Gonadal Hormones & Inhibitors Dr Safaeian Isfahan University of Medical Sciences
Female Gonads: Ovary Ovarian Hormones: Estrogen, Progesterone Gametogenic functions and hormonal activity. A cyclic function: menstrual cycle Ovarian Hormones: Estrogen, Progesterone Small amounts of androgens Inhibin (inhibits FSH secretion) Activin (increases FSH secretion) Relaxin (decreases uterine contractility)
Regulation of Gonads GnRH (gonadotropin – releasing hormone) is secreted by hypothalamus and transported to anterior pituitary gland ► synthesis and release of gonadotropins: LH , FSH
Regulation of Gonads Follicle-stimulating hormone (FSH) ► enlargement of follicles, ovulation, secretion of estrogen. Luteinizing hormone (LH) ► ovulation, release of estrogens and progesterone. estrogens appear to inhibit FSH release and may lead to regression of the smaller, less mature follicles.
- Surge in LH and FSH release Ovulation in midcycle. - Estrogen secretion reaches a peak just before midcycle. - Surge in LH and FSH release Ovulation in midcycle.
Estrogens
Natural Estrogens Estradiol (E2) (major product of ovary), Estrone (E1), Estriol (E3) (are formed in ovary, liver or in peripheral tissues) Equine estrogens: Equilenin and Equilin (excreted in large quantities in urine of stallion) + Estrone sulfate (converted to estradiol) → Conjugated Estrogens: with hydrophilic side-groups attached (sulfate) Estrogen-mimetic compounds: Flavonoids (in soybeans and other foods) Bisphenols, Alkylphenols (in manufacture of plastics) Estrone (E1), Estriol (E3) (are formed in liver from estradiol or in peripheral tissues from androstenedione and other androgens by aromatase) during the first part of the menstrual cycle estrogens are produced in the ovarian follicle by the theca and granulosa cells. After ovulation, the estrogens as well as progesterone are synthesized by the luteinized granulosa and theca cells of the corpus luteum,
Biosynthesis and metabolism of estrogens and testosterone
Estrogens Preparation Natural Estradiol Plaster, Patch, Vaginal TAB, Vaginal GEL, Topical GEL Estradiol Valerate TAB, AMP Estradiol Hemihydrate Patch Conjugated Estrogens (Premarin) TAB, AMP, Vaginal Cream Synthetic Ethinyl estradiol TAB Nonsteroidal compounds with estrogenic activity Dienestrol Vaginal Cream A variety of chemical alterations have been applied to the natural estrogens. The most important effect of these alterations has been to increase their oral effectiveness.
Estrogens: Pharmacokinetics Estradiol binds strongly to α2 globulin (sex hormone-binding globulin [SHBG]). Free fraction is physiologically active. Estradiol is converted by liver and other tissues to estrone and estriol and hydroxylated and conjugated metabolites → excreted in bile and small in breast milk.
Estrogens: Pharmacokinetics Conjugates may be hydrolyzed in intestine to active compounds ► Enterohepatic Circulation. Orally estrogens have hepatic and undesirable effects: synthesis of clotting factors and plasma renin substrate. Vaginal, transdermal, or injection routes ► avoid first-pass liver exposure: ↓Hepatic effects
Estrogens: Mechanism Two estrogen receptor isoforms: ERα, ERβ Found predominantly in the nucleus bound to heat shock proteins (Hsp90). Binding of hormone to ER → releases it from Hsp90 and forms homodimers → bind to transcription factors and to estrogen response Elements (EREs)→ regulate gene transcription and protein synthesis. Members of superfamily of steroid, sterol, retinoic acid, and thyroid receptors. Hsp90 (heat shock protein 90) is a molecular chaperone and is one of the most abundant proteins expressed in cells.[3] It is a member of the heat shock protein family which is upregulated in response to stress one of the most common of the heat related proteins. The protein is named "HSP" for obvious reasons whereas the "90" comes from the fact that it weighs roughly 90 kiloDaltons. The function of Hsp90 includes assisting in protein folding, cell signaling, and tumor repression
Estrogens: Physiologic Effects Female Maturation Development of vagina, uterus, and uterine tubes and secondary sex characteristics, stromal development and ductal growth in the breast Accelerated growth phase and closing of epiphyses of the long bones at puberty Distribution of body fat to produce typical female body contours
Estrogens: Physiologic and Pharmacologic Effects Endometrial Effects Development of endometrial lining Continuous exposure to estrogens for prolonged periods ► Hyperplasia of endometrium with abnormal bleeding
Estrogens: Physiologic and Pharmacologic Effects Metabolic and Cardiovascular Effects Maintenance of normal structure and function of skin and blood vessels ↓Rate of resorption of bone by promoting apoptosis of osteoclasts and by antagonizing the osteoclastogenic effects of parathyroid hormone. ↑HDL, slight ↓LDL, ↓total cholesterol, ↑TG
