Polycystic ovary syndrome (PCOS): manipulation of hormonal, metabolic and ovarian phenotypes using a developmental model

Polycystic ovary syndrome (PCOS) is common: more than one in 1 in 15 young women has this condition. There are many associated health problems including abnormal periods, miscarriages, infertility, excess hair, acne, weight gain, diabetes and heart disease. As we do not understand what causes PCOS we can only treat the various symptoms rather than the condition itself. We think that the seeds for PCOS are sown at the beginnings of life before birth. Although sheep don?t normally suffer from PCOS if we slightly change the hormonal environment before birth they develop a lot of the features of PCOS as adults. We think that similar changes in the environment before birth in women is associated with the development of PCOS. In order to try to prevent it happening we need to study what happens before birth and what are the initial changes that start the ball rolling towards PCOS as adults. We have developed new techniques to study the very earliest changes so that we can work out how to stop them happening. As well as this we need to ensure that we can develop and test the best treatments for PCOS when it has occurred. We will use these sheep to test new treatments and how treatments focussing on different aspects of PCOS work. Together this research will help us try to reduce the development of this distressing condition and optimise the treatments if it has occurred.

This research is focussed on understanding the molecular aetiology and developing new treatments for polycystic ovary syndrome (PCOS). We are utilising a prenatal androgenisation ovine model that develops hormonal, ovarian and metabolic phenotypes reminiscent of PCOS. We have developed a strategy for direct fetal manipulation using ultrasound guided fetal injection. Exposure of the fetus to androgens using a fetal route as well as the maternal route of exposure produces the disparate PCOS phenotype. However fetal testosterone exposure, by either route, is associated with increased fetal estradiol and cortisol. In addition nutritional stress during pregnancy has parallel ovarian and metabolic changes. This research builds on our recent experience and our novel fetal injection model to address three important areas: 1) The first area deconstructs possible mediators of testosterone action in the fetus by their direct manipulation. We will study the direct effects of adrenal manipulation, cortisol, estradiol and nutritional stress in utero on fetal and adult hormonal, ovarian and metabolic phenotypes. 2) The second area uses the established androgenisation model to investigate therapeutic strategies. We will study the molecular and phenotypic effects of novel and conventional direct ovarian, hormonal and metabolic manipulation. 3) The third area is the development of novel strategies to dissect the direct effects on the ovary from the effects on the hormonal and metabolic environment. We will utilise our direct fetal intervention model to facilitate the development of ovarian transplantation models. Together these research areas: dissect out fetal changes as antecedents to increase our understanding of mechanisms and therapeutic targets, assess interventions focussing on different phenotypic targets and develop manipulative strategies to investigate the direct ovarian phenotype. This research involves a partnership between a clinician scientist and basic scientists, all of whom have experience in ovine large animal modelling, in an ideal environment and collaborative framework. They are particularly well placed to dissect out the antecedents and focussed manipulative strategies to help women blighted with the reproductive and lifelong metabolic consequences of PCOS.