Progesterone for Endometriosis: Treatment Recommendations
Progesterone therapy is effective for treating endometriosis-related pain, with oral progestins reducing or eliminating pain symptoms in approximately 90% of patients, though no single progestin has proven superior to others or to alternative endometriosis treatments. 1
Recommended Dosing Regimens
Oral Progesterone (Micronized)
- 200 mg orally at bedtime for 12 days sequentially per 28-day cycle when used for endometrial protection in postmenopausal women 2
- 400 mg orally daily has been studied for endometriosis, though this is higher than FDA-approved dosing for other indications 2
- Take as a single daily dose at bedtime due to potential drowsiness, dizziness, blurred vision, or difficulty walking 2
Depot Medroxyprogesterone Acetate (DMPA)
- Commonly used in adolescents with endometriosis, though many patients ultimately transition to other methods 3
- Standard dosing applies (150 mg IM every 3 months), though specific endometriosis dosing is not detailed in the evidence
Levonorgestrel Intrauterine Device (IUD)
- Emerged as the most popular final treatment choice in adolescents with endometriosis who failed other hormonal methods 3
- Provides continuous local progestin delivery
Mifepristone (Progesterone Receptor Modulator)
- 5 mg or 10 mg daily appears more effective than 2.5 mg for treating dysmenorrhea and dyspareunia 4
- At 3 months, reduces dysmenorrhea rates significantly (OR 0.08) compared to placebo 4
- Reduces dyspareunia (OR 0.23) compared to placebo 4
- Major side effects: Nearly 90% experience amenorrhea and 24% have hot flushes 4
Clinical Approach Algorithm
First-Line Treatment
- Start with continuous oral progestins (not sequential dosing) as this has been the standard for over 50 years 1
- Monitor for pain relief over 3 months
- If effective, continue long-term
Second-Line Options (If First-Line Fails)
- Consider levonorgestrel IUD - particularly effective in patients who have tried multiple oral methods 3
- Alternative: Mifepristone 5-10 mg daily if progesterone resistance is suspected 4
Special Considerations for Adolescents
- Progesterone-only pills are most commonly successful as initial therapy 3
- If DMPA is tried and fails, transition to levonorgestrel IUD rather than continuing to cycle through oral options 3
Critical Caveats
Progesterone Resistance
- A significant proportion of endometriosis patients exhibit progesterone resistance, characterized by reduced progesterone receptor levels (particularly PR-B isoform) and failure to metabolize estradiol 5, 6
- This explains why some patients do not respond to progestin therapy despite adequate dosing 1, 5
- Progesterone resistance is linked to deficient 17β-HSD-2 expression, leading to high local estradiol concentrations that drive endometriosis growth 6
Contraindications (FDA-Labeled)
- Allergy to peanuts (progesterone capsules contain peanut oil) 2
- Unusual vaginal bleeding, current or prior cancers (breast/uterus), stroke, heart attack, blood clots, liver problems, or pregnancy 2
Monitoring Requirements
- Watch for serious side effects: changes in vision/speech, severe headaches, chest/leg pain, dizziness, vomiting 2
- Common side effects include headaches, breast pain, irregular bleeding, abdominal cramps, nausea, hair loss, fluid retention 2
- Patients may experience extreme drowsiness, dizziness, blurred vision, or difficulty walking - take medication at bedtime in standing position with water 2
Evidence Quality Notes
The evidence base shows that continuous progestin use effectively treats endometriosis-related pain in most patients, but no progestin has demonstrated superiority over others 1. The moderate-quality evidence for mifepristone's effectiveness is balanced against high rates of amenorrhea 4. The phenomenon of progesterone resistance explains treatment failures and suggests that patients unresponsive to standard progestins may benefit from progesterone receptor modulators like mifepristone or alternative non-progestin therapies 5, 6.