HIF-1α Promotes Luteinization via NDRG1 Induction in the Human Ovary

Background/Objectives: Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays a crucial role in various physiological and pathological processes of the ovary. However, the timing of HIF-1α expression and its specific biological function in the follicular development of the human ovary remain unclear. Therefore, in this study, we aimed to examine whether HIF-1α and its downstream gene, N-myc downstream-regulated gene 1 (NDRG1), exhibit stage-specific expression during the follicular development process in the human ovary. Methods: We used ovarian tissues from eight women with regular menstrual cycles who were not undergoing hormonal treatment. We investigated HIF-1α and NDRG1 expression and localization using immunohistochemistry. Further, we transfected human ovarian granulosa (KGN) cells with HIF-1α small interfering RNA (siRNA) to investigate the influence of HIF-1α on NDRG1 expression and progesterone synthesis. Results: The immunohistochemical analysis of human ovarian tissues revealed that HIF-1α was localized in the cytoplasm of granulosa cells (GCs) at both the primary and secondary follicular stages. Conversely, in tertiary and later developmental stages, HIF-1α was observed exclusively in the nucleus of GCs. Furthermore, while NDRG1 was not detected in primary follicles, it was present in all GCs beyond the tertiary stage. Notably, transfection of KGN cells with HIF-1α siRNA significantly decreased NDRG1 expression, at both the mRNA and protein levels, and in progesterone synthesis. Conclusion: Our results indicate that HIF-1α and NDRG1 are integral to follicular development and the early luteinization of pre-ovulatory follicles.