Androgen receptor mediated activity in the ovary : implications for Polycystic Ovary Syndrome
Date
2006
Authors
Hickey, Theresa E
Editors
Advisors
Norman, Robert John
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Thesis
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Abstract
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.
School/Discipline
School of Paediatrics and Reproductive Health
Dissertation Note
Thesis (Ph.D.)--School of Paediatrics and Reproductive Health, 2006.
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