Goodman and Gilman Manual of Pharmacology and Therapeutics
Hormones and Hormone Antagonists
TESTOSTERONE AND OTHER ANDROGENS
In men, testosterone is the principal secreted androgen. Leydig cells synthesize the majority of testosterone by the pathways shown in Figure 41–1. In women, testosterone also is the principal androgen and is synthesized in the corpus luteum and the adrenal cortex by similar pathways. The testosterone precursors androstenedione and dehydroepiandrosterone are weak androgens that can be converted peripherally to testosterone.
Figure 41–1 Pathway of synthesis of testosterone in the Leydig cells of the testes. In Leydig cells, the 11 and 21 hydroxylases (present in adrenal cortex) are absent but CYP17 (17 α-hydroxylase) is present. Thus, androgens and estrogens are synthesized; corticosterone and cortisol are not formed. Bold arrows indicate favored pathways.
SECRETION AND TRANSPORT OF TESTOSTERONE. Testosterone secretion is greater in men than in women at almost all stages of life, a difference that explains many of the other differences between men and women. In the first trimester in utero, the fetal testes begin to secrete testosterone, the principal factor in male sexual differentiation, probably stimulated by human chorionic gonadotropin (hCG) from the placenta. By the beginning of the second trimester, the serum testosterone concentration is close to that of mid-puberty, ~250 ng/dL (Figure 41–2). Testosterone production then falls by the end of the second trimester, but by birth the value is again ~250 ng/dL, possibly due to stimulation of the fetal Leydig cells by luteinizing hormone (LH) from the fetal pituitary gland. The testosterone value falls again in the first few days after birth, but it rises and peaks again at ~250 ng/dL at 2-3 months after birth and falls to <50 ng/dL by 6 months, where it remains until puberty. During puberty, from ~12 to 17 years of age, the serum testosterone concentration in males increases so that by early adulthood the serum testosterone concentration is 500 ng/dL to 700 ng/dL in men, compared to 30 ng/dL to 50 ng/dL in women. The magnitude of the testosterone concentration in the male is responsible for the pubertal changes that further differentiate men from women. As men age, their serum testosterone concentrations gradually decrease, which may contribute to other effects of aging in men.
Figure 41–2 Schematic representation of the serum testosterone concentration from early gestation to old age.
LH, secreted by the pituitary gonadotropes (see Chapter 38), is the principal stimulus of testosterone secretion in men, perhaps potentiated by follicle-stimulating hormone (FSH), also secreted by gonadotropes. The secretion of LH by gonadotropes is positively regulated by hypothalamic gonadotropin-releasing hormone (GnRH); testosterone directly inhibits LH secretion in a negative feedback loop. LH is secreted in pulses, which occur approximately every 2 h and are greater in magnitude in the morning. The pulsatility appears to result from pulsatile secretion of GnRH from the hypothalamus. Testosterone secretion is likewise pulsatile and diurnal, the highest plasma concentrations occurring at ~8 A.M. and the lowest at ~8 P.M. The morning peaks diminish as men age. Sex hormone-binding globulin (SHBG) binds ~40% of circulating testosterone with high affinity, rendering the bound hormone unavailable for biological effects. Albumin binds almost 60% of circulating testosterone with low affinity, leaving ~2% unbound or free. In women, LH stimulates the corpus luteum (formed from the follicle after release of the ovum) to secrete testosterone. Under normal circumstances, however,estradiol and progesterone, not testosterone, are the principal inhibitors of LH secretion in women.
METABOLISM OF TESTOSTERONE TO ACTIVE AND INACTIVE COMPOUNDS. Testosterone has many different effects in tissues, both directly and through its metabolism to dihydrotestosteroneand estradiol (Figure 41–3). The enzyme 5α-reductase catalyzes the conversion of testosterone to dihydrotestosterone. Dihydrotestosterone binds the androgen receptor (AR) with higher affinity than testosterone and activates gene expression more efficiently. Two forms of 5α-reductase have been identified: type I, which is found predominantly in nongenital skin, liver, and bone; and type II, which is found predominantly in urogenital tissue in men and genital skin in men and women. The enzyme complex aromatase, present in many tissues, catalyzes the conversion of testosterone to estradiol. This conversion accounts for ~85% of circulating estradiol in men; the remainder is secreted directly by the testes. Hepatic metabolism converts testosterone to the biologically inactive compounds androsterone and etiocholanolone (see Figure 41–3). Dihydrotestosterone is metabolized to androsterone, androstanedione, and androstanediol.
