Hormone Therapy — Key Rules
WHI — Two Arms, Two Profiles
Never Conflate CEE+MPA vs CEE Alone
- CEE + MPA (intact uterus): breast cancer increased, coronary heart disease increased, venous thromboembolism increased
- CEE alone (hysterectomized): no breast cancer increase, hip fracture reduced
- Breast cancer signal = medroxyprogesterone acetate component, not estrogen alone
- Transdermal estradiol + micronized progesterone was NOT tested in Women's Health Initiative
Timing Rule & Route Selection
When and How to Prescribe
- Start within 10 years of menopause or before age 60: favorable cardiovascular profile
- Start more than 10 years after menopause: net cardiovascular harm
- VTE risk factors: transdermal estradiol (bypasses portal first-pass, no VTE increase)
- Intact uterus: must add progestin (endometrial protection)
- Hysterectomy: estrogen alone (no progestin needed)
- Breast cancer risk concern: micronized progesterone preferred over medroxyprogesterone acetate
Selective Estrogen Receptor Modulators — Tissue Effects
| SERM |
Breast Effect |
Uterine Effect |
Bone Effect |
Key Clinical Point |
| Tamoxifen |
Antagonist (blocks proliferation) |
Partial agonist → endometrial cancer risk |
Partial agonist (maintains bone density) |
CYP2D6 → endoxifen. Avoid paroxetine/fluoxetine. Use venlafaxine for hot flushes. |
| Raloxifene |
Antagonist |
Antagonist (no endometrial cancer risk) |
Agonist (osteoporosis approved) |
Preferred for chemoprevention in postmenopausal women; no uterine cancer risk vs tamoxifen |
| Ospemifene |
Antagonist |
Mild agonist |
Neutral |
Oral SERM for dyspareunia (vulvovaginal atrophy); systemic VTE risk; hot flushes common |
GnRH Agonists vs. Antagonists
GnRH Agonists (Leuprolide, Goserelin, Nafarelin)
Downregulation After Initial Flare
- Mechanism: continuous stimulation → receptor downregulation → suppression
- Onset: 2–4 weeks to achieve therapeutic suppression
- Initial flare: weeks 1–2 — transient sex hormone surge
- Prostate cancer: cover flare with antiandrogen for 4 weeks
- Route: depot injection (1-, 3-, or 6-month intervals)
- Duration without add-back: maximum 6 months (bone mineral density loss)
- Add-back extends safe use to 12+ months
GnRH Antagonists (Elagolix, Relugolix)
Immediate Suppression, No Flare
- Mechanism: competitive receptor blockade → immediate suppression
- Onset: hours (no flare period)
- Cessation: rapid recovery of gonadotropin secretion
- Elagolix: oral, endometriosis; dose-dependent partial vs complete suppression
- Relugolix: oral, prostate cancer (Orgovyx)
- Relugolix + estradiol + norethindrone acetate (Myfembree): fibroids with built-in add-back
- Advantage: titratable, flare-free, rapidly reversible
Endometriosis & Uterine Fibroids — Treatment Hierarchy
Endometriosis (Estrogen-Dependent)
Treatment Ladder
- First-line: combined oral contraceptives, progestin-only (norethindrone, medroxyprogesterone acetate, implant), levonorgestrel intrauterine device
- Second-line: GnRH agonists with add-back, GnRH antagonists (elagolix)
- Levonorgestrel intrauterine device: highly effective for dysmenorrhea and bleeding; preferred initial option
Uterine Fibroids (Estrogen + Progesterone Dependent)
Medical Options
- Levonorgestrel intrauterine device (52 mg): first-line for bleeding when cavity not distorted
- GnRH agonists: reduce fibroid volume preoperatively (surgical bridge only)
- Fibroid regrowth occurs rapidly after stopping agonist
- Relugolix + add-back (Myfembree): first approved long-term non-surgical option
Tamoxifen Drug Interaction Rule
Tamoxifen requires CYP2D6 conversion to active metabolite endoxifen. Paroxetine and fluoxetine (potent CYP2D6 inhibitors) reduce endoxifen by up to 75% → potential loss of oncological benefit. For hot flushes in women on tamoxifen: use venlafaxine or gabapentin, not paroxetine or fluoxetine.