Is There a Role for SARS-CoV-2/COVID-19 on the Female Reproductive System?

Silvia D'Ippolito, Francesca Turchiano, Amerigo Vitagliano, Gennaro Scutiero, Antonio Lanzone, Giovanni Scambia, Pantaleo Greco, Silvia D'Ippolito, Francesca Turchiano, Amerigo Vitagliano, Gennaro Scutiero, Antonio Lanzone, Giovanni Scambia, Pantaleo Greco

Abstract

Coronavirus disease (COVID-19) has emerged as a very serious pandemic caused by the rapidly evolving transmission of the coronavirus SARS-CoV-2. Since its outbreak in 2020, the SARS CoV-2 has represented an important challenge for the physicians due to its well known respiratory sequelae. To date, the role of SARS-CoV-2 infection on organs and systems other than lungs and respiratory tract remains less clear. In particular, it remains to be investigated whether the reproductive system can be affected by the SARS-CoV-2 in the long term-period or, in alternative, drugs used to treat COVID-19 might impact the reproductive systems and, in turn, fertility. What is known is that SARS-Cov-2 binds to target cells of host through different receptors including angiotensin-converting enzyme 2 (ACE2), neuropilin-1, AXL and antibody-FcɣR complexes. ACE2 physiologically regulates both the expression of angiotensin II (Ang II) as well as Ang-(1-7) to exerts its physiological functions. The reproductive system abundantly expresses ACE2 and produces Ang-(1-7), starting from precursors which are locally generated or derived from systemic circulation. Ang-(1-7) plays an important role of stimulus to the growth and maturation of ovarian follicle as well as to ovulation. Also human endometrium expresses Ang-(1-7), mainly during the post-ovulatory phase. Animal and human observational studies demonstrated that Ang-(1-7) is involved in the maternal immune response to pregnancy and its deficiency is associated with a defective placenta development. In our manuscript, we review the current knowledge about whether SARS-CoV-2 may impact the female reproductive system. We further explain the possible molecular mechanism by which SARS-CoV-2 might affect ovarian, endometrial and female genital tract cells.

Keywords: Coronavirus disease (COVID-19); SARS-CoV-2; SARS-CoV-2 colonization; female fertility; pregnancy.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 D’Ippolito, Turchiano, Vitagliano, Scutiero, Lanzone, Scambia and Greco.

Figures

FIGURE 1
FIGURE 1
Human coronaviruses (HCoVs) comparison of RNA Features, Receptor, Receptor binding sites, Timeline. To date, seven human coronaviruses (HCoVs) have been detected: HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, severe acute respiratory syndrome coronavirus (SARS-CoV*), Middle East respiratory syndrome coronavirus (MERS-CoV**) and SARS-CoV-2***. Four of these viruses, including HCoV-229E, -NL63, -HKU1, and -OC43, usually cause mild-to-moderate respiratory diseases with a seasonal pattern. Three new HCoVs have recently emerged with a significant mortality rate. Despite the fact that all HCoVs share similarities in viral replication, they differ in their accessory proteins, incubation period and pathogenicity (Modified by Kesheh et al., 2021).
FIGURE 2
FIGURE 2
Epidemics Human Coronaviruses (HCoVs) structure of genome. The genomes of epidemics Human CoVs contain a single-stranded, positive-sense RNA ranging of 27–32 kb in size. One third of the genome, expressed at the 3′ terminal, encodes the main proteins of the virus involved in the virus-cell receptor binding and virion activity. In particular, four structural proteins: E: envelope protein, M: membrane protein, N: nucleocapsid protein, S: spike protein. The S protein of HCoVs consists of two subunits, S1 and S2. S1 subunit consist of a C-Terminal Domain (CTD) – also named Receptor Binding Domain (RBD) – and a N-Terminal Domain (NTD). S2 subunit contains a fusion peptide (FP), transmembrane domain (TM) region, heptad repeat 1-2 (HR1, HR2). SP, signal peptide; CP, cytoplasmic peptide; ORF, open reading frame (Modified by Zhao et al., 2020b).

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