How do I initiate progesterone (a hormone) therapy for Hormone Replacement Therapy (HRT)?

How to Initiate Progesterone for Hormone Replacement Therapy

For postmenopausal women with an intact uterus requiring HRT, prescribe micronized progesterone 200 mg orally at bedtime for 12-14 consecutive days per 28-day cycle, combined with transdermal 17β-estradiol 50-100 μg daily. 1, 2

Progesterone Component Selection

Micronized progesterone is the strongly preferred progestogen due to its superior safety profile compared to synthetic progestins, with lower risks of cardiovascular disease, venous thromboembolism, stroke, and breast cancer. 1, 3, 4

Standard Dosing Regimens

Sequential (cyclical) regimen:

• Micronized progesterone 200 mg orally at bedtime for 12-14 consecutive days per 28-day cycle 1, 2
• This provides proven endometrial protection when combined with continuous estrogen 1, 2
• Expect predictable withdrawal bleeding after completing each progesterone cycle 5

Continuous combined regimen (if patient prefers amenorrhea):

• Micronized progesterone 100 mg orally daily at bedtime 1, 6
• Prevents withdrawal bleeding entirely while maintaining endometrial protection 1
• Breakthrough bleeding typically resolves within first 3 months 1

Alternative vaginal route:

• Micronized progesterone 200 mg vaginally daily for 12-14 days per month provides equivalent endometrial protection 1, 5
• Consider this route if oral side effects (drowsiness, dizziness) are problematic 5

Critical Duration Requirement

Never prescribe progesterone for fewer than 12 days per cycle in sequential regimens—this provides inadequate endometrial protection and increases hyperplasia risk. 1, 2 The 12-14 day duration is non-negotiable for endometrial safety. 1

Estrogen Component Pairing

Always pair progesterone with transdermal 17β-estradiol 50-100 μg daily (via patch or gel), not oral estrogen or conjugated equine estrogens. 7, 1 Transdermal delivery has significantly lower cardiovascular and thrombotic risk, particularly important since stroke, venous thromboembolism, and coronary events occur within the first 1-2 years of HRT. 1

Practical Prescribing Details

Timing and administration:

• Instruct patients to take progesterone capsules at bedtime due to common drowsiness and dizziness 2
• Have patients take capsules with a full glass of water while standing to prevent swallowing difficulties 2
• Warn patients about potential extreme dizziness, drowsiness, blurred vision, difficulty speaking, or difficulty walking during initial therapy 2
• Advise caution when driving or operating machinery, especially during the first few days 2

Contraindications to screen for:

• Active liver disease 1
• Current or history of breast cancer or hormone-sensitive malignancies 1
• Pregnancy (progesterone can cause fetal harm including cleft palate, cleft lip, cardiac defects) 2
• Peanut allergy (capsules contain peanut oil) 2

Monitoring Protocol

Annual clinical review focusing on:

• Compliance with therapy 7, 1
• Bleeding pattern assessment 1
• Symptom control 1
• Reassessment of risks versus benefits 1

No routine laboratory monitoring is required unless specific symptoms or concerns arise. 7, 1

If breakthrough bleeding occurs:

• First, ensure patient is taking progesterone for the full 12-14 days 1
• If bleeding persists beyond 3 months, consider switching to continuous combined regimen (100 mg daily) 1
• Evaluate endometrial thickness by ultrasound if bleeding is irregular or prolonged 6

Special Populations

Women with premature ovarian insufficiency (POI):

• Begin cyclic progesterone only after at least 2 years of estrogen therapy alone, or when breakthrough bleeding occurs 7, 1
• Use micronized progesterone 100-200 mg daily for 12-14 days per month 7, 1
• Continue treatment until average age of natural menopause (45-55 years) 1

Adolescents with POI:

• Start with estrogen alone for 2 years to allow breast development 7
• Then add progesterone 100-200 mg daily for 12-14 days per month, or dydrogesterone 5-10 mg daily for 12-14 days per month 7, 1

Evidence for Endometrial Protection

The FDA-approved regimen of micronized progesterone 200 mg daily for 12 days per cycle combined with conjugated estrogens demonstrated only 6% incidence of endometrial hyperplasia over 3 years, compared to 64% with estrogen alone. 2 This dramatic reduction in hyperplasia risk (from 64% to 6%) validates the critical importance of adequate progesterone dosing and duration. 2

Common Pitfalls to Avoid

• Insufficient duration: Prescribing progesterone for fewer than 12 days per cycle leaves endometrium inadequately protected 1, 2
• Wrong estrogen formulation: Using oral estrogen or conjugated equine estrogens instead of transdermal 17β-estradiol increases cardiovascular and thrombotic risk 7, 1
• Premature discontinuation: Stopping therapy before 3 months doesn't allow adequate time to assess bleeding pattern and therapeutic effect 1, 6
• Ignoring patient preference: Not discussing whether patient prefers withdrawal bleeding (sequential) versus amenorrhea (continuous) leads to poor compliance 7

Alternative Synthetic Progestogens (Second-Line)

If micronized progesterone is unavailable or not tolerated:

• Dydrogesterone 10 mg daily for 12-14 days per month (sequential) or 5 mg daily (continuous) 1, 8
• Medroxyprogesterone acetate 10 mg daily for 12-14 days per month (sequential) or 2.5 mg daily (continuous) 1
• Norethisterone 1 mg daily (continuous only) 1

However, synthetic progestins carry higher cardiovascular and breast cancer risks compared to micronized progesterone, making them less preferred options. 1, 3, 4