Antiandrogens and Androgen Inhibitors

Males

Androgens affect biology at different stages of life. Virilization of the male urogenital tract occurs between 8 and 12 weeks of embryogenesis, and androgens are essential for the development of the male phenotype. Before puberty, testicular androgen secretion is minimal, and the adrenal cortex suppresses gonadotropin secretion. At puberty, gonadotropins become less sensitive to feedback inhibition. The testes enlarge and testicular Leydig cells produce testosterone. Thereafter, the penis and scrotum enlarge and pubic hair appears. The adrenal glands also produce small quantities of testosterone. Androgens have growth-promoting properties that cause an increase in height and the development of a masculine skeletal musculature. Androgens also modulate immune responses. Androgen and estrogen receptors are present on most immune competent cells and sex hormones are known to affect T-helper 1(Th1)/Th2 cell balance.

When androgen secretion increases at puberty, the skin becomes thicker and oilier (seborrhea). This occurs because of the interaction of androgens with AR on hair follicles and sebaceous glands. There may be enhanced follicular keratinization, proliferation of sebaceous glands and sebum secretion. Q34.2 Pilosebaceous units consequently can become prone to follicular plugging and bacterial colonization, which predisposes to acne vulgaris. Secondary sexual characteristics develop: growth of axillary, facial, and body hair, because of the conversion of vellus to terminal hairs, and voice changes occur because of growth of the larynx. Males who inherit the genes for AGA may show signs of frontal hairline recession and thinning over the vertex scalp later in puberty. The last growth spurt comes to an end in later puberty as the epiphyses of long bones close.

Females

In women, androgens are derived from the ovaries, adrenal gland, and also from conversion of various steroids in the liver and peripheral tissues such as adipose tissue, skin and skin appendages. The circulating androgens include testosterone, dihydrotestosterone (DHT), androstenedione, dehydroepiandrosterone (DHEA) and its metabolite dehydroepiandrosterone sulfate (DHEA-S). Testosterone and androstenedione can both be metabolized to the more potent androgen DHT, by 5α-reduction in the liver and skin ( Fig. 34.1 ). The average daily rate of testosterone production in women is approximately 0.25 mg, with a quarter derived from the ovary, a quarter from the adrenal gland, and the remaining half from peripheral conversion of androstenedione. Androstenedione is produced equally from the ovary and the adrenal gland, while greater than 90% of DHEA/DHEA-S are secreted by the adrenal gland.

Fluctuations in plasma concentrations of testosterone and androstenedione occur during the menstrual cycle, and in women, testosterone levels range from 15 to 65 ng/dL (0.5–2.3 nM). Only about 1% to 2% of the total testosterone concentration is biologically active. It is only the free (unbound) steroid that is able to act on the AR. The remaining amount is bound to hepatic sex hormone-binding globulin (SHBG), and is unable to enter cells.

Mechanism of Action

Testosterone has minimal biologic activity in many androgen-responsive tissues including the prostate and pilosebaceous unit until it is converted to the more potent androgen DHT by the enzyme 5-α reductase in local tissues. Q34.3 There are two isoenzyme forms of 5-α reductase: type I and type II. The biochemical characteristics and distributions of these two isoenzyme forms vary, as shown in Table 34.1 . Both enzymes are located in the pilosebaceous unit, but differ quantitatively depending on the location. Both testosterone and DHT exert their biological effects by binding to the intracellular AR, which is a member of the steroid and thyroid hormone receptor superfamily. This hormone–receptor complex subsequently binds to specific nuclear hormone regulatory elements in deoxyribonucleic acid (DNA) and acts to increase or reduce the synthesis of specific messenger ribonucleic acid (mRNA) and resultant proteins. AR are present on cells in many organ systems: striated muscle (leading to a muscular habitus), cardiovascular and endocrine systems, the liver and the skin. In the liver androgens can inhibit hepatic SHBG production and in skin, DHT can increase 5-α reductase levels and AR levels. The net result of androgen action in the liver and skin is a positive feedback loop with further augmentation of androgenic activity.

Q34.2 In women, dermatologic androgen excess disorders include acne, female-patterned hair loss (FPHL, also known as AGA), and hirsutism (see Box 34.1 ). Hidradenitis suppurativa is also described as an androgen-dependent condition, although the role of androgens is not fully delineated. These disorders may result from systemic hyperandrogenemia because of androgen overproduction in the ovary or adrenal gland, or from cutaneous hyperandrogenism. Cutaneous hyperandrogenism may be attributed to altered 5-α reductase levels, AR levels, aromatase levels or other local enzyme-level abnormalities at the pilosebaceous unit such as 3β-hydroxysteroid dehydrogenase (3β-HSD1) or 17β-hydroxysteroid dehydrogenase (17β-HSD3). Aromatase converts testosterone to estradiol and diverts androstenedione metabolism away from the production of testosterone to form estrone in the adipose tissue. 3β-HSD1, 17β-HSD3, and 5-α reductase are major steroidogenic enzymes present in the skin and its appendages, and are responsible for the formation of potent androgens locally in specific tissues (see Fig. 34.1 ). In women with CHA, underlying disorders must be considered, such as polycystic ovary syndrome (PCOS), other endocrine disorders, and tumors among other causes. Testing testosterone (total, free) and DHEA-S levels is of clinical value in select patients. Although measurable circulating hormone levels are normal in most women with acne and AGA, the etiology is likely the result of abnormalities in local androgen metabolism at the tissue level rather than the result of increased secretion of circulating androgens. Patients with hirsutism are more likely to have serum androgen level abnormalities. Further discussion of testing and the hyperandrogenemic disorders is beyond the scope of this chapter.

