Estrogens & androgens ا.م.د.اسامة ايوب lec:4-6

Transcription

1 Estrogens & androgens ا.م.د.اسامة ايوب lec:4-6

2 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 Aromatization is the last step in estrogen synthesis

3 Estrogens Estradiol also known as 17β-estradiol, is the most potent estrogen produced and secreted by the ovary. It is the principal estrogen in the premenopausal woman. Estrone is a metabolite of estradiol it is one third the estrogenic potency, it is the primary circulating estrogen after menopause, and it is generated mainly from conversion of androstenedione in peripheral tissues Estriol is another metabolite of estradiol, is significantly less potent than estradiol. It is present in significant amounts during pregnancy, because it is the principal estrogen produced by the placenta.

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6 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 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.

7 Estrogens The estrogen receptor is composed of six functional domains including a DNA-binding domain, a ligand-binding domain, and additional regions critical for gene expression. In the absence of ligand, the receptor is sequestered within the cell nucleus and maintained in an inactive state. Similarly to the other nuclear receptors, the protein is prevented from binding to DNA and kept in a conformation that facilitates ligand binding by heat shock proteins.

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9 Estrogens Upon ligand binding, the ER receptor undergoes a conform-ational change and forms homodimers. The ligand-receptor complex then binds to specific estrogen response elements on DNA

10 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 I. activation of an estrogen receptor in the membranes of hypothalamic cells has been shown to couple to a G protein II. in addition, estrogen-mediated dilation of coronary arteries occurs by the increased formation and release of nitric oxide and prostacyclin in endothelial cells.

11 Therapeutic uses Estrogens are most frequently used for contraception and postmenopausal hormone therapy Estrogens were previously widely used for prevention of osteoporosis, but current guidelines recommend use of other therapies such as alendronate over estrogen Estrogen deficiency can be due to inadequate functioning of the ovaries (hypogonadism), premature menopause, or surgical menopause

12 Therapeutic uses 1-Postmenopausal HT: 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. HT should be prescribed at the lowest effective dose for the shortest possible time to relieve menopausal symptoms(compared with contraception) Estradiol transdermal patch is also effective in treating postmenopausal symptoms. For vaginal atrophy local estrogen preferred over systemic

13 2-Contraception: The combination of an estrogen and progestogen provides effective contraception via the oral or transdermal route. Yasamin (Drospirenone3mg+Ethinylestradiol 0.03mg) Microgynon(Levonorgestrel0.15mg+Ethinylestradiol 0.03mg) Sunya(Gestodene 75ug+ Ethinylestradiol 0.02mg) Katya (Gestodene 75ug+ Ethinylestradiol 0.03mg) Marvelone(Desogestrel 0.15mg+Ethinylestradiol 0.03mg)

14 3-Estrogen therapy usually in combination with a progestogen, is instituted to stimulate development of secondary sex characteristics in young women (11 to 13 years of age) with primary hypogonadism. 4-Estrogen and progestogen replacement therapy is used for women who have premature menopause or premature ovarian failure. 5-Estrogen may be used for prevention of osteoporosis if other therapies are inappropriate or not tolerated.

15 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 Synthetic estrogen analogs: These compounds, such as ethinyl estradiol, mestranol, and estradiol valerate, are well absorbed after oral administration. Mestranol is quickly demethylated to ethinyl estradiol 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.

16 Pharmacokinetics Estrogens are transported in the blood bound to serum albumin or sex hormone binding globulin. bioavailability of estrogen taken orally is low due to first pass metabolism. To reduce first-pass metabolism, the drugs may be administered via transdermal route (patch, topical gel, topical emulsion, or spray), intravaginally (tablet, cream, or ring), Or by injection. The parent estrogen drugs and their metabolites undergo excretion into the bile and are then reabsorbed through the enterohepatic circulation.

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

18 Selective Estrogen-Receptor Modulators class of estrogen-related compounds that display selective agonism or antagonism for estrogen receptors depending on the tissue type. The pharmacological goal of these drugs is to produce: beneficial estrogenic actions in certain tissues (e.g., bone, brain, and liver) This category includes tamoxifen, toremifene, raloxifene, clomiphene, and ospemifene.

