While this virus affects individuals of all genders, it has become increasingly evident that it has a disproportionately greater impact on males, often resulting in more severe illness and higher mortality rates [2].
COVID-19 is a complex disease that can manifest in various ways, ranging from asymptomatic infection to life-threatening complications. Moreover, there is growing awareness of a condition known as “long COVID-19,” which involves a myriad of persistent and often debilitating symptoms that persist or emerge beyond four weeks following the initial SARS-CoV-2 infection [3].
Long COVID-19: A Multifaceted Syndrome
While our understanding of its natural progression remains incomplete, it is clear that individuals of different age groups, particularly those aged 36 to 50, who initially experienced mild, non-hospitalized COVID-19, are susceptible to its long-term consequences [4]. It is estimated that over 65 million people worldwide are grappling with the effects of long COVID-19, but this figure likely underestimates the true prevalence due to many subclinical and unreported cases [3, 5].
SARS-CoV-2 and Male Fertility
One understudied aspect of COVID-19 is its potential impact on male fertility. Emerging evidence suggests that SARS-CoV-2 infection may have adverse effects on sperm quality and male reproductive health [6, 7]. These effects appear to be linked to the severity of the disease, with more severe cases causing more pronounced alterations in sperm parameters such as volume, concentration, motility, and viability [6, 7]. Even mild or asymptomatic cases have been associated with reduced sperm concentration, total sperm count, sperm motility, and normal sperm morphology [8].
Moreover, the absence of baseline semen quality data before infection makes it challenging to conclusively establish the causal relationship between COVID-19 and sperm quality alterations [8]. Additionally, the long-term consequences of SARS-CoV-2 infection on sperm quality and male fertility potential remain largely uncharted due to the lack of comprehensive cohort studies [4, 8].
A Case Study: Asymptomatic COVID-19 and Sperm Quality
In this article, we present a case study that sheds light on the potential impact of asymptomatic SARS-CoV-2 infection on male fertility. The subject of our study was a male individual with previously normal sperm parameters. Shortly after being confirmed as a COVID-19 carrier, the patient experienced a sudden decline in sperm quality. This decline progressed rapidly, initially leading to oligoasthenozoospermia, which subsequently evolved into azoospermia. Over time, the condition further worsened, resulting in persistent severe oligonecrozoospermia.
The case is particularly noteworthy because the patient had no prior fertility issues and had normal sperm parameters before contracting COVID-19. This suggests a direct link between the viral infection and the subsequent deterioration in sperm quality. However, it is essential to acknowledge that this is just one case, and more extensive research is needed to establish a definitive connection between COVID-19 and male fertility.
Case Presentation
In this chapter, we present the remarkable case of a 42-year-old male with a history of primary infertility, initially seeking treatment due to his partner’s low ovarian reserve and poor oocyte quality. Neither the patient nor his wife had any previous children, and they had been attending the reproductive outpatient clinic for seven years. The patient’s medical history revealed a varicocelectomy (grade 3 varicocele) in 2010, with no other significant medical conditions or recent urogenital infections in the past three years. He was a non-smoker, did not use drugs, and occasionally consumed alcohol. Furthermore, he reported no known exposure to toxins, pollutants, radiation, or high temperatures.
Baseline Semen Analysis
A baseline semen analysis performed on January 26th, 2021, revealed normal sperm quality parameters, indicating an overall normal semen quality. The analysis showed a semen volume of 4.6 mL, sperm concentration of 41.82 x 10^6/mL, a total sperm count of 192.4 x 10^6 spermatozoa, total motility of 46%, and viability of 79%. Crucially, there were no signs of leukocytospermia or anti-sperm antibodies (Table 1). This assessment was particularly noteworthy as the patient had provided semen samples for regular controls since February 2014, all of which showed consistently good sperm quality over the preceding seven years (Table 1).
Treatment Plan and Unexpected Findings
Following counseling, the couple decided to pursue in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) and intrauterine embryo transfer as part of their treatment plan for infertility. However, on April 15th, 2021, when the first ICSI procedure was scheduled, a new semen analysis delivered surprising results.
The analysis showed a dramatic decrease in sperm quality parameters compared to the baseline assessment, with a sperm volume of 2.6 mL, sperm concentration of 6.67 x 10^6/mL, a total sperm count of 17.3 x 10^6 spermatozoa, 0% motility, and only 4% viability. No leukocytospermia or anti-sperm antibodies were detected (Table 1).
The patient’s wife disclosed that she had experienced mild COVID-19, and subsequent questioning revealed that the patient had also contracted SARS-CoV-2, albeit asymptomatically, with confirmation on February 25th, 2021. Importantly, this infection did not require hospitalization or any medication. The patient was unvaccinated against COVID-19, and no other significant lifestyle changes or events were reported in the preceding three months.
Sudden Sperm Quality Deterioration
Six days after the initial semen analysis revealing altered sperm quality, a follow-up assessment on April 21st, 2021, confirmed the persistence of sperm quality alterations, demonstrating marked oligoasthenozoospermia and necrozoospermia (Table 1).
Notably, magnetic resonance imaging (MRI) of the pelvis and scrotum revealed no obstructions or abnormalities in any urogenital tract organs, including the testicles, epididymides, vas deferens, seminal vesicles, or the prostate.
Subsequent semen analyses conducted on May 13th, 2021, June 1st, and July 5th, 2021, consistently showed severe oligozoospermia and total necrospermia, despite the patient strictly adhering to a prescribed antioxidant supplementation regimen consisting of vitamin C and E (both 1g/day) for six months.
