Polycystic ovary syndrome (PCOS) is the most common endocrinology condition in premenopausal women, with a prevalence of 8%-12% in this population. The presentation can vary between individuals, and although obesity is not part of the current diagnostic criteria, rates of obesity can range between 50%-80% in this patient population. PCOS is a common cause of anovulatory infertility, which an increased body mass index can compound. Lifestyle interventions with or without pharmacotherapy remain the mainstay of treatment, with bariatric surgery currently considered an experimental treatment.

The first part of this thesis will address the impact of insulin sensitiser pharmacotherapy on metabolic and reproductive outcomes in women with PCOS who have overweight and obesity through a comprehensive systematic review, meta-analysis and meta- regression. Following this, the BAMBINI randomised controlled clinical trial will compare the effectiveness of medical care to bariatric surgery in improving the number of ovulatory cycles over 52 weeks in women with PCOS who have obesity.

The use of an insulin sensitiser in women with PCOS who have overweight, or obesity resulted in a significant improvement in metabolic outcomes and some reproductive hormones; however, there was a lack of data for hard reproductive outcomes.
Bariatric surgery proved superior to medical care in improving anthropometric, metabolic, and reproductive outcomes in women with PCOS who have obesity. Further

randomised controlled trials are needed to investigate this effect and its impact on pregnancy outcomes.

The second part will focus on the melanocortin system and its role in glucose homeostasis through melanocortin receptor agonism. Animal studies have shown that α-melanocyte stimulating hormone (α-MSH) – a melanocortin receptor agonist, increases skeletal muscle glucose uptake following a glucose load. In this first-in-human,
double-blind, randomised, cross-over experimental study, healthy volunteers received α- MSH (initially at three different doses) and saline during an oral glucose tolerance test and subsequent euglycaemic hyperinsulinaemic clamp. The oral glucose tolerance tests were repeated in a different group of healthy volunteers with high dose α-MSH and saline. Infusion with α-MSH significantly reduced mean plasma glucose and serum insulin concentrations compared to saline.