Estrogens: Physiologic and Pharmacologic Effects Metabolic and Cardiovascular Effects ↑Renin substrate, ↑fibrinogen Retention of sodium and water and edema ↑Coagulation factors II, VII, IX, and X, ↓antithrombin III ↑Coagulability of blood Effects on CNS Excitability
Estrogens: Clinical Uses Primary Hypogonadism (primary failure of development of ovaries) Postmenopausal Hormonal Therapy Treatment of intractable dysmenorrhea, hirsutism and amenorrhea due to excessive secretion of androgens by ovary and for contraception → suppression of ovarian function combined with progestins Estrogens combined with progestins can be used to suppress ovulation رام نشدني in patients with intractable dysmenorrhea
Postmenopausal Hormonal Therapy (Hormonal “replacement" therapy: HRT or HT) Control of vasomotor symptoms, Prevention and treatment of osteoporosis, Protective effect against Alzheimer's disease, ↑Sense of well-being, ↓Depression Dosages Estrogen: 0.3–1.25 mg/d of conjugated estrogen or 0.01–0.02 mg/d of ethinyl estradiol on the first 21–25 days of each month. Administration of progestin + estrogen → prevention of endometrial hyperplasia and ↓risk of cancer: medroxyprogesterone 10 mg/d is added during the last 10–14 days. (hot flushes, sweating), insomnia, atrophic vaginitis
Estrogens: Adverse Effects Postmenopausal Uterine Bleeding Cancer: ↑incidence of breast cancer in prolonged therapy, ↑risk of endometrial carcinoma in taking estrogens alone Nausea and breast tenderness as seen with Contraceptives (minimized by ↓estrogen dose ) Hyperpigmentation, ↑cholestasis, gallbladder disease ↑Frequency of migraine, hypertension Melasma is characterized by uneven pigmentation. The pigment cells underlying the pigmentation are genetically programmed to respond to the effects of hormones estrogen and progesterone by producing excessive pigment compared to normal pigment cells. The hormones cause excessive production of melanin and this corresponds to darkening of the skin.
Estrogens: Contraindications Estrogen-dependent neoplasms (carcinoma of endometrium and breast) Undiagnosed genital bleeding Liver disease History of thromboembolic disorder Heavy smokers
Progestins
Natural Progestins Progesterone: most important progestin A precursor of estrogens, androgens, and adrenocortical steroids. It is synthesized in ovary, testis, adrenal and placenta from circulating cholesterol.
Synthetic Progestins Hydroxyprogesterone Medroxyprogesterone Megestrol Progesterone derivates (21-carbon compounds): Hydroxyprogesterone Medroxyprogesterone Megestrol Dydrogesterone Progestins without androgenic activity include desogestrel, norgestimate, and gestodene.
Lower androgenic activity ↑Progestins Generations Synthetic Progestins Progestins Generations: (19-nor, 13-ethyl steroid or 19-nortestosterone derivates; 1st, 2nd and 3rd ) 1st : Norethindrone, Lynestrenol 2nd : Norgestrel, Levonorgestrel 3rd : Desogestrel, Norgestimate 4th : Drospirenone (17α-Spirolactone), Gestonorone (19-Norprogesterone) Gestonorone caproate Progestins without androgenic activity include desogestrel, norgestimate, and gestodene. Lower androgenic activity ↑Progestins Generations
Progestins: Pharmacokinetics Progesterone: Completely metabolized in liver to pregnanediol and conjugated with glucuronic acid ► ineffective in orally route. Excreted into urine. Pregnanediol in the urine: An index of progesterone secretion. New preparations have adequate progestational effect after orally administration. Progestins Mechanism: Through intracellular receptor like other steroids
Progesterone: Physiologic and Pharmacologic Effects ↑Lipoprotein lipase activity ↑Insulin levels, glycogen storage ↓Na+ renal reabsorption ↑Body temperature Depressant and Hypnotic effects Alveolobular development of breast ↓Plasma amino acids, ↑urinary nitrogen excretion Thickening of cervical mucus compete with aldosterone for the mineralocorticoid receptor . compete with aldosterone for the mineralocorticoid receptor of the renal tubule
Synthetic Progestins: Pharmacologic Effects 21-carbon progesterone analogs: Antagonize aldosterone-induced sodium retention Support pregnancy Progestins generations: Do not support pregnancy More effective gonadotropin inhibitors May have minimal estrogenic and androgenic or anabolic activity compete with aldosterone) for the mineralocorticoid receptor
Progestins: Clinical Uses Hormone replacement therapy Hormonal contraception Dysmenorrhea, Endometriosis, Bleeding disorders, Premenstrual syndrome Ovarian Suppression To delay premature labor Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur in the one to two weeks before a woman's period. Symptoms often vary between women and resolve around the start of bleeding. Common symptoms include acne, tender breasts, bloating, feeling tired, irritability, lower back pain, joint or muscle pain,abdominal cramps, constipation/diarrhea,and mood changes. Often symptoms are present for around six days.
