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Title: Exploration of the role of androgens and adipokines in the development of polycystic ovary syndrome
Author: Comim, Fabio Vasconcellos
ISNI:       0000 0004 2710 2226
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women being characterized by reproductive and metabolic abnormalities. Our hypothesis is that overproduction of ovarian androgens during early development is a key factor in the development of PCOS. The objective of the work in this thesis was to explore, using both an animal model of PCOS and human ovarian tissue, the role of androgens in the development of the ovarian abnormalities in PCOS and how these relate to disorders in fat metabolism. The expression of the key steroidogenic enzymes in androgen biosynthesis was determined in histological sections of polycystic and normal ovaries. Results supported the concept of intrinsic up-regulation of P450c17 enzyme in theca cells. In ovaries from ewes exposed prenatally to excess androgen, a similar disruption of P450c17 was observed along with increased androgen receptor expression and increased granulosa cell proliferation in preantral follicles. The interaction of adipokines and ovarian function was studied using both human ovarian tissue and bovine theca cells in culture. A significant decrease in the expression of the protein for adiponectin receptor 1 and 2 was detected in theca cells from polycystic ovaries in comparison with ovaries from normal women. In bovine theca cells, the administration of adiponectin, but not other adipokines (leptin, visfatin, resistin) resulted in a decrease in androstenedione production, accompanied by significant reduction of gene expression of key steroidogenic enzymes. In addition, the knockdown of genes for ADIPOR1 and ADIPOR2 was associated with higher rates of androstenedione secretion by theca cells. In summary, these results support the hypothesis that dysregulation of ovarian follicle development and androgen production can be induced by prenatal androgenisation. The results also provide evidence of a link between fat cell metabolism and steroidogenesis which is important in understanding the development of metabolic abnormalities in PCOS.
Supervisor: Franks, Steve ; Hardy, Kate Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral