Abstract: Induction with clomiphene citrate is usually the first line therapy for anovulatory or oligo-ovulatory women with polycystic ovary syndrome (PCOS) wishing to conceive. Use of progestin is recommended to induce a withdrawal bleed before administration of clomiphene. Few published data are available on the benefit of this practice or its possible detrimental effects.
The aim of this study was to evaluate the effect of progestin-induced endometrial shedding before ovulation induction with either clomiphene citrate, metformin, or a combination of both, on ovulation, conception, and live birth rates in women with PCOS. This retrospective report performed a secondary analysis of data on 626 women with PCOS enrolled in a double-blind trial, at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network study. Patients had been randomized to clomiphene citrate alone, metformin alone, or clomiphene citrate plus metformin for up to 6 cycles. Outcome measures assessed included occurrence of ovulation, conception, and live birth in relation to previous bleeding episodes (after either ovulation or exogenous progestin-induced withdrawal bleed).
Ovulation rates were significantly higher in cycles preceded by previous spontaneous endometrial shedding than in cycles after progestin withdrawal or in cycles without progestin withdrawal (P < 0.001). Both conception and live birth rates, however, were significantly higher after anovulatory cycles without progestin-induced withdrawal bleeding: live births per cycle were 2.2% for spontaneous menses, 1.6% for anovulatory with progestin withdrawal, and 5.3% for anovulatory without progestin withdrawal (P < 0.001). The difference was more marked when live birth rates were calculated as a function of the preceding cycle menstrual status: rates were 3.0% for spontaneous menses, 5.4% for anovulatory with progestin withdrawal, and 19.7% for anovulatory without progestin withdrawal (P < 0.001).
These findings suggest that endometrial shedding, whether spontaneous or progestin-induced before ovarian stimulation, reduces the rate of conception and live birth among anovulatory women with PCOS. These data challenge the common clinical practice of routinely administering progestin to induce a withdrawal bleed in anovulatory women undergoing ovulation induction.