What is the recommended dosage and treatment protocol for progesterone pellets in a peri- or post-menopausal woman considering hormone replacement therapy (HRT)?

Progesterone Pellets Are Not Recommended for Hormone Replacement Therapy

Custom compounded bioidentical hormones, including progesterone pellets, are not recommended due to lack of data supporting their safety and efficacy, and the FDA has not approved any type or class of bioidentical hormone therapy including pellet formulations. 1, 2

Why Pellets Should Be Avoided

• The USPSTF identified no randomized trials studying the potential benefits or harms of bioidentical hormones (including pellets) for menopausal women 2
• Custom compounded bioidentical hormones lack the robust safety and efficacy data available for FDA-approved formulations 2
• Pellet formulations provide no ability to titrate dosing or discontinue therapy rapidly if adverse effects occur, unlike oral or transdermal preparations 1

Recommended Alternative: FDA-Approved Progesterone Formulations

For women with an intact uterus requiring progesterone for endometrial protection, oral micronized progesterone 200 mg daily at bedtime for 12-14 days per 28-day cycle is the first-line recommendation when combined with estrogen therapy. 1, 3, 4

Specific Dosing Protocol

• Oral micronized progesterone 200 mg at bedtime for 12-14 days sequentially per 28-day cycle provides proven endometrial protection with the most favorable cardiovascular and metabolic safety profile 1, 3, 4, 5
• This regimen reduces endometrial cancer risk by approximately 90% compared to unopposed estrogen 1, 4
• The 12-14 day duration is critical—shorter durations provide inadequate endometrial protection 3

Estrogen Component to Pair with Progesterone

• Transdermal 17β-estradiol 50-100 μg daily via patch (changed twice weekly) is the preferred estrogen formulation due to lower cardiovascular and thrombotic risk compared to oral preparations 1, 3
• Oral 17β-estradiol 1-2 mg daily is an acceptable alternative if transdermal is not tolerated 3

Alternative Progesterone Regimens

For Continuous Combined Therapy (Avoiding Withdrawal Bleeding)

• Oral micronized progesterone 100 mg daily continuously (without interruption) when combined with continuous estradiol 1, 3
• This regimen avoids withdrawal bleeding but requires daily administration 3

Alternative Progestins (Second-Line Options)

• Dydrogesterone 10 mg daily for 12-14 days per month (sequential regimen) or 5 mg daily continuously 3
• Medroxyprogesterone acetate 10 mg daily for 12-14 days per month (sequential regimen) or 2.5 mg daily continuously 3, 4
• Micronized progesterone remains preferred over synthetic progestins due to lower rates of venous thromboembolism and breast cancer risk 1, 6

Vaginal Administration (Off-Label)

• Vaginal micronized progesterone 100 mg every other day or 4% gel (45 mg/day) for at least 10 days per month may provide endometrial protection for up to 3-5 years 3, 5
• This route achieves good endometrial protection with minimal systemic absorption 3

Clinical Evidence Supporting Micronized Progesterone

• The E3N Study showed that transdermal estrogen combined with progesterone did not lead to an increase in breast cancer rates (RR: 1.08), unlike synthetic progestins 6
• Progesterone does not negatively impact HDL/LDL cholesterol ratio, carbohydrate metabolism, hemostasis, blood pressure, or body weight due to its anti-mineralocorticoid effect 6
• In a 3-month RCT, progesterone 300 mg at bedtime caused a 55% reduction in vasomotor symptoms with no withdrawal-related rebound 7
• Multiple RCTs confirm that progesterone 300 mg daily at bedtime does not cause depression and improves deep sleep 7

Duration and Monitoring

• Use the lowest effective dose for the shortest duration consistent with treatment goals 1, 4
• Annual clinical review focusing on compliance, bleeding patterns, and symptom control is required 1, 3
• No routine laboratory monitoring is needed unless specific symptoms arise 1, 3
• Breast cancer risk with combined estrogen-progestin therapy does not appear until after 4-5 years of use, but cardiovascular risks (stroke, VTE) emerge within the first 1-2 years 1

Critical Contraindications to All Progesterone Therapy

• Personal history of breast cancer or other hormone-sensitive malignancies 1, 3, 4
• Active or history of venous thromboembolism or pulmonary embolism 1, 4
• Active or history of stroke or coronary heart disease 1, 4
• Active liver disease 1, 4
• Antiphospholipid syndrome or positive antiphospholipid antibodies 1
• Pregnancy or suspected pregnancy 4
• Peanut allergy (for oral micronized progesterone capsules containing peanut oil) 4

Common Pitfalls to Avoid

• Never prescribe progesterone pellets or other compounded bioidentical formulations—they lack safety data and FDA approval 1, 2
• Never use progesterone for fewer than 12 days per cycle in sequential regimens—this provides inadequate endometrial protection 3
• Never prescribe estrogen alone to women with an intact uterus—this dramatically increases endometrial cancer risk (10- to 30-fold if continued for 5 years or more) 1
• Never initiate hormone therapy solely for chronic disease prevention in asymptomatic women—this increases morbidity and mortality 1