NCLEX: Estrogens and Androgens

Sex hormones produced by the gonads are necessary for conception, embryonic maturation, and development of primary and secondary sexual characteristics at puberty. The gonadal hormones are used therapeutically in replacement therapy, for contraception, and in management of menopausal symptoms. Several antagonists are effective in cancer chemotherapy. All gonadal hormones are synthesized from the precursor, cholesterol, in a series of steps that includes shortening of the hydrocarbon side chain and hydroxylation of the steroid nucleus. Aromatization is the last step in estrogen synthesis.

Estrogens and Androgens

Estrogens and Androgens

Estrogens and Androgens: ESTROGENS

Focus topic:  Estrogens and Androgens

Estradiol [ess-tra-DYE-ole], also known as 17β-estradiol, is the most potent estrogen produced and secreted by the ovary. It is the principal estrogen in premenopausal women. Estrone [ESS-trone] is a metabolite of estradiol that has approximately one-third the estrogenic potency of estradiol. Estrone is the primary circulating estrogen after menopause, and it is generated mainly from conversion of androstenedione in peripheral tissues. Estriol [ess-TRI-ole], another metabolite of estradiol, is significantly less potent than is estradiol. It is present in significant amounts during pregnancy, because it is the principal estrogen produced by the placenta. A preparation of conjugated estrogens containing sulfate esters of estrone and equilin (obtained from urine of pregnant mares) is an oral preparation used for hormone replacement therapy. Plant-derived conjugated estrogen products are also available. Synthetic estrogens, such as ethinyl estradiol [ETH-ih-nil ess-tra-DYE-ole], undergo less first-pass metabolism than do naturally occurring steroids and, thus, are effective when administered orally at lower doses. Nonsteroidal compounds that bind to estrogen receptors and exert either estrogenic or antiestrogenic effects on target tissues are called selective estrogen receptor modulators (SERMs). These include tamoxifen and raloxifene, among others.

A. Mechanism of action

Focus topic:  Estrogens and Androgens

After dissociation from their binding sites on sex hormone–binding globulin or albumin in the plasma, steroid hormones diffuse across the cell membrane and bind with high affinity to specific nuclear receptor proteins. The activated steroid–receptor complex interacts with nuclear chromatin to initiate hormone-specific RNA synthesis. This results in the synthesis of specific proteins that mediate a number of physiologic functions. [Note: The steroid hormones may elicit the synthesis of different RNA species in diverse target tissues and, therefore, are both receptor and tissue specific.] Other pathways that require these hormones have been identified that lead to more rapid actions. For example, activation of an estrogen receptor in the membranes of hypothalamic cells has been shown to couple to a G protein, thereby initiating a second-messenger cascade. In addition, estrogen-mediated dilation of coronary arteries occurs by the increased formation and release of nitric oxide and prostacyclin in endothelial cells.

Estrogens and Androgens

B. Therapeutic uses

Focus topic:  Estrogens and Androgens

Estrogens are most frequently used for contraception and postmenopausal hormone therapy (HT). Estrogens were previously widely used for prevention of osteoporosis, but current guidelines recommend use of other therapies such as alendronate over estrogen. Estrogens are also used for replacement therapy in premenopausal patients who are deficient in this hormone. Estrogen deficiency can be due to inadequate functioning of the ovaries (hypogonadism), premature menopause, or surgical menopause.

  • Postmenopausal HT: The primary indication for estrogen therapy in postmenopausal women is menopausal symptoms, such as vasomotor instability (for example, “hot flashes” or “hot flushes”) and vaginal atrophy. For women who have an intact uterus, a progestogen is always included with the estrogen therapy, because the combination reduces the risk of endometrial carcinoma associated with unopposed estrogen. For women who have undergone a hysterectomy, unopposed estrogen therapy is recommended because progestins may unfavorably alter the beneficial effects of estrogen on lipid parameters. [Note: The amount of estrogen used in replacement therapy is substantially less than the doses used in oral contraception. Thus, the adverse effects of estrogen replacement therapy are usually less pronounced than those seen in women taking estrogen for contraceptive purposes.] Delivery of estradiol by transdermal patch or gel is also effective in treating postmenopausal symptoms. Due to concerns over the risks of HT (increased risk of cardiovascular events and breast cancer), HT should be prescribed at the lowest effective dose for the shortest possible time to relieve menopausal symptoms. Women who only have urogenital symptoms, such as vaginal atrophy, should be treated with vaginal rather than systemic estrogen.
  • Contraception: The combination of an estrogen and progestogen provides effective contraception via the oral, transdermal, or vaginal route.
  • Other uses: Estrogen therapy mimicking the natural cyclic pattern, and usually in combination with a progestogen, is instituted to stimulate development of secondary sex characteristics in young women with primary hypogonadism. Continued treatment is required after growth is completed. Similarly, estrogen and progestogen replacement therapy is used for women who have premature menopause or premature ovarian failure.

