Chapter 40. Gonadal Hormones & Inhibitors

The gonadal hormones include the steroids of the ovary (estrogens and progestins) and testis (chiefly testosterone). Because of their importance as contraceptives, many synthetic estrogens and progestins have been produced. These include synthesis inhibitors, receptor antagonists, and some drugs with mixed effects (ie, agonist effects in some tissues and antagonist effects in other tissues). Mixed agonists with estrogenic effects are called selective estrogen receptor modulators (SERMs). Synthetic androgens, including those with anabolic activity, are also available for clinical use. A diverse group of drugs with antiandrogenic effects is used in the treatment of prostate cancer and benign prostatic hyperplasia in men and hyper-androgenism in women.

The ovary is the primary source of gonadal hormones in women during the childbearing years (ie, between puberty and menopause). When properly regulated by follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary, each menstrual cycle consists of the following events: A follicle in the ovary matures, secretes increasing amounts of estrogen, releases an ovum, and is transformed into a progesterone-secreting corpus luteum. If the ovum is not fertilized and implanted, the corpus luteum degenerates; the uterine endometrium, which has proliferated under the stimulation of estrogen and progesterone, is shed as part of the menstrual flow, and the cycle repeats. The mechanism of action of both estrogen and progesterone involves entry into cells, binding to cytosolic receptors, and translocation of the receptor–hormone complex into the nucleus, where it modulates gene expression (see Figure 39–1).

Estrogens

The major ovarian estrogen in women is estradiol. Estradiol has low oral bioavailability but is available in a micronized form for oral use. It can also be administered via transdermal patch, vaginal cream, or intramuscular injection. Long-acting esters of estradiol that are converted in the body to estradiol (eg, estradiol cypionate) can be administered by intramuscular (IM) injection. Mixtures of conjugated estrogens from biologic sources (eg, Premarin) are used orally for hormone replacement therapy (HRT). Synthetic estrogens with high bioavailability (eg, ethinyl estradiol, mestranol) are used in hormonal contraceptives.

Effects

Estrogen is essential for normal female reproductive development. It is responsible for the growth of the genital structures (vagina, uterus, and uterine tubes) during childhood and for the appearance of secondary sexual characteristics and the growth spurt associated with puberty. Estrogen has many metabolic effects: It modifies serum protein levels and reduces bone resorption. It enhances the coagulability of blood and increases plasma triglyceride levels while reducing low-density lipoprotein (LDL) cholesterol and increasing high-density lipoprotein (HDL) cholesterol. Continuous administration of estrogen, especially in combination with a progestin, inhibits the secretion of gonadotropins from the anterior pituitary (Figure 40–1).

Clinical Use

Estrogens are used in the treatment of hypogonadism in young females (Table 40–1). Another use is as HRT in women with estrogen deficiency resulting from premature ovarian failure, menopause, or surgical removal of the ovaries. HRT ameliorates hot flushes and atrophic changes in the urogenital tract. It is effective also in preventing bone loss and osteoporosis. The estrogens are components of hormonal contraceptives (see later discussion).

Toxicity

In hypogonadal girls, the dosage of estrogen must be adjusted carefully to prevent premature closure of the epiphyses of the long bones and short stature. When used as HRT, estrogen increases the risk of endometrial cancer; this effect is prevented by combining the estrogen with a progestin. Estrogen use by postmenopausal women is associated with a small increase in the risk of breast cancer and cardiovascular events (myocardial infarction, stroke). Dose-dependent toxicity includes nausea, breast tenderness, increased risk of migraine headache, thromboembolic events (eg, deep vein thrombosis), gallbladder disease, hypertriglyceridemia, and hypertension.

Diethylstilbestrol (DES), a nonsteroidal estrogenic compound, is associated with infertility, ectopic pregnancy, and vaginal adenocarcinoma in the daughters of women who were treated with the drug during pregnancy in a misguided attempt to prevent recurrent spontaneous abortion. These effects appear to be restricted to DES because there is no evidence that the estrogens and progestins in hormonal contraceptives have similar effects or other teratogenic effects.

