Research sheds light on the role of ACE2 in ovulation

Angiotensin converting enzyme 2 (ACE2) is involved in vital cyclic ovarian functions and thus COVID-19 may impact female reproductive health.

It is known that SARS-CoV-2, the virus which causes the disease COVID-19, enters cells via ACE2 receptors. These receptors are present on the surface of many cell types, including those of the human female reproductive tract. This current study conducted by Dr Misung Jo's lab at the University of Kentucky College of Medicine, aimed to discover the expression of ACE2 in the human ovary throughout the follicular phase, which accounts for the first half of the menstrual cycle, and is also known as the periovulatory phase.

The scientists state in their paper: 'Our comprehensive in vivo study... is the first report documenting the ovulatory induction of ACE2 expression in naturally cycling women and the only report showing the dramatic and rapid up-regulation after ovulatory induction among any species studied so far.'

The ovary undergoes a series of cyclic changes during the menstrual cycle that requires precisely controlled angiogenesis and an acute inflammatory response. ACE2 is known to play an important role in both angiogenesis and inflammatory responses, the scientists propose that ACE2 may also be expressed and involved in these processes in the human ovary.

The cyclic changes are initiated by a surge in luteinising hormone (LH), which induces the expression of specific genes. The proteins produced exert their biological actions to bring about necessary cellular and extracellular changes required for ovulation and early pregnancy.

Thirty premenopausal women undergoing surgery for tubal ligation and 16 premenopausal women undergoing IVF took part in the study. Dominant follicles were collected before the LH surge and throughout the follicular phase from patients who had ovulation induced by human chorionic gonadotropin (hCG), which is a hormone normally produced by the placenta. The follicles were processed for immunohistochemical or gene expression analysis.

Published as a journal pre-proof in Fertility and Sterility, this study revealed that the expression of ACE2 is quickly induced after hCG administration throughout the follicular phase of ovulation.

This study further provided evidence that the induction of ACE2 expression in the ovaries was mediated by hCG and hCG-induced steroid hormones, progesterone and glucocorticoid, in ovarian follicles.

The scientists also set out to discover whether ACE2 is also expressed in cumulus cells, a cluster of cells that surround and protect the egg, and granulosa cells, which surround the oocytes as they grow. They collected cumulus and granulosa cells, immediately prior to ovulation, from women undergoing IVF procedures at the time of oocyte retrieval and found the expression of ACE2 in both cell types. However, the levels were higher in cumulus cells compared to those in granulosa cells from all patients tested.

This research suggests the potential involvement of ACE2 as a critical enzyme for the LH surge-induced cyclic events of ovulation. Furthermore, this may implicate the possible impact of COVID-19 in vital cyclic ovarian functions and women's overall reproductive health.

The scientists conclude that 'our current findings showing the rapid and dramatic induction of ACE2 expression... offer a compelling possibility that the ovary could be a target of SARS-CoV-2, [which is] particularly vulnerable during the periovulatory period.'