Abstract
Ovarian follicles mature through preantral and antral stages before reaching the preovulatory stage, however, in anovulatory polycystic ovary syndrome (PCOS) this maturation is disrupted, resulting in an accumulation of small and medium antral follicles that undergo repeated atresia and repeated ovulatory failure. The maturation and selection of follicles that reach the preovulatory stage is dependent on positive and negative feedback mechanisms between the brain and ovary. Inhibin and oestradiol (E2) are the primary negative and positive regulators produced by the ovary, suppressing follicle stimulating hormone (FSH) and promoting luteinising hormone (LH), respectively, yet their expression patterns across follicle development in mice is not well detailed. It was hypothesised that in anovulatory PCOS, the increased number of small and medium antral follicles produces an excessive amount of inhibin, preventing follicle growth to a stage where E2 can stimulate maturation and ovulation. The expression of these two hormones was examined across the stages of folliculogenesis and the oestrous cycle in wildtype mice via the inhibin-α subunit (inhibin), and CYP17A1 and aromatase (E2) hormones. Experiments were also performed to determine if pulsatile hypersecretion of LH or a generalised increase of LH develops follicles to a stage where they are capable of producing inhibin and upregulating aromatase. Mathematical modelling was utilised to estimate the endocrine-producing capacity of small and medium antral follicles associated with altered follicle populations in PCOS, to conceptualise whether increased inhibin is a plausible cause of anovulatory PCOS. This thesis finds that in mice, inhibin and CYP17A1 are first produced in small antral follicles and progressively increase as follicles develop to the preovulatory stage, whilst aromatase shows minimal expression in the early antral stages, becoming upregulated at the dominant large antral and preovulatory stages. Additionally, inhibin is found to downregulate immediately before ovulation. Chronic LH promoted premature ovulation once follicles reached the dominant stage, while pulsatile LH hypersecretion resulted in increased numbers of small and medium antral follicles, with no development of dominant follicles, reminiscent of anovulatory PCOS. Follicles from both groups retained the ability to produce inhibin but did not show upregulated aromatase. Mathematical modelling illustrated a 2-3 fold increase in small and medium antral follicle numbers, as iii seen in PCOS, is capable of secreting an equivalent amount of inhibin as the dominant follicle cohort in healthy mice, suggesting that excessive inhibin during the early follicular phase could be responsible for the repeated atresia seen in anovulatory PCOS. This work provides the first detailed characterisation of inhibin production in the female mouse. Together, these findings indicate that inhibin production begins prior to the upregulation of aromatase and synthesis of E2, indicating a greater influence on early follicle dynamics, and that the larger population of early antral follicles could produce enough inhibin to suppress FSH and cause repeated atresia in anovulatory PCOS.