Progestins

Progesterone is the major progestin in humans. A micronized form is used orally for HRT, and progesterone-containing vaginal creams are also available. Synthetic progestins (eg, medroxyprogesterone) have improved oral bioavailability. The 19-nortestosterone compounds differ primarily in their degree of androgenic effects. Older drugs (eg, L-norgestrel and norethindrone) are more androgenic than the newer progestins (eg, norgestimate, desogestrel).

Effects

Progesterone induces secretory changes in the endometrium and is required for the maintenance of pregnancy. The other progestins also stabilize the endometrium but do not support pregnancy. Progestins do not significantly affect plasma proteins, but they do affect carbohydrate metabolism and stimulate the deposition of fat. High doses suppress gonadotropin secretion and often cause anovulation in women.

Clinical Use

Progestins are used as contraceptives, either alone or in combination with an estrogen. They are used in combination with an estrogen in HRT to prevent estrogen-induced endometrial cancer. Progesterone is used in assisted reproductive technology methods to promote and maintain pregnancy.

Toxicity

The toxicity of progestins is low. However, they may increase blood pressure and decrease HDL. Long-term use of high doses in premenopausal women is associated with a reversible decrease in bone density (a secondary effect of ovarian suppression and decreased ovarian production of estrogen) and delayed resumption of ovulation after termination of therapy.

Hormonal Contraceptives

Hormonal contraceptives contain either a combination of an estrogen and a progestin or a progestin alone. Hormonal contraceptives are available in a variety of preparations, including oral pills, long-acting injections, transdermal patches, vaginal rings, and intrauterine devices (IUDs) (Table 40–1). Three types of oral contraceptives for women are available in the United States: combination estrogen-progestin tablets that are taken in constant dosage throughout the menstrual cycle (monophasic preparations); combination preparations (biphasic and triphasic) in which the progestin or estrogen dosage, or both, changes during the month (to more closely mimic hormonal changes in a menstrual cycle); and progestin-only preparations.

The postcoital contraceptives (also known as "emergency contraception") prevent pregnancy if administered within 72 h after unprotected intercourse. Oral preparations containing a progestin (L-norgestrel) alone, estrogen alone, or the combination of an estrogen and a progestin are effective. The progestin-only preparation causes fewer side effects than the estrogen-containing preparations.

Mechanism of Action

The combination hormonal contraceptives have several actions, including inhibition of ovulation (the primary action) and effects on the cervical mucus glands, uterine tubes, and endometrium that decrease the likelihood of fertilization and implantation. Progestin-only agents do not always inhibit ovulation and instead act through the other mechanisms listed. The mechanisms of action of postcoital contraceptives are not well understood. When administered before the LH surge, they inhibit ovulation. They also affect cervical mucus, tubal function, and the endometrial lining.

Other Clinical Uses and Beneficial Effects

Combination hormonal contraceptives are used in young women with primary hypogonadism to prevent estrogen deficiency. Combinations of hormonal contraceptives and progestins are used to treat acne, hirsutism, dysmenorrhea, and endometriosis. Users of combination hormonal contraceptives have reduced risks of ovarian cysts, ovarian and endometrial cancer, benign breast disease, and pelvic inflammatory disease as well as a lower incidence of ectopic pregnancy, iron deficiency anemia, and rheumatoid arthritis.

Toxicity

The incidence of dose-dependent toxicity has fallen since the introduction of the low-dose combined oral contraceptives.

Thromboembolism

The major toxic effects of the combined hormonal contraceptives relate to the action of the estrogenic component on blood coagulation. There is a well-documented increase in the risk of thromboembolic events (myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism) in older women, smokers, women with a personal or family history of such problems, and women with genetic defects that affect the production or function of clotting factors. However, the risk of thromboembolism incurred by the use of these drugs is usually less than that imposed by pregnancy.

