Steroid

Steroid, any of a class of natural or synthetic

organic compounds characterized by a TABLE OF CONTENTS
molecular structure of 17 carbon atoms
Introduction
arranged in four rings. Steroids are important
in biology, chemistry, and medicine. The steroid History of steroids
group includes all the sex hormones, adrenal Steroid numbering system and
cortical hormones, bile acids, and sterols of nomenclature
vertebrates, as well as the molting hormones of Methods of isolation
insects and many other physiologically active Determination of structure and methods
substances of animals and plants. Among the of analysis
synthetic steroids of therapeutic value are a Total synthesis of steroids
large number of anti-in ammatory agents,
Partial synthesis of steroids
anabolic (growth-stimulating) agents, and oral
Biological significance of steroids
contraceptives.
Pharmacological actions of steroids
Different Biosynthesis and metabolism of steroids
categories
Structural relationships of the principal
of steroids categories of steroids
are
frequently
distinguished from each other by names that relate
Many important physiological functions of
vertebrates are controlled by steroid to their biological source—e.g., phytosterols (found in
hormones. plants), adrenal steroids, and bile acids—or to some
Encyclopædia Britannica, Inc.
important physiological function—e.g., progesterones
(promoting gestation), androgens (favouring
development of masculine characteristics), and cardiotonic steroids (facilitating proper
heart function).

Steroids vary from one another in the nature of attached groups, the position of the
groups, and the con guration of the steroid nucleus (or gonane). Small modi cations in
the molecular structures of steroids can produce remarkable differences in their biological
activities.

This article covers the history, chemistry, biological signi cance, and basic pharmacology
of steroids. For more information about the physiological relevance and the
pharmacological applications of steroids, see human endocrine system, endocrine system,
and drug.

History of steroids
The rst therapeutic use of steroids occurred in the 18th century when English physician
William Withering used digitalis, a compound extracted from the leaves of the common
foxglove (Digitalis purpurea), to treat edema. Studies of steroids commenced in the early
19th century with investigations of the unsaponi able (i.e., remaining undissolved after
heating with excess of alkali) material, largely cholesterol, of animal fat and gallstones and
of acids obtainable from bile. This early work, with which many of the noted chemists of
the time were associated, led to the isolation of cholesterol and some bile acids in
reasonable purity and established some signi cant features of their chemistry.

Insight into the complex polycyclic steroid structure,

however, came only after the beginning of the 20th
century, following the consolidation of chemical
theory and the development of chemical techniques
by which such molecules could be broken down step
by step. Arduous studies, notably by the research
groups of German chemists Adolf Windaus and
Heinrich Wieland, ultimately established the
structures of cholesterol; of the related sterols,
stigmasterol and ergosterol; and of the bile acids.
Foxglove (Digitalis purpurea) is the Investigation of ergosterol was stimulated by the
source of the cardiac glycoside digitalis.
realization that it can be converted into vitamin D.
The therapeutic use of digitalis was first
described in the late 18th century, when Only in the nal stages of this work (1932) was the
it was used to treat edema, a condition arrangement of the component rings of the nucleus
associated with heart failure.
clari ed by results obtained by pyrolytic (heat-
Derek Fell
induced bond-breaking) dehydrogenation and X-ray
crystallography.

With the foundations of steroid chemistry rmly laid, the next decade saw the elucidation
of the structures of most of the physiologically potent steroid hormones of the gonads
and the adrenal cortex. Added impetus was given to steroid research when American
physician Philip S. Hench and American chemist Edward C. Kendall announced in 1949
that the hitherto intractable symptoms of rheumatoid arthritis were dramatically
alleviated by the adrenal hormone cortisone. New routes of synthesis of steroids were
developed, and many novel analogs were therapeutically tested in a variety of disease
states. From these beginnings has developed a ourishing steroid pharmaceutical
industry—and with it a vastly expanded fundamental knowledge of steroid reactions that
has in uenced many other areas of chemistry.

Knowledge of the biochemistry of steroids has grown at a comparable rate, assisted by

the use of radioisotopes and new analytical techniques. The metabolic pathways
(sequences of chemical transformations in the body), both of synthesis and of
decomposition, have become known in considerable detail for most steroids present in
mammals, and much research relates to control of these pathways and to the
mechanisms by which steroid hormones exert their effects. The hormonal role of steroids
in other organisms is also of growing interest.

Steroid numbering system and nomenclature

All steroids are related to a characteristic molecular structure composed of 17 carbon
atoms—arranged in four rings conventionally denoted by the letters A, B, C, and D—
bonded to 28 hydrogen atoms.

This parent structure (1), named gonane (also known as the steroid nucleus), may be
modi ed in a practically unlimited number of ways by removal, replacement, or addition
of a few atoms at a time; hundreds of steroids have been isolated from plants and
animals, and thousands more have been prepared by chemical treatment of natural
steroids or by synthesis from simpler compounds.

The steroid nucleus is a three-dimensional structure, and atoms or groups are attached to
it by spatially directed bonds. Although many stereoisomers of this nucleus are possible
(and may be synthesized), the saturated nuclear structures of most classes of natural
steroids are alike, except at the junction of rings A and B. Simpli ed three-dimensional
diagrams may be used to illustrate stereochemical details. For example, androstane,
common to a number of natural and synthetic steroids, exists in two forms (2 and 3), in
which the A/B ring fusions are called cis and trans, respectively.

