A review on human reproductive systems encountering with the severe acute respiratory syndrome coronavirus 2 infection

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the leading cause of the new deadly pneumonia named coronavirus disease 2019 (COVID-19) pandemic. This pathogen has different co-receptors on various tissues, resulting in vast pathophysiological circumstances. Here, we present a comprehensive narrative review focusing on the impact of SARS-CoV2 on human reproduction. Evidence-based literature revealed inconsistent results for this virus in the reproductive organs of patients with COVID-19, even in the critical phase. Conversely, numerous satisfactory data represented those different reproductive activities, from gametogenesis to pregnancy, can be targeted by SARS-CoV2. The severity of COVID-19 depends on the differential expression of the host cellular components required to enter SARS-CoV2. The cytokine storm and oxidative stress coming out during COVID-19 are associated with complications in reproductive endocrinopathies. Men are naturally more susceptible to COVID-19, especially accompanied by orchitis and varicocele. Synergistically the interaction of SARS-CoV2 and female reproductive failures (polycystic ovary syndrome and endometriosis) increases the susceptibility to COVID-19. Thus, pharmaceutical interventions that ameliorate the complications in individuals with reproductive disorders can be helpful to achieve good outcomes in assisted reproductive techniques. Soon, an increase in the infertility rate will likely be an overall impact of SARS-CoV2 in patients who recovered from COVID-19.


Introduction
The severe acute respiratory syndrome  (4). However, the ACE-2 receptor is highly expressed in the small intestine, male and female reproductive systems, kidney, heart, and thyroid, moderately expressed in the lung, liver, bladder, colon, and adrenal gland, and slightly in the brain, spleen, bone marrow, and blood cells (5). Also, the reproductive system is not permissive to this viral infection, and the problems caused by COVID-19 can be associated with reproductive failures (10).

SARS-2 and complications in the male reproductive system
The renin-angiotensin system plays a pivotal role in the regulation of male hormones (testosterone) and the production and concentration of sperms in the testis and epididymis. ACE-2 is differentially expressed in various regions of the male reproductive system. The ACE-2 level is high in Leydig, Sertoli, spermatogonia, prostate epithelial cells, and fibroblast cells. Therefore, these cells are likely to be targeted by SARS-2. In contrast, these targets have low-expression levels in the prostate's hillock area and club cells (11).
Also, ACE-2 is slightly expressed in spermatocytes, spermatids, and other somatic cells. This molecule in Leydig cells modulates the production of testosterone, the production volume of semen, and the health of sperms (11,12

SARS-2 in direct or indirect paths?
It is still not clear whether the sex organs such as the testis, epididymis, and sex glands are directly infected by SARS-2 itself or indirectly by the infection of the renal system (14). It is also surprising how this virus reaches the reproductive system. But according to recent reports, these events are more likely to happen through viremia (15). The other possibility is that due to the nature of SARS-2 and the increased temperature of the body during the pathogenesis of COVID-19, the blood/testis barrier can be damaged by these temperature changes, especially in the testis sac (scrotum). Therefore, the direct presence of the virus itself is not needed for the complications in the male reproductive organs.
On the other hand, the influence of SARS-2 on different tissues, especially the brain, and uncontrolled inflammation, such as cytokine storm and disturbance in hormone secretion,

SARS-2 and ROSs generation as a big challenge
The oxygen-free radicals (hydroxyl and

SARS-2 in semen: A conflicting noise
SARS-2 has been detected in many body fluids.
This virus is present in the semen in vitro even  Table I presents evidence showing conflicting data on the presence of SARS-Cov2 in the male reproductive system during the critical phase of COVID-19, particularly in intensive care unit (ICU) patients.
As a result, a meta-analysis is needed to further clarify the association between the severity of COVID-19 and complications in the male reproductive system.

Putative mechanisms of men's high susceptibility to COVID-19
There is convincing evidence that the risk of COVID-19 in men is higher than in women, without

Sensitivity of female reproductive system to SARS-CoV2 infection
Because of endocrine changes in the female reproductive system, the expression of ACE-2 and its proteases varies during the different menstrual cycles (puberty, pregnancy, and menopause).  Table II provides evidence for the complications in women with COVID-19, particularly in ICU.

Conflict of Interest
The authors do not have any affiliation beside any organization as an indirect or direct financial contribution the subject matter mentioned in the manuscript.
All authors have taken part in (1)  We have not submitted this manuscript yet, furthermore it is not under review with another journal or publishing venue.