Our study indicates that alterations of semen parameters observed shortly after recovering from COVID-19 may be transient as most patients show an improvement of semen quality after three months although an inflammatory status of the male genital tract seems to persist.
Several viruses, including HBV, HCV, HPV, HSV, Mumps, may cause an impairment of testicular function and can be detected in semen14. Some viruses such as MuV, HIV and SARS-CoV can affect testicular cells, resulting in severe orchitis, which can compromise male fertility15. During the very first weeks after recovery from Covid-19, the majority of men show high semen levels of IL-8, and at least one-fourth of these men, show alterations of semen parameters7. A recently published systematic review based on data collected from 70 studies confirms these data16. In particular, the Authors suggest that COVID-19 may cause an inflammatory condition of the testis which is correlated to the severity of the disease16.
SARS-CoV-2 is very contagious and has already infected a higher proportion of young men during the second pandemic wave, as compared with the first one17. Since the highest expression of ACE2 in testicular cells occurs at about thirty years of age, the interaction between SARS-CoV-2 and ACE2 receptor and TMPRSS may cause severe damage to the testis in young males, rising concerns about male fertility18. Impaired gonadal function can be due to inflammation an autoimmune response12 as well as high fever and medications during the course of the disease19. In particular, a significant increase of semen levels of inflammatory cytokines, such as IL-6 and TNF-α was observed in COVID-19 patients1. Furthermore, evidence suggests that both testicular function and semen quality may be reduced following severe COVID-19, due to several aspects of the disease including high fever and medications, indicating the need for andrological evaluation of recovered men 7, 9. Such a recommendation is also indicated in the official website of the government of Hubei Province which posted a bulletin inviting all men recovered from SARS-CoV-2 to undergo fertility checks, suggesting a big concern for a possible link between this novel disease and the male reproductive system20.
In the present study, we report a longitudinal prospective case series of sexually active men based on two consecutive sperm analysis performed after healing from COVID-19 and 3 months later, after a complete new cycle of spermatogenesis. Overall, 3 out of 7 (43%) oligo-crypto-azoospermic patients at the time of recovery, showed an improvement of testicular function with an increase of sperm number, 3 months after healing, suggesting that the detrimental effects of COVID-19 could be temporary. However, in few cases, no improvement in sperm number has been achieved. Since semen quality of these men before COVID-19 was not available, whether or not persistence of crypto/azoospermia is due to the illness cannot be ascertained. However, 6 out of 7 patients (86%) reported paternity before COVID-197.
In most patients, an improvement of sperm progressive motility was observed, but values still remained below the 5th percentile of the WHO reference values in 6 of them.
As previously reported, IL-8 is a cytokine associated with inflammation of prostate, seminal vesicles and epididymis13. Semen IL-8 concentrations 1 month after recovery from COVID-19 were related with severity of the illness, including the need of hospitalization, intensive care, oxygen therapy and invasive ventilation7. Interestingly, semen IL-8 levels remain high (more than double of the cut-off value of 3.8 ng/ml) in most of the enrolled patients also 3 months after COVID-19 healing, suggesting the persistence of an inflammatory condition in the male genital tract that may require further assessment. Similarly, semen levels of 7 cytokines which are part of the SARS-CoV-2 cytokine storm21 resulted elevated both one and 3 months after COVID-19 recovery in all patients recruited in this study, with the exception of IL-6 which decreased significantly after 3 months. In particular, levels of some cytokines (IL-8, IL-1, IL-6, INF gamma and TNF-alpha), resulted higher respect to those found in patients affected by prostatitis (Table 4)13, indicating that the inflammatory status of the male genital tract of patients recovering from COVID-19 may be similar or even more compromised.
A limitation of our study regards the lack of semen parameters before COVID-19 diagnosis. Another limitation regards the small cohort of evaluated patients. However, our intent was to determine whether those patients that showed alterations of semen quality 1 month after healing from COVID-197, could recover after 3 months, representing an entire spermatogenetic cycle. Our study has also strengths. To our knowledge, this is the first study comparing semen parameters in healed men from COVID-19 at 1 and 3 months after recovery, although in a small number of subjects. In addition, we evaluated a wide panel of seminal plasma cytokines involved in male genital tract inflammation.
In conclusion, our study demonstrates that, despite an overall amelioration of semen quality, COVID-19 induced inflammation in the male reproductive tract may persist 3 months after recovery, with a possible detrimental effect on male fertility. Further studies are needed to understand the link between the cytokine storm during COVID-19 and the damage to reproductive system in order to minimize the potential sequelae on male fertility. Our study indicates that a careful follow up is needed for patients in reproductive age recovering from COVID-19.
The dataset(s) supporting the conclusions of this article is(are) included within the article.