Breast Cancer

Evidence suggests that the lifetime risk of breast cancer in women who are current or past users of hormonal contraceptives is not changed, but there may be an earlier onset of breast cancer.

Other Toxicities

The low-dose combined oral and progestin-only contraceptives cause significant breakthrough bleeding, especially during the first few months of therapy. Other toxicities of the hormonal contraceptives include nausea, breast tenderness, headache, skin pigmentation, and depression. Preparations containing older, more androgenic progestins can cause weight gain, acne, and hirsutism. The high dose of estrogen in estrogen-containing postcoital contraceptives is associated with significant nausea.

Selective Estrogen Receptor Modulators

Selective estrogen receptor modulators (SERMs) are mixed estrogen agonists that have estrogen agonist effects in some tissues and act as partial agonists or antagonists of estrogen in other tissues.

Tamoxifen

Tamoxifen is a SERM that is effective in the treatment of hormone-responsive breast cancer, where it acts as an antagonist to prevent receptor activation by endogenous estrogens (Figure 40–2). Prophylactic use of tamoxifen reduces the incidence of breast cancer in women who are at very high risk. As an agonist of endometrial receptors, tamoxifen promotes endometrial hyperplasia and increases the risk of endometrial cancer. The drug also causes hot flushes (an antagonist effect) and increases the risk of venous thrombosis (an agonist effect). Tamoxifen has more agonist than antagonist action on bone and thus prevents osteoporosis in postmenopausal women. Toremifene is structurally related to tamoxifen and has similar properties, indications, and toxicity.

Raloxifene

Raloxifene, approved for prevention and treatment of osteoporosis in postmenopausal women, has a partial agonist effect on bone. Like tamoxifen, raloxifene has antagonist effects in breast tissue and reduces the incidence of breast cancer in women who are at very high risk. Unlike tamoxifen, the drug has no estrogenic effects on endometrial tissue. Adverse effects include hot flushes (an antagonist effect) and an increased risk of venous thrombosis (an agonist effect).

Clomiphene

Clomiphene is a nonsteroidal compound with tissue-selective actions. It is used to induce ovulation in anovulatory women who wish to become pregnant. By selectively blocking estrogen receptors in the pituitary, clomiphene reduces negative feedback and increases FSH and LH output. The increase in gonadotropins stimulates ovulation.

Pure Estrogen Receptor Antagonists

Fulvestrant is a pure estrogen receptor antagonist (in all tissues). It is used in the treatment of women with breast cancer that has developed resistance to tamoxifen.

Synthesis Inhibitors

Aromatase Inhibitors

Anastrozole and related compounds (eg, letrozole) are nonsteroidal competitive inhibitors of aromatase, the enzyme required for the last step in estrogen synthesis. Exemestane is an irreversible aromatase inhibitor. These drugs are used in the treatment of breast cancer.

Danazol

Danazol inhibits several cytochrome P450 enzymes involved in gonadal steroid synthesis and is a weak partial agonist of progestin, androgen, and glucocorticoid receptors. The drug is sometimes used in the treatment of endometriosis and fibrocystic disease of the breast.

Gonadotropin-Releasing Hormone Analogs and Antagonists

As discussed in Chapter 37, the continuous administration of gonadotropin-releasing hormone (GnRH) agonists (eg, leuprolide) suppresses gonadotropin secretion and thereby inhibits ovarian production of estrogens and progesterone. The GnRH agonists are used in combination with other agents in controlled ovarian hyperstimulation (Chapter 37) and are also used for treatment of precocious puberty in children and short-term (<6 mo) treatment of endometriosis and uterine fibroids in women. Treatment beyond 6 mo in premenopausal women can result in decreased bone density. The GnRH receptor antagonists ganirelix and cetrorelix are used for controlled ovarian hyperstimulation (see Chapter 37).

