Structure and Functions

Steroids are a group of organic compounds that are distinguished by a unique molecular arrangement of
seventeen carbon atoms situated in four adjacent rings. This set of four rings is referred to as the steroid nucleus
and is common to all steroid compounds. Three of these rings are hexagonal six-carbon rings arranged in a
bent-line fashion to form what is called a phenanthrene group. The fourth group or ring contains only five carbon
atoms. Steroids vary with the nature of the attached groups, the position of a given attached group, or some
alteration to the configuration of the steroid nucleus. Small chemical differences in the structure of steroids can
reflect very great differences in specific biological effects. Steroids are included in the lipid category of biological
molecules because they are nonpolar and insoluble in water.
Any steroid that contains a hydroxyl group (-OH) is called a sterol. This term comes from a Greek word meaning
“solid”; sterols were so named because they were among the earliest compounds that were found to be solid at
room temperature. Once chemical structures were determined, then other compounds with similar structures
were given the name steroid, which means "sterol-like." The suffix "-oid" comes from the Greek and means
“similar to.”
Chemists have isolated hundreds of different steroids from plants and animals; additionally, thousands have
been manufactured by chemically modifying natural steroids or by synthesizing the entire molecule. The parent
compound for steroids is acetic acid. Assisted by a variety of enzymes, acetic acid is altered and transformed
into several other compounds before cholesterol is formed. Cholesterol serves as the parent, or precursor
compound, for bile acids and for the steroids that are biologically important to the body.
Cholesterol is the most common steroid in the human body, as it is a structural component of cellular membranes.
The prefix "chole-" comes from the Greek word for liver bile, which is a digestive fluid manufactured by the liver
and secreted into the intestines. The name is appropriate since the bile contains a considerable amount of
cholesterol. Bile is stored in the gallbladder and becomes concentrated there. Cholesterol is not very soluble,
and if it accumulates in great enough quantities, it will form small crystals in the bile. These crystals may join
together to form larger particles that can block the narrow duct that leads from the gallbladder to the intestines.
These aggregations of particles are called gallstones and are composed of almost pure cholesterol. The
blockage can result in a buildup of pressure and cause much pain. Often, surgery is required to remove the
obstruction.
Cholesterol is also an important molecule because it is the precursor or parent molecule for the steroid hormones
produced by the gonads and the adrenal cortex. The gonads, a collective term referring to the testes and ovaries,
secrete the sex steroids. These sex steroids include estradiol and progesterone from
the ovaries and testosterone from the testes. The adrenal cortex secretes the corticosteroids, which
include cortisol and aldosterone as well as other steroid compounds. Most of the steroid hormones are
specialized in their function and do not produce general effects on metabolism. The sex hormones influence
reproduction by acting on sexual organs to stimulate their development and function, by influencing sexual
behavior, and by stimulating the development of secondary sex characteristics. Some of the steroids secreted
by the adrenal cortex have more general effects on the metabolism of carbohydrates and proteins in many
tissues.
Steroid hormones combine with specific receptors that are located in the cytoplasm of the responsive tissues.
Since these hormones are lipid-soluble, they pass readily through cell membranes, which are largely composed
of lipids. Inside the cytoplasm, a steroid-specific protein receptor will bind to the hormone. Upon binding, the
hormone-receptor complex becomes activated or transformed and is then translocated to the nucleus. In the
nucleus, the activated steroid receptor complex binds to the chromatin, or genetic material, causing an activation
of a certain set of genes. Gene activation results in the production of messenger molecules that induce the
production of specific proteins that are either used by the cell or secreted elsewhere.
The steroid hormones of the adrenal cortex fall into three categories, each having separate actions and sites of
action. Aldosterone is the principal mineralocorticoid and plays an important role in regulating body levels of
sodium and potassium. Cortisol, the major glucocorticoid, regulates carbohydrate metabolism. Adrenal
androgens are also produced, but they have only weak activity and play a minor physiological role under most
conditions. All adrenal steroids are derived from cholesterol.
