Hormones PDF

Hormones Presented by: Dr Karishma Jeeboo Learning Objectives Know they uses of the different types of gonadal hormones. Examples of hormones used in the various therapies (generic and brands). And under these know: Mechanism of actions Pharmacokinetics Side effe...

Hormones Presented by: Dr Karishma Jeeboo Learning Objectives Know they uses of the different types of gonadal hormones. Examples of hormones used in the various therapies (generic and brands). And under these know: Mechanism of actions Pharmacokinetics Side effects Contraindications Drug interactions Introduction 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. – SERM’s Gonadal hormones are produced from cholesterol. Estrogens Estradiol – used in many combinations - Qlaira Estrone – Menest Ethinyl Estradiol – used in many COCs e.g. Microgynon, Nordette, Yasmin, Yaz, Femiane, Diane 35, logynon. Mestranol Estrogens Estradiol - the most potent estrogen produced and secreted by the ovary. Principal estrogen in the premenopausal woman. Estrone - metabolite of estradiol that has approximately one-third the estrogenic potency of estradiol. Primary circulating estrogen after menopause. Estriol, another metabolite of estradiol, is significantly less potent. It is present in significant amounts during pregnancy, because it is the principal estrogen produced by the placenta. Estrogens A preparation of conjugated estrogens containing sulfate esters of estrone and equilin— obtained from pregnant mare's urine—is a widely used oral preparation for hormone replacement therapy. E.g. Premarin Plant-derived conjugated estrogen products are also available. Nonsteroidal compounds that bind to estrogen receptors and exert either estrogenic or antiestrogenic effects on target tissues are called selective estrogen-receptor modulators - include tamoxifen and raloxifene, among others. Estrogens Synthetic estrogens, such as ethinyl estradiol, undergo less first-pass metabolism than naturally occurring steroids and, thus, are effective when administered orally at lower doses. Mechanism of Action: 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. Estrogens – Mechanism of Action Two estrogen-receptor subtypes, α and β, mediate the effects of the hormone. The α receptor may be considered as the classic estrogen receptor; the β receptor is highly homologous to the α receptor. However, the N-terminal portion of the α receptor contains a region that promotes transcription activation, whereas the β receptor contains a repressor domain. As a result, the transcriptional properties of the α and β estrogen receptors are different. Affinity for the receptor type varies with the particular estrogen. Estrogens – Mechanism of Action The activated steroid-receptor complex interacts with nuclear chromatin to initiate hormone-specific RNA synthesis. The attachment of two estrogen-linked receptors (estrogen receptor dimer) to the genome is required for a response. This results in the synthesis of specific proteins that mediate a number of physiologic functions.  Therapeutic uses of Estrogens Contraception (COCs) and postmenopausal hormone therapy, also called estrogen- progestogen therapy (EPT). Recent concerns over the risks of EPT, the National American Menopause Society recommends that EPT be prescribed at the lowest effective dose for the shortest possible time to relieve vasomotor symptoms (hot flashes/flushes) and reverse vaginal atrophy (vulva, vagina, urethra)-vaginal estrogen given (Premarin cream). Women with an intact uterus, progesterone is added to therapy – which reduces the risk of endometrial carcinoma associated with unopposed estrogen. Therapeutic uses of Estrogens Estrogens were previously widely used for prevention and treatment of osteoporosis – decreases bone resorption, but current guidelines recommend use of other therapies over estrogen (alendronate/ Fosamax). Primary hypogonadism: Estrogen therapy mimicking the natural cyclic pattern, and usually in combination with progestins, is instituted to stimulate development of secondary sex characteristics in young women (11–13 years of age) with hypogonadism.  Pharmacokinetics Naturally occurring estrogens: readily absorbed through gastrointestinal tract. 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. Also administered via transdermal patch, vaginal ring or IM injections Synthetic estrogen analogues: ethinyl estradiol and mestranol - well absorbed after oral administration or through the skin or mucous membranes (TD patches). Mestranol is quickly demethylated to ethinyl estradiol, metabolized more slowly than the naturally occurring estrogens by the liver and peripheral tissues. Being fat soluble, they are stored in adipose tissue, from which they are slowly released. Therefore, synthetic estrogen analogues have a prolonged action, and a higher potency compared to those natural estrogens. Adverse Effects of Estrogens Common – nausea and breast tenderness. Postmenopausal uterine bleeding can occur. Risk of thromboembolic event. Myocardial infarction, hypertension, headaches Peripheral edema. Risk of Breast and endometrial cancer increased, hence CoCsi Selective Estrogen-Receptor Modulators (SERMs) Relatively new class of estrogen-related compounds. Brought confusion in the past since they were called antiestrogens. SERM is now reserved for compounds that interact at estrogen receptors but have different effects on different tissues display selective agonism or antagonism according to the tissue type, e.g., tamoxifen