The ovarian antral follicle: living on the edge of hypoxia or not?

Abstract

Oocytes within antral follicles are thought to have restricted access to oxygen (O2) as the follicle vascularity is not adjacent and both granulosa and cumulus cells are metabolically active. Indeed, measured follicular antrum pO2 is regarded as low, but accurate and direct measurement represents a technical challenge that has yet to be overcome. The oocyte itself is highly dependent on oxidative phosphorylation for survival and competence for further development following fertilization, and it has been suggested that follicular pO2 levels are correlated with this capacity for further development. It is clear that gonadotrophins are involved in regulating antrum formation, follicle vascularization, cellular differentiation and the Hypoxia Inducible Factors (HIF), which are mainly regulated by dissolved O2 concentration. A newly discovered player in this story is the intracellular production of hemoglobin by both granulosa and cumulus cells, as well as the oocyte. Furthermore, cellular hemoglobin levels are dynamic, responding to the ovulatory luteinizing hormone (LH) surge. We hypothesize that this gas transport and antioxidant molecule is involved in: (a) the prevention of hypoxic-response signaling via HIFs within the pre-ovulatory antral follicle; (b) the transition of granulosa cells to luteal tissue, by facilitating the stabilization of HIFs, enabling the induction of luteinization signaling. Another possible role is via sequestering nitric oxide (NO) during the ovulatory period, which may facilitate the resumption of meiosis in the oocyte. Testing these hypotheses will be challenging, but important if the regulation of ovarian function is to be fully understood.