Trends in Endocrinology & Metabolism

Centre for Research Excellence in Polycystic Ovary Syndrome (CRE in PCOS) members Dr Kirsty Walters (UNSW, lead author), Professor Helena Teede (Monash University) and Professor David Handelsman AO (ANZAC Research Institute) have teamed up in a recent review published in the journal Trends in Endocrinology & Metabolism. This review entitled ‘New perspectives on the pathogenesis of PCOS: Neuroendocrine originshighlights the recent key basic and clinical research publications that have provided the basis for a new perspective, that PCOS has neuroendocrine origins.

Polycystic ovary syndrome (PCOS) is the most common endocrine condition in reproductive-aged women. It is characterised by reproductive, endocrine, metabolic and psychological features. It causes infertility, and is also associated with serious metabolic abnormalities including obesity, insulin resistance, and increased cardiovascular risk. Unfortunately, as the origin of PCOS remains unknown, there is neither cure nor specific treatment and patient management is suboptimal as it focuses on treating symptoms only. Hence, there is a pressing need to develop evidence-based treatments for PCOS. Recently, significant advances have been made in this field with strong evidence now supporting PCOS as having a neuroendocrine origin. In particular, aberrant hypothalamic-pituitary function and associated hyperandrogenism are supported as major drivers of the mechanisms underpinning the development of PCOS. This important information now opens up new treatment avenues, as it provides a target site and potential mechanism for the future development of novel, targeted and mechanism-based effective therapies for the treatment of PCOS.

In this review article the authors provide an overview of PCOS characteristics, health risks and diagnosis, discuss the development and use of pre-clinical animal PCOS models to deciphering the key sites of origin involved in the pathogenesis of PCOS, and outline the evidence supporting brain specific mechanisms as key drivers of PCOS. Clinical observations and findings from PCOS animal models induced by AMH or androgen excess convincingly now put aberrant hypothalamic-pituitary function at the centre of the origins of PCOS. In particular, abnormal GABAergic wiring to GnRH neurons has been highlighted as a potential key mechanism involved in the origins of neuroendocrine dysfunctions of PCOS.

This timely review succinctly outlines the evidence supporting the new perspective that the brain plays a critical role in the origins of PCOS. The recent significant advances in the field of PCOS, described in this review, are now changing the direction and refocusing the targets of future research, with the hope that ensuing research defining the primary mediator(s) of PCOS may in the future pave the way for the development of a mechanism-based treatment of PCOS.