Slide 1Control of androgen secretion in malesSlide 3Steroid synthesisSlide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Hormonal relationships of the human menstrual cycleSlide 13Slide 14Slide 15Slide 16Slide 17Structural Formulas of Selected EstrogensPhysiological and Pharmacological Actions of EstrogenSlide 20Slide 21Estrogen Receptor IsoformsSlide 23Slide 24Slide 25Slide 26Therapeutic Uses of E2:Physiological and Pharmacological Actions of Progesterone:Physiological and Pharmacological Actions of Progesterone:Progesterone ReceptorSlide 31Slide 32Slide 33Hormone Replacement Therapy and Fertility DrugsSlide 35MenopauseSlide 37Routes and CompoundsExamples of HRT PreparationsSlide 40GONADAL HORMONES:ESTROGENS AND ANDROGENSRich Minshall, Associate Professor of [email protected] 40. The Gonadal Hormones & Inhibitors1Control of androgen secretion in males2(1)competitive inhibition ofGnRH receptors(2) stimulation (+, pulsatile administration) or inhibition via desensitization of GnRH receptors(–, continuous administration) Lupron: synthetic analog to GnRH,(3)decreased synthesis oftestosteronein the testis(4)decreased synthesis of dihydrotestosterone by inhibition of 5a-reductase(5) competition for binding to cytosol androgen receptors3Sertoli cells in the testis synthesize and secrete a variety of active proteins, including müllerian duct inhibitory factor, inhibin, and activin.Leydig cells, upon LH stimulation, produced testosterone in the spaces between the seminiferous tubules.As in the ovary, inhibin and activin appear to be the product of three genes that produce a common a subunit and two bsubunits, A and B.Activin is composed of the twob subunits, stimulates pituitary FSH release Inhibins (A and B), which contain theasubunit and one of theb subunits, in conjunction withtestosteroneand dihydrotestosterone ,are responsible for the feedback inhibition of pituitary FSH secretion TestisSteroid synthesis4The biosynthetic pathwayof the androgens and estrogens19-carbon precursors are synthesized primarily in the ovaries, testes, and adrenals56ANDROGEN REPLACEMENT THERAPY IN MENAndrogenproduction falls with age in men and may contribute to the decline in muscle mass, strength, and libido.USE AS PROTEIN ANABOLIC AGENTSUSE AS GROWTH STIMULATORSANABOLIC STEROID AND ANDROGEN ABUSE IN SPORTSAGINGClinical Uses of Androgens7replace or augment endogenousandrogensecretion in hypogonadal menused rather thangonadotropinexcept when normal spermatogenesis is desiredfor hypopituitarism, androgens are not added to the treatment regimen until puberty, started with long-acting agents such astestosterone enanthateor cypionate in doses of 50 mg intramuscularly, initially every 4, then every 3, and finally every 2 weeks, with each change taking place at 3-month intervals. The dose is then doubled to 100 mg every 2 weeks until maturation is complete. Finally, it is changed to the adult replacement dose of 200 mg at 2-week intervals.ANDROGEN REPLACEMENT8Table 40–6 Androgen Preparations for Replacement Therapy.Drug Route of AdministrationDosageMethyltestosterone Oral 25–50 mg/d Sublingual (buccal) 5–10 mg/dFluoxymesterone Oral 2–10 mg/dTestosterone enanthate Intramuscular See textTestosterone cypionate Intramuscular See textTestosterone Transdermal 2.5–10 mg/d Topical gel (1%) 5–10 g/d9ANTIANDROGENSInhibition of Steroid Precursor Conversion to AndrogensKetoconazole-an inhibitor of adrenal and gonadal steroid synthesisAbiraterone- inhibits the 17-hydroxylation ofprogesteroneor pregnenolone to androgensFinasteride,a steroid-like orally active inhibitor of of 5a-reductase that causes a reduction in dihydrotestosterone levels. Moderately effective in reducing prostate size in men with benign prostatic hyperplasia and is approved for this use in the USA. The dosage is 5 mg/d.Dutasterideis a similar orally active steroid derivative with a slow onset of action and a much longer half-life than finasteride. The dose is 0.5 mg daily.Receptor InhibitorsFlutamide- potentanti-androgen that has been used in the treatment of prostatic carcinoma. Although not a steroid, it behaves like a competitive antagonist at theandrogenreceptor.Cyproteroneandcyproterone acetateare effective antiandrogens that inhibit the action of androgens at the target organBicalutamideandnilutamide- potent orally active antiandrogens that can be administered as a single daily dose and are used in patients with metastatic carcinoma of the prostate.Spironolactone-a competitive inhibitor of aldosterone that also competes with dihydrotestosterone for theandrogenreceptors in target tissues. It also reduces 17-hydroxylase activity, lowering plasma levels oftestosteroneand androstenedione. It is used in dosages of 50–200 mg/d in the treatment of hirsutism in women and appears to be as effective asfinasteride,flutamide, orcyproteronein this condition.GOSSYPOL-abandoned as a candidate male contraceptive.ANDROGEN SUPPRESSIONANDROGEN SUPPRESSION11Control of ovarian secretion and the actions of its hormones.In the follicular phase, the ovary produces mainly estrogens; In the luteal phase, it produces estrogens andprogesterone. SERMs, selective estrogen receptor modulators12Hormonal relationships of the human menstrual cycleEstrogen and Progesterone production and negative feedback14Consider the normal menstrual cycle:1) Estrogen released from the ovary - increases the expression of estrogen receptors.2) Estrogen increases the expression of progesterone receptors.3) Progesterone down regulates the expression of estrogen receptors.4) With the progesterone-elicited decrease in estrogen receptor numbers - there will be a decrease in the ability of estrogen to stimulate the production of progesterone receptors - in this way - progesterone turns itself off.15Estrogen production from progesterone and testosteronevia Aromatase16Estrogen and synthetic analogs17Progesterone and synthetic analogsStructural Formulas of Selected Estrogens18Physiological and Pharmacological Actions of EstrogenDevelopmental Actions:-Puberty and secondary sexual characteristics of females-growth and development of the vagina, uterus, and fallopian tubes-with other hormones cause enlargement of the breasts, promotion of ductal growth, stromal development, and the accretion of fat; molding body contours, shaping the skeleton,
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