Mineralocorticoids are the adrenal steroids that regulate levels of potassium and sodium in the body.
Aldosterone, the most potent mineralocorticoid, is secreted by the adrenal cortex at the rate of about 0.1 milligram
per day. Mineralocorticoids affect the distal tubules of the kidney by stimulating the excretion of potassium and
the reabsorption of sodium. The net effect of these actions is to increase the volume of body fluids.
Glucocorticoids are the adrenal steroids that regulate glucose metabolism. In humans, cortisol is responsible for
most of the glucocorticoid activity. It is secreted by the adrenal cortex at the rate of about 20 milligrams per day
and metabolically affects tissues throughout the body. Cortisol is regulated by the central nervous system and
by permissive or stimulatory messenger molecules of the body. Generally, glucocorticoids stimulate the
production of glucose and enhance the use of fat and protein as energy sources.
Androgens are steroid hormones that are secreted primarily by the testes but also by the adrenal glands and
ovaries. Testosterone is the principal androgen that is secreted by the testes; it regulates the development and
function of male sex accessory organs. Increased testosterone secretion during puberty is required for the growth
of the seminal vesicles and prostate. Removal of androgens by castration results in these organs undergoing
atrophy.
Androgens stimulate growth of the larynx and cause lowering of the voice. They increase hemoglobin synthesis,
which is higher in males than females, and affect bone growth by causing the conversion of cartilage to bone.
Androgens also promote protein synthesis or anabolic activity in skeletal muscle, bone, and kidneys. As a class
of compounds, androgens are reasonably safe drugs, since they have a limited and relatively predictable set
of side effects. In human males, testosterone is synthesized by the testes at the rate of about 8 milligrams per
day.
Estrogens and progesterones are primarily produced in the ovaries of nonpregnant adult women. In pregnancy,
the placenta is the major site of estrogen and progesterone production. Smaller amounts of estrogen synthesis
involve the liver, kidney, skeletal muscle, and testes. Estrogens cause the growth of the female reproductive
organs and are responsible for the expression of female secondary sex characteristics, such as breast
enlargement, female body contours, skin texture, and distribution of body hair. Estrogens are thought to protect
against atherosclerosis and heart attacks, since occurrence of these health problems in mature women is much
lower than in males of similar ages.
Uses and Complications
When cortisone was initially discovered, it was labeled a "wonder drug" and was thought to possess widespread
effectiveness in many areas of medicine. Although these expectations have not been realized, a variety of
steroids are found to be effective in medical practice and treatment. Steroids are commonly prescribed to serve
as replacements for those persons whose bodies are unable to produce specific steroid hormones in adequate
quantities. Steroids are effective as anti-inflammatory agents, reducing inflammatory reactions in a variety of
body tissues. They are also prescribed for patients who have undergone an organ transplantation or have highly
sensitive allergies, because they inhibit the responsiveness of the immune system.
The primary therapeutic use of androgens is for testicular deficiency in which the induction and maintenance of
male secondary sex characteristics are desired. In these cases, supplemental doses of androgens are given to
stimulate and enhance the development of sexual and accessory sex characteristics. Androgens are effective
also in the therapy of some anemias when persons have reduced levels of red blood cells. Androgens are used
to treat osteoporosis, which is a decrease in bone or skeletal mass. Androgens are given to women in the
treatment of breast cancer and are effective about 20 percent of the time. They are used to treat the abnormal
growth of endometrial tissue in the peritoneal cavity of women, a disease called endometriosis, and are effective
in that role.
Steroids also have anabolic activities that are manifested by stimulating increases in protein production, by
enhancing the uptake of amino acids into cells, and by inhibiting the glucocorticoids from breaking down proteins.
They influence embryonic development, especially the differentiation of the central nervous system and the male
reproductive tract. The excitatory function of androgens occurs at puberty, during which the reproductive organs
are activated to produce sex cells. Androgens also maintain the body’s sexual characteristics in the adult. Thus,
in cases of androgen deficiency there is a regression of male sexual behavior, libido, and reproductive function;
this regression is reversible with treatment.