In the cis isomer, bonds to the methyl group, CH , and to the hydrogen atom, H, both
3
project upward from the general plane de ned by the rest of the molecule, whereas in
the trans isomer, the methyl group projects up and the hydrogen projects down. Usually,
however, steroid structures are represented as plane projection diagrams such as 4 and 5,
which correspond to 2 and 3, respectively.

The stereochemistry of rings A and B must be speci ed by showing the orientation of the
hydrogen atom attached at C5 (that is, carbon atom number 5; steroid numbering is
explained below) as either above the plane of the diagram (designated β) or below it (α).
The α-, β- symbolism is used in a similar manner to indicate the orientation of any
substituent group that is attached to a saturated (fully substituted) carbon within the
steroid ring system. Groups attached to unsaturated carbons lie in the same plane as the
adjacent carbons of the ring system (as in ethylene), and no orientation need be speci ed.
When the orientation of a substituent is unknown, it is assigned the symbol ξ. Bonding of
β-attached substituents is shown diagrammatically as in 4 by a full line, that of α-
substituents by a broken line, as in 5, and that of ξ-substituents by a wavy line.

Each carbon atom of a steroid molecule is numbered, and the number is reserved to a
particular position in the hypothetical parent skeletal structure (6) whether this position is
occupied by a carbon atom or not.

Steroids are named by modi cation of the names of skeletal root structures according to
systematic rules agreed upon by the International Union of Pure and Applied Chemistry.
By attaching pre xes and suf xes to the name of the appropriate root structure, the
character of substituent groups or other structural modi cation is indicated. The pre xes
and suf xes include numbers, called locants, indicative of the position in the carbon
skeleton at which the modi cation occurs, and, where necessary, the orientation of a
substituent is shown as α- or β-. The carbon atom at position 3, for example, is referred to
as C3; a hydroxyl group attached to C3 is referred to as a 3-OH group or, more speci cally,
as a 3α-OH or 3β-OH group. In addition to differences in details of the steroid nucleus, the
various classes of steroids are distinguished by variations in the size and structure of an
atomic group (the side chain) attached at position 17. For unambiguous use of the names
of the fundamental structures of steroids, the orientation (α or β) of hydrogen at C5 must
be speci ed. If no other modi cation is indicated, the nucleus is assumed to be as shown
in 2 and 3, except in the cardanolides and bufanolides; compounds of these types
characteristically possess the 5β,14β con gurations, which, however, are speci ed.

For brevity in discussion and in trivial nomenclature, a number of pre xes are often
attached, with locants, to the names of steroids to indicate speci c modi cations of the
structure. In addition to the usual chemical notations for substituent groups replacing
hydrogen atoms (e.g., methyl-, chloro-, hydroxy-, oxo-), the following pre xes are
commonly used: dehydro- (lacking two hydrogen atoms from adjacent positions);
dihydro- (possessing two additional hydrogen atoms in adjacent positions); deoxy-
(hydroxyl group replaced by a hydrogen atom); epi- (differing in con guration of a carbon
atom bonded to two other carbon atoms); iso- (differing in con guration of a carbon atom
bonded to three other carbon atoms); nor- (lacking one carbon atom); homo- (possessing
one additional carbon atom); cyclo- (with a bond between two carbons that are normally
not united); and seco- (with a carbon-carbon bond of the nucleus broken).

Depending on the number and character of their functional groups, steroid molecules
may show diverse reactivities. Moreover, the reactivity of a functional group varies
according to its location within the molecule (for example, esters are formed readily by 3-
OH groups but only with dif culty by the 11β-OH group). An important property of steroids
is polarity—i.e., their solubility in oxygen-containing solvents (e.g., water and alcohols)
rather than hydrocarbon solvents (e.g., hexane and benzene). Hydroxyl, ketonic, or
ionizable (capable of dissociating to form electrically charged particles) groups in a steroid
molecule increase its polarity to an extent that is strongly in uenced by the spatial
arrangement of the atoms within the molecule.

Methods of isolation
Procedures for isolation of steroids differ according to the chemical nature of the steroids
and the scale and purpose of the isolation. Steroids are isolated from natural sources by
extraction with organic solvents, in which they usually dissolve more readily than in the
aqueous uids of tissues. The source material often is treated initially with an alcoholic
solvent, which dehydrates it, denatures (renders insoluble) proteins associated with the
steroids, and dissolves many steroids. Saponi cation either of whole tissues or of
substances extracted from them by alcohol splits the molecules of sterol esters,
triglycerides, and other fatty esters and permits the extraction of the sterols by means of
water-immiscible solvents, such as hexane or ether, with considerable puri cation. Intact
sterol esters or hormonal steroids and their metabolites (compounds produced by
biological transformation) that are sensitive to strong acids or alkalies, however, require
essentially neutral conditions for isolation, and, although some procedures for analysis of
urinary steroids employ acid treatment, milder hydrolysis, as by enzymes, is preferred. The
acidity of some steroids allows them to be held in alkaline solution, while nonacidic
impurities are extracted with organic solvents.

