How should I start hormone replacement therapy in a perimenopausal woman who is still menstruating and has an intact uterus?

Starting HRT in a Perimenopausal Woman Still Cycling

For a perimenopausal woman with an intact uterus who is still menstruating, initiate a sequential (cyclic) combined estrogen-progestin regimen using transdermal 17β-estradiol 50 μg twice weekly plus oral micronized progesterone 200 mg at bedtime for 12-14 consecutive days each month. 1

Regimen Selection for Cycling Perimenopausal Women

First-Line Estrogen Component

• Start with transdermal 17β-estradiol patches 50 μg applied twice weekly (every 3-4 days) continuously without interruption. 1, 2
• Transdermal delivery bypasses hepatic first-pass metabolism, reducing cardiovascular and thromboembolic risks compared to oral formulations—critical because stroke and venous thromboembolism risks emerge within 1-2 years of oral estrogen use. 1
• 17β-estradiol is explicitly preferred over conjugated equine estrogens or ethinylestradiol for all perimenopausal women. 3, 2

Mandatory Progestin Component (Intact Uterus)

• Add oral micronized progesterone 200 mg taken at bedtime for 12-14 consecutive days each 28-day cycle (sequential regimen). 1, 2, 4
• This sequential dosing induces predictable withdrawal bleeding, which is appropriate for women still cycling and expecting menstrual patterns. 2
• Micronized progesterone is the preferred progestin because it provides adequate endometrial protection (reducing cancer risk by ~90% versus unopposed estrogen) while offering superior breast safety and lower cardiovascular risk compared to synthetic progestins like medroxyprogesterone acetate. 1, 2, 4
• The 12-14 day duration is critical—shorter durations provide inadequate endometrial protection. 2

Alternative Progestin Options (If Micronized Progesterone Not Tolerated)

• Medroxyprogesterone acetate 10 mg daily for 12-14 days per month (sequential). 1, 2
• Dydrogesterone 10 mg daily for 12-14 days per month. 1, 2
• Norethisterone 5 mg daily for 12-14 days per month. 3, 2

Timing and Initiation

When to Start

• Initiate HRT at the onset of bothersome vasomotor symptoms (hot flashes, night sweats) or genitourinary symptoms during perimenopause—do not delay until postmenopause. 1
• The most favorable benefit-risk profile exists for women under 60 years or within 10 years of menopause onset. 1
• HRT should be prescribed for symptom management, not for chronic disease prevention (osteoporosis, cardiovascular disease). 1

Pre-Treatment Assessment

Before prescribing, verify absence of absolute contraindications:

• History of breast cancer or estrogen-dependent neoplasia. 3, 1
• Active or prior venous thromboembolism or pulmonary embolism. 3, 1
• History of stroke or coronary heart disease. 3, 1
• Active liver disease. 3, 1
• Antiphospholipid syndrome or positive antiphospholipid antibodies. 3, 1
• Unexplained vaginal bleeding (requires investigation before HRT). 1
• Obtain baseline blood pressure (hypertension amplifies stroke risk with oral estrogen, though transdermal is safer). 3, 1

Expected Outcomes and Risk-Benefit Profile

Benefits

• 75% reduction in vasomotor symptom frequency (hot flashes, night sweats). 1
• 22-27% reduction in all clinical fractures through prevention of accelerated bone loss. 1
• Improvement in genitourinary symptoms (vaginal dryness, dyspareunia). 3, 1

Risks (Per 10,000 Women-Years on Combined Estrogen-Progestin)

• 8 additional invasive breast cancers (risk emerges after 4-5 years of continuous use). 1
• 8 additional strokes (with oral estrogen; transdermal does not increase stroke risk). 1
• 8 additional venous thromboembolic events (with oral estrogen; transdermal has lower risk). 1
• 7 additional coronary heart disease events. 1
• Balanced against: 6 fewer colorectal cancers and 5 fewer hip fractures. 1

Monitoring and Duration

Ongoing Management

• Annual clinical review focusing on symptom control, medication adherence, bleeding patterns, and reassessment of risks versus benefits. 3, 1, 2
• No routine laboratory monitoring (estradiol, FSH levels) is required—management is symptom-based. 1
• Monitor for abnormal vaginal bleeding, which may signal endometrial hyperplasia despite progestin protection. 1, 4

Duration Principles

• Use the lowest effective dose for the shortest duration necessary to control symptoms. 3, 1
• Attempt dose reduction or discontinuation once symptoms are stable, typically after 1-2 years. 1
• At age 65, reassess necessity and strongly consider discontinuation—initiating HRT after 65 is explicitly contraindicated. 1

Common Pitfalls to Avoid

• Never prescribe estrogen-alone therapy to women with an intact uterus—this increases endometrial cancer risk 10- to 30-fold after 5+ years. 1, 4
• Do not use progestin for fewer than 12 days per cycle in sequential regimens—inadequate endometrial protection. 2
• Avoid initiating HRT solely for osteoporosis or cardiovascular disease prevention in asymptomatic women—this carries a USPSTF Grade D recommendation (recommends against). 1
• Do not start with oral estrogen if transdermal is available—oral formulations carry significantly higher stroke and VTE risks. 1
• Avoid continuous combined regimens (daily progestin) in cycling perimenopausal women—sequential regimens with predictable withdrawal bleeding are more appropriate for this population. 2

Special Considerations for Perimenopausal Women

• If contraception is also needed, consider switching to combined oral contraceptives containing 17β-estradiol (with nomegestrol acetate or dienogest) as first choice instead of traditional HRT. 3, 2
• For persistent genitourinary symptoms despite adequate systemic HRT, add low-dose vaginal estrogen preparations (rings, suppositories, creams) without increasing systemic dose or requiring additional progestin. 3, 1
• If the patient is a smoker over age 35, smoking cessation is the single most important intervention before considering HRT, as smoking significantly amplifies cardiovascular and thrombotic risks. 1