It should be noted that anabolic steroids are frequently abused because of these kinds of effects. Athletes and
body builders in search of accelerated muscle building or physical definition are two groups in which such abuse
has been seen. A complication has been that the stimulatory effects of the anabolic steroids make the drug
administrations reinforcing and therefore loaded with addiction potential. As such, frequent users of anabolic
steroids should be aware of conditions such as dependence, as well as withdrawal and other problematic side
effects of heavy steroid use. Such effects may include increased periods of sleep disturbance, paranoia, anger
and agitation, mood swings or instability of mood, violence or other impulsive behavior, and concentration and
memory disturbance. Physical problems may include severe acne, jaundice, excess water retention, decreased
sperm count, high cholesterol, liver problems, and difficulty with blood sugar control.
The condition known as Addison’s disease is caused by a failure of the adrenal gland to secrete adequate
amounts of both glucocorticoids and mineralocorticoids. The symptoms of this disease are imbalances of body
levels of sodium and potassium, dehydration, reduced blood pressure, rapid weight loss, and generalized
weakness. A person with Addison’s disease will die if not treated with corticosteroids, because of the
severe electrolyte imbalance and dehydration.
Another disorder, Cushing’s syndrome, results when the adrenal gland secretes corticosteroids in excessive
quantities. Symptoms include high blood pressure, alterations in protein and carbohydrate metabolism, high
blood sugar concentrations, and muscular weakness. This syndrome is often caused by a tumor in the adrenal
gland that promotes the secretion of corticosteroids. Surgical intervention is often used to remove the portion of
the gland that is malfunctioning. Symptoms similar to those seen in Cushing’s syndrome are found in people with
inflammatory diseases who receive lengthy treatments with corticosteroids in order to reduce the inflammation.
Adrenogenital syndrome results from an excessive level of sex steroids, usually caused by hyperactivity of the
adrenal gland. Androgen is the major sex steroid involved in this clinical condition, which causes a premature
puberty and enlarged genital sex organs when it occurs in young children. Other characteristics are increased
amounts of body and facial hair as well as deepening of the voice.
The greatest use of estrogens as therapeutic agents is in oral contraception, or birth control pills. This method is
convenient, reversible, and relatively inexpensive; its use is worldwide and includes approximately 16 percent of
American women of childbearing age and 25 percent of all contraceptive users. Most oral contraceptives are
active combinations of estrogen and progesterone. Users take a daily pill containing both steroids for twenty or
twenty-one days of the menstrual cycle and then a placebo for seven or eight days. Withdrawal bleeding occurs
two to three days after discontinuing the pill. The mechanism for the effectiveness of these steroids involves
inhibiting the release of hormones that would normally stimulate ovulation. Hormones were also once the primary
treatment for menopausal symptoms. However, the Women’s Health Initiative Study showed that while hormone
therapy had some benefits, it also increased the risk for blood clots, breast cancer, heart attacks, and strokes.
Antiandrogens are substances that prevent or depress the action of androgens, or testosterone, on the body.
They are of value in the management of patients whose bodies are producing abnormally high levels of
androgens, who are undergoing a premature puberty, or who are affected with acne, hirsutism (excessive
hairiness, especially in women), and certain tumors or neoplasms. Potentially, these drugs can be utilized to
cause sterility in males.
Natural body androgens stimulate the growth of the prostate gland in males and enhance the proliferation of
many prostate cancers . Treatment of abnormal growths, malignant cancers, or benign tumors in the male
prostate gland has frequently used either natural or synthetic steroids. Estradiol, a form of the female sex steroid
estrogen, is used to control the advancement of prostate carcinoma in some males and can induce remission in
50 to 80 percent of the cases of prostate tumors. Estrogens exert their effect by interfering with androgen
production or by inhibiting the function of androgen-responsive tissues. Thus, in some cases, estrogens inhibit
abnormal cellular growth. A manufactured synthetic drug, cyproterone acetate, is also used in the treatment of
benign prostatic enlargement in men. Cyproterone acetate is very effective in treating prostate cancers and
tumors, and it does not have the feminizing side effects of the estrogens; however, it does cause inhibition of
sperm production and loss of sexual drive.
