Context : The expression of androgen receptors ( AR ) in follicular granulosa cells ( GC ) of mammals suggests a role for direct AR - mediated androgen activity in the regulation of folliculogenesis, however this role and the mechanistic pathways involved have not been fully characterised. In women, excess androgen is a characteristic feature of polycystic ovary syndrome ( PCOS ), but AR - mediated activity has not been widely investigated in relation to the pathophysiology of this disorder. Hypotheses : The current thesis tested two general hypotheses related to AR activity in PCOS : 1 ) The polymorphic ( CAG ) n repeat region in the AR gene, which has functional implications for receptor activity, influences the manifestation of PCOS and 2 ) AR signalling is disrupted in GC from women with PCOS. Results : In a cross - sectional population analysis, this thesis reports an association between PCOS and long CAG repeat tracts in the AR gene, which functionally represent reduced androgen sensitivity. The association was further enhanced by compensating for the influence of X chromosome inactivation ( XCI ) on expression of specific AR alleles. Preferential expression of long CAG repeat tracts positively correlated with serum testosterone levels in PCOS patients. In an analysis of sister pairs with the same CAG repeat genotype at the AR locus, different patterns of XCI were evident when sisters had a different clinical manifestation of PCOS. Collectively, these results provide evidence that supports the hypothesis that the ( CAG ) n polymorphism in the AR influences the manifestation of PCOS, the effects of which are modulated by variable allele expression via a mechanism involving XCI. These findings accord with the concept that both genetic and environmental factors are determinants of this disorder. At the level of the ovary, AR - mediated signalling in follicular GC was influenced by proximity to the oocyte in both pigs and humans. In particular, the ability of androgen to directly induce porcine GC proliferation in vitro was dependent upon presence of the oocyte or the oocyte mitogen, growth differentiation 9 ( GDF9 ). This finding provides a potential mechanism to explain how androgens may enhance early follicle growth. Granulosa cells from women with PCOS had normal mRNA expression for AR signalling molecules, but GC surrounding the oocyte in vivo had reduced AR protein content and diminished responses to androgen in culture as compared to those from normal ovaries. GC from women with PCOS also expressed mRNA for an androgen - regulated serine protease ( hKLK3 ), which did not occur in normal GC. Therefore, follicular GC from women with PCOS have evidence of perturbed AR - mediated signalling which is likely to contribute to the pathophysiology of this disorder. As AR - mediated signalling is influenced by the oocyte, the differences in AR - mediated signalling in GC from women with PCOS may be indicative of dysregulated signals emanating from the oocyte. Conclusion : The results of this thesis indicate that abnormal AR action occurs in PCOS, but further investigation is required to determine whether this phenomenon represents a primary disruption or a secondary consequence of another primary disruption in the sequence of events that leads to aberrant folliculogenesis in this disorder. / Thesis (Ph.D.)--School of Paediatrics and Reproductive Health, 2006.

Sex differences have been established in a number of behaviours, including aspects of cognition, aggression, and sexuality. Although there has been a considerable amount of research concerning the influence of estrogen on sexually dimorphic behaviours, there has been a dearth of investigations on the role of testosterone (T) in these behaviours in women. The studies presented here were undertaken to elucidate the role of T in sexually-dimorphic aspects of psychological functioning in women. In Study 1, users and non-users of oral contraceptives were tested with a battery of neuropsychological tests and questionnaires at two different phases of the menstrual cycle. Results showed that women with chronic low levels of free T induced by oral contraceptives demonstrated better verbal fluency and visuospatial memory performance and reported lower levels of verbal aggression than naturally-cycling women whose free T levels were within the normal female range. Furthermore, although self-ratings of hostility fluctuated across test sessions concomitant with changes in free T levels, performance on cognitive tests did not appear to be influenced by the fluctuations in T levels across the menstrual cycle. In Study 2, women with elevated free T levels due to polycystic ovary syndrome (PCOS) demonstrated worse verbal fluency, verbal memory, manual dexterity, and visuospatial working memory performance, but reported higher levels of anger than healthy, matched control women. Women with PCOS also reported lower levels of sexual cognition and arousal than healthy controls. In Study 3, women with PCOS were randomly assigned to receive 3 months of treatment with an anti-androgen or placebo. Anti-androgen treatment resulted in significant reductions in free T levels and in improvements in verbal fluency performance. Taken together, the results of these three studies suggest that T has a detrimental effect on aspects of cognitive functioning in women, particu

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