Sex Hormones: Estrogens and Progestins

Estrogens & SERMs - Femme Fatale Hormones

• Estrogens (e.g., Estradiol, Estrone, Estriol):
  • MOA: Bind nuclear Estrogen Receptors (ER-α, ER-β) → alter gene transcription.
  • Effects: Female development, endometrial proliferation, bone: ↓resorption, lipids: ↑HDL/↓LDL, procoagulant.
  • Uses: Hormone Replacement Therapy (HRT), contraception (with progestins), primary hypogonadism.
  • AEs: Nausea, breast tenderness, thromboembolism (VTE), endometrial hyperplasia/cancer (if unopposed), gallstones.
• SERMs (Selective Estrogen Receptor Modulators): Tissue-specific actions.
  • Tamoxifen:
    • Antagonist: Breast (ER+ breast cancer treatment/prevention).
    • Agonist: Bone (prevents osteoporosis), Endometrium (↑risk of endometrial cancer, hyperplasia), Lipids.
    • 📌 Breast antagonist, Uterus agonist.
  • Raloxifene:
    • Antagonist: Breast, Endometrium (no ↑ endometrial cancer risk).
    • Agonist: Bone (postmenopausal osteoporosis treatment/prevention). ↑VTE risk.
  • Clomiphene Citrate:
    • Antagonist: Hypothalamic ER → ↓negative feedback → ↑GnRH, FSH, LH → ovulation induction (PCOS infertility).
    • AEs: Multiple pregnancies, OHSS.

  ⭐ Tamoxifen, a SERM, is used for ER+ breast cancer but paradoxically increases the risk of endometrial cancer.

Anti-Estrogens - Estrogen Blockade Brigade

• Selective Estrogen Receptor Modulators (SERMs): Mixed agonist/antagonist activity.
  • Tamoxifen: Breast cancer (ER+), osteoporosis prevention. Risk: Endometrial Ca, thromboembolism.
  • Raloxifene: Osteoporosis (postmenopausal), breast cancer prevention. No endometrial Ca risk.
  • Clomiphene: Ovulation induction (anovulatory infertility). Acts on hypothalamus/pituitary.
• Aromatase Inhibitors (AIs): Block estrogen synthesis from androgens.
  • Anastrozole, Letrozole (non-steroidal); Exemestane (steroidal, irreversible).
  • Use: ER+ breast cancer (postmenopausal).
• Pure Estrogen Receptor Antagonist:
  • Fulvestrant: ER+ metastatic breast cancer (after tamoxifen). Degrades ER.

⭐ Tamoxifen is a prodrug, metabolized by CYP2D6; efficacy ↓ with inhibitors (e.g., SSRIs like fluoxetine).

Progestins & Antiprogestins - Pro-Gestation & Foes

• Progestins (Pro-gestational): 📌 "PROgestins PREpare & PROtect PREgnancy."

  • Natural: Progesterone.
    • Actions: Endometrial support (secretory), thick cervical mucus, ↓ uterine motility.
  • Synthetic (Progestogens):
    • Estranes (19-nortestosterone): Levonorgestrel (androgenic); Desogestrel (less androgenic).
    • Pregnanes (17α-OHP): Medroxyprogesterone acetate (MPA).
    • Others: Drospirenone (antiandrogenic, antimineralocorticoid).
  • Uses: Contraception, HRT (with estrogen to prevent endometrial hyperplasia), DUB, endometriosis.
  • AEs: Weight gain, mood changes, acne, breakthrough bleeding, altered lipids (older agents: ↓HDL, ↑LDL).

• Antiprogestins:

  • Mifepristone (RU-486): Progesterone receptor antagonist.
    • Uses: Medical abortion (with misoprostol), emergency contraception (EC).
  • Ulipristal Acetate: Selective Progesterone Receptor Modulator (SPRM).
    • Uses: EC (up to 120 hrs post-coitus), uterine fibroids.

    ⭐ Mifepristone, a progesterone receptor antagonist, is combined with misoprostol (a prostaglandin analogue) for effective medical abortion.

Hormonal Contraceptives - Cycle Control Crew

• MoA:
  • Estrogen: ↓FSH → inhibits follicle dev., stabilizes endometrium.
  • Progestin: ↓LH surge → inhibits ovulation, thickens cervical mucus, endometrial atrophy.
• Types:
  • COCs: Estrogen + Progestin.
  • POPs: For lactation, smokers >35y, VTE risk.
  • Others: Patch, ring, injectables (DMPA), implants, hormonal IUDs.
• Benefits: Contraception, cycle control, ↓dysmenorrhea, ↓ovarian/endometrial Ca risk.
• AEs: Nausea, headache, VTE. 📌 ACHES: Abdominal pain, Chest pain, Headaches, Eye problems, Severe leg pain.
• CIs: Hx VTE, CAD, CVA, ER+ tumor, active liver disease, smokers >35y.

⭐ Progestin-only contraceptives are preferred in lactating women as estrogens can reduce milk production.

High‑Yield Points - ⚡ Biggest Takeaways

• Estrogens (e.g., estradiol) are key for female sexual development and endometrial proliferation.
• Progestins (e.g., progesterone) ensure endometrial secretory changes and maintain pregnancy.
• SERMs like Tamoxifen (breast cancer, ↑ endometrial risk) and Raloxifene (osteoporosis) have tissue-specific actions.
• Combined OCPs primarily inhibit ovulation; major risk is thromboembolism.
• HRT for menopausal symptoms carries risks like VTE and breast cancer.
• Mifepristone (progesterone antagonist) is used for medical abortion.
• Clomiphene (estrogen antagonist at hypothalamus) induces ovulation anovulatory infertility cases.