Endocrine_Lecture_V sex hormones-1

Endocrine_Lecture_V sex hormones-1 - Endocrine Pharmacology...

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Unformatted text preview: Endocrine Pharmacology Part V: Sex hormones Joshua Gray Department of Pharmacology 732 445 0219 gray@rci.rutgers.edu Pharmacology II 03/24/08 Outline of lecture Sex hormones the big picture Effects of sex hormones Regulation of sex hormones Synthesis of sex hormones Estrogen Testosterone Axes Controlled via the Anterior Pituitary Hypothalamus Prolactin ACTH Anterior pituitary Breast FSH/LH Adrenal cortex GH TSH Testes Ovary Liver Bone Muscle Thyroid Regulation of Hormone Release Hypothalamus GHRH (+) SOMATOSTATIN (-) PIH (DOPAMINE) (-) PRH (+) CRH (+) TRH (+) GNRH (+) Pituitary GH (+) (Somatotropin) GH (-) Prolactin (-) Prolactin (+) ACTH (+) TSH (+) FSH (+) LH (+) Target Organ Liver and others Liver and others Breast Breast Adrenal Cortex Thyroid Gonads Glucocorticoid, mineralocorticoid T3, T4 Estrogen, progesterone, testosterone Hormone Somatomedin (IGF-1) Pituitary Gland Small round gland attached to base of brain Three lobes: Anterior (adenohypophysis) Intermediate Posterior . Feedback Regulation of Hormone Release CNS (+) (-) Hypothalamus Release hormones/factors Release-inhibiting hormones/factors (-) INPUT (-) or (+) (-) Anterior Pituitary Trophic hormones (-) (-) (-) Target Organs Hormone Physiological Effect Pituitary-Hypothalamus Hypothalamus (-) GNRH (-) Anterior Pituitary FSH, LH Gonads estrogen, progesterone, testosterone GNRH gonadotropin releasing hormone FSH - follicle stimulating hormone LH - luteinizing hormone Gonadotropin Releasing Hormone (GRH) GRH: 10 amino acids; found in all mammals; analogs have been synthesized with increased potency and duration Feedback regulation of FSH and LH release by estrogens and androgens Production of FSH and LH increase after puberty Males: constant plasma levels Females: varies with menstrual cycle Pulsatile release of GRH controls whether FSH or LH is produced Gonadotropic Hormones Follicle stimulating hormone (FSH) Luteinizing hormone (LH) Chorionic gonadotropin (CG) -Required for ovulation, spermatogenesis, biosynthesis of estrogens and androgens; -Used therapeutically to promote fertility -Produced and secreted by gonadotrophs in anterior pituitary -Secretion regulated by hypothalamusgonadotropin releasing hormone (GRH) Follicle Stimulating Hormone (FSH) Principle function: stimulate follicular development in females and spermatogenesis in males Actions of FSH on follicle and oocyte also require LH FSH acts on sertoli cells in testes to stimulate production of androgen binding protein Luteinizing Hormone (LH) Principle function: regulate gonadal steroid hormone production Acts on Leydig cells in testes to stimulate androgen production Acts on ovary with FSH to stimulate follicular development Acts on mature follicle to induce ovulation and stimulate corpus luteum to produce progesterone Corpus luteum leftover structure after egg release from ovary, maintains pregnancy after fertilization occurs Chorionic Gonadotropin Principle function: maintain pregnancy Produced by embryo, then placenta Acts on corpus luteum to prevent degradation of that organ Corpus luteum, in turn, produces progesterone to maintain pregnancy Basis for pregnancy tests Therapeutic Uses of Gonadotropins Infertility: FSH, LH, and CG used in combination to promote follicular development and spermatogenesis Diagnostic: GnRH used diagnostically to distinguish between delayed puberty and hypogonadotrophy - Why? Pituitary-Hypothalamus Hypothalamus (-) GNRH (-) Anterior Pituitary FSH, LH Gonads estrogen, progesterone, testosterone GNRH gonadotropin releasing hormone FSH - follicle stimulating hormone LH - luteinizing hormone EFFECTS OF SEX HORMONES Gonadal Hormones Estrogens and Progesterone Androgens Characteristics: Steroid hormones Bind to cytoplasmic receptors Alter DNA transcription Stop linear bone growth (fuse epiphysis) How does this relate to the height of women versus men? Androgens There are many androgens Testosterone, dehydroepiandrosterone (DHEA) Subtypes are differentially produced in adrenal cortex, testes, and ovaries Peaks in young adults Secondary sex characteristics Estrogens Induced during puberty Secondary sex characteristics Many roles: coagulation, GI function, fluid balance, Also important in men Estrogens and Progestins u Steroid Hormones: common steroid nucleus common structure n Biologic properties determined by substitutions on nucleus n naturally occurring estrogens: (estrane nucleus) C-18 n naturally occurring progestins: (pregnane nucleus) C-18, C-19, C20, C-21 Structural similarity testosterone estrogen Estrogens and Progestins Estrogens: Potency (females): 17-estradiol > estrone > estriol estriol: increases greatly during pregnancy estriol (index fetal viability) Progestins: most important: progesterone Synthesis: major site in