is an estrogen antagonist in breast cancer tissue but can cause endometrial hyperplasia by acting as a partial agonist in the uterus. Other SERMs are toremifene and raloxifene. Clomiphene is also sometimes designated as a SERM. Tamoxifen competes with estrogen for binding to the estrogen receptor in breast tissue and is currently used in the palliative treatment of metastatic breast cancer in postmenopausal women. may also be used as adjuvant therapy following mastectomy or radiation and to reduce the risk of breast cancer in high-risk patients. Normal breast growth is stimulated by estrogens. It is therefore not surprising that some breast tumors regress following treatment with tamoxifen. Tamoxifen Adverse Effects: hot flashes, nausea and vomitting. Menstrual irregularities and vaginal bleeding has also occurred. Due to its estrogenic activity in the endometrium, hyperplasia and malignancies have been reported in women who have been maintained on tamoxifen. Raloxifene (Evista) second-generation SERM. decrease bone resorption and overall bone turnover - Bone density is increased, and vertebral fractures are decreased. apparently has little to no effect on the endometrium and, therefore, may not predispose to uterine cancer. lowers total cholesterol and LDL in the serum, has no effect on HDL or TG levels. Does not reduce the risk significantly of coronary events. raloxifene has an increased risk of deep- vein thrombosis, pulmonary embolism, and retinal-vein thrombosis Clomiphene (Clomid) By acting as a partial estrogen agonist and interfering with the negative feedback of estrogens on the hypothalamus, clomiphene increases the secretion of gonadotropin- releasing hormone and gonadotropins (FSH), leading to a stimulation of ovulation. The drug has been used successfully to treat infertility associated with anovulatory cycles, but it is not effective in women with ovulatory dysfunction due to pituitary or ovarian failure. Adverse effects are dose related and include headache, nausea, vasomotor flushes, visual disturbances, and ovarian enlargement. Progestins Norethindrone, norgestimate norethindrone acetate, drospirenone - Yaz, Yasmin Norgestrel Dienogest - Qlaira levonorgestrel Gestodene - Femiane desogestrel Cyproterone - Diane 35 Progestins Progesterone, the natural progestin, 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. Promotes the development of a secretory endometrium that can accommodate the implantation of a newly forming embryo. Further Actions of Progestins Progestins exert their mechanism of action in a manner analogous to that of the other steroid hormones. They cause: an increase in hepatic glycogen—probably through an insulin-mediated mechanism; a decrease in Na+ reabsorption in the kidney due to competition with aldosterone at the mineralocorticoid receptor; an increase in body temperature through an unknown mechanism; a decrease in some plasma amino acids; and an increase in excretion of urinary nitrogen. Therapeutic uses of progestins to rectify a hormonal deficiency for contraception, in combination with estrogens or in a sequential manner. Most synthetic progestins used in oral contraceptives (for example, norethindrone, norethindrone acetate, norgestrel, levonorgestrel) are derived from 19-nortestosterone and possess some androgenic activity because of their structural similarity to testosterone. Therapeutic uses of progestins Medroxyprogesterone (Depo Provera; Provera) acetate is an injectable contraceptive, and the oral form is a common progestin component of postmenopausal EPT. Other clinical uses of the progestins are in the control of dysfunctional uterine bleeding, treatment of dysmenorrhea, and management of endometriosis. Progestins – Adverse Effects Major adverse effects associated with the use of progestins are headache, depression, weight gain, and changes in libido. Some progestins, such as the 19-nortestosterone derivatives, have androgenic activity and can increase the ratio of LDL to HDL cholesterol and cause acne and hirsutism. Less androgenic progestins, such as norgestimate and drospirenone, may be preferred in women with acne. Injectable medroxyprogesterone acetate has been associated with an increased risk of osteoporosis Antiprogestin Mifepristone (RU 486) progesterone antagonist with partial agonist activity. Also has potent antiglucocorticoid activity. administration of this drug to females early in pregnancy results, in most cases (up to 94 percent), in abortion of the fetus due to the interference with progesterone and the decline in human chorionic gonadotropin. major adverse effects are significant uterine bleeding and the possibility of an incomplete abortion. However, administration of misoprostol orally or intravaginally after a single oral dose of mifepristone effectively terminates gestation. Mifepristone is being investigated as an oral contraceptive and an emergency contraceptive agent. Contraceptives decrease fertility by a number of different mechanisms: Prevent ovulation impairing gametogenesis or gamete maturation interfering with gestation. interference with ovulation is the most common pharmacologic intervention for preventing pregnancy COCs are the most common form Monophasic combination pills contain a constant dose of estrogen and progestin given over 21 days. Contraceptives Triphasic oral contraceptive products attempt to mimic the natural female cycle and contain a constant dose of estrogen with increasing doses of progestin given over three successive 