Commercially, abundant steroids usually are puri ed by repeated crystallization from

solvents. Small-scale laboratory isolations for investigative or assay purposes usually
exploit differing polarities of the steroid and of its impurities, which may be separated by
partitioning between solvents differing in polarity or by chromatography (see below
Determination of structure and methods of analysis). Occasionally, special reagents may
selectively precipitate or otherwise sequester the desired steroid. A classical example is
the precipitation of 3β-hydroxy sterols such as cholesterol by the natural steroid derivative
digitonin. New steroids of great physiological interest often are isolated from tissue only
with extreme dif culty, because they are usually trace constituents. In one example, 500
kg (1,100 pounds) of silkworm pupae yielded 25 mg (0.0008 ounce) of pure molting
6
hormone, the steroid ecdysone (i.e., 20 × 10 -fold puri cation). In such cases each isolation
step is followed by an assay for the relevant physiological activity to ensure that the
desired material is being puri ed. The percentage recovery of known steroid hormones
during their assay in small biological samples usually is assessed by adding a trace of the
same steroid in radioactive form to the initial sample, followed by radioassay (analysis
based on radioactivity) after puri cation is complete. The ef ciency of recovery of the
radioactive steroid is assumed to be the same as that of the natural substance.

Determination of structure and methods of analysis

The systematic, stepwise breakdown by chemical methods of the steroid ring systems,
used in early investigations of structure, is mainly of historical interest. The small number
of different nuclear structures found in steroids often has permitted establishment of the
structure of a new steroid by conversion to related compounds of known structure.
Structure elucidation in the steroid eld, as in all areas of organic chemistry, depends
heavily on physical methods, particularly nuclear magnetic resonance, infrared
spectroscopy, mass spectrometry, and X-ray crystallography. Data obtained by these
methods reinforce and often replace the classical criteria of characterization of steroids:
melting point, optical rotation, elemental analysis, and ultraviolet absorption at a xed
wavelength.

Chromatography is a crucial technique in steroid chemistry. The behaviour of a steroid in

selected chromatographic systems often identi es it with a high degree of probability.
The identi cation may be made virtually certain by the conversion of the material to
derivatives that in turn are examined chromatographically. Abundant data for the
behaviour of steroids in paper chromatography, thin-layer chromatography, liquid
chromatography, and gas-liquid chromatography show that individual features of
molecular structure determine the chromatographic properties of steroids in a
predictable manner. The gas-liquid chromatograph or liquid chromatograph linked
directly to the mass spectrometer permits characteristic mass-spectral fragmentation
patterns and critical gas-liquid chromatographic data to be obtained simultaneously,
using a sample containing less than a microgram of a steroid. This powerful technique is
of growing importance in the structural analysis of steroids in extracts of such body uids
as blood and urine.

Total synthesis of steroids

In most total syntheses of steroids, a monocyclic starting material such as a quinone
provides one ring upon which the other rings of the nucleus are elaborated step-by-step
by condensation reactions with smaller molecules to give the desired stereochemistry in
successive ring fusions. Each new ring closure must also provide functional groups that
can be used in building up the next ring. In a quite different approach, stereochemical
control of ring fusions is achieved by using the fact that under acidic conditions open-
chain molecules containing suitably located double bonds cyclize to multiring structures
that have the necessary stereochemistry and that can be relatively easily converted to
steroids. From its analogy with the cyclization of squalene 2,3-oxide to lanosterol in the
biosynthesis of cholesterol (see below Biosynthesis and metabolism of steroids:
Cholesterol), this method is said to involve biogenetic-type cyclization.

Partial synthesis of steroids

Although total synthesis of steroids has proved commercially feasible, it is often more
practical to prepare them by partial synthesis—that is, by modi cation of other naturally
abundant steroids. To be useful as a starting material for partial synthesis, the naturally
occurring steroid must possess a molecular structure that can be easily converted to that
of the desired product. For the synthesis of cortisol, cortisone, and their analogs, which
carry an oxygen function at C11, a preexisting oxygen function at this position or at the
adjacent C12 is highly desirable. Indeed, prior to the advent of methods for microbiological
oxidation, this was a crucial requirement, since the introduction of any functional group at
C11 of most steroids was extremely dif cult.
In the early commercial synthesis of androgenic steroids, cholesterol was the main
starting material. Cholic acid and deoxycholic acid, inexpensive by-products from
slaughterhouses, were starting materials for production of cortisone. Today most steroid
drugs are manufactured from the abundant steroids of plant origin, notably the
sapogenins. Diosgenin, obtainable from several varieties of yams in the genus Dioscorea,
is used in the commercial manufacture of progesterone. Progesterone can be converted
to androgenic and estrogenic hormones and to the more complex adrenal steroid
hormones, such as cortisone and cortisol. A most important advance in this eld was the
discovery that microorganisms such as Rhizopus nigricans introduce hydroxyl groups into
a variety of steroids at C11 and elsewhere: they are used in the commercial synthesis of a
large number of steroid hormone analogs. A sapogenin, hecogenin, obtainable in quantity
from the waste of sisal plants, is used for synthesis of cortisol. Stigmasterol, which is
readily obtainable from soybean oil, can be transformed easily to progesterone and to
other hormones, and commercial processes based on this sterol have been developed.

