Chapter 41: Androgens

LH, secreted by the pituitary gonadotropes (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), and testosterone directly inhibits LH secretion in a negative feedback loop. LH is secreted in pulses, which occur approximately every 2 hours and are greater in magnitude in the morning. The pulsatility appears to result from pulsatile secretion of GnRH from the hypothalamus. Pulsatile administration of GnRH to men who are hypogonadal due to hypothalamic disease results in normal LH pulses and testosterone secretion, but continuous administration does not (Crowley et al., 1985). 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 (Bremner et al., 1983).

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. 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 some testosterone assays, the latter two components are considered as "bioavailable" testosterone.

The androgen receptor has an amino-terminal domain that contains a polyglutamine repeat of variable length, a DNA-binding domain consisting of two Zn finger motifs, and a carboxyterminal ligand-binding domain. The polyglutamine repeat of variable length is unique to the androgen receptor; a shorter length appears to increase its activity. In the absence of a ligand, the androgen receptor is located in the cytoplasm associated with a heat-shock protein complex. When testosterone or dihydrotestosterone binds to the ligand-binding domain, the androgen receptor 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 (Agoulnik and Weigel, 2008; Brinkmann and Trapman, 2000).

The importance of the androgen receptor is illustrated by the consequences of its mutations. Predictably, mutations that either alter the primary sequence of the protein or cause a single amino acid substitution in the hormone- or DNA-binding domains result in resistance to the action of testosterone, beginning in utero (McPhaul and Griffin, 1999). Male sexual differentiation therefore is incomplete, as is pubertal development.

Another kind of mutation occurs in patients who have spinal and bulbar muscular atrophy, known as Kennedy's disease. These patients have an expansion of the CAG repeat, which codes for glutamine, at the amino terminus of the molecule (Walcott and Merry, 2002). The result is very mild androgen resistance, manifest principally by gynecomastia (Dejager, 2002), and progressively severe motor neuron atrophy. The mechanism by which the neuronal atrophy occurs is unknown but pharmacological induction of autophagy in a model cell system degrades the mutant AR and rescues the cells from damage (Montie et al, 2009). Other trinucleotide repeats are also associated with neurological disorders (Molla et al., 2009).

Other kinds of androgen receptor mutations may explain why prostate cancer that is treated by androgen deprivation eventually becomes androgen-independent. At the time of its clinical presentation, prostate cancer is usually androgen-sensitive, and this sensitivity forms the basis for the initial treatment of metastatic prostate cancer by androgen deprivation. Metastatic prostate cancer often regresses initially in response to this treatment but then becomes unresponsive to continued deprivation. The androgen receptor not only continues to be expressed in androgen-independent prostate cancer, but its signaling remains active, as indicated by expression of the androgen receptor-dependent prostate-specific antigen (PSA). It has been postulated that these observations can be explained by mutations in the androgen receptor gene or changes in androgen receptor co-regulatory 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, a drug in late stages of clinical development (Chapter 63) (Heinlein and Chang, 2004).

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: the epididymis, vas deferens, and seminal vesicles. Further away, in the anlage of the external genitalia, testosterone is converted to dihydrotestosterone, which causes the development of the male external genitalia: the penis, scrotum, and prostate. 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; not surprisingly, the first sign of puberty is an increase in testicular size. 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 virtually 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. Full development of the latter two may not occur until 10 years after the start of puberty and marks the completion of puberty. 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. The increase in muscle mass and bone result in a pronounced increase in weight. 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 also 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 changes that can occur in the prostate gland during adulthood are of much greater medical significance. One is the gradual development of 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 (Wilson, 1980).

The other change that can occur in the prostate during adulthood is the development of 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 (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 (Harman et al., 2001). 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 (Forbes, 1976) and strength (Murray et al., 1980), 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). A causal role is suggested by the occurrence of similar changes when men develop hypogonadism at a younger age caused by known diseases, as discussed later in this chapter.

