Introduction
Male infertility is a mans inability to get a woman pregnant due to low sperm concentration or poor sperm quality.
Since December 2019, the SARS-CoV-2 virus has presented the world with the clinical condition associated with massive cytokine storm which affect several organs systems. This condition which became a subject of focus on the news and the economy is popularly called COVID-19 (Coronavirus Disease 2019). Clinically, COVID-19 presents with a persistent fever, cough, pneumonia, and loss of smell and taste.
There has also been pathological evidence of massive intravascular micro-thrombotic phenomenon in multiple organs, including the lungs, heart, kidneys, brain, and testes. The interaction of the SARS-CoV-2 viral Spike protein and ACE2 on cells co-expressing ACE2 and the cellular transmembrane protease serine 2 (TMPRSS2) has been identified as the mechanism of cellular entry for the SARS-CoV-2 virus (Yan et al., 2020; Hallak et al., 2021).
Vastly, researchers report on the virus attacks on the respiratory and gastrointestinal systems, also testicular damage and dysregulation of gonadotropins associated with inflammation. With scarce evidence for the detection of SARS-CoV-2 virus in the testis, the current evolving pandemic, frequently updated medical interventions and public policies leading to delays of care can play a role in fertility.
This review aims to summarize on how COVID-19 may influence male fertility. This summary assesses the relationship as it relates to hormonal regulation and the hypothalamic pituitary axis (HPG), systemic inflammation, the potential of direct testicular infection, semen parameters and interactions of medical interventions for COVID-19.
Conceptual framework
Although not all tissues that express ACE2 are susceptible to SARS-CoV-2 infection, organ involvement has been found to be positively correlated with ACE2 expression (Hallak et al., 2021). Since the testes express ACE2 receptors, investigations into the possible influences of COVID-19 on male fertility are being actively explored (Chen et al., 2020).
The hypothalamic-pituitary-gonadal axis (HPG) endocrinologically links the brain and testis. This link is achieved through the production of gonadotropins and testosterone and the HPG feedback loop. Precise regulation of this axis is required for optimal sex hormone production and fertility. COVID-19’s effects on the hypothalamic-pituitary-gonadal axis require further evaluation; however, Selvaraj and His colleagues (2021) reported that abnormal levels of gonadotropins have been identified in COVID-19 patients. Thus, it makes this analysis imperative for further investigations about the reproductive lives of COVID-19 patients.
COVID-19 and the Hypothalamic-Pituitary-Gonadal Axis
A selection of studies has produced data to support that COVID-19 can impact testicular hormone production. When reviewing these studies, it is important to recall that physiological stressors such as illness are associated with fluctuations in baseline hormone levels. A study by Ma et al. (2021) compared 119 reproductive aged males with SARS-CoV-2 to 273 age matched controls. They found high luteinizing hormone (LH) levels and lower testosterone to LH ratios in SARS-CoV-2 patients. The authors suggest these findings are associated with the systemic inflammation present in the evaluated patients. These abnormalities could indicate disruption in sex hormone secretion associated with COVID-19 disease (Ma et al., 2021). Another study compared 89 COVID-19 patients to 30 patients suffering from other respiratory infections and 143 healthy controls. The COVID-19 patients were found to have significantly lower testosterone, higher LH and prolactin, and equivalent FSH when compared to both sets of controls (Pazir et al., 2021). Rastrelli et al (2021) found that in a group of 31 patients, 12.9% of patients who died or had severe COVID-19 exhibited lower total and free testosterone and elevated LH when compared to more moderate cases.
Hypothalamic pathology associated with SARS-CoV-2 infection in the brain is still being studied. SARS-CoV-2 has been shown to cross the blood brain barrier.7 Once past the barrier, it infects ACE2 expressing cells, leading to neuroinflammation. This inflammation can disrupt normal physiologic functions such as temperature regulation and hormone balance (Wu et al., 2020; Baig et al., 2020). Testicular pathology associated with hyperthermia has been established previously. Fevers are the body’s response to systemic inflammation, and over 80% of COVID-19 patients are reported to develop a fever, which tends to be prolonged with an average duration of 10 days (Gul et al., 2021). It has been reported by Jung and Schuppe (2007) that a fever of > 39°C for over 3 days can lead to significant reduction in semen concentration and motility.
