What is a recommended regimen for female hormone replacement therapy (HRT)?

Recommended Regimen for Female Hormone Replacement Therapy

For postmenopausal women under 60 or within 10 years of menopause onset with moderate to severe vasomotor symptoms, initiate transdermal 17β-estradiol 50 μg/day (applied twice weekly) combined with micronized progesterone 200 mg orally for 12-14 days every 28 days if the uterus is intact, or estradiol alone if hysterectomized. 1, 2

Patient Selection and Timing

• Initiate HRT at symptom onset during perimenopause or early menopause without waiting for complete cessation of menses 1, 2
• The most favorable risk-benefit profile exists for women ≤60 years old or within 10 years of menopause onset 1, 2
• For women with premature ovarian insufficiency from chemotherapy or radiation, initiate HRT immediately at diagnosis and continue until age 51 years, then reassess 1, 2

Estrogen Component Selection

Transdermal 17β-estradiol is the first-line choice because it:

• Bypasses hepatic first-pass metabolism, reducing cardiovascular and thromboembolic risks 3, 2
• Maintains physiological estradiol levels more effectively than oral formulations 3
• Has superior effects on bone mineral density compared to ethinylestradiol-based contraceptives 3
• Demonstrates better profiles for lipids, inflammation markers, and blood pressure 3

Dosing:

• Start with 50 μg/day transdermal patches, changed twice weekly 3, 2
• Alternative oral option: 1-2 mg oral 17β-estradiol daily 3
• For women who cannot use transdermal: 0.625 mg conjugated equine estrogens daily 3

Progestogen Component (Women with Intact Uterus)

Progestogen is mandatory in non-hysterectomized women to prevent endometrial hyperplasia and reduce endometrial cancer risk by approximately 90% 1, 2

First-line choice: Micronized progesterone (MP) 200 mg orally for 12-14 days every 28 days because:

• Minimizes cardiovascular risks compared to synthetic progestogens 3
• Has neutral or beneficial effects on blood pressure 3
• Shows the best safety profile for thrombotic risk 3
• Recommended by the European Society for Human Reproduction and Embryology 3

Alternative progestogens:

• Medroxyprogesterone acetate (MPA) 10 mg daily for 12-14 days per month (most data available for endometrial protection but less favorable cardiovascular profile) 3
• Dydrogesterone 10 mg daily for 12-14 days 3, 2
• Combined transdermal patches: estradiol 50 μg + levonorgestrel 10 μg daily 2

Continuous vs. Sequential Regimens:

• Sequential (cyclic) regimen: Progestogen for 12-14 days every 28 days—allows withdrawal bleeding and earlier pregnancy recognition 3
• Continuous regimen: Daily progestogen—prevents withdrawal bleeding, preferred by many women 3, 4

Estrogen-Only Therapy (Hysterectomized Women)

• No progestogen needed after hysterectomy unless residual intra-peritoneal endometriosis exists 3
• Use transdermal 17β-estradiol 50 μg/day or oral 17β-estradiol 1-2 mg daily 3
• Alternative: 0.625 mg conjugated equine estrogens daily 3, 5

Duration and Monitoring

• Use the lowest effective dose for the shortest duration consistent with treatment goals 1, 6, 5
• Reassess necessity every 3-6 months 5
• For women with natural menopause: Continue as long as symptoms persist, typically 4-5 years 7
• For women with premature ovarian insufficiency: Continue until age 51 years, then reassess 1

Absolute Contraindications

Do not prescribe HRT if any of the following exist:

• History of breast cancer or estrogen-dependent neoplasia 1, 6
• Active coronary heart disease or prior myocardial infarction 1, 6
• History of stroke 1, 6
• History of venous thromboembolism (DVT/PE) 1, 6
• Active liver disease 3, 1
• Antiphospholipid syndrome or positive antiphospholipid antibodies 1

Risk-Benefit Context

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

• Risks: 7 additional CHD events, 8 more strokes, 8 more pulmonary emboli, 8 more invasive breast cancers 1, 2, 6
• Benefits: 6 fewer colorectal cancers, 5 fewer hip fractures 1, 2

Critical distinction: Unopposed estrogen (in hysterectomized women) shows NO increase in breast cancer risk and may even reduce it slightly (RR 0.80), while the addition of synthetic progestins drives the increased breast cancer risk 1

Common Pitfalls to Avoid

• Do not initiate HRT in women >60 years or >10 years post-menopause for chronic disease prevention—this increases morbidity and mortality 1, 2
• Do not use oral estrogen when transdermal is available—oral formulations have higher cardiovascular and thrombotic risks 3, 2
• Do not prescribe estrogen without progestogen in women with an intact uterus—this dramatically increases endometrial cancer risk 1, 2, 5
• Do not continue HRT beyond symptom management needs—breast cancer risk increases with duration, particularly beyond 5 years 1, 6
• Do not assume family history of breast cancer is an absolute contraindication—only personal history or confirmed BRCA mutations with personal cancer history are absolute contraindications 1

Special Population: Premature Ovarian Insufficiency

For women with chemotherapy or radiation-induced POI:

• Higher doses may be needed than standard menopausal HRT 2
• Continue until at least age 45-55 years (average age of natural menopause) 2
• Use sequential regimens to allow withdrawal bleeding for earlier pregnancy recognition (spontaneous ovulation occurs in 20-25% of POI patients) 3
• Transdermal estradiol is particularly important for bone health in this population 3