Progesterone Replacement: Daily vs. Sequential Regimens
For females with unmeasurable progesterone requiring replacement therapy, progesterone can be administered either sequentially (12-14 days per cycle) or continuously (every day), depending on whether the goal is to mimic natural cycling or provide continuous endometrial protection. 1, 2
Sequential (Cyclic) Regimen: 12-14 Days Per Month
The sequential regimen is NOT limited to 21 days—it requires a minimum of 12-14 days of progesterone per 28-day cycle to provide adequate endometrial protection. 1, 2, 3, 4
Recommended Dosing for Sequential Therapy:
- Micronized progesterone: 200 mg orally daily for 12-14 days per 28-day cycle (preferred first-line due to superior cardiovascular safety profile) 1, 2
- Alternative: Medroxyprogesterone acetate 10 mg daily for 12-14 days per month 1, 5
- Alternative: Dydrogesterone 10 mg daily for 12-14 days per month 1
- Vaginal route: 200 mg micronized progesterone daily for 12-14 days provides equivalent endometrial protection 1, 5
Critical Duration Requirement:
Using progestin for fewer than 10 days per cycle provides inadequate endometrial protection and increases endometrial cancer risk (relative risk 1.87 per 5 years). 3, 4 The sharp distinction between 7 days versus 10+ days of progestin use suggests that adequate endometrial sloughing requires at least 10 days, with 12-14 days being the evidence-based standard. 1, 4
Continuous (Daily) Regimen: Every Day
Progesterone can be given every single day without interruption as an alternative to sequential therapy. 1, 5, 2
Recommended Dosing for Continuous Therapy:
- Micronized progesterone: 100 mg orally daily (continuous) 1, 6
- Alternative: Medroxyprogesterone acetate 2.5 mg daily 1, 5
- Alternative: Dydrogesterone 5 mg daily 1
- Alternative: Norethisterone 1 mg daily 1
Advantages of Continuous Therapy:
- Eliminates monthly withdrawal bleeding 2, 6
- Provides consistent endometrial protection without cycling 2, 3
- May be preferred by women who wish to avoid regular menses 6
Choosing Between Sequential and Continuous Regimens
Use Sequential (12-14 days) When:
- Patient desires regular, predictable withdrawal bleeding 2, 6
- Mimicking natural menstrual cycling is therapeutically desirable 1, 6
- Patient is younger or perimenopausal and benefits from cyclic hormones 1
Use Continuous (Every Day) When:
- Patient prefers to avoid monthly bleeding 6
- Amenorrhea is the therapeutic goal 6
- Patient is postmenopausal and has no need for cyclic bleeding 1, 2
Critical Pitfalls to Avoid
Never prescribe progesterone for only 7 days per cycle—this provides inadequate endometrial protection and increases cancer risk. 3, 4 The minimum effective duration is 10 days, but 12-14 days is the evidence-based standard. 1, 2, 4
Never use progesterone alone without estrogen in women with premature ovarian insufficiency or hypoestrogenism—progesterone replacement requires concurrent estrogen therapy. 7, 1 The exception is women who have undergone hysterectomy, who may receive estrogen-only therapy. 7
Administration Considerations
Micronized progesterone should be taken at bedtime as a single daily dose to minimize transient drowsiness, which is the primary side effect. 2, 6 Taking it with a glass of water while standing helps women who experience difficulty swallowing capsules. 2
Transdermal progesterone is NOT recommended for endometrial protection, as skin permeability does not allow administration of physiologically adequate quantities (up to 25 mg/day). 8 Only oral or vaginal routes provide sufficient systemic and local uterine exposure. 1, 5, 8
Monitoring and Duration
No routine laboratory monitoring is required unless specific symptoms arise. 1 Annual clinical review should assess compliance, side effects, and the woman's tolerance and feeling of wellbeing. 1
For women with premature ovarian insufficiency, treatment should continue until the average age of natural menopause (45-55 years). 1