What are the appropriate routes of administration for progesterone in postmenopausal hormone therapy?

Routes of Administration for Progesterone in Postmenopausal Hormone Therapy

Oral micronized progesterone is the preferred first-line route for postmenopausal women requiring endometrial protection, with vaginal administration as an acceptable alternative and transdermal formulations providing inadequate endometrial protection. 1, 2

Oral Route (First-Line)

Oral micronized progesterone 200 mg daily for 12-14 days per month in sequential regimens provides proven endometrial protection with the most favorable cardiovascular and metabolic safety profile. 1, 3, 2

Sequential Regimen Dosing

• 200 mg daily at bedtime for 12-14 days per 28-day cycle when combined with continuous estrogen therapy 1, 3, 2
• The FDA-approved dose for prevention of endometrial hyperplasia is 200 mg orally for 12 days sequentially per 28-day cycle 3
• This 12-14 day duration is critical—shorter durations provide inadequate endometrial protection 1

Continuous Regimen Dosing

• 100 mg daily continuously (without interruption) for women preferring amenorrhea 1, 4
• Research demonstrates that 100 mg/day given for 25 days per month efficiently protects the endometrium and induces amenorrhea in over 90% of postmenopausal women 4

Why Oral Micronized Progesterone is Preferred

• Lower risk of cardiovascular disease and venous thromboembolism compared to synthetic progestins 1
• Neutral or beneficial effects on blood pressure 5
• Minimizes hormonal-related cardiovascular risks compared to synthetic progestogens 5
• Best safety profile regarding thrombotic risk 5

Vaginal Route (Alternative)

Vaginal micronized progesterone 200 mg daily for 12-14 days per month is an acceptable off-label alternative with good endometrial protection. 1, 2

Specific Vaginal Dosing

• 200 mg daily for at least 10-14 days per month provides endometrial protection for up to 3-5 years 2
• 4% vaginal gel (45 mg/day) applied sequentially for at least 10 days per month is another option 2
• 100 mg every other day for at least 10 days per month has been studied 2

When to Consider Vaginal Route

• Patients experiencing systemic side effects from oral progesterone 1
• Women with gastrointestinal absorption issues 2
• Those experiencing excessive drowsiness from oral administration 6

Important Caveat

• Vaginal administration is off-label use and requires more careful monitoring 2
• Consider baseline and annual endometrial ultrasound when using vaginal regimens 7

Transdermal Route (NOT Recommended)

Transdermal micronized progesterone does NOT provide adequate endometrial protection and should not be used for this indication. 2

• Research clearly demonstrates insufficient endometrial protection with transdermal delivery 2
• Combined estrogen-progestin patches are available in some countries but use synthetic progestins, not micronized progesterone 1

Alternative Synthetic Progestins (Second-Line)

When micronized progesterone is unavailable or not tolerated, synthetic progestins can be used orally:

Medroxyprogesterone Acetate (MPA)

• 10 mg daily for 12-14 days per month (sequential) or 2.5 mg daily (continuous) 1, 7
• Most extensively studied alternative with proven endometrial protection 5, 7
• Less favorable cardiovascular and metabolic profile than micronized progesterone 5, 7

Dydrogesterone

• 10 mg daily for 12-14 days per month (sequential) or 5 mg daily (continuous) 1
• Recommended by ESHRE as an alternative option 5
• Limited evidence in postmenopausal populations compared to MPA 7

Norethisterone/Norethindrone Acetate

• 1 mg daily continuously for continuous regimens 1, 7
• Superior cardiovascular and metabolic profile compared to MPA 7
• Better alternative than MPA when micronized progesterone unavailable 7

Intrauterine Route (Special Circumstances)

The levonorgestrel intrauterine system provides reliable endometrial protection with minimal systemic effects, particularly useful for women experiencing systemic progestogen side effects. 7

• Delivers progestogen directly to the uterus 7
• Fewer systemic adverse effects than oral or vaginal routes 7
• Consider for patients with intolerance to systemic progestogens 7

Critical Pitfalls to Avoid

• Never use progesterone for fewer than 12 days per cycle in sequential regimens—this provides inadequate endometrial protection 1
• Never prescribe estrogen alone in women with an intact uterus—unopposed estrogen dramatically increases endometrial cancer risk 1, 8
• Do not assume transdermal progesterone provides endometrial protection—it does not 2
• Take oral progesterone at bedtime to minimize drowsiness, the only specific side effect 6
• For women with difficulty swallowing capsules, administer with a glass of water while standing 3

Monitoring Requirements

• Annual clinical review focusing on compliance, bleeding patterns, and symptom control 1
• No routine laboratory monitoring required unless specific symptoms arise 1
• Baseline endometrial ultrasound recommended when using off-label vaginal regimens 7
• Reassess risks versus benefits annually, as cardiovascular and thrombotic risks occur within the first 1-2 years of therapy 1