Is 100 mg of micronized progesterone (progesterone) sufficient for hormone replacement therapy in postmenopausal women with an intact uterus?

Can 100 mg Progesterone Be Used for Endometrial Protection in Postmenopausal HRT?

Yes, 100 mg of micronized progesterone daily for 12-14 days per month provides adequate endometrial protection in postmenopausal women with an intact uterus receiving estrogen therapy, though 200 mg is the FDA-approved dose and may be preferred for optimal protection. 1

FDA-Approved Dosing

• The FDA label for progesterone capsules specifies 200 mg daily for 12 days per 28-day cycle in combination with conjugated estrogens 0.625 mg/day as the approved regimen for endometrial protection 1
• This dosing demonstrated only 6% incidence of hyperplasia over 36 months compared to 64% with estrogen alone in a randomized trial of 358 postmenopausal women 1
• The FDA study showed that discontinuation rates due to hyperplasia with the 200 mg dose were similar to placebo and significantly lower than estrogen alone 1

Evidence Supporting Lower 100 mg Dose

• A multicenter European study of 101 postmenopausal women demonstrated that 100 mg daily for 25 days per month efficiently protects the endometrium by fully inhibiting mitoses, with no hyperplasia found on biopsy after 6 months 2
• This lower dose induced amenorrhea in 91.6% of women at 6 months and was associated with better compliance to long-term therapy 2
• The 100 mg dose produced endometrial biopsies showing 61% quiescent without mitosis, 23% mildly active with rare mitoses, and 8% partial secretory endometrium—all protective patterns 2

Current Guideline Recommendations

• Micronized progesterone at 100-200 mg daily for 12-14 days every 28 days is recommended as first choice due to its physiological and safe profile, particularly in young women with premature ovarian insufficiency 3
• The American College of Physicians cites evidence that medroxyprogesterone acetate 2.5 mg/day (continuous combined) provides adequate protection with only 6% hyperplasia incidence 4
• The protective effect of progestogens is dose and duration dependent, requiring at least 10-14 days per month 5

Dosing Algorithm for Clinical Practice

For sequential (cyclical) regimens:

• Standard dose: 200 mg daily for 12-14 days per month (FDA-approved) 1
• Alternative dose: 100 mg daily for 25 days per month (European evidence, higher monthly exposure) 2
• Both regimens provide endometrial protection but differ in bleeding patterns and compliance 2, 6

For continuous combined regimens:

• Lower daily doses may be considered but are less well-studied for micronized progesterone specifically 4

Key Clinical Considerations

• The 100 mg dose for 25 days monthly provides more total monthly progesterone exposure (2,500 mg) than 200 mg for 12 days (2,400 mg), which may explain its efficacy 2
• Micronized progesterone has superior safety profiles compared to synthetic progestins regarding cardiovascular and thrombotic risks 3, 7
• The main side effect is mild transient drowsiness, minimized by bedtime dosing 6, 8
• Continuous combined regimens generally confer better endometrial protection than sequential regimens across all progestogen types 7

Common Pitfalls to Avoid

• Do not use progesterone doses below 100 mg daily or for fewer than 10 days per month, as protection may be inadequate 5, 6
• Avoid assuming all progestogens are equivalent—micronized progesterone has distinct metabolic advantages over synthetic progestins like medroxyprogesterone acetate 7, 9
• Do not prescribe progestogen to women who have had a hysterectomy unless residual endometriosis is present 5
• For women with peanut allergies, use vaginal progesterone gel instead of oral capsules containing peanut oil 5

Monitoring Requirements

• Annual clinical review once established on therapy, with attention to compliance 5, 10
• Endometrial assessment may be warranted if breakthrough bleeding occurs or if there are concerns about adequacy of protection 3