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Predicting Outcome of Treating Anovulation
Introduction
Treatment of anovulatory infertility aims at restoring normal ovarian physiology, that is, mono-follicular growth and mono-ovulation. First-line ovulation induction treatment with anti-estrogen clomiphene citrate (CC) has the advantage of a high response rate and low costs as well as minor side effects and complications. In case of clomiphene-resistant anovulation (CRA) or failure to conceive (CRF), second-line treatment to induce ovulation consists of daily administration of exogenous FSH. To enhance the ovarian sensitivity for FSH stimulation, laparoscopic electrocoagulation of the ovaries (LEO, Chapter 18) and the use of insulin sensitizers (i.e., Metformin, Chapter 17) are proposed. These modalities are utilized in patients after CRA and may be combined with the use of CC or FSH. Although effective, treatment with CC and FSH is complicated by the limited control of ovarian response due to large inter- and intrapatient variability. Development of prediction models taking into account individual patient characteristics may be a step forward in optimizing the decision-making process in the treatment of normogonadotropic anovulation, resulting in a more patient-tailored treatment.
Overview of Existing Evidence
Clomiphene Citrate
Over the last decades, several prediction models for success with ovulation induction have been proposed. In general, these prediction models used clinically easily accessible parameters.
In a prospective longitudinal single-center study, Imani et al. developed a model to predict the individual chances of live birth after CC administration using two distinct prediction models combined in a normo-gram. Univariate and multivariate analyses were used to identify these predictors. In this study population, a cumulative conception rate of 73% was reached within nine CC-induced ovulatory cycles. Body mass index and hyperandrogenemia were observed to be the predominant predictors for ovulation after CC treatment whereas age and cycle history dictated pregnancy chances in ovulatory women (1). These conclusions have been largely confirmed about 10 years later in an independent study population (2).
FSH
In addition, similar models have been considered for FSH low-dose ovulation induction. Age, duration of infertility, and insulin/glucose ratio were combined to predict live birth rate in clomiphene-resistant anovulatory women receiving FSH treatment (3). In this study, clomiphene-resistant anovulatory women receiving FSH achieved a cumulative 2-year live birth rate of 71%. Cox regression was used for univari-ate and multivariate analysis relating initial screening characteristics to the cumulative pregnancy rate, leading to singleton live birth. Subsequently, the latter prediction model was validated in an independent cohort of patients with polycystic ovary syndrome (4). Veltman et al. also included BMI resulting in a better predictive index of live birth: 60% at 12 months and 78% at 24 months.
Insulin Sensitizers (See Also Chapter 17)
The presumed central role of insulin resistance in hyperandrogenism in PCOS is the reason that insulin sensitizers were introduced in ovulation induction. By lowering insulin resistance, ovarian dysfunction may diminish and ovarian responsiveness to FSH improve. This effect might be more evident in overweight (BMI >28) and insulin-resistant PCOS patients. Clinically, Metformin is proving to be effective as an adjuvant to CC in CRA patients. In only a few small studies, it is suggested that Metformin cotreatment in gonadotropin induction of ovulation results in a decreased amount of FSH needed, a significantly shorter stimulation period, and more monofollicular cycles.
Laparoscopic Electrocautery of the Ovaries (LEO) or Laparoscopic Drilling of the Ovaries (LOD, See Also Chapter 18)
Patient characteristics reported to predict chances for ovulation and pregnancy after LEO in a WHO 2 infertility population, failing to ovulate or conceive after CC treatment, were hyperandrogenism (T and FAI) and BMI whereas elevated LH serum levels increased chances for pregnancy (5). These data could not be confirmed by a smaller prospective study in a group of patients with CRA (6). Only age at men-arche and LH/FSH ratio were significantly related to treatment response.
Genetic Factors