19 Selective Estrogen-Receptor Modulators Tamoxifen Considered to be the first SERM it competes with estrogen for binding to the estrogen receptor in breast tissue and uterus. tamoxifen inhibits the proliferation of cultured human breast cancer cells and reduces tumor size Raloxifene is a second-generation SERM: antagonism of estrogen receptors in the breast tissue. Therefore, some breast tumors regress following treatment with these agents

20 Selective Estrogen-Receptor Modulators Acts as an estrogen agonist in bone leading to decreased bone resorption, increased bone density, and decreased vertebral fractures has little to no effect on the endometrium and, therefore, may not predispose to uterine cancer. lowers total cholesterol and (LDL) in the serum, but it has no effect on (HDL) or TG.

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22 has antioestrogenic effects on breast and uterus but oestrogenic effects on bone, lipid metabolism and blood coagulation. It is used for prevention and treatment of postmenopausal osteoporosis produces a dose-dependent increase in osteoblast activity and reduction in osteoclast action Clomiphene acts as a partial estrogen agonist and interferes with the negative feedback of estrogens on the hypothalamus. So increases the secretion of gonadotropin-releasing hormone and stimulating ovulation.

23 Therapeutic uses Tamoxifen used in the palliative treatment of metastatic breast cancer adjuvant therapy following mastectomy or radiation in breast cancer as a prophylactic therapy to reduce the risk of breast cancer in high risk patients. Raloxifene prophylaxis of breast cancer in high-risk women for the prevention and treatment of osteoporosis in postmenopausal women Clomiphene to treat infertility associated with anovulatory cycles, is not effective in women with ovulatory dysfunction due to pituitary or ovarian failure. Ospemifene is indicated for the treatment of dyspareunia (painful sexual intercourse) related to menopause.

24 Adverse effects Tamoxifen hot flashes and nausea Menstrual irregularities and vaginal bleeding hyperplasia and malignancies have been reported in women who have been maintained on tamoxifen(uterus) DDI is important(amiodarone, haloperidol, risperidone) reduce Active metabolite Raloxifene hot flashes and leg cramps an increased risk of deep-vein thrombosis, pulmonary embolism, and retinal-vein thrombosis Clomiphene dose related and include headache, nausea,, visual disturbances, and ovarian enlargement The risk of multiple births (twins or triplets) with clomiphene is 3 to 5 percent

25 PROGESTOGENS Progesterone (the natural progestogen) is produced in response to (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). Progesterone is very important for the maintenance of pregnancy. Progesterone suppresses menstruation and uterine contractility, It is also synthesized by the adrenal cortex in both sexes. 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 (the luteal phase) inhibit the production of gonadotropin and, therefore, prevent further ovulation.

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27 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. Mechanism of action involves intracellular receptor/altered gene expression, as for other steroid hormones. Oestrogen stimulates synthesis of progesterone receptors, whereas progesterone inhibits synthesis of oestrogen receptors.

28 Action 1) an increase in hepatic glycogen, probably through an insulin-mediated mechanism(progesterone increases basal insulin levels and the insulin response to glucose). 2)a decrease in Na+ reabsorption in the kidney due to competition with aldosterone at the mineralocorticoid receptor; 3) an increase in body temperature through an unknown mechanism; 4) a decrease in some plasma amino acids; and an increase in excretion of urinary nitrogen.

29 Therapeutic uses Medroxyprogesterone acetate is an injectable contraceptive, and the oral form is a common progestin component of postmenopausal HT. The major clinical uses of progestogens are to treat a hormonal deficiency and for contraception For contraception, they are generally used with estrogens Progesterone by itself is not used widely as a contraceptive therapy because of its rapid metabolism, resulting in low bioavailability. Synthetic progestogens used in contraception are more stable to first pass metabolism, allowing lower doses when administered orally These agents include desogestrel, dienogest, drospirenone, levonorgestrel, norethindrone, norgestimate, and norgestrel

30 Therapeutic uses Progestins are also used for the control of dysfunctional uterine bleeding, treatment of dysmenorrhea (Norethisterone),, and management of endometriosis and infertility. For successful implantation of ova and for prevention of threated and habitual abortion allylestrenol dydrogesterone hydroxy progesterone

31 Pharmacokinetics Progesterone has a short half-life in the plasma and is almost completely metabolized by the liver. 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.

32 Adverse effects headache, depression, weight gain, and changes in libido. Progestins that are derived from 19-nortestosterone (norethindrone,, norgestrel, levonorgestrel) possess some androgenic activity can increase the ratio of LDL to HDL cholesterol and can cause acne and hirsutism. Less androgenic progestins, such as norgestimate and drospirenone, may be preferred in women with acne. raise serum potassium due to anti mineralocorticoid effects, and concurrent use with other drugs that increase potassium (for example, angiotensin-converting enzyme inhibitors) may increase the risk of hyperkalemia.