Perspective and Prospects
The use of steroids as therapeutic agents began in the early 1930s. At that time, Philip Showalter Hench, who
was working in the Mayo Clinic, noticed that the symptoms of arthritic women were alleviated when they became
pregnant. He suggested that increased secretions from the adrenal cortex might be the responsible agents.
Later, clinical trials were conducted to test the role of corticosteroids in treating acute arthritis. With the use of
adequate dosages, the clinical response was impressive. The 1950 Nobel Prize in Physiology or Medicine was
awarded to Hench and his coworkers for their finding that cortisone was effective in treating arthritis.
Pharmaceutical firms have manufactured numerous steroid derivatives, all of which have different effectiveness
levels as glucocorticoids, mineralocorticoids, or sex steroids. Organic chemists synthesize analogues of adrenal
steroids in order to create compounds that produce heightened biological effects with a minimum or lack of side
effects. As a consequence, hundreds of different steroids are available. Most of these are characterized
according to their biological effectiveness, such as their ability to reduce inflammation or to inhibit the immune
system. When determining a course of treatment, a physician chooses a particular steroid that enhances the
effects that are desired and has minimal effects in related areas. Some pharmaceutical derivatives of adrenal
steroids are very poorly absorbed by the skin. These derivatives are especially useful to apply to the skin when
a maximal local effect is desired without a generalized effect on other body regions.
Steroids, however, can also have negative, and sometimes dangerous, effects on the body, whether they are
ingested (cholesterol) or injected (anabolic steroids). Evidence indicates that high blood cholesterol levels are
associated with an increased risk of atherosclerosis, a clinical condition in which localized plaques (or atheromas)
build up in the walls of arteries, reducing blood flow. Atheromas serve as locations for blood clot formation, which
can further block the blood supply to a vital organ such as the heart, brain, or lung. High blood cholesterol may
result from a diet rich in cholesterol and saturated fat, or it may result from an inherited condition in which affected
individuals have extremely high cholesterol concentrations regardless of their diet. In the later case affected
persons usually suffer heart attacks during their childhood.
Cholesterol is found in foods that are based on animal products. Cholesterol-rich foods include most meats,
eggs, and dairy products such as cheese, cream, and butter. Humans readily absorb cholesterol from dietary
sources. Most Western diets contain 400 to 600 milligrams of cholesterol per day, of which about 75 percent is
readily absorbed into the bloodstream from the dietary tract. Cholesterol is carried to the arteries by proteins in
the blood plasma called low-density lipoproteins (LDLs). A given cell may engulf the LDLs and use the
cholesterol for different purposes. The LDLs in a given location may stimulate other cells to secrete growth
factors that either begin or contribute to the development of an atheroma. Thus, the risk of atherosclerosis is
greatly increased. Most people can significantly lower their blood cholesterol levels through controlled exercise
and diet. Since saturated fat raises blood cholesterol levels, many health experts recommend that foods such
as fatty meat, egg yolk, and liver should be eaten sparingly so that fat contributes less than 30 percent to the
total calories of a diet, though others have challenged this assumption.
The use and abuse of anabolic steroids to increase muscle mass and strength is widespread in both amateur
and professional sports. Although those promoting steroid use claim increases in muscle mass, strength, and
endurance, controlled clinical trials show minimal, if any, enhancement of muscle mass and strength.
Testosterone may also enhance training efforts by promoting aggressive behavior. Use of these compounds
poses ethical questions and increases the risk of serious toxicity because of the extremely high doses that are
administered, often as much as one hundred times the usual therapeutic dosages.