The endocrine and local control of ovarian follicle development in the ewe

Follicle development can be divided into gonadotrophin-independent, gonadotrophin-responsive and gonadotrophin-dependent phases. The basic level of control of folliculogenesis lies with the actions of an extensively observed but poorly understood range of somatic and germ cell derived local factors that constitute an intrafollicular developmental cascade that regulates the proliferative and differentiative phases of follicle development. As follicle development progresses, the follicle become increasingly responsive to the actions of the pituitary gonadotrophins FSH and LH and during these phases of development local factors act to modulate the actions of gonadotrophins so that the fate of each follicle depends on an intrafollicular balance between local factors which augment or attenuate gonadotrophic actions. Gonadotrophins are therefore not a prerequisite for the continued growth of gonadotrophin-responsive pre-antral follicles, but FSH does appear to stimulate development and these actions are modulated by local growth factors, such as IGFs, AMH and BMPs. Naturally occurring mutations in sheep for a number of these factors or there receptors have provided insights into their roles during both the early and terminal stages of follicle development and we have recently produced extensive evidence supporting a major role for members of the BMP system in regulating follicle selection mechanisms through increased activation of gonadotrophic augmentors (BMP-6), decreased activation of attenuators (BMP-15, GDF-9, AMH) or a combination of these two mechanisms resulting in the deregulation of the normal follicle selection mechanisms. The terminal stages of follicle development, however, remain primarily under the control of the pituitary gonadotrophins, with both FSH and LH having essential and inter-related roles in regulating final maturation and selection of the ovulatory follicle and the oocyte which it contains.