Lab head: Prof David J Handelsman
Location: ANZAC Research Institute (Concord Hospital)
Role of androgens in Polycystic Ovary Syndrome
Primary supervisor: Kirsty Walters
Polycystic ovary syndrome (PCOS) is one of the most common causes of anovulation, infertility and hyperandrogenism in women, affecting between 5-10% of women of reproductive age worldwide. Despite substantial research trying to define the cause of PCOS its origins are unknown. Androgens have been implicated in the development of PCOS with hyperandrogenism being the most consistent PCOS trait. Women with PCOS exhibit enhanced activity in steroidogenic enzymes involved in androgen biosynthesis, and an increased frequency of dysregulation of the androgen receptor (AR) gene (due to CAG repeat polymorphism), implying that AR mediated androgen actions influence the disease processes leading to PCOS. Aromatizable (testosterone (T), androstenedione (A4) and dehydroepiandrosterone (DHEA)) and non-aromatizable (dihydrotestosterone (DHT)) androgens can induce anovulation. Recent data from animal studies has associated fetal androgen excess as a potential origin for PCOS, with the androgen antagonist flutamide reversing acyclicity in prenatally androgenized mice. Hence, acquiring a deeper insight into the pathogenesis of PCOS is essential to developing novel, rational, evidence-based improvements for better management of this common female reproductive disorder. The ethical and logistic constraints on the invasive studies required to identify such AR-mediated androgen actions in the pathophysiology of PCOS, makes suitable experimental animal models indispensable. Recently, exploiting the fact that androgen action is necessarily mediated via the androgen receptor (AR), we used Cre/LoxP genetic engineering to create androgen resistant female mice, homozygous for an inactivated AR (1). Using this innovative AR knockout (AR-/-) female mouse model, we proved a direct role for androgens mediated by the AR in female reproductive physiology (1; 2), beyond the role of T as a steroidogenic precursor for estradiol (E2) synthesis.
Research hypothesis: We will test our hypothesis that AR-mediated androgen action plays a key role in the development of PCOS.
Project: We will induce PCOS in our novel androgen resistant female androgen receptor knockout (AR-/-) mouse models (1; 3)and evaluate reproductive (fertility, cyclicity, follicle populations), metabolic (obesity, insulin resistance) and endocrine (steroid and hormone levels) features of human PCOS. If the PCOS phenotype is unaffected by the loss of AR action, then PCOS is more likely a cause of the hyperandrogenism whereas if the PCOS phenotype is abolished by androgen resistance, then this is evidence for hyperandrogenism as an important etiologic mechanism for PCOS. The Honours students will gain experience in a range of laboratory techniques (histology, immunohistochemistry, assay) and mouse models.
1. Walters KA, Allan CM, Jimenez M, Lim PR, Davey RA, Zajac JD, Illingworth P and Handelsman DJ. Female mice haploinsufficient for an inactivated androgen receptor (AR) exhibit age-dependent defects that resemble the AR null phenotype of dysfunctional late follicle development, ovulation, and fertility. Endocrinology 148: 3674-3684, 2007.
2. Walters KA, McTavish KJ, Seneviratne MG, Jimenez M, McMahon AC, Allan CM, Salamonsen LA and Handelsman DJ. Subfertile female androgen receptor knockout mice exhibit defects in neuroendocrine signaling, intraovarian function, and uterine development but not uterine function. Endocrinology 150: 3274-3282, 2009.
3. Walters KA, Middleton LJ, Joseph SR, Hazra R, Jimenez M, Simanainen U, Allan CM and Handelsman DJ. Targeted loss of androgen receptor signaling in murine granulosa cells of preantral and antral follicles causes female subfertility. Biol Reprod 87: 151, 2012.
Keywords: Androgens, Female fertility, Ovary