Pharmacology of Reproductive Hormones

• Natural and Synthetic Female (Ovarian) Sex Hormones: Agonists and Inhibitors

Module Objectives

• Identify the actions, medical uses, and adverse reactions of natural and synthetic female sex hormone agonists and inhibitors
• Describe the physiological effects of major endogenous estrogens and progestogens
• Give examples of clinically relevant natural and synthetic estrogens and progestogens and their respective inhibitors, and describe their therapeutic uses and adverse reactions

Sex Hormones and The Hypothalamic-Pituitary-Endocrine Axis

• The hypothalamus releases Gonadotropin-Releasing Hormone (GnRH), which stimulates the anterior pituitary
• The anterior pituitary releases Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH)
• FSH and LH act on the ovary, leading to maturation and the production of estrogens and progesterone

Main Female Reproductive Hormones

• FSH, secreted by the anterior pituitary, initiates the development of ovarian follicles and stimulates the secretion of estrogen by follicle cells
• LH, secreted by the anterior pituitary, causes ovulation, converts the ruptured ovarian follicle into the corpus luteum, and stimulates progesterone secretion by the corpus luteum
• Estrogen, secreted by the ovary (follicle) and the placenta during pregnancy, promotes maturation of ovarian follicles, promotes the growth of blood vessels in the endometrium, and initiates the development of secondary sex characteristics
• Progesterone, secreted by the ovary (corpus luteum) and the placenta during pregnancy, promotes more growth of blood vessels in the endometrium and storage of nutrients and inhibits contractions of the myometrium

Estrogen Synthesis

• Cholesterol is converted into Pregnenolone, a progestagen with 21 carbons, via the cholesterol side-chain cleavage enzyme
• Pregnenolone can be converted to 17a-hydroxypregnenolone via 17a-hydroxylase
• Both Pregnenolone and 17a-hydroxypregnenolone can then be converted into androgens (19 Carbons)
• Androgens can be converted into estrogens (18 carbons) via aromatase

Estrogen: Key Effects

• Inhibits gonadotropin secretion by the pituitary
• Causes proliferation of the uterus
• Lowers LDL and raises HDL
• Induces vasodilation
• Improves bone density by inhibiting osteoclasts and enhancing osteoblast activity
• Promotes breast tissue proliferation

Estrogens: Ethinyl Estradiol

• Used as a hormone replacement therapy (HRT) in postmenopausal women
• Used as a treatment for senile vaginitis
• Used to treat delayed puberty in girls
• Used to treat dysmenorrhea by inducing anovulatory cycles in painful menstruation
• Estrogen will inhibit androgen release by inhibiting gonadotropin release from the pituitary, treating acne
• Progestin may be added as an adjunct to treat dysfunctional uterine bleeding
• Palliative treatment for prostate cancer
• Risks of use include nausea, vomiting, headache, breast discomfort, hypertension, endometriosis, endometrial carcinoma, deep vein thrombosis (DVT), and acceleration of breast cancer

Anti-Estrogens: Clomiphene Citrate

• Blocks estrogen feedback inhibition of the hypothalamus, leading to increased FSH and LH release
• Uses include fertility treatment in females and treating oligozoospermia in males
• Risks include multiple pregnancies, hot flashes, ovarian tumors, hypertension, and increased risk of endometrial carcinoma

Selective Estrogen Receptor Modulators (SERMs)

• SERMs like Tamoxifen, Toremifene, and Raloxifene have both estrogenic and antiestrogenic effects in a tissue-specific manner

Tamoxifen

• Estrogenic effects act as agonists of estrogen receptors on the uterus, pituitary, bone, and liver
• Antiestrogenic effects act as antagonists on estrogen receptors of the breast and blood vessels
• Used to treat ER+ breast cancer in pre- and postmenopausal women and is effective in treating male breast cancer
• Risks include Vomiting, hot flashes, vaginal bleeding (endometrial proliferation), DVT, and risk of endometrial carcinoma

Selective Estrogen Receptor Down Regulators (SERDs)

• Fulvestrant inhibits ER dimerization to suppress ER-induced nuclear activity
• For use in ER+ breast cancer in postmenopausal women who do not respond to tamoxifen
• Adverse effects include menopausal symptoms like hot flashes and mood changes, and GIT effects like nausea, vomiting, and diarrhea

Aromatase Inhibitors

• Examples include Letrozole, Anastrozole, and Exemestane
• They reversibly inhibit aromatization
• Used in early and advanced breast cancer after tamoxifen failure in postmenopausal women
• The adverse effects include hot flashes, nausea, diarrhea, bone loss, and hair thinning

Progesterone

• Key to Reproduction, birth control, female and male secondary sexual characteristics, salt and water balance, regulation of blood pressure, stress adaptation, thermoregulation, protection against tumors, neurogenesis, and neuroprotection

Progesterone: Physiological Effects

• Thickens endometrium for implantation
• Supports pregnancy after the implementation process
• Causes breast engorgement
• Increases body temperature
• Causes mood swings and Odema
• Irregular bleeding can occur
• Causes low HDL levels
• Carbohydrate intolerance can occur

Synthetic Progestins: C-21 Compounds

• Medroxyprogesterone acetate, Hydroxyprogesterone, Megestrol acetate, and Nomegestrol
• Weak antiovulatory action
• Used as an adjuvant alongside estrogen in HRT, treats threatened abortions, and treats endometriosis

Synthetic Progestins: C-19 Compounds

• C-19 Nortestosterone progestins include Estranes (Norethindrone/Norethindrone acetate, Ethynodiol diacetate, Lynestrenol, Norethynodrel) and Gonanes (Norgestrel, Levonorgestrel/Norgestimate, Desogestrel, Gestodene, Dienogest)
• Estranes have potent antiovulatory action, but they also exhibit androgenic and anabolic effects
• Gonanes have little or no androgenic/anabolic action
• Mainly used for contraception

Selective Progesterone Receptor Modulators (SPRMs): Mifepristone

• Exhibits potent antiprogestational, antiglucocorticoid, and antiandrogenic actions
• Decreases follicular development and inhibits ovulation
• Blocks progesterone support to the endometrium, leading to contractions and menstruation
• Dislodges the conceptus
• Used for termination of pregnancy (up to 7 weeks), inducing labor, and postcoital contraception/emergency (within 72h of unprotected intercourse)
• Adverse reactions include abdominal pain, fatigue, vaginal bleeding/heavy bleeding, and potential birth defects if the pregnancy continues

Selective Progesterone Receptor Modulators (SPRMs): Ulipristal

• Suppresses the luteinizing hormone (LH) surge to inhibit ovulation, resulting in its use as an emergency contraceptive
• Adverse drug reactions include headache, nausea, stomach pain, plus unusual tiredness and weakness

This module explores the use of drugs affecting the reproductive system. It covers mechanisms of action, therapeutic uses, and side effects of natural and synthetic hormones. Focus areas include fertility treatments and hormone therapies.