Polycystic Ovarian Syndrome: modelling development, phenotype and progression using a developmental paradigm

Polycystic ovarian syndrome (PCOS) is common: more than one in twenty young women has this condition. There are many associated health problems including abnormal periods, miscarriages, infertility, excess hair, acne, weight gain and diabetes. 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 beginning of life before birth. Although sheep don?t normally suffer from PCOS, if we change the hormonal environment slightly before birth they develop a lot of features of PCOS as adults. We think similar changes in the environment before birth in women is associated with the development of PCOS. We plan to study the growth and development of these sheep to understand how the different problems of PCOS develop. This will help us understand how PCOS develops and we can use that knowledge to prevent or modify its development. We can then investigate whether there are any changes before puberty that will predict the development of PCOS, study the effects of current treatments and develop and test new treatments.

Polycystic ovarian syndrome (PCOS) is the commonest endocrine disorder in women, and it presents with heavy infrequent periods, amenorrhoea, hirsuitism, female infertility and recurrent miscarriage. It is also associated with an increased risk of obesity, endometrial carcinoma and type II diabetes mellitus. We do not understand its aetiology or its variable phenotype and current treatment options are limited and largely symptomatic in nature. Twenty percent of women have polycystic ovaries but only some will experience the hyperandrogenism and abnormal gonadotrophins of PCOS, and some of these will be insulin resistant. Recently, a developmental origin of PCOS has been suggested, as female monkeys and sheep exposed to increased androgen concentrations in utero show many of its features when they reach adulthood. We hypothesise that the PCOS phenotype results from abnormal exposure to androgens during development, and a hierarchy of androgen effects results in variable phenotypic penetrance, depending on the level of prenatal androgen exposure. We aim to use the androgen-treated fetal sheep as a model to study the development of the phenotype, and the effect of variable androgen exposure. The ovarian phenotype and function, steroidogenesis, pituitary function, and metabolic phenotype of sheep prenatally exposed to different concentrations androgens will be fully characterised. Androgen and synthesis action in the fetus will be studied by localising androgen receptors and metabolising enzymes. The long-term cellular effects of androgen exposure will be studied using sheep fetuses exposed to variable concentrations of androgens, and the short-term effects studied in fetal tissues in primary culture. Using the androgen treated fetal sheep, the development of the ovarian phenotype will be studied by localising and quantifying the key genes involved in tissue and vascular remodelling in ovarian tissue at different stages of development. This research programme will afford the scientific opportunities to understand the development of PCOS and the medical opportunities for the development and testing of new treatment strategies.