Endocrine Abstracts

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder, affecting 10–18% of women of reproductive age. Based on the Rotterdam consensus, PCOS is diagnosed by at least two of the following three criteria: oligo- or anovulation, hyperandrogenism, and polycystic ovaries on ultrasound. Thus, four different phenotypes can be recognized. In addition, PCOS is also a metabolic disorder since many affected women present with obesity, insulin resistance and associated metabolic comorbidities. This makes PCOS a very heterogeneous disease and explains why, despite its prevalence, the pathophysiology is still not understood.

Genetic predisposition and environmental exposure are thought to play a major role in the pathophysiology of PCOS. Recent genome-wide association studies (GWAS) in women of Han Chinese and Western European descent have identified several genetic loci associated with PCOS. Importantly, these PCOS-susceptibility loci account for maximally 10% of the estimated heritability, suggesting that there is missing heritability. It will be important to determine whether the different diagnostic criteria for PCOS account for different biological subtypes with a distinct genetic architecture. Studies are ongoing to address this question.

In addition, variants with a lower allele frequency, not detected by GWAS, may contribute to this missing heritability. Recent studies have identified rare PCOS-specific variants in anti-Müllerian hormone (AMH) and its receptor (AMHR2). This strongly suggests that serum AMH is not only a marker for the polycystic morphology in PCOS, but that aberrant AMH signaling may also contribute to the pathophysiology of PCOS.

In conclusion, the technical advancement in sequencing techniques allows for improved genotype-phenotype studies. Combined with functional studies, this will aid in deciphering the potentially different biological mechanisms involved in PCOS.