Androgens

Androgens (Figure 37-2) are derived from a 19-carbon tetracyclic hydrocarbon nucleus known as androstane. One of the most potent androgenic hormones, testosterone, is synthesized by the Leydig cells of the testes, the thecal cells of the ovary, and the adrenal cortex. In men, testosterone is the principal plasma androgen and is reduced to dihydrotestosterone, the mediator of most actions of the hormone.³² The irreversible metabolic conversion of testosterone to dihydrotestosterone occurs only in tissues that contain the enzyme 5α-reductase.⁵¹ Testosterone (but not dihydrotestosterone) can also be aromatized to estradiol by numerous extragonadal tissues (primarily adipose tissue and skeletal muscle), a common route of estrogen production in men. In women, the major plasma androgen is androstenedione (androst-4-ene-3,17-dione), which can be secreted into the bloodstream or converted into either testosterone or estradiol by the ovary.

FIGURE 37-2 Structural formulas of testosterone and other androgens.

When secreted into the bloodstream, most androgens are transported to their sites of action by a liver-secreted carrier protein termed sex hormone–binding globulin (44% bound) and serum albumins and other proteins (54% bound).⁷ Secreted plasma androgens are also metabolized to physiologically weak or inactive molecules consisting of either 17-ketosteroids or polar compounds (diols, triols, and conjugates) for excretion by the kidney or liver.²⁰

Androgens may be administered orally, topically, or through intramuscular injections (Table 37-1). Testosterone is generally not administered enterally because extensive first-pass hepatic metabolism rapidly reduces plasma concentrations. The bioavailability of androgens is increased by intramuscular injections in an oil vehicle, by transdermal application, or by alkylation at C17, which significantly decreases hepatic metabolism and makes oral administration therapeutically possible.

The biologic activities of androgens are manifested in virtually every tissue of the body. Important functions of androgens include (1) male sexual differentiation of wolffian ducts, external genitalia, and brain in utero; (2) development of adult male phenotype, including growth and maintenance of male sex accessory organs and anabolic actions on skeletal muscle, bone, and hair; (3) facilitation of human sexual behavior; and (4) regulation of specific metabolic processes in the liver, kidney, and salivary glands.³²

Estrogens

Estrogens (Figure 37-3)—estrone, estradiol, and estriol—are characterized by an aromatic A ring, a hydroxyl group at C3, and either hydroxyl groups (C16 and C17) or a ketone group (C17) on the D ring. Estradiol is the most potent estrogen and is secreted by the ovary, testes, placenta, and peripheral tissues. Estrone is also secreted by the ovary; however, the principal source in women and men is through extragonadal conversion of androstenedione in peripheral tissues.⁴³ In premenopausal women, the most abundant physiologic estrogen is estradiol; in men and postmenopausal women, the most abundant estrogen in the plasma is estrone.⁵⁴ Similar to other lipid-soluble hormones, estrogens are transported in the blood principally bound to carrier proteins; estradiol in the plasma is bound by either albumin (60%) or sex hormone–binding globulin (38%), leaving only 2% of the hormone free.⁵³ Estradiol and estrone are metabolized principally to estriol, which is the major estrogen detected in the urine.

FIGURE 37-3 Structural formulas of estradiol and other estrogens.

Estrogens may be administered orally, topically, or through intramuscular injections (Table 37-2). Although estradiol is available for enteral administration, it is generally not used in this manner because concentrations in the bloodstream remain low because of extensive hepatic metabolism.¹⁰ The half-life of estrogenic compounds can be increased by synthetic substitutions on the C or D ring (see Figure 37-3). The half-life of estradiol is a few minutes, whereas the half-life of ethinyl estradiol (ethinyl substitution at the C17 position) may be more than 13 hours. Nonsteroidal compounds may also have estrogenic activity; examples of such compounds include diethylstilbestrol, flavones, isoflavones, and certain pesticides (e.g., p,p′-DDT) and plasticizers (e.g., bisphenol A).

The biologic activities of estrogens in women include (1) development, growth, and maintenance of secondary sex characteristics; (2) uterine growth; (3) pulsatile release of luteinizing hormone from the pituitary; (4) thickening of the vaginal mucosa; and (5) ductal development in the breast. In men, the physiologic significance of estrogens is largely unknown, but may be involved in the regulation of plasma androgen and estrogen levels and sexual behavior.

Progestins

Progestins (Figure 37-4), or steroids that have progestational activity, are derived from a 21-carbon saturated steroid hydrocarbon known as pregnane. The principal progestational hormone secreted into the bloodstream is progesterone, which is synthesized and secreted by the corpus luteum, placenta, and adrenal cortex. As with androgens, most progesterone is transported in the bloodstream by plasma proteins; however, progesterone in humans is primarily nonspecifically bound to globulin and albumin proteins. The fate of plasma progesterone depends on hepatic, extrahepatic, and extra-adrenal metabolism. 5-α-Dihydroprogesterone and deoxycorticosterone are the most probable active progesterone metabolites. Metabolic inactivation of progesterone to pregnanediol is accomplished by the liver.

