COVID-19 has negative impact on female fertility, finds Fert- Sert Study
Since the beginning of the COVID-19 pandemic, heightened attention has been given to angiotensin converting enzyme 2 (ACE2) as it acts as an entry receptor for SARS-COV-2, a novel strain of the virus that causes COVID-19. However, this role of ACE2 in the viral cellular entry is in contrast to its original reported function as a component of the renin-angiotensin system (RAS).
The ovary undergoes constant remodeling and cyclic ovulation that requires precisely controlled angiogenesis and an acute inflammatory response. Given that ACE2 has been shown to play an important role in both angiogenesis and inflammatory responses, it is conceivable that this enzyme is expressed and involved in these processes in the human ovary. Moreover, accumulating evidence indicates that SARS-COV-2 can infect multiple organs including the ovary, but the long term health impact of COVID-19 is yet to be determined. Therefore, it is critically important to assess the expression of ACE2 in the human ovary.
In the present study, Choi Y et al sought to: 1) characterize the expression pattern of ACE2 (mRNA and protein) using dominant follicles collected before the LH surge and throughout the periovulatory period from naturally cycling women with ovulation induced by hCG and 2) dissect the cellular regulatory mechanism controlling ACE2 expression using primary human granulosa/lutein cells.
It was an experimental prospective clinical study and laboratory-based investigation carried out at University Medical Center and private IVF center. Thirty premenopausal women undergoing surgery for tubal ligation and 16 premenopausal 8 women undergoing IVF were included. Intervention included administration of hCG and harvesting of preovulatory/ovulatory follicles by timed laparoscopy and collection of granulosa/lutein cells and cumulus cells at the time of oocyte retrieval. Main outcome was to detemine expression and localization of ACE2 in granulosa cells and dominant follicles collected across the periovulatory period of the menstrual cycle and in hGLC using qPCR, immunoblotting, and immunohistochemistry.
ACE2 expression (mRNA and protein) is up-regulated in human ovulatory follicles after hCG administration. ACE2 expression was higher in cumulus cells than granulosa cells. hCG increased the expression of ACE2 in primary hGLC cultures, but the increase was inhibited by both RU486 (an antagonist for progesterone receptor and glucocorticoid receptor) and CORT125281 (a selective glucocorticoid receptor), but not by AG1478 (an EGF-receptor tyrosine kinase inhibitor) or by dexamethasone.
In the present study, authors revealed that the expression of ACE2, an enzyme with carboxypeptidase activity and a primary receptor for SARS-COV-2, is rapidly and dramatically induced after hCG administration in dominant follicles obtained from naturally cycling women throughout the periovulatory period. Using the primary hGLC model that can recapitulate key ovulatory changes in gene expression, this study further provided experimental evidence that the ovulatory induction of ACE2 expression was mediated by hCG and hCG-induced steroid hormones, progesterone and glucocorticoid, in ovulatory follicles. Noteworthy is also the finding of the higher expression of ACE2 in cumulus cells than granulosa cells collected immediately prior to ovulation. Together, not only does this novel information suggest the potential involvement of ACE2 as a critical enzyme for the LH surge-induced cyclic events of ovulation, cumulus expansion, oocyte maturation, and luteal formation, but also implicate the possible impact of COVID-19 in vital cyclic ovarian functions, thus women's overall reproductive health.
Another intriguing finding is the unique localization pattern for ACE2 protein observed in human ovulatory follicles. The initial induction of ACE2 staining was localized evenly throughout the granulosa and theca cell layer during the early ovulatory phase, and then, the staining became more intense and progressively more sporadic among cells when the dominant follicle progressed toward ovulation and transformed into the CL.
The uneven, localized staining of ACE2 did not appear to be in non-follicular cells such as endothelial cells or leukocytes when compared to PECAM1 staining pattern in serial sections of the same follicle. Consistent with this finding, qPCR analysis of ACE2 mRNA levels showed little to undetectable levels of ACE2 mRNA in leukocytes compared to granulosa cells. One possible explanation for this unique localization pattern might be that ACE2 exists in two different forms: the membrane-bound form and secreted form.
During the early ovulatory phase when the level of ACE2 mRNA was rapidly up-regulated, ACE2 would have been processed and expressed as a single-pass type I membrane protein. Then, with the progression toward the late and post ovulatory phases, the enzymatically active extracellular domain of ACE2 could be cleaved, released, and aggregated onto specific cells or the area where the substrates for ACE2 are present. This possibility needs to be explored in future studies.
In the scenario of SARS-COV-2 infection in the ovary, this virus could elicit negative impacts on female fertility, not only by blocking the physiological action of ACE2 necessary for oocyte maturation, ovulation, and CL formation but also destroying a mature oocyte and ovulatory follicle.
The hormone-regulated expression of ACE2 in granulosa cells suggests a potential role of ACE2 in the ovulatory process. These data also implicate the possible impact of COVID-19 in a vital cyclic event of ovarian function, thus women's overall reproductive health. However, SAR-COV-2 infection in ovarian cells in vivo or in vitro has yet to be determined.
Source: Choi Y, Jeon H, Brännström M, Akin JW, Curry Jr. TE, Jo M, The ovulatory up-regulation of ACE2, a receptor for SARS-COV-2, in dominant follicles of the human ovary., Fertility and Sterility (2021),