Development of an acute ovine model of polycystic ovaries to assess the effect of ovarian denervation.

Introduction: Polycystic ovary syndrome (PCOS) seems to be associated with increased ovarian sympathetic nerve activity and in rodent models of PCOS reducing the sympathetic drive to the ovary, through denervation or neuromodulation, improves ovulation rate. We hypothesised that sympathetic nerves work with gonadotropins to promote development and survival of small antral follicles to develop a polycystic ovary phenotype. Methods: Using a clinically realistic ovine model we showed a rich sympathetic innervation to the normal ovary and reinnervation after ovarian transplantation. Using needlepoint diathermy to the nerve plexus in the ovarian vascular pedicle we were able to denervate the ovary resulting in reduced intraovarian noradrenaline and tyrosine hydroxylase immunostained sympathetic nerves. We developed an acute polycystic ovary (PCO) model using gonadotrophin releasing hormone (GnRH) agonist followed infusion of follicle stimulating hormone (FSH) with increased pulsatile luteinising hormone (LH). This resulted in increased numbers of smaller antral follicles in the ovary when compared to FSH infusion suggesting a polycystic ovary. Results: Denervation had no effect of the survival or numbers of follicles in the acute PCO model and did not impact on ovulation, follicular and luteal hormone profiles in a normal cycle. Discussion: Although the ovary is richly inervated we did not find evidence for a role of sympathetic nerves in ovarian function or small follicle growth and survival.

Insights into Manipulating Postprandial Energy Expenditure to Manage Weight Gain in Polycystic Ovary Syndrome.

Women with polycystic ovary syndrome (PCOS) are more likely to be obese and have difficulty in losing weight. They demonstrate an obesity-independent deficit in adaptive energy expenditure. We used a clinically realistic preclinical model to investigate the molecular basis for the reduced postprandial thermogenesis (PPT) and develop a therapeutic strategy to normalize this deficit. Sheep exposed to increased androgens before birth develop the clinical features of PCOS. In adulthood they develop obesity and demonstrate an obesity-independent reduction in PPT. This is associated with reduced adipose tissue uncoupling protein expression and adipose tissue noradrenaline concentrations. These sheep are insulin resistant with reduced insulin signaling in the brain. Increasing brain insulin concentrations using intranasal insulin administration increased PPT in PCOS sheep without any effects on blood glucose concentrations. Intranasal insulin administration with food is a potential novel strategy to improve adaptive energy expenditure and normalize the responses to weight loss strategies in women with PCOS.