Multiple roles of hypoxia in ovarian function: roles of hypoxia-inducible factor-related and -unrelated signals during the luteal phase.

There is increasing interest in the role of oxygen conditions in the microenvironment of organs because of the discovery of a hypoxia-specific transcription factor, namely hypoxia-inducible factor (HIF) 1. Ovarian function has several phases that change day by day, including ovulation, follicular growth and corpus luteum formation and regression. These phases are regulated by many factors, including pituitary hormones and local hormones, such as steroids, peptides and cytokines, as well as oxygen conditions. Hypoxia strongly induces angiogenesis because transcription of the potent angiogenic factor vascular endothelial growth factor (VEGF) is regulated by HIF1. Follicular development and luteal formation are accompanied by a marked increase in angiogenesis assisted by HIF1-VEGF signalling. Hypoxia is also one of the factors that induces luteolysis by suppressing progesterone synthesis and by promoting apoptosis of luteal cells. The present review focuses on recent studies of hypoxic conditions, as well as HIF1-regulated genes and proteins, in the regulation of ovarian function.