For a woman in perimenopausal years, should hormone replacement therapy (HRT) start with a combination of estrogen and progesterone, or just testosterone?

Hormone Replacement Therapy for Perimenopausal Women

For a perimenopausal woman, start with combined estrogen and progesterone (if she has an intact uterus), not testosterone alone. Testosterone is not a first-line or standard treatment for perimenopausal symptoms and is not addressed in major guidelines for this indication. 1, 2

Critical Decision Point: Uterus Status

Women with an intact uterus MUST receive combined estrogen plus progestin therapy to prevent endometrial cancer—this reduces endometrial cancer risk by approximately 90%. 1 Unopposed estrogen in women with a uterus significantly increases endometrial cancer risk and is contraindicated. 2

Women who have had a hysterectomy can use estrogen-alone therapy safely, which actually shows no increased breast cancer risk and may even be protective (HR 0.80). 3, 1

Recommended Initial Regimen

For Women with Intact Uterus:

• Transdermal estradiol patch 50 μg daily (0.05 mg/day), changed twice weekly 1
• PLUS micronized progesterone 200 mg orally at bedtime 1

Transdermal estradiol is superior to oral formulations because it bypasses hepatic first-pass metabolism, reducing cardiovascular and thromboembolic risks while maintaining physiological estradiol levels. 1 Micronized progesterone is preferred over medroxyprogesterone acetate due to lower rates of venous thromboembolism and breast cancer risk. 1

For Women Post-Hysterectomy:

• Transdermal estradiol patch 50 μg daily alone 1
• No progestin needed 2

Why Not Testosterone?

Testosterone monotherapy is not recommended or supported by any major guideline for managing perimenopausal symptoms. 1 The evidence base focuses on estrogen-based therapy (with or without progestin) for vasomotor symptoms, genitourinary symptoms, and bone health. 3, 1

Timing Considerations for Perimenopause

HRT can be initiated during perimenopause when vasomotor symptoms begin—it does not need to be delayed until postmenopause. 1 The most favorable benefit-risk profile exists for women under 60 years of age or within 10 years of menopause onset. 1

Risk-Benefit Profile

For every 10,000 women taking combined estrogen-progestin for 1 year, expect: 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, 75% reduction in vasomotor symptom frequency

This risk-benefit calculation is most favorable in younger perimenopausal women (under 60 or within 10 years of menopause onset) who are symptomatic. 1

Absolute Contraindications to HRT

Do not initiate HRT if the patient has: 1

• History of breast cancer
• Coronary heart disease or prior MI
• Previous venous thromboembolic event or stroke
• Active liver disease
• Antiphospholipid syndrome or positive antiphospholipid antibodies
• Thrombophilic disorders

Duration and Monitoring

Use the lowest effective dose for the shortest duration necessary to control symptoms. 1, 2 Patients should be reevaluated periodically (every 3-6 months) to determine if treatment is still necessary. 2

Breast cancer risk increases with duration beyond 5 years, so HRT should not be continued beyond symptom management needs. 1

Common Pitfall to Avoid

Never initiate HRT solely for chronic disease prevention in asymptomatic women—the USPSTF gives this a Grade D recommendation (recommends against). 3, 1, 4 HRT is indicated for symptom management (hot flashes, night sweats, vaginal atrophy), not for preventing osteoporosis or cardiovascular disease in asymptomatic women. 1