Antiprogestins

Mifepristone (RU 486) is an orally active steroid antagonist of progesterone and glucocorticoids (Chapter 39). Its major use is as an abortifacient in early pregnancy (up to 49 d after the last menstrual period). The combination of mifepristone and the prostaglandin E analog misoprostol (Chapters 18 and 59) achieves a complete abortion in over 95% of early pregnancies. The most common complication is failure to induce a complete abortion. Side effects, which are primarily due to the misoprostol, include nausea, vomiting, and diarrhea plus the vaginal cramping and bleeding associated with passing the pregnancy. Rarely, patients who used mifepristone and misoprostol for medical abortion have experienced serious infection, sepsis, and even death due to unusual infection (eg, Clostridium sordelli).

(See Chapters 4 and 61)

Hormonal contraceptives usually contain the lowest doses of the estrogen and progestin components that prevent pregnancy. The margin between effective and ineffective serum concentrations of the steroids is narrow, which presents a risk of breakthrough bleeding and also unintended pregnancy resulting from drug–drug interactions. Most steroidal contraceptives are metabolized by cytochrome P450 isozymes.

1. How many drugs can you identify that decrease the efficacy of hormonal contraceptives by increasing their metabolism?

2. When one of these drugs is prescribed for a woman who already is using a combined hormonal contraceptive, what should be done to prevent pregnancy?

The Skill Keeper Answers appear at the end of the chapter.

Testosterone and related androgens are produced in the testis, the adrenal, and, to a small extent, the ovary. Testosterone is synthesized from progesterone and dehydroepiandrosterone (DHEA). In the plasma, testosterone is partly bound to sex hormone-binding globulin (SHBG), a transport protein. The hormone is converted in several organs (eg, prostate) to dihydrotestosterone (DHT), which is the active hormone in those tissues. Because of rapid hepatic metabolism, testosterone given orally has little effect. It may be given by injection in the form of long-acting esters or transdermal patch. Orally active variants are also available (Table 40–1).

Many androgens have been synthesized in an effort to increase the anabolic effect (see Effects, discussed later) without increasing androgenic action. Oxandrolone and stanozolol are examples of drugs that, in laboratory testing, have an increased ratio of anabolic-androgenic action. However, all the so-called anabolic steroids have full androgenic agonist effects when used in humans.

Mechanism of Action

Like other steroid hormones, androgens enter cells and bind to cytosolic receptors. The hormone-receptor complex enters the nucleus and modulates the expression of target genes.

Effects

Testosterone is necessary for normal development of the male fetus and infant and is responsible for the major changes in the male at puberty (growth of penis, larynx, and skeleton; development of facial, pubic, and axillary hair; darkening of skin; enlargement of muscle mass). After puberty, testosterone acts to maintain secondary sex characteristics, fertility, and libido. It also acts on hair cells to cause male-pattern baldness.

The major effect of androgenic hormones, in addition to development and maintenance of normal male characteristics, is an anabolic action that involves increased muscle size and strength and increased red blood cell production. Excretion of urea nitrogen is reduced, and nitrogen balance becomes more positive. Testosterone also helps maintain normal bone density.

Clinical Use

The primary clinical use of the androgens is for replacement therapy in hypogonadism (Table 40–1). Androgens have also been used to stimulate red blood cell production in certain anemias and to promote weight gain in patients with wasting syndromes (eg, AIDS patients). The anabolic effects have been exploited illicitly by athletes to increase muscle bulk and strength and perhaps enhance athletic performance.

Toxicity

Use of androgens by females results in virilization (hirsutism, enlarged clitoris, deepened voice) and menstrual irregularity. In women who are pregnant with a female fetus, exogenous androgens can cause virilization of the fetus's external genitalia. Paradoxically, excessive doses in men can result in feminization (gynecomastia, testicular shrinkage, infertility) as a result of feedback inhibition of the pituitary and conversion of the exogenous androgens to estrogens. In both sexes, high doses of anabolic steroids can cause cholestatic jaundice, elevation of liver enzyme levels, and possibly hepatocellular carcinoma.