females: ovary and fetoplacental unit (90%); peripheral (10%) major site in males and postmenopausal females: peripheral (100%) Mechanism of Action gonadal hormones receptor H/R Nucleus DNA transcription hormone receptor complex REGULATION OF SEX HORMONES Gonadal Hormone Binding Proteins Both estrogens and androgens bind reversibly to plasma proteins; prolong half life; only 2% hormones circulate unbound: biologically active Sex Hormone Binding Globulin (SHBG): gamma globulin; specific, high affinity (58% binding); levels of binding vary with estrogen and androgen levels nonspecific, low affinity, high capacity (40% binding) Albumin: Regulation of Estrogen and Progestin Synthesis (-) Hypothalamus GnRH Anterior Pituitary FSH LH Ovary (-) (-) estrogen, progestin uterus vagina cervix Menstrual Cycle Cyclic changes in blood levels of FSH, LH, 17- estradiol and progesterone Modulate development of ova, and corpus luteum and ovulation Follicular Phase (day 1-14): increasing levels of LH, FSH and estradiol; peak day 14 (ovulation) Luteal Phase (day 14-28): increasing levels of progesterone; slowly declining estradiol; low levels LH and FSH Follicular and Luteal Phases Plasma Hormone Levels Ovary Theca cells surround the egg, express receptors for luteinizing hormone, and produce estrogen Granulosa cells produce hormones and growth factors that influence egg development follicle G ovum T T T G Follicular Phase FSH: stimulates development of granulosa cells in ovarian follicles; n after 5-6 days one develops more rapidly LH: stimulates production of testosterone in theca cells of ovary; testosterone diffuses into granulosa cells; testosterone + FSH stimulate aromatase; converts testosterone to 17 -estradiol; peaks midcycle; triggers surge of LH and FSH from anterior pituitary; subsequently estradiol feeds back on HT, GnRH, LH and FSH Ovary: LH, FSH, and estrogen promote follicular development; at peak blood levels, mature follicle ruptures, releasing egg (ovulation) Uterus: proliferative phase; endometrial division preparing for implantation n n Follicular Phase Testosterone + FSH stimulate aromatase in granulosa cells; converts testosterone to estradiol; peaks mid cycle; causes follicle to rupture follicle FSH G ovum T T T G testosterone estradiol LH Luteal Phase Follows LH and FSH surge Ruptured follicle fills with blood; debris (luteum) LH peak (towards end of luteal phase): theca and granulosa cells begin to proliferate; replace blood, develop into corpus luteum Peak of FSH + estradiol decrease aromatase in theca cells resulting in increased testosterone and decreased estradiol Testosterone + FSH stimulate progesterone production by corpus luteum Progesterone feeds back and inhibits LH and FSH by pituitary => estradiol Luteal Phase Ovary Peak LH corpus luteum progesterone FSH testosterone T aromatase testosterone Peak estradiol and FSH Luteal Phase No Pregnancy: prostaglandins cause regression of corpus luteum; progesterone and estrogen levels decline; shedding of endometrial lining of uterus (menstruation) Pregnancy: progesterone and estrogen levels maintained by corpus luteum which is maintained by human chorionic gonadotropin produced by the placenta Human Chorionic Gonadotropin (hCG) hCG from placenta: Signals corpus luteum not to degenerate until placenta secretes adequate [hormones] Prevents immunological rejection of implanting embryo Has thyroid-stimulating ability Produces effects similar to LH Basis of pregnancy test Insert fig. 20.46 Luteal Phase Uterus: decreasing estradiol and increasing progesterone decreased proliferation Progestesterone Secretory phase -Stimulates development of uterine glands, which become engorged with glycogen -Endometrium becomes thick, vascular, and spongy -Cervical mucus thickens and becomes sticky Other actions of estrogens and progestins affect vaginal epithelium, breasts, growth and development; cardiovascular actions Cycle of Ovulation and Menstruation Insert fig. 20.35 Pharmacology of Estrogens and Progestins Natural: rapidly metabolized Synthetic: increased half life; decreased binding to plasma proteins Specificity of action depends on cytoplasmic receptor; receptor-hormone complex translocates to nucleus, binds to transcription factors, alters gene expression SYNTHESIS OF SEX HORMONES Estrogen and Progesterone Biosynthesis Glucose/lipid metabolism oxidation/ side-chain cleavage **rate-limiting Acetate Cholesterol LH Progesterone Pregnenolone Androstenedione peripheral Testosterone ovary (aromatase) 17--estradiol Estrone Testosterone Synthesis u n Leydig Cells: synthesize testosterone (LH) Sertoli Cells: important in spermatogenesis (FSH); synthesize androgen binding protein; testosterone resevoir and transport protein; secreted into seminiferous tubules n n LH: regulates testosterone synthesis activates adenyl cyclase on Leydig cells FSH: regulates sertoli cell function DISEASES AND THERAPIES Estrogens and Progestins Synthetic