Pharmacology: Estrogens and Androgens PDF

PHARMACOLOGY ESTROGENS AND ANDROGENS D.SALAH ABDALMONIM IZZELDIN ESTROGENS AND ANDROGENS These hormones are necessary for conception,embryonic maturation, and development of primary and secondary sexual characteristics at puberty. The sex hormones are used therapeutically for contr...

PHARMACOLOGY ESTROGENS AND ANDROGENS D.SALAH ABDALMONIM IZZELDIN ESTROGENS AND ANDROGENS These hormones are necessary for conception,embryonic maturation, and development of primary and secondary sexual characteristics at puberty. The sex hormones are used therapeutically for contraception, management of menopausal symptoms, and replacement therapy in hormone deficiency. Several antagonists are effective in the treatment or prevention of hormone responsive cancers. ESTROGENS Estradiol [ess-tra-DYE-ole] is the most potent estrogen produced and secreted by the ovary. It is the principal estrogen in premenopausal women. Estrone is the primary circulating estrogen after menopause 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 synthesized by the placenta. Synthetic estrogens, such as ethinyl estradiol [ETH-ih-nil esstra-DYE-ole], undergo less first-pass metabolism than do naturally occurring hormones and, thus, are effective when administered orally at lower doses. THERAPEUTIC USES 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 A common oral preparation: conjugated equine estrogens (obtained from urine of pregnant mares) esterified estrogens and estropipate [Note: The potency of estrogen used in HT is substantially less than that of estrogens used in contraception. Thus, the adverse effects of estrogen replacement therapy are usually less pronounced than those seen in women taking estrogen for contraceptive purposes.] Use of HT has been associated with an increased risk of cardiovascular events and breast cancer. Thus, HT should be prescribed at the lowest effective dose for the shortest possible time Women who only have urogenital symptoms, such as vaginal atrophy, should be treated with vaginal rather than systemic estrogen to minimize the risks of use. 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 institutedbto stimulate development of secondary sex characteristics in young women with primary hypogonadism. ADVERSE EFFECTS 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 the use of estrogen therapy. [Note: The increased risk of endometrial cancer can be offset by including a progestogen along with the estrogen therapy.] SELECTIVE ESTROGEN RECEPTOR MODULATORS 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, raloxifene, bazedoxifene, clomiphene, and ospemifene. MECHANISM OF ACTION Tamoxifen [tah-MOKS-ih-fen] 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 hormoneresponsive breast tumors regress following treatment with these agents.] In addition raloxifene acts as an estrogen agonist in bone, leading to decreased bone resorption Unlike estrogen and tamoxifen, raloxifene does not stimulate growth of the endometrium and, therefore, does not predispose to endometrial cancer. antagonizes the action of estrogen on the uterus. The drug reduces the risk of endometrial hyperplasia with estrogen use. Clomiphene [KLOE-mi-feen] 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. ADVERSE EFFECTS adverse effects of tamoxifen 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. Hot flashes and leg cramps are common adverse effects with raloxifene. In addition, there is an increased risk of deep vein thrombosis and pulmonary embolism. Women who have a past or active history of venous thromboembolic events should not take the drug. 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 gestation, usually twins. PROGESTOGENS 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). 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. The decline in progesterone stimulates the onset of menstruation. THERAPEUTIC USES The major clinical uses of progestogens are for contraception or hormone replacement therapy. For both contraception and HT, progestogens are often used in combination with estrogens. Synthetic progestogens (that is, progestins) used for 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 [lee-voe-nor-JES-trel], norethindrone [nor-ETH-in-drone], norethindrone acetate, norgestimate [nor-JES-tih-mate], and norgestrel [nor-JES-trel]. Medroxyprogesterone [me-DROK-seeproe-JES-ter-one] acetate is an injectable contraceptive, oral form is a common progestin component of postmenopausal HT. Oral medroxyprogesterone acetate has a half-life of 30 hours. When injected intramuscularly or subcutaneously, the drug has a half-life of about 40 to 50 days and provides contraception for approximately 3 months. 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. ANTIPROGESTIN Mifepristone [mih-feh-PRIH-stone] is a progesterone antagonist. Administration of this drug results in termination of pregnancy due to interference with the progesterone needed to maintain pregnancy. Mifepristone is often combined with the prostaglandin analog misoprostol to induce uterine contractions. TYPES OF HORMONAL CONTRACEPTIVES Combination oral contraceptives: A combination of estrogen and progestin is the most common type of oral contraceptive. [Note: The most common estrogen in 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. 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.  Progestin-only pills: Progestin-only pills (the “mini-pill”) contain a progestin, usually norethindrone, and are administered daily to deliver a low, continuous dosage of drug. These preparations are less effective than combination oral contraceptives,and irregular menstrual cycles may be more frequent. Progestin-only pills may be used in patients who are breastfeeding (unlike estrogen, progestins do not have an effect on milk production) or who have intolerance or contraindications to estrogen-containing products. Injectable progestin: Medroxyprogesterone acetate This product provides high sustained levels of progestin, and many women experience amenorrhea with medroxyprogesterone acetate. In addition, return to fertility may be delayed for several months after discontinuation. Weight gain is a common adverse effect. 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 in the upper arm, the etonogestrel implant offers contraception for up to 3 years. the contraceptive effect is reversible when removed. [Note: Progestin implants and intrauterine devices are known as long-acting reversible contraceptives (LARC).] Adverse effects: include 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. MECHANISM OF ACTION Exogenously administered estrogen in contraceptives provides negative feedback which blunts release of follicle stimulating hormone (FSH) by the pituitary gland and progestin inhibits LH secretion, 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. ADVERSE EFFECTS 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, myocardial infarction, and stroke may occur with use of estrogen- containing contraceptives. Although rare, thromboembolism, thrombophlebitis, myocardial infarction, and stroke may occur with use of estrogen-containing contraceptives. These severe adverse effects are most common among women who are over age 35 and smoke, and estrogen-containing contraceptives should be avoided in this population. Progestin-only products are preferred in older women who are smokers, due to a lower risk of severe adverse effects. Antibiotics that alter normal gastrointestinal flora may reduce enterohepatic recycling of estrogen, thereby diminishing effectiveness of oral contraceptives. 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.