7-day periods. Active pills are taken for 21 days, followed by 7 days of placebo. Contraceptives Transdermal Patch: contain ethinyl estradiol and the progestin norelgestromin. Progestin-only pills – norethindrone (mini-pill) is less effective than the COCs. Injectable progestin – depoprovera every three months. Progestin implants: subdermal implant containing etonogestrel (3 yrs). Nearly as reliable as sterilisation, and the effect is totally reversible when surgically removed. Contraceptives Progestin Intrauterine device: levonorgestrel-releasing intrauterine system ; highly effective method of long-term contraception (5 years.) Suitable method of contraception for women who already have at least one child and do not have a history of pelvic inflammatory disease or ectopic pregnancy Contraceptives Postcoital contraception: Postcoital or emergency contraception reduces the probability of pregnancy to between 0.2 and 3 percent. Emergency contraception uses high doses of progestin (for example, 0.75 mg of levonorgestrel) or high doses of estrogen (100 µg of ethinyl estradiol) plus progestin (0.5 mg of levonorgestrel) administered within 72 hours of unprotected intercourse (the “morning-after” pill) A single dose of mifepristone has also been used for emergency contraception Contraceptives Mechanism of action: not completely understood. It is likely that the combination of estrogen and progestin administered over an approximately 3-week period inhibits ovulation. The estrogen provides negative feedback on the release of LH and follicle-stimulating hormone (FSH) by the pituitary gland, thus preventing ovulation. The progestin also inhibits LH release and thickens the cervical mucus, thus hampering the transport of sperm. Withdrawal of the progestin stimulates menstrual bleeding during the placebo week. Contraceptives Adverse Effects: Most adverse effects are believed to be due to the estrogen component, but cardiovascular effects reflect the action of both estrogen and progestin. The incidence of adverse effects with oral contraceptives is relatively low and is determined by the specific compound. The major adverse effects are breast fullness, depression, fluid retention, headache, nausea, and vomiting. Contraceptives Oral contraceptives have been shown to decrease the incidence of endometrial and ovarian cancer. Contraindications: 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. Androgens Androgens androgens are a group of steroids that have anabolic and/or masculinizing effects in both males and females. Testosterone, the most important androgen in humans, is synthesized by Leydig cells in the testes and, in smaller amounts, by cells in the ovary of the female 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. Androgens LH stimulates steroidogenesis in the Leydig cells, whereas FSH is necessary for spermatogenesis. 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 Androgens Testosterone undergoes rapid hepatic catabolism when replaced orally. TESTOSTERONE ESTERS: Esterifying a fatty acid to the 17αhydroxyl group of testosterone creates a compound that is even more lipophilic than testosterone itself. Administered intramuscularly every 2-4 weeks to hypogonadal men. Testosterone enanthate/undecanoate/cypionate  Androgens ALKYLATED ANDROGENS. Several decades ago, chemists found that adding an alkyl group to the 17α-position of testosterone retards its hepatic catabolism. Consequently, 17α-alkylated androgens are androgenic when administered orally; however, they are less androgenic than testosterone and cause hepatotoxicity, whereas native testosterone does not. Some 17αalkylated androgens show greater anabolic effects than androgenic effects compared to native testosterone in laboratory tests in rats; however, these "anabolic“ steroids, so favoured by athletes to illicitly improve performance, have not been convincingly demonstrated to have such a differential effect in human beings. Citing potentially serious health risks, the FDA has recommended against the use of bodybuilding products that are marketed as containing steroids or steroid like substances. Androgens Endometriosis: Danazol, a mild androgen, is used in the treatment of endometriosis (ectopic growth of the endometrium) and fibrocystic breast disease. Weight gain, acne, decreased breast size, deepening voice, increased libido, and increased hair growth are among the adverse effects. Danazol has been reported occasionally to suppress adrenal function. In athletes: Use of anabolic steroids, (for example, DHEA or nandrolone by athletes can cause premature closing of the epiphysis of the long bones, which stunts growth and interrupts development. The high doses taken by these young athletes may result in reduction of testicular size, hepatic abnormalities, increased aggression (“roid rage”), major mood disorders, and the other adverse effects described above. Antiandrogens Antiandrogens counter male hormonal action by interfering with the synthesis of androgens or by blocking their receptors. Finasteride and dutasteride agents used for the treatment of benign prostatic hypertrophy - inhibit 5α-reductase. The resulting decrease in formation of DHT in the prostate leads to a reduction in prostate size. Antiandrogens, such as flutamide act as competitive inhibitors of androgens at the target cell. Flutamide is used in the treatment of prostatic carcinoma in males. bicalutamide and nilutamide are effective orally for the treatment of metastatic prostate cancer.