Detection of SARS-CoV-2 in Semen and Sperm Parameters
Feldmann (2018) reported that nearly 30 viruses have been identified in human semen. Of these, the most notable are HIV, hepatitis B, herpes simplex virus (HSV), and adenoviruses. Most semen studies have involved recovering patients and have found that after 1 month, recovering patients did not have detectable levels of SARS-CoV-2 in their semen (Pan et al, 2020). The largest study by Ruan et al. consisted of 74 patients recovering from COVID-19 and 174 age matched controls. No SARS-CoV 2 RNA was detected in any of the patients, however, sperm concentration count and motility were reduced (Ruan et al., 2021). Several other studies with smaller sample sizes also failed to identify SARS-CoV 2 RNA in semen samples. Hajizadeh et al. studied semen quality in patients recovering from COVID-19; comparing 84 recovering COVID-19 patients to 104 healthy controls, they found impaired sperm parameters including concentration, progressive motility, and morphology in all COVID-19 patients (Hajizadeh and Tartibian, 2021). The smaller sample sized studies reported varying reports of reduced sperm parameters, with some finding reduction, others no change, and some claiming an association with severity of COVID-19 disease (Rawlings et al., 2020; Pavone et al., 2020). Two studies have reported identifying SARS-CoV-2 RNA in the semen. One study analyzed the semen of 38 patients diagnosed with COVID-19, 15 in an acute state and 23 recovering. 6 of 38 patients were found to have SARS-COV-2 RNA in their semen, 4 of those 6 patients were in the acute stage of infection and 2 were in recovery. It is also important to recognize that even if COVID-19 is transmissible through semen, it is unlikely to provide a significant source of infection in comparison to respiratory droplets. However, consideration should be made for those attempting to become pregnant or those donating or preserving sperm (Li et al, 2020).
COVID-19 Vaccines
Despite the pandemic ravaging the world, there is still vaccine hesitancy. Best et al (2021) asserted that potential fertility implications after receiving a COVID-19 vaccine are a source of anxiety for many patients, as reproductive toxicity was not evaluated in clinical trials. A vaccine that uses the actual virus could theoretically also directly affect the testes. However, the Pfizer and Moderna vaccines are only mRNA vaccines, which stimulate the recipient’s immune system to produce the SARS-CoV-2 spike protein, and thus does not bind to receptors via the same mechanism that SARS-COV-2 virus does (Meo et al., 2021). The Johnson & Johnson vaccine utilizes viral vector technology, combining SARS-CoV-2 spike gene with a weakened adenovirus. This leads to expression of the spike protein on cellular surfaces for immune cell interaction (Livingston et al., 2021). Although unlikely, there is a theoretical risk for expressed spike protein interaction in the testis.
A single centered prospective study out of the University of Miami investigated the effects of COVID-19 vaccination on semen parameters. A sample of 45 healthy male volunteers provided semen samples before the first vaccination dose and again, 70 days after the second dose administration. Semen samples were analyzed for the following parameters: semen volume, sperm concentration, sperm motility and total motile sperm count. No significant decreases in any of the above parameters were found (Gonzlez et al., 2021). There is a potential for a temporary decrease in sperm production post-vaccine, related to vaccine induced fevering. A fever can temporarily impact sperm count, and in the Pfizer vaccine clinical trials, about 16% of men experienced a fever after the second vaccine dose. However, this brief impact on sperm after vaccination is likely of much less magnitude than any potential effects of having the full clinical syndrome of COVID-19 (Meo et al., 2021).
Conclusion
While much is left to be studied, COVID-19 does appear to impact male fertility, at least temporarily. From review of the current literature, it has become evident that COVID-19 can lead to a reduction in testosterone production and a state of temporary hypogonadism. It was originally hypothesized that since the testes are prone to direct infection by the SARS-CoV-2 virus due to their ACE2 expression, male fertility is adversely affected. Although controversy remains, the data supports that a reduction in testosterone production is more likely associated with indirect testicular damage due to systemic or local inflammation. Additionally, with the rapidly evolving pandemic, it is important to maintain vigilance for potential interventions and delays of care that can lead to lasting effects on fertility. Moving forward, further studies are required to investigate the potential long term fertility effects of the COVID-19 disease, treatments, and vaccines.
REFERENCES
Baig, A., Khaleeq, A., Ali, U. and Syeda, H. (2020). Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem. Neurosci, 11: pp. 995-998.
Best, J. C., Kuchakulla, M. and Khodamoradi, K. et al. (2021). Evaluation of SARS-CoV-2 in human semen and effect on total sperm number: a prospective observational study. World J. Mens Health, 39: pp. 489-495.
Chen, Y., Guo, Y., Pan, Y. and Zhao, Z. (2020). Structure analysis of the receptor binding of 2019-nCoV. Biochem. Biophys. Res. Commun.
Czeisler, M.É. (2020). Delay or Avoidance of Medical Care Because of COVID-19–Related Concerns — United States, June 2020 MMWR Morb. Mortal. Wkly. Rep (2020), p. 69.
Feldmann, H. (2018). Virus in Semen and the Risk of Sexual Transmission N. Engl. J. Med, 378: pp. 1440-1441.
Gonzalez, D.C., Nassau, D.E. and Khodamoradi, K. et al. (2021). Sperm parameters before and after COVID-19 mRNA vaccination. JAMA, 326: pp. 273-274.
Gul, M. H., Htun, Z. M. and Inayat, A. (2021). Role of fever and ambient temperature in COVID-19, Expert Rev. Respir. Med. (n.d.) 1–3. doi:10.1080/17476348.2020.1816172.
Hajizadeh, B. and Tartibian, B. (2021). COVID-19 and male reproductive function: a prospective, longitudinal cohort study. Reprod. Camb. Engl, 161: pp. 319-331.
