What are the options for vaginal progesterone (a hormone) therapy in a female patient?

Options for Vaginal Progesterone Therapy

For postmenopausal women requiring endometrial protection with hormone replacement therapy, vaginal micronized progesterone 200 mg daily for 12-14 days per 28-day cycle is the recommended first-line option, paired with transdermal 17β-estradiol 50-100 μg daily. 1

Primary Indication: Endometrial Protection in Hormone Replacement Therapy

Vaginal micronized progesterone 200 mg daily for 12-14 days per month is the preferred formulation when combined with continuous estrogen therapy in postmenopausal women with an intact uterus. 1 This regimen provides proven endometrial protection while avoiding the cardiovascular and thrombotic risks associated with synthetic progestins. 1

Key Dosing Parameters:

• Sequential regimen: 200 mg vaginal progesterone daily for 12-14 days every 28 days induces withdrawal bleeding and is appropriate when bleeding is acceptable 1
• Duration is critical: The 12-14 day duration is essential—shorter durations provide inadequate endometrial protection 1
• Alternative continuous regimen: 100 mg vaginal progesterone daily continuously can be used to avoid withdrawal bleeding, though this is less well-studied 1

Alternative Vaginal Progesterone Formulations

Lower Dose Options:

• 100 mg vaginal progesterone daily was studied in early trials for preterm birth prevention and showed efficacy in some populations 2
• 90 mg vaginal progesterone gel daily has been evaluated but showed no benefit in women with prior preterm birth 2

Higher Dose for Specific Indications:

• 400 mg vaginal progesterone daily (200 mg twice daily) is used for threatened miscarriage in women with previous pregnancy losses and current bleeding 3
• This higher dose showed a 5% absolute increase in live birth rates for women with prior miscarriage(s) and current pregnancy bleeding (75% vs 70%, P=0.003) 3

Pharmacokinetic Advantages of Vaginal Administration

Vaginal progesterone achieves preferential uterine uptake through direct vagina-to-uterus transport, resulting in higher endometrial progesterone concentrations despite lower systemic levels. 4, 5 This "uterine first-pass effect" provides several clinical advantages:

• Avoids hepatic first-pass metabolism, eliminating the dizziness and drowsiness caused by progesterone metabolites with oral administration 5
• Single 100 mg vaginal dose achieves peak concentration (Cmax) of 31.53 nmol/L at approximately 7 hours, with a terminal half-life of 16.4 hours 4
• Vaginal tablets produce significantly higher Cmax than vaginal capsules (31.95 vs 23.85 nmol/L, P<0.05) 4

Comparison with Other Progesterone Routes

Why Vaginal Over Oral for HRT:

The evidence strongly favors vaginal over oral progesterone for endometrial protection because:

• Oral progesterone undergoes >90% first-pass hepatic metabolism, requiring higher doses and causing sedation 5
• Vaginal administration provides adequate endometrial protection with lower systemic exposure, reducing side effects 5
• No adverse effects on liver or lipid profiles with continuous vaginal progesterone use 4

Why NOT Intramuscular 17-Hydroxyprogesterone Caproate:

• For women with prior preterm birth, 17-hydroxyprogesterone caproate 250 mg IM weekly is preferred over vaginal progesterone based on 2012 SMFM guidance 2
• However, vaginal progesterone is NOT effective for preventing recurrent preterm birth in women with prior spontaneous preterm birth—multiple large trials (O'Brien 2007, OPPTIMUM 2016) showed no benefit 2, 6
• Vaginal progesterone IS effective for women with sonographic short cervix (<25 mm) WITHOUT prior preterm birth 2

FDA-Approved Oral Progesterone Dosing (For Context)

The FDA label for oral progesterone capsules specifies: 7

• Endometrial protection: 200 mg orally at bedtime for 12 continuous days per 28-day cycle
• Secondary amenorrhea: 400 mg orally at bedtime for 10 days
• Contains peanut oil—contraindicated in peanut allergy 7

Contraindications to Vaginal Progesterone

Do not use vaginal progesterone in women with: 7

• Peanut allergy (micronized progesterone formulations contain peanut oil)
• Undiagnosed abnormal genital bleeding
• Known or suspected breast cancer
• Active or history of venous thromboembolism or arterial thromboembolism
• Known liver dysfunction or disease
• Known or suspected pregnancy (except for specific indications like threatened miscarriage)

Clinical Monitoring and Safety

• Annual clinical review focusing on compliance, bleeding patterns, and symptom control is recommended 1
• No routine laboratory monitoring is required unless specific symptoms arise 1
• No cases of endometrial hyperplasia were reported with continuous vaginal progesterone use in pharmacokinetic studies 4
• Adjust dose according to tolerance and wellbeing 1

Common Pitfalls to Avoid

• Never use vaginal progesterone for fewer than 12 days per cycle in sequential regimens—this provides inadequate endometrial protection 1
• Do not prescribe vaginal progesterone alone for women with prior preterm birth expecting it to prevent recurrence—the evidence shows no benefit and 17-hydroxyprogesterone caproate is preferred 2
• Do not assume all vaginal progesterone doses are equivalent—200 mg daily for 12-14 days is the evidence-based dose for endometrial protection in HRT 1
• Always pair with appropriate estrogen (preferably transdermal 17β-estradiol 50-100 μg daily) for hormone replacement therapy 1