Antiandrogens and androgen inhibitors can block or reverse the biologic effects of androgens at the cutaneous level ( Table 34.2 ). Table 34.3 lists key pharmacologic concepts for antiandrogens and androgen inhibitors, and Fig. 34.2 illustrates antiandrogen mechanisms of action.

Spironolactone

Pharmacology

Q34.4 Spironolactone (see Table 34.2 ) is an aldosterone antagonist (antimineralocorticoid) and a relatively weak antiandrogen that blocks the AR, thereby competitively inhibiting DHT activity at the receptor level (see Fig. 34.2 ) It is not purely an antiandrogen and has been shown to inhibit androgen biosynthesis. For example, it may be converted to other active metabolites via progesterone 17-hydroxylase, and these metabolites reversibly inhibit adrenal and ovarian cytochrome P-450 (CYP) enzymes, resulting in a net decrease in testosterone and DHT production. Spironolactone has also been shown to have some inhibitory effect on 5-α reductase activity. Spironolactone has variable progestational activity. The drug influences the ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH) by reducing the response of LH to GnRH.

Spironolactone is a steroid molecule containing the basic steroid nucleus of four rings ( Fig. 34.3 ). It resembles the mineralocorticoids, possessing an esterified lactone ring. Bioavailability from oral administration is at least 90%, but varies depending on the manufacturer. Q34.4 Spironolactone is 98% protein bound, and the primary metabolite, canrenone, is at least 90% protein bound. Canrenone is the active aldosterone antagonist and is the primary metabolite contributing to the diuretic and antiandrogen activities of spironolactone (see Table 34.3 ).

Food increases the absorption of spironolactone. The liver rapidly metabolizes spironolactone. The primary metabolite, canrenone, can be interconverted enzymatically to its hydrolytic product, canrenoate. The unmetabolized drug does not appear in the urine. Metabolites of spironolactone are excreted in urine and bile.

A linear relationship between a single dose of spironolactone and plasma levels of canrenone occurs within 96 hours when administered in a dose range of 25 to 200 mg. The half-life is approximately 19.2 hours for canrenone; for spironolactone it is 12.5 hours.

Progestins

See Tables 34.2 and 34.3 for general information and key pharmacologic concepts of progestins. Progestogens, include both endogenous progesterone secreted by the ovary, and synthetic steroids (progestins). Progestins suppress ovulation through their antigonadotrophic activity and further exert contraceptive function by altering the quality of cervical mucus, inducing endometrial changes and altering Fallopian tube motility. Progestins are biologically active through their interaction with the progesterone receptor (PR). All progestins bind to the PR, with varying affinity. Depending upon their chemical structure, progestins also interact with other steroid hormone receptors, including the androgen, estrogen, mineralocorticoid, and glucocorticoid (corticosteroid) receptors and may act as agonists or antagonists. Knowledge of these interactions is important to understanding the biological activity and AE of the various progestins.

Progesterone and testosterone share basic structural similarity possessing the same steroid A, B, C, D rings. Because of this structural similarity, progestins can bind to the AR and either block it or activate it. The different progestins vary in activity from androgenic to antiandrogenic to mildly antiandrogenic or neutral. Synthetic progestins are classified according to three tetracyclic structures: estranes and gonanes (both testosterone derivatives), and pregnanes or 19-norpregnanes (derived from progesterone). Drosperinone (DRSP), unlike the other progestins, is a 17α-spironolactone derivative ( Table 34.5 ). The estranes correspond to first-generation progestogens and include norethisterone, norethindrone, and ethynodiol diacetate. Also, included here is dienogest, which shares the 19-nortestosterone structure but lacks the ethynyl structure shared by this group and is cyanomethylated. Gonanes correspond to both second-generation levonorgestrel and norgestrel and third-generation desogestrel, gestodene (not available in the United States) and norgestimate. In general, the testosterone-derived progestins are androgenic (with the exception of dienogest) and later generations are generally less androgenic than earlier generations, although biological activity is difficult to predict from chemical structure alone. The progesterone-derived pregnanes (medroxyprogesterone acetate, cyproterone acetate [CypA], chlormadinone acetate) and 19-norpregnanes (a newer group that includes nomegestrol acetate, trimegestone, and segesterone acetate [Nestorone]) have no androgenic activity with the exception of medroxyprogesterone acetate, which is mildly androgenic. The newer 19-norpregnane derivatives have greater PR specificity and negligible androgenic, estrogenic, glucocorticoid, and mineralocorticoid activity, thereby more closely mimicking endogenous progesterone.

Q34.8 CypA is the progestin with the most potent antiandrogen properties. The drug has long been used in Europe and Canada as the progestin in a COC named Diane or Dianette. This progestin is not available in the United States. Potent antiandrogenic effects are exerted by competition of cyproterone with DHT for the AR-binding site. The drug also has strong progestational activity thereby suppressing gonadotropin secretion and testosterone production. When given to pregnant animals, CypA blocks the actions of androgens in the male fetus and induces a form of pseudohermaphroditism. In Canada, Diane (2 mg CypA/0.035 mg ethinyl estradiol [EE]) is approved by Health Canada for the treatment of androgen-sensitive skin conditions. Off-label uses include AGA, hirsutism, and virilizing syndromes. Although it provides effective birth control, it does not have official approval for this indication.

Q34.8 Dienogest (a 19-nortestosterone derivative) and drosperinone (a spironolactone derivative), both possess antiandrogenic activity equivalent to roughly 30% to 40% of the potency of cyproterone acetate. Drosperinone also has antimineralocorticoid activity (3-mg dose of DRSP is comparable with a 25-mg dose of spironolactone). Chlormadinone acetate (available in Europe) also has moderate antiandrogenic activity. The newer 19-norprogesterone derivatives nomogestrol acetate and trimegestone show mild antiandrogenic activity similar to that of endogenous progesterone.