Prescribing Micronized Progesterone: Cyclical vs. Daily Regimen
For a 50-year-old woman with irregular heavy bleeding due to presumed progesterone deficiency, prescribe micronized progesterone (Prometrium) 200 mg orally at bedtime for 12–14 consecutive days each month (cyclical regimen), not daily.
Rationale for Cyclical Dosing in Premenopausal Women
The cyclical regimen is the evidence-based standard for women with irregular bleeding who still have ovarian function. 1, 2
Medroxyprogesterone acetate 10 mg daily for 12–14 days per month is the most extensively studied regimen for inducing withdrawal bleeding and providing endometrial protection in women with anovulatory cycles or progesterone deficiency. 1, 2
Micronized progesterone 200 mg orally at bedtime for 12–14 days per month is the preferred alternative to synthetic progestins, offering superior cardiovascular and breast safety while maintaining full endometrial protection. 1, 2, 3
The 12–14 day duration replicates the natural luteal phase and ensures complete secretory transformation of the endometrium; shorter durations (< 10–12 days) provide inadequate protection and increase endometrial cancer risk approximately 1.8-fold. 1, 4
Why Not Daily (Continuous) Dosing?
Continuous daily progesterone is designed for postmenopausal women on estrogen replacement therapy, not for premenopausal women with irregular cycles. 1, 5
Continuous micronized progesterone 100 mg daily is used in postmenopausal hormone therapy to induce amenorrhea and avoid withdrawal bleeding—this is inappropriate for a 50-year-old woman who needs regular monthly cycling to regulate her periods. 1, 5
In premenopausal women with oligomenorrhea or amenorrhea, the goal is to induce predictable withdrawal bleeding every 28 days to prevent endometrial hyperplasia, not to suppress bleeding entirely. 2
Specific Dosing Protocol
Start micronized progesterone 200 mg orally at bedtime on day 15 of a 28-day cycle (or after 14 days of no progesterone), continue for 12–14 consecutive nights, then stop. 1, 2, 4
Withdrawal bleeding typically occurs 2–3 days after the last progesterone dose, establishing a predictable monthly cycle. 1
If the patient has prolonged amenorrhea (> 3 months), you can start progesterone at any time after confirming she is not pregnant, then repeat the 12–14 day course monthly. 2
The bedtime dosing minimizes the mild drowsiness and dizziness that can occur with oral micronized progesterone. 3, 6
Endometrial Protection Evidence
Cyclical micronized progesterone 200 mg for 12–14 days per month provides complete endometrial protection for up to 5 years, with no cases of hyperplasia reported in long-term studies. 4
In a multicenter trial of 101 postmenopausal women, oral micronized progesterone 100 mg daily for 25 days per month (continuous regimen) resulted in 61% quiescent endometrium without mitosis, 23% mildly active with rare mitoses, and zero cases of hyperplasia. 5
The same study showed that 200 mg daily for 12–14 days (sequential regimen) fully inhibits endometrial mitoses and induces withdrawal bleeding in > 90% of women. 5, 4
Vaginal micronized progesterone 100 mg every other day or 4% gel (45 mg) daily for 10–14 days per month may provide endometrial protection, but this is off-label use with less robust data than oral dosing. 4
Advantages Over Synthetic Progestins
Micronized progesterone has a superior safety profile compared to medroxyprogesterone acetate or norethisterone, particularly for cardiovascular and breast cancer risk. 1, 3, 6
Oral micronized progesterone exhibits neutral or beneficial effects on blood pressure, lipid profiles, and vascular function, whereas synthetic progestins suppress the vasodilating effects of estrogen and adversely affect coagulation factors. 1, 6
Micronized progesterone is associated with the lowest thrombotic risk among all progestogen options, making it the safest choice for women with cardiovascular risk factors. 1, 3
Unlike synthetic progestins, micronized progesterone exerts anti-mineralocorticoid effects (reducing fluid retention) and has no androgenic activity (avoiding acne or hirsutism). 7, 6
Common Pitfalls to Avoid
Never prescribe progesterone for fewer than 12 days per cycle in sequential regimens—this provides inadequate endometrial protection and increases cancer risk. 1, 4
Do not use continuous daily progesterone (100 mg) in premenopausal women with irregular bleeding—this regimen is designed to induce amenorrhea in postmenopausal women on estrogen therapy, not to regulate cycles. 1, 5
If the patient is already on estrogen therapy (e.g., for perimenopausal symptoms), you must add progesterone to prevent endometrial hyperplasia; unopposed estrogen increases endometrial cancer risk 10- to 30-fold after 5 years. 1
Confirm the patient is not pregnant before starting progesterone, especially if she has prolonged amenorrhea. 2
When to Consider Combined Oral Contraceptives Instead
If the patient also needs contraception or has polycystic ovary syndrome (PCOS), combined oral contraceptives are the preferred first-line treatment over progesterone-only therapy. 2
COCs suppress ovarian androgen production, increase sex hormone-binding globulin, reduce endometrial cancer risk, and provide reliable contraception—benefits that progesterone alone does not offer. 2
However, if COCs are contraindicated (e.g., history of venous thromboembolism, stroke, migraine with aura, active liver disease, or smoking > 35 years old), then cyclical micronized progesterone 200 mg for 12–14 days per month is the appropriate alternative. 1, 2
Monitoring and Follow-Up
Schedule a follow-up visit after 3 months to assess bleeding pattern, symptom control, and adherence. 1
If withdrawal bleeding does not occur after the first progesterone course, repeat the cycle and consider endometrial biopsy or transvaginal ultrasound to rule out structural abnormalities or hyperplasia. 1
Annual clinical review is recommended, focusing on compliance, bleeding patterns, and any new contraindications (e.g., development of breast cancer, venous thromboembolism, or liver disease). 1
No routine laboratory monitoring (hormone levels, liver function tests) is required unless specific symptoms or concerns arise. 1