Gonadal Hormones & Inhibitors

Gonadal Hormones & Inhibitors

• Estrogens, progestins, oral contraceptives, inhibitors, and ovulation-inducing agents are discussed.
• The hypothalamus releases GnRH, which stimulates the pituitary to release FSH and LH, leading to estrogen production in the ovary.
• Natural estrogens are well-absorbed orally but are rapidly metabolized. Most estrogens are absorbed through skin and mucous membranes, allowing for transdermal administration.
• Topical vaginal administration is also possible, with some absorption occurring.
• Natural estrogens (like estradiol) undergo first-pass metabolism, resulting in low bioavailability when taken orally.
• Semisynthetic estrogens (like ethinyl estradiol) are potent, taken orally, and protected from liver inactivation. Mestranol is rapidly oxidized to ethinyl estradiol and stored in fat tissue for long-term availability.

Estrogen Mechanisms

• Estrogens act through two primary mechanisms: genomic and non-genomic.
• Genomic: Steroid hormones bind to specific nuclear receptors, initiating RNA synthesis and protein production for various physiological functions.
• Non-genomic: Estrogen receptor activation in hypothalamic membranes couples with G proteins, triggering second messenger cascades for faster actions.

Estrogen Therapeutic Uses

• Contraception with progestogens
• Postmenopausal hormone therapy (HT): Used for menopausal symptoms (hot flushes, vaginal atrophy) in conjunction with progestogen to reduce endometrial cancer risk. Doses are lower than oral contraceptives to minimize side effects.
• Replacement therapy: Used in primary hypogonadism (ovarian failure) and premature menopause for hormone replacement.

Estrogen Adverse Effects

• Nausea, breast tenderness are common.
• Increased blood clotting (thromboembolic events, myocardial infarction).
• Salt and water retention (edema, hypertension).
• Increased blood sugar levels
• Increased risk of breast and/or endometrial cancer.

Progesterone (Progestogens)

• Progesterone is the natural progestational hormone.
• Preparations include natural progesterone (rapidly metabolized), and synthetic derivatives (effective orally) including medroxyprogesterone acetate and norethindrone/norgestrel.
• Therapeutic uses include oral contraception, and treatment of functional uterine bleeding, dysmenorrhea, amenorrhea, and endometriosis.
• Adverse effects include weak androgenic actions (edema, psychic depression), increased cholesterol, and atherosclerosis.

Contraception Methods

• Combination oral contraceptives: Estrogen + progestin taken for 21 days with a 7-day break for menstruation. Available as monophasic, biphasic, or triphasic formulations.
• Progestin-only contraceptives: Norethindrone or levonorgestrel, taken daily without interruption. This approach has fewer side effects compared to combination pills.
• Depot therapy: Medroxyprogesterone acetate injection every 3 months. Useful post-delivery as it doesn't affect lactation.
• Subcutaneous implants: Progestins released slowly via implants. Long-term, reversible, and doesn't depend on patient compliance.

Post-coital Contraceptives

• Estrogen alone: Diethylstilbestrol taken in high doses within 72 hours of intercourse
• Estrogen + progestogen: Taken in two doses within 72 hours.

Contraindications to Hormonal Contraceptives

• History of thromboembolic disorders, certain types of cancer (estrogen-dependent).
• Other conditions, as listed.

Drug Interactions

• Oral contraceptives can influence the effects of anticoagulants, antihypertensives, and antihyperlipidemics.
• Enzyme inducers like phenytoin and rifampicin can increase estrogen metabolism.

Anti-Estrogens & Anti-Progestogens

• Selective estrogen receptor modulators (SERMs): Tamoxifen & raloxifene
• Anti-progestogens: Mifepristone, used in early pregnancy termination and as post-coital contraceptive.

Ovulation-Inducing Agents

• Clomiphene citrate: Blocks estrogen's negative feedback, leading to follicle-stimulating hormone (FSH) increases, stimulating ovulation . Adverse effects include hot flashes, headache, and visual disturbances.
• Human menopausal gonadotropins (hMG): contains FSH and LH, stimulating ovarian follicle maturation followed by human chorionic gonadotropin to trigger ovulation
• Metformin: Often used in women with polycystic ovarian syndrome to normalize irregular cycles and induce ovulation.
• Aromatase inhibitors: Decrease estrogen synthesis e.g. Letrozole.