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The impact of COVID-19 on the male genital tract: A qualitative literature review of sexual transmission and fertility implications

  • Received : 2021.03.23
  • Accepted : 2021.12.27
  • Published : 2022.03.31

Abstract

The angiotensin-converting enzyme 2 receptor (ACE2) appears to be widely expressed in cells in the testes, predominantly in spermatogonia, Sertoli cells, and Leydig cells, and its co-expression with transmembrane protease serine 2 (TMPRSS2) is essential for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For this reason, the male reproductive system could be considered a potential target for SARS-CoV-2, as well as a possible reservoir of infection. However, to date, there is very little evidence about the presence of SARS-CoV-2 in semen and testicular samples. The aim of this paper was to review the current evidence regarding the impact of SARS-CoV-2 on male fertility and sexual health, with a particular focus on reproductive hormones, the presence of the virus in seminal fluid and testis, and its impact on fertility parameters. We found very limited evidence reporting the presence of SARS-CoV-2 in semen and testicular samples, and the impact of SARS-CoV-2 on reproductive hormones and fertility parameters is unclear. The quality of the examined studies was poor due to the small sample size and several selection biases, precluding definitive conclusions. Hence, future well-designed prospective studies are needed to assess the real impact of SARS-CoV-2 on male reproductive function.

Keywords

References

  1. Liu W, Han R, Wu H, Han D. Viral threat to male fertility. Andrologia 2018;50:e13140. https://doi.org/10.1111/and.13140
  2. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-9. https://doi.org/10.1001/jama.2020.1585
  3. Wong SF, Chow KM, Leung TN, Ng WF, Ng TK, Shek CC, et al. Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome. Am J Obstet Gynecol 2004;191:292-7. https://doi.org/10.1016/j.ajog.2003.11.019
  4. Alfaraj SH, Al-Tawfiq JA, Memish ZA. Middle east respiratory syndrome coronavirus (MERS-CoV) infection during pregnancy: report of two cases & review of the literature. J Microbiol Immunol Infect 2019;52:501-3. https://doi.org/10.1016/j.jmii.2018.04.005
  5. Duggal NK, Ritter JM, Pestorius SE, Zaki SR, Davis BS, Chang GJ, et al. Frequent Zika virus sexual transmission and prolonged viral RNA shedding in an immunodeficient mouse model. Cell Rep 2017;18:1751-60. https://doi.org/10.1016/j.celrep.2017.01.056
  6. Deen GF, Broutet N, Xu W, Knust B, Sesay FR, McDonald SL, et al. Ebola RNA persistence in semen of ebola virus disease survivors: final report. N Engl J Med 2017;377:1428-37. https://doi.org/10.1056/NEJMoa1511410
  7. Pike JF, Polley EL, Pritchett DY, Lal A, Wynia BA, Roudebush WE, et al. Comparative analysis of viral infection outcomes in human seminal fluid from prior viral epidemics and Sars-CoV-2 may offer trends for viral sexual transmissibility and long-term reproductive health implications. Reprod Health 2021;18:123. https://doi.org/10.1186/s12978-021-01172-1
  8. Mansuy JM, Suberbielle E, Chapuy-Regaud S, Mengelle C, Bujan L, Marchou B, et al. Zika virus in semen and spermatozoa. Lancet Infect Dis 2016;16:1106-7. https://doi.org/10.1016/S1473-3099(16)30336-X
  9. Dejucq N, Jegou B. Viruses in the mammalian male genital tract and their effects on the reproductive system. Microbiol Mol Biol Rev 2001;65:208-31. https://doi.org/10.1128/MMBR.65.2.208-231.2001