estrogens: steroidal or nonsteroidal; substitutions on steroid nucleus; affect pharmacological properties; nonsteroidoid: DES Antiestrogens: antagonize actions of estrogens; ex., clomiphene and tamoxifen (nonsteroidal) Clinical Uses: Contraceptives Oral Contraceptives (use limited by side effects) -Combination pill: low dose synthetic estrogen and progesterone combined; taken once each day for 3 weeks after the last day of menstruation; negative feedback anterior pituitary; prevents surge of FSH and LH; inhibits ovulation; causes thinning of uterine lining (prevents implantation); Placebo pill taken the 4th week permits menstruation; failure rate 3-8%; side effects: abnormal blood clotting and heart attacks, cancer, gallbladder disease; headaches, acne, weight gain, vaginal infections, depression Emergency contraceptive pill (morning after pill): high dose combination pill -Progestin only (mini-pill): Change lining of uterus; prevents implantation; maybe safer reduced vascular risks; Health risks and side effects include ectopic pregnancy, depression, and menstrual cycle disturbances Clinical Uses: Contraceptives Contraceptive Implants and Patches Norplant (levonorgestrel): five plastic rods containing progestin placed under skin; five year contraceptive; Common side effects- menstrual disturbances, headaches, acne, weight gain, nausea, anxiety, hair loss, ovarian cysts Patch: (Ortho Evra)- dermal delivery; replaced once/week, on the same day for three consecutive weeks, fourth week- "patch-free." Same as oral contraceptives (synthetic estrogen and progestin; less effective for women over 198 lbs Injectables (Depo-Provera)- progestin; given once every three months; failure rate 0.5%; effects may persist even after cessation; amenhorrea; immune suppression (?) Mifepristone (Mifeprex, RU486) and Misoprostol (prostaglandin): RU486- causes abortion by interfering with placental function; blocks progesterone; administered with prostaglandins which cause uterine contractions; actions occur over several days Clinical Uses Menopause 90% decrease in estrogen 99% decrease in progesterone Vasomotor, urogenital atrophy, osteoporosis, psychological factors Other replacement therapy infertility induces ovulation cancer Estrogen/Progestin Therapy Side Effects Nausea, weight gain, edema, depression, headache; develop tolerance Drug Interaction Antibiotics decrease efficacy Contraindications (oral contraceptives) heart disease, vascular, liver failure (jaundice), breast cancer, smoking Androgens and Anabolic Steroids Three major androgens: Testosterone: principle androgen; 90% synthesized from pregnenolene by leydig cells in testis Androstenedione: synthesized in testis and adrenal cortex Dihydroepiandrosterone (DHEA): produced by adrenal cortex; weak androgen Regulation of Plasma Testosterone HT (-) GnRH Ant pit (-) Inhibin testis (-) LH Sertoli cell Leydig cell Testosterone FSH S Androgen binding protein L Spermatogenesis Mechanism of Action Testosterone Diffuses into target cell Metabolized to dihydrotestosterone Binds to cytoplasmic receptor Active complex translocates to nucleus, binds to promoter regions on genes (transcription factor sites) and alters gene transcription Pharmacologic Actions Virilizing (masculinization) Effects gonadotropin regulation; spermatogenesis; sexual development Protein Anabolic Effects increase in bone density, muscle mass, RBC mass Pharmacologic Actions Morphogenic Actions: irreversible; occur during embryogenesis; androgen insensitivity syndrome Excitatory Actions: puberty (hair, vocal chords, long bones) Maintenance Actions: reversible; behavior, libido, reproductive function Other Actions: decreases lymphoid tissue; stimulate erythropoiesis. Clinical Uses Replacement Therapy Hypogonadism prepuberal: congenital and acquired; treat 2-3 yr until puberty; low maintenance dose; low-acting testosterones (ex., enathate, cypionate, propionate) postpuberal: primary testicular dysfunction; secondary to destruction of anterior pituitary Aging and Impotence Clinical Uses Breast Cancer; Endometriosis limited use due to virilizing effects Protein Anabolic Action: increase amino acid uptake; increase RNA polymerase in skeletal muscle; antagonize the actions of glucocorticoids which are catabolic; used to treat short stature (19-nortestosterone); Athletes: used for anabolic and virilizing effects Adverse Reactions Masculinization in females; dependent upon dose, duration and drug Decreases spermatogenesis (feedback) Fluid retention, edema: congestive heart failure, kidney failure Anti-Androgens Used to treat prostate cancer, hirsutism, precocious puberty n Gonadotropin Antagonists (DES, estradiol); decrease LH synthesis; decrease steroidogenesis; prostate cancer high dose ketaconazole n Androgen Biosynthesis Inhibitors n Androgen Receptor Antagonists spironolactone (mineralocorticoid antagonist) ...
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