Pharmacology_lec.8.pdf

Pharmacology Estrogens and Androgens Lec 8 Pharmacology | Estrogens and Androgens Contents : Introduction 3 ESTROGENS 5 Selective estrogen receptor modulators 23 PROGESTOGENS 43 Antiprogestin 44 Pharmacology | Estrogens and Androgens Estrogens and androgens are sex hormones produced by the gonads. T...

Pharmacology Estrogens and Androgens Lec 8 Pharmacology | Estrogens and Androgens Contents : Introduction 3 ESTROGENS 5 Selective estrogen receptor modulators 23 PROGESTOGENS 43 Antiprogestin 44 Pharmacology | Estrogens and Androgens Estrogens and androgens are sex hormones produced by the gonads. 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 1. Contraception. 2. management of menopausal symptoms. 3. replacement therapy in hormone deficiency. Pharmacology | Estrogens and Androgens Several antagonists are effective in the treatment or prevention of hormone-responsive cancers. Sex 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. Pharmacology | Estrogens and Androgens ESTROGENS Estradiol is the most potent estrogen produced and secreted by the ovary. It is the principal estrogen in premenopausal women. Estrone is a metabolite of estradiol that has approximately one-third the estrogenic potency of estradiol. Pharmacology | Estrogens and Androgens Estrone is the primary circulating estrogen after menopause, and it is generated mainly from conversion of dehydroepiandrosterone [DHEA] in adipose tissue. Estriol , 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. Pharmacology | Estrogens and Androgens Synthetic estrogens, such as ethinyl estradiol, undergo less first-pass metabolism than do naturally occurring hormones and, thus, are effective when administered orally at lower doses. Pharmacology | Estrogens and Androgens Mechanism of action After dissociation from their binding sites on sex hormone-binding globulin or albumin in the plasma, steroid hormones (for example, estradiol) 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. Pharmacology | Estrogens and Androgens Pharmacology | Estrogens and Androgens Therapeutic uses Estrogens are most frequently used for contraception and postmenopausal hormone therapy (HT). In the past, estrogens were widely used for prevention of osteoporosis; however, due to risks associated with estrogen therapy, current guidelines recommend use of other therapies, such as bisphosphonates. Pharmacology | Estrogens and Androgens 1. 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 used for the treatment of menopausal symptoms is conjugated equine estrogens (obtained from urine of pregnant mares), which primarily contains sulfate esters of estrone and equilin. Other estrone-based oral preparations include esterified estrogens and estropipate. Pharmacology | Estrogens and Androgens Transdermal preparations of estradiol are also effective in treating menopausal symptoms. For women with 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. Women who have undergone a hysterectomy may use estrogen alone. 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. Pharmacology | Estrogens and Androgens 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 to relieve menopausal symptoms. 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. Pharmacology | Estrogens and Androgens 2. Contraception The combination of an estrogen and progestogen provides effective contraception via the oral, transdermal, or vaginal route. Pharmacology | Estrogens and Androgens 3. 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. Similarly, replacement therapy is used for women who have hormonal deficiencies due to surgical menopause or premature ovarian failure. Pharmacology | Estrogens and Androgens Pharmacokinetics 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 has better bioavailability. Although estradiol is subject to first-pass metabolism, it is still effective when taken orally. Pharmacology | Estrogens and Androgens Synthetic estrogens These compounds, such as ethinyl estradiol and estradiol valerate are well absorbed after oral administration. Estradiol valerate is a prodrug of estradiol which is rapidly cleaved to estradiol and valeric acid. The synthetic estrogens are fat soluble, stored in adipose tissue, and slowly released. These compounds have a prolonged action and a higher potency compared to the natural estrogens. Pharmacology | Estrogens and Androgens Metabolism Bioavailability of estradiol after oral administration is low due to first-pass metabolism. To reduce first-pass metabolism, estradiol may be administered via a transdermal patch, topical formulation (gel or spray), intravaginal preparation (tablet, cream, or ring), or injection. Following oral administration, estradiol is metabolized to estrone and estriol. Pharmacology | Estrogens and Androgens Estrogens are transported in the blood bound to serum albumin or sex hormone-binding globulin. Estradiol and its metabolites subsequently undergo glucuronide and sulfate conjugation. Pharmacology | Estrogens and Androgens 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. Other effects of estrogen therapy are shown in Figure below. Pharmacology | Estrogens and Androgens Pharmacology | Estrogens and Androgens 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. Pharmacology | Estrogens and Androgens Mechanism of action Tamoxifen and raloxifene compete with estrogen for binding to the estrogen receptor in breast tissue. In addition, raloxifene acts as an estrogen agonist in bone, leading to decreased bone resorption, increased bone density, and decreased vertebral fractures. Unlike estrogen and tamoxifen, raloxifene does not stimulate growth of the endometrium and, therefore, does not predispose to endometrial cancer. Note: Normal breast growth is stimulated by estrogens. Therefore, some hormoneresponsive breast tumors regress following treatment with these agents. Pharmacology | Estrogens and Androgens Raloxifene also lowers serum total cholesterol and low-density lipoprotein (LDL). Like raloxifene, bazedoxifene antagonizes the action of estrogen on the uterus. The drug reduces the risk of endometrial hyperplasia with estrogen use. Pharmacology | Estrogens and Androgens Clomiphene (ClomidR) acts as a partial estrogen agonist and interferes with the negative feedback of estrogens on the hypothalamus. This effect increases the secretion of gonadotropinreleasing hormone and gonadotropins, thereby leading to stimulation of ovulation. Pharmacology | Estrogens and Androgens 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. Pharmacology | Estrogens and Androgens Clomiphene is used in the treatment of infertility. Ospemifene is indicated for the treatment of dyspareunia (painful sexual intercourse) related to menopause. Bazedoxifene is available in a combination product with conjugated estrogens. The combination is indicated for the treatment of menopausal symptoms in women with an intact uterus. Pharmacology | Estrogens and Androgens Pharmacokinetics The SERMs are rapidly absorbed after oral administration. Tamoxifen is extensively metabolized by cytochrome P450 system, including the formation of active metabolites via the CYP3A4/5 and CYP2D6 isoenzymes. 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. Note: Patients with a genetic polymorphism in CYP2D6 may produce less active metabolite, resulting in diminished activity of tamoxifen Pharmacology | Estrogens and Androgens Adverse effects The most frequent 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. Pharmacology | Estrogens and Androgens Because it is metabolized by various CYP450 isoenzymes, tamoxifen is subject to many drug interactions. Some CYP450 inhibitors may prevent the formation of active metabolites of tamoxifen and possibly reduce the efficacy (for example, amiodarone, haloperidol, paroxetine). Hot flashes and leg cramps are common adverse effects with raloxifene. Note: Tamoxifen is also an inhibitor of P-glycoprotein. Pharmacology | Estrogens and Androgens ln 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. Pharmacology | Estrogens and Androgens Ospemifene may stimulate endometrial growth, and addition of a progestogen in women with an intact uterus should be considered. Pharmacology | Estrogens and Androgens 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). It is also synthesized by the adrenal cortex in both sex. Pharmacology | Estrogens and Androgens Mechanism of action Progestogens exerts their effects 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. Pharmacology | Estrogens and Androgens 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. Pharmacology | Estrogens and Androgens 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. Progesterone is not used as a contraceptive therapy because of its rapid metabolism, resulting in low bioavailability. Pharmacology | Estrogens and Androgens Synthetic progestogens (like, progestins) used for contraception are more stable to first-pass metabolism, allowing lower doses when administered orally. These agents include : Desogestrel. Dienogest. Levonorgestrel. norethindrone, norethindrone acetate. norgestimate. norgestrel. Pharmacology | Estrogens and Androgens Medroxyprogesterone acetate is an injectable contraceptive, and the oral form is a common progestin component of postmenopausal HT. Progestogens are also used for the control of dysfunctional uterine bleeding, treatment of dysmenorrhea, and management of endometriosis and infertility. Pharmacology | Estrogens and Androgens Pharmacokinetics A micronized preparation of progesterone is rapidly absorbed after oral administration. It has a short half-life in the plasma and is metabolized by the liver to pregnanediol and glucuronide and sulfate conjugates. The metabolites are excreted primarily in the urine. Synthetic progestins are less rapidly metabolized. Pharmacology | Estrogens and Androgens 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. The other progestins have half-lives of 7 to 30 hours, allowing for once-daily dosing. Pharmacology | Estrogens and Androgens 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 19nortestosterone (for example, norethindrone, norethindrone acetate, norgestrel, levonorgestrel) possess some androgenic activity because of their structural similarity to testosterone and can cause acne and hirsutism. Pharmacology | Estrogens and Androgens 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. Pharmacology | Estrogens and Androgens Antiprogestin Mifepristone (also designated as RU-486) 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.