GONADAL HORMONES ESTROGENS AND ANDROGENS Rich Minshall Associate Professor of Pharmacology rminsh uic edu Chapter 40 The Gonadal Hormones Inhibitors 1 Control of androgen secretion in males 1 competitive inhibition of GnRH receptors 2 stimulation pulsatile administration or inhibition via desensitization of GnRH receptors continuous administration Lupron synthetic analog to GnRH 3 decreased synthesis of testosterone in the testis 4 decreased synthesis of dihydrotestosterone by inhibition of 5a reductase 5 competition for binding to cytosol androgen receptors 2 Testis Sertoli cells in the testis synthesize and secrete a variety of active proteins including m llerian 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 b subunits A and B Activin is composed of the two b subunits stimulates pituitary FSH release Inhibins A and B which contain the a subunit and one of the b subunits in conjunction with testosterone and dihydrotestosterone are responsible for the feedback inhibition of pituitary FSH secretion 3 Steroid synthesis 4 The biosynthetic pathway of the androgens and estrogens 19 carbon precursors are synthesized primarily in the ovaries testes and adrenals 5 Clinical Uses of Androgens ANDROGEN REPLACEMENT THERAPY IN MEN Androgen production falls with age in men and may contribute to the decline in muscle mass strength and libido USE AS PROTEIN ANABOLIC AGENTS USE AS GROWTH STIMULATORS ANABOLIC STEROID AND ANDROGEN ABUSE IN SPORTS AGING 6 ANDROGEN REPLACEMENT replace or augment endogenous androgen secretion in hypogonadal men used rather than gonadotropin except when normal spermatogenesis is desired for hypopituitarism androgens are not added to the treatment regimen until puberty started with long acting agents such as testosterone enanthate or cypionate in doses of 50 mg intramuscularly initially every 4 then every 3 and finally every 2 weeks with each change taking place at 3month 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 7 Table 40 6 Androgen Preparations for Replacement Therapy Drug Methyltestosterone Fluoxymesterone Testosterone enanthate Testosterone cypionate Testosterone Route of Administration Oral Sublingual buccal Oral Intramuscular Intramuscular Transdermal Topical gel 1 Dosage 25 50 mg d 5 10 mg d 2 10 mg d See text See text 2 5 10 mg d 5 10 g d 8 ANDROGEN SUPPRESSION ANTIANDROGENS Inhibition of Steroid Precursor Conversion to Androgens Ketoconazole an inhibitor of adrenal and gonadal steroid synthesis Abiraterone inhibits the 17 hydroxylation of progesterone or pregnenolone to androgens Finasteride 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 Dutasteride is 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 Inhibitors Flutamide potent anti androgen that has been used in the treatment of prostatic carcinoma Although not a steroid it behaves like a competitive antagonist at the androgen receptor Cyproterone and cyproterone acetate are effective antiandrogens that inhibit the action of androgens at the target organ Bicalutamide and nilutamide 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 the androgenreceptors in target tissues It also reduces 17 hydroxylase activity lowering plasma levels of testosterone and androstenedione It is used in dosages of 50 200 mg d in the treatment of hirsutism in women and appears to be as effective as finasteride flutamide orcyproterone in this condition GOSSYPOL abandoned as a candidate male contraceptive 9 ANDROGEN SUPPRESSION Control 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 and progesterone SERMs selective estrogen receptor modulators 11 Hormonal relationships of the human menstrual cycle 12 Estrogen and Progesterone production and negative feedback Consider 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 14 Estrogen production from progesterone and testosterone via Aromatase 15 Estrogen and synthetic analogs 16 Progesterone and synthetic analogs 17 Structural Formulas of Selected Estrogens 18 Physiological and Pharmacological Actions of Estrogen Developmental 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 and growth spurt of the long bones growth of axillary and pubic hair and pigmentation of the genital region regional pigmentation of the nipples and areolae that occur after the first term of pregnancy Metabolic Effects of E blocks bone resorption and increases bone formation increases the level of the hydroxylase that converts vitamin D to 1 25dihydroxyvitamin D3 in the kidney slightly elevates serum triglycerides and reduces total serum cholesterol levels increases HDL levels and decreases LDL values alters bile composition by increasing cholesterol secretion and decreasing bile acid secretion leading to increased saturation of bile with cholesterol which may be the basis for increased gallstone formation decrease slightly fasting levels of glucose and insulin increase plasma levels of cortisol binding globulin CBG or
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