer's disease is usually found in post-menopausal women who have had a long history of goiter. Postmenopausal women frequently present with only cardiovascular symptoms such as atrial fibrillation and goiter. Reproductive age women present with the following symptomsnervousness, disturbed sleep, weight loss, sweating and palpitations or irregular heart beat and diarrhea. Grave's disease is caused by autoantibodies that behave like TSH to cause overproduction of T3 and T4. Grave's disease is confirmed when TSH receptor antibodies are found in the bloodstream. The menstrual cycles of women with hyperthyroidism can vary from long to none. In this condition TSH levels are very low and T4 and free T4 levels are increased.

The treatment of hyperthyroidism is usually radioactive iodine. The radioactive iodine is used in non-pregnant patients. The radioactive iodine is taken up by the thyroid and kills thyroid cells. Some women opt for surgical removal of the thyroid gland instead. Eventually both treatments will require treatment for an under functioning thyroid-hypothyroidism. Women with thyroid nodules need evaluation to make sure that the nodules are not cancerous. This usually involves sampling the nodule with a small aspiration needle and radioactive iodine uptake tests. If cancer is found then thyroid gland removal is performed. Patients with hyperthyroidism during pregnancy are initially treated with propylthiouracil (PTU). This drug prevents iodine uptake in the thyroid and decreases the production of T3 and T4. Some pregnant patients with hyperthyroidism will present with nausea and vomiting.

### Prolactin Disorders

Prolactin is produced in the anterior pituitary. Dopamine is produced in the hypothalamus. It is released into the portal circulation and suppresses the secretion of prolactin into the general circulation. There is no known prolactin releasing factor in humans.

During pregnancy prolactin levels rise from the normal levels of 10-25 ng/mL to a high of 200-400 ng/mL at term. Although prolactin stimulates breast growth, only colostrum is produced during pregnancy. Full lactation is inhibited by progesterone. The hormonal trigger to allow prolactin to stimulate milk production is the disappearance of progesterone and estrogen from the circulation after child birth.

After delivery prolactin stimulates the production of casein, the primary breast milk protein, lactose and lipids. Three to four days after delivery, milk secretion and breast enlargement occur. Prolactin levels drop by fifty percent during the first week postpartum. The infant suckling at the breast causes a prolactin spike which initiates milk production and release. Breastfeeding continues milk production by continuing an increased baseline prolactin level and each suckling episode produces a two fold increase above baseline levels of prolactin that continues milk production. Suckling also causes the posterior pituitary gland to release oxytocin. Oxytocin makes the muscle cells surrounding the alveolus to contract leading to milk let down and ejection. Lactation is discontinued when suckling stops.

### Inappropriate lactation-galactorrhea

When the breast secretes a milky fluid not related to pregnancy or lactation it is called galactorrhea. Galactorrhea should be evaluated in a woman who has never had a child or a woman who is more than twelve months after a delivered pregnancy or twelve months after weaning.

An increase in prolactin levels is the main cause of galactorrhea. Dopamine is the inhibitory hormone for prolactin secretion. Many medications inhibit the hypothalamus from releasing dopamine. These include phenothiazines (phenergan type drugs), reserpine derivatives, amphetamines, opiates (narcotics), diazepams (valium, xanax type drugs), butyrophenones, verapamil, alpha methyldopa, and tricyclic antidepressants, and metoclopramide (Reglan).

Hypothyroidism can cause galactorrhea as TRH acts as a prolactin releasing factor to increase prolactin levels. Thoracotomy scars, breast surgery scars, cervical spinal lesions, and herpes zoster can induce prolactin release through nerve reflex pathways that simulate suckling. Similarly intense repetitive suckling can cause and increase in prolactin to cause galactorrhea. Trauma, surgery, and general anesthesia can cause milk production and release. Alterations of the hypothalamus such as tumors, pituitary stalk lesions and compression of the pituitary can cause increased prolactin levels leading to galactorrhea.

When a patient has galactorrhea they should have fasting prolactin and TSH blood tests. If the thyroid is abnormal it should be treated and the hyperprolactinemia should resolve and thus cause the galactorrhea to resolve. If the prolactin level is elevated it should be repeated. Minor elevations of prolactin can be treated with medication. If there is a significant elevation your doctor may want to order a test to study the pituitary gland. This test is either an MRI or a CT scan. Lesions can be treated with dopamine like drugs such as cabergoline (Dostinex), Permax (pergolide), and bromocriptine (Parlodel). Rarely a prolactin producing tumor may require surgical excision. Medical treatment will typically resolve the milky breast discharge and restore regular menstrual cycles and ovulation. Pregnancy will soon hopefully follow.

### The Adrenal Gland

The adrenal glands are small pair of glands that adhere to the upper poles of each kidney. They mainly secrete cortisol, corticosterone, aldosterone and small amounts of androgens. Aldosterone regulates blood volume, blood pressure, and the sodium potassium balance of the body. The adrenal corticosteroids regulation occurs through the hypothalamic pituitary adrenal axis. Corticotrophin releasing hormone (CRH) produced in the hypothalamus and released in to the portal vessels stimulates the release of adrenocorticotropin (ACTH). ACTH in turn cusses the release of corticosteroids. The corticosteroids negatively feedback the release of CRH and ACTH.

Cortisol increases in the blood stream have major effects on the body. Cortisol causes blood volume expansion and a blood pressure increase. With excessive corticosteroid production cell mediated immunity is impaired leading to impaired inflammation and wound healing. This is how prednisone works to decrease inflammation and pain, but makes you prone to infection when you take it.

When there is inadequate secretion of corticosteroids by the adrenal gland it is called adrenal insufficiency or Addison's disease. This can be a result of insufficient secretion of ACTH or destruction of all or part of the adrenal glands.

Cushing's syndrome results from excessive amounts of glucocorticoids or cortisol. The main cause is the use of glucocorticoid drugs for the treatment of non-endocrine diseases. Cushing's disease refers to adrenal hyperplasia resulting from excessive secretion of pituitary ACTH. This is responsible for seventy to eighty percent of Cushing's syndrome cases.

When a patient is suspected of having Cushing's syndrome the usual screening test is a twenty four hour urine collection to measure the amount of cortisol excretion into the urine. If this is abnormal then other tests can be performed such as dexamethasone suppression tests, serum ACTH measurements, and CT or MRI scans of the adrenal glands, pituitary gland and hypothalamus. Treatments will be based on the etiology found.

### Congenital Adrenal Hyperplasia

There are steroid production enzyme defects that are responsible for increased or decreased steroid production. More severe enzyme defects are called congenital adrenal hyperplasia (CAH) and can affect the development of a fetus and cause birth defects of the external genitalia, penis, clitoris, vagina, and vulva. Enzyme defects that are less severe are called late onset adrenal hyperplasia (LOAH) as their effects are not usually exhibited until puberty when the adrenals start producing increased amounts of hormones. The most common enzyme defects that are of concern can cause increased androgen production, irregular menstrual cycles or no menstrual cycles. These defects can also cause excessive hair growth and acne. Proper identification and treatment may restore fertility and prevent offspring from abnormal genital development. The most common enzyme deficiency is 21 hydroxylase deficiency and can be screened for with a serum seventeen hydroxyprogesterone level. The treatments for these types adrenal hyperplasia involve the use of corticosteroids to decrease the adrenals' production of the excessive hormones.

The endocrine systems discussed above are involved in the control of reproduction. There are more complex interactions which involve the above systems which are beyond the scope of this chapter. The higher brain, hypothalamus, pituitary, and ovaries regulate egg production and the menstrual cycle. The hypothalamus, pituitary and testicles regulate sperm production. Together these two systems form the essentials of human reproduction. The thyroid gland, adrenal glands and prolactin system help the testicular and ovarian systems with their vital functions. Now you understand the basic endocrinology of the menstrual cycle, spermatogenesis and fertility. This side track on your fertility journey has allowed you to appreciate the beauty of the endocrinology of fertility and understand how it all works together. Now you are ready to get back onto the fast track to fertility.

# Chapter 14  
Miscarriage and Recurrent Pregnancy Loss

While most of this book focuses on conceiving, many patients with infertility may also suffer from one or more miscarriages. A miscarriage is a true loss for a couple, and its emotional and physical impact should not to be underestimated, especially in couples who may have been trying for years to get pregnant. This chapter deals with the subject of miscarriage and its appropriate workup and treatment.

A miscarriage occurs when a pregnancy is lost less than 20 weeks from the last menstrual period. Losses after this time period are considered births, even if the baby is not born alive or dies soon after delivery. Miscarriages are extremely common. About 20 percent of all pregnancies will end in a clinical miscarriage. That doesn't even include all the early losses which we call biochemical pregnancies that occur before a pregnancy sac forms in the uterus. These biochemical pregnancies are typically recognized as a delayed menstrual period in women with normal cycles where the pregnancy test is slightly positive for a few days followed by spontaneous menstruation.

A true miscarriage typically will occur between 6 and 20 weeks of pregnancy. For a miscarriage to occur, a clinical pregnancy must first be established. A clinical pregnancy is one in which an examination reveals an enlarged uterus or a pregnancy sac is seen in the uterus by ultrasound. These definitions may seem a bit narrow, but it is important to understand that biochemical pregnancies are even more common than miscarriages. It is estimated that as many as 60 percent of all early identified pregnancies end in biochemical losses. Biochemical pregnancies are not abnormal. For that matter miscarriage is not abnormal. Both are nature's way of not letting an abnormal pregnancy continue to result in an abnormal birth. Both processes can be nature's way of increasing your chance of having a healthy baby.

If you have ever had a miscarriage, you have undoubtedly wondered why it happened. Was it something you did or didn't do? Was it a medication you took? Does it have anything to do with level of activity? Most miscarriages are completely beyond the control of the couple or their physician, and they occur spontaneously because of chromosomal or genetic problems existing within a particular fetus. An embryo or fetus with the wrong number of chromosomes is called aneuploidic. The most common aneuploidies involve either an extra chromosome that may not be compatible with life or a missing chromosome that is necessary for life. Some kinds of aneuploidy can still result in a live birth (examples are Turner's syndrome or Down syndrome), but many result in miscarriage. The vast majority of losses in which a fetus without a heart beat is seen on ultrasound are due to chromosomal errors.

The chance of a chromosomal error and miscarriage increases dramatically with the age of the mother. While the risk of miscarriage in the general population is about 20 percent, in women 40 or more years of age it is a staggering 40-50 percent! That is why we want you to try to get pregnant while you are younger, so you do not have to face these tough odds.

In addition to the age of the mother, other poorly controlled medical conditions such as diabetes, high blood pressure and asthma can increase the risk of miscarriage. Abnormalities or scarring of the uterus and cervix may pose anatomic risks for recurrent miscarriage. Also, if you or your partner carries a genetic abnormality such as a translocation (one piece of genetic material in an abnormal place), your risk is increased. Smoking, drinking and use of recreational drugs such as marijuana or cocaine can also increase the risk of loss. Caffeine can increase the risk of miscarriage. Most studies show that more than 200 milligrams per day needs to be consumed to significantly increase the risk of miscarriage. A serving of coffee, tea, or a caffeinated soft drink can contain up to 100 milligrams of caffeine. A common sense measure is therefore to limit your self to one or two caffeinated beverages per day. Rarely an infection can cause a miscarriage. Examples of infections associated with miscarriage include viral infections such as cytomegalovirus (CMV), rubella and measles. Sometimes bacterial infections such as Streptococcus or gonorrhea can cause a pregnancy loss.

Certain medications taken during the first trimester may also increase miscarriage risks. These include chemotherapy and some antiseizure drugs. Chemical substances in the environment can also cause miscarriage. Some examples are lead, which is found in car batteries, and formaldehyde, arsenic and radiation. Age of the father is also a risk factor, although to a much lesser extent than age of the mother. If you have had two or more consecutive miscarriages, your risk of miscarriage is also increased, and you may want to seek help from a reproductive endocrinologist before trying to conceive again.

**How do you know if a miscarriage is happening?** Heavy bleeding and uterine cramping are the most common signs of an impending miscarriage. Bear in mind, though, that light bleeding or spotting coupled with mild uterine cramps are very common in early pregnancy and usually do not progress to miscarriage. Less commonly, bleeding and cramping in early pregnancy can be a sign of tubal or ectopic pregnancy. With ectopic pregnancy the pain is often on one side of the abdomen and is more severe.