33 Antiprogestin Mifepristone 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 misoprostol (administered orally or intravaginally) to induce uterine contractions. The major adverse effects are significant uterine bleeding and the possibility of an incomplete abortion.

34 Antiprogestin In 2010, the FDA approved ulipristal acetate, a partial agonist at the progsterone receptor, for emergency contraception. at least as effective when taken up to 72 hours after unprotected sexual intercourse In addition, ulipristal remains effective up to 120 hours (5 days) after intercourse, making ulipristal a more versatile emergency contraceptive than levonorgestrel The most severe side headache and some abdominal pain.

35 CONTRACEPTIVES Major classes of contraceptives: Monophasic combination pills contain a constant dose of estrogen and progestin given over 21 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. With either type of combination oral contraceptive, active pills are taken for 21 days followed by 7 days of placebo. 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.

36 CONTRACEPTIVES Antibiotics are alleged to reduce blood concentrations and, therefore, the ultimate effectiveness of oral contraceptive agents. The proposed mechanisms of these antibiotic-associated interactions include 1. hepatic microsomal enzyme induction 2. interference with enterohepatic 3. interference with oral contraceptive absorption 4. alterations in plasma-protein binding 5. increased excretion of the oral contraceptive

37 2) Transdermal patch contraceptive patch containing ethinylestradiol and the progestin norelgestromin. One contraceptive patch is applied each week for 3 weeks to the abdomen, or buttock. Week 4 is patch free, and withdrawal bleeding occurs. less effective in women weighing greater than 90 kilograms. Total estrogen exposure with the transdermal patch may be significantly greater than that seen with oral contraceptives 3) 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. Week 4 is ring free, and withdrawal bleeding occurs.

38 4) Progestin-only pills Progestin-only pills deliver a low, continuous dosage of drug. These preparations are less effective than the combination pill and they may produce irregular menstrual cycles more frequently than the combination product. The progestin-only pill may be used for patients who are breastfeeding, are intolerant to estrogen, are smokers, or have other contraindications to estrogen-containing products. 5-Progestin implants: A subdermal implant containing etonogestrel offers longterm contraception. 4-cm capsule is placed subdermally in the upper arm and provides contraception for approximately 3 years. Principal side effects of the implants are irregular menstrual bleeding and headaches.

39 6-Injectable progestin: Medroxyprogesterone acetate is a contraceptive that is administered via I.M. or S.C. injection every 3 months. Weight gain is a common adverse effect. Because this product provides high sustained levels of progestin, many women experience amenorrhea 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

40 7-Progestin intrauterine device: A levonorgestrel-releasing intrauterine system offers a highly effective method of longterm contraception. This intrauterine device provides contraception for up to 5 years. 8-Postcoital contraception: Postcoital or emergency contraception reduces the probability of pregnancy after unprotective intercourse. 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 preferably within 72 hours. An alternative emergency contraceptive is the progesterone agonist/antagonist ulipristal. It is indicated for emergency contraception within 5 days of unprotected intercourse.

41 Mechanisms of action 1. estrogen provides a negative feedback on the release of LH and FSH by the pituitary gland, thus preventing ovulation. 2. Progestogen negative feedback decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus Progestogen inhibit (LH) surge 3. inhibition of sperm penetration through the cervix into the upper genital tract by decreasing the water content and increasing the viscosity of the cervical mucus 4. Withdrawal of the progestin stimulates menstrual bleeding during the placebo week.

42 Adverse effects Breast fullness, depression, fluid retention, headache, nausea, and vomiting. Thromboembolism, hypertension, increased incidence of myocardial infarction, and cerebral and coronary thrombosis. Carcinogenicity, Abnormal glucose tolerance Estrogen causes an increase in HDL and a decrease in LDL (a desirable occurrence), whereas progestins may negate some of the beneficial effects of estrogen. 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

43 ANDROGENS The 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. dihydrotestosterone (DHT), androstenedione, and dehydroepiandrosterone (DHEA) testosterone secretion by Leydig cells is controlled by GRH from the hypothalamus, which stimulates the anterior pituitary gland to secrete FSH and LH.

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46 ANDROGENS LH stimulates steroidogenesis in the Leydig cells FSH is necessary for spermatogenesis in sertoli cells 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.

