Hormone Replacement Therapy for Perimenopausal Symptoms
Primary Recommendation: Transdermal Estradiol Plus Micronized Progesterone
For a generally healthy perimenopausal woman with an intact uterus, start with transdermal 17β-estradiol 50 μg patches (applied twice weekly) combined with oral micronized progesterone 200 mg at bedtime for 12-14 days per month. 1, 2
This regimen provides the most favorable cardiovascular and thrombotic risk profile while ensuring adequate endometrial protection. 1, 2
Estrogen Component: Why Transdermal 17β-Estradiol is Preferred
Transdermal 17β-estradiol is explicitly preferred over oral conjugated equine estrogens or ethinylestradiol because it bypasses hepatic first-pass metabolism, reducing cardiovascular and thromboembolic risks. 3, 1, 2
Start with 50 μg patches applied twice weekly (or weekly depending on brand), which represents the lowest effective dose for most women. 1, 2
If symptoms persist after 4-8 weeks, titrate upward to 100 μg patches based on symptom control, not laboratory values. 2
Transdermal delivery demonstrates superior bone mass accrual and avoids adverse hepatic effects on coagulation factors. 2
Progestogen Component: Endometrial Protection is Mandatory
Women with an intact uterus must receive progestogen to prevent endometrial cancer—unopposed estrogen increases endometrial cancer risk 10- to 30-fold after 5 years of use. 1, 2
First-Line Progestogen: Micronized Progesterone
Oral micronized progesterone 200 mg at bedtime for 12-14 days per 28-day cycle is the preferred progestogen due to superior cardiovascular and breast safety compared to synthetic progestins. 1, 2, 4
The 12-14 day duration is critical—shorter durations provide inadequate endometrial protection. 1
This sequential regimen induces predictable withdrawal bleeding, which is acceptable for most perimenopausal women. 1
Warning: This product contains peanut oil and should not be used if allergic to peanuts. 5
Some women experience extreme dizziness, drowsiness, blurred vision, or difficulty walking after taking progesterone—take at bedtime with water while standing. 5
Alternative Progestogen Options (If Micronized Progesterone Unavailable or Not Tolerated)
Medroxyprogesterone acetate (MPA) 10 mg daily for 12-14 days per month is a widely available alternative with extensive safety data, though it has less favorable metabolic effects on lipid profiles. 1, 6
Dydrogesterone 10 mg daily for 12-14 days per month is another option with enhanced oral bioavailability. 1, 6
Norethisterone acetate 1 mg daily continuously offers superior cardiovascular and metabolic profiles compared to MPA while maintaining endometrial protection. 1, 6
Levonorgestrel intrauterine system (52 mg) provides local endometrial protection with minimal systemic absorption, particularly useful for women experiencing systemic progestogen side effects. 2, 6
Continuous Combined Regimen (Alternative to Sequential)
Micronized progesterone 100 mg daily continuously (without interruption) can be used for women who prefer amenorrhea over withdrawal bleeding. 1, 2
This regimen avoids predictable bleeding but may cause irregular spotting initially. 1
Dosing Summary Table
| Component | First-Line Regimen | Frequency |
|---|---|---|
| Estrogen | Transdermal 17β-estradiol 50 μg patch | Twice weekly |
| Progestogen | Oral micronized progesterone 200 mg | Nightly for 12-14 days/month |
Duration and Monitoring
Use the lowest effective dose for the shortest duration necessary to control symptoms—HRT is indicated for symptom management, not chronic disease prevention. 1, 2, 7
Annual clinical review focusing on compliance, bleeding patterns, symptom control, and reassessment of risks versus benefits. 3, 1, 2
No routine laboratory monitoring (FSH, estradiol levels) is required unless specific symptoms arise. 3, 2
Attempt dose reduction or discontinuation once symptoms are controlled, typically after 1-2 years. 2
Absolute Contraindications to HRT
- Personal history of breast cancer or other hormone-sensitive malignancies 3, 2
- Active or history of venous thromboembolism or pulmonary embolism 3, 2
- Active or history of stroke 3, 2
- Active or history of coronary heart disease or myocardial infarction 3, 2
- Active liver disease 3, 2
- Antiphospholipid syndrome or positive antiphospholipid antibodies 3, 2
- Unexplained vaginal bleeding 5
- Known or suspected pregnancy 5
- Allergy to peanuts (for micronized progesterone) 5
Risk-Benefit Profile: What to Counsel Patients
For every 10,000 women taking combined estrogen-progestin for 1 year: 1, 2, 7
Risks:
- 8 additional invasive breast cancers
- 8 additional strokes
- 8 additional pulmonary emboli
- 7 additional coronary heart disease events
Benefits:
- 75% reduction in vasomotor symptom frequency
- 6 fewer colorectal cancers
- 5 fewer hip fractures
These risks are most relevant for women over 60 or more than 10 years past menopause—the risk-benefit profile is most favorable for women under 60 or within 10 years of menopause onset. 1, 2
Critical Pitfalls to Avoid
Never prescribe estrogen alone to women with an intact uterus—this dramatically increases endometrial cancer risk (RR 2.3-9.5). 1, 2
Never use progestogen for fewer than 12 days per cycle in sequential regimens—this provides inadequate endometrial protection. 1, 4
Never initiate HRT solely for chronic disease prevention (osteoporosis, cardiovascular disease) in asymptomatic women—this carries a USPSTF Grade D recommendation (recommends against). 2, 7
Never delay HRT initiation in perimenopausal women with severe symptoms—the window of opportunity for favorable risk-benefit is time-sensitive. 2
Do not assume all progestogens are equivalent—micronized progesterone has superior cardiovascular and breast safety compared to synthetic progestins. 1, 6, 8
When to Consider Alternative Regimens
For women requiring contraception: Consider 17β-estradiol-based combined oral contraceptives with nomegestrol acetate or dienogest instead of traditional HRT. 1
For women with persistent genitourinary symptoms despite systemic HRT: Add low-dose vaginal estrogen (rings, suppositories, creams) without increasing systemic dose. 2
For women with hypertension: Transdermal estradiol is the preferred delivery method. 3
For women with migraine: Consider changing dose, route, or regimen if migraine worsens during HRT. 3
Special Considerations for Perimenopausal Women
Perimenopausal women can initiate HRT at symptom onset—do not delay until postmenopause. 2
The most favorable benefit-risk profile exists for women under 60 years of age or within 10 years of menopause onset. 2
For women with premature ovarian insufficiency (before age 40), HRT should continue at least until the average age of natural menopause (51 years), then reassess. 3, 1
HRT in women with POI has not been found to increase breast cancer risk before the age of natural menopause. 3