Biological signi cance of steroids

That such diverse physiological functions and effects should be exhibited by steroids, all of
which are synthesized by essentially the same central biosynthetic pathway, is a
remarkable example of biological economy. Most of these functions, especially those of a
hormonal type, involve the transmission of biologically essential information. The speci c
information content of the steroid resides in the character and arrangement of its
substituent groups and in other subtle structural modi cations.

Sterols and bile acids

The most generally abundant steroids are sterols, which occur in all tissues of animals,
green plants, and fungi such as yeasts. Evidence for the presence of steroids in bacteria
and in primitive blue-green algae is con icting. The major sterols of most tissues are
accompanied by traces of their precursors—lanosterol in animals and cycloartenol in
plants—and of intermediates between these compounds and their major sterol products.
In mammalian skin one precursor of cholesterol, 7-dehydrocholesterol, is converted by
solar ultraviolet light to cholecalciferol, vitamin D , which controls calci cation of bone by
3
regulating intestinal absorption of calcium. The disease rickets, which results from lack of
exposure to sunlight or lack of intake of vitamin D, can be treated by administration of the
vitamin or of the corresponding derivative of ergosterol, ergocalciferol (vitamin D ).
2

Sterols are present in tissues both in the nonesteri ed (free) form and as esters of
aliphatic fatty acids. In the disease atherosclerosis, fatty materials containing cholesterol
form deposits (plaques), especially in the walls of the major blood vessels, and vascular
function may be fatally impaired. The disease has many contributory factors but typically
is associated with elevated concentrations of cholesterol in the blood plasma. One aim of
medical treatment is to lower the plasma cholesterol level.

Free sterols appear to stabilize the structures of cellular and intracellular membranes.
Because the sheath of nerve bres is a deposit of many layers of the membranes of
neighbouring cells, mature mammalian nerve tissue (e.g., beef brain) is the richest source
of cholesterol. Cholesterol also is converted in animals to steroids that have a variety of
essential functions and in plants to steroids whose functions are less clearly understood.
The bile acids (cholanoic acids, also called cholanic acids) of higher vertebrates form
conjugates with the amino acids taurine and glycine, and the bile alcohols (cholane
derivatives) of lower animals form esters with sulfuric acid (sulfates). These conjugates and
sulfates enter the intestine as sodium salts and assist in the emulsi cation and absorption
of dietary fat, processes that may be impaired when bile acid secretion is reduced, as in
some liver diseases and in obstructive jaundice. The mixture of bile acids found in feces
re ects the actions of intestinal microorganisms on the primary bile-acid secretory
products (e.g., deoxycholic acid arises by bacterial transformation of cholic acid).
Sex hormones

Steroids that have a phenolic ring A (i.e., those in which ring A is aromatic and bears a
hydroxyl group) are ubiquitous products of the ovary of vertebrate animals. These are the
estrogens, of which estradiol is the most potent. They maintain the female reproductive
tissues in a fully functional condition, promote the estrous state of preparedness for
mating, and stimulate development of the mammary glands and of other feminine
characteristics. Estrogenic steroids have been isolated from urines of pregnant female
mammals of many species, including humans, from placental and adrenal tissues, and,
unexpectedly, from the testes and urines of stallions.

The corpus luteum, a modi cation of vertebrate ovarian tissue that forms following
ovulation (release of the mature egg cell from the ovary), produces progesterone and its
derivatives. Progesterone is also secreted by the adrenals and placenta. Progesterone, in
combination with estrogen, regulates the metabolism of the uterus to permit
implantation and subsequent development of the fertilized ovum in mammals. In birds,
estrogen and progesterone stimulate the development of the oviduct and its secretion of
albumin. Estrogen and progesterone suppress ovulation; this fact is the basis of action of
steroid antifertility drugs (see below Pharmacological actions of steroids: Steroid
contraceptives). Estrogen and progesterone occur in primitive invertebrates, but their
functions in those animals are obscure.

In male vertebrates the androgens—steroids secreted by the testes—maintain

spermatogenesis and the tissues of the reproductive tract.
Androgens promote male sexual behaviour and aggressiveness, muscular development,
and, in humans, the growth of facial and body hair and deepening of the voice.
Testosterone and androstenedione are the principal androgens of the testes. Testosterone
is more potent than androstenedione, but in the sexual tissues it appears to be converted
to 5α-dihydrotestosterone, an even more potent androgen.

Adrenal hormones

The adrenal cortex of vertebrates synthesizes oxygenated progesterone derivatives. These

compounds are hormones that are vital to survival and are classi ed according to their
biological activity. The glucocorticoids promote the deposition of glycogen in the liver and
the breakdown of body proteins. Mineralocorticoids stimulate retention of sodium in the
extracellular body uids. Cortisol is the principal glucocorticoid in many species, including
humans; in most rodents this role is lled by corticosterone. The most potent
mineralocorticoid of all species is aldosterone. Aldosterone has about 20 percent of the
glucocorticoid activity of cortisol, which, conversely, has about 0.1 percent of the
mineralocorticoid activity of aldosterone. Either steroid can maintain life in an animal
from which the adrenal glands have been removed. The secretion of glucocorticoids is
exquisitely responsive to injury and fear in animals and is primarily responsible for
metabolic adaptation to stressful conditions. Failure of the adrenal cortex in humans gives
rise to Addison disease, a formerly fatal condition that can now be successfully treated
with synthetic adrenal steroids.

