What is a suitable second choice for progestogen in hormone replacement therapy if Prometrium (progesterone) is not covered?

Second-Line Progestogen Options When Prometrium Is Not Covered

If Prometrium (micronized progesterone) is not covered, medroxyprogesterone acetate (MPA) 10 mg daily for 12-14 days monthly (sequential) or 2.5-5 mg daily (continuous) is the most widely available and evidence-based alternative, though norethindrone acetate 1 mg daily offers a superior cardiovascular and metabolic profile. 1, 2

Primary Alternative: Medroxyprogesterone Acetate (MPA)

MPA remains the most commonly prescribed alternative due to extensive safety data and widespread availability, despite its less favorable metabolic profile compared to natural progesterone. 1

Dosing Regimens:

• Sequential regimen: MPA 10 mg daily for 12-14 days every 28 days when using transdermal 17β-estradiol patches (50-100 μg daily) 2
• Continuous regimen: MPA 2.5-5 mg daily provides full endometrial protection long-term and prevents withdrawal bleeding 2, 3

Important Caveats:

• MPA has documented adverse effects on lipid profiles, vasomotion, and carbohydrate metabolism compared to natural progesterone 1
• The continuous combined regimen is superior to sequential for long-term endometrial protection 2, 4
• MPA may obscure the cardioprotective effects of estrogen 4

Preferred Alternative: Norethindrone Acetate

Norethindrone acetate 1 mg daily offers better metabolic and cardiovascular outcomes than MPA while maintaining excellent endometrial protection. 1, 5

Key Advantages:

• Lower doses (1 mg) are as effective as higher doses (5 mg) for endometrial protection with minimal lipid changes 6
• Superior bleeding control and endometrial protection compared to other progestogens 5
• Positive effects on bone metabolism, increasing bone mass more than expected 5
• Does not negatively influence serum lipids when given in correct dosage 5

Practical Considerations:

• Use 1 mg daily in continuous combined regimens to minimize androgenic effects 6
• The 12-14 day duration in sequential regimens is critical for adequate endometrial protection 2, 6

Third-Line Option: Dydrogesterone

Dydrogesterone is listed among ESHRE-recommended progestogens, though evidence in premature ovarian insufficiency populations is limited. 1

• Enhanced oral bioavailability compared to natural progesterone 1
• Lacks robust endometrial safety data in POI populations 1

Alternative Delivery System: Levonorgestrel IUS

The levonorgestrel intrauterine system provides reliable endometrial protection with fewer systemic adverse effects than oral routes. 2

• Delivers progestogen directly to the uterus 2
• Recommended by the British Menopause Society as an alternative delivery method 2
• Particularly useful for patients experiencing systemic progestogen side effects

Critical Safety Monitoring

Perform baseline endometrial ultrasound to document endometrial thickness before initiating any progestogen regimen. 2

• Consider annual endometrial thickness monitoring, especially with off-label regimens 2
• Sequential regimens require at least 12-14 days of progestogen monthly to prevent endometrial hyperplasia 2, 6
• Continuous combined regimens provide superior long-term endometrial protection compared to sequential 2, 4

Common Pitfalls to Avoid

• Never use sequential progestogen for fewer than 12 days monthly—this provides insufficient endometrial protection 2, 6
• Avoid high-dose MPA when lower-dose norethindrone acetate (1 mg) can achieve the same endometrial protection with better metabolic effects 6
• Do not assume all progestogens have equivalent cardiovascular safety profiles—natural progesterone and lower-dose norethindrone acetate are preferable to MPA 1, 4
• Be cautious with norethindrone in patients with thromboembolism history, uncontrolled hypertension, or cardiovascular disease 7, 8