Medicine: Department of Surgery and Cancer, Imperial College London
Doi
Abstract
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
