Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition, affecting up to 18% of women worldwide, and characterized by a range of endocrine, reproductive, and metabolic abnormalities. As the origin of PCOS remains largely unknown, there is neither a cure nor mechanism-based treatments leaving patient management suboptimal and focused solely on symptomatic treatment. The condition was originally classified as a reproductive disorder as it represents the most common cause of anovulatory infertility in women. Today, it is well known that PCOS has other long-term health repercussions, including obesity, metabolic syndrome and type-2 diabetes. As a consequence, the syndrome has a significant impact on the quality of life and represents an economic burden for patients and society. There is thus an urgent need to design effective therapeutic strategies aimed at curing and/or alleviating the reproductive and metabolic health-related burden of women with PCOS.
The international evidence-based guideline for the assessment and management of PCOS endorses the use of the Rotterdam diagnostic criteria, where a woman must have 2 out of the following 3 criteria for the diagnosis to be reached: sporadic or absent ovulation (oligo-anovulation, OA), biochemical or clinical evidence of hyperandrogenism (HA), and polycystic ovarian morphology (PCOM). HA is a common feature among women with PCOS, affecting nearly 80% of women diagnosed using the Rotterdam definition, which significantly contributes to the OA. The key neuroendocrine aberration in women with PCOS is increased luteinizing hormone (LH) pulse frequency, documented in 75 % of women with PCOS, regardless of their body mass index (BMI). This suggests an increase in activity of gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus. GnRH neurons are the master regulators of reproductive functions in mammals as they control fertility by driving the secretion of LH, and follicle-stimulating hormone (FSH) from the pituitary gland. These factors regulate the development and functions of the gonads in all vertebrates. In women with PCOS, the LH hyper-pulsatility contributes to increased ovarian thecal androgen secretion and failure of ovulation, constituting a pivotal pathogenic role in the syndrome. These evidences suggest that deregulation of GnRH neuronal activity/secretion could be the basis for neuroendocrine anomalies that accompany the reproductive disturbances in the syndrome.
The GRASP proposal is based on data and concepts originating from the ERC Consolidator Grant REPRODAMH where we have shown, using a robust PCOS mouse model that we have generated (PAMH animals), the pivotal role of Anti-Müllerian Hormone (AMH) and GnRH in the onset of the reproductive and metabolic traits of PCOS. Importantly, we have demonstrated that intermittent delivery of low doses of a GnRH antagonist reversed neuroendocrine (LH and Testosterone, T) and reproductive (oestrous cycles and ovulation) PCOS traits in PAMH mice. In GRASP we have tested the hypothesis that a subtherapeutic dose of a GnRH antagonist, aimed at tempering LH secretion/pulsatility, can ameliorate both reproductive and metabolic PCOS traits in PAMH mice and we have performed a pilot clinical study in women with PCOS to explore the dose relationship of the effect of low GnRH antagonism in circulating hormones’ dynamics. Altogether, our data indicate that GnRH antagonism could pave the way towards a novel therapeutic strategy to ameliorate the reproductive and metabolic alterations associated with PCOS.