Estrogens and Androgens

C. Pharmacokinetics

Focus topic:  Estrogens and Androgens

  • Naturally occurring estrogens: These agents and their esterified or conjugated derivatives are readily absorbed through the gastrointestinal tract, skin, and mucous membranes. Taken orally, estradiol is rapidly metabolized (and partially inactivated) by the microsomal enzymes of the liver. Micronized estradiol is available and has better bioavailability. Although there is some first-pass metabolism, it is not sufficient to lessen the effectiveness when taken orally.
  • Synthetic estrogen analogs: These compounds, such as ethinyl estradiol, mestranol [MES-trah-nole], and estradiol valerate, are well absorbed after oral administration. Mestranol is quickly demethylated to ethinyl estradiol, which is metabolized more slowly than the naturally occurring estrogens by the liver and peripheral tissues. Estradiol valerate is rapidly cleaved to estradiol and valeric acid. Being fat soluble, they are stored in adipose tissue, from which they are slowly released. Therefore, the synthetic estrogen analogs have a prolonged action and a higher potency compared to those of natural estrogens.
  • Metabolism: Estrogens are transported in the blood bound to serum albumin or sex hormone–binding globulin. As mentioned above, bioavailability of estrogen taken orally is low due to first pass metabolism. To reduce first-pass metabolism, the drugs may be administered via the transdermal route (patch, topical gel, topical emulsion, or spray), intravaginally (tablet, cream, or ring), or by injection. They are hydroxylated in the liver to derivatives that are subsequently glucuronidated or sulfated. The parent drugs and their metabolites undergo excretion into bile and are then reabsorbed through the enterohepatic circulation. Inactive products are excreted in urine.

D. Adverse effects

Focus topic:  Estrogens and Androgens

Nausea and breast tenderness are among the most common adverse effects of estrogen therapy. In addition, the risk of thromboembolic events, myocardial infarction, and breast and endometrial cancer is increased with use of estrogen therapy. [Note: The increased risk of endometrial cancer can be offset by including a progestogen along with the estrogen therapy.]

Estrogens and Androgens

Estrogens and Androgens: SELECTIVE ESTROGEN RECEPTOR MODULATORS

Focus topic:  Estrogens and Androgens

SERMs are a class of estrogen-related compounds that display selective agonism or antagonism for estrogen receptors depending on the tissue type. This category includes tamoxifen, toremifene, raloxifene, clomiphene, and ospemifene.

A. Mechanism of action

Tamoxifen [tah-MOKS-ih-fen], toremifene [tore-EM-i-feen], and raloxifene [rah-LOX-ih-feen] compete with estrogen for binding to the estrogen receptor in breast tissue. [Note: Normal breast growth is stimulated by estrogens. Therefore, some breast tumors regress following treatment with these agents.] In addition, raloxifene acts as an estrogen agonist in bone, leading to decreased bone resorption, increased bone density, and decreased vertebral fractures (Figure 26.5). Unlike estrogen and tamoxifen, raloxifene does not have appreciable estrogen receptor agonist activity in the endometrium and, therefore, does not predispose to endometrial cancer. Raloxifene also lowers serum total cholesterol and low-density lipoprotein (LDL). Clomiphene [KLOE-mifeen] acts as a partial estrogen agonist and interferes with the negative feedback of estrogens on the hypothalamus. This effect increases the secretion of gonadotropin-releasing hormone and gonadotropins, thereby leading to stimulation of ovulation.

B. Therapeutic uses

Tamoxifen is currently used in the treatment of metastatic breast cancer, or as adjuvant therapy following mastectomy or radiation for breast cancer. Both tamoxifen and raloxifene can be used as prophylactic therapy to reduce the risk of breast cancer in high-risk patients. Raloxifene is also approved for the prevention and treatment of osteoporosis in postmenopausal women. Clomiphene is useful for the treatment of infertility associated with anovulatory cycles. Ospemifene is indicated for the treatment of dyspareunia (painful sexual intercourse) related to menopause.

