Lowest Effective Dose of Progesterone in Hormone Replacement Therapy
The lowest effective dose of progesterone for endometrial protection in HRT is 100 mg daily of micronized progesterone when administered for 25 days per month in a continuous regimen. 1
Progesterone Dosing Options Based on Administration Pattern
Sequential Regimens
- Standard dose: 200 mg oral micronized progesterone daily for 12-14 days per 28-day cycle 2, 3, 4
- Alternative: 200 mg vaginal micronized progesterone daily for 12-14 days per month 2, 3
- Medroxyprogesterone acetate (MPA) 10 mg daily for 12-14 days can be used as an alternative 2, 3
Continuous Regimens
- Lowest effective dose: 100 mg oral micronized progesterone daily for 25 days per month provides adequate endometrial protection and induces amenorrhea in over 90% of women 1
- This lower dose (100 mg) efficiently protects the endometrium by inhibiting mitoses and induces amenorrhea in the majority of postmenopausal women 1
Route of Administration Considerations
- Oral micronized progesterone is effective at 200 mg daily when given sequentially for 12-14 days/month for up to 5 years 5
- Vaginal micronized progesterone may provide endometrial protection at 45 mg/day (4% formulation) or 100 mg every other day when used sequentially for at least 10 days/month 5
- Transdermal micronized progesterone does not provide adequate endometrial protection 5
Clinical Efficacy of Low-Dose Progesterone
- Studies show that 100 mg of micronized progesterone daily for 25 days produces an atrophic endometrium in most women, while 200 mg ensures atrophic endometrium in all women 6
- Lower doses (50 mg) are associated with increased breakthrough bleeding, particularly in the first cycle 6
- The FDA-approved dose for endometrial protection is 200 mg daily for 12 days per 28-day cycle in combination with conjugated estrogens, which significantly reduces the risk of endometrial hyperplasia compared to estrogen alone (6% vs 64%) 4
Important Clinical Considerations
- For women with an intact uterus, progestin must be added to estrogen therapy to reduce endometrial cancer risk 7
- Micronized progesterone is preferred over synthetic progestins due to its lower risk of cardiovascular disease and venous thromboembolism 3, 7, 8
- The side effects of synthetic progestins can be minimized through the use of natural progesterone, which is identical to the steroid produced by the corpus luteum 8
- Micronized progesterone has been widely used in Europe since 1980 at various dosages depending on whether regular monthly bleeding is desired or amenorrhea is preferred 8
Potential Side Effects and Management
- The main side effect of oral micronized progesterone is mild and transient drowsiness, which can be minimized by taking the medication at bedtime 8
- Unlike synthetic progestins, micronized progesterone has not been associated with negative effects on lipid profiles, coagulation factors, or blood pressure 9
- Micronized progesterone exhibits anti-estrogenic, anti-androgenic, and anti-mineralocorticoid effects that may be beneficial in certain clinical scenarios 9
Remember that while 100 mg daily for 25 days per month is the lowest effective dose for continuous regimens, the standard FDA-approved dose for sequential regimens remains 200 mg daily for 12-14 days per cycle.