Selective Androgen-Receptor Modulators. Stimulated by the development of selective estrogen receptor modulators, which have estrogenic effects in some tissues but not others (Chapter 40), investigators are attempting to develop selective androgen receptor modulators. Another stimulus is the desirable effects of testosterone in some tissues, such as muscle and bone, and the undesirable effects in other tissues, such as the prostate. Nonsteroidal molecules have been developed that bind to the androgen receptor and have greater effect on muscle and bone than on the prostate. Some of these compounds have begun trials in humans (Narayanan et al., 2008).

Monitoring for Efficacy. The goal of administering testosterone to a hypogonadal man is to mimic as closely as possible the normal serum concentration. Therefore, measuring the serum testosterone concentration during treatment is the most important aspect of monitoring testosterone treatment for efficacy. When the serum testosterone concentration is measured depends on the testosterone preparation used (Figure 41–7). Occasional random fluctuations can occur, however, so measurements should be repeated for any dose. When the enanthate or cypionate esters of testosterone are 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 (Findlay et al., 1989; Snyder and Lawrence, 1980).

Normalization of the serum testosterone concentration induces normal virilization in prepubertal boys and restores virilization in 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 (Snyder et al., 2000).

Monitoring for Deleterious Effects. When testosterone itself is administered, as in one of the transdermal preparations or as an ester that is hydrolyzed to testosterone, it 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 from prepubertal or mid-pubertal levels to that of an adult male at any age 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. For example, stimulation of erythropoiesis would increase the hematocrit from subnormal to normal in a healthy man but would raise the hematocrit above normal in a man with a predisposition to erythrocytosis, such as in chronic pulmonary disease. Similarly, the mild degree of sodium and water retention with testosterone replacement would have no clinical effect in a healthy man but would exacerbate preexisting congestive heart failure. 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's serum testosterone concentration has been in the normal adult male range for many years, whether from endogenous secretion or exogenous administration, and he 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. Case reports of cancer regression after androgen cessation suggest a possible causal role, but an etiologic link is unproven. The 17α-alkylated androgens, especially in large amounts, may lower serum high-density lipoprotein cholesterol.

Monitoring at the Anticipated Time of Puberty. Administration of testosterone to testosterone-deficient boys at the anticipated time of puberty should be guided by the considerations just described but also by the fact that 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 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.

Kinds of Androgens Used. Virtually all androgens produced for human or veterinary purposes have been taken by athletes. When use by athletes began more than two decades 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, preparations 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 national governments or athletic organizations.

A new development in use of androgens by athletes is represented by 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 (Figure 41-6) and rapid catabolism.

Efficacy. There have been few controlled studies of the effects of pharmacological doses of androgens on muscle strength. In one controlled study, 43 normal young men were randomized to one of four groups: strength training ± 600 mg of testosterone enanthate once a week (more than six times the replacement dose); or no exercise ± testosterone. The men who received testosterone experienced an increase in muscle strength compared to those who received placebo, and the men who exercised simultaneously experienced even greater increases (Bhasin et al., 1996). In another study, normal young men were treated with a GnRH analog to reduce endogenous testosterone secretion severely and in a random blinded fashion, weekly doses of testosterone enanthate from 25 mg to 600 mg. There was a dose-dependent effect of testosterone on muscle strength (Bhasin et al., 2001).

In a double-blind study of androstenedione, men who took 100 mg three times a day for 8 weeks did not experience an increase in muscle strength compared to men who took placebo. Failure of this treatment to increase muscle strength is not surprising because it also did not increase the mean serum testosterone concentration (King et al., 1999).

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 (Drinka et al., 1995).

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 also appear to be much more likely than others, when administered in high doses, to affect serum lipid concentrations, specifically to decrease high-density lipoprotein (HDL) cholesterol and increase low-density lipoprotein (LDL) cholesterol. Other side effects have been suggested by many anecdotes but have not been confirmed, including psychological disorders and sudden death due to cardiac disease, possibly related to changes in lipids or to coagulation activation.