It is usually not possible to know immediately what type of pregnancy is occurring in the face of cramping and bleeding. Blood tests can diagnose pregnancy at the time of missed menses. Two weeks later an ultrasound can see an early six-week pregnancy in the uterus. The risk of miscarriage will drop after we see the fetal heart beat on ultrasound. This is usually seen six to eight weeks after the last menstrual period. If you think you are miscarrying, call your doctor. In most cases he or she will see you as soon as is feasible and perform an exam and an ultrasound and possibly blood tests to evaluate your situation. If you show signs of miscarriage your doctor may ask you to reduce activity, although it is not clear that this will reduce your chance of losing the pregnancy. Most practitioners will also ask you to abstain from intercourse during this time. Tylenol is the most commonly prescribed medication to treat the cramping pain.

What are the treatment options if I know my pregnancy is not progressing but I have not miscarried?

There are basically three treatment options for women who have been diagnosed with a nonviable pregnancy in the uterus but have not passed the fetal tissue yet. The first option is expectant management. In other words, we do nothing and wait one or two weeks to see if your body naturally expels the tissue. If more than two weeks go by without bleeding, then some other treatment may be warranted.

Some women elect to have medical therapy. Hormones that are often used to induce labor in women who go past their due date can also be used to help induce the body to expel the fetal tissue once we are positive that the pregnancy is not progressing. These tablets are usually taken vaginally and can be very effective within one or two days of initiating treatment. After either a natural or an induced miscarriage, a physician should examine you to make sure the uterus is completely emptied.

Finally, some women will opt to have a D&C (dilatation and curettage). This is a surgical procedure in which the cervix is gently dilated and the uterus is emptied using a suction instrument. This is often done under general anesthesia, but can also be performed with mild sedation and a local anesthetic block placed in the cervix. The advantage of the D&C is that it spares the patient the pain of heavy bleeding and cramping associated with a natural miscarriage. A D&C can also be scheduled so that the event occurs at a predictable time. Disadvantages to the D&C include the minor risks of anesthesia or surgical complications such as injuring or scarring the uterus. These complications probably occur in less than 1-2 percent of cases. If a D&C is performed it is now common to get chromosome studies on the miscarriage material. This can give important clues as to the cause. The most common cause of a miscarriage is an incorrect number of chromosomes when the egg and sperm are united. A missing chromosome is called a monosomy. The most common such monosomy causing miscarriage is Turner's Syndrome (45X). An extra chromosome is called a trisomy. The most common trisomies causing miscarriage are of chromosomes 13, 16, 18 and 21. Trisomy 21 is called Down Syndrome. Chromosomal errors of this type become increasingly common after the maternal age of 35 and account for the increased chance of miscarriage in this age group.

After any type of miscarriage or ectopic pregnancy, you may need a shot of Rhogam if your blood type is "Rh negative" (e.g. O negative, A negative, etc.). This shot will help prevent complications in future pregnancies related to potential incompatibilities in blood types between partners. Following a D&C or natural miscarriage, you can expect your menstrual period to restart within six weeks if you had regular periods prior to conception. Your menstrual cycles will then resume their normal pattern.

**When can you try to get pregnant again?** The length of time you should wait before trying to conceive again may depend on the type of miscarriage, how it was treated, or if there were any complications. Most couples, however, can resume their conception efforts after one to three cycles. You should discuss this with your doctor, as it will vary from case to case.

**Does having one miscarriage increase the risk of future miscarriage?** The answer in most cases is no! Miscarriage is a common part of human reproduction. That is not to say that experiencing a miscarriage is easy. It is a miserable, depressing experience. The good news after a miscarriage, however, is that you did manage to conceive. This usually means that the reproductive system is working to a certain degree. If you have had two or three consecutive pregnancy losses, then your risk of future miscarriage may be increased, and a workup should be contemplated. Even if you have had three consecutive miscarriages, your chances of a future live birth are still almost 70 percent. The glass is definitely more than half full!

**What is the evaluation for recurrent miscarriages?** If you have experienced more than two or three consecutive pregnancy losses, your physician may recommend doing an evaluation to identify certain treatable risk factors. A study of the internal structure of the uterus should be performed, either through an x-ray of the uterus (hysterosalpingogram or HSG) or a sonohysterogram, which is an ultrasound done after instilling fluid into the uterine cavity. In some cases there is a deformity in the uterus, such as a wall or septum inside the uterus or a double uterus.

Some deformities of the uterus are imaged below:

Normal uterus

Unicornuate uterus

Double or didelphic uterus

Septate uterus

Bicornuate uterus

If there is a septum or scarring in the uterus, then surgery performed as an outpatient (hysteroscopic surgery) can be used to correct this (see Chapter 7). The greatest benefit in repair is with the septate uterus. Studies in patients with a septate uterus have shown that, before surgery about 70 percent of all pregnancies are miscarried while after surgery only 30 percent are lost to miscarriage. It is not possible to enlarge the unicornuate uterus, and a didelphic uterus can rarely be repaired.

In addition to examining the structure of the uterus, your doctor will likely order some blood tests. Checking the chromosomes (the genetic structure of the cells) of the male and female can be helpful. In some cases, one member of the couple may have a piece of one chromosome that has shifted to another area of the gene structure. This is called a translocation and can increase your risk for miscarriage. If you have this condition, it is possible to do _in vitro_ fertilization and test the embryo's genetic makeup by a process called preimplantation genetic diagnosis (PGD). This process is described in the section on _in vitro_ fertilization in Chapter 8. Also as indicated above chromosomal testing of the miscarried material can be informational. This is usually done during the second or third miscarriage.

Other common testing may screen for immunologic problems in the female partner. Antibodies to phospholipids can disrupt an early pregnancy. Testing for this includes: lupus anticoagulant, anticardiolipin antibody, and beta 2 glycoprotein 1 antibodies.

Rarely clots that form in the bed of the placenta can cause pregnancy loss, especially after 12 weeks. Testing for blood clotting disorders is complex, and only currently suggested if you have had a blood clot in the past or if you have a strong family history of blood clot formation. Some of the more common tests look for lupus anticoagulant, anticardiolipin antibody, Factor V Leiden, and the prothrombin gene mutation. If you have a clotting disorder you may need anticoagulation treatment (or blood thinners) during pregnancy. This is in the form of heparin, aspirin or other medications. Anticoagulation should be used only when there is a clear need because it carries with it an increased risk of bleeding.

Endocrine testing is also part of the evaluation of recurrent pregnancy loss. You may be screened for thyroid disease, diabetes, or high prolactin levels. Fortunately, except for the uterine testing, most of the workup simply involves blood work. For couples experiencing multiple losses, genetic or chromosomal testing of the fetal tissue may also be revealing. This is usually best accomplished at the time of a D&C. It is now suggested that at the time of a second miscarriage, if a D&C is performed, chromosomal studies of the pregnancy tissue should be obtained.

Ovulation problems can contribute to early losses which occur prior to 8 weeks. One such condition is called a luteal phase defect. Cycles can be shorter or longer than the average of 28 days. If this condition is diagnosed, treatment can be initiated with an ovulation inducing agent. Correction of this problem will dramatically improve outcome.

A newly recognized cause of miscarriage is reduced ovarian reserve. As the number of eggs in the ovary decreases, the quality also suffers. This results in longer times to conception and more observed miscarriages. An AMH level is an excellent screen for this. AMH levels of 1.2 or above are considered normal. Values below 0.3 are associated with reduced ovarian reserve.

In most cases, a specific cause of the miscarriage is not identified. Many women in this case may elect to take a baby aspirin that may help reduce inflammation or blood clotting tendencies. But take heart, even after repetitive miscarriages, many couples are still able to deliver healthy babies.

What is the treatment for recurrent miscarriage?

Once a diagnosis has been made, treatment can begin. Treatment is based on the identified cause. If the cause is a structural problem such as a septum, surgical correction can be utilized. If we have identified a problem with immune antibody such as anticardiolipin antibody or lupus anticoagulant, blood thinners such as heparin can be used. If an ovulation defect such as luteal phase defect is the cause, ovulation medication can be given. If no problem is isolated then you need to talk to your doctor about his/her suggestions and recommendations. Some physicians suggest a baby aspirin a day and others suggest you attempt to conceive while optimizing environmental factors. They suggest you take prenatal vitamins and eat a healthy diet while limiting negative factors such as caffeine, alcohol and smoking.

The good news: 70% of patients with a history of recurrent pregnancy loss will go on to experience a live birth! This statistic means that there is more hope for success than most people think.

# Chapter 15  
Third Party Reproduction:  
Donor Eggs, Donor Sperm, Donor Embryos, Surrogacy, and Gestational Carriers

As you have read throughout this book, you have learned that there are multiple options when it comes to fertility treatments. While pregnancy success rates have improved dramatically over the last decade, more conventional fertility treatment may provide little or no hope of successful conception and delivery for certain patients. For these patients, or for those for whom conventional therapy has failed, the Fast Track to fertility may involve help from both your doctor and another special volunteer.

### Donor Eggs (Oocyte Donation)

The age of the female partner is probably the single most important factor in determining delivery rates in couples undergoing fertility therapy. Most fertility therapies (including _in vitro fertilization_ ) have a relatively low success rate for women over 42 using their own eggs. In addition to decreased pregnancy rates, miscarriage rates increase dramatically in women in their late 30's and early 40's. Even in women who do manage to get pregnant and get past the initial miscarriage risk, the risk of chromosomal or genetic problems like Down syndrome in the live born infants soars when using their own eggs.

Most of these discouraging trends are related to the quantity, the quality or the health of the eggs (oocytes) available in women as they age. As the DNA within the oocytes starts to break down, the function of the eggs suffers dramatically. Most people are amazed to learn that a woman has the maximum number of eggs she'll ever have (around 6 to 7 million) by 20 weeks gestation as a fetus. By the time a baby girl is born, the number of eggs has dropped through a natural process of attrition to around 1 to 2 million. By puberty, this number declines even further to approximately 300,000 eggs, of which only 400 or 500 will typically be released at ovulation over the course of a normal reproductive life. Menopause is reached when this egg pool is depleted. Although the average age of menopause in this country is around 52, reproductive function falls off long before menopause. Surprisingly, about 1 percent of normal women reach menopause before the age of 35.

The following are some common situations where egg donation is beneficial:

  1. women who are in their 40s

  2. younger women who do not respond well to even aggressive ovarian stimulation protocols

  3. IVF patients who have failed treatment because of relatively poor quality eggs or embryos

  4. patients who have lost ovarian function

  5. patients who have had their ovaries removed for cysts or tumors

  6. patients who have reduced ovarian reserve following chemotherapy or radiation

  7. those patients who were born with reduced ovarian function (for example Turner's syndrome patients), women with genetic diseases, and for other women with medical risk factors preventing ovarian stimulation

During oocyte donation, a volunteer egg donor is matched with the intended mother. The donor may be anonymous or known. A known donor can be a friend or a relative such as a sister or step sister. An anonymous donor can be recruited by the center or through the use of a donor broker. Both the intended mother (called the "recipient") and the egg donor are then given medications to temporarily suppress their menstrual cycles until they are synchronized together. Following that, the egg donor undergoes ovarian stimulation and egg retrieval just like any other IVF patient. On the day of egg retrieval, the eggs are fertilized in the laboratory using the intended father's sperm. Meanwhile, during the donor's stimulation treatment, the recipient takes a simple combination of estrogen and progesterone hormones to make the uterus receptive to the embryos and ready for implantation. Sometime between two and six days after fertilization, an agreed upon number of embryos (usually one or two) are transferred to the recipient's uterus, where they will have a chance to implant and grow. The recipient will then stay on estrogen and progesterone supplementation until the placenta begins to secrete adequate amounts of hormones at about eight or nine weeks of gestation.

While the physical medication regimen is actually much less demanding on a recipient than a traditional IVF cycle, the process of oocyte donation is a difficult one for some women to accept, since the resulting child will not have their genetic contribution. However, it is important to point out that the recipient will still have the gestational relationship with the baby, while her husband will still have the genetic relationship with the resulting baby. In addition the recipient mother will still exert epigenetic control over the genetic activity of the fetus. Epigentic control is a process where the recipient will activate and deactivate certain genes which are present in the fetus. The recipient physical and emotional state has a huge impact over fetal development through this system of biologic control. The recipient will also still be pregnant, nourish the baby in the womb, go through labor and delivery, and be able to breast-feed the child naturally. No one will ever know that the couple has elected to use egg donation unless they choose to disclose this to family and friends. We have had literally hundreds of babies born through our practice with oocyte donation, and, over the years, no couple has ever returned to us and said they felt that their baby was anything less than 100 percent theirs together as a couple.

While adoption is a great option for many couples, oocyte donation has several potential advantages such as the genetic and gestational relationships described above, a reduced risk of having a birth couple change their mind at the last minute, and recipient control over the prenatal situation. Once pregnant, an ovum recipient knows she is not smoking, not using drugs, not having multiple partners, and is going to her prenatal visits. The level of control over the pregnancy course is much greater than with adoption. Also of note, for many couples one to two cycles of oocyte donation may actually be less expensive than the entire adoption process.