Notably, elevated levels of pro-inflammatory cytokines TNF, IL-1β, and IL-6 were detected in semen (Table 2). Moreover, a significant increase in sperm reactive oxygen species (ROS) production was observed in the fraction of viable sperm by flow cytometry, indicating oxidative stress as a potential contributor to the observed necrozoospermia (Fig. 1B).
Exclusion of Other Causes
To rule out potential underlying causes of sperm quality deterioration, extensive investigations were conducted. Screening for known uropathogens, including viruses, bacteria, fungi, and parasites, returned negative results. Additionally, serum hormone levels, including testosterone, FSH, LH, prolactin, and estradiol, were all within normal reference ranges, indicating the absence of endocrine disruptions (Table 2).
Persistent Oligonecrozoospermia
Remarkably, the patient’s sperm quality did not recover, even after nearly two years from the asymptomatic SARS-CoV-2 infection. The most recent semen analysis conducted on January 22nd, 2022, continued to show severe oligozoospermia and complete necrozoospermia (Table 1).
In summary, this case report highlights the development of persistent severe oligonecrozoospermia following an episode of asymptomatic SARS-CoV-2 infection, offering unique insights into the potential long-term consequences of COVID-19 on male fertility. The precise mechanisms behind this sperm quality deterioration and the duration of its effects remain subjects of ongoing research.
Discussion
The COVID-19 pandemic has presented numerous challenges to healthcare systems worldwide, and its impact on various aspects of human health continues to be a subject of extensive research. One of the intriguing aspects of the disease is its potential influence on male fertility, an area that has garnered increasing attention due to emerging evidence of sperm quality alterations associated with SARS-CoV-2 infection. In this discussion, we will delve into the complex relationship between COVID-19 and male fertility, with a focus on a rare case of persistent severe oligonecrozoospermia following an asymptomatic SARS-CoV-2 infection.
COVID-19 and Male Vulnerability
The epidemiological data unequivocally demonstrate that men are more susceptible to severe COVID-19 outcomes, including higher morbidity and mortality rates, compared to women [10]. While significant progress has been made in understanding the pathophysiology of COVID-19, many aspects of the disease, particularly its long-term consequences, remain enigmatic [3][4][11].
Semen Quality and Male Fertility Potential
A growing body of research has explored the relationship between SARS-CoV-2 infection and male fertility potential. The available evidence has yielded conflicting results, with some studies reporting associations between COVID-19 and alterations in semen quality parameters such as total sperm count, sperm concentration, motility, and viability [6, 12-16]. Conversely, several other investigations have failed to find substantial impacts of the virus on sperm quality [19-25]. This heterogeneity in findings can be attributed to variations in study designs, diagnostic criteria, and patient populations.
One notable limitation in many of these studies is the absence of baseline semen quality data before infection, which complicates the interpretation of results [8][18][26][27]. Therefore, it remains unclear whether SARS-CoV-2 infection leads to persistent deleterious effects on sperm quality and male fertility potential [3][4].
A Unique Case of Persistent Oligonecrozoospermia
The case presented in this article is exceptional in that it involves a 42-year-old male with normal baseline semen parameters, who developed progressive oligoasthenozoospermia, eventually progressing to severe oligonecrozoospermia following an asymptomatic SARS-CoV-2 infection. Remarkably, this patient had retrospective data spanning seven years before the infection, all indicating normal semen quality. The rapidity with which the patient’s sperm quality deteriorated following infection is striking, with total sperm motility and viability dropping to null values shortly after diagnosis. Even more remarkable is that these alterations persisted for almost two years after the infection episode.
This case adds to a limited body of literature that suggests SARS-CoV-2 infection can have profound and prolonged effects on sperm quality. Prior studies have reported cases of azoospermia and oligozoospermia after COVID-19 recovery [6][12][29]. In some instances, these alterations in sperm parameters were reversible after two to three cycles of spermatogenesis [17][18][31][32]. However, the case presented here is unique in its observation of persistent oligonecrozoospermia, which has not resolved even after nearly two years.
Possible Mechanisms and Implications
The mechanisms underlying the observed sperm alterations following SARS-CoV-2 infection are multifaceted. The virus may directly impact testicular function, potentially through the expression of ACE2 and TMPRSS2 receptors in testicular cells [35][36][37]. Alternatively, other receptors and co-receptors such as CD147 and cathepsin L may also play a role in facilitating viral entry into testicular cells [43][44]. Histopathological alterations observed in the testes of COVID-19 patients support the notion of direct testicular damage [29][33].
Inflammation and oxidative stress are key contributors to impaired spermatogenesis in COVID-19 patients. Elevated levels of inflammatory cytokines such as IL-6, TNF, and IL-1β have been detected in the semen of individuals with COVID-19 [6][24][29][47][48]. These cytokines, along with oxidative stress, can induce apoptosis in spermatogonia and spermatozoa [50][51][52][53][54]. Additionally, a recent study suggested that SARS-CoV-2 infection may induce senescence in testicular cells through the MAPK pathway, further disrupting spermatogenesis [55].
Anatomical obstructions and hormonal imbalances were ruled out in the presented case, highlighting the unique nature of this persistent oligonecrozoospermia. Fever, medication use, smoking, and exposure to toxins or pollutants were also eliminated as potential causes.
Conclusion and Future Research
This case study underscores the need for continued research into the long-term effects of SARS-CoV-2 infection on male fertility. While most reported sperm alterations appear to resolve within months, this rare case demonstrates that persistent severe oligonecrozoospermia can occur. Large-scale, longitudinal studies with pre-infection semen quality data are essential to provide more comprehensive insights into the relationship between COVID-19 and male fertility. Such research is crucial for understanding the full spectrum of consequences of SARS-CoV-2 infection and for providing guidance on reproductive health for individuals who have recovered from the virus.
