Since the COVID-19 pandemic started in December 2019, much more information has become available to understand the course of the disease, to evaluate the systems it affects, and to prevent its spread. Evaluating the adverse effects of different organ systems on humans over time, including the male reproductive system, remains an important issue for clinicians [12]. The testicles are mainly composed of seminiferous tubules and intertubular tissue. The seminiferous tubules are where semen is produced. Tubules consist of sperm-producing cells (spermatogonia) and supporting Sertoli cells.
ACE2 is highly expressed in testicular cells, principally observed in spermatogonia, Leydig, and Sertoli cells [9],[13],[14]. The spermatogenesis process will be affected if the virus damages these cells [15]. Consequently, the testis may likely be a potential target for SARS-CoV-2. The presence of ACE2 and transmembrane serine protease 2 (TMPRSS2) along the male genitourinary tract cause the male reproductive organs to become vulnerable to the harm of SARS-CoV-2 infection. The effect of testosterone on these organs and the presence of the androgen receptor supporting the TMPRSS2 gene are likely to further explain viral uptake [9],[16]. Angiotensin 2 also affects sperm fertilization and motility by stimulating the angiotensin 2 type 1 receptor (AT1R) and type 2 receptor (AT2R) [17],[18]. Prolonged high levels of Angiotensin 2 can result in apoptosis and cellular senescence in sperm cells.
In recent years, researchers have shown that the SARS-CoV-2 virus interacts with human spermatozoa and may play a significant role in the pathogenesis of male fertility[17]. These cells are likely to have the complete repertoire of receptors needed to support angiotensin signaling pathways, including ACE2, the cellular entry point of the coronavirus. It can thus be suggested that the angiotensin system plays an essential role in sustaining sperm viability and function, and contact with the virus will have adverse effects on reproductive system of infected males [17]. Previous meta-analysis has reported that the effects of COVID-19 on the male reproductive system may involve several mechanisms. Firstly, the combination of SARS-CoV-2 and ACE2 might directly harm sperm or testicular function. Second, the immune response to COVID-19 might adversely affect the male reproductive system, and finally, the effect of hormone levels on male fertility [15].
So far, few studies have examined the association between semen analysis and COVID-19. Li and colleagues were one of the first to examine the testicular and epididymal autopsies of patients who died from COVID-19. They detected interstitial edema, congestion, and red blood cell exudation in these organs [12]. It has been noted that the concentration of apoptotic cells in the seminiferous tubules of patients who died due to COVID-19 was significantly higher compared to control cases. Li et al. also found oligozoospermia, leukospermia, and increased interleukin-6 (IL-6) levels in semen from inpatient COVID-19 patients [12]. In another study, Holtmann et al. grouped patients as mild and moderate symptomatic according to the severity of COVID-19 symptoms [19]. The design of the study was based on investigating the effects of symptomatic severity on semen analysis by comparing it with a control group. The cohort was divided into two groups according to mild symptoms and control groups. The authors revealed that patients with moderate symptoms had impaired total sperm count and total motility. However, no abnormality was found in the semen analysis of the mildly symptomatic group. In addition, the participants were divided into two groups based on with and without fever. Although impairment in semen analysis parameters was observed in the group with fever, the values were within normal limits. Ruan et al. [20] compared the patients with COVID-19 with a control group. Sperm concentration, total sperm count, and total motility were significantly decreased in the group with COVID-19, but the values were within the normal range. Also, different COVID-19 symptom groups made no significant difference in semen parameters. The paper noted that semen parameters may deteriorate in patients with a longer recovery period. Gacci et al. investigated the presence of the SARS CoV-2 genome in the saliva, urine, semen, and post-ejaculatory urine of 43 sexually active men who had recovered from COVID-19 and its impact on semen parameters. Reporting low levels of the SARS-CoV-2 genome in the biological fluid sample, the authors also reported oligozoospermia and azoospermia in a few of the patients [24]. It has been suggested that the development of azoospermia was associated with the severity of COVID-19 since most of the azoospermic patients were in severe COVID-19 [21]. However, these findings are limited by a small sample size, inter-patient variation in the severity of COVID-19 infection, and inadequate study design [25]. These studies suffer from a lack of pre-COVID-19 data as a reference point and are instead based on comparisons with healthy controls [22]. Other studies have concluded that there is a significant reduction in total sperm count and total motility, which may be associated with direct sperm harm mediated by the SARS-CoV-2 [23],[24].