Steroids of insects, fungi, and other organisms

An area of increasing interest is the role of steroids in the reproduction, development, and
self-defense of organisms such as insects. Insects and crustaceans produce the
ecdysones, steroid hormones that promote molting and the development of adult
characteristics.

Steroids also occur in fungi. For example, in the aquatic fungus Achlya bisexualis, the
steroid antheridiol (12) of the female stimulates male gamete formation.

Many plants, especially ferns and conifers, contain steroids that may protect them against
some predatory insects, although this function is not established. Progesterone, 11-
deoxycorticosterone, and related steroids with no known endocrine function in insects are
released into the water by several species of water beetles to repel predatory sh, and the
sea cucumbers (Holothuroideae) produce the holothurinogenins, a group of lanosterol
derivatives toxic to nerve tissue. An example of a holothurinogenin (13) is shown here.

Cardanolide and bufanolide derivatives, found in many plants and in the skin of toads,
cause vomiting, visual disturbances, and slowing of the heart in vertebrates and are
strong deterrents to predators. Birds and other predators instinctively avoid certain
grasshoppers and butter ies that store cardenolides of the plants upon which they feed.
The skin of the poison frog, Phyllobates aurotaenia, produces a deadly alkaloid,
batrachotoxin (14), which is used by tribal peoples as an arrow poison. The skin of
salamanders secretes a comparably poisonous alkaloid—samandarin (15).

Many steroid alkaloids occur in plants, but their functions, like those of the steroid
saponins, are unknown. It is possible that the taste of many of these compounds deters
grazing animals or attracts certain insect species to the plant.

Pharmacological actions of steroids

Aside from their principal physiological effects, all steroid hormones have generalized
in uences on metabolic systems throughout the body. These are sometimes seen as
powerful pharmacological side effects when, either during hormone therapy or through
some endocrine abnormality, the body is exposed to excessive amounts of a naturally
occurring steroid hormone. In some synthetic analogs of the natural hormones, a desired
activity is accentuated, whereas others are minimized. Furthermore, just as naturally
occurring steroid hormones of differing biological activity (estrogens, androgens,
glucocorticoids, and mineralocorticoids) often act antagonistically, the many steroid
analogs include a number of inhibitors of the natural hormones.

Androgens and anabolic steroids

A growing number of amateur and professional athletes have made use of synthetic
analogs of testosterone to accelerate muscular development and to improve strength.
Medical researchers have determined that the use of anabolic steroids may lead to heart
disease, sexual and reproductive disorders, immune de ciencies, liver damage, stunted
growth (in teenagers and young adults), and aggressive, violent behaviour.
Androgens secreted or administered in abnormally large amounts can cause
development of male characteristics in the female and precocious sexual development in
the male. Conversely, hypogonadism of the male (inadequate testicular function) leads to
retarded sexual development and retention of feminine bodily characteristics
(eunuchoidism), which can sometimes be remedied by administration of androgenic
steroids. Several esters of testosterone are commonly used by injection for this purpose.
Many orally active analogs of testosterone are also available in which activity is greatly
enhanced, and often the ratio of androgenic activity to anabolic activity is shifted
markedly in favour of the latter. This ratio primarily determines the therapeutic value of
these compounds as anabolic agents. They are used together with growth hormone to
promote growth in children in whom physical development is retarded. They are also
used to promote physical recovery from debilitating diseases.

Steroid contraceptives

The most effective method of contraception uses combinations of synthetic estrogen and
progesterone that prevent ovulation and render the uterine environment unfavourable to
conception and to the development of the ovum. Unlike the natural hormones, these
synthetic steroids are highly active when taken orally as tablets.

Estrogens that have been used in oral contraceptives include estranol, which has about
the same potency as estradiol, and mestranol, which is less potent. The main differences
between preparations are the character of the progesterones and the quantities and
ratios of the steroids. Synthetic progesterone is also used to correct irregularities of the
menstrual cycle and to maintain pregnancy in cases of threatened abortion.

Contraceptive steroid preparations are also used for

oral contraceptive; birth control pill
control of breeding cycles and synchronization of estrus
A 28-day package of birth control pills.
in farm animals. Synthetic estrogens can be used to
© cristi180884/Shutterstock.com
alleviate the unpleasant physical and psychic symptoms
of menopause in women and for the treatment of
prostate cancer in men and breast cancer in women. They are also used in some cases to
suppress the plasma cholesterol concentrations in people with advanced atherosclerosis,
a disease that is prevalent in men and postmenopausal women. (For more information
about oral contraceptives, see birth control and contraception.)

Cardiotonic steroids

Preparations in which cardiotonic steroids of both vegetable and animal origin are the
active principles have been used as emetics, diuretics, and arrow poisons for centuries.
The use of digitalis, ouabain, and strophanthin glycosides to slow the rate and strengthen
the contractility of the failing heart is one of the most important methods of treatment of
this condition. Of these agents, the digitalis glycosides are the most widely used. The
therapeutic effects of these agents are related to their in uence on muscle cells of the
heart.

