What is a suitable hormone replacement therapy (HRT) regimen for a menopausal woman?

Hormone Replacement Therapy Regimen for Menopausal Women

For a menopausal woman with an intact uterus, use transdermal estradiol 50 μg daily (changed twice weekly) combined with micronized progesterone 200 mg orally at bedtime; for women who have had a hysterectomy, use transdermal estradiol alone at the lowest effective dose. 1, 2

Determining the Appropriate Regimen

Step 1: Assess Uterine Status

Women WITH an intact uterus:

• Must receive combined estrogen-progestin therapy to prevent endometrial hyperplasia and cancer 2, 3, 4
• Unopposed estrogen increases endometrial hyperplasia risk dramatically (OR 15.0 at 36 months, with 62% developing some form of hyperplasia) 4
• The addition of progestogen reduces endometrial cancer risk by approximately 90% 1

Women WITHOUT a uterus (post-hysterectomy):

• Can use estrogen-alone therapy safely 5, 2
• No progestin needed, which actually reduces some risks (estrogen-alone shows RR 0.80 for breast cancer vs. combined therapy) 1

Step 2: Choose Estrogen Formulation and Route

Transdermal estradiol is superior to oral formulations and should be first-line: 1

• Avoids hepatic first-pass metabolism, reducing cardiovascular and thromboembolic risks 1
• Lower rates of venous thromboembolism and stroke compared to oral preparations 1
• More physiological estradiol levels 1

Specific dosing:

• Start with patches releasing 50 μg estradiol daily (0.05 mg/day), applied twice weekly 1
• Alternatively, oral conjugated equine estrogen 0.625 mg daily if transdermal not tolerated 5, 2

Step 3: Add Progestin (If Uterus Present)

First-line progestin choice: Micronized progesterone 200 mg orally at bedtime 1

• Preferred over synthetic progestins due to more favorable cardiovascular and thrombotic risk profile 6
• Lower rates of venous thromboembolism and breast cancer compared to medroxyprogesterone acetate 1

Alternative progestin options if micronized progesterone not tolerated:

• Medroxyprogesterone acetate 2.5 mg daily (continuous) or 10 mg daily for 12-14 days monthly (sequential) 5, 1
• Dydrogesterone 10 mg daily for 12-14 days every 28 days 6, 1
• Combined estradiol/levonorgestrel patches (50 μg estradiol + 10 μg levonorgestrel daily) 1

Step 4: Choose Continuous vs. Sequential Regimen

Continuous combined therapy (estrogen + progestin daily):

• More protective against endometrial hyperplasia at longer durations 4
• More irregular bleeding in first year, but less bleeding after year 2 4
• Preferred for women >1 year postmenopausal 1

Sequential therapy (estrogen daily + progestin 12-14 days/month):

• Less irregular bleeding in first year 4
• Monthly withdrawal bleeding expected 1
• Avoid long-cycle sequential (progestin every 3 months) due to higher hyperplasia risk 4

Critical Timing and Duration Considerations

Age and timing matter significantly for risk-benefit profile:

• Most favorable benefit-risk ratio: women <60 years or within 10 years of menopause onset 1
• Women >60 years or >10 years past menopause have excess stroke risk with oral estrogen 1
• Do not initiate HRT after age 65 for chronic disease prevention - this increases morbidity and mortality 1

Duration principles:

• Use lowest effective dose for shortest duration necessary 5, 6, 2
• Reassess necessity every 3-6 months 2
• Breast cancer risk increases significantly beyond 5 years of use (RR 1.23-1.35) 1

Absolute Contraindications to HRT

Do not prescribe HRT if any of the following are present: 1

• Personal history of breast cancer
• Active liver disease
• History of venous thromboembolism or stroke
• Coronary heart disease or myocardial infarction
• Antiphospholipid syndrome or positive antiphospholipid antibodies
• Known estrogen-dependent neoplasia
• Thrombophilic disorders

Risk-Benefit Profile

Per 10,000 women taking combined estrogen-progestin for 1 year: 1

• Harms: 7 additional CHD events, 8 more strokes, 8 more pulmonary emboli, 8 more invasive breast cancers
• Benefits: 6 fewer colorectal cancers, 5 fewer hip fractures

The progestin component drives breast cancer risk, not estrogen alone - combined therapy shows HR 1.26 for breast cancer, while estrogen-alone shows RR 0.80 (protective effect) 1

Common Pitfalls to Avoid

• Never initiate HRT solely for chronic disease prevention (osteoporosis, cardiovascular disease) - the USPSTF gives this a Grade D recommendation (harms exceed benefits) 5
• Never use unopposed estrogen in women with an intact uterus - this dramatically increases endometrial cancer risk 2, 3, 4
• Never use custom compounded bioidentical hormones or pellets - lack safety and efficacy data 1
• Never continue HRT beyond symptom management needs - breast cancer risk increases with duration 1
• Never assume higher doses are better - risks increase with dose, use lowest effective dose 1, 7

Special Populations

Premature menopause (surgical menopause before age 45):

• HRT should be initiated immediately and continued until at least age 51 (average menopause age) 1
• 32% increased stroke risk if not treated 1
• Transdermal estradiol preferred (no clear stroke risk unlike oral) 1

Family history of breast cancer (without personal history or BRCA mutation):

• NOT an absolute contraindication 1
• Can use HRT until age 51, then reassess 1
• Consider BRCA testing given family history 1