Figure 41–3 Metabolism of testosterone to its major active and inactive metabolites.
PHYSIOLOGICAL AND PHARMACOLOGICAL EFFECTS OF ANDROGENS
Testosterone is the principal circulating androgen in men. The varied effects of testosterone are due to its ability to act by at least 3 mechanisms: by binding to the AR; by conversion in certain tissues to dihydrotestosterone, which also binds to the AR; and by conversion to estradiol, which binds to the estrogen receptor (Figure 41–4).
Figure 41–4 Direct effects of testosterone and effects mediated indirectly via dihydrotestosterone or estradiol.
EFFECTS THAT OCCUR VIA THE ANDROGEN RECEPTOR. Testosterone and dihydrotestosterone act as androgens via a single AR, a member of the nuclear receptor superfamily and is designated as NR3A.
In the absence of a ligand, the AR is located in the cytoplasm associated with a heat-shock protein complex. When testosterone or dihydrotestosterone binds to the ligand-binding domain, the AR dissociates from the heat-shock protein complex, dimerizes, and translocates to the nucleus. The dimer then binds via the DNA-binding domains to androgen response elements on certain responsive genes. The ligand-receptor complex recruits coactivators and acts as a transcription factor complex, stimulating or repressing expression of those genes.
Mutations in the hormone or DNA-binding regions of AR result in resistance to the action of testosterone, beginning in utero. Male sexual differentiation therefore is incomplete, as is pubertal development. Other AR mutations occur in patients with spinal and bulbar muscular atrophy, known as Kennedy disease. These patients have an expansion of the CAG repeat, which codes for glutamine, at the amino terminus of the molecule. The result is very mild androgen resistance, manifest principally by gynecomastia, and progressively severe motor neuron atrophy. The mechanism by which the neuronal atrophy occurs is unknown. Other mutations in AR may explain why metastatic prostate cancer often regresses initially in response to androgen deprivation treatment, but then becomes unresponsive to continued deprivation. AR continues to be expressed in androgen-independent prostate cancer, and its signaling remains active. The ligand-independent signaling may result from mutations in the AR gene or changes in AR coregulatory proteins. In some patients resistant to standard androgen deprivation therapy, the tumor responds to further depletion of androgens by inhibitors of adrenal androgen synthesis, such as abiraterone.
EFFECTS THAT OCCUR VIA THE ESTROGEN RECEPTOR. Certain effects of testosterone are mediated by its conversion to estradiol, catalyzed by CYP19.
In the rare males deficient in CYP19 or the estrogen receptor, the epiphyses do not fuse and long-bone growth continues indefinitely; moreover, such patients are osteoporotic. Estradiol corrects the bone abnormalities in patients with aromatase deficiency but not in those with an estrogen-receptor defect. Because men have larger bones than women, and bone expresses the AR, testosterone also may have an effect on bone via the AR. Administration of estradiol to a male with CYP19 deficiency can increase libido, suggesting that the effect of testosterone on male libido may be mediated by conversion to estradiol.
EFFECTS OF ANDROGENS AT DIFFERENT STAGES OF LIFE
In Utero. When the fetal testes, stimulated by hCG, begin to secrete testosterone at about the eighth week of gestation, the high local concentration of testosterone around the testes stimulates the nearby Wolffian ducts to differentiate into the male internal genitalia. In the anlage of the external genitalia, testosterone is converted to dihydrotestosterone, which causes the development of the male external genitalia. The increase in testosterone at the end of gestation may result in further phallic growth.
Infancy. The consequences of the increase in testosterone secretion by the testes during the first few months of life are not yet known.
Puberty. Puberty in the male begins at a mean age of 12 years with an increase in the secretion of FSH and LH from the gonadotropes, stimulated by increased secretion of GnRH from the hypothalamus. The increased secretion of FSH and LH stimulates the testes. The increase in testosterone production by Leydig cells and the effect of FSH on the Sertoli cells stimulate the development of the seminiferous tubules, which eventually produce mature sperm. Increased secretion of testosterone into the systemic circulation affects many tissues simultaneously, and the changes in most of them occur gradually during the course of several years. The phallus enlarges in length and width, the scrotum becomes rugated, and the prostate begins secreting the fluid it contributes to the semen. The skin becomes coarser and oilier due to increased sebum production, which contributes to the development of acne. Sexual hair begins to grow, initially pubic and axillary hair, then hair on the lower legs, and finally other body hair and facial hair. Muscle mass and strength, especially of the shoulder girdle, increase, and subcutaneous fat decreases. Epiphyseal bone growth accelerates, resulting in the pubertal growth spurt, but epiphyseal maturation leads eventually to a slowing and then cessation of growth. Bone also becomes thicker. Erythropoiesis increases, resulting in higher hematocrit and hemoglobin concentrations in men than boys or women. The larynx thickens, resulting in a lower voice. Libido develops. Other changes may result from the increase in testosterone during puberty. Men tend to have a better sense of spatial relations than do women and to exhibit behavior that differs in some ways from that of women, including being more aggressive.
