Grant: China-Canada Joint Health Research Initiative

Androgen excess is one of the most well characterized clinical features of the female-specific disease known as polycystic ovary syndrome (PCOS) that affects about 1 in 15 women of reproductive age. Yet, the etiology of PCOS is still largely unknown and no single factor or gene fully accounts for the spectrum of abnormalities associated with this disease. In collaboration with our Chinese partners at Zhejiang University, we have recently discovered a novel and important role for the male sex hormone receptor (androgen receptor, AR) and its splice variants in PCOS women. Our exciting preliminary results demonstrate the expression of two AR splice variant mRNAs in human ovarian granulosa cells from PCOS patients, but not control women. The AR variants are expressed in 65% of PCOS women examined and are associated with higher serum total testosterone and follicular fluid free androgen index. The studies outlined in this proposal are designed to test the novel hypothesis that androgen excess induces epigenetic alterations in the AR gene which promote the expression of AR splice variants in human granulosa cells. Expression of dysfunctional AR variants alters the regulation of downstream target genes such as aromatase, contributing to androgen excess in PCOS. The proposal to understand the role of specific splice variants of the male sex hormone receptor in the pathogenesis of PCOS (a female-specific disease) is highly original. Achieving this goal will represent a significant advancement in the promotion of women's reproductive health.