C. Pharmacokinetics

The SERMs are rapidly absorbed after oral administration. Tamoxifen is extensively metabolized by cytochrome P450 isoenzymes, including formation of active metabolites via the CYP3A4/5 and CYP2D6 isoenzymes. [Note: Patients with a genetic polymorphism in CYP2D6 may produce less active metabolite, resulting in diminished activity of tamoxifen.] Raloxifene is rapidly converted to glucuronide conjugates through first-pass metabolism. These agents undergo enterohepatic cycling, and the primary route of excretion is through the bile into feces.

D. Adverse effects

The most frequent adverse effects of tamoxifen and toremifene are hot flashes and nausea. Due to its estrogenic activity in the endometrium, endometrial hyperplasia and malignancies have been reported with tamoxifen therapy. This has led to recommendations for limiting the length of time on the drug for some indications. Because it is metabolized by various CYP450 isoenzymes, tamoxifen is subject to many drug interactions. [Note: Tamoxifen is also an inhibitor of CYP3A4 and P-glycoprotein.] Some CYP450 inhibitors may prevent the formation of active metabolites of tamoxifen and possibly reduce the efficacy (for example, amiodarone, haloperidol, risperidone). Hot flashes and leg cramps are common adverse effects with raloxifene. In addition, there is an increased risk of deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. Women who have a past or active history of venous thromboembolic events should not take the drug. Cholestyramine can significantly reduce the absorption of raloxifene, and concurrent use should be avoided. Adverse effects of clomiphene are dose related and include headache, nausea, vasomotor flushes, visual disturbances, and ovarian enlargement. Use of clomiphene increases the risk of multiple births (twins or triplets).

Estrogens and Androgens

Estrogens and Androgens: PROGESTOGENS

Focus topic:  Estrogens and Androgens

Progesterone, the natural progestogen, is produced in response to luteinizing hormone (LH) by both females (secreted by the corpus luteum, primarily during the second half of the menstrual cycle, and by the placenta) and by males (secreted by the testes). It is also synthesized by the adrenal cortex in both sexes.

A. Mechanism of action

Progestogens exert their mechanism of action in a manner analogous to that of the other steroid hormones. In females, progesterone promotes the development of a secretory endometrium that can accommodate implantation of a newly forming embryo. The high levels of progesterone that are released during the second half of the menstrual cycle (the luteal phase) inhibit the production of gonadotropin and, therefore, prevent further ovulation. If conception takes place, progesterone continues to be secreted, maintaining the endometrium in a favorable state for the continuation of the pregnancy and reducing uterine contractions. If conception does not take place, the release of progesterone from the corpus luteum ceases abruptly. This decline stimulates the onset of menstruation.

 Estrogens and Androgens

B. Therapeutic uses of progestogens

The major clinical uses of progestogens are for contraception or the treatment of hormone deficiency. For contraception, they are often used in combination with estrogens. Progesterone by itself is not used widely as a contraceptive therapy because of its rapid metabolism, resulting in low bioavailability. Synthetic progestogens (that is, progestins) used in contraception are more stable to first pass metabolism, allowing lower doses when administered orally. These agents include desogestrel [des-oh-JES-trel], dienogest [dye-EN-oh-jest], drospirenone [droe-SPY-re-none], levonorgestrel [leevoe-nor-JES-trel], norethindrone [nor-ETH-in-drone], norethindrone acetate, norgestimate [nor-JES-tih-mate], and norgestrel [nor-JEStrel]. Medroxyprogesterone [me-DROK-see-proe-JES-ter-one] acetate is an injectable contraceptive, and the oral form is a common progestin component of postmenopausal HT. Progestins are also used for the control of dysfunctional uterine bleeding, treatment of dysmenorrhea, and management of endometriosis and infertility.

C. Pharmacokinetics

A micronized preparation of progesterone is rapidly absorbed after oral administration. It has a short half-life in the plasma and is almost completely metabolized by the liver. The glucuronidated metabolite is excreted primarily by the kidney. Synthetic progestins are less rapidly metabolized. Oral medroxyprogesterone acetate has a half-life of 30 days. When injected intramuscularly or subcutaneously, it has a half-life of about 40 to 50 days and provides contraceptive activity for approximately 3 months. The other progestins have half-lives of 1 to 3 days, allowing for once-daily dosing.

