Progestins-and-Hormone-Modulators..........
- 1. Progestins and Hormone Modulators Progestins have significant physiologic effects on the female reproductive system, converting proliferative to secretory endometrium, thickening cervical mucus to impede sperm, reducing uterine contractions, raising basal body temperature, promoting breast lobule- alveolar growth, and blunting estrogen effects on the endometrium.
- 2. Progestins – Non-contraceptive Uses Abnormal Uterine Bleeding Regulate cycles in anovulatory DUB; stop acute heavy bleeding Endometriosis Induce decidualization/atrophy of endometrial implants (e.g. continuous MPA or dienogest) HRT (with estrogen) Prevent endometrial hyperplasia in menopause therapy Pregnancy Support Progesterone support in first trimester (if luteal phase insufficiency); 17-OH progesterone injections in high-risk pregnancies (to reduce preterm birth) Other Uses Progestins (e.g. megestrol) in oncology for appetite stimulation; part of transgender care for trans men, etc.
- 3. Progestins – Adverse Effects Androgenic Effects Acne, hirsutism, weight gain (notably with 19- nortestosterone derivatives); lipid changes ( HDL, ↓ ↑ LDL with older progestins) Bleeding Irregularities Unpredictable spotting or amenorrhea (especially progestin-only methods); need to counsel patients CNS Mood depression, fatigue, somnolence (some experience PMS-like symptoms) Breast Tenderness, mastalgia (especially in combination with estrogen) Long-term Bone loss with Depo-Provera (due to hypoestrogenism); slight insulin resistance (high- ↑ dose MPA) Drospirenone-specific Hyperkalemia risk (anti-mineralocorticoid) – caution with K⁺-sparing drugs
- 4. SERMs – Selective Estrogen Receptor Modulators 1 Tamoxifen ER antagonist in breast (treats ER+ breast cancer); ER agonist in uterus & bone – benefits bone, but endometrial CA risk ↑ and causes uterine bleeding. Used in premenopausal and postmenopausal breast cancer adjuvant therapy, and prevention in high-risk women. Side effects: Hot flashes, endometrial hyperplasia/cancer, DVT/PE risk, cataracts (long-term) 2 Raloxifene ER antagonist in breast & uterus, agonist in bone – for osteoporosis in postmenopausal women and breast cancer risk reduction. Does not cause endometrial proliferation. Side effects: Hot flashes, leg cramps, DVT/PE risk ↑ (contraindicated if history of VTE) 3 Ormeloxifene (Centchroman) Weekly oral SERM for contraception and DUB. Estrogenic on bone, anti-estrogenic on uterus & breast. Side effects: Delayed/irregular menstruation, mild weight gain, headache (no estrogen-like serious risks reported)
- 5. SERD Mechanism Pure ER antagonist binds and → degrades ER (downregulator) Uses Used in metastatic ER+ breast cancer resistant to tamoxifen Effects Eliminates estrogen signaling in tumor Side Effects Menopausal symptoms (hot flash, etc.), injection site reactions
- 6. Aromatase Inhibitors Function Block estrogen synthesis from androgens (aromatase enzyme) Effect Profound estrogen reduction (~95%) Types Anastrozole, Letrozole: Non-steroidal competitive inhibitors (reversible) Exemestane: Steroidal irreversible inhibitor (suicide substrate)
- 7. Aromatase Inhibitors Uses and Adverse Effects Uses • Postmenopausal breast cancer (adjuvant or metastatic) – often first-line instead of tamoxifen • Letrozole for ovulation induction (off-label) Adverse Effects • Hot flashes • Arthralgias/myalgias • Osteoporosis (bone loss, fractures) • Vaginal dryness No endometrial cancer or VTE risk (advantage over SERMs)
- 8. Summary - Part 1 Gonadotropins Replace/enhance FSH/LH activity – used for infertility; main risks = OHSS, multiples Estrogens Broad physiological effects; used in HRT, etc.; risks = thrombosis, cancer (mitogenic effects) Progestins Oppose estrogen on endometrium, support pregnancy; used for bleeding disorders, endometriosis, HRT; side effects vary by androgenic potency (choose newer agents to minimize acne/hirsutism)
- 9. Summary - Part 2 SERMs Tissue-selective ER agonist/antagonists – exploit beneficial estrogenic effects (bone) while blocking harmful ones (breast). Tailored uses (tamoxifen for breast CA, raloxifene for bone+breast prevention, ormeloxifene for contraception/DUB). Monitor for hot flashes and thrombosis. SERD (Fulvestrant) Complete ER blockade – for advanced breast cancer; induces ER degradation (no agonist activity). Aromatase Inhibitors Cut off estrogen supply in postmenopausal women – superior in ER+ breast cancer (postmeno) but watch bone health; not for use in premenopausal (unless ovarian suppression).