|dc.description.abstract||Polycystic ovary syndrome (PCOS) is a common and complex endocrine condition with
reproductive and metabolic complications, affecting up to 10% of reproductive-age women.
Hyperandrogenemia, ovulatory dysfunction, and luteinising hormone hypersecretion are
characteristic traits of PCOS however, it seems that the most concerning long-term key issues
are metabolic problems associated with the syndrome, such as hyperinsulinemia, insulin
resistance, obesity, dyslipidaemia and non-alcoholic liver disease.
Despite the numerous studies on PCOS, its origin and pathophysiology are still not fully
understood. However, there is increasing evidence that the adult PCOS phenotype is
programmed in fetal life by androgen excess. Exposure to increased levels of testosterone in
utero in rodents, sheep and monkeys result in adult reproductive and metabolic pathologies
that parallel those seen in PCOS women. Since hyperandrogenemia is a hallmark of PCOS
and daughters of PCOS mothers have elevated levels of androgens at birth, it is likely that
prenatal androgenisation during early life predispose to the future development of PCOS.
Animal models of PCOS provide an opportunity to examine the developmental aetiology and
molecular mechanisms underlying the pathogenesis of this condition. Over last 10 years our
lab has successfully utilised a well-established ovine model of PCOS, where pregnant ewes
were treated with testosterone propionate (TP) through mid-gestation. From this model, we
had a large sample bank of fixed and frozen tissues from the fetal, lamb and adolescent
prenatally androgenised animals that allowed to carry a broad range of experiments. In
addition, a new cohort of prenatally androgenised adult sheep enabled additional in vivo
analysis. Past research documented that prenatal androgenisation result in hyperinsulinemia
with altered pancreas structure and function, and early fatty liver without difference in body
weight in adolescent sheep. This thesis examines the effects and consequences of increased in
utero androgen exposure on metabolic dysregulation in adolescent and adult female sheep.
During puberty, but not fetal or early life, there was decreased adipogenesis in subcutaneous
adipose tissue (SAT), but not visceral adipose tissue (VAT), accompanied by decreased
circulating concentrations of fibroblast growth factor 21 (FGF21), leptin and adiponectin, and
increased concentrations of fasting free fatty acids (FFA) in prenatally androgenised sheep.
This was countered by upregulated expression of FFA transporters in liver. As adults, TP-exposed
animals had increased body weight, elevated fasting insulin and FFA concentrations
but normal FGF21, leptin and adiponectin levels. Histological analysis revealed that adult TP-exposed
animals had SAT hypertrophy, which was associated with increased expression of
inflammatory markers and correlated with increased fasting FFA. Therefore, it is likely that
impaired preadipocyte differentiation in SAT during adolescence resulted in hypertrophy and
inflammation of adult SAT. This consequently lowered capacity of SAT to safely store fat and
potentially explains metabolic perturbations observed in PCOS-like female sheep.
To further investigate potential causes of obesity in adult PCOS-like sheep postprandial
thermogenesis (PPT), an important constituent of energy expenditure, was measured through
implantation of datalogger thermometers into interscapular adipose tissue. Adult prenatally
androgenised sheep had decreased amplitude of PPT, without difference in basal body
temperature, despite receiving the same caloric intake, and independent of obesity. These
findings indicate that adult PCOS-like sheep have reduced capacity for energy expenditure,
which is mirrored in women with PCOS. This reduced capacity for postprandial thermogenesis
was correlated with hyperinsulinemia decreased noradrenaline levels and reduced thermogenic
potential of brown and/or beige adipose tissue. This suggests that women with PCOS might
be prenatally programmed to become obese.
In summary, findings documented in this thesis provide better understanding into the
pathophysiology of PCOS from puberty to adulthood and give opportunities for early clinical
intervention to ameliorate the metabolic phenotype of PCOS.||en
|dc.relation.hasversion||Ramaswamy S, Grace C, Mattei AA, Siemienowicz K, Brownlee W, MacCallum J, et al. Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion. Sci Rep. 2016;6:27408.||en