  10. Tur-Kaspa I, Tur-Kaspa T, Hildebrand G, Cohen D. COVID-19 may affect male fertility but is not sexually transmitted: a systematic review. F S Rev 2021;2:140-9.
  11. Xu J, Qi L, Chi X, Yang J, Wei X, Gong E, et al. Orchitis: a complication of severe acute respiratory syndrome (SARS). Biol Reprod 2006;74:410-6. https://doi.org/10.1095/biolreprod.105.044776
  12. Pan F, Xiao X, Guo J, Song Y, Li H, Patel DP, et al. No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertil Steril 2020;113:1135-9. https://doi.org/10.1016/j.fertnstert.2020.04.024
  13. Verma S, Saksena S, Sadri-Ardekani H. ACE2 receptor expression in testes: implications in coronavirus disease 2019 pathogenesis. Biol Reprod 2020;103:449-51. https://doi.org/10.1093/biolre/ioaa080
  14. Stanley KE, Thomas E, Leaver M, Wells D. Coronavirus disease-19 and fertility: viral host entry protein expression in male and female reproductive tissues. Fertil Steril 2020;114:33-43. https://doi.org/10.1016/j.fertnstert.2020.05.001
  15. Song H, Seddighzadeh B, Cooperberg MR, Huang FW. Expression of ACE2, the SARS-CoV-2 receptor, and TMPRSS2 in prostate epithelial cells. Eur Urol 2020;78:296-8. https://doi.org/10.1016/j.eururo.2020.04.065
  16. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-4. https://doi.org/10.1038/nature02145
  17. Wang Z, Xu X. scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, Leydig and Sertoli cells. Cells 2020;9:920. https://doi.org/10.3390/cells9040920
  18. Shastri A, Wheat J, Agrawal S, Chaterjee N, Pradhan K, Goldfinger M, et al. Delayed clearance of SARS-CoV2 in male compared to female patients: high ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs. medRxiv [Preprint]. 2020 [cited 2022 Jan 10]. Available from: https://doi.org/10.1101/2020.04.16.20060566.
  19. Vishvkarma R, Rajender S. Could SARS-CoV-2 affect male fertility? Andrologia 2020;52:e13712.
  20. Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med 2020;14:185-92. https://doi.org/10.1007/s11684-020-0754-0
  21. Xu J, Xu Z, Jiang Y, Qian X, Huang Y. Cryptorchidism induces mouse testicular germ cell apoptosis and changes in bcl-2 and bax protein expression. J Environ Pathol Toxicol Oncol 2000;19:25-33.
  22. Ma L, Xie W, Li D, Shi L, Mao Y, Xiong Y, et al. Effect of SARS-CoV-2 infection upon male gonadal function: a single center-based study. medRxiv [Preprint]. 2020 [cited 2022 Jan 10]. Available from: http://medrxiv.org/content/early/2020/03/30/2020.03.21.20037267.
  23. Schroeder M, Schaumburg B, Mueller Z, Parplys A, Jarczak D, Roedl K, et al. High estradiol and low testosterone levels are associated with critical illness in male but not in female COVID-19 patients: a retrospective cohort study. Emerg Microbes Infect 2021;10:1807-18. https://doi.org/10.1080/22221751.2021.1969869
  24. Rastrelli G, Di Stasi V, Inglese F, Beccaria M, Garuti M, Di Costanzo D, et al. Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Andrology 2021;9:88-98. https://doi.org/10.1111/andr.12821
  25. Ma L, Xie W, Li D, Shi L, Ye G, Mao Y, et al. Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients. J Med Virol 2021;93:456-62. https://doi.org/10.1002/jmv.26259
  26. Paoli D, Pallotti F, Colangelo S, Basilico F, Mazzuti L, Turriziani O, et al. Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab. J Endocrinol Invest 2020;43:1819-22. https://doi.org/10.1007/s40618-020-01261-1
  27. Rawlings SA, Ignacio C, Porrachia M, Du P, Smith DM, Chaillon A. No evidence of SARS-CoV-2 seminal shedding despite SARSCoV-2 persistence in the upper respiratory tract. Open Forum Infect Dis 2020;7:ofaa325. https://doi.org/10.1093/ofid/ofaa325
