COVID-19 in men: with or without a virus in the semen,...

Herr,

We would like to inform you of the review recently published in Andrologia with the title “Could SARS-CoV-2 affect male fertility?” (Vishvkarma R & Rajender S, 2020). In just a few months, several million people were infected with the severe coronavirus 2 (SARS-CoV-2) with acute respiratory syndrome. This brutal pandemic known as Coronavirus-19 Disease (COVID-19) affects men disproportionately and can have lasting effects on aspects such as fertility. Some of these effects are described in the literature, others may be published in the coming months. Today the literature focuses on whether the virus is present in sperm, a possibility that is causing significant panic in the media and the public as the presence of the virus in ejaculate would turn COVID-19 into a sexually transmitted infection (STI) . Beyond the answer to that question, however, there are symptoms of COVID-19 (e.g. fever) with the known andrological effects that should be highlighted.

1 presence or absence of viruses in semen?

The SARS-CoV-2 virus uses angiotensin converting enzyme-2 receptors (ACE2) to enter human cells, and the spike protein (protein S) is prepared by transmembrane serine protease (TMPRSS2). The male reproductive system is believed to express both the ACE2 and TMPRSS2 receptors in the testes (Spermatogonia, Sertoli, and Leydig cells) and in prostate epithelial cells (for a review see Hamdi et al., 2020;; Vishvkarma R & Rajender S, 2020). When receptors for the virus are present at various stages of the male reproductive system, it is not inappropriate to believe that the virus can be found in sperm either by altering the blood-testicular barrier but also by excreting it in the prostate fluid. So far, five studies have not identified any virus in the semen of 91 patients infected with COVID-19 (Guo et al., 2020;; Holtmann et al. 2020;; Pan et al., 2020;; Paoli et al., 2020;; Song et al., 2020). While these data were comforting, one manuscript mentions the presence of viruses in the semen of six patients infected with COVID-19 (4 in the acute phase of the disease and 2 cured) (Li et al., 2020). Some authors have questioned the conditions of sperm collection or the detection limits of the quantitative reverse transcription polymerase chain reaction (qRT-PCR) tests used. It should be noted that the diagnostic accuracy of many commercial quantitative reverse transcription polymerase chain reaction (qRT-PCR) kits available for the detection of SARS-CoV-2 has a sensitivity and / or specificity 2012). Therefore, both false positive and false negative results could be obtained. While SARS-CoV-2 is not expected to adhere to sperm, it has not yet been assessed. Are infertile men using assisted reproductive technologies (ARTs) at risk of vaccinating the egg during intracytoplasmic sperm injection (ICSI) or vaccinating the woman’s uterus during intrauterine insemination (IUI)? If these questions go unanswered, then ART activities in infertile men must take these factors into account.

1.1 DEREGULATION OF SPERMATOGENESIS

Apart from the presence or absence of a virus in the sperm, it is clear that COVID-19 can be associated with a deregulation of spermatogenesis.

1.2 SERTOLI CELLS AND SPERMATOGENESIS

Since Sertolis cells have receptors for SARS-CoV-2, it is not inappropriate to believe that they could be infected with the virus and therefore see their functions changed (Shen et al., 2020;; Verma et al., 2020). Sertolis cells play a key role in spermatogenesis and a change could alter spermatogenesis. Future research would be interesting. It would be possible to investigate the in vitro influence of SARS-CoV-2 on sertolic cell lines or, more simply, to investigate in vivo sertolic hormone secretions (anti-Müllerian hormone, inhibin B) in COVID-19-positive patients. This research would make it possible to evaluate the possible effects of the virus on the functions of Sertoli cells, if any.

1.3 Fever and altered spermatogenesis

Fever is a symptom seen in over 80% of patients infected with COVID-19. This fever alone can negatively affect the physiological mechanisms of scrotal thermoregulation, which are overwhelmed when the body temperature rises even one degree Celsius. Therefore, even a fever of limited duration can decrease sperm count and / or motility and alter the DNA integrity of the sperm. The return to the basic state of the sperm parameters can take a long time, sometimes almost three months (Sergerie, Mieusset, Croute, Daudin & Bujan, 2007;; Carlsen et al., 2003;; Lazarus & Zorgniotti, 1975). Fever induced by COVID-19 can therefore change the sperm parameters even if there is no virus in the sperm. In infertile men with altered basic sperm parameters, this fever could have more damaging effects. For this reason, it was recently recommended that sperm parameters be monitored and ART management be delayed by three months in men diagnosed with COVID-19 who developed a fever (Hamdi et al., 2020).

1.4 COVID-19 AND TESTOSTERONE: A POSSIBLE HORMONAL DEREGULATION OF SPERMATOGENESIS?

The links between androgens and COVID-19 are complex. Some authors have described a promoting effect of testosterone on the risk of COVID-19 infection (Pozzilli & Lenzi, 2020). Conversely, one study found possible primary hypogonadism in patients with severe forms of COVID-19, while the balance of andrological hormones observed in patients with milder symptoms was normal (Rastrelli et al., 2020). Is hypogonadism a cause or a consequence of the severity of COVID-19 symptoms? Is this relationship between hypogonadism and the severity of COVID-19 associated with a confounding factor (e.g. age of the patient) or is it simply coincidental? What influence could hypogonadism have on sperm parameters and for how long? If SARS-CoV-2 infection was found to trigger hypogonadism, what would the pathophysiology look like? It could be assumed that damage to the Leydig cells and / or the gonadotropic axis (and more precisely the hypothalamic GnRH neurons) could be observed in coronaviruses; The primary or secondary character of COVID-19-related hypogonadism (if any), however, cannot be formally established based on current knowledge, and more extensive cohort studies are required. Regardless of the nature of the relationship between testosterone and COVID-19, an andrological exam, assessment of sperm parameters, and hormonal assessment are required at the time of diagnosis of COVID-19 and a few months later.

2 CONCLUSION

SARS-CoV-2 can have negative effects on spermatogenesis and male fertility. Even in cure patients, the presence of the virus in the sperm is not impossible, and apart from the presence of the virus in the sperm, spermatogenesis can be affected by COVID-19 fever. Therefore, precautionary clinical, hormonal, and seminal parameter evaluations of patients diagnosed with COVID-19 are recommended at the time of infection and during follow-up examinations (3 and 6 months), especially in severe forms. In infertile men, postponing ART activities to three months after infection is advisable.