A steroid is a biologically active organic
compound with four rings arranged in a specific
molecular configuration.
Steroids have two principal biological functions:
as important components of cell membranes
which alter membrane fluidity; and as signaling
molecules.
Hundreds of steroids are found in plants,
animals and fungi.
All steroids are manufactured in cells from
the sterols lanosterol (opisthokonts) or cycloartenol
(plants).
Lanosterol and cycloartenol are derived from
the cyclization of the triterpene squalene.The
steroid core structure is typically composed
of seventeen carbon atoms, bonded in four
"fused" rings: three six-member cyclohexane
rings (rings A, B and C in the first illustration)
and one five-member cyclopentane ring (the
D ring).
Steroids vary by the functional groups attached
to this four-ring core and by the oxidation
state of the rings.
Sterols are forms of steroids with a hydroxy
group at position three and a skeleton derived
from cholestane.
Steroids can also be more radically modified,
such as by changes to the ring structure,
for example, cutting one of the rings.
Cutting Ring B produces secosteroids one of
which is vitamin D3.
Examples include the lipid cholesterol, the
sex hormones estradiol and testosterone, and
the anti-inflammatory drug dexamethasone.
== Nomenclature ==
Gonane, also known as steran or cyclopentaperhydrophenanthrene,
the simplest steroid and the nucleus of all
steroids and sterols, is composed of seventeen
carbon atoms in carbon-carbon bonds forming
four fused rings in a three-dimensional shape.
The three cyclohexane rings (A, B, and C in
the first illustration) form the skeleton
of a perhydro derivative of phenanthrene.
The D ring has a cyclopentane structure.
When the two methyl groups and eight carbon
side chains (at C-17, as shown for cholesterol)
are present, the steroid is said to have a
cholestane framework.
The two common 5α and 5β stereoisomeric
forms of steroids exist because of differences
in the side of the largely planar ring system
where the hydrogen (H) atom at carbon-5 is
attached, which results in a change in steroid
A-ring conformation.
Isomerisation at the C-21 side chain produces
a parallel series of compounds, referred to
as isosteroids.Examples of steroid structures
are:
In addition to the ring scissions (cleavages),
expansions and contractions (cleavage and
reclosing to a larger or smaller rings)—all
variations in the carbon-carbon bond framework—steroids
can also vary:
in the bond orders within the rings,
in the number of methyl groups attached to
the ring (and, when present, on the prominent
side chain at C17),
in the functional groups attached to the rings
and side chain, and
in the configuration of groups attached to
the rings and chain.For instance, sterols
such as cholesterol and lanosterol have a
hydroxyl group attached at position C-3, while
testosterone and progesterone have a carbonyl
(oxo substituent) at C-3; of these, lanosterol
alone has two methyl groups at C-4 and cholesterol
(with a C-5 to C-6 double bond) differs from
testosterone and progesterone (which have
a C-4 to C-5 double bond).
== Species distribution and function ==
In eukaryotes, steroids are found in fungi,
animals, and plants.
=== Fungal steroids ===
Fungal steroids include the ergosterols, which
are involved in maintaining the integrity
of the fungal cellular membrane.
Various antifungal drugs, such as amphotericin
B and azole antifungals, utilize this information
to kill pathogenic fungi.
Fungi can alter their ergosterol content (e.g.
through loss of function mutations in the
enzymes ERG3 or ERG6, inducing depletion of
ergosterol, or mutations that decrease the
ergosterol content) to develop resistance
to drugs that target ergosterol.
Ergosterol is analogous to the cholesterol
found in the cellular membranes of animals
(including humans), or the phytosterols found
in the cellular membranes of plants.
All mushrooms contain large quantities of
ergosterol, in the range of tens to hundreds
of milligrams per 100 grams of dry weight.
Oxygen is necessary for the synthesis of ergosterol
in fungi.
Ergosterol is responsible for the vitamin
D content found in mushrooms; ergosterol is
chemically converted into provitamin D2 by
exposure to ultraviolet light.
Provitamin D2 spontaneously forms vitamin
D2.
However, not all fungi utilize ergosterol
in their cellular membranes; for example,
the pathogenic fungal species Pneumocystis
jiroveci does not, which has important clinical
implications (given the mechanism of action
of many antifungal drugs).
Using the fungus Saccharomyces cerevisiae
as an example, other major steroids include
ergosta‐5,7,22,24(28)‐tetraen‐3β‐ol,
zymosterol, and lanosterol.