Adulthood. The serum testosterone concentration and the characteristics of the adult man are maintained largely during early adulthood and midlife. One change during this time is the gradual development of male pattern baldness, beginning with recession of hair at the temples and/or at the vertex. Two other conditions are of great medical significance. One is benign prostatic hyperplasia, which occurs to a variable degree in almost all men, sometimes obstructing urine outflow by compressing the urethra as it passes through the prostate. This development is mediated by the conversion of testosterone to dihydrotestosterone by 5α-reductase II within prostatic cells. The other change is the development of prostate cancer. Although no direct evidence suggests that testosterone causes the disease, prostate cancer depends on androgen stimulation. This dependency is the basis of treating metastatic prostate cancer by lowering the serum testosterone concentration or by blocking its action at the receptor.
Senescence. As men age, the serum testosterone concentration gradually declines (see Figure 41–2), and the SHBG concentration gradually increases, so that by age 80, the total testosterone concentration is ~80% and the free testosterone is ~40% of those at age 20. This fall in serum testosterone could contribute to several other changes that occur with increasing age in men, including decreases in energy, libido, muscle mass and strength, and bone mineral density. Androgen deprivation also leads to insulin resistance, truncal obesity, and abnormal serum lipids, as observed in patients with metastatic prostate cancer receiving this treatment (see also Chapter 63).
CONSEQUENCES OF ANDROGEN DEFICIENCY
The consequences of androgen deficiency depend on the stage of life during which the deficiency first occurs and on the degree of the deficiency.
DURING FETAL DEVELOPMENT. Testosterone deficiency in a male fetus during the first trimester in utero causes incomplete sexual differentiation. Complete deficiency of testosterone secretion results in entirely female external genitalia. Testosterone deficiency at this stage of development also leads to failure of the Wolffian ducts to differentiate into the male internal genitalia, but the Müllerian ducts do not differentiate into the female internal genitalia as long as testes are present and secrete Müllerian inhibitory substance. Similar changes occur if testosterone is secreted normally but its action is diminished because of an abnormality of the AR or of the 5α-reductase. Abnormalities of the AR can have quite varied effects. The most severe form results in complete absence of androgen action and a female phenotype; moderately severe forms result in partial virilization of the external genitalia; and the mildest forms permit normal virilization in utero and result only in impaired spermatogenesis in adulthood. Abnormal 5α-reductase results in incomplete virilization of the external genitalia in utero but normal development of the male internal genitalia, which requires only testosterone. Testosterone deficiency during the third trimester impairs phallus growth. The result, microphallus, is a common occurrence in boys later discovered to be unable to secrete LH due to abnormalities of GnRH synthesis. In addition, with testosterone deficiency, the testes fail to descend into the scrotum; this condition, cryptorchidism, occurs commonly in boys whose LH secretion is subnormal (see Chapter 38).
BEFORE COMPLETION OF PUBERTY. When a boy can secrete testosterone normally in utero but loses the ability to do so before the anticipated age of puberty, the result is failure to complete puberty. All of the pubertal changes previously described, including those of the external genitalia, sexual hair, muscle mass, voice, and behavior, are impaired to a degree proportionate to the abnormality of testosterone secretion. In addition, if growth hormone secretion is normal when testosterone secretion is subnormal during the years of expected puberty, the long bones continue to lengthen because the epiphyses do not close. The result is longer arms and legs relative to the trunk. Another consequence of subnormal testosterone secretion during the age of expected puberty is enlargement of glandular breast tissue, called gynecomastia.
AFTER COMPLETION OF PUBERTY. When testosterone secretion becomes impaired after puberty (e.g., castration or anti-androgen treatment), regression of the pubertal effects of testosterone depends on both the degree and the duration of testosterone deficiency. When the degree of testosterone deficiency is substantial, libido and energy decrease within a week or 2, but other testosterone-dependent characteristics decline more slowly. A clinically detectable decrease in muscle mass in an individual does not occur for several years. A pronounced decrease in hematocrit and hemoglobin will occur within several months. A decrease in bone mineral density probably can be detected by dual energy absorptiometry within 2 years. A loss of sexual hair takes many years.