Biosynthesis and metabolism of steroids

In plants and animals, steroids appear to be biosynthesized by similar reactions,
beginning with acetic acid, assisted by a type of enzyme. The isoprenoid hydrocarbon
called squalene, which occurs widely in nature, is thought to be the starting material from
which all steroids are made. Enzymatic transformation of squalene produces lanosterol in
animals and cycloartenol in plants, which yield cholesterol in both animals and plants.
Cholesterol is then converted to bile acids and steroid hormones in animals and to
steroids such as alkaloids in plants.

In animals, molecules of acetic acid

Cholesterol
(acetate) serve as precursors in the
biosynthesis of steroid hormones. Steroids are probably synthesized in all vertebrates
Encyclopædia Britannica, Inc. and in many invertebrates by the same pathway,
which includes cholesterol. Biosynthesis of cholesterol
is especially vigorous in the liver of vertebrates but also occurs in the intestine, gonads,
skin, and immature brain. Cholesterol is barely detectable in the adult brain. The insects,
certain mollusks, annelids, and some protozoa do not synthesize cholesterol but must
obtain it, or a related sterol, in their diets.

Cholesterol and other steroids are biosynthesized by

Structural formula of cholesterol.
extension of the enzyme pathway by which terpenoids are
Encyclopædia Britannica, Inc.
synthesized. Acetate fragments derived from common
nutrient materials are converted into mevalonic acid, from
which the terpenoid hydrocarbon squalene (16a) is formed. One end of the squalene
molecule is then oxidized, giving squalene 2,3-oxide (16b), which, by an intramolecular
reaction (cyclization) and structural rearrangement, yields the steroid lanosterol (16c). This
enzyme-controlled reaction may be initiated by introduction of a positive charge into the
oxide ring, because it is remarkably similar to the nonenzymic, acid-catalyzed cyclizations
of certain unsaturated hydrocarbons similar in structure to squalene. Cholesterol (16d) is
formed from lanosterol by further structural changes.
The principal forms in which cholesterol is excreted by vertebrates are the bile acids,
which are synthesized in the liver. Their formation involves speci c modi cations of the
steroid nucleus and formation of a carboxylic acid group that is linked to the amino acids
taurine or glycine to give the forms in which the bile acids are secreted into the bile. The
biosynthesis of cholesterol is in uenced by feedback mechanisms that suppress the
formation of mevalonic acid and, consequently, of cholesterol when levels of cholesterol
and bile acids in the tissues are elevated.

Steroid hormones

In vertebrates, cholesterol is the central precursor of all steroid hormones secreted by the
testes of the male, the ovaries of the female, and the adrenals of both sexes. These tissues
share an embryonic tissue of origin and, in consequence, many enzymes for the
transformation of cholesterol. A major (though not exclusive) common pathway involves
conversion to progesterone (17a). Progesterone is secreted by the corpus luteum of the
ovary, but in the adrenal cortex it is further metabolized to steroid hormones
(corticosteroids) such as cortisol (17b) and aldosterone (17d). In both ovary and testis,
progesterone is transformed further to the androgenic steroid androstenedione (17c),
which, together with its derivative testosterone (17e), is secreted by the testis. In the ovary,
androstenedione is modi ed to the estrogen estradiol (17f). Normally, each organ secretes
its own characteristic pattern of hormones, but in some disease states (e.g., genetic
defects and some tumours of these endocrine glands), these patterns may be profoundly
distorted.

Many tissues, but mainly the liver, metabolize the steroid hormones to physiologically
inactive products that are voided mainly in the urine, though some are also eliminated via
the bile and, ultimately, the feces. Diagnosis of endocrine abnormalities may be assisted
by analysis of urinary steroids. Urinary 17-ketosteroids (androstane derivatives with a C=O
function at C17) arise principally through oxidation of adrenal steroid hormones in the liver
and thus are used to gauge secretion by the adrenal gland rather than by the testis. In
pregnancy the urinary excretion of pregnanediol, the principal metabolite of
progesterone, measures placental progesterone output. Its decline before term may
forewarn of abortion, which may be averted by administration of progestational
hormones.

Steroid metabolism in plants

The early steps in the biosynthesis of steroids of both plants and animals are the same,
except that in plants lanosterol is replaced by the related compound cycloartenol, which
contains a three-membered ring (C9, C10, C19) in lieu of the nuclear double bond of
lanosterol. The side chains of the phytosterols, such as stigmasterol, and of the sterol
ergosterol of yeasts and other fungi contain extra carbon atoms that are incorporated in
reactions involving S-adenosylmethionine, which donates methyl groups in numerous
biological processes. Although most plant tissues contain only traces of cholesterol, this
sterol is the biogenetic precursor of such important plant steroids as the sapogenins,
glycosides, and alkaloids. Because pregnane derivatives are intermediates in some of
these transformations, plants and animals appear to have important features of steroid
metabolism in common.

