The cell surface receptors of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 have been proven to be the binding components of SARS-CoV-2 entry to the host cells and integration of its contents for replication [12]. Therefore, the higher sex-based susceptibility to catch COVID-19 disease among males could be attributed to the higher levels of ACE2 in males than females. Males may also have lower capabilities of viral load clearance than females [2], and hence the testes should be regarded as high-risk organs and potential targets for COVID-19 in males at the reproductive age [5, 13]. Many authors have shown concern that the majority of COVID-19 patients fall within the reproductive age category, ranging from 15–49 years [5, 6]. This risk was a strong motivator to conduct the current study on patients in this age category. We used CO-RAD to define the mild-to-moderate pulmonary involvement as the most common tool of diagnosis and as an indicator of the disease burden. Moreover, exclusion of patients with hypoxia and fever eliminated their proposed confounding effects on spermatogenesis with the COVID-19 effect [1].
On the other hand, the current study employed strict patient selection criteria to avoid the confounding factors. These criteria provided a sample of patients with demographic and clinical characteristics that may not be representative to their corresponding groups in the general populations. Among these characteristics, the body mass index (BMI) is slightly higher than that of the average population of the young adults. This can be attributed to that the potential associations between the high BMI and COVID-19 infections, regarding the severity and mortality of COVID-19 [14]. The means of normal sperm morphology in the two seminal analyses were higher than 20% which were significantly higher than the known means in the fertile males [9]. Similarly, this finding can be attributed to the strict exclusion criteria which resulted in exclusion of patients with comorbidities that may influence the seminal quality, including varicoceles, previous surgeries, chronic systemic diseases, and any other testicular diseases.
The mechanisms of action by COVID-19 so far considered include multiple pathways of pathophysiological alterations. Direct invasion and damage of the testis has recently been proven [2, 12]. SARS-CoV-2 disturbs the immunological characteristics and provokes high systemic levels of the inflammatory mediators, which include the pro-inflammatory cytokines, defined as a ‘cytokine storm’ effect, and disturbed seminal antioxidant defense mechanisms [4, 6]. The constitutional stressors of COVID-19 such as fever, hypoxia and medications, may also play a role in the effects on spermatogenesis in those patients [2, 5]. Therefore, we excluded patients with severe clinical symptoms, to avoid their confounding effects on semen quality.
Despite this evidence of influences on the male reproductive system by various mechanisms, the presence of SARS-CoV-2 in the testis and semen of COVID-19 patients remains a matter of debate [13, 15]. Most reports in the literature have reported that SARS-CoV-2 is undetectable in the semen samples of COVID-19 patients [16,17,18]. On the other hand, patients’ semen parameters have been found to be significantly affected by SARS-CoV-2 infection, resulting in oligoasthenoteratozoospermia or one of its components as spermatogenic outcomes [6, 16, 19]. On the clinical and academic levels, this has raised a major concern whether COVID-19 should clinically be flagged as a cause of male subfertility with uncertain duration of recoverability [6, 19, 20]. Our study considered this clinical concern and compared semen parameter values of two consecutive spermatogenic cycles, representing the infection and recovery phases of COVID-19 in a duration of 5–6 months.
While many studies have reported semen quality changes during COVID-19 infection, studying the long-term reversibility is warranted [1, 6, 15, 16, 19]. In one study of semen quality, COVID-19 patients had significantly lower values of semen volume, progressive sperm motility, normal sperm morphology, sperm concentration, and number of spermatozoa relative to the control group. Their results showed enhanced numbers of spermatozoa and percentages of progressive motility in semen analyses performed through the following 60 days, relative to the baseline value among the COVID-19 patients. Although they observed a form of improvement of semen quality towards normal, full recoverability of these parameters seemed uncertain within 60 days [6]. The current results come in parallel with these findings, where the improvement was significantly better with longer duration after COVID-19 resolution. Li et al. [1] reported that 39.1% of hospitalized patients with COVID-19 had oligozoospermia, attributing impairment of spermatogenesis to an elevated immune response and autoimmune orchitis [1]. Other researchers have found significant changes in sperm morphology during the infection phase of the disease and attributed them to the acute stress of COVID-19 [16, 19]. Similarly, the current results revealed that the changes in sperm morphology were the most prominent abnormality in sperm characteristics during the infection phase with significant improvement after recovery from the disease.
The pathophysiological mechanisms of testicular damage by COVID-19, including the relations between the receptors and frequent viral mutations, represent a principal point in the relevant literature. The effects of COVID-19 on the hypothalamic-pituitary-gonadal axis have been addressed by the ongoing studying. This is in concordance to the research efforts required for testicular protection against COVID-19 by developing standardized treatment strategies [2, 21]. Regarding the effects on fertility outcomes, the clinical aspect of testicular effects of COVID-19 is primarily directed towards its potential effects on semen quality. However, the long-term effect is not yet fully understood [2,3,4]. Hence, the current study may be useful in providing a step forward in studying the temporal effects of COVID-19 on spermatogenesis.
The limitations of the current study include the non-testing of the hormonal profiles of those patients, and the lack of baseline semen quality, which may have detected spermatogenic defects before disease onset. Although the exclusion of patients with severe COVID-19 was to avoid the effect of the constitutional effects of the disease on spermatogenesis, it is a form of selection bias. However, this should not be the important, because the current study and the results were strictly relevant to the patients with mild-to-moderate COVID-19.