IN WOMEN. Loss of androgen secretion in women results in a decrease in sexual hair, but not for many years. The loss of androgens (especially with the severe loss of ovarian and adrenal androgens that occurs in panhypopituitarism) may result in the loss of effects associated with libido, energy, muscle mass and strength, and bone mineral density.
THERAPEUTIC ANDROGEN PREPARATIONS
Ingestion of testosterone is not an effective means of replacing testosterone deficiency due to the rapid hepatic catabolism. Most pharmaceutical preparations of androgens, therefore, are designed to bypass hepatic catabolism of testosterone.
TESTOSTERONE ESTERS. Esterifying a fatty acid to the 17α-hydroxyl group of testosterone creates a compound that is even more lipophilic than testosterone itself. When an ester, such as testosterone enanthate (heptanoate) or cypionate (cyclopentylpropionate) (Table 41–1), is dissolved in oil and administered intramuscularly every 2-4 weeks to hypogonadal men, the ester hydrolyzes in vivo and results in serum testosterone concentrations that range from higher than normal in the first few days after the injection to low normal just before the next injection (Figure 41–5). Attempts to decrease the frequency of injections by increasing the amount of each injection result in wider fluctuations and poorer therapeutic outcomes. The undecanoate ester of testosterone, when dissolved in oil and ingested orally, is absorbed into the lymphatic circulation, thus bypassing initial hepatic catabolism. Testosterone undecanoate in oil also can be injected and produces stable serum testosterone concentrations for 2 months. The undecanoate ester of testosterone is not currently marketed in the U.S.
Androgens Available for Therapeutic Use
Figure 41–5 Pharmacokinetic profiles of testosterone preparations during chronic administration to hypogonadal men. Doses of each were given at time 0. Shaded areas indicate range of normal levels. A.Data adapted from Snyder PJ, et al. J Clin Endocrinol Metab, 1980;51:1535-1539. B. Data adapted from Dobs AS, et al. J Clin Endocrinol Metab, 1999;84:3469-3478. C. Data adapted from Swerdloff RS, et al. J Clin Endocrinol Metab, 2000;85:4500-4510.
ALKYLATED ANDROGENS. Several decades ago, chemists found that adding an alkyl group to the 17α position of testosterone retards its hepatic catabolism. Consequently, 17α-alkylated androgens are androgenic when administered orally; however, they are less androgenic than testosterone and cause hepatotoxicity, whereas native testosterone does not. Some 17α-alkylated androgens show greater anabolic effects than androgenic effects compared to native testosterone in laboratory tests in rats; however, these “anabolic” steroids, so favored by athletes to illicitly improve performance, have not been convincingly demonstrated to have such a differential effect in human beings. Citing potentially serious health risks, the FDA has recommended against the use of body-building products that are marketed as containing steroids or steroid-like substances.
TRANSDERMAL DELIVERY SYSTEMS. Chemicals called excipients are used to facilitate the absorption of native testosterone across the skin in a controlled fashion. These transdermal preparations provide more stable serum testosterone concentrations than do injections of testosterone esters. The first such preparations were patches, 1 of which (ANDRODERM) is still available. Newer preparations include gels (ANDROGEL, TESTIM, Bio-T-Gel) and a buccal tablet (STRIANT) (see Figure 41–5).
SELECTIVE ANDROGEN RECEPTOR MODULATORS. Selective estrogen receptor modulators (SERMs) have been developed (see Chapter 40). Are selective AR modulators possible that exhibit desirable effects of testosterone in some tissues, such as muscle and bone, without the undesirable effects in other tissues, such as prostate? Nonsteroidal molecules with these properties have been developed and are being tested in humans.
THERAPEUTIC USES OF ANDROGENS
MALE HYPOGONADISM. The best established indication for administration of androgens is testosterone deficiency in men. Any of the testosterone preparations or testosterone esters described can be used to treat testosterone deficiency.