S. cerevisiae utilizes 5,6‐dihydroergosterol
in place of ergosterol in its cell membrane.
=== Animal steroids ===
Animal steroids include compounds of vertebrate
and insect origin, the latter including ecdysteroids
such as ecdysterone (controlling molting in
some species).
Vertebrate examples include the steroid hormones
and cholesterol; the latter is a structural
component of cell membranes which helps determine
the fluidity of cell membranes and is a principal
constituent of plaque (implicated in atherosclerosis).
Steroid hormones include:
Sex hormones, which influence sex differences
and support reproduction.
These include androgens, estrogens, and progestogens.
Corticosteroids, including most synthetic
steroid drugs, with natural product classes
the glucocorticoids (which regulate many aspects
of metabolism and immune function) and the
mineralocorticoids (which help maintain blood
volume and control renal excretion of electrolytes)
Anabolic steroids, natural and synthetic,
which interact with androgen receptors to
increase muscle and bone synthesis.
In popular use, the term "steroids" often
refers to anabolic steroids.
=== Plant steroids ===
Plant steroids include steroidal alkaloids
found in Solanaceae and Melanthiaceae (specially
the genus Veratrum), cardiac glycosides, the
phytosterols and the brassinosteroids (which
include several plant hormones).
=== Prokaryotes ===
In prokaryotes, biosynthetic pathways exist
for the tetracyclic steroid framework (e.g.
in mycobacteria) – where its origin from
eukaryotes is conjectured – and the more-common
pentacyclic triterpinoid hopanoid framework.
== Types ==
=== 
By function ===
The major classes of steroid hormones, with
prominent members and examples of related
functions, are:
Corticosteroids:
Glucocorticoids:
Cortisol, a glucocorticoid whose functions
include immunosuppression
Mineralocorticoids:
Aldosterone, a mineralocorticoid which helps
regulate blood pressure through water and
electrolyte balance
Sex steroids:
Progestogens:
Progesterone, which regulates cyclical changes
in the endometrium of the uterus and maintains
a pregnancy
Androgens:
Testosterone, which contributes to the development
and maintenance of male secondary sex characteristics
Estrogens:
Estradiol, which contributes to the development
and maintenance of female secondary sex characteristicsAdditional
classes of steroids include:
Neurosteroids such as DHEA and allopregnanolone
Aminosteroid neuromuscular blocking agents
such as pancuronium bromideAs well as the
following class of secosteroids (open-ring
steroids):
Vitamin D forms such as ergocalciferol, cholecalciferol,
and calcitriol
=== By structure ===
==== 
Intact ring system ====
Steroids can be classified based on their
chemical composition.
One example of how MeSH performs this classification
is available at the Wikipedia MeSH catalog.
Examples of this classification include:
The gonane (steroid nucleus) is the parent
17-carbon tetracyclic hydrocarbon molecule
with no alkyl sidechains.
==== Cleaved, contracted, and expanded rings
====
Secosteroids (Latin seco, "to cut") are a
subclass of steroidal compounds resulting,
biosynthetically or conceptually, from scission
(cleavage) of parent steroid rings (generally
one of the four).
Major secosteroid subclasses are defined by
the steroid carbon atoms where this scission
has taken place.
For instance, the prototypical secosteroid
cholecalciferol, vitamin D3 (shown), is in
the 9,10-secosteroid subclass and derives
from the cleavage of carbon atoms C-9 and
C-10 of the steroid B-ring; 5,6-secosteroids
and 13,14-steroids are similar.Norsteroids
(nor-, L. norma; "normal" in chemistry, indicating
carbon removal) and homosteroids (homo-, Greek
homos; "same", indicating carbon addition)
are structural subclasses of steroids formed
from biosynthetic steps.
The former involves enzymic ring expansion-contraction
reactions, and the latter is accomplished
(biomimetically) or (more frequently) through
ring closures of acyclic precursors with more
(or fewer) ring atoms than the parent steroid
framework.Combinations of these ring alterations
are known in nature.
For instance, ewes who graze on corn lily
ingest cyclopamine (shown) and veratramine,
two of a sub-family of steroids where the
C- and D-rings are contracted and expanded
respectively via a biosynthetic migration
of the original C-13 atom.
Ingestion of these C-nor-D-homosteroids results
in birth defects in lambs: cyclopia from cyclopamine
and leg deformity from veratramine.