D. Adverse effects

The major adverse effects associated with the use of progestins are headache, depression, weight gain, and changes in libido. Progestins that are derived from 19-nortestosterone (for example, norethindrone, norethindrone acetate, norgestrel, levonorgestrel) possess some androgenic activity because of their structural similarity to testosterone and can cause acne and hirsutism. Less androgenic progestins, such as norgestimate and drospirenone, may be preferred in women with acne. Drospirenone may raise serum potassium due to antimineralocorticoid effects, and concurrent use with other drugs that increase potassium (for example, angiotensin-converting enzyme inhibitors) may increase the risk of hyperkalemia.

E. Antiprogestin

Mifepristone [mih-feh-PRIH-stone] (also designated as RU-486) is a progesterone antagonist with partial agonist activity. Administration of this drug to females early in pregnancy usually results in abortion of the fetus due to interference with the progesterone needed to maintain pregnancy. Mifepristone is often combined with the prostaglandin analog misoprostol (administered orally or intravaginally) to induce uterine contractions. The major adverse effects are significant uterine bleeding and the possibility of an incomplete abortion.

 Estrogens and Androgens

 Estrogens and Androgens: CONTRACEPTIVES

Focus topic:  Estrogens and Androgens

Currently, interference with ovulation is the most common pharmacologic intervention for prevention of pregnancy.

A. Major classes of contraceptives

Focus topic:  Estrogens and Androgens

  • Combination oral contraceptives: Products containing a combination of an estrogen and a progestin are the most common type of oral contraceptives. Monophasic combination pills contain a constant dose of estrogen and progestin given over 21 to 24 days. Triphasic oral contraceptive products attempt to mimic the natural female cycle and most contain a constant dose of estrogen with increasing doses of progestin given over three successive 7-day periods. [Note: The combination of estradiol valerate and dienogest is available as a four-phasic oral contraceptive.] With most oral contraceptives, active pills are taken for 21 to 24 days, followed by 4 to 7 days of placebo, for a total regimen of 28 days. Withdrawal bleeding occurs during the hormone-free (placebo) interval. [Note: The most common estrogen in the combination pills is ethinyl estradiol. The most common progestins are norethindrone, norethindrone acetate, levonorgestrel, desogestrel, norgestimate, and drospirenone.] These preparations are highly effective in achieving contraception. Use of extended-cycle contraception (84 active pills followed by 7 days of placebo) results in less frequent withdrawal bleeding. A continuous oral contraceptive product (active pills taken every day) is also available.
  • Transdermal patch: An alternative to combination oral contraceptives is a transdermal patch containing ethinyl estradiol and the progestin norelgestromin. One contraceptive patch is applied each week for 3 weeks to the abdomen, upper torso, or buttock. No patch is worn during the 4th week, and withdrawal bleeding occurs. The transdermal patch has efficacy comparable to that of the oral contraceptives, but it is less effective in women weighing greater than 90 kg. Contraindications and adverse effects for the patch are similar to those of oral contraceptives. Total estrogen exposure with the transdermal patch may be significantly greater than that seen with oral contraceptives. Increased exposure to estrogen may increase the risk of adverse events such as thromboembolism.
  • Vaginal ring: An additional contraceptive option is a vaginal ring containing ethinyl estradiol and etonogestrel. The ring is inserted into the vagina and is left in place for 3 weeks and then removed. No ring is used during the fourth week, and withdrawal bleeding occurs. The contraceptive vaginal ring has efficacy, contraindications, and adverse effects similar to those of oral contraceptives.
  • Progestin-only pills: Products containing a progestin only, usually norethindrone (called a “mini-pill”), are taken daily on a continuous schedule. Progestin-only pills deliver a low, continuous dosage of drug. These preparations are less effective than combination products, and they may produce irregular menstrual cycles more frequently. The progestin-only pill may be used for patients who are breast-feeding (unlike estrogen, progestins do not have an effect on milk production), are intolerant to estrogen, are smokers, or have other contraindications to estrogen- containing products.
  • Injectable progestin: Medroxyprogesterone acetate is a contraceptive that is administered via intramuscular or subcutaneous injection every 3 months. Weight gain is a common adverse effect. Because this product provides high sustained levels of progestin, many women experience amenorrhea with medroxyprogesterone acetate. In addition, return to fertility may be delayed for several months after discontinuation. Medroxyprogesterone acetate may contribute to bone loss and predispose patients to osteoporosis and/or fractures. Therefore, the drug should not be continued for more than 2 years unless the patient is unable to tolerate other contraceptive options.
  • Progestin implants: After subdermal placement, the etonogestrel implant offers contraception for approximately 3 years. The implant is nearly as reliable as sterilization, and the effect is totally reversible when surgically removed. Principal side effects of the implant are irregular menstrual bleeding and headaches. The etonogestrel implant has not been studied in women who weigh more than 130% of ideal body weight and may be less effective in this population.
  • Progestin intrauterine device: A levonorgestrel-releasing intrauterine system offers a highly effective method of contraception for 3 to 5 years depending on the system. It is a suitable method of contraception for women who desire long-term contraception and those who have contraindications to estrogen therapy. It should be avoided in patients with pelvic inflammatory disease or a history of ectopic pregnancy.
  • Postcoital contraception: Postcoital or emergency contraception reduces the probability of pregnancy after an episode of coitus without effective contraception to between 0.2% and 3%. Emergency contraception uses high doses of levonorgestrel (preferred) or high doses of ethinyl estradiol plus levonorgestrel. For maximum effectiveness, emergency contraception should be taken as soon as possible after unprotected intercourse and preferably within 72 hours. The progestin-only emergency contraceptive regimens are generally better tolerated than the estrogen–progestin combination regimens. An alternative emergency contraceptive is the progesterone agonist/antagonist ulipristal [ue-li-PRIS-tal]. It is indicated for emergency contraception within 5 days of unprotected intercourse.