Monitoring for Efficacy. The goal of administering testosterone to a hypogonadal man is to mimic as closely as possible the normal serum concentration (see Figure 41–5). Therefore, measuring the serum testosterone concentration during treatment is the most important aspect of monitoring testosterone treatment for efficacy. When the enanthate or cypionate ester of testosterone is administered once every 2 weeks, the serum testosterone concentration measured midway between doses should be normal; if not, the dosage schedule should be adjusted accordingly. If testosterone deficiency results from testicular disease, as indicated by an elevated serum LH concentration, adequacy of testosterone treatment also can be judged indirectly by the normalization of LH within 2 months of treatment initiation. Normalization of the serum testosterone concentration induces normal virilization in prepubertal boys and restores virilization in adult men who became hypogonadal as adults. Within a few months, and often sooner, libido, energy, and hematocrit return to normal. Within 6 months, muscle mass increases and fat mass decreases. Bone density, however, continues to increase for 2 years.
Monitoring for Deleterious Effects. Testosterone administered by itself as a the transdermal preparation has no “side effects” (i.e., no effects that endogenously secreted testosterone does not have), as long as the dose is not excessive. Modified testosterone compounds, such as the 17α-alkylated androgens, do have undesirable effects even when dosages are targeted at physiological replacement. Some of these undesirable effects occur shortly after testosterone administration is initiated, whereas others usually do not occur until administration has been continued for many years. Raising the serum testosterone concentration can result in undesirable effects similar to those that occur during puberty, including acne, gynecomastia, and more aggressive sexual behavior. Physiological amounts of testosterone do not appear to affect serum lipids or apolipoproteins. Replacement of physiological levels of testosterone occasionally may have undesirable effects in the presence of concomitant illnesses. If the testosterone dose is excessive, erythrocytosis and, uncommonly, salt and water retention and peripheral edema occur even in men who have no predisposition to these conditions. When a man is >40 years of age, he is subject to certain testosterone-dependent diseases, including benign prostatic hyperplasia and prostate cancer. The principal adverse effects of the 17α-alkylated androgens are hepatic, including cholestasis and, uncommonly, peliosis hepatis, blood-filled hepatic cysts. Hepatocellular cancer has been reported rarely. The 17α-alkylated androgens, especially in large amounts, may lower serum high-density lipoprotein cholesterol.
Monitoring at the Anticipated Time of Puberty. Testosterone accelerates epiphyseal maturation, leading initially to a growth spurt but then to epiphyseal closure and permanent cessation of linear growth. Consequently, the height and growth-hormone status of the boy being treated, must be considered. Boys who are short because of growth-hormone deficiency should be treated with growth hormone before their hypogonadism is treated with testosterone.
MALE SENESCENCE. Preliminary evidence suggests that increasing the serum testosterone concentration of men whose serum levels are subnormal for no reason other than their age will increase their bone mineral density and lean mass and decrease their fat mass. It is uncertain, however, if such treatment will worsen benign prostatic hyperplasia or increase the incidence of prostate cancer.
FEMALE HYPOGONADISM. In a study of women with low serum testosterone concentrations due to panhypopituitarism, increasing the testosterone concentration to normal was associated with small increases in bone mineral density, fat-free mass, and sexual function compared to placebo.
ENHANCEMENT OF ATHLETIC PERFORMANCE. Some athletes take drugs, including androgens, to attempt to improve their performance. Citing potentially serious health risks, the FDA has recommended against the use of body-building products that are marketed as containing steroids or steroid-like substances.
Kinds of Androgens Used. Virtually all androgens produced for human or veterinary purposes have been taken by athletes. When such use by athletes began more than 25 years ago, 17α-alkylated androgens and other compounds that were thought to have greater anabolic effects than androgen effects relative to testosterone (so-called anabolic steroids) were used most commonly. Because these compounds can be detected readily by organizations that govern athletic competitions, other agents that increase the serum concentration of testosterone itself, such as the testosterone esters or hCG, have increased in popularity. Testosterone precursors, such as androstenedione and dehydroepiandrosterone (DHEA), also have increased in popularity recently because they are treated as nutritional supplements and thus are not regulated by athletic organizations. A new development in use of androgens by athletes is tetrahydrogestrinone (THG), a potent androgen that appears to have been designed and synthesized in order to avoid detection by antidoping laboratories on the basis of its novel structure (see Table 41–1) and rapid catabolism.
Efficacy. The few controlled studies of the effects of pharmacological doses of androgens do suggest a dose-dependent effect of testosterone on muscle strength that acts synergistically with exercise. In another trial, androstenedione did not produce an increase in muscle strength in men compared to placebo; the treatment also did not increase the mean serum testosterone concentration.