Hallak, J., Teixeira, T. A., Bernardes, F.S. et al. (2021). SARS-CoV-2 and its relationship with the genitourinary tract: Implications for male reproductive health in the context of COVID-19 pandemic. Andrology, 9 (2021), pp. 73-79.
Hoffmann, F.M., Kleine-Weber, H. and Schroeder, S. et al.(2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181 : pp. 271-280.e8.
Holtmann, N., Edimiris, P., and Andree, M. et al. (2020). Assessment of SARS-CoV-2 in human semen—a cohort study. Fertil. Steril, 114 (2020), pp. 233-238.
Jung, A. and Schuppe, H. (2007). Influence of genital heat stress on semen quality in humans. Andrologia, 39: pp. 203-215.
Li, D., Jin, M., Bao, P., Zhao, W. and Zhang, S. (2020). Clinical characteristics and results of semen tests among men with coronavirus disease 2019. JAMA Netw. Open, 3.
Livingston, E.H., Malani, P.N. and Creech, C.B. (2021). The Johnson & Johnson vaccine for COVID-19. JAMA.
Ma, L., Xie, W., Li, D., Shi, L., Ye, G. and Y. Mao, et al. (2021). Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients. J. Med. Virol, 9: pp. 456-462.
Meo, S.A., Bukhari, I.A., Akram, J., Meo, A.S. and Klonoff, D.C. (2021). COVID-19 vaccines: comparison of biological, pharmacological characteristics and adverse effects of Pfizer/BioNTech and Moderna Vaccines. Eur. Rev. Med. Pharmacol. Sci, 25:pp. 1663 -1669.
Moghimi, N., Eslami Farsani, B. and Ghadipasha, M. et al. (2021). COVID-19 disrupts spermatogenesis through the oxidative stress pathway following induction of apoptosis. Apoptosis Int. J. Program. Cell Death, 26: pp. 415-430.
Pan, F., Xiao, X. and Guo, J. et al. (2020). No evidence of severe acute respiratory syndrome–coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertil. Steril, 113: pp. 1135-1139.
Patel, D.P., Punjani, N., Guo, J., Alukal, J.P., Li, P.S. and Hotaling, J. M. (2021). The impact of SARS-CoV-2 and COVID-19 on male reproduction and men’s health. Fertil. Steril, 115 : pp. 813-823.
Pavone, C., Giammanco, G. and Baiamonte, D. et al (2020). Italian males recovering from mild COVID-19 show no evidence of SARS-CoV-2 in semen despite prolonged nasopharyngeal swab positivity. Int. J. Impot. Res, 32 (2020), pp. 560-562.
Pazir, Y., Eroglu, T., Kose, A., Bulut, T.B., Genc, C. and Kadihasanoglu, M. (2021). Impaired semen parameters in patients with confirmed SARS-CoV-2 infection: A prospective cohort study. Andrologia, 53 (2021), p. e14157.
Rastrelli, G., Di Stasi, V., Inglese, F., Beccaria, M., Garuti, M. and Di Costanzo, D. et al. (2021). Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Andrology, 9 (2021), pp. 88-98.
Rawlings, S., Ignacio, C., Porrachia, M., Du, P., Smith, D. and Chaillon, A. (2020). No evidence of SARS-CoV-2 seminal shedding despite SARS-CoV-2 persistence in the upper respiratory tract. Open Forum Infect. Dis. p. ofaa325.
Reis, A. B., Araújo, F.C., Pereira, V.M. Dos Reis, A.M., Santos, R.A. and Reis, F.M. (2021). Angiotensin (1-7) and its receptor Mas are expressed in the human testis: implications for male infertility. J. Mol. Histol, 41: pp. 75-80.
Ruan, Y., Hu, B. and Liu, Z. et al. (2021). No detection of SARS-CoV-2 from urine, expressed prostatic secretions, and semen in 74 recovered COVID-19 male patients: A perspective and urogenital evaluation. Andrology, 9: pp. 99-106.
Selvaraj, K., Ravichandran, S., Krishnan, S., Radhakrishnan, R., Manickam, N. and Kandasamy, M. (2021). Testicular atrophy and hypothalamic pathology in COVID-19: possibility of the incidence of male infertility and HPG axis abnormalities. Reprod. Sci (2021), pp. 1-8.
Stanley, K.E., Thomas, E., Leaver, M. and Wells, D. (2020). Coronavirus disease-19 and fertility: viral host entry protein expression in male and female reproductive tissues. Fertil. Steril, 114: pp. 33-43.
Temiz, Z., Dincer, M. and Hacibey, I. et al (2021). Investigation of SARS-CoV-2 in semen samples and the effects of COVID-19 on male sexual health by using semen analysis and serum male hormone profile: A cross-sectional, pilot study. Andrologia, 53 (2021), p. e13912.
Wu, Y., Xu, X. and Chen, Z. et al. (2020). Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain. Behav. Immun, 87 (2020), pp. 18-22.
Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y. and Zhou, Q. (2020). Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science, 367: pp. 1444-1448