Sequential Hormone Replacement Therapy Administration

Introduction to Sequential HRT

The American College of Obstetricians and Gynecologists recommends 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, 3

The Endocrine Society recommends transdermal 17β-estradiol as 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 2, 3
Apply patches releasing 50-100 μg daily, changed twice weekly or weekly depending on the specific brand 2, 3
Alternatively, vaginal gel can be used at doses of 0.5-1 mg daily if patches are not tolerated 2
Administer estrogen continuously without interruption (not cyclically) 2, 3
If oral estrogen is necessary, use micronized estradiol 1-2 mg daily, though this is second-line 1

Add progestogen for 12-14 days every 28 days (never less than 12 days) to ensure adequate endometrial protection 1, 2, 4
The North American Menopause Society recommends micronized progesterone 200 mg daily as the preferred progestogen due to minimal cardiovascular risk, lowest thrombotic risk profile, and neutral effects on blood pressure 2, 4, 3
Administer orally or vaginally during days 15-28 (or 15-26) of each 28-day cycle 1, 2
If micronized progesterone is unavailable or not tolerated, medroxyprogesterone acetate 10 mg daily for 12-14 days is an acceptable alternative 1, 3

Withdrawal bleeding typically occurs during or shortly after the progestogen phase (days 15-28) 2, 3
If breakthrough bleeding occurs outside the expected withdrawal period, increase the progestogen dose to 200 mg daily or extend duration to 14 days 4

Conduct clinical review annually once established on therapy, focusing on compliance 1
Reassess at 3 months to evaluate bleeding pattern and symptom control 4
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

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 2

Women with cardiovascular risk factors should preferentially receive micronized progesterone rather than synthetic progestogens like medroxyprogesterone acetate 3
Continue HRT until the average age of natural menopause (45-55 years) in women with premature ovarian insufficiency 3

The American College of Obstetricians and Gynecologists recommends avoiding progestogens with anti-androgenic effects in women with low libido or sexual dysfunction, and instead consider alternative options such as micronized progesterone, which has a more favorable safety profile 5
The use of dydrogesterone 10 mg daily for 12-14 days monthly is considered a third choice for progestogen therapy, offering endometrial protection with a relatively favorable side effect profile, according to the Blood Reviews journal 5