Linking 11-oxygenated androgens, skeletal muscle glucose metabolism and diabetes risk in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) affects up to 10% of all women. It is characterised by increased blood levels of hormones called androgens, as well as irregular menstrual cycles and multiple small cysts on the ovaries. Traditionally PCOS has been predominantly perceived as a reproductive disorder impacting on fertility. However it is increasingly clear that PCOS is associated with adverse consequences for female health across the lifespan. These outcomes include an increased risk of diabetes, fatty liver disease and cardiovascular problems. Research from our group have shown that excess androgens are a major driver of these health risks. Furthermore, we have shown that a new subclass of androgens, known as 11-oxygenated androgens, make up the majority of androgens in the blood of women with PCOS. Interestingly, unlike testosterone, 11-oxygenated androgens do not decline with age, as is the case with testosterone, and can remain elevated throughout the life of a woman with PCOS. In this research proposal, we will study the role that 11-oxygenated androgens play in increasing the risk of diabetes in PCOS.

In order to test our hypothesis, our research proposal has two distinct components. Firstly, we will administer tablets containing 11-oxygenated and classic androgens to women with PCOS. We will determine the impact of androgens on the body's ability to manage glucose by performing detailed testing before and 7 days after androgen exposure.

For the second component of the study, we will obtain blood and urine samples from a large group of women with PCOS. Hormones and other blood markers will be linked to the results of specialised diabetes tests using specialised analysis. Taken together, these results will characterise the role played by 11-oxygenated androgens in mediating a risk of diabetes in women with PCOS, and help to identify new markers of diabetes risk in this condition.

The overarching aim of this research proposal is to delineate the association between 11-oxygenated androgens and the risk of diabetes in women with PCOS, with the ultimate goal of identifying novel biomarkers and disease-specific targets for treatment of androgen-related metabolic dysfunction. I will achieve this goal with a combination of cutting edge in vivo and ex vivo physiology approaches, in parallel with the development of a large prospective metabolic phenotyping cohort of women with PCOS in Ireland.

Award Date
14 February 2020
Award Value
€774,703.44
Principal Investigator
Professor Arnold Hill
Host Institution
Royal College of Surgeons in Ireland
Scheme
ECSA Full Application 2020