Previous study has documented a significant impact of COVID-19 on many parameters of semen quality, including semen volume, total motility, percentage of forward motile sperm, and normal sperm morphology [25]. Similarly, Erbay and colleagues grouped patients as mild and moderate symptomatic in a multicenter study. In this study in which semen analyses of COVID-19 patients at least three months after recovery were compared with the pre-COVID-19 period, Erbay et al. found that while vitality, progressive, and total motility decreased in mild symptomatic group compared to pre-COVID-19, all sperm parameters were negatively affected by the disease in the moderate symptomatic group [26]. Cases reported from an IVF clinic in India had semen analysis data pre- and post-COVID-19. Patients were normospermic pre-COVID-19, but semen analysis showed that the post-first month of COVID-19 revealed a dramatic decrease in sperm count, motility, morphology, and DNA integrity. The most surprising aspect of the data was that DNA and morphology continued to deteriorate in the 4th month post-COVID-19, and the sperm count and motility did not reach pre-COVID-19 levels [27].
This study was designed to compare patients’ pre-COVID-19 semen analysis with their post-COVID-19 parameters. To increase the objectivity of the comparison, patients with normal pre-COVID-19 semen analysis parameters were included in our study. Perhaps the most striking finding was that 40.9% of patients with normal semen analysis pre-COVID-19 had abnormalities in their post-COVID-19 semen analysis. When the patients were divided into two groups based on their semen analysis on post-COVID-19, we observed that semen pH was high and immotile sperm percentage increment in the abnormality group; motility, percentage of progressive motility, and morphology parameters were low levels. In addition, one of the patients with abnormal semen analysis had asthenospermia and five had asthenoteratospermia. There was no significant decrease in concentration and total sperm count compared with the normal group. These results support previous research on the significant effect of COVID-19 on various parameters [25],[26],[27].
To date, few studies have examined the association between the effect of COVID-19 infection on semen quality [22]. Maleki and Tartibian’s informative study make a valuable contribution in terms of suppressed semen volume, progressive motility, morphology, sperm count, and DNA integrity following COVID-19 infection. In addition, decreased semen quality, as well as increased sperm DNA damage, correlated with markers of oxidative stress and inflammation [28]. These results align with recent studies indicating that oxidative stress is a significant contributor to the impaired semen quality seen in patients following COVID-19 infection [29]. The research to date has not been able to show a link between oxidative stress and the decrease in semen quality observed following COVID-19 [22]. However, it is not yet clear whether any observed changes in semen quality directly reflect the virus’s effect on spermatogenesis and sperm function or an indirect reflection of the cytokine storm accelerated by the disease and the accompanying increase in oxidative stress [22]. Another study suggests that since the long-term sperm quality in men recovering from COVID-19 is not yet clearly known, they may consider fertility evaluation to assess sperm quality [30].
This paper tests the hypothesis that COVID-19 may cause harmful effects on male fertility parameters, especially sperm motility and morphology. Hence, it could conceivably be hypothesized that even after a mild COVID-19 infection, sperm motility and morphology may not return to normal values in a short time, and it may take longer than estimated to return to normal. An implication of this is the possibility that COVID-19 infection leads to male infertility in a certain percentage of patients within a certain time, even if not in all patients. Considering all this evidence, it seems that COVID-19 infection may adversely affect spermatogenesis, at least temporarily.
The main strength of this study is the single-center nature of our study, the existence of inclusion criteria, and the exclusion of the presence of abnormality infertile patients before infection to better understand the effects of infection on semen analysis objectively. The limitations of this study are the small number of patients in the study, the inability to evaluate the level of leukocytes for each patient in the semen analysis, and its retrospective nature. Further studies are needed to understand better the long-term results of COVID-19 with a wider patient population.