Pharmacogenomics of Ovulation Induction: Facilitating Decisions on Who, When and How to Treat

Abstract

response to clomiphene citrate is complex. Many have tried to find phenotypic factors that might inf luence the response to clomiphene [5–10]. However, to date no model has been proposed that can reliably predict outcome in ovulation induction with clomiphene citrate. Recently, we studied the relationship between a known polymorphism on the FSH receptor (p.N680S, rs6166) and clomiphene citrate resistance. In normal ovulatory women, this polymorphism results in different FSH levels within the normal range, pointing out a difference in sensitivity of the receptor [11]. It has been demonstrated that patients harboring the least sensitive variant (Ser/Ser) need higher doses of exogenous FSH for ovarian stimulation in ART [12–19]. In our data in women with PCOS, we could not find a difference in the FSH levels between different variants of the polymorphism, but found that the Ser/Ser variant was significantly more often present in women resistant to clomiphene citrate. This is probably caused by faulty feedback in the pituitary of PCOS patients. In women harboring the Ser/Ser-variant of the FSH receptor polymorphism, it is more difficult to overcome the FSH threshold after which follicle maturation start [20]. On the latest ESHRE congress in Amsterdam, data was presented showing that harboring the Ser/Ser variant of the FSH receptor polymorphism was significantly associated with a decreased chance of pregnancy when treated with clomiphene citrate [21]. For tamoxifen, a drug structurally much alike clomiphene citrate, pharmacogenomic data is accumulating. The same mechanisms that explain poor response to tamoxifen could be applicable for clomiphene citrate resistance (for example, CYP2D6 poly morphism) [22] and in this way might be a source for new hypotheses in the field of ovulation induction. If clomiphene citrate does not lead to ovulation (clomiphene resistance) or subsequent pregnancy (clomiphene failure), second-line Polycystic ovary syndrome (PCOS) is the most common form of anovulatory infertility. Estimating its prevalence is difficult due to the different criteria that are used to diagnose this syndrome. According to the NIH criteria, diagnosis is based on the presence of chronic anovulation and clinical or biochemical signs of hyper androgenism [1]. In 2003, the Rotterdam European Society of Human Reproduction and Embryology (ESHRE)/American Society of Reproductive Medicine (ASRM)-Sponsored PCOS Consensus Workshop Group agreed to base the diagnosis on the presence of two of three possible features: clinical or biochemical hyperandro genism, oligoor an-ovulation, and the presence of polycystic ovaries on ultrasound examination [2]. The view of the Androgen Excess-PCOS Society Task Force is that PCOS should be defined by the presence of hyperandrogenism (clinical and/or biochemical), ovarian dysfunction (oligo-anovulation and/or polycystic ovaries) and the exclusion of related disorders [3]. Due to this lack of consistency in phenotyping, PCOS is a heterogeneous syndrome, making tailored treatment difficult.