Mechanisms regulating ovarian reserve
The population of follicles within the mammalian ovary declines steadily with age. The majority of follicles in the ovary are at the primordial (resting) stage of development, each consisting of a small oocyte surrounded by a single layer of flattened granulosa cells (GCs). The rate at which follicles enter the growing phase, involving oocyte growth and GC shape change and proliferation, is a major determinant of the rate at which the reserve of primordial follicles is depleted. Deviations in the rate at which follicles initiate growth will have a significant bearing on fertility, the age of the menopause and disorders of ovulation in women, such as primary ovarian failure and polycystic ovary syndrome (PCOS). Studies of follicle development in mice lacking specific genes, and in ovaries or pieces of ovary cultured under different conditions in vitro, suggest that early follicle development is mainly regulated by local growth factor signals. However, while a number of growth factors have been implicated in early follicle development, particularly members of the transforming growth factor-β superfamily, the source and identity of the factor or factors that signal a follicle to start growing remain unclear. We have recently developed an alternative strategy for identifying the source and action (stimulatory or inhibitory) of local signals by analysing the spatial distribution of primordial and growing follicles within the ovary. These studies have provided insight into the local ovarian signals that determine whether a follicle is quiescent or starts to grow and provide us with important leads in the investigation of candidate growth factor pathways. Such studies will provide a better understanding of, and treatments for, ovarian disorders.