Challenges with oocyte donation include the fact that there are more potential recipients than volunteer donors; so sometimes waiting for a donor match can take time. But oocyte donation constitutes such a growing percentage of the IVF procedures done in this country that agencies that help recruit and screen donors are available all over the country. Care must be taken to work with a very reputable agency in this burgeoning field. The federal government through the FDA regulates donor screening carefully, so the egg donor is screened for infectious diseases, drug use, personality disorders, and genetic diseases.

Cost can also be a barrier for some couples, as oocyte donation can be expensive. However, keep in mind that oocyte donation may be your most _cost effective_ way to stay on the Fast Track to fertility. If you are 42 years old, one $18,000 egg donation cycle will probably give you a higher healthy delivery rate than four combined cycles of IVF using your own eggs at $9,000 per cycle ($36,000 total).

The dramatic improvement in outcome for reproductively older women electing to undergo egg donation can be seen in the figures below, which are reported by the federal government and represent data from over 400 fertility centers around the United States. As you can see, live birth rates for women over 40 using their own eggs plummet to less than 10-15 percent per cycle, while live birth rates for women in their 40s using egg donation skyrocket to 50-60 percent.

As can be seen below the miscarriage rate increases dramatically with age. This contributes negatively to the overall birth rate.

As can be seen below once donor eggs are utilized the live birth rate returns to high levels. The data shows that the chance of live birth with donor egg is the same whether you are a 30 year old woman with premature ovarian failure or a 47 year old woman with premature menopause!

In addition to the increase in pregnancy rates, egg donation offers the advantage of a markedly diminished rate of miscarriage or genetic birth defects. At age 44, the risk of miscarriage in an IVF pregnancy generated from a woman's own eggs is approximately 70 percent. With pregnancies resulting from oocyte donation, the miscarriage risk goes back to the age of the egg donor. Since most donors are under 32 years old, this risk usually drops to less than 15 percent. Also, the risk of a genetic or chromosomal disorder for a woman who conceives using her own eggs at the age of 44 is about 1 in 26 overall, and about 1 in 38 for Down syndrome. The same risk for a woman conceiving with eggs donated from a 20 year old falls to approximately 1 in 500 overall, and about 1 in 1,600 for Down syndrome. As can be seen, oocyte donation is a clearly superior option for many women!

At the time of the writing of this book, the vast majority of donor egg cycles are done with "fresh" IVF as described above. However, many centers are beginning oocyte cryopreservation (egg freezing) programs. This technology will allow for the creation of "egg banks," just as sperm banks are currently available. Such banks have the potential to make oocyte donation cycles more time and cost efficient for the recipient couples. Only mature eggs should be frozen. Not every frozen egg will survive thaw and fertilization. If frozen eggs are used a group of 5-6 are typically utilized. The cost of obtaining eggs from and egg bank is high.

Egg freezing is also helpful for those patients who may need to undergo chemotherapy or radiation that may destroy their ovarian function before they have completed their families. It may also be applicable to "fertility extension," the practice whereby young women freeze their young eggs with the thought that they may eventually want to have children and would have access to their eggs at a later date. But this technology is still new, and the outcomes are still very limited compared to fresh IVF.

### Sperm Donation

Male factor infertility accounts for 40-50 percent of infertility in this country. The advent of ICSI (intracytoplasmic sperm injection; see Chapter 8), has revolutionized the care of the couple with male factor infertility and has allowed men to be the biologic father of their own children in cases that would have been considered hopeless ten to fifteen years ago. Outstanding pregnancy rates can even be achieved for a select group of men with no sperm at all in their ejaculate. Despite these recent advances, some couples may elect to pursue sperm donation as the best option when trying to conceive.

Unlike eggs or oocytes that have a very high percentage of water for their size and are therefore vulnerable to the formation of ice crystals when freezing and thawing, sperm freeze extremely well. Therefore, there are literally hundreds of FDA approved sperm banks from which sperm can be readily purchased online and shipped directly to the office of your fertility specialist for use with insemination. Frozen donor sperm is thawed and then inseminated right when ovulation is predicted to occur. Ovulation may be monitored by urine predictor kits or more accurately by ultrasound and the use of an ovulation triggering injection.

Insemination may be performed in several different ways. Intravaginal insemination just places the sperm inside a woman's vagina. This is typical of the "do it yourself" home kits that some couples elect to try. Placing the sperm inside a cervical cap or diaphragm that is then left in place against the cervix for several hours comprises a cervical insemination. Sperm can also be injected into the cervical canal, a process called intracervical insemination. The most effective type is an intrauterine insemination, or IUI (see Chapters 6 and 10), during which the sperm is actually injected into the very top of the uterus, right near the openings of the fallopian tubes. Remember, fertilization normally takes place inside the fallopian tube, so this gives the sperm a big head start in the right direction. Only a health care provider can safely perform IUI.

Good candidates for sperm donation include couples in whom the man has no sperm at all available either in the ejaculate or in the testis, post-vasectomy men who do not wish to undergo a sperm retrieval or vasectomy reversal procedure, couples with male factor for whom IVF is not a reasonable ethical or financial option, men who have been left sterile following chemotherapy, radiation, or injury, as well as women without a male partner who wish to conceive. Some couples in which the man carries a serious inheritable disease that is not amenable to preimplantation genetic diagnosis may also elect to pursue donor inseminations to avoid passing on the disease to their offspring.

The FDA also regulates sperm donation, so certified sperm banks have uniform procedures for screening their donors for genetic and infectious diseases. Some sperm banks separate their donors based on profession or educational achievement in addition to ethnic background, and some even provide online photo matching services between the donor and intended father.

Donor insemination is relatively easy and significantly less expensive than _in vitro_ fertilization for many couples, but it is less efficient. Whereas almost 50 percent of young women may conceive from a single IVF process, four to six attempts is a realistic time frame in which to expect pregnancy even in young healthy women undergoing insemination therapy. However, if insemination is performed using a woman's own menstrual cycle without any additional fertility medications, there is no increased risk of multiples or side effects. Donor insemination is a rewarding and successful option for many, many patients. One word of caution to single women who want to conceive with donor sperm: don't wait until you're 40!! Act now and get on the Fast Track to fertility before it's too late!

### Donor Embryos

The vast majority of couples undergoing therapy with in vitro fertilization will use all of their fresh and frozen embryos in efforts to complete their own families. However, as success rates with IVF steadily progress, some couples may find that they have completed their families and still have excess frozen embryos from prior treatment cycles. Many of these couples will elect to donate their embryos to another infertile couple for embryo adoption. Just like traditional adoption, this may be performed in either an open or anonymous setting.

Embryo adoption is a tremendous opportunity for many couples that otherwise may not be able to afford IVF or may not be good candidates for IVF. It is also a great opportunity for couples considering using both donor eggs and donor sperm. Preparing the uterus for implantation with donated embryos can be a very simple process involving a minimum of medications and no injections at all for the embryo recipient.

Typically the adopting mother will take oral estrogen and progesterone supplementation to prepare the uterus for embryo transfer. Frozen embryos are then thawed and transferred to the uterus in an outpatient setting. Pregnancy rates will vary depending on the age of the biologic donating woman and both the number and quality of the embryos transferred, but they are typically several times higher than those achieved with insemination therapy. The number of embryos transferred is usually limited to two or three. Embryo adoption not only allows many couples to have a unique chance at conception, but it also allows the donating couple to make a loving contribution with their extra embryos.

### Surrogacy

True surrogacy occurs when one individual woman serves as both the egg donor and the gestational pregnancy carrier for a second woman who is the intended parent of the resulting child. This arrangement is relatively uncommon, since the true surrogate has both a genetic and gestational link to the resulting child. This can make legal matters complicated for the intended parents in many states. Nonetheless, true surrogacy is a very viable option for many couples that want to have a child but are unable to do so because of medical conditions making ovarian stimulation or pregnancy unsafe for the intended mother.

True surrogacy is typically accomplished through natural cycle insemination. The surrogate is monitored for ovulation, and she is inseminated with the intended father's sperm close to the time of egg release. This process may be made more efficient by combining insemination with ovarian stimulation or even IVF with the surrogate. Pregnancy rates will depend on the method employed and the age of the surrogate, but are usually excellent. In order to avoid the potential legal and psychosocial issues resulting from true surrogacy, many couples elect to pursue oocyte donation with one volunteer combined with a second volunteer gestational carrier.

### Gestational Surrogacy

A gestational carrier (also known as a gestational surrogate) is a woman who undergoes embryo transfer with embryos generated from the intended parents' IVF cycle and then carries the resulting pregnancy for the intended parents. This may be a volunteer friend or family member, but may also be a paid surrogate arranged through an agency or legal office.

The preparation and technical aspects of the process are identical to those described above for oocyte donation. In this circumstance, however, the intended mother is the egg donor and the carrier is the recipient. The most common indication for gestational surrogacy is a medical condition that would make pregnancy very risky for the intended mother (e.g. uncontrolled diabetes, severe kidney disease, or significant heart disease). However, some women with recurrent miscarriages, repetitive preterm labor or delivery, or recurrent pregnancy complications may choose to pursue surrogacy to improve their reproductive outcomes. This therapy is also appropriate for women with structural problems of the uterus or those who still have their ovaries but had to undergo a hysterectomy (e.g., for fibroids or cervical cancer or dysplasia).

Pregnancy rates for gestational surrogacy can approach or exceed those for oocyte donation in young women with no history of infertility, but will be more limited by age for intended mothers in their late 30s or early 40s.

### Conclusion

After reading this chapter, you may realize that one or a combination of these third party reproductive choices may be your best fertility option. But keep in mind that some techniques may require several months to accurately arrange and initiate. If you think that you will be best served buy one of these options, then stay on the Fast Track and ask your fertility specialist to start the process now!

# Chapter 16  
Sex Selection/ Family Balancing

Most couples reading this book are extremely eager to conceive and would be thrilled at the prospect of having a baby, regardless of the gender of their new family addition. However, some couples have been fortunate enough to conceive and deliver more than one healthy baby, sometimes of the same sex. Many of these couples, as well as couples who have a family or genetic tendency for severe inheritable diseases that are linked to gender, may be seeking methods to attempt to conceive a baby of one particular gender or the other. The politically correct and ethically less-charged name for tipping the odds with these processes is "family balancing." It is also known in the community as "gender selection" or "sex selection."

Now, two of the authors has been extraordinarily blessed with three children of the same gender (one of us has three girls, the other has three boys), and neither of us could be happier with our completed families. But we do understand that some couples, especially those with inheritable diseases, may strongly desire to "gender balance" their family. Since eggs will normally always contribute an X chromosome to the equation, the genetic gender (XX for a girl or XY for a boy) is determined at the time of fertilization by the DNA message being carried by the sperm. Sperm carrying the X chromosome will generate a female embryo. Sperm carrying the Y chromosome will generate a male embryo.

Aristotle is believed to have recommended cutting off the left testicle when trying to conceive a boy and the right testicle for a girl. While we certainly don't recommend anything quite so drastic, dozens of "natural" methods that do not involve any medical intervention have been promoted to help conceive a child of a specific gender. Most of these have little or no clear proof to suggest that they work. For couples choosing gender selection in order to avoid a fatal inheritable disease, none of these "natural" methods is effective enough to risk using, and we strongly recommend against any of them for that indication. For other couples _without fertility concerns_ that are interested in trying something without resorting to medical interventions, these methods may be worth trying. After all, they're bound to work about half the time!

For couples that want demonstrated and proven methods to pursue a gender-specific pregnancy, there are effective and safe procedures widely available, especially for those with inheritable genetic diseases. Specifically, Microsort and preimplantation genetic diagnosis (PGD) will be discussed. Since none of these methods are foolproof, however, it is important to keep in mind for family balancing that no pregnancy should be attempted unless you are ready and willing to lovingly accept a healthy baby of either gender into your family.

### Natural Methods

Most of these methods are free, noninvasive, and can be used in the privacy of your own home. Lots of anecdotal stories and web- or magazine-based hype exist about these methods, and everybody has a friend who swears by one of them. Unfortunately, despite the hype, there are few if any good data to suggest that any of these methods are very effective at gender selection. Some rely on astrology or diet, but most rely on the specific timing of intercourse in relation to ovulation to sway the odds for a "pink" or "blue" conception.

