Available Hormonal Therapies for Menopause
The primary hormonal therapies available for menopause are systemic estrogen (for women post-hysterectomy) and combined estrogen-progestin therapy (for women with an intact uterus), with the critical distinction that progestin must be added to estrogen in women with a uterus to prevent endometrial cancer. 1
Core Hormonal Therapy Options
For Women WITH an Intact Uterus
Combined estrogen-progestin therapy is mandatory to prevent endometrial hyperplasia and cancer, as unopposed estrogen dramatically increases endometrial cancer risk (RR 2.3, escalating to RR 9.5 after 10 years of use). 2, 3
Available regimens include:
Continuous combined therapy: Daily estrogen plus daily progestin (e.g., medroxyprogesterone acetate 2.5 mg daily with conjugated equine estrogen 0.625 mg daily) to minimize breakthrough bleeding 4, 1
Sequential/cyclic therapy: Daily estrogen with progestin added for 10-14 days per month (e.g., medroxyprogesterone acetate 10 mg for 10-14 days monthly), though this may result in monthly withdrawal bleeding 4
Micronized progesterone: An alternative progestin option that some evidence suggests may have a more favorable safety profile regarding breast cancer risk compared to synthetic progestins 5, 6
Bazedoxifene combined with estrogen: A selective estrogen receptor modulator (SERM) that can be used instead of progestin for endometrial protection 7, 8
For Women WITHOUT a Uterus (Post-Hysterectomy)
Estrogen-alone therapy is appropriate since there is no endometrial cancer risk without a uterus. 9, 1
Estrogen monotherapy paradoxically shows a small reduction in invasive breast cancer risk (about 8 fewer cases per 10,000 person-years) compared to combined therapy 2
However, estrogen-alone still carries risks including stroke, DVT, gallbladder disease, and urinary incontinence 9
Available Estrogen Formulations
Multiple delivery systems exist:
Oral estrogen: Conjugated equine estrogen, estradiol tablets 1, 7
Transdermal estrogen: Patches, gels, sprays 7
Injectable estrogen: Less commonly used 7
Vaginal estrogen: Low-dose local therapy for genitourinary symptoms (does not require progestin co-administration due to minimal systemic absorption) 9
Critical Clinical Context
These therapies are FDA-approved for:
- Short-term treatment of menopausal vasomotor symptoms (hot flashes) 9, 1
- Treatment of vulvovaginal atrophy/genitourinary syndrome of menopause 9
- Prevention of osteoporosis 9, 1
These therapies are NOT recommended for:
- Primary prevention of chronic conditions (cardiovascular disease, dementia, fractures in asymptomatic women) - this carries a Grade D recommendation from USPSTF 9
Risk Profile Requiring Informed Decision-Making
Combined estrogen-progestin therapy increases risk of:
- Invasive breast cancer (RR 1.24-1.26) 9, 2, 1
- Stroke (33 vs 25 cases per 10,000 woman-years) 9
- Venous thromboembolism (DVT RR 1.95, PE RR 2.13) 9, 2
- Probable dementia in women ≥65 years (RR 2.05) 1, 10
- Gallbladder disease requiring surgery (2-4 fold increase) 9, 1
- Urinary incontinence 9
Combined estrogen-progestin therapy decreases risk of:
- Hip fractures (11 vs 16 cases per 10,000 woman-years) 9
- Colorectal cancer (10 vs 16 cases per 10,000 woman-years) 9
Prescribing Principles
Use the lowest effective dose for the shortest duration consistent with treatment goals, as mandated by FDA labeling. 1
The type of progestin matters: Evidence suggests natural progesterone and dydrogesterone may confer lower breast cancer risk than synthetic progestins structurally related to testosterone (RR 3.35 for testosterone-related progestins). 3, 6
Sequential regimens may carry lower breast cancer risk than continuous combined regimens according to observational data, though this requires monthly withdrawal bleeding. 6
Common Pitfall to Avoid
Never prescribe estrogen alone to a woman with an intact uterus - this is the most critical error, as unopposed estrogen increases endometrial cancer risk nearly 10-fold after prolonged use, with elevated risk persisting for at least 5 years after discontinuation. 2, 3