Antagonizing GnRH signaling as a “holistic” therapeutic strategy for Polycystic Ovary Syndrome

Introduction

PCOS is the most common endocrine disorder affecting up to 18% of women worldwide. The syndrome imposes a heavy health burden, covering infertility, obesity, type 2 diabetes, and metabolic syndrome.

Need for Treatment Options

The development of treatment options is an urgent need since there is currently neither a cure nor mechanism-based treatments. This leaves patient management suboptimal and focused solely on symptomatic treatment.

Neuroendocrine Aberration

One key neuroendocrine aberration in most women with PCOS is increased luteinizing hormone (LH) pulse frequency. This suggests an increase in the activity of gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus.

Role of LH Hyper-Pulsatility

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 alterations of GnRH neuronal activity/secretion could be the basis for neuroendocrine anomalies that accompany the reproductive disturbances in the syndrome.

GRASP Hypothesis

In GRASP, we will test the hypothesis that low administration doses of a GnRH antagonist, aimed at tempering LH secretion/pulsatility, can ameliorate both reproductive and metabolic PCOS traits in animal models of PCOS and in women with PCOS.

Specific Objectives of GRASP

The specific objectives of GRASP are to:

1. Dose-range GnRH antagonism to rectify LH pulse amplitude and frequency in PCOS-like mice.
2. Perform a long-term treatment with the selected doses of GnRH antagonist to assess its potential beneficial outcomes in correcting reproductive and metabolic alterations of this preclinical model.
3. Conduct a pilot dose-effect clinical investigation testing the ability of sub-therapeutic doses of GnRH antagonist to rectify the altered hormonal dynamics in women with PCOS.

Overall Goal

The overall goal of GRASP is to provide a proof-of-concept for future long-duration randomized controlled trials of this approach to appraise its clinical benefits in women with PCOS and to move forward towards therapeutic innovation.