Many couples turn to the Chinese calendar found online, in the back of women's magazines, or in lay pregnancy books to help pre-determine the gender of a pregnancy. This method utilizes a woman's year of birth as well as the month of conception to predict the gender outcome of the pregnancy. While many women use this method to try to predict the gender of an existing pregnancy, it has also been used to time the month of conception to attempt to sway the odds. We know of no good data to support the utility of this method.

Many maternal dietary adjustments have been tried in an effort to change the chemistry of the egg as well as to alter the acid environment of the vagina to make it more or less hospitable to sperm in an effort to promote conception of either a boy or a girl. These may include diets high in potassium and sodium to improve the chances of a Y-bearing sperm (male) or diets high in calcium and magnesium to improve the chances of an X-bearing (girl) sperm making it through the vaginal, cervical, and tubal gauntlet to achieve fertilization. Again, we know of no clear data that suggest these methods work effectively by themselves.

One old-fashioned remedy for menstrual irregularities, infertility, and "female problems" popular as far back as the end of the 19th century was Lydia Pinkham's herbal compound. Today, this compound has made a comeback in women attempting natural female gender selection. Potentially the compound may render the vaginal environment more acidic, or the plant-derived estrogen compounds may alter a woman's uterine environment to favor conception with an X-bearing sperm. Despite the long history of favorable responses to this compound (perhaps in part because the original formula is reputed to have been 20 percent alcohol), we know of no clear data to support its use for gender selection.

Perhaps one of the best-known natural methods for gender-specific conception is that set forth by Dr. Landrum Shettles. His book about timing of intercourse for gender selection has sold over one million copies, and, indeed, Dr. Shettles deserves a recognized place in the history of reproductive medicine as one of the early pioneers of human egg development and _in vitro_ fertilization.

Shettles' theory boils down to the assumption that Y-bearing "male" sperm are lighter, faster, and more fragile than their X-bearing female counterparts. Therefore, if intercourse is timed exactly with ovulation, then the Y-bearing sperm should win the footrace to the egg and improve the odds of having a boy. Along the lines of "slow and steady wins the race" theory, the heartier X-bearing sperm will live longer and be available for fertilization if intercourse is timed further away from ovulation.

We have reviewed the data and remain unconvinced that this is a reliable method for gender selection. Furthermore, if you are having fertility concerns and using this method, the timing of intercourse remote from ovulation in an effort to obtain a girl may actually significantly decrease your odds of conceiving each month. Don't get bumped off the fertility Fast Track by unproven methods of gender selection!

One final "natural" method worth discussing is the "Ovulation plus 12" or "O+12" method for attempting to conceive a female fetus. This method is based on the fact that a large study from New Zealand (which incidentally showed that the Shettles method was not very reliable) showed that there may have been a tendency to conceive with a girl if intercourse was timed about 12 hours after ovulation. Again, there are no significant studies to suggest that this method is very effective in selecting for females. In addition, because ovulation may be missed, it may impair monthly fertility rates and is therefore not a good option for couples with infertility.

### Medical techniques for Gender Selection

Two low-tech medical interventions for family balancing may be the Ericsson method (which runs sperm through a special preparation of albumin protein) or sperm spinning. These methods are purported to separate X and Y sperm, but repeated genetic studies on the sperm have shown that most samples still contain an equal ratio of X- and Y-bearing sperm. Because these methods are used with intrauterine insemination in otherwise healthy women, pregnancy rates can be very good. However, the data for their efficacy in gender selection is very minimal with the exception of a slight advantage for male babies with the Ericsson method.

For couples truly wanting or needing to sway the odds in their favor for conception with one gender or the other before fertilization takes place, then Microsort sperm selection is an excellent option. Normal ejaculated sperm will contain about 50 percent X-bearing and 50percent Y-bearing sperm. Because the X chromosome contains more DNA than the Y chromosome, a special technique called flow cytometry can be used to help separate X-bearing sperm from Y-bearing sperm. A concentrated specimen of either X- or Y-bearing sperm can then be used to attempt fertilization to create a pregnancy of one gender or the other.

With Microsort, a man gives a sample of sperm either at the central facility in Fairfax, Virginia or at his local fertility clinic, where the sperm is frozen and sent to the central facility. During the flow cytometry process, the DNA in the sperm is stained with a special fluorescent dye. Because of the differing amounts of DNA, the X and the Y-bearing sperm will stain differently. The sperm is then sent down a special tube where a laser beam causes the dye to "glow." The more brightly glowing X-bearing sperm are then sent one direction while the Y-bearing sperm are sent another. The resulting samples will have an enriched proportion (although not 100%) of the desired type of sperm. At the time of the writing of this edition of the book, Microsort is available in several countries but not in the United States. At present it is not FDA approved for use in the U.S.

Finally, we'd like to discuss the most reliable technique for gender balancing: Preimplantation Genetic Diagnosis (or PGD). This is a post-fertilization procedure that is more than 99 percent accurate in predicting the gender of the fetus. PGD is very high tech and very complex and involves extensive coordination of a very large team of physicians, nurses, embryologists, geneticists, and laboratory staff.

During the PGD process, a couple undergoes a relatively standard in vitro fertilization cycle to create embryos (see Chapter 8 on IVF). Approximately three to five days after fertilization, a small slit is made in the shell surrounding the embryo and a microscopic instrument is used to extract one or a few cell from the embryo. A special genetic test is then used to analyze the chromosomes from the embryo to predict the sex of the fetus. This testing can also help predict other chromosomal abnormalities in an embryo such as Down syndrome or other severe genetic diseases. In fact it is now possible to analyze all 23 chromosome pairs of the embryo. You can determine that an embryo is male or female and if there are any chromosomal errors such as Down syndrome. Chapter 8 on IVF has an excellent description of PGD.

Healthy embryos of the desired gender are then transferred back to the mother's uterus in an attempt to create a pregnancy. In most cases, pregnancy will occur between 25 and 55 percent of the time with each attempt (extra embryos can be frozen for subsequent attempts), but success will vary dramatically with the age of the mother. This testing is not 100 percent accurate because of the limitations of the actual testing process as well as the fact that a single cell may not accurately represent the chromosomal features of the entire fetus. However, it is an extremely powerful and effective new tool. Amazingly enough, removing one of the embryo's 6 or 8 cells does not seem to harm the subsequent development of the fetus.

Other drawbacks involved with PGD include the ethical concerns that this process raises for some couples. Since this is a post-fertilization procedure, healthy embryos of the gender not hoped for by the couple are often generated. While these can be frozen and given to other couples through the growing embryo donation network, some couples may choose to discard these embryos based solely on their gender. For this reason, many fertility centers that willingly provide PGD for eliminating genetic diseases such as cystic fibrosis or Tay Sachs or sickle cell anemia may not offer PGD for family balancing.

Remember that, except for couples at risk for inheritable gender-linked diseases, family balancing is generally a bonus try for couples with normal fertility. Couples with infertility problems risk falling off the fertility Fast Track by delaying attempts or sabotaging monthly conception rates by spending valuable time on unreliable methods of gender selection!

# Chapter 17  
The Fertility Lifestyle

Every couple suffering from fertility concerns is looking for ways to maximize their chances of conception. Friends, family and the internet are full of opinions and often less-than-helpful advice. Some of the more common suggestions center on lifestyle issues. What is the right diet? What about caffeine and alcohol? Is exercise okay and, if so, how much? Can too much exercise be bad? Is acupuncture good or bad? Should you take vitamins and herbal supplements? What should you tell friends and family? Can you tell them too little or too much? Are their constant questions getting on your last nerve? Although these issues have been touched on earlier in the book, this chapter is designed to address some of these common concerns in depth. Some of the questions are tough to answer, since in many cases there are few or conflicting data to suggest the correct response. In helping you search for answers, we will attempt to be as objective as possible.

### The Fertility Diet

Remember the old saying "You are what you eat"? Our diet does affect us and some attention to diet, especially at the extremes of the weight spectrum, will help improve fertility. Although there is no general agreement as to what constitutes the best "fertility diet," most nutritional specialists suggest some basic guidelines.

There is general agreement that a balanced diet is both good for your health and good for your fertility. A diet that contains fresh fruits and vegetables as well as proteins and whole grains is best. Try to avoid a lot of sugars and highly processed foods. Protein sources can include meat, chicken and fish. Some large fish, such as shark, swordfish or Albacore tuna, live a long time and become quite large. They can accumulate large amounts of mercury, which is undesirable for pregnant women. However small fish do not accumulate mercury and are safer to consume. Because this is confusing, the Food and Drug Administration (FDA) suggests the following guidelines:

1. Do not eat shark, swordfish, king mackerel, or tilefish because they are particularly high in mercury.

2. Eat up to 12 ounces (two average meals) per week of a variety of fish and shellfish that are lower in mercury. This would include shrimp, crab, scallops, oysters, cod, pollock, tilapia, fresh water trout, salmon and canned light tuna.

3. If you choose albacore white tuna instead of canned light tuna, eat only up to 6 ounces (one average meal) per week.

Fish contains proteins and healthy omega 3 fats. You don't have to cut it out of your diet. Most of the commonly available fish are the safe ones which you can have 2 servings per week of.

For vegetarians, protein-rich foods include cheese, beans and tofu. Over the last two decades, dietary trends have reduced fat intake. While eliminating too much saturated fat from your diet can improve cholesterol and potentially reduce the risk of heart disease, the shift away from fats has led to the intake of too much processed carbohydrates. Ironically your body can process large amounts of carbohydrate and turn them into fat! Most people will actually gain more weight on a high carbohydrate diet than on a high fat diet. Carbohydrates are digested more rapidly and cause higher levels of circulating insulin, which is a fat-storing hormone, leading to greater weight gain.

As far as a specific diet is concerned, recent research from the Nurses' Health Study offers some important insights. The Nurses' Health Study was started at Harvard and its affiliated hospitals in 1976 with federal funding. It is an ongoing investigation of the effects of various factors on women's health. Drs. Chavarro and Willett in their recent book _The Fertility Diet_ analyzed data from 18,000 women followed in the Nurses' Health Study. They looked at the impact of dietary and other factors on fertility in these women. After 8 years of follow up, one in six women had difficulty conceiving. **They confirmed that diet can affect the risk of ovulatory infertility.** There is no information here for men, since only women were included in the study. It is also important to know that no other cause of infertility (such as tubal blockage) was correlated with diet. Other studies confirm these findings. The only clear link between diet and fertility appears to be related to ovulatory function, but ovulation problems account for roughly 30 percent of infertility in women. For a complete discussion of the normal menstrual cycle and anovulation see Chapters 2 and 3.

Dr. Jeremy Groll, in his book _Fertility Foods_ , makes the case for a low carbohydrate diet. Carbohydrates are made of sugars. Eating carbohydrates results in insulin secretion. Insulin forces excess sugars that are not immediately used by the muscle into the fat cells. Complicating things further is the fact that many women with infertility have polycystic ovary syndrome (see Chapter 12). These patients already have too much insulin in their system (a condition called insulin resistance) that contributes to lack of ovulation and weight gain. Additional weight gain worsens insulin resistance. Excessive carbohydrate intake in these women will perpetuate a vicious cycle.

All carbohydrates, however, are not created equally. Some carbohydrates have a high glycemic index, meaning that they are rapidly metabolized into sugars that are absorbed into the bloodstream, causing weight gain and insulin resistance. Obesity and insulin resistance will in turn disrupt normal ovulation. Examples of carbohydrates that very quickly raise insulin levels are white rice, white bread, potatoes, cookies, and regular sodas. "Slow" carbohydrates are broken down more slowly and cause a slower rise in insulin and have a low glycemic index. These foods are better for women trying to conceive. They include brown rice, whole grain pasta, sweet potatoes, and dark whole grain breads.

If you are overweight and have polycystic ovaries, your doctor may pair your diet with an insulin lowering drug such as metformin (Glucophage, see Chapter 12 and Chapter 6). The combination of medication and diet can be very effective. Remember that many of our favorite snacks such as pretzels, potato chips, cookies, crackers, and ice cream are high in carbohydrates. If you are overweight and have irregular periods, a weight reduction of just 10 percent of your body weight may give you up to a 30 percent chance of resuming normal ovulation. If diet alone is not enough to trigger ovulation, at least the weight loss will help you respond better to treatment with ovulation drugs.

