What are the rates of amenorrhea in women treated with novel oral, continuous hormonal therapy of body identical 17β-estradiol (estrogen) and micronized progesterone (progestin)?

Amenorrhea Rates with Continuous Oral 17β-Estradiol and Micronized Progesterone

Continuous combined oral therapy with 17β-estradiol (1-2 mg daily) and micronized progesterone (100-200 mg daily) achieves amenorrhea rates of 91-93% by 6 months of treatment, with over 80% of women experiencing no bleeding episodes.

Evidence from Clinical Trials

The most robust data comes from a multicenter study specifically evaluating continuous combined regimens:

• Amenorrhea rates reached 93.3% at 3 months and 91.6% at 6 months when using percutaneous 17β-estradiol (1.5 mg/day) combined with oral micronized progesterone (100 mg/day) given continuously for 21-25 days per cycle 1

• More than 80% of women experienced no bleeding at all during the treatment period with this continuous low-dose progesterone regimen 1

• The 100 mg daily dose of micronized progesterone given for 25 days per cycle efficiently protected the endometrium by fully inhibiting mitoses, with no hyperplasia detected in any patient 1

FDA-Approved Combination Product Data

More recent evidence from the REPLENISH trial (which led to FDA approval of Bijuva) demonstrates:

• High rates of amenorrhea that improved over time with the bioidentical 17β-estradiol/progesterone combination capsule taken continuously 2

• The 1 mg/100 mg dose (FDA-approved formulation) showed the most favorable bleeding profile among the tested doses 2

• All doses met the primary endpoint of endometrial safety while maintaining high amenorrhea rates 2

Comparison with Sequential Regimens

Sequential regimens (where progesterone is given only 12-14 days per month) show markedly different bleeding patterns:

• Sequential micronized progesterone (200 mg/day for days 14-25) resulted in only 7.8% amenorrhea over 937 evaluated cycles, with 73.6% experiencing regular withdrawal bleeding 3

• Micronized progesterone in sequential regimens induced more irregular bleeding episodes compared to synthetic progestogens like dydrogesterone or nomegestrol acetate 3

Clinical Implications and Dosing Strategy

For women seeking to avoid withdrawal bleeding, continuous combined regimens are superior:

• Start with 17β-estradiol 1-2 mg orally daily plus micronized progesterone 100 mg daily continuously (not cyclically) 4

• If using transdermal estradiol patches (50-100 μg/day), combine with oral micronized progesterone 100-200 mg daily continuously for optimal amenorrhea rates 5, 6

• Continuous dosing (every day without breaks) is the key to achieving amenorrhea, as opposed to sequential regimens that intentionally induce withdrawal bleeding 4

Important Caveats

• Breakthrough bleeding may occur during the first 3-6 months as the endometrium adjusts to continuous hormone exposure; amenorrhea rates improve with continued treatment 1, 2

• Baseline endometrial ultrasound is recommended before initiating therapy to document endometrial thickness 5

• If breakthrough bleeding persists beyond 6 months, endometrial assessment is warranted rather than automatic dose adjustment 7

• The 100 mg daily continuous dose provides full endometrial protection long-term, whereas sequential regimens may have insufficient protection 5

Alternative Formulations

For women who cannot tolerate oral therapy:

• Combined transdermal patches with 17β-estradiol and levonorgestrel administered continuously (without interruptions) also achieve high amenorrhea rates 4

• Example: patches releasing 50 μg of 17β-estradiol and 7 μg of levonorgestrel daily applied continuously 4