What is the minimal effective dose of progesterone (progestin) needed to protect the uterus in women on estrogen (estrogen therapy) for menopausal symptoms?

Minimal Progesterone Dose for Endometrial Protection

Direct Answer

For women with an intact uterus on estrogen therapy, the minimal effective dose is medroxyprogesterone acetate 2.5 mg orally daily (continuous combined regimen) or 10 mg orally daily for 10-14 days per month (sequential regimen), as established by FDA-approved formulations and clinical trial data. 1

FDA-Approved Dosing Regimens

The FDA label for progesterone provides two validated approaches for endometrial protection:

• Continuous combined therapy: Medroxyprogesterone acetate 2.5 mg orally every day minimizes side effects while maintaining endometrial protection 2, 1
• Sequential therapy: Medroxyprogesterone acetate 10 mg orally daily for 10-14 days each month 2

For micronized progesterone specifically, the FDA-approved dose is:

• 200 mg orally at bedtime for 12 continuous days per 28-day cycle when combined with conjugated estrogens 0.625 mg/day 1

Clinical Trial Evidence Supporting Minimal Doses

The Women's Health Initiative established that oral conjugated equine estrogen 0.625 mg/day combined with medroxyprogesterone acetate 2.5 mg/day (continuous) provided adequate endometrial protection, with only 6% incidence of hyperplasia over 36 months compared to 64% with estrogen alone 3, 1

For micronized progesterone:

• Oral micronized progesterone 200 mg/day for 12-14 days per month provides endometrial protection for up to 5 years of use 4
• Vaginal micronized progesterone 100 mg every other day or 4% gel (45 mg/day) for at least 10 days per month may provide protection for 3-5 years, though this is off-label use 4

Route-Specific Considerations

• Oral formulations are the most extensively studied and FDA-approved for endometrial protection 5
• Transdermal micronized progesterone does not provide adequate endometrial protection and should not be used for this purpose 4
• Vaginal progesterone at 100 mg every other day or 4% gel may work but represents off-label use with less robust evidence 4

Bioidentical Hormone Considerations

The FDA-approved bioidentical combination (Bijuva) contains:

• 17β-estradiol 1 mg combined with progesterone 100 mg daily in a single capsule, which demonstrated endometrial safety in the REPLENISH trial 6

Lower doses (0.5 mg/100 mg, 0.5 mg/50 mg, 0.25 mg/50 mg) also met endometrial safety endpoints, though the 1 mg/100 mg dose received FDA approval 6

Critical Pitfalls to Avoid

• Never use estrogen alone in women with an intact uterus - this increases endometrial hyperplasia risk from 3% to 64% over 3 years 1
• Do not assume transdermal progesterone provides endometrial protection - it does not, regardless of dose 4
• Avoid compounded bioidentical hormones - the FDA has not approved these products, and their safety/effectiveness for endometrial protection has not been established through proper drug approval processes 3
• Do not reduce progestogen dose below established minimums - inadequate dosing or duration increases endometrial cancer risk 7, 4

Duration and Monitoring Requirements

• Sequential regimens require at least 10-14 days of progestogen exposure per month - shorter durations do not provide adequate protection 2, 4
• Continuous combined therapy requires daily administration without breaks to maintain endometrial suppression 2, 1
• Any unusual vaginal bleeding warrants immediate evaluation regardless of the regimen used 1