Just as being overweight can hurt your chances of pregnancy, being underweight can also be a problem. Low body weight will make your menstrual cycles irregular and in some cases ovulation will not occur. Low body weight can be due to excessive exercise or to issues with control over weight such as anorexia. There is clear evidence that when your weight dips below the lower normal weight limit for your selected body frame, your cycles will become irregular. Below is a table of ideal body weights for women:

Regular menstruation requires not only a normal body weight, but a normal body composition as well. Low body weight is often associated with low body fat. A certain amount of body fat is critical for normal hormonal function. It can be just as difficult for some women to gain weight as it is for others to lose weight. If you are trying to conceive, we recommend that you try to gain enough weight to be in the middle of your weight bracket. In most cases a return to normal weight will restore normal ovulatory cycles. For some women with a history of eating disorders, the signals between the brain and ovary may be permanently disrupted. Fortunately, these women will respond well to treatment with certain ovulation drugs (see the section on gonadotropins in Chapter 6).Some fats, called essential fatty acids, are healthy for you and needed by your body. Many prenatal vitamins are fortified with essential fatty acids. Natural foods containing these fats include fish and fish oils and some nuts. Most fats found in our food can be divided as saturated or unsaturated based on their chemical structure.

During the past decade we were told that using a lot of saturated fats such as butter was not good for your heart. Recently we discovered that a type of unsaturated fat, called a trans fat, is also not good for you. These fats are manufactured by a process of hydrogenation of oils to create a product which when used in cooking results in a high shelf like for foods. Trans fats are bad for your heart and your fertility. The FDA now requires food labeling that details the amount of trans fats in food products. Some cities such as New York have banned the use of trans fats from all their restaurants. Be careful with the following foods that can be high in trans fats: French fries, stick margarines, shortening, potato chips, doughnuts and cake.

Proteins are another essential component of our diet. These include the well known animal proteins such as beef, pork, chicken and fish. In general, proteins have fewer calories than fats and do not raise insulin levels the way carbohydrates do. Less well known are proteins from some vegetable sources. These include beans, peas and tofu (soy bean derivative). Peanuts and other nuts are also a good source of vegetable proteins. But remember, too much of any good thing can be bad. Excessive soy intake can actually thin the lining of the uterus and cause infertility, and nuts are very high in calories.

Milk has been a source of controversy, with some studies showing that it helps fertility and other studies showing a harmful effect. A recent study showed that two servings per day of whole milk or products of whole milk were beneficial to women trying to conceive. A glass of milk and a cup of yogurt would count as two servings. In this study whole was better than skim, but the study did not account for body weight. If your weight is increased, you may need to substitute skim milk since the effect of the weight is itself significant and unfortunately whole milk and its dairy products are rich in calories.

### Alcohol and Caffeine

While an occasional glass of wine (especially during your period) will not hurt your fertility, women who are trying to conceive should minimize alcohol consumption. Studies have shown that even moderate alcohol intake (about five drinks per week) by women trying to conceive can cut the chance of pregnancy in half. Consistent modest alcohol intake while pregnant can cause serious birth defects, the worst of which is termed Fetal Alcohol Syndrome.

Men who are trying to have a family should also limit alcohol consumption. The ingestion of moderate amounts of alcohol by men can eventually depress sperm counts, while heavier drinking can also affect testosterone levels. Again, a glass of wine or one to two beers once or twice a week is probably not harmful. But regular drinking or binge drinking is definitely not helpful to male fertility. Limiting alcohol intake can be a difficult topic to broach with your partner. Try not to attack each other. Instead, express your concerns in a caring way and remind your partner that it is your goal together to achieve the family you desire.

Caffeine intake is probably not as harmful as alcohol. There is little evidence that caffeine in men causes any fertility problems. In fact, some caffeine intake can actually improve sperm motility. Some caffeine restrictions may be advisable for men with heart or blood pressure problems. There is conflicting data regarding the effect of caffeine intake on women's fertility and miscarriage rates. Caffeine intake at levels of 200 or more milligrams per day can cause infertility and miscarriage. A caffeinated beverage can contain as much as 100 mg per serving. We suggest that women limit their intake to one or two caffeinated beverages per day. Don't torture yourself! If you like to have a cup of coffee in the morning before work, go ahead. Remember that soft drinks and tea (whether iced or hot) may contain caffeine. Be wary of energy drinks. Most of them have very high concentrations of caffeine as well as sugar.

While we are on the topic of soft drinks, we remind patients that regular soft drinks are loaded with calories containing essentially no nutritional value. Many patients who drink two cans a day of regular soda can lose one pound per week by doing nothing more than eliminating soda from their diet. That can add up to 50 pounds in a year if all other consumption and exercise stays the same!! Water and sports drinks which are low in calories can be a health alternative.

### Tobacco

Smoking and smokeless tobacco are big problems throughout the world. Smoking is not only bad for your health, it is also terrible for your fertility. In men, smoking decreases sperm count and motility. It also causes abnormalities in sperm structure or morphology. Smoking in women causes a host of problems including a high risk of miscarriage and tubal pregnancy. It can also cause premature menopause and egg depletion. Smoking during pregnancy can contribute to high blood pressure and cause problems with the baby's growth. In fact, studies in women smokers undergoing in vitro fertilization have shown very high levels of cotinine (the body's breakdown product of nicotine) right in the egg fluid. You are literally poisoning your eggs every time you light a cigarette!

Unfortunately it is not enough to say, "I'll stop as soon as I'm pregnant." It takes months to clear the smoke and its byproducts from the human body. Admittedly, thousands of women have smoked, gotten pregnant, and beaten the odds by delivering a healthy baby. But, if you're reading this book you're probably not one of them! We are not talking absolutes here, but we are saying that your odds of conceiving and delivering a healthy baby will be dramatically better if you quit smoking!

Saying you want to quit smoking and actually quitting are two different things. You need a plan. Your plan could be to use a nicotine gum or patch. You could join a support group through the American Cancer Society. You could try one of the many prescription drugs available. You could try hypnosis. Everyone who has quit smoking likes a different plan. Try to be supportive of your partner during this process. It is tough to quit. Smoking is highly addictive. It takes a lot of will power to quit. There are often setbacks. Try to be positive and encouraging while remembering that quitting is not only good for your health but will also help you stay on the Fast Track to fertility!

"Recreational drugs" can also impair your fertility. These drugs include, but are not limited, to marijuana, cocaine, crack cocaine, and methamphetamines. These drugs disturb both sperm production and ovulation. During pregnancy they can cause serious medical problems such as stroke in the mother, fetal death, and addiction in the newborn. If you suffer from such an addiction, please be honest with your doctor and take time for treatment before attempting pregnancy.

### Exercise

Exercise is part of a healthy life style. There is no evidence that moderate exercise is harmful in any way while trying to conceive naturally. Spending thirty minutes to one hour three to five times per week will help keep you in shape and help make you physically fit to endure the extra strain of pregnancy. There are unlimited choices for exercising, and the best program for you is one that you enjoy so that you will stick to it. Mixing up your routine can help keep boredom from setting in. Almost any exercise is better than nothing, and even simple walking at a brisk pace is great exercise. If you are busy with work, as most of you probably are, try a thirty minute walk before or after dinner. Exercise early in the morning is beneficial in boosting your metabolism throughout the day. The ideal routine would be to alternate aerobic exercise such as brisk walking, running, soccer, etc. with muscle building exercise such as working with weights or resistance bands.

If you are using injectable ovulation drugs such as Follistim or Gonal-F, or Menopur, your doctor may advise you to limit your activity to low impact exercises so you do not jar your enlarged ovaries. _In vitro_ fertilization typically requires low impact activities for the same reason. Clomid rarely stimulates your ovaries to the point that you have to limit exercise. You can also let your body be your guide while you are undergoing fertility treatment. If your exercise routine gives you pelvic cramps, stop and talk to your doctor. After embryo transfer, we usually recommend limiting exercise to mild walking or an easy swim until your pregnancy test comes back.

Just as with food and supplements, too much of any good thing can be a problem. Sometimes too much exercise can shut down your ovulation. Typically this occurs in serious runners, dancers, and gymnasts, and may be associated in combination with caloric intake restriction. If you are running more than twelve miles per week and you notice that your periods are getting irregular, you may want to discuss this with your doctor. He or she may advise you to reduce your level of activity. Also if your exercise is bringing your weight below the lower limit of normal, you may have to reduce your workout schedule or eat more. Some people are "addicted" to running and find it difficult to cut down. That needs to be taken into consideration, and your doctor can advise you on a reasonable compromise.

### Yoga and Meditation

Yoga and other forms of meditation are designed to put the body in a relaxed state and to enhance spiritual channels. Meditation can slow down the heart rate and reduce blood pressure. Reducing psychological stress is probably the primary mechanism for this. There is a definite "mind over body" component. While no one is saying that stress is causing infertility per se, infertility and its treatment is very stressful. Yoga and meditation can be a very effective and appropriate way of dealing with this stress. There are no definitive studies which say that yoga will help you to get pregnant. It can definitely help you to endure the condition of infertility and to deal with its treatments, but yoga can also be a great form of low impact exercise and stress reduction.

### Acupuncture

Acupuncture uses a series of very thin sterile needles to channel and balance the energy flow within your body. Most people who have tried acupuncture report that the needles are not painful, and the experience of having acupuncture needles placed is somewhat relaxing. Usually a series of treatments are planned which last for weeks or months. Acupuncture is not covered by most insurance companies and falls into the self-pay category. Studies about acupuncture have been mixed. Many have shown some benefit and others have shown no more benefit than with a placebo. Some recent studies have shown no benefit or even lower pregnancy rates with acupuncture for patients undergoing treatment in successful U.S. IVF clinics. Other studies from Germany have shown a benefit to acupuncture with IVF, but pregnancy rates with IVF in Europe are about half of what they are in the U.S. There is no standard training or certification for acupuncture, so it is difficult to judge the credentials of acupuncture therapists. Acupuncture has been shown to be effective in the treatment of other medical conditions such as headaches and nausea. Its role in infertility treatment is at present considered uncertain.

### Vitamins and Herbal Supplements

There is general agreement that a prenatal vitamin taken prior to conception is a good idea. This vitamin will contain Folic acid, which reduces the chance of a spinal cord defect in the baby. A newer component of the prenatal vitamin is essential fatty acids. These are supposed to be good for the fetal brain development. Who wouldn't want a smarter child? Some vitamin regimens come as two tablets, with the second one containing the essential fatty acids. Prenatal vitamins are best absorbed on an empty stomach. If you cannot tolerate them because of nausea, it is better to take them with food than not at all. Unless your doctor approves your regimen, don't take a lot of other vitamins. Some fat soluble vitamins such as Vitamin A, D, E and K can accumulate in your system with ill effects. Too much of a good thing can be bad.

Herbs and other nutritional supplements are difficult to evaluate. There are no standard ways for evaluating what is in them or if one batch is the same as another. Some Chinese medical studies show these supplements to be effective in treating conditions such as infertility and endometriosis. There is no such information in Western medicine. Some herbal supplements such as ephedra taken in large doses can cause problems such as high blood pressure. Too much thyroid extract can cause hyperthyroidism. If you choose to use herbal medicine, you are in uncharted western territory. They are not known to be safe or harmful. Please let your doctor know.

### Guided Imagery

Guided imagery is a technique that uses either audiovisual media or a live instructor to channel your thought towards certain visual images. Practitioners believe that guided imagery is underutilized and can help to reduce stress and relieve anxiety. A typical session can last from 20 to 40 minutes and is performed with candles in the room or low lighting conditions. Frequently relaxing music is used as the guide takes you through a mental visual journey. The goal is to feel relaxed and energized at the end of the session. While there is no proof that guided imagery will improve pregnancy rates, it certainly will relax you. Less stress will at the very least make the treatment easier to deal with, and at best it may increase your success rate.

### Massage Therapy

There are some claims that a massage can break up scarring in pelvis and open up blocked tubes. Several uncontrolled trials have shown a benefit. In most cases the couples were also free to pursue traditional medical treatment at the same time, making it difficult to say with certainty that massage by itself was effective. There are other studies showing that massage therapy enhances traditional treatments such as IVF. Massage therapy can certainly be relaxing and great at reducing stress. You may want to use it during treatment much like you might use guided imagery. Make sure the massage therapist knows that you are doing infertility treatment in order to avoid too much pelvic pressure.

### Prayer

If you have religious faith, you may find prayer a great help in progressing through your fertility treatments. Many studies claim that prayer has been shown to improve the outcome of many medical treatments, including cardiac surgery. Other studies have contested these finding. Some studies have shown that the individual praying will help, and others have shown that having another person (even a stranger) praying for you can help improve outcomes. Unfortunately, one of the best publicized studies authored by internationally recognized physicians suggesting that prayer improved fertility outcome turned out to be fraudulent. The falsified article was withdrawn by the journal that published it. Regardless of the medical findings, your religious faith may be a tremendous asset to you as you navigate your way through the infertility maze. It may offer you the comfort and support that you need during a trying time.