47 Mechanism of action bind to a specific nuclear receptor in a target cell testosterone itself is the active ligand in muscle and liver prostate, seminal vesicles, epididymis, and skin, testosterone is converted by 5α-reductase to DHT which binds to the receptor The hormone-receptor complex binds to DNA and stimulates the synthesis of specific RNAs and proteins. Testosterone analogs that cannot be converted to DHT have less effect on the reproductive system than they do on the skeletal musculature.

48 Therapeutic uses 1-Androgenic effects males with inadequate androgen secretion primary hypogonadism secondary hypogonadism 2-Anabolic effects senile osteoporosis chronic wasting associated with HIV or cancer as adjunct therapy in severe burns and to speed recovery from surgery or chronic debilitating diseases 3-Unapproved use: Anabolic steroids are used to increase lean body mass, muscle strength, and endurance in athletes and body builders. use has been banned from the Olympics and in major professional and sports

49 4-Anti-aging : DHEA (a precursor of testosterone and estrogen) has been touted as the anti-aging hormone as well as performance enhancer. 5- Endometriosis: Danazol, a weak androgen, is used in the treatment of endometriosis (ectopic growth of the endometrium) and fibrocystic breast disease. Danazol also possesses antiestrogenic activity among the adverse effects: Weight gain, acne, decreased breast size, deepening voice, increased libido, and increased hair growth

50 Danazol Gonadotropin inhibitor Danazol suppresses the pituitaryovarian axis, of gonadotrophins (FSH and LH). and consequently reduces oestrogen synthesis in the ovary. In men, it reduces androgen synthesis and spermatogenesis. used in sex hormone-dependent conditions including endometriosis, breast dysplasia and gynaecomastia. Unwanted effects are common, and include gastrointestinal disturbances, weight gain, fluid retention, dizziness, menopausal symptoms, muscle cramps and headache. Danazol has a virilising action in females. Danazol has been reported occasionally to suppress adrenal function.

51 Transdermal patches, topical gels, and buccal tablets of testosterone are also available. Alkylation of the 17 position of testosterone allows oral administration of the hormone. Testosterone and its esters demonstrate a 1:1 relative ratio of androgenic to anabolic activity fluoxymesterone & mesterolone 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 is another orally active testosterone derivative with anabolic activity 3 to 13 times that of testosterone Hepatic adverse effects have been associated with the alkylated androgens

52 Adverse effects in females: Masculinization Acne growth of facial hair deepening of the voice male pattern baldness, and excessive muscle development. In males: Priapism(painful, erection that lasts for more than four hours and occurs without sexual stimulation. ) impotence, decreased spermatogenesis gynecomastia Androgens can also stimulate growth of the prostate.

53 In children: Adverse effects Androgens can cause abnormal sexual maturation and growth disturbances resulting from premature closing of the epiphyseal plates. General effects: Androgens increase serum LDL and lower serum HDL levels; therefore, they increase the LDL:HDL ratio and potentially increase the risk for premature coronary heart disease. Androgens can also cause fluid retention, leading to edema. In athletes: premature closing of the epiphysis of the long bones(young ) which stunts growth and interrupts development(young) may result in reduction of testicular size(young ) hepatic abnormalities, increased aggression & mood disorders.

54 Antiandrogens Anti androgens counter male hormonal action by interfering with the synthesis of androgens or by blocking their receptors. ketoconazole inhibits several of the cytochrome P450 enzymes involved in steroid synthesis Finasteride and dutasteride agents used for the treatment of benign prostatic hypertrophy, inhibit 5α-reductase leads to a reduction in prostate size Flutamide, bicalutamide and nilutamide act as competitive inhibitors of androgens at the target cell effective orally for the treatment of prostate cancer..

55 Antiandrogens Cyproterone a derivative of progesterone and has weak progestational activity It is a partial agonist at androgen receptors, competing with dihydrotestosterone for receptors in androgen-sensitive target tissues. It is used as an adjunct in the treatment of prostatic cancer It is also used in the therapy of precocious puberty in males masculinisation and acne in women decreasing libido, and has been used to treat hypersexuality in male sexual offenders In female used in facial hair groth

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58 Quize Mechanism of action of 1-mifiprestone 2-PTU Mechanism of action 1-ADH 2-raloxifen

59 Quize Mention the effect of CS on the following(support your answer with mechanisms: 1- Blood cell levels in plasma 2- Resistance to stress 3- Inflammatory response 4-Gastric effect 5- Bone Although bleeding may occur with extended or continuous OCPs, due to atrophic changes in the endometrium, there is no typical endometrium to shed.