By Lucy Hamer
In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered an outbreak of coronavirus disease 2019 (COVID-19) in Wuhan City, China (Harapan et al., 2020). 10 months down the line, there have now been 38 million cases globally, causing the loss of over 1 million lives (Worldometer, 2020). Whilst the main symptoms of COVID-19 are plastered all over shop windows, restaurants and tube stations, the long-term effects of infection remain unknown. Recently, concerns have been raised that males of reproductive age may suffer reproductive consequences as a result of contracting COVID-19. Viral infection has long been linked to male infertility, with human papillomavirus (HPV), herpes simplex virus (HSV) and human immunodeficiency viruses (HIVs) all wreaking havoc on the male reproductive system (Batiha et al., 2020), but the effect of SARS-CoV-2 on male fertility has yet to be fully clarified.
SARS-CoV-2 is a Betacoronavirus, along with Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) (Harapan et al., 2020). Coronaviruses are characterised by their crown-like appearance caused by the abundance of glycoprotein spikes on their surface (Illiano et al., 2020). These envelope proteins are also incredibly important in the initial stages of viral infection, binding to host receptors and facilitating the entry of the virus into cells. As such, the surface proteins dictate which host cells the virus is capable of infecting (Batiha et al., 2020). Extensive structural analysis has demonstrated that SARS-CoV-2 has a 79% similarity to SARS-CoV, sharing many structural motifs including remarkably similar envelope spike proteins. Despite some amino acid variation, it appears that SARS-CoV-2 binds to the same host receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2) (Lu et al., 2020). The binding of Spike glycoproteins on the surface of SARS-CoV-2 to ACE2 receptors on host cell membrane triggers fusion of the two membranes, allowing the virus to release its genome and replicate intracellularly (Batiha et al., 2020).
As SARS-CoV-2 enters cells by binding to ACE2 receptors, it is likely that any region of the body with high ACE2 expression is vulnerable to SARS-CoV-2 infection (Batiha et al., 2020). ACE2 is expressed in various organs including the lungs, kidneys, liver, intestine and heart (Younis et al., 2020), but the abundance of ACE2 receptors in the male testis may also indicate that testicular cells are vulnerable to SARS-CoV-2 infection (Illiano et al., 2020), with damaging implications for male fertility (Batiha et al., 2020). The literature concerning the expression of ACE2 in the human testis is not wholly consistent, but most researchers agree that ACE2 is highly expressed in the Leydig and Sertoli cells (Younis et al., 2020; Wang & Xu, 2020; Illiano et al., 2020). Wang & Xu also discovered that some spermatogonia were enriched for ACE2 expression and notably, the ACE2-positive immature sperm cells had elevated expression of genes related to viral infection but diminished expression of genes related to spermatogenesis (Wang & Xu). Whilst it appears likely that cells within the testis are susceptible to SARS-CoV-2 infection, most of the investigations conducted so far are limited by small sample sizes so the implications of COVID-19 on male spermatogenesis remain unclear.
It is also possible that SARS-CoV-2 infection may influence male fertility indirectly, by inducing manifestations that have knock on effects on the male reproductive system. Fever, defined as a sustained increase in body temperature, is a COVID-19 symptom that affects over 80% of patients. As a result, male patients with COVID-19 experience elevated testicular temperature (Younis et al., 2020). Mammalian spermatogenesis is widely appreciated as a complicated, sensitive process (Evenson et al., 2013), and although there have not yet been any studies conducted to assess the effect of COVID-19-induced fever on male fertility, studies based on other viral infections provide a solid basis to suggest that heightened testicular temperature likely impairs the ability of the male reproductive system to produce healthy, viable sperm (Jung & Schuppe, 2007). Notably, Evenson et al. reported that sperm samples collected from a patient presenting with Influenza, and an associated high fever, had much higher sperm DNA fragmentation scores (Evenson et al., 2013). The sperm DNA fragmentation index is used to classify sperm based on the integrity of their genetic material, and high scores often indicate subfertility (Reproductive Health Group, 2020). These findings are corroborated by Sergerie et al., who demonstrated that total sperm count and sperm motility were significantly decreased in semen samples from a fertile volunteer following a febrile episode (Sergerie et al., 2007). Whilst COVID-19 is likely to weaken testicular production of mature sperm by increasing testicular temperature, any effect on fertility will be transient and will only last until the testicles are able to regenerate new sperm. Impairments to sperm count and motility in the investigation by Sergerie et al., were corrected within 80 days (Sergerie et al., 2007). It is estimated that the period of subfertility caused by COVID-19 infection may last months at most (Medium Coronavirus Blog, 2020).
In mid-March 2020, the World Health Organisation declared COVID-19 a pandemic, as infection has spread to every continent of the globe (Illiano et al., 2020). In addition to exerting devastating effects on the physical health of millions of people across the world, the pandemic has also exacerbated rates of acute stress and depression. A US-based study found that rates of mental health problems rose in accordance with the COVID-19 death rates between the months of March and April (Holman et al., 2020). Unfortunately, prolonged psychological stress has been recognised as a potential risk factor for male infertility (Pederson, 2020). Analyses of semen from men who have endured trying situations such as war, an examination period or a recent bereavement found that psychological stress impaired total sperm counts as well as other important fertility parameters. However, some studies have also concluded that there is no association between stress levels and fertility, and unfortunately due to the difficulties in studying the impact of stress on the human testis, it is not likely that this relationship will be elucidated any time soon (Nargund, 2020).
There is a significant lack of data clarifying the impact of COVID-19 infection on the male reproductive system which makes it incredibly hard to draw any definitive conclusions. Further investigation is required to determine whether the SARS-CoV-2 virus is capable of infecting testicular cells, as well as whether or not this has any implications for male fertility. It is incredibly important that direct analysis of semen from patients that have contracted COVID-19 is performed in order to fully elucidate whether SARS-CoV-2 infection does result in higher rates of poor sperm quality.
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