Ovulatory dysfunction is a major cause of infertility; ovulation induction is often the initial treatment. Traditionally, clinical practice has been that ovulation induction is initiated following administration of progestins to induce menses. This practice has not been supported by direct experimental data and recent findings challenges this routine practice. The analysis revealed that progestin withdrawal adversely affects outcomes of ovulation induction with clomiphene. This review attempts to account for this observation based on prior studies while recognizing the critical need for both prospective assessment of the effect of progestin-induced withdrawal bleeding prior to ovulation induction, and that proposed mechanisms of a detrimental impact require experimental verification. In addition, while we await definitive determination of whether there is a direct procreational benefit of eliminating progestin withdrawal bleeding, such a practice would potentially allow for increased opportunities to conceive within a given period of time.
PCOS and ovulation induction
In women with polycystic ovarian syndrome (PCOS), ovulatory dysfunction is one of the most common causes of infertility. Infertility often presents in PCOS in the setting of amenorrhea, irregular menses, and hirsutism.1, 2) When other significant infertility factors are excluded, ovulation induction is the initial treatment of choice for most anovulatory or oligo-ovulatory infertile women.1 Progestins are often used to induce a withdrawal bleed before ovulation induction, as described by the practice committee of The American Society for Reproductive Medicine.1 However, recent studies suggest that a progestin-induced withdrawal bleed may reduce conception and live birth rates in women undergoing ovulation induction with clomiphene citrate. This finding, if confirmed in appropriately designed and conducted prospective studies, has the potential to radically change our current management of anovulatory infertility, while presenting many important questions:
- Does a clomiphene cycle (or other ovulating inducing agent cycles) need to be preceded by some form of endometrial shedding?
- If not, should a patient with spontaneous onset of menses wait before starting clomiphene? And how long should the wait last?
- Also, are such findings relevant to women who do not have PCOS, and are they pertinent in frozen embryo transfer cycles? Understanding the mechanism of how administration of progestins may negatively affect pregnancy outcome following ovulation induction is essential to answering these questions.
Unfortunately, little data exist regarding the effect of endometrial shedding on infertility treatment outcome in anovulatory women. The traditional practice of inducing progestin withdrawal before initiation of ovulation induction has not been supported by evidence. Neither has the decision to avoid progestin withdrawal, until recently. Hurst et al3 described a novel clomiphene stair-step protocol in which, after cycles with ovulation failure, clomiphene was immediately increased and administered beginning approximately cycle day 20, rather than after induction of a withdrawal bleed. The authors found that use of this stair-step protocol decreased time to ovulation compared to a traditional protocol. They therefore concluded that menses induction before clomiphene administration was not necessary in nonresponsive (i.e. non-ovulating) patients with PCOS (so-called clomiphene-resistant patients).3 However, this report did not describe conception or live birth outcomes.
Diamond et al4 retrospectively investigated the effect of endometrial shedding on ovulation induction outcomes (both conception and birth rates). A secondary analysis of the Reproductive Medicine Network (RMN), Pregnancy in Polycystic Ovary Syndrome I study sought to determine whether progestin administration to induce a withdrawal bleed immediately before initiation of ovulation induction would affect ovulation, conception, and live birth. Results revealed that a menstrual bleed immediately before the cycle, whether induced or not, is associated with a reduced chance of conception and live birth in a subsequent cycle of ovulation induction. Although ovulation was observed more often in cycles preceded by spontaneous menses, the highest rates of conception and live birth were observed in cycles with anovulation without progestin withdrawal. Moreover, that relationship was observed when examining each individual treatment arm: clomiphene alone, metformin alone, and clomiphene plus metformin.4
Similarly, in a retrospective study, Dong et al5 sought to determine whether a progesterone-induced endometrial bleed before ovulation induction affected pregnancy rates. The control group included cycles with spontaneous menses. They found that patients in the induced shedding group had significantly thinner peak endometrium (n=184 cycles) compared to the controls (n=57 cycles). Although, rates of pregnancy and live birth were higher in the progesterone withdrawal group compared to the control group, the difference was not significant.5