Studies have shown that SARS-CoV-2 can directly or indirectly affect the male reproductive tract and possibly make them infertile. However, information on the presence of SARS-CoV-2 in the semen of patients with coronavirus disease 2019 (COVID-19) and related sperm parameter changes is limited and contradictory. Review: The potential role of SARS-CoV-2 in male fertility: A narrative review. Image credit: WHITE MARKERS / Shutterstock
About the review
In the present review, researchers summarized the potential mechanisms of SARS-CoV-2-related reproductive system damage and potential male infertility.
Angiotensin converting enzyme 2 receptor, sex hormones and the testis
SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) receptor for host invasion, the expression of which is reported to be high in the testes, including Leydig cells, Sertoli cells, spermatozoa, and spermatogonia. Higher rates of ACE2 positivity have been reported in the testes of male infertile patients with COVID-19 compared to fertile patients. Orchitis is considered a possible clinical manifestation of SARS-CoV-2 infections. The higher mortality rate among men due to COVID-19 may be due to a possible sex-dependent susceptibility resulting from high ACE2 expression in men. Furthermore, higher levels of ACE2 messenger ribonucleic acid (mRNA) have been reported among middle-aged men compared to younger men. ACE2 is a component of the RAAS (renin-angiotensin-aldosterone system), which regulates spermatogenesis, steroidogenesis, sperm function and epididymal contractility. ACE2-positive spermatogenesis in patients with COVID-19 have shown reduced spermatogenesis. In addition, the presence of SARS-CoV-2 with altered serum parameters in the semen of patients with COVID-19 has been reported. Lower testosterone levels, testosterone/LH ratio, and follicle-stimulating hormone (FSH)/LH ratio and higher luteinizing hormone (LH) levels indicate primary testicular damage (especially Leydig cell damage) and have been observed in patients with COVID-19. Additionally, a negative correlation has been observed between the testosterone/LH ratio and C-reactive protein (CRP) levels, the increase of which is proportional to the severity of COVID-19. Lower testosterone levels are also associated with erectile dysfunction in patients with COVID-19. The findings suggest that COVID-19 may contribute to male infertility through ACE2-mediated pathways and that infertile men may be more susceptible to COVID-19. Major mechanisms of male reproductive system damage in SARS-CoV2 infection. LH= luteinizing hormone; FSH: follicle-stimulating hormone. ACE2-R= Angiotensin converting enzyme receptor 2; IL-6= Interleukin 6; TNF-α = Tumor Necrosis Factor a.
Orchitis and autoimmunity
Testicular pain and epididymitis-orchitis have been documented in SARS-CoV-2-positive individuals, and heightened testicular immune responses have been implicated as causative for testicular injury and changes in sperm parameters. In addition, autopsy examinations of deceased patients with COVID-19 showed interstitial congestion, erythrocytes, and edema in epididymal and testicular tissues with high levels of seminal interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Semen samples from patients with COVID-19 also showed increased expression of interferon (IFN)-α, IFN-γ, IL-1β,8,10, transforming growth factor-beta (TGF-β), reactive oxygen species (ROS) and caspases-3 , 8 and 9. Levels of ubiquitin-protein ligase E3, dynein regulatory complex subunit-7, and insulin-like factor-3 were significantly lower in the testes of covid-19 patients. Findings correlate with altered sperm morphology, concentration, motility, sperm count and volume in COVID-19. Increased ROS production in COVID-19 indicates higher oxidative stress and ROS-induced sperm functional impairments due to sperm membrane lipid peroxidation and intracellular oxidative damage. Specifically, sperm deoxyribonucleic acid (DNA) fragmentation is affected, indicative of disturbed fertilization, implantation or embryo development. In addition, electron microscopy has revealed the presence of SARS-CoV-2 in testes with leukocyte and macrophage infiltration. SARS-CoV-2 infections can compromise the testicular barrier and favor the production of anti-sperm autoantibodies (ASA) resulting in testicular destruction. High ASA titers have been associated with low sperm motility and concentration [especially immunoglobulin A (IgA)], particularly in mild cases of COVID-19 without pulmonary involvement; however, sperm parameters have shown recovery within three months. Sperm lesions and SARS-CoV-2 IgG titers against SARS-CoV-2 spike (S) protein subunit 1 (S1) and S1 RBD (receptor binding domain) have been strongly correlated, indicating immune pathogenesis of reproductive tract disorders in male patients with COVID-19. An inverse association between SARS-CoV-2 detection rates in semen and time of diagnosis of COVID-19 was significantly greater among samples obtained <11 days of diagnosis. Patients with COVID-19 have been reported to have teratozoospermia in association with fever associated with COVID-19. However, studies have reported no correlation between the severity of COVID-19 and fever with sperm parameters. In contrast, COVID-19 convalescents were reported as crypto-, oligo-, or azoospermic, the extent of which correlated significantly with the severity of COVID-19, and oligozoospermia has been reported in fertile men. In conclusion, the review findings showed that SARS-CoV-2 infections could cause male infertility. However, further research is needed to improve understanding of the underlying mechanisms and reversibility of direct and indirect testicular damage associated with COVID-19. Future studies need to assess the precise localization and replication dynamics of the virus in the testes by comparative evaluations of sperm parameters before and after the diagnosis of COVID-19.
