Lowest Dose of Progesterone with Uterine Protecting Effects
For endometrial protection in postmenopausal women receiving estrogen therapy, the minimum effective dose is 100 mg oral micronized progesterone daily for 25 days per month, which fully inhibits mitoses and prevents hyperplasia. 1
Evidence-Based Minimum Dosing
Continuous Regimens
- 100 mg oral micronized progesterone daily for 25 days per month is the lowest proven effective dose for endometrial protection, achieving 93.3% amenorrhea rates and complete mitotic inhibition with no hyperplasia observed in multicenter trials 1
- This dose produces an atrophic endometrium in most women after 4 months of treatment when combined with estrogen 2
- 2.5 mg medroxyprogesterone acetate (MPA) daily represents the minimum for continuous combined regimens per Endocrine Society guidelines 3
Sequential/Cyclic Regimens
- 200 mg oral micronized progesterone daily for 12-14 days per month is the FDA-approved minimum for cyclic regimens, reducing hyperplasia incidence from 64% (estrogen alone) to 6% over 36 months 4
- This dose induces complete secretory transformation in 45% of women versus 0% with placebo 4
- 10 mg medroxyprogesterone acetate daily for 12-14 days per month serves as an alternative minimum for sequential regimens 3
Dose-Response Relationship
Suboptimal Doses
- 50 mg oral micronized progesterone produces suboptimal endometrial effects with inadequate secretory transformation and increased breakthrough bleeding 2, 5
- Doses below 100 mg fail to achieve complete mitotic suppression and adequate endometrial protection 5
Optimal Protection Threshold
- 100 mg daily for extended duration (25 days/month) achieves full endometrial protection through complete mitotic inhibition 1
- 200-300 mg daily for shorter duration (10-14 days/month) provides equivalent protection through dose-response compensation 4, 5
- 300 mg daily for 10 days achieves responses within the physiological range for all measured parameters including DNA synthesis suppression and estrogen receptor downregulation 5
Route-Specific Considerations
Oral Administration
- Micronized formulations overcome the rapid hepatic first-pass metabolism that previously limited oral progesterone use 6
- Oral micronized progesterone 200 mg daily reproduces the anti-estrogenic effect on the endometrium without adverse effects on lipids, coagulation, or blood pressure 6
Vaginal Administration
- 200 mg vaginal micronized progesterone daily provides equivalent endometrial protection to oral administration and may be used as an alternative route 3
Clinical Context: Preterm Birth Prevention
While the question asks about uterine protection generally, the preterm birth literature provides additional context:
- 90 mg vaginal progesterone gel or 200 mg suppository daily is recommended for singleton pregnancies with short cervical length ≤20 mm 7
- 250 mg 17-hydroxyprogesterone caproate (17P) IM weekly is used for singleton pregnancies with prior spontaneous preterm birth 7
Critical caveat: These preterm birth doses address a completely different therapeutic goal (myometrial quiescence) than endometrial protection in hormone replacement therapy and should not be conflated 7
Practical Algorithm for Dose Selection
For postmenopausal hormone replacement requiring endometrial protection:
First-line choice: 100 mg oral micronized progesterone daily for 25 days/month (minimizes bleeding, lowest effective dose) 1
If monthly bleeding desired: 200 mg oral micronized progesterone daily for 12-14 days/month 4
If oral route contraindicated: 200 mg vaginal micronized progesterone daily for 12-14 days/month 3
Avoid doses below 100 mg as they produce suboptimal endometrial protection with increased breakthrough bleeding risk 2, 5