### Dealing with Friends and Family

During times of stress we turn to friends and family for support. Although they mean well, they probably don't know much about infertility and may not have any beneficial advice to offer. For example, nothing is more annoying when you are knee deep in IVF treatment to be told at a party to relax and you'll get pregnant. Who needs to hear nonsense like that when you are pumped up full of hormones! When you encounter experiences like these, try not to let them annoy you. Educate the person who made the ill-informed comment. Explain to them the true causes of infertility and how stressful going through therapy can be. Explain to them gently but firmly that relaxing doesn't unblock tubes or cure a hormonal problem. Also tell them how to be supportive. Perhaps they can wish you good luck with treatment or offer to listen when you need someone to talk to. Tell them not to ask you all the time if you are pregnant yet. Promise to tell them when you are.

Remember that some of the treatments such as IVF are very new. Your parents and older relatives may not be comfortable with these forms of treatment or with talking about them. Also remember that people with children who conceived easily don't know the pain of infertility. It's easy for them to say, "If it's meant to be, it's meant to be." How many of these same people if they had a heart attack would refuse medical care and say, "If I'm meant to live through this, I will"?

If you decide to tell friends and family you are undergoing fertility treatment, be prepared to discuss how treatment is going. If you want your privacy, don't tell them about treatment until you are actually pregnant. You also need to negotiate the flow of information with your partner. Otherwise you may be upset that information you thought was just for the two of you is leaked out.

Some treatments you may want to discuss with no one but your resulting child. This may be especially true for couples choosing egg or sperm donation as a treatment option. Open communication between you and your partner will go a long way towards avoiding hurt feelings. While having some privacy can be appropriate, don't underestimate the value of having a close support network to talk to during this time of stress. This resource can be priceless and could be your partner, your friend, or your mom. If you have someone like this, you're lucky. Don't expect everyone to be supportive. You'll just be setting yourself up for disappointment.

### Prioritizing and Balancing

How do you deal with your job, your treatment and keeping your home going? There is no simple answer. You will have to prioritize! First of all, find out from your doctor how long treatment is likely to take so you have realistic expectations. How many visits will a particular treatment entail, and how much is it likely to cost? If you have more time and less money, you can go with simpler, slower treatments, hoping to have a successful pregnancy at lower cost. If you have more money and less time, perhaps you need to go with a more effective and expensive treatment such as IVF that is likely to work more quickly. See if your fertility practice has appointments early in the morning, during lunch, or later in the day to help accommodate your work schedule. Find out if the office typically runs on time or late, as this may help you plan your tight schedule.

Unfortunately, money is almost always a factor for our patients, since we do not practice in a state that requires employers or Medicaid to provide infertility benefits. Difficult choices between lifestyle and treatment often arise. What if you want to buy a house and do IVF? Which do you do first? If you are young and have more time, either one may be reasonable. If you are in your late thirties or early forties, the success of treatment will decrease over time and you should definitely consider doing IVF first.

Such decisions are not easy and will require an honest discussion with your partner. Compromise may be necessary if you do not both feel the same way. Perhaps you want to pursue aggressive treatment and your partner wants to do simpler things. Try to be open and listen to each other. Remember, you didn't choose infertility but you do have to choose how to deal with it and how to stay on the Fast Track.

# Chapter 18  
Emotional Balance

### Are the Emotions of Infertility Taking Over Your Life?

Now that you have read most of this book, you realize that the Fast Track to fertility is about getting results (your children) as quickly as possible with the least amount of physical stress and disruption of your emotional equilibrium. If you are a male, you may have a tendency to want to avoid discussing your feelings with your partner, as in, "I'll let her take care of that part." But please stay with us. You'll find that maintaining emotional balance is truly a team effort. In this chapter, we will explore why being an "infertility patient" feels so frustrating and we'll discuss the steps you may take to feel better and get back on track to emotional wellness.

### COMMON STRESSORS

Infertility causes a great deal of stress. Before discussing how to deal with stress, take a look at some real factors that contribute to your everyday stress as a person with impaired fertility:

1. Strain on your relationship: you or your partner may feel more to blame for the infertility. Partner A may feel as though he or she is just pulling partner B into the roller coaster of fertility treatments.

2. Loss of spontaneous sexual expression: what was formerly pleasurable and creative is now another chore or even an aversive activity. Intercourse on demand almost always leads to reduced libido for both members of the couple and sometimes manifests itself in erectile dysfunction in men.

3. Financial drain: exhausting savings, accruing debt to pay for medical procedures

4. Ticking "biological clock": how much longer will your eggs be viable? What are the risks of mental impairments in the baby as your age at delivery advances? Will you need donated eggs, embryos?

5. Intrusive or just insensitive comments: even family members and friends, from whom you expected more empathic support, make remarks such as, "When are you going to have kids?" "Why don't you just adopt?"

6. Side effects from fertility medications: you may feel bloating as well as symptoms that may occur with the down-regulation of your cycle, such as depression, irritability, reduced concentration, hot flushes, etc.

7. Discomfort around pregnant women: they seem to be everywhere at work and in your neighborhood. When your kid sister announces her third unplanned pregnancy, you may feel that someone has just rubbed a little more salt into your wound.

8. Intense guilt or shame from self-talk that you are causing your infertility by something you are (or are not) doing or thinking: you can't manage your stress. "How do I keep a positive attitude after a series of unsuccessful inseminations and IVF cycles?" "Am I causing my own stress?" The American Society for Reproductive Medicine (ASRM) has published a fact sheet stating that stress per se does not cause infertility, but infertility, generally, causes stress.

9. Perceived pressure to appear joyous when you are feeling sad: celebrations such as Mother's Day or Father's Day, holidays (especially at the end of the year) like Thanksgiving, Christmas, and New Year's. The pressure to put on a happy face at these times may deepen your feelings of isolation.

10. Limited support for those dealing with secondary infertility: this can be a special dilemma as fertile friends assume that you have chosen to have one or a limited number of children, and often don't readily understand your desire for another child. Those with primary infertility view you as extremely fortunate to have one child. They often cannot empathize with your desperate desire to increase your family. You are left feeling awkward at best, often guilty or greedy at worst.

11. Special challenges confronting those who are not able to use their own gametes (egg, sperm) or carry a pregnancy: issues such as bonding, disclosure, etc., are key when you use third party reproduction, including the use of a gestational carrier.

### RESTORING YOUR EMOTIONAL BALANCE

The following are steps you may take to deal with the grief and handle the added stress of suffering from infertility. The overall idea is to give yourselves permission to grieve and recognize these stressors, and then to be pro-active in reducing negative feelings.

### 1. Put your best effort into nurturing your relationship as a couple

Researchers find that the single most important factor in coping with the emotional side of infertility is the empathic support of the partner. After working with and counseling literally thousands of individuals and couples suffering with reproductive loss, we believe this research is valid. Your significant other plays a critical role in how quickly you move through the grief process and how well you handle stressors. Both of you can learn ways to enhance your communication, thereby making life more satisfying while you pursue your dreams.

## Make "I" Statements

Using this communication tool will dramatically improve the way you and your loved one interact. By opening conversations with an "I" followed by your authentic feelings, you immediately take responsibility for those feelings, rather than blame the other person and put him or her on the defensive. Along the same lines, this is the best way to ask for what you need without risking that your partner will feel guilty about not being able to satisfy your needs.

## Example of interaction not using the "I" statement

Wife: (Angry tone of voice) "You are so insensitive! Can't you see how hard this is for me? You should be feeling upset, too."

Husband: (Irritated tone of voice) "I am upset...why are you taking this out on me? You make me feel like I can't do anything right for you."

In this example, the wife not only has a blaming tone, she is telling her husband how he should feel. She doesn't ask him for what she wants. The husband responds in kind, takes a victim's stance and probably provokes guilt in her.

## Example of interaction using the "I" position

Wife (calm, gentle tone of voice): "I feel so discouraged, and I'd really like you to listen to me. I feel rejected when you start to read just when I'm trying to express myself to you. I really value your attention and feel so appreciated when you listen to me."

Husband: "Okay. Sorry. I just don't know what to say anymore. I think that I should be able to make you feel better, and when I can't, I feel helpless, like I'm failing you."

In this example, both are taking responsibilities for their feelings, not putting the other on the defensive, and the wife takes the positive step of requesting a specific behavior. The husband also expresses his own pain in a way the wife can understand.

## Timing is everything

Make a diligent effort to choose a time and circumstance to discuss feelings that are close to your heart. The minute your partner walks in the door from a grueling day usually is not a good time. You might try a "heads up" approach such as, "I know right now isn't a good time for us to talk, but after dinner this evening could we spend ten minutes or so talking about our upcoming IVF cycle?"

## Sexual satisfaction improves when you can talk about it

Try to disconnect the mental link between infertility treatment and sex. Enhance your sexual desire by spending time appreciating your sensual nature. Make an effort to create romantic interludes. During non-fertile parts of your cycle, refrain from intercourse unless you are in the mood. Instead, concentrate on the sensual effects of massage, foot rubs and simple caresses. Just as dialogue takes thought, time, and planning, your sexual relationship deserves as much. Be courageous enough to ask your partner for what you want; both of you will benefit.

## Refuse to place blame, especially on yourself or your partner

Rather than placing blame, understand that bad things really do happen to good people.

Your welfare as an individual and a couple depends on taking positive steps to reach your goals. Practice forgiveness instead of blame.

## Understand gender differences about the expression of feelings

Typically when speaking with infertile couples, the female partner will relate the stressful life experiences which have accompanied their infertility. She has no trouble recalling the losses, the stresses, and the resulting grief. Conversely, the male partner says he worries about how the stress is affecting her. Gender differences are attributable to maternal drive as well as the obvious facts that she is getting the shots, ultrasounds, cramps, etc. Give each other credit for understanding and accepting the ways in which you are different.

## Modify your activities so that stress is minimal

When you are infertile, otherwise joyous activities such as attending baby showers or visiting newborn infants in the hospital can border on martyrdom. You don't need these activities during this phase of your life. Mailing a gift for the baby is better for your emotional health. On occasions such as Mother's Day, try some of the following: a) concentrate on your own parents or grandparents, aunts, uncles if possible, or someone else who would appreciate your company, b) talk with your clergy person about how isolated you feel, c) avoid the most painful situations, d) plan an enjoyable day with your partner, e) create your own traditions.

Another way to minimize your stress is to reduce those activities which drain your energy, the things you think you "should" do. This is the time to build your inner resources, not deplete them. Learn to say "no" to activities you dread or that you do just to please others.

For these and other key issues in helping your relationship thrive, please see the book, How to Become Your Own Best Infertility Counselor by Dr. Joyce Friedeman. In it you will find information on how to help each other express anger in constructive ways, be honest but respect the feelings of your partner, avoid using disparaging generalizations (labeling) toward your loved one, pay attention not only to what is said but also to non-verbal expression, and remember how soothing a gentle touch can be.

Keep in mind that every interaction with your loved one is important and can either help or hinder your relationship. Although the journey through infertility can be incredibly stressful, remember that for most couples who have a healthy relationship, this journey can help you become closer and stronger.

### 2. Find empathic, non-judgmental confidants

For women especially, finding a person besides your partner who will listen with empathy and without passing judgment is vital. Be your own best friend by expressing your thoughts on paper (soul writing). In addition, you'll find many opportunities to chat with other infertile people on the web or in community support groups. Many infertility centers as well as religious-based organizations and national infertility organizations run such support groups on a regular basis.

### 3. Give yourselves positive feedback

Criticism is easy. A wise individual once said, "It takes a thousand 'at a boy's' to wipe out one negative remark." You might give your partner and yourself one compliment a day to offset the perceived failure that you may experience with each negative pregnancy test. Place self-affirming messages on your bulletin board or refrigerator to remind yourselves how brave and competent you actually are. Make a list of your accomplishments in this and other areas of your lives.

### 4. Try stress-busting techniques to enhance overall well being

Simply sitting still without distraction for ten minutes twice a day to focus on your breathing has been scientifically shown to decrease blood pressure, respiration, heartbeat and calm anxiety (The Relaxation Response by Herbert Benson and Miriam Klipper). This and other mind-body techniques including yoga and tai chi reportedly improve mental functioning, thereby improving communication not only with your significant other, but also with the medical staff at your fertility center. In addition, these activities often help people persevere in their fertility treatment thus optimizing their chances of success. Please be cautious of anyone claiming that a mind-body exercise, imaging, hypnosis or even consuming particular herbs will automatically result in pregnancy. There is no acceptable research that proves that mind-body techniques per se substantially improve pregnancy rates.