FIGURE 37-4 Structural formulas of progesterone and progestins.

Progestins may be administered orally, topically, or through intramuscular injections (Table 37-3). Progesterone is available for enteral administration; however, it is generally not administered in this manner because concentrations in the bloodstream remain low because of extensive first-pass hepatic metabolism. The bioavailability of progestins can be increased by intramuscular injections in oil, by vaginal suppositories, or by ethinyl or other substitution at C17, which significantly decreases hepatic metabolism.

The biologic activities of progestins are principally observed during the luteal phase of the menstrual cycle and pregnancy. Progesterone is necessary for glandular endometrial development before nidation, the development of mammary lobules and alveoli, and the maintenance of pregnancy (i.e., endometrial gland function, decreased excitability of myometrium, and possible effects on the immune system to decrease rejection of the developing fetus). Progesterone also decreases hepatic secretion of very-low-density lipoprotein and high-density lipoprotein, diminishes insulin action, stimulates the hypothalamic respiratory center, elevates basal core body temperature at ovulation, and enhances sodium excretion by the kidneys.

Steroid Hormone Receptor Structure

The receptors for steroid hormones are able to initiate a wide assortment of responses yet are very similar to one another, not only in their mechanism of action, but also in their structure.^9,22 In general, steroid hormone receptors consist of asymmetric protein subunits with long (10 :10 1) axial ratios. These subunits, which form either dimers or tetramers at low ionic strengths, range in weight from 80 to 100 kDa. As a class of regulatory proteins, the different steroid hormone receptors have a high degree of homology. Each protein can be divided into six sections, designated as regions A through F.³²

The A/B regions located at the N-terminal are exceedingly variable in size (50 to >500 amino acids) and have negligible amino acid similarities between different receptors. The C region, located between the N-terminus and C-terminus, is a remarkably conserved area that contains the DNA-binding domain. The hydrophilic D region is not conserved in length or sequence but may serve as a hinge between the hormone-binding and DNA-binding domains. The E/F regions located at the C-terminal are similar in size (250 to 300 amino acids), have moderate amino acid homology among the different steroid receptor proteins, and contain the hormone-binding domain. Areas in the N-terminal and the C-terminal are responsible for the transcriptional activation of the DNA.^13,23

From these six regions, two important binding domains are present for sex steroid hormone receptors. In one binding domain, the functional activation of the receptor depends on a distinct, high-affinity binding site for a specific hormone. This steroid hormone-binding domain is a large hydrophobic region located near the C-terminal. The other receptor-binding domain recognizes specific sites on DNA. This DNA-binding domain of the steroid receptor is a highly conserved area that contains a tetrahedral arrangement of four cysteine residues around a zinc ion to form a zinc finger-like structure.³⁰ On activation of the receptor, the receptor-steroid complex binds to a specific site on the DNA that is referred to as a steroid responsive element. Steroid responsive elements are unique for each receptor but have common nucleotide characteristics.

Androgens

The least controversial and principal indication for androgen therapy is for the treatment of testosterone deficiency in adolescent boys and men. Transdermal testosterone preparations have been used to mimic normal serum levels for testosterone-deficient boys to develop normal genitalia and secondary sex characteristics and for the normal virilization of hypogonadal men. Other, less common and more controversial applications for androgens include uses for male senescence, female hypogonadism, enhancement of athletic performance, male contraception, catabolic and wasting states, angioneurotic edema, and blood dyscrasias.

Estrogens

The two principal reasons for the prescription of estrogens are for the prevention of conception and to reduce the sequelae associated with declining hormone levels after menopause. Oral contraceptives are among the most widely used medications in the world and most often are a combination of estrogens and progestins (Table 37-4). Combination oral contraceptives principally affect conception by suppressing the surge of luteinizing hormone, which consequently prevents ovulation (Figure 37-5).²⁴ The estrogen component of combination oral contraceptives usually contains either ethinyl estradiol or mestranol. In these preparations, the estrogen content ranges from 20 to 50 µg; pills containing less than 35 µg are usually considered low-dose contraceptives.

TABLE 37-4 Examples of Contraceptive Agents

* 24-day formulation followed by 4 days of inert tablets.

† Continuous therapy, without a placebo or pill-free period.

‡ Emergency, postcoital preparation.

FIGURE 37-5 Hormonal changes during the normal menstrual cycle. The gonadotropins follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are measured in mU/mL; the sex steroids estradiol and progesterone are plotted in units (1 unit = 100 pg/mL of estradiol and 2 ng/mL of progesterone). Combination oral contraceptives prevent ovulation by inhibiting LH (and FSH) secretion, resulting in no LH peak at mid-cycle.

Combination oral contraceptives include monophasic, biphasic, or triphasic preparations. Monophasic preparations maintain a fixed dose of estrogen and progesterone over a 21-day period; biphasic contraceptives maintain a fixed dose of estrogen but increase the progestin dose over a 21-day per/>