 Estrogens and Androgens

 Estrogens and Androgens

 Estrogens and Androgens

B. Mechanism of action

Focus topic:  Estrogens and Androgens

Estrogen provides a negative feedback on the release of LH and follicle-stimulating hormone (FSH) by the pituitary gland, thus preventing ovulation. Progestin also thickens the cervical mucus, thus hampering the transport of sperm. Withdrawal of the progestin stimulates menstrual bleeding during the placebo week.

C. Adverse effects

Focus topic:  Estrogens and Androgens

The incidence of adverse effects with oral contraceptives is determined by the specific compounds and combinations used. The most common adverse effects with estrogens are breast fullness, fluid retention, headache, and nausea. Increased blood pressure may also occur. Progestins may be associated with depression, changes in libido, hirsutism, and acne. Although rare, thromboembolism, thrombophlebitis, myocardial infarction, and stroke may occur with use of oral contraceptives. These severe adverse effects are most common among women who are over age 35 and smoke. The incidence of cervical cancer may be increased with oral contraceptives, because women are less likely to use additional barrier methods of contraception that reduce exposure to human papillomavirus (the primary risk factor for cervical cancer). [Note: Oral contraceptives are associated with a decreased risk of cervical and ovarian cancer.] Oral contraceptives are contraindicated in the presence of cerebrovascular and thromboembolic disease, estrogen-dependent neoplasms, liver disease, and pregnancy. Combination oral contraceptives should not be used in patients over the age of 35 who are heavy smokers. Drugs that induce the CYP3A4 isoenzyme (for example, rifampin and bosentan) may significantly reduce the efficacy of oral contraceptives. Concurrent use of these agents with oral contraceptives should be avoided, or an alternate barrier method of contraception should be utilized. Antibiotics that alter the normal gastrointestinal flora may reduce enterohepatic recycling of the estrogen component of oral contraceptives, thereby diminishing the effectiveness. Patients should be warned of the possible interaction between antibiotics and oral contraceptives, along with the potential need for an alternate method of contraception during antibiotic therapy.

 Estrogens and Androgens: ANDROGENS

Focus topic:  Estrogens and Androgens

The androgens are a group of steroids that have anabolic and/or masculinizing effects in both males and females. Testosterone [tess-TOSS-terone], the most important androgen in humans, is synthesized by Leydig cells in the testes and, in smaller amounts, by thecal cells in the ovaries and by the adrenal gland in both sexes. Other androgens secreted by the testes are 5α-dihydrotestosterone (DHT), androstenedione, and dehydroepiandrosterone (DHEA) in small amounts. In adult males, testosterone secretion by Leydig cells is controlled by gonadotropin-releasing hormone from the hypothalamus, which stimulates the anterior pituitary gland to secrete FSH and LH. Testosterone or its active metabolite, DHT, inhibits production of these specific trophic hormones through a negative feedback loop and, thus, regulates testosterone production. The androgens are required for 1) normal maturation in the male, 2) sperm production, 3) increased synthesis of muscle proteins and hemoglobin, and 4) decreased bone resorption. Synthetic modifications of the androgen structure modify solubility and susceptibility to enzymatic breakdown (thus prolonging the half-life of the hormone) and separate anabolic and androgenic effects.