Side Effects. All androgens suppress gonadotropin secretion when taken in high doses and thereby suppress endogenous testicular function. This decreases endogenous testosterone and sperm production, resulting in diminished fertility. If administration continues for many years, testicular size may diminish. Testosterone and sperm production usually return to normal within a few months of discontinuation but may take longer. High doses of androgens also cause erythrocytosis. When administered in high doses, androgens that can be converted to estrogens, such as testosterone itself, cause gynecomastia. Androgens whose A ring has been modified so that it cannot be aromatized, such as dihydrotestosterone, do not cause gynecomastia even in high doses. The 17α-alkylated androgens are the only androgens that cause hepatotoxicity. These androgens, when administered in high doses, affect serum lipid concentrations, specifically to decrease high-density lipoprotein (HDL) cholesterol and increase low-density lipoprotein (LDL) cholesterol. Women and children experience virilization, including facial and body hirsutism, temporal hair recession in a male pattern, and acne. Boys experience phallic enlargement, and women experience clitoral enlargement. Boys and girls whose epiphyses have not yet closed experience premature closure and stunting of linear growth.
CATABOLIC AND WASTING STATES. Testosterone, because of its anabolic effects, has been used in attempts to ameliorate catabolic and muscle-wasting states, but this has not been generally effective. One exception is in the treatment of muscle wasting associated with acquired immunodeficiency syndrome (AIDS), which often is accompanied by hypogonadism.
ANGIOEDEMA. Chronic androgen treatment of patients with angioedema effectively prevents attacks. The disease is caused by hereditary impairment of C1-esterase inhibitor or acquired development of antibodies against it. The 17α-alkylated androgens (e.g., stanozolol, danazol) stimulate hepatic synthesis of the esterase inhibitor. Alternatively, concentrated C1-esterase inhibitor derived from human plasma (CINRYZE) may be used for protection in patients with hereditary angioedema.
BLOOD DYSCRASIAS. Androgens, such as danazol, still are used occasionally as adjunctive treatment for hemolytic anemia and idiopathic thrombocytopenic purpura that are refractory to first-line agents.
INHIBITORS OF TESTOSTERONE SECRETION. Analogs of GnRH effectively inhibit testosterone secretion by inhibiting LH secretion. GnRH analogs, given repeatedly, downregulate the GnRH receptor and are available for treatment of prostate cancer.
Some antifungal drugs of the imidazole family, such as ketoconazole (see Chapter 57), inhibit CYPs and thereby block the synthesis of steroid hormones, including testosterone and cortisol. Because they may induce adrenal insufficiency and are associated with hepatotoxicity, these drugs generally are not used to inhibit androgen synthesis but sometimes are employed in cases of glucocorticoid excess (seeChapter 42).
INHIBITORS OF ANDROGEN ACTION. These drugs inhibit the binding of androgens to the AR or inhibit 5α-reductase.
ANDROGEN RECEPTOR ANTAGONISTS.
Flutamide, Bicalutamide, Nilutamide, and Enzalutamide. These relatively potent AR antagonists have limited efficacy when used alone because the increased LH secretion stimulates higher serum testosterone concentrations. They are used primarily in conjunction with a GnRH analog in the treatment of metastatic prostate cancer (see Chapter 63). Flutamide also has been used to treat hirsutism in women; however, its association with hepatotoxicity warrants caution against its use for this cosmetic purpose.
Spironolactone (ALDACTONE; see Chapter 25) is an inhibitor of aldosterone that also is a weak inhibitor of the AR and a weak inhibitor of testosterone synthesis. When the agent is used to treat fluid retention or hypertension in men, gynecomastia is a common side effect. In part because of this adverse effect, the selective mineralocorticoid receptor antagonist eplerenone (INSPRA) was developed. Spironolactone can be used in women to treat hirsutism. Cyproterone acetate is a progestin and a weak anti-androgen by virtue of binding to the AR. It is effective in reducing hirsutism but is not approved for use in the U.S.
5α-REDUCTASE INHIBITORS. Finasteride (PROSCAR) and dutasteride (AVODART) are antagonists of 5α-reductase. They block the conversion of testosterone to dihydrotestosterone, especially in the male external genitalia. These drugs are approved to treat benign prostatic hyperplasia.
Impotence is a documented, albeit infrequent, side effect of this use. Gynecomastia is a rare side effect. Finasteride also is approved for use in the treatment of male pattern baldness under the trade name PROPECIA, and is effective in the treatment of hirsutism.