Reduction of androgen effects is an important mode of therapy for both benign and malignant prostate disease, precocious puberty, hair loss, and hirsutism. Drugs are available that act at different sites in the androgen pathway (Figure 40–2).

Receptor Inhibitors

Flutamide and related drugs are nonsteroidal competitive antagonists of androgen receptors. These drugs are used to decrease the action of endogenous androgens in patients with prostate carcinoma. Spironolactone, a drug used principally as a potassium-sparing diuretic (Chapter 15), also inhibits androgen receptors and is used in the treatment of hirsutism in women.

5α-Reductase Inhibitors

Testosterone is converted to DHT by the enzyme5α-reductase. Some tissues, most notably prostate cells and hair follicles, depend on DHT rather than testosterone for androgenic stimulation. This enzyme is inhibited by finasteride, a drug used to treat benign prostatic hyperplasia and, at a lower dose, to prevent hair loss in men. Because the drug does not interfere with the action of testosterone, it is less likely than other antiandrogens to cause impotence, infertility, and loss of libido. Dutasteride is a newer 5α-reductase inhibitor with a much longer half-life than that of finasteride.

Gonadotropin-Releasing Hormone Analogs and Antagonists

Suppression of gonadotropin secretion, especially LH, reduces the production of testosterone. This can be effectively accomplished with long-acting depot preparations of leuprolide or similar gonadotropin-releasing hormone (GnRH) agonists (Chapter 37). These analogs are used in prostatic carcinoma. During the first week of therapy, an androgen receptor antagonist (eg, flutamide) is added to prevent the tumor flare that can result from the surge in testosterone synthesis caused by the initial agonistic action of the GnRH agonist. Within several weeks, testosterone production falls to low levels. As discussed in Chapter 37, the GnRH receptor antagonists abarelix and degarelix are approved for advanced prostate cancer.

Combined Hormonal Contraceptives

Combined hormonal contraceptives are used in women with androgen-induced hirsutism. The estrogen in the contraceptive acts in the liver to increase the production of sex hormone-binding globulin, which in turn reduces the concentration of the free androgen in the blood that is causing the male-pattern hair growth characteristic of hirsutism.

Inhibitors of Steroid Synthesis

Ketoconazole, an antifungal drug (Chapter 48), inhibits gonadal and adrenal steroid synthesis. The drug has been used to suppress adrenal steroid synthesis in patients with steroid-responsive metastatic prostate cancer.

(See Chapters 4 and 61)

1. Gonadal steroids and their derivatives are metabolized primarily by the cytochrome P450 3A4 (CYP3A4) family of enzymes. Inducers of CYP3A4 include barbiturates, carbamazepine, corticosteroids, griseofulvin, phenytoin, pioglitazone, rifampin, and rifabutin. The potential reduction in contraceptiveefficacy of hormonal contraceptives by carbamazepine and phenytoin are of particular importance because these drugs are known teratogens. St. John's wort, an unregulated herbal product, contains an ingredient that induces CYP3A4 enzymes and can reduce the efficacy of hormonal contraceptives.

2. To prevent an unwanted pregnancy, it would be advisable to use a combined hormonal contraceptive pill with a higher dose of estrogen (eg, a formulation containing 50 mcg of ethinyl estradiol). Alternatively, or additionally, women may use a barrier form of contraception or switch to an IUD.

When you complete this chapter, you should be able to:

• □ Describe the hormonal changes that occur during the menstrual cycle.
• □ Name 3 estrogens and 4 progestins. Describe their pharmacologic effects, clinical uses, and toxicity.
• □ List the benefits and hazards of hormonal contraceptives.
• □ List the benefits and hazards of postmenopausal estrogen therapy.
• □ Describe the use of gonadal hormones and their antagonists in the treatment of cancer in women and men.
• □ List or describe the toxic effects of anabolic steroids used to build muscle mass.
• □ Name 2 SERMs and describe their unique properties.