Coordination of Ovulation and Oocyte Maturation: A Good Egg at the Right Time

Abstract

Ovulation is the appropriately timed release of a mature, developmentally competent oocyte from the ovary into the oviduct, where fertilization occurs. Importantly, ovulation is tightly linked with oocyte maturation, demonstrating the interdependency of these two parallel processes, both essential for female fertility. Initiated by pituitary gonadotropins, the ovulatory process is mediated by intrafollicular paracrine factors from the theca, mural, and cumulus granulosa cells, as well as the oocyte itself. The result is the induction of cumulus expansion, proteolysis, angiogenesis, inflammation, and smooth muscle contraction, which are each required for follicular rupture. These complex intercellular communication networks and the essential ovulatory genes have been well defined in mouse models and are highly conserved in primates, including humans. Importantly, recent discoveries in regulation of ovulation highlight new areas of investigation.

Figure 1.

Essential genes coordinating ovulation and oocyte maturation within the ovarian follicle. (1) Cumulus cell specification occurs as oocyte-secreted factors (OSFs) differentiate their adjacent granulosa cells into the cumulus cell lineage. Cumulus cells directly communicate with the oocyte and vice versa through transzonal projections (TZPs). (2) The LH surge binds LH receptors (LH-R) expressed on mural granulosa cells and activates ERK1/2 kinases, which in turn induce the expression and secretion of epidermal growth factor–like ligands (EGF-Ls), as well as production of a cohort of transcription factors, including CCAAT enhancer–binding protein (C/EBP)α/β and progesterone receptor (PGR). (3) EGF-Ls induce the production of cumulus matrix proteins, such as pentraxin 3 (PTX3) and hyaluronan synthase 2 (HAS2), which cause cumulus oocyte complex (COC) expansion. Granulosa cells produce a suite of inflammatory [prostaglandin synthase 2 (PTGS2)], matrix (versican), and protease [a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-1)] genes that are essential for ovulation and that are biomarkers of oocyte quality.

Figure 2.

Recent advances provide new insights into the biological mechanisms linking ovulation and oocyte quality but also lead to new areas of investigation. Novel modes of communication between oocytes and somatic cells are emerging, yet their regulation by mechanisms intrinsic to the oocyte vs external maternal factors needs to be dissected. Cumulus expansion is essential for ovulation, and cumulus matrix genes are consistently identified as biomarkers of oocyte developmental competence; yet the function of this unique matrix is not understood. Ovulation can be observed in vitro using a few specialized culture systems, yet visualization in vivo would provide a more holistic view of follicular events, such as vascularization and inflammation. The discovery of leukemia inhibitory factor as a mediator of ovulation in primates highlights that there are some differences with mouse models, which likely also include the bioactivity of oocyte-secreted factors.