How to Take Sequential HRT
Sequential HRT should be administered as transdermal 17β-estradiol 50-100 μg daily continuously, combined with oral micronized progesterone 200 mg daily (or medroxyprogesterone acetate 10 mg daily) for 12-14 days every 28 days. 1, 2
Estrogen Component
Transdermal 17β-estradiol is the preferred first-line route over oral formulations due to avoidance of first-pass hepatic metabolism, superior cardiovascular risk profile, better bone mass accrual, and lower venous thromboembolism risk 1, 2
Apply patches releasing 50-100 μg daily, changed twice weekly or weekly depending on the specific brand 1, 2
Alternatively, vaginal gel can be used at doses of 0.5-1 mg daily if patches are not tolerated 1
Administer estrogen continuously without interruption (not cyclically) 1, 2
If oral estrogen is necessary, use micronized estradiol 1-2 mg daily, though this is second-line 1, 3
Progestogen Component
Add progestogen for 12-14 days every 28 days (never less than 12 days) to ensure adequate endometrial protection 1, 4
Micronized progesterone 200 mg daily is the preferred progestogen due to minimal cardiovascular risk, lowest thrombotic risk profile, and neutral effects on blood pressure 1, 4, 2
Administer orally or vaginally during days 15-28 (or 15-26) of each 28-day cycle 1
If micronized progesterone is unavailable or not tolerated, medroxyprogesterone acetate 10 mg daily for 12-14 days is an acceptable alternative 1, 2
Dydrogesterone 5-10 mg daily for 12-14 days is another option with favorable metabolic effects 1
Expected Bleeding Pattern
Withdrawal bleeding typically occurs during or shortly after the progestogen phase (days 15-28) 1, 2
This mimics a menstrual cycle pattern with predictable monthly bleeding 5, 6
If breakthrough bleeding occurs outside the expected withdrawal period, increase the progestogen dose to 200 mg daily or extend duration to 14 days 4
Monitoring and Adjustments
Conduct clinical review annually once established on therapy, focusing on compliance 1
Reassess at 3 months to evaluate bleeding pattern and symptom control 4, 3
No routine monitoring tests are required unless prompted by specific symptoms or concerns 1
If breakthrough bleeding persists beyond 3 months despite optimized sequential regimen, consider switching to continuous combined therapy (estrogen plus progestogen daily without interruption) 4
Special Populations
For adolescents with premature ovarian insufficiency:
- Begin cyclic progestogen only after at least 2 years of estrogen therapy or when breakthrough bleeding occurs 1
- Start with lower estrogen doses (transdermal 6.25-25 μg daily) and gradually increase over 2-3 years to adult doses 1
For women requiring contraception:
- Consider 17β-estradiol-based combined oral contraceptives (with nomegestrol acetate or dienogest) as first choice instead of traditional sequential HRT 1
Critical Cautions
Sequential regimens with only 10 days of progestogen carry a 5.3% risk of complex endometrial hyperplasia and 0.7% risk of atypical hyperplasia—this is why 12-14 days minimum is mandatory 5
Women with cardiovascular risk factors should preferentially receive micronized progesterone rather than synthetic progestogens like medroxyprogesterone acetate 2
Any undiagnosed persistent or recurring abnormal vaginal bleeding requires endometrial sampling to rule out malignancy before continuing HRT 3
Continue HRT until the average age of natural menopause (45-55 years) in women with premature ovarian insufficiency 2