Structural relationships of the principal categories of

steroids
Sterols
A large group, the sterols, is composed of the common 3-monohydroxy steroids of the
cholestane, ergostane, and stigmastane series and their methyl sterol biogenetic
precursors: lanosterol, cycloartenol, and certain derivatives of these sterols, such as
lophenol. Most sterols have a 3β-hydroxyl group, and many (though not the 4-methyl
sterols) have a double bond between carbon atoms 5 and 6. Various sterols have double
bonds at other positions in the nucleus corresponding to stages in the biosynthesis of
cholesterol and other steroids that resemble it in the structure of ring A. Animal sterols,
especially in embryonic tissues and skin, and phytosterols (e.g., stigmasterol) also may
have a double bond in the side chain. Sterols of feces (e.g., coprostanol) have a 3α-hydroxyl
group and cis- (5β-) linked rings A and B; they are formed by metabolism of other sterols
by intestinal bacteria. Certain sterols are transformed to calciferols (D vitamins) by
ultraviolet light; this process occurs naturally in the skin and is used commercially in the
manufacture of vitamin D (ergocalciferol) from ergosterol and of vitamin D
2 3
(cholecalciferol) from synthetic 7-dehydrocholesterol.

Bile acids and alcohols

The molecular structures of metabolites of cholesterol form an evolutionary series from

the bile alcohols, such as myxinol and scymnol of the elasmobranch shes (e.g., sharks
and rays) and the related alcohols of some bony shes and frogs, through the 5β-
cholestanoic acids of crocodiles and alligators, to the 5β-cholanoic acids of the birds and
mammals. They are not exclusively con ned to the species indicated; for example,
chenodeoxycholic acid is a major bile acid in humans and many other mammals, and
cholic acid is found in many nonmammalian species, together with primitive bile acids or
alcohols that are not found in mammals.

Estrogens

The estrogens of the ovary of vertebrates are steroids that are abundant in the urines of
pregnant mares and of stallions. The most potent natural estrogen is estradiol; the less-
potent estrogens—estrone, estriol, and other oxygenated phenolic steroids—are
metabolites of estradiol. Some species, notably the Equidae, secrete the less-active
estrogen equilenin. Estrone, synthesized from diosgenin, has been used as a starting
material for synthesis of androgenic and progestational steroids lacking a C19 methyl
group (19-nor steroids). Synthetic estrogens, such as estranol or mestranol (18), commonly
used in oral contraceptives and for other therapeutic purposes, have acetylenic
(containing triple bonds between carbon atoms) substituents. Nonsteroidal synthetic
estrogens—e.g., diethylstilbestrol (19) and related compounds—are used clinically and also
in animal husbandry to promote fattening of livestock and poultry and to improve the
quality of their meat.

Progesterones

Three naturally occurring steroids of the corpus luteum and placenta have progestational
action; these are progesterone and two of its metabolites. All possess an unsaturated
ketonic structure in ring A. Pregnanediol, the main metabolite of progesterone, lacks both
this structural feature and progestational activity.

Synthetic progestational steroids that are used in oral contraceptives and for other
therapeutic purposes (see above Pharmacological actions of steroids: Steroid
contraceptives) are derivatives of progesterone or of 19-nortestosterone. Among the latter
is norethandrolone (20).
Androgens

Testosterone and androstenedione are the major testicular androgens. Several other less-
active androgens occur naturally. Major metabolites of testosterone are androsterone and
etiocholanolone. The latter compound is androgenically inactive, but it is a pyrogen (e.g., a
fever-producing agent) that has been associated clinically with some febrile conditions.

Adrenal cortical hormones

The steroids of the adrenal cortex are progesterone derivatives that bear hydroxyl groups
at positions 11, 17α, or 21. The potent mineralocortoid aldosterone carries an aldehyde
function in place of the more usual C18 methyl group. Glucocorticoid potency is higher in
the trihydroxy derivative cortisol of humans, monkeys, and dogs than in the dihydroxy
steroid corticosterone of rats and mice. Every adrenal steroid hormone has a ketone group
at C3 and a double bond between C4 and C5. In the liver their physiological activities are
lost when ring A is reduced, and they are partially inactivated when the 11β-hydroxyl is
oxidized to a ketone group (as in cortisone and 11-dehydrocorticosterone). The adrenal
corticoids are among the most chemically reactive of the steroid hormones; they are
sensitive to strong acids and alkalies and to elevated temperatures. In many synthetic
analogs of cortisol and cortisone, physiological activity is modi ed.

Ecdysones

The molting hormones (zooecdysones) of insects and crustaceans are generally

derivatives of cholestane. All possess a ketone group at position 6, a double bond between
positions 7 and 8, and 2β-, 3β-, and 14α-hydroxyl groups. The side chain is hydroxylated at
C22 and variously at C20, C25, and C26. Some of these compounds occur in plants, many
of which also contain potent ecdysone analogs (phytoecdysones) with ergostane and
stigmastane side chains.
The ecdysones show cross-species activity; that is, the ecdysone of one species induces
molting in another species. The preponderance of ecdysones related to cholestane even
in phytophagous insects probably re ects their capacity to convert dietary phytosterols to
cholestane derivatives.

Cardiac glycosides and aglycones

Many species of plants contain toxic (speci cally, heart-arresting) steroids of the
cardanolide type as glycosides (compounds that contain structural groups derived from
sugars) of up to four sugar residues, which may include glucose, rhamnose, and 10 other
sugars characteristic of this group of natural products. Typically, these compounds are 5β-
steroids and have 3β- and 14β-hydroxyl groups, but hydroxyl groups may occur in many
other positions. In all cases, the aglycone (the steroid that results when the sugar groups
are removed) is less active than its glycosides, but generally activity declines with
increasing numbers of sugar residues after the rst. The structures of the sugars have
important but not predictable effects on activity.