A. Mechanism of action

Focus topic:  Estrogens and Androgens

Like the estrogens and progestins, androgens bind to a specific nuclear receptor in a target cell. Although testosterone itself is the active ligand in muscle and liver, in other tissues it must be metabolized to derivatives, such as DHT. For example, after diffusing into the cells of the prostate, seminal vesicles, epididymis, and skin, testosterone is converted by 5α-reductase to DHT, which binds to the receptor.

B. Therapeutic uses

Focus topic:  Estrogens and Androgens

Androgenic steroids are used for males with primary hypogonadism (caused by testicular dysfunction) or secondary hypogonadism (due to failure of the hypothalamus or pituitary). Anabolic steroids can be used to treat chronic wasting associated with human immunodeficiency virus or cancer. An unapproved use of anabolic steroids is to increase lean body mass, muscle strength, and endurance in athletes and body builders (see below). DHEA (a precursor of testosterone and estrogen) has been touted as an anti-aging hormone as well as a “performance enhancer.” There is no definitive evidence that it slows aging, however, or that it improves performance at normal therapeutic doses. Danazol [DAH-nah-zole], a weak androgen, is used in the treatment of endometriosis (ectopic growth of the endometrium) and fibrocystic breast disease. [Note: Danazol also possesses antiestrogenic activity.] Weight gain, acne, decreased breast size, deepening voice, increased libido, and increased hair growth are among the adverse effects.

C. Pharmacokinetics

Focus topic:  Estrogens and Androgens

  • Testosterone: This agent is ineffective orally because of inactivation by first-pass metabolism. As with the other sex steroids, testosterone is rapidly absorbed and is metabolized to relatively or completely inactive compounds that are excreted primarily in the urine. C17-esters of testosterone (for example, testosterone cypionate or enanthate) are administered intramuscularly. [Note: The addition of the esterified lipid makes the hormone more lipid soluble, thereby increasing its duration of action.] Transdermal patches, topical gels, and buccal tablets of testosterone are also available.
  • Testosterone derivatives: Alkylation of the 17α position of testosterone allows oral administration of the hormone. Agents such as fluoxymesterone [floo-ox-ee-MESS-teh-rone] have a longer half-life in the body than that of the naturally occurring androgen. Fluoxymesterone is effective when given orally, and it has a 1:2 androgenic-to-anabolic ratio. Oxandrolone [ox-AN-droe-lone] is another orally active testosterone derivative with anabolic activity 3 to 13 times that of testosterone. Hepatic adverse effects have been associated with the 17α-alkylated androgens.

 Estrogens and Androgens

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D. Adverse effects

Focus topic:  Estrogens and Androgens

  • In females: Androgens can cause masculinization, acne, growth of facial hair, deepening of the voice, male pattern baldness, and excessive muscle development. Menstrual irregularities may also occur. Testosterone should not be used by pregnant women because of possible virilization of the female fetus.
  • In males: Excess androgens can cause priapism, impotence, decreased spermatogenesis, and gynecomastia. Cosmetic changes such as those described for females may occur as well. Androgens can also stimulate growth of the prostate.
  • In children: Androgens can cause abnormal sexual maturation and growth disturbances resulting from premature closing of the epiphyseal plates.
  • General effects: Androgens can increase serum LDL and lower serum high-density lipoprotein levels. Whether these changes in the lipid profile predispose patients to heart disease is unknown. Androgens can also cause fluid retention, leading to edema.
  • In athletes: Use of anabolic steroids (for example, DHEA) by athletes can cause premature closing of the epiphysis of the long bones, which stunts growth and interrupts development. High doses taken by young athletes may result in reduction of testicular size, hepatic abnormalities, increased aggression (“roid rage”), major mood disorders, and other adverse effects described above.

E. Antiandrogens

Focus topic:  Estrogens and Androgens

Antiandrogens counter male hormonal action by interfering with the synthesis of androgens or by blocking their receptors. Finasteride [fin-AS-ter-ide] and dutasteride [doo-TAS-ter-ride] inhibit 5α-reductase resulting in decreased formation of dihydrotestosterone. These agents are used for the treatment of benign prostatic hyperplasia (see Chapter 32). Antiandrogens, such as flutamide [FLOO-tah-mide], bicalutamide [bye-ka-LOO-ta-mide], enzalutamide [enz-a-LOO-tamide], and nilutamide [nye-LOO-ta-mide], act as competitive inhibitors of androgens at the target cell and are effective orally for the treatment of prostate cancer.

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