Progesterone Regimen for PCOS with Amenorrhea and Fertility Desire
For a PCOS patient with amenorrhea who desires pregnancy, medroxyprogesterone acetate (MPA) 10 mg daily for 12-14 days should be given to induce withdrawal bleeding, followed immediately by clomiphene citrate for ovulation induction. 1
Progesterone for Endometrial Protection and Cycle Normalization
The primary progesterone regimen is medroxyprogesterone acetate (MPA) 10 mg orally daily for 12-14 days per month, which induces withdrawal bleeding and provides critical endometrial protection against hyperplasia and cancer risk from unopposed estrogen in anovulatory PCOS patients. 1 MPA is the only progestin with robust evidence demonstrating full effectiveness in inducing secretory endometrium when used cyclically. 1
Alternative Progesterone Options
If MPA is not tolerated or contraindicated:
Oral micronized progesterone (OMP) 200 mg daily for 12-14 days per month is an effective alternative with a superior safety profile, including lower cardiovascular risk and better thrombotic safety profile compared to synthetic progestogens. 1 OMP does not significantly alter circulating androgen levels in PCOS patients, making it safe for timing blood sampling and ovulation induction. 2
Dydrogesterone 10 mg daily for 12-14 days per month is another synthetic progesterone option with enhanced oral bioavailability. 1
Vaginal progesterone 200 mg daily for 12-14 days can be used if oral administration causes side effects or is contraindicated. 1
Critical Timing for Fertility Goals
Do not use progesterone for long-term monthly cycling if pregnancy is actively desired. Instead, use progesterone strategically:
Induce one withdrawal bleed with progesterone to reset the endometrium and create a favorable hormonal environment. 3
Immediately proceed to ovulation induction with clomiphene citrate after the withdrawal bleeding, as this is the first-line treatment for ovulation induction in PCOS with good evidence (80% ovulation rate, 50% conception rate among ovulators). 1
Progesterone treatment before clomiphene may improve clomiphene responsiveness by modulating LH pulsatility, reducing pituitary sensitivity to GnRH, and creating a more favorable environment for ovulation. 3
Important Caveats
Avoid repeated progesterone-induced withdrawal bleeds before each ovulation induction cycle, as progesterone exerts a negative effect on endometrial development, resulting in thinner peak endometrium and lower endometrial thickness ratios, though pregnancy rates remain similar to spontaneous menses. 4
Weight optimization is paramount before ovulation induction. The Endocrine Society recommends BMI ≥18.5 kg/m² before offering ovulation induction, and even 5% weight loss improves metabolic and reproductive abnormalities in PCOS. 5, 1
When Combined Oral Contraceptives Are NOT Appropriate
Combined oral contraceptives (COCs) are contraindicated in this patient because she desires pregnancy. 1 While COCs are first-line for long-term PCOS management in women NOT attempting to conceive (they suppress ovarian androgen production, increase SHBG, and reduce endometrial cancer risk), they prevent ovulation and pregnancy. 1, 6
Algorithm for This Patient
Administer MPA 10 mg daily for 12-14 days to induce withdrawal bleeding and provide endometrial protection. 1
Wait for withdrawal bleeding to occur (typically within 2-7 days after completing progesterone). 7
Start clomiphene citrate on cycle day 3-5 after withdrawal bleeding for ovulation induction. 1
If clomiphene fails after 3-6 cycles, consider low-dose gonadotropin therapy or pulsatile GnRH therapy (though GnRH is less commonly available). 5, 1
Do NOT continue monthly progesterone cycling once ovulation induction begins, as the goal is pregnancy, not cycle regulation. 1