The most important cardiac glycosides, medicinally, are those occurring in foxglove
(Digitalis): digitoxin, gitoxin, and digoxin. Each of these contains a speci c aglycone (e.g.,
digitoxigenin [23] is the aglycone of digitoxin) linked to three molecules of the sugar
digitoxose and is derived from a more complex glycoside (digilanides A, B, and C,
respectively) from which glucose and acetic acid are removed during the isolation
procedures.
The squill, or sea onion, Scilla maritima, a seashore plant, contains several toxic glycosides,
the aglycones of which are bufadienolides more typical of the toad poisons than of plant
products. (In a bufadienolide, two double bonds are present in the bufanolide side chain.)

A white form of the squill produces the glycoside scillaren A, which contains the aglycone
scillarenin, whereas a red form produces scilliroside, which is speci cally toxic to rodents
and has long been used as a rat poison. The contribution of the side chain to cardiac
activity differs little between the bufanolides and the cardanolides.

Toad poisons

Defensive venoms secreted by skin glands (principally the parotid glands) of the toad owe
their high toxicity to bufadienolides that occur both free (bufogenins) and combined
(bufotoxins). These compounds have digitalis-like properties and have been used
medicinally in a traditional Chinese preparation, Chan Su. The best characterized is
bufotoxin (24), from the European toad Bufo vulgaris and the Asian toad Bufo
gargarizans, the bufogenin of which is bufotalin, a close structural relative of gitoxin.
Sapogenins and saponins

Sapogenins are steroids of the spirostan type that occur widely and in great variety in
plants. They are linked to sugars as glycosides, usually through a 3β-hydroxyl group. The
glycosides are saponins, so called because they form soapy solutions and have other
surface active (e.g., hemolytic) properties. Since saponins are dif cult to purify, the
complete structures of only a few are known. Among these is dioscin (25)—from certain
yams, genus Dioscorea; the steroid portion of this saponin is diosgenin.

The nature and number of sugar residues per molecule are known for many saponins.

These include the common sugars glucose, xylose, galactose, rhamnose, and arabinose. In
most cases, however, the structure of only the sapogenin, which can be released from the
saponin by acid hydrolysis, is known with certainty. Linkage of rings A and B may be cis
(5β) or trans (5α) or may involve unsaturation at C5. A hydroxyl group is nearly always
present at position 3, and hydroxyl or ketonic groups may be present at positions 1, 2, 4, 5,
6, 11, 12, or 15. Many pairs of natural sapogenins differ only in con guration at C25. Their
structural features and abundance make diosgenin and hecogenin useful as starting
materials for steroid hormone manufacture.

Antiandrogens and antiestrogens

The estrogens and synthetic progesterones, such as medroxyprogesterone acetate and

chlormadinone acetate (26), have antiandrogenic properties that are the basis for their
use against benign or malignant hyperplasia of androgen-dependent tissues such as the
prostate. Other antiandrogens are cyproterone (27) and A-nortestosterone and A-
norprogesterone and their derivatives.

Synthetic antiestrogens include methyltestosterone, uoxymesterone, norethindrone

(norethisterone), and norgestrel. Since estrogens block the release of the pituitary
hormone responsible for ovulation, a potent antiestrogen can stimulate ovulation by
inhibiting this action of estrogens.

Glucocorticoids and cortisol

The anti-in ammatory and glucocorticoid activities of cortisol are enhanced, in some
cases with relative reduction of its mineralocorticoid activity, by various structural
modi cations. For example, a 9α- uorine atom enhances the glucocorticoid activity of
cortisol about 10-fold but its salt-retaining activity about 50-fold. On the other hand,
unsaturation at C1 increases glucocorticoid, but not mineralocorticoid, activity, and 6α-
uorine or methyl, and 16-methyl or hydroxyl, groups (and especially 16α,17α-acetonides—
i.e., compounds formed from 16α,17α-dihydroxy compounds and acetone) enhance anti-
in ammatory activity while reducing salt activity. These groupings, therefore, appear in
various combinations in anti-in ammatory steroids, many of which, however, lack the salt-
retaining activity necessary for total adrenal-replacement therapy. Cortisol analogs, such
as dexamethasone, are used to treat many in ammatory and rheumatic diseases, to
suppress the immune response in allergies and in organ transplantation, and to delay the
progress of leukemia. They are also widely used for treating local in ammatory reactions.
A synthetic steroid of a quite different type, spironolactone (Aldactone A), is used as an
antagonist to the action of aldosterone in certain cases of hypertension.
Raymond Brazenor Clayton Ronald H. Kluger

CITATION INFORMATION
ARTICLE TITLE: Steroid
WEBSITE NAME: Encyclopaedia Britannica
PUBLISHER: Encyclopaedia Britannica, Inc.
DATE PUBLISHED: 01 tháng 8 2019
URL: https://www.britannica.com/science/steroid
ACCESS DATE: tháng 11 11, 2019