Progestins: Adverse Effects ↑Blood pressure in some patients (very lower than estrogens) ↓HDL (by androgenic progestins ) ↑Breast cancer risk Depression Acne and oily skin, hirsutism ↑Appetite, Weight gain Breast cancer risk significantly compared with the risk in women taking estrogen alone
Estrogen & Progesterone Inhibitors & Antagonists
Tamoxifen & Related Partial Agonist Estrogens Selective Estrogen Receptor Modulator (SERM): Tamoxifen: nonsteroidal competitive partial agonist inhibitor of estradiol at estrogen receptor Orally administration for palliative treatment and chemoprevention of breast cancer Adverse Effects: hot flushes, nausea, vomiting
Tamoxifen & Related Partial Agonist Estrogens (SERM) Raloxifene: for prevention of postmenopausal osteoporosis and prophylaxis of breast cancer in women with risk factors. Clomiphene: a weak estrogen and an ovulation-inducing agent
Clomiphene Inhibits action of stronger estrogens ► ↑Secretion of gonadotropins and estrogens by inhibiting estradiol's negative feedback. Clinical Use: oligomenorrhea, amenorrhea and ovulatory dysfunction (polycystic ovary syndrome) Adverse Effects: hot flushes, eye symptoms (intensification and prolongation of afterimages), ovarian enlargement, nausea, vomiting, nervous tension, depression, breast soreness, weight gain, urinary frequency, and heavy menses. پس تصوير
Mifepristone (RU-486) Antagonist at progesterone and glucocorticoid receptor Luteolytic properties if given in midluteal period. A single dose (600 mg)→ emergency contraception May be useful in treatment of endometriosis, Cushing's syndrome, breast cancer, and other neoplasms such as meningiomas. Its major use: Abortifacient to terminate early pregnancies. Meningiomas are a diverse set of tumors arising from the meninges, the membranous layers surrounding the central nervous system.[1] They arise from the arachnoid "cap" cells of the arachnoid villi in the meninges.[2] These tumors are usually benign in nature; however, a small percentage are malignant.[3] Many meningiomas are asymptomatic, producing no symptoms throughout a person's life, and require no treatment other than periodic observation. Most meningiomas contain progesterone receptors.
Danazol Weak progestational, androgenic and glucocorticoid activities → An inhibitor of gonadal function Inhibits midcycle surge of LH and FSH It inhibits P450scc (cholesterol side chain-cleaving enzyme), P450c17 (17α-hydroxylase), P450c11 (11β-hydroxylase) → inhibition of synthesis of steroid compounds ↑Clearance of progesterone (by competing with hormone for binding proteins) Its major metabolite (Ethisterone) has progestational and mild androgenic effects. in which endometrial-like cells appear and flourish in areas outside the uterine cavity, most commonly on the ovaries.
Danazol Its major use: treatment of endometriosis Other uses: treatment of fibrocystic disease of breast, hematologic or allergic disorders, (hemophilia, idiopathic thrombocytopenic purpura, angioneurotic edema). Adverse effects: weight gain, edema, ↓breast size, acne and oily skin, ↑hair growth, deepening of the voice, headache, hot flushes, changes in libido, and muscle cramps, hepatocellular damage. Angioedema (BE: angiooedema) or Quincke's edema is the rapid swelling (edema) of the dermis, subcutaneous tissue,[1] mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis.[1] The term angioneurotic oedema was used for this condition in the belief that there was nervous system involvement but this is no longer thought to be the case.
Other Inhibitors Anastrozole: a selective nonsteroidal inhibitor of aromatase (the enzyme required for estrogen synthesis) Effective in breast tumors are resistant to tamoxifen. Letrozole is similar. Exemestane, a steroid molecule, irreversible inhibitor of aromatase, used for advanced breast cancer.