  28. Holtmann N, Edimiris P, Andree M, Doehmen C, Baston-Buest D, Adams O, et al. Assessment of SARS-CoV-2 in human semen-a cohort study. Fertil Steril 2020;114:233-8. https://doi.org/10.1016/j.fertnstert.2020.05.028
  29. Kayaaslan B, Korukluoglu G, Hasanoglu I, Kalem AK, Eser F, Akinci E, et al. Investigation of SARS-CoV-2 in semen of patients in the acute stage of COVID-19 infection. Urol Int 2020;104:678-83. https://doi.org/10.1159/000510531
  30. Ning J, Li W, Ruan Y, Xia Y, Wu X, Hu K, et al. Effects of 2019 novel coronavirus on male reproductive system: a retrospective study. Preprints [Preprint]. 2020 [cited 2022 Jan 10]. Available from: https://doi.org/10.20944/ preprints202004.0280.v1.
  31. Cui P, Chen Z, Wang T, Dai J, Zhang J, Ding T, et al. Clinical features and sexual transmission potential of SARS-CoV-2 infected female patients: a descriptive study in Wuhan, China. medRxiv [Preprint]. 2020 [cited 2022 Jan 10]. Available from: https://doi.org/10.1101/2020.02.26.20028225.
  32. Li D, Jin M, Bao P, Zhao W, Zhang S. Clinical characteristics and results of semen tests among men with coronavirus disease 2019. JAMA Netw Open 2020;3:e208292. https://doi.org/10.1001/jamanetworkopen.2020.8292
  33. Song C, Wang Y, Li W, Hu B, Chen G, Xia P, et al. Detection of 2019 novel coronavirus in semen and testicular biopsy specimen of COVID-19 patients. medRxiv [Preprint]. 2020 [cited 2022 Jan 10]. Available from: https://doi.org/10.1101/2020.03.31.20042333.
  34. Flaifel A, Guzzetta M, Occidental M, Najari BB, Melamed J, Thomas KM, et al. Testicular changes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Arch Pathol Lab Med 2021;145:8-9. https://doi.org/10.5858/arpa.2020-0487-LE
  35. Yang M, Chen S, Huang B, Zhong JM, Su H, Chen YJ, et al. Pathological findings in the testes of COVID-19 patients: clinical implications. Eur Urol Focus 2020;6:1124-9. https://doi.org/10.1016/j.euf.2020.05.009
  36. Achua JK, Chu KY, Ibrahim E, Khodamoradi K, Delma KS, Iakymenko OA, et al. Histopathology and ultrastructural findings of fatal COVID-19 infections on testis. World J Mens Health 2021;39:65-74. https://doi.org/10.5534/wjmh.200170
  37. Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A 2020;117:11727-34. https://doi.org/10.1073/pnas.2003138117
  38. Al-Qahtani AA. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): emergence, history, basic and clinical aspects. Saudi J Biol Sci 2020;27:2531-8. https://doi.org/10.1016/j.sjbs.2020.04.033
  39. Aitken RJ. COVID-19 and human spermatozoa: potential risks for infertility and sexual transmission? Andrology 2021;9:48-52. https://doi.org/10.1111/andr.12859
  40. Kohn FM, Muller C, Drescher D, Neukamm C, el Mulla KF, Henkel R, et al. Effect of angiotensin converting enzyme (ACE) and angiotensins on human sperm functions. Andrologia 1998;30:207-15. https://doi.org/10.1111/j.1439-0272.1998.tb01162.x
  41. Zhang S, Wang X, Zhang H, Xu A, Fei G, Jiang X, et al. The absence of coronavirus in expressed prostatic secretion in COVID-19 patients in Wuhan city. Reprod Toxicol 2020;96:90-4. https://doi.org/10.1016/j.reprotox.2020.06.006
  42. Aassve A, Cavalli N, Mencarini L, Plach S, Livi Bacci M. The COVID-19 pandemic and human fertility. Science 2020;369:370-1. https://doi.org/10.1126/science.abc9520
  43. Cocci A, Giunti D, Tonioni C, Cacciamani G, Tellini R, Polloni G, et al. Love at the time of the Covid-19 pandemic: preliminary results of an online survey conducted during the quarantine in Italy. Int J Impot Res 2020;32:556-7. https://doi.org/10.1038/s41443-020-0305-x