Semen Impairment and Occurrence of SARS-CoV-2 Virus in Semen After Recovery From COVID-19

M. Gacci; M. Coppi; E. Baldi; A. Sebastianelli; C. Zaccaro; S. Morselli; A. Pecoraro; A. Manera; R. Nicoletti; A. Liaci; C. Bisegna; L. Gemma; S. Giancane; S. Pollini; A. Antonelli; F. Lagi; S. Marchiani; S. Dabizzi; S. Degl'Innocenti F. Annunziato; M. Maggi; L. Vignozzi; A. Bartoloni; G.M. Rossolini; S. Serni

Disclosures

Hum Reprod. 2021;36(6):1520-1529. 

In This Article

Discussion

In our sample, the age range was from 30 to 64 years. This study demonstrates that young and sexually active men with proven recovery from COVID-19 have a significant risk of developing oligo-crypto-azoospermia.

Prolonged viral shedding from the nasopharynx in convalescent patients, up to at least 3 weeks after recovery from symptoms, has been previously reported (Young et al., 2020). According to the European Centre for Disease Prevention and Control (ECDC) we considered as healed from SARS-CoV-2 infection those men with two upper respiratory tract samples that were negative for SARS-CoV-2 RNA, and showing clinical resolution of symptoms (https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19-Discharge-criteria.pdf). However, in our population, one patient died from COVID-19 after clinical relapse and four tested positive again for SARS-CoV-2 infection by NP swab during the screening phase (from March 2020 to May 2020). Moreover, three men presented with persistence of SARS-COV-2 RNA in biological fluids 3–9 weeks after double negative NP swabs.

The occurrence of the virus in saliva, urine, and semen of asymptomatic patients several weeks after double negative NP swabs was demonstrated in a very small percentage of men in our cohort; nevertheless previous studies (Guo et al., 2020; Ma et al., 2020; Pan et al., 2020) did not report occurrence of virus in semen of healed patients or in their recovery phase. Interestingly, none of the partners of these three newly positive patients tested positive for SARS-CoV-2 including the patient with a positive test result for semen. Overall, these studies suggest that the occurrence of virus in semen is a rare event. Further studies will be required to determine the risk of SARS-CoV-2 transmission by sexual intercourse.

The occurrence in the male reproductive system, in particular testis, has been described for several viral strains. The HIV and mumps virus might lead to male infertility as a result of direct damage to the testicular structure (Masarani et al., 2006; Garolla et al., 2013). Abnormal sperm parameters have been observed in other viral infections such as herpes simplex virus, hepatitis virus B, or hepatitis virus C (Garolla et al., 2013). Recent findings seem to support an influence of SARS-CoV-2 infection on male sex hormones, with an increase in plasma levels of LH and a marked decrease in testosterone and FSH (Ma et al., 2020).

In our study, we found that one out of four (11/43, 25.5%) of COVID-19 healed patients were oligo-crypto-azoospermic, a percentage clearly exceeding that reported for the general population (about 1% for azoospermia, Jarow et al., 1989; 3% for oligozoospermia, Ombelet et al., 2009). Interestingly, all azoospermic patients reported a previous unimpaired fertility status (five had one child, two had two children, and one had three children), and only one out of three oligo-crypto-azoospermic men reported no parenthood (while the other two each had two children). Occurrence of azoospermia could be related to antibiotics or other drugs used for the treatment of patients during COVID-19. Indeed, antibiotics, antiviral drugs, chloroquine, corticosteroids, and immunomodulators might affect male fertility status (Semet et al., 2017). However, a contribution to impairment of testicular function from SARS-COV-2 infection cannot be excluded, considering that, on average, the time from recovery was around 30 days, which is below the length of a complete cycle of human spermatogenesis. The virus may localize in the testis owing to the elevated expression of ACE and TMPRSS2 in the organ, and COVID-19 patients with active infection show low testosterone levels (Rastrelli et al., 2020; Wang et al., 2020). Moreover, although antibiotics have long been suspected of contributing to male infertility (Semet et al., 2017), limited data support this hypothesis (Samplaski and Nangia, 2015). Semen quality could also be affected by febrile illness, even if limited data are currently available. In particular, semen concentration was significantly influenced by fever occurring during the meiosis and postmeiotic period, with a mean decrease of 32.6% and 35%, respectively (Carlsen et al., 2003). Moreover, a large variation in sperm concentration was observed, and semen recovery was obtained almost 60 days after temperature normalization (MacLeod, 1951). In our cohort of patients, one crypto-azoospermic semen was analyzed 4 weeks after temperature normalization and one oligospermic after 6 weeks, while the other nine oligo-crypto-azoospermic patients were tested at least 8 weeks after COVID-19 clinical healing. Moreover, 8 out of 11 men with semen impairment were crypto-azoospermics and three were oligospermics. Thus, the impact of fever on semen quality seems negligible.

Furthermore, the virus can have direct (viral replication and dissemination in the testis) and indirect (fever and immunopathology) effects on testicular function (Carlsen et al., 2003). Leukocytospermia is associated with male accessory gland infection (MAGI). However, the pathophysiology of leukocytes in semen is unclear and the diagnostic significance is still debated (Grande et al., 2018). New seminal biomarkers, including some cytokines, have been reported as the most promising putative markers of infection (Grande et al., 2018). IL-8 is a chemokine involved in several inflammatory diseases, comprising inflammation of the prostate, seminal vesicles, and epididymis (Penna et al., 2007; Lotti and et al., 2012; Lotti and Maggi, 2013). Therefore, IL-8 has been proposed as a specific marker for silent MAGI (Lotti et al., 2011). The high levels of sIL-8 found in a high percentage of our patients support the persistence of an inflammatory condition within the male genitourinary tract (Penna et al., 2007) after healing. In addition, reanimation treatments (e.g., invasive ventilation, administration of sedative drugs, specific organ support therapy) and body distress can affect testicular function (Vishvkarma and Rajender, 2020). Clearly, in order to understand whether these men can recover from poor testicular function, they should be reassessed at least 3 months after complete healing from COVID-19.

Our study has some limitations. First, the number of enrolled patients (43) may limit the statistical power of our study regarding the cause-effect relationship between COVID-19 infection, semen quality, and sexual transmission. However, ours is the largest among studies published to date reporting on semen quality and occurrence of virus genome in the semen of sexually active men who were previously infected and who recovered from COVID-19 (12 patients in Ma et al., 2020; 23 in Guo et al., 2020). Another limitation of our study is that semen quality before infection of the men that demonstrated severe oligo-crypto-azoospermia after COVID-19 was not known. However, all patients who were crypto-azoospermic had previously had children.

The strength of our study is that that the SARS-CoV-2 genome has been analyzed in four different biological samples, from different anatomical sites, collected simultaneously. Finally, the study was performed over a short time frame, and in a single center: this allows us to minimize biases related to virus modifications or analytic procedures.

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