Certain side effects occur specifically in women and children. Both 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.

Detection. An androgen other than testosterone can be detected by gas chromatography and mass spectroscopy if the athlete is still taking it when he is tested. Exogenous testosterone itself can be detected by one of two methods. One is the T/E ratio, the ratio of testosterone glucuronide to its endogenous epimer, epitestosterone glucuronide, in urine. Administration of exogenous testosterone suppresses secretion of both testosterone and epitestosterone and replaces them with only testosterone, so the T/E ratio is higher than normal. This technique is limited, however, by heterozygosity in the UDP-glucuronosyl transferase that converts testosterone to testosterone glucuronide. An athlete who has a deletion of one or both copies of the gene coding for this enzyme and who takes exogenous testosterone will have a much lower T/E ratio than one who have both copies (Schulze, 2008).

A second technique for detecting administration of exogenous testosterone employs gas chromatography-combustion-isotope ratio mass spectrometry to detect the presence of ¹³C and ¹²C compounds. Urinary steroids with a low ¹³C/¹²C ratio are likely to have originated from pharmaceutical sources as opposed to endogenous physiological sources (Aguilera et al., 2001).

Male Contraception. Androgens inhibit LH secretion by the pituitary and thereby decrease endogenous testosterone production. Based on these observations, scientists have tried for more than a decade to use androgens, either alone or in combination with other drugs, as a male contraceptive. Because the concentration of testosterone within the testes, ∼100 times that in the peripheral circulation, is necessary for spermatogenesis, suppression of endogenous testosterone production greatly diminishes spermatogenesis. Initial use of testosterone alone, however, required supraphysiologic doses, and addition of GnRH antagonists required daily injections. A more promising approach is the combination of a progestin with a physiological dose of testosterone to suppress LH secretion and spermatogenesis but provide a normal serum testosterone concentration (Bebb et al., 1996). One trial employed injections of testosterone undecanoate with a depot progestin every 2 months (Gu et al., 2004). Another androgen being tested as part of a male contraceptive regimen is 7α-methyl-19-nortestosterone, a synthetic androgen that cannot be metabolized to dihydrotestosterone (Cummings et al., 1998).

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. Treatment of men with AIDS-related muscle wasting and subnormal serum testosterone concentrations increases their muscle mass and strength (Bhasin et al., 2000).

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 (Cicardi et al., 1998). The 17α-alkylated androgens, such as stanozolol and danazol, stimulate the hepatic synthesis of the esterase inhibitor. In women, virilization is a potential side effect. In children, virilization and premature epiphyseal closure prevent chronic use of androgens for prophylaxis, although they are used occasionally to treat acute episodes. As an alternative to prophylactic androgens, concentrated C1-esterase inhibitor derived from human plasma (cinryze) may be used for protection in patients with hereditary angioedema.

Blood Dyscrasias. Androgens once were employed to attempt to stimulate erythropoiesis in patients with anemias of various etiologies, but the availability of erythropoietin has supplanted that use. 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.

Spironolactone. Spironolactone (aldactone; Chapter 25) is an inhibitor of aldosterone that also is a weak inhibitor of the androgen receptor 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 (Caminos-Torres et al., 1977). 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; it is moderately effective (Cumming et al., 1982) but may cause irregular menses.

Cyproterone Acetate. Cyproterone acetate is a progestin and a weak antiandrogen by virtue of binding to the androgen receptor. It is moderately effective in reducing hirsutism alone or in combination with an oral contraceptive (Venturoli et al., 1999) but is not approved for use in the U.S.

Finasteride also is approved for use in the treatment of male pattern baldness under the trade name PROPECIA, even though that effect is presumably mediated via the type I enzyme. It appears to be as effective as flutamide and the combination of estrogen and cyproterone in the treatment of hirsutism (Venturoli et al., 1999).