A further C-nor-D-homosteroid (nakiterpiosin)
is excreted by Okinawan cyanobacteriosponges.
e.g., Terpios hoshinota, leading to coral
mortality from black coral disease.
Nakiterpiosin-type steroids are active against
the signaling pathway involving the smoothened
and hedgehog proteins, a pathway which is
hyperactive in a number of cancers.
== Biological significance ==
Steroids and their metabolites often function
as signalling molecules (the most notable
examples are steroid hormones), and steroids
and phospholipids are components of cell membranes.
Steroids such as cholesterol decrease membrane
fluidity.
Similar to lipids, steroids are highly concentrated
energy stores.
However, they are not typically sources of
energy; in mammals, they are normally metabolized
and excreted.
Steroids play critical roles in a number of
disorders, including malignancies like prostate
cancer, where steroid production inside and
outside the tumour promotes cancer cell aggressiveness.
== Biosynthesis and metabolism ==
The hundreds of steroids found in animals,
fungi, and plants are made from lanosterol
(in animals and fungi; see examples above)
or cycloartenol (in plants).
Lanosterol and cycloartenol derive from cyclization
of the triterpenoid squalene.Steroid biosynthesis
is an anabolic pathway which produces steroids
from simple precursors.
A unique biosynthetic pathway is followed
in animals (compared to many other organisms),
making the pathway a common target for antibiotics
and other anti-infection drugs.
Steroid metabolism in humans is also the target
of cholesterol-lowering drugs, such as statins.
In humans and other animals the biosynthesis
of steroids follows the mevalonate pathway,
which uses acetyl-CoA as building blocks for
dimethylallyl pyrophosphate (DMAPP) and isopentenyl
pyrophosphate (IPP).
In subsequent steps DMAPP and IPP join to
form geranyl pyrophosphate (GPP), which synthesizes
the steroid lanosterol.
Modifications of lanosterol into other steroids
are classified as steroidogenesis transformations.
=== Mevalonate pathway ===
The mevalonate pathway (also called HMG-CoA
reductase pathway) begins with acetyl-CoA
and ends with dimethylallyl pyrophosphate
(DMAPP) and isopentenyl pyrophosphate (IPP).
DMAPP and IPP donate isoprene units, which
are assembled and modified to form terpenes
and isoprenoids (a large class of lipids,
which include the carotenoids and form the
largest class of plant natural products.
Here, the isoprene units are joined to make
squalene and folded into a set of rings to
make lanosterol.
Lanosterol can then be converted into other
steroids, such as cholesterol and ergosterol.
Two classes of drugs target the mevalonate
pathway: statins (like rosuvastatin), which
are used to reduce elevated cholesterol levels,
and bisphosphonates (like zoledronate), which
are used to treat a number of bone-degenerative
diseases.
=== Steroidogenesis ===
Steroidogenesis is the biological process
by which steroids are generated from cholesterol
and changed into other steroids.
The pathways of steroidogenesis differ among
species.
The major classes of steroid hormones, as
noted above (with their prominent members
and functions), are the Progestogen, Corticosteroids
(corticoids), Androgens, and Estrogens.
Human steroidogenesis of these classes occurs
in a number of locations:
Progestogens are the precursors of all other
human steroids, and all human tissues which
produce steroids must first convert cholesterol
to pregnenolone.
This conversion is the rate-limiting step
of steroid synthesis, which occurs inside
the mitochondrion of the respective tissue.
Cortisol, corticosterone, aldosterone, and
testosterone are produced in the adrenal cortex.
Estradiol, estrone and progesterone are made
primarily in the ovary, estriol in placenta
during pregnancy, and testosterone primarily
in the testes (some testosterone is also produced
in the adrenal cortex).
Estradiol is converted from testosterone directly
(in males), or via the primary pathway DHEA
- androstenedione - estrone and secondarily
via testosterone (in females).
Stromal cells have been shown to produce steroids
in response to signaling produced by androgen-starved
prostate cancer cells.
Some neurons and glia in the central nervous
system (CNS) express the enzymes required
for the local synthesis of pregnenolone, progesterone,
DHEA and DHEAS, de novo or from peripheral
sources.
=== Alternative pathways ===
In plants and bacteria, the non-mevalonate
pathway uses pyruvate and glyceraldehyde 3-phosphate
as substrates.During diseases pathways otherwise
not significant in healthy humans can become
utilized.
