Gonadotropin and intra-ovarian signals regulating follicle development and atresia: the delicate balance between life and death

Abstract

Regulation of mammalian follicular development is tightly regulated by both cell death and survival signals, including endocrine (e.g. gonadotropin) and intra-ovarian regulators (e.g. Nodal and GDF9). The destiny of the individual follicle (growth/ovulation or atresia) is dependent on a delicate balance in the expression and action of factors promoting follicular cell proliferation, growth and differentiation, and of those promoting programmed cell death (apoptosis). Development of the follicle from the primordial to preantral stage is regulated by oocyte-derived factors including GDF9 and BMP15, and is not dependent on gonadotropin support (gonadotropin-independent stage). As the follicle transits into the early antral stage it becomes responsive to gonadotropin (gonadotropin-responsive stages) and further development renders the follicle completely dependent on the presence of gonadotropin while modulated by intra-ovarian regulators (gonadotropin-dependent). Follicle fate is also regulated by pro-apoptotic factors such as the intraovarian regulator Nodal, which is secreted by the theca and promotes apoptosis of differentiated granulosa cells through a mechanism involving Smad2 signaling and suppression of the PI3K/Akt pathway. The intracellular protein prohibitin (PHB) appears to have a dual role during folliculogenesis; acting as a cell survival factor in undifferentiated cells, and as a pro-apoptotic factor following differentiation. Further investigations of the interplay between these endocrine and ovarian regulators will lead to a better understanding into the regulation of follicular development and atresia, allowing development of new techniques for assisted reproduction.

Caspase‐2L, caspase‐9, and caspase‐3 during in vitro maturation and fragmentation of the mouse oocyte

“…Whereas few follicles pursue their growth and reach the ovulatory stage, most degenerate by atresia during the animal's lifetime, together with the oocytes they enclose. The fate of an individual follicle, growth/ovulation or atresia, depends on a delicate balance between factors promoting follicular cell proliferation, growth, and differentiation, or programmed cell death (Craig et al, 2007). It is now widely accepted that the somatic follicular cells surrounding the oocyte die by apoptosis (Hughes and Gorospe, 1991;Tilly et al, 1991;Johnson and Bridgham, 2002;Matsuda-Minehaya et al, 2006).…”

The roles of glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor and nerve growth factor during the final stage of folliculogenesis: a focus on oocyte maturation

“…Considerable insights have been gained into understanding the factors and mechanisms that regulate the assembly, growth and development of ovarian follicles, from the initial differentiation of primordial follicles to the proliferation of granulosa cells and the ability of later stage follicles to respond to FSH, which are the topics reviewed elsewhere (Dierich et al 1998, Kezele et al 2002, Skinner 2005, Craig et al 2007. Over the last several decades, neurotrophic factors, originally identified as affecting cells of the CNS, have also been recognized to play important roles in peripheral tissues, including the highly innervated ovary.…”

Concentrations of bone morphogenetic protein-15 (BMP-15) and growth differentiation factor-9 (GDF-9) in follicular cysts, mono - and polyoocyte follicles in gilts

“…Follicles selected for further development are thought to receive precise gonadotropic and intra-ovarian regulatory signals for survival, whereas follicular atresia is a consequence of inadequate growth support [27]. Since ovarian dysfunctions are the consequence of this transitional stage-specifi c dysregulated follicle growth, understanding the molecular and cellular mechanisms in the control of follicular development during the preantral early antral transition may provide important insight into the pathophysiology of these conditions [28].…”