### 5. Attend to your spiritual needs and ethical values

How does your spirituality relate to your reproductive situation? Obviously, we'd be presumptuous in defining how infertility affects your spiritual beliefs. Some patients have told us that the loss of a child, a pregnancy, or even the dream of having children has changed the way they understand divine intervention or even prayer. In listening to clients discuss their spiritual concerns, two major themes often emerge. The first theme is the meaning of infertility in your lives. The second is how your values or beliefs influence which treatment options you decide to pursue. What is the meaning of infertility in your life? Many infertile people view their reproductive losses in the context of their religious beliefs, or their philosophy or attitudes about suffering in general. A heartfelt discussion with your spiritual advisor can help clarify some of these complex issues for you.

Another issue is the degree to which your values influence which treatment options you choose. Most initial fertility treatments such as taking medications that enhance ovulation are accepted by most religions as clearly promoting life. Conflicts may arise, however, when a couple must decide if they want to follow their doctor's recommendation to use intrauterine inseminations (IUI) or undergo in vitro fertilization (IVF). Over the years, we've seen that, in general, Roman Catholics, Orthodox Jews, some followers of the Hindu religion and a few other Protestant denominations have beliefs that challenge the techniques involved in IVF and sometimes even IUI.

The counter argument, of course, which is espoused by most of the patients we work with, is that "God helps those that help themselves." In other words, couples may say, "God made it possible for scientists and doctors to have the ability to help infertile people with these techniques, so we are benefiting from God's work." Many couples do not realize that there are multiple ways to approach even high tech fertility techniques like IVF and that your fertility specialist can usually find a method that accommodates your religious and moral beliefs.

If a particular treatment option poses a moral dilemma for an individual couple, we recommend that they seek the counsel of their minister, rabbi, priest or other religious figure. The cleric will attempt to help the couple discover the essence of their own beliefs, before advising them on a choice. In short, the individuals must believe that the path they are pursuing is right for them. Books that offer spiritual guidance which, in our opinion, are timeless classics for comforting the souls of people in grief are: When Bad Things Happen to Good People by Rabbi Harold Kushner, and Don't Take My Grief Away by Doug Manning, a protestant minister. These books may be in your local library. You certainly will find other resources to help you think through your spiritual convictions. If you are advised by your doctor to consider third-party reproduction, you may have more soul searching on your agenda.

### 6. Telling your child about third-party reproduction

Some of you reading this book will need donor eggs, donor sperm, a gestational carrier (GC) or donor embryos in order to reach your dreams of parenthood. In most cases, you will meet with a psychosocial consultant well before the procedure. This counselor will help you sort out your thoughts and feelings regarding your options. If you use your own gametes (eggs and sperm) and use a gestational carrier (GC), you will probably tell your child, when he or she is mature enough, about why you needed a GC. Keeping this fact a secret from your child is not a practical option because people in your family and community already will know that you did not carry the pregnancy. You will want your child to learn this from you and not inadvertently from someone else. Most parents envision themselves telling the birth story, including the GC, to their school-age children without much difficulty. If you are using donated gametes, the birth story becomes much more complicated and sometimes ethically challenging.

A critical issue that is often foremost on the minds of gamete recipients is how to tell the resulting child about the donation. When third-party reproduction began, the doctors, nurses and mental health professionals were, for the most part, unsure of how to advise recipients about disclosure to children. However, research has emerged showing that secrets in families, especially about genetic origins, are harmful. See the book by Baron and Panor, Lethal Secrets, Warner Books, 1993.

After about ten years of experience with families using third party reproduction, and with some urging by mental health professionals, the American Society for Reproductive Medicine (ASRM) published guidelines from its Ethics Committee. The report entitled "Informing Offspring of their Conception by Gamete Donation" was published in the journal Fertility and Sterility in March of 2004. This report states that the committee supported disclosure from parents to offspring about the use of donor gametes. It added references for suggestions regarding policies of fertility programs and sperm banks. This report represents a landmark decision on the part of the ASRM, i.e., taking a stand on a rather sensitive ethical controversy. To read more about disclosure issues, guidelines for how to tell children about their origins and more references, please see Building Your Family Through Egg Donation, 2nd ed, Jolance Press, 2007.

The ethical ramifications of assisted reproductive technologies are complex. This is merely a summary of selected salient moral and ethical issues facing people on their journey through fertility resolution. We do not presume to have any of the answers in the field of morality and spirituality, but we hope to have underscored some of the important issues.

### 7. Know when to seek professional counseling

When it comes to caring for yourself, are you prone to put your own needs last? Often it is the person who easily takes on the care-taking or take-charge role who has the most difficulty asking others for help. Given the grief and stress that you encounter on the infertility roller coaster, you may want to consider a few sessions with an experienced infertility counselor. Sometimes you need the objective assessment of a mental health professional whose special area of expertise is infertility, reproductive loss and, if appropriate, third party reproduction. Many patients may need only one or two counseling sessions to help them choose a reproductive option or give them suggestions on how to cope with a certain situation.

In the case of serious emotional/mental disturbance, some of the indications for immediate and sustained psychotherapy are the following: loss in the ability to feel any pleasure in food, sex, hobbies, important relationships; isolation, marital conflict, hopelessness, uncontrollable weeping, insomnia or sleeping too much; overwhelming fears, unusual physical complaints after a thorough physical examination by a competent medical professional; substance abuse, suicidal thoughts or behaviors, confusion or disturbances in memory.

Just as picking the right fertility specialist is an important step, so, too, is picking the right counselor. There are certain qualifications to look for when seeking a psychosocial counselor specializing in infertility. In addition to a master's or doctorate degree in the mental health field, the professional must have a license to practice in your state and at least one year of clinical experience providing infertility counseling under the supervision of a qualified infertility counselor. The Mental Health Professional Group of the ASRM describes the required training of this specialty in the medical aspects of infertility indicating knowledge of a) basic reproductive physiology, b) testing, diagnosis and treatment of reproductive problems, c) the causes of male and female infertility and d) assisted reproductive technologies and third party reproduction. The group also describes mandated training in the psychology of infertility from legal and ethical issues and typical/atypical responses to family building alternatives and crisis intervention.

You may find a qualified infertility counselor by asking your doctors, nurses and fertility center staff whom they recommend. Another excellent resource may be your local infertility support group. Your goal should be to spend the least amount of time in counseling while gaining the most understanding, support and insight available.

### Summary

As you go through your own infertility journey, you should seek to balance your emotions and maintain your emotional equilibrium as much as possible. Strive to take special care of yourself and your partner, and understand that there will be periods of time when you will need a shoulder to cry on or extra reassurance from the special people in your lives that they understand and accept your needs. Be assured that there are thousands of people like you who are experiencing infertility and are trying to build a family. Our hope is that you will find peace and joy on your Fast Track to fertility.

# Chapter 19  
Dealing with Medical Insurance

In previous chapters, you read that early diagnosis and treatment can help keep you on the Fast Track to fertility. A similar statement can be made about insurance coverage for infertility treatment. Discovering that you don't have fertility benefits after treatment has already begun can be more than just a "bump in the road". In this chapter we will share with you our experience and knowledge of insurance coverage for infertility, how best to determine if you have coverage, and which procedures may be included in your coverage.

When you initially obtained your medical benefit, either through your employer or on your own, you most likely received a brief (rather than detailed) plan summary. Your first step in determining coverage is to obtain the detailed version of the plan summary from your insurance provider. Most insurers do not automatically provide this document unless specifically requested. This detailed plan summary is important to have, not only for infertility benefits, but for other medical services as well. Because of the recent HIPAA (patient privacy) regulations enacted by Congress, usually the person who is the policyholder or an individual named on the policy has to request the actual contract from the insurance company or their employer. If you are insured through work, the requested detailed plan may likely be sent to your employer's address and not to your home address. In an effort to reduce printing costs, some insurance companies put contracts online. Look at your insurance card for any websites that may provide access to your benefit information.

Once you have obtained the detailed summary, you should read it thoroughly. If you have not already done so, familiarize yourself with the basic policy coverage. Your research should give you the answers to the following questions:

• Do you have an annual deductible? If so, how much is it and have you met it yet?

• What is the beginning and ending date of your plan's benefit year? Most plans run from January 1st to December 31st, but you should check to be sure.

• Do you have an out-of-pocket expense for the year? If so, how much?

• Will you be responsible for a certain percentage of the charges?

• Do you have In Network benefits only or does your policy include Out of Network coverage?

• Does your policy restrict the use of outside facilities, such as hospitals, labs, or pharmacies?

• Does your policy include medications, or are medications covered on a separate drug card or policy?

• What is your lifetime maximum benefit, if any?

Now that you have general information about your plan, you're ready to find out the specifics about infertility benefits. In your detailed plan description, you should first refer to the section titled "Covered Expenses," "Included Benefits," or a similar phrase indicating which services qualify for reimbursement under your plan. Most insurance companies put fertility under its own subtitle. But, occasionally, fertility benefits will be categorized under Family Planning, Maternity, or Other Services.

About 85 percent of our patients find that their medical benefits do include _some_ fertility services. While this sounds promising, the definition of "some" can vary enormously between plans. At one end of the spectrum, a couple may get their initial consult paid by insurance but nothing else. At the other end of the spectrum, a couple may have coverage for any and all services connected to the diagnosis and treatment of infertility, including IVF. In reality, most patients' benefits fall somewhere in between. Often the coverage is limited to a specific dollar amount or number of cycles either per year or per lifetime. Generally, medications are a separate benefit but may be included in the allotted amount.

Reading your fertility benefit closely is paramount. If the benefit states "For the diagnosis of infertility only," understand that this statement does not include treatment. This means that a patient with such a policy would have coverage for an initial office visit, blood tests to check hormone levels, an HSG (hysterosalpingogram) to check the fallopian tubes, and an ultrasound to make sure there were no underlying conditions such as fibroids or endometriosis. These services would likely be paid. But if this same patient proceeded with an artificial insemination cycle including prescribed medications, ultrasounds and blood tests related to that treatment cycle, the insurance would probably not pay for anything, as this patient would now be receiving "treatment." You want to be as informed as possible as to what your policy states so that you can take full advantage of your benefit.

If you have discovered in the "Covered Expenses" section that you have fertility coverage, do not stop reading your contract. You also need to read the information under "Non Covered Expenses" or "Exclusions." Under this section you may discover that treatment you assumed would be an eligible expense is listed as a specific exclusion on your policy. The following illustration is an excerpt that was taken from an actual patient's policy under "Covered Services:"

Fertility services; In Network: 80% covered after plan deductible is met; Infertility counseling, testing and treatment services. Fertility Services; Out of Network: 55% covered after plan deductible is met; Infertility counseling, testing and treatment services.

By reading the above, one might assume that this patient would have 80 percent coverage at an In Network facility with an In Network physician for all fertility treatment including _in vitro_ fertilization (IVF). After all, isn't IVF the ultimate form of infertility treatment? Actually, when it comes to insurance coverage, the answer is often "no." When we looked at the "Exclusions" section of this patient's policy, IVF, GIFT, ZIFT, Donor Egg, as well as Gestational Carrier or Surrogacy were specifically non-covered, excluded services. This patient had great coverage for basic services such as ultrasounds, diagnostic testing, etc. But when she advanced to IVF, the entire cost of the treatment became her responsibility.

Previously we indicated that about 85 percent of patients might have some form of infertility coverage. But when it comes to the Assisted Reproductive Technologies, only about 15 percent of patients have coverage for IVF, and less than 1 percent are covered for oocyte donation, surrogacy, or gestational carrier care. The major caveat to this rule exists within "mandated" states. There are about fifteen states that legally require insurance companies to provide IVF coverage to the majority of residents within those states.

Over the years, insurance companies have become very specific when printing the policies for fertility coverage. It is not unusual to see language that states any service leading up to, in conjunction with, or associated to an IVF cycle will not be covered. By obtaining the _Current_ _Procedural Terminology_ _Codes_ (commonly referred to as CPT Codes) from the billing staff at your fertility center and discussing these codes with your insurance company, you may become better informed about exactly which services will be covered by insurance and which will not. By being proactive, patients can usually determine prior to initiating treatment if they have fertility benefits and which treatments, if any, are covered, thereby avoiding disappointment later.

In addition to the CPT Codes, your insurance customer service representative will ask for an ICD.9 Code. This _International Classification of Diseases 9_ th _Revision_ code tells the insurance company "why" a treatment is to be done, while the CPT code tells the insurance company "what" treatment is to be done. It is often the "why" that determines coverage. This is especially true for couples whose treatment involves surgery. Problems such as endometriosis, fibroids, ovulatory problems, and scarring on the fallopian tubes for women, and varicoceles, infections, hormonal imbalances, or blockages for men are usually considered "medical" problems. The insurance company may cover treatment for these conditions even if the policy excludes other types of infertility coverage. Many surgical procedures designed to alleviate medical conditions that also may lead to a greater chance of future conception can be performed by a Reproductive Endocrinologist and be considered a covered benefit on a "no fertility benefit" policy. Your physician's office cannot submit fraudulent codes, but it can be as precise and specific as possible when coding your medical care.