For example, in one form of congenital adrenal
hyperplasia a deficiency in the 21-hydroxylase
enzymatic pathway leads to an excess of 17α-Hydroxyprogesterone
(17-OHP) – this pathological excess of 17-OHP
in turn may be converted to dihydrotestosterone
(DHT, a potent androgen) through among others
17,20 Lyase (a member of the cytochrome P450
family of enzymes), 5α-Reductase and 3α-Hydroxysteroid
dehydrogenase.
== Catabolism and excretion ==
Steroids are primarily oxidized by cytochrome
P450 oxidase enzymes, such as CYP3A4.
These reactions introduce oxygen into the
steroid ring, allowing the cholesterol to
be broken up by other enzymes into bile acids.
These acids can then be eliminated by secretion
from the liver in bile.
The expression of the oxidase gene can be
upregulated by the steroid sensor PXR when
there is a high blood concentration of steroids.
Steroid hormones, lacking the side chain of
cholesterol and bile acids, are typically
hydroxylated at various ring positions or
oxidized at the 17 position, conjugated with
sulfate or glucuronic acid and excreted in
the urine.
== Isolation, structure determination, and
methods of analysis ==
Steroid isolation, depending on context, is
the isolation of chemical matter required
for chemical structure elucidation, derivitzation
or degradation chemistry, biological testing,
and other research needs (generally milligrams
to grams, but often more or the isolation
of "analytical quantities" of the substance
of interest (where the focus is on identifying
and quantifying the substance (for example,
in biological tissue or fluid).
The amount isolated depends on the analytical
method, but is generally less than one microgram.
The methods of isolation to achieve the two
scales of product are distinct, but include
extraction, precipitation, adsorption, chromatography,
and crystallization.
In both cases, the isolated substance is purified
to chemical homogeneity; combined separation
and analytical methods, such as LC-MS, are
chosen to be "orthogonal"—achieving their
separations based on distinct modes of interaction
between substance and isolating matrix—to
detect a single species in the pure sample.
Structure determination refers to the methods
to determine the chemical structure of an
isolated pure steroid, using an evolving array
of chemical and physical methods which have
included NMR and small-molecule crystallography.
Methods of analysis overlap both of the above
areas, emphasizing analytical methods to determining
if a steroid is present in a mixture and determining
its quantity.
== Chemical synthesis ==
Microbial catabolism of phytosterol side chains
yields C-19 steroids, C-22 steroids, and 17-ketosteroids
(i.e. precursors to adrenocortical hormones
and contraceptives).
The addition and modification of functional
groups is key when producing the wide variety
of medications available within this chemical
classification.
These modifications are performed using conventional
organic synthesis and/or biotransformation
techniques.
=== Precursors ===
==== Semisynthesis ====
The semisynthesis of steroids often begins
from precursors such as cholesterol, phytosterols,
or sapogenins.
The efforts of Syntex, a company involved
in the Mexican barbasco trade, used Dioscorea
mexicana to produce the sapogenin diosgenin
in the early days of the synthetic steroid
pharmaceutical industry.
==== Total synthesis ====
Some steroidal hormones are economically obtained
only by total synthesis from petrochemicals
(e.g. 13-alkyl steroids).
For example, the pharmaceutical Norgestrel
begins from Methoxy-1-tetralone, a petrochemical
derived from phenol.
== Research awards ==
A number of Nobel Prizes have been awarded
for steroid research, including:
1927 (Chemistry) Heinrich Otto Wieland — Constitution
of bile acids and sterols and their connection
to vitamins
1928 (Chemistry) Adolf Otto Reinhold Windaus
— Constitution of sterols and their connection
to vitamins
1939 (Chemistry) Adolf Butenandt and Leopold
Ruzicka — Isolation and structural studies
of steroid sex hormones, and related studies
on higher terpenes
1950 (Physiology or Medicine) Edward Calvin
Kendall, Tadeus Reichstein, and Philip Hench
— Structure and biological effects of adrenal
hormones
1965 (Chemistry) Robert Burns Woodward — In
part, for the synthesis of cholesterol, cortisone,
and lanosterol
1969 (Chemistry) Derek Barton and Odd Hassel
— Development of the concept of conformation
in chemistry, emphasizing the steroid nucleus
1975 (Chemistry) Vladimir Prelog — In part,
for developing methods to determine the stereochemical
course of cholesterol biosynthesis from mevalonic
acid via squalene
== See also