As new fertility procedures are introduced, the medical industry will work with the insurance companies to clarify treatment and introduce new codes. IVF with PGD (Pre-implantation Genetic Diagnosis) is a good example. Couples may choose to have PGD performed for a variety of reasons, and many couples having PGD do not have infertility issues at all. They may have experienced recurrent pregnancy loss or carry a genetic disorder they wish to avoid passing on to their potential offspring. In these cases their treatment involves a common infertility procedure (IVF) for a purpose other than infertility. Using a genetic code rather than an infertility code may help these couples utilize medical insurance even though they have no fertility benefit.

On the road to the fertility, patients will encounter many caution flags along the way. One is reimbursement or coverage for medications. As mentioned earlier, a patient's drug benefit may be separate from his or her medical plan. Patients should use caution and not assume drug coverage or lack of coverage based on the medical policy, because the coverage rules may vary. An employer may allow the drug plan to pay for medications but not allow the medical plan to pay for treatment. The employer may allow a limited dollar amount for treatment, but no limit on drugs. Ultimately, having a separate drug policy may not matter. The employer may have chosen to exclude coverage for fertility treatment as well as fertility drugs. Generally we have found that a policy that excludes any service in connection to infertility treatment will not pay for fertility medications on a separate drug plan, but you should check your own plan carefully!

Patients should also never assume that a plan that covered procedures or medications for "low tech" treatment such as artificial inseminations would extend to "high tech" procedures such as IVF. If the IVF procedure is not covered, it is VERY likely that the medication will not be covered either, even though the medications may be exactly the same as those used during a covered artificial insemination cycle. Pre-authorizations, letters of medical necessity, and/or pre printed insurance forms must often be completed prior to ordering medications. Your physician's staff, as well as the pharmacy personnel, will work with your insurer to complete all necessary paperwork to help maximize your medication benefit.

Patients who do have fertility benefits need to understand that patient responsibilities also accompany those benefits. Not knowing what these responsibilities are could bump you off the Fast Track. For example, at the time of this printing, one of the larger insurance carriers requires its policyholders to call and register on its fertility line. If the patient fails to do so, payment for all services will be denied as unauthorized. That same insurance company requires the results of a "day three" blood test of the female's FSH level (follicle stimulating hormone). If this level is higher than 19, the insurer will not pay for the IVF cycle even though the patient has coverage. Not all insurers are this restrictive, but they all have guidelines that must be met to allow reimbursement. Important questions to ask that help avoid unpleasant surprises later include:

• Does your plan mandate a referral? If so, does this need to come from your Primary Care Physician or your OB/GYN?

• Do you have to be treated at a specific hospital or lab or can you choose your providers and facilities?

• Do you have to do a certain number of insemination cycles before you can proceed to an IVF cycle?

Asking your customer service representative about your plan's stipulations and limitations _before_ you begin treatment may ease future financial surprises and disappointments.

Just as the patient has responsibilities, so too does the physician. He or she can submit pre-determination letters or letters of medical necessity, tests results, and progress notes to verify that the plan's requirements have been met. Fertility practices are familiar with many patients' benefits. But keep in mind that there are hundreds of insurance carriers and thousands of plans, and it is virtually impossible for your physician's office to know them all. Be prepared to give your medical practice a copy of your stated fertility benefit, your insurance card, as well as any other pertinent information that will help them help you.

Infertility benefits are often in dollar amounts. A few lucky patients have unlimited coverage with no restrictions. Most people, however, have a stated limit, either per year or per lifetime. This can be a little tricky because someone has to keep track of these calculations, and whoever is doing the calculations needs to know the benefit well. Does the amount include medication benefits? If your employer changes insurance carriers each year, does the benefit start over or is it cumulative?

The good news is that this benefit goes much further than people think. The amount of the benefit is based on the amount the insurance company _pays_ to your physician and not what the physician _charges_. This is important because, in most cases, insurance companies require providers to take a "contractual write-off." Let's suppose that you have a $5000 annual benefit. Your physician may charge $100 for a service and only receive $30 from your insurance company. In this situation, you would have used only $30 of your $5000 benefit, not $100.

Even patients who have 100 percent coverage may find that they are still responsible for a portion, or possibly all, of their treatment costs. It is very common for services such as embryo cryopreservation, embryo storage, or semen storage to be non-covered services regardless of the benefit. And many patients have been greatly disappointed when they discovered that, because they had a tubal ligation or a vasectomy, their benefit does not apply. It's important to have a lot of patience when dealing with fertility issues and insurance companies. Maintain good records of conversations with insurance representatives. Be a pack rat when it comes to documents, receipts, copies of explanations of benefits, and any financial notes during your treatment. Searching, reading, knowing what questions to ask and avoiding assumptions will keep you on the Fast Track.

But what if you've discovered your plan excludes fertility treatment altogether? Who determines if an insurance plan offers fertility benefits? Many people mistakenly believe that it is the insurance companies who determine if a patient gets fertility coverage. In reality, it is the employer who purchases the plan who specifies if infertility treatment will be covered as a health benefit to their employees. As mentioned above, patients who are lucky enough to live in a mandated insurance state will automatically receive coverage. People get excited when they hear their state has a mandate to offer infertility benefits. But this mandate may be for HMOs only, be a miniscule amount, or may have strict limitations. In any case, health care reimbursement for fertility treatment is employer or administratively driven and not insurance driven.

Those patients who have infertility benefits receive a substantial discount off their charges because of the contractual agreement between providers and insurance companies. Insurance pays a negotiated rate for each service. This is true for most medical care. Practices know that financing infertility can be difficult. To pay for care, patients may opt to use credit cards or apply for a loan at the financial institution that is working with their fertility center. Even pharmaceutical companies are working with patients to help with costs. Some offer discounts on medications after a specific number of cycles or discounts for couples in a specified income bracket.

On more than one occasion, infertility patients have lamented that dealing with medical insurance was more difficult than the treatment itself. We have found that being proactive rather than reactive can substantially reduce financial difficulties. We hope that, by using the knowledge we have shared with you in this chapter, you will have one less hurdle to overcome while taking the Fast Track on your journey to parenthood.

# Summary

Infertility is an extremely common disorder. In the past fifteen years, the treatment of infertility has undergone dramatic change, with diagnosis and therapy becoming much more specific and targeted. Many procedures that were once experimental, such as _in vitro_ fertilization, are now available on a routine basis and offer excellent success rates with rapidly diminishing risks of multiple births. We hope that this book, which is the result of our combined clinical and research experience as well as that of our contributing colleagues, will serve as your comprehensive, modern guide to dealing with infertility and the many facets of its treatment.

Throughout this book we have stressed the fact that, in order to enhance the results of therapy, it is essential that you do not delay in having a complete initial investigation followed by targeted, specific therapy under the guidance of a specially trained physician. Delay in the diagnosis or treatment of infertility is a significant mistake that can dramatically reduce your chances of a successful pregnancy. Remember that seeking appropriate care as soon as possible will allow you to achieve the best results as quickly as possible with the least expense. We have called this approach, aimed at achieving a successful pregnancy in the least amount of time in the most cost-effective manner, the Fast Track to fertility. Each couple must choose the best option that is consistent with their values and ethical beliefs while trying to beat the biologic clock. We wish you and the thousands of other couples struggling with infertility the best of luck.

# About the Authors

### Sherif G. Awadalla, M.D.

Dr. Awadalla serves as Medical Director at the Institute for Reproductive Health (IRH). He is also co-director of the In Vitro Fertilization program at IRH. Dr. Awadalla holds the title of volunteer Assistant Professor in the Division of Reproductive Endocrinology and Infertility in the department of Obstetrics and Gynecology at the University of Cincinnati College of Medicine. Previous positions include director of Reproductive Research at Bethesda Hospital, and Assistant Professor of Obstetrics and Gynecology at West Virginia University. Dr. Awadalla also served as Medical Director for the In Vitro Fertilization Program at West Virginia University.

Dr Awadalla is Board Certified in Reproductive Endocrinology and Infertility as well as Obstetrics and Gynecology. He is a member of numerous professional societies including: Society for Reproductive Endocrinologists, the American Society for Reproductive Medicine, American Medical Association, Ohio State Medical Association, Cincinnati Academy of Medicine and the Cincinnati Obstetrics and Gynecology Society.

Dr Awadalla completed his fellowship training in Reproductive Endocrinology and Infertility at the Ohio State University in 1987. He completed his residency in Obstetrics and Gynecology at the University of New Mexico in 1985. He graduated from the University of Cincinnati College of Medicine in 1981. He completed his bachelor of science degree from McGill University in 1977.

Dr Awadalla has conducted and published numerous research projects in the areas of endometriosis, microsurgery, infertility, in vitro fertilization, GIFT, ovulation induction, and gamete maturation. His current areas of interest include leading edge treatments of infertility such as in vitro fertilization with all of its variation. He is active in pelvic reparative surgery both by microsurgical techniques, such as tubal reversal surgery, as well as laparoscopic laser and robotic techniques.

### Michael D. Scheiber, MD, MPH, FACOG

Dr. Scheiber earned his undergraduate degree from Stanford University, his M.D. from the University of California at San Francisco, and two additional graduate degrees from the University of California at Berkeley. He completed his OB/GYN internship and residency training at the University of California at San Diego and his fellowship in Reproductive Endocrinology and Infertility at the University of Cincinnati College of Medicine. Dr. Scheiber is board certified in both Reproductive Endocrinology & Infertility and OB/GYN. He is a Fellow of the American College of Obstetricians and Gynecologists and a member of the American Society for Reproductive Medicine and the Society for Reproductive Endocrinology & Infertility.

Dr. Scheiber previously served as a Section Chairman for the Junior Fellowship of the American College of Obstetricians and Gynecologists as well as the Chairman of the Associate Membership of the Society for Reproductive Endocrinology. He was elected to the Alpha Omega Alpha Honor Medical Society by the University of California, and he currently serves on the Editorial Board of the Journal of Gynecologic Surgery. He has been the recipient of both the Ortho Pharmaceutical Award for Excellence in Research as well as the Berlex Foundation Award for Resident Education. Dr. Scheiber received the Newhouse Foundation Fellowship for Outstanding Scholarship at the University of California at Berkeley and was the previous Director of Women's Health at the Palau Community Health Center in Koror, Palau.

Dr. Scheiber has authored numerous peer-reviewed articles as well as book chapters and currently serves as the Co-Director of In Vitro Fertilization Services and the Director of Reproductive Research at the Institute for Reproductive Health in Cincinnati, Ohio. He also serves as Volunteer Associate Professor of OB/GYN at the University of Cincinnati. His professional interests include IVF-embryo transfer, preimplantation genetic diagnosis, ovulation induction, PCOS, and laparoscopic/ hysteroscopic surgery. He lives in Cincinnati with his wife of more than 20 years and their three wonderful daughters.

### Thomas H. Burwinkel, MD, FACOG

Dr. Burwinkel joined the Institute for Reproductive Health in January of 2011. He previously served as the medical director at Kettering Reproductive Medicine where he worked for ten years. He served as an assistant professor, and clinical associate professor at Wright State University in the department of Obstetrics and Gynecology for eighteen years teaching practicing physicians, residents and medical students.

Dr. Burwinkel is board certified in Obstetrics and Gynecology and Reproductive Endocrinology and Infertility. He has membership in the American College of Obstetrics and Gynecology where he has served as the Ohio Section Council Chair, Vice Chair, and member of the District V Advisory Council. He is also a member of the Society for Reproductive Endocrinology, Society for Assisted Reproductive Technology, American Medical Association, Ohio State Medical Association, Cincinnati Academy of Medicine, and Cincinnati Obstetrics and Gynecology Society.

Dr. Burwinkel completed his fellowship training at the University of Tennessee, Memphis where he was awarded the Mead Johnson Clinical Research Fellowship. He completed his residency at Bethesda Hospital of the Tri-Health Medical System and medical school training at the University of Cincinnati. He graduated from Miami University.

Dr. Burwinkel has conducted basic science and clinical research. Previous research has included studying endometriosis, fibroids, ovulation induction, in vitro fertilization, micromanipulation, in vitro maturation, co-culture systems, polycystic ovarian syndrome, and surgical adhesion prevention. He performs pelvic surgery to help infertile women using operative laparoscopy, robotic surgery, operative hysteroscopy as well as traditional open procedures including microsurgical techniques, such as tubal anastomosis procedures. He has been married for over 20 years and has three children.

