Male infertility along with the era of coronavirus infection SARS-CoV-2

Russian and foreign epidemiological data suggest that males may have an increased risk of morbidity and mortality associated with COVID‑19. It is known that due to the high expression of ACE2 in spermatogonia, Leydig and Sertoli cells, the testicle, as an organ producing male germ cells, is a potential target for the COVID‑19 virus, which directly affects the reproductive health of men. To date, several factors of the influence of the SARS-CoV‑2 virus on the male reproductive system are known. To begin with, when infected, the virus has a direct damaging effect on the testicle itself with the provocation of orchitis. In addition to the previous statement, high body temperature during inflammation contributes to an increase in testicular temperature, which can lead to a deterioration in the quality of sperm. Furthermore, a pronounced inflammatory reaction promotes the circulation of a large number of cytokines and damage to the hemato-testicular barrier. Also, the increased activity of immunocytes leads to an imbalance of the antioxidant system of men, an increase in the level of reactive oxygen species and the formation of oxidative stress. In a Nutshell, Leydig cell dystrophy provokes the development of secondary hypogonadism. Thus, COVID‑19, like a “multifaceted Janus”, has a polysymptomatic manifestation, but at the same time has a multifactorial effect on the reproductive function of a man. All these factors of the impact of the SARS-CoV‑2 virus on the testicle must be considered when rehabilitating the patient. It should be kept in mind that the deterioration of sperm quality is observed both during the acute period of coronavirus infection and during recovery period. Therefore, laboratory evaluation of the ejaculate in dynamics and its correction is necessary for males, especially those who plan to realize their reproductive potential.

Conclusion. COVID‑19 generally has a negative impact on spermatogenesis and male fertility. To date, the timing and degree of restoration of a man’s reproductive function after a coronavirus infection remains completely unknown. Therefore, both in the early and late rehabilitation period, men of reproductive age need the supervision of an andrologist.

1. Zhukovskaya SJr, Zhukovskaya SV. COVID-19 impact on male fertility: review. Reproductive Health Eastern Europe 2020;10(6):701– 709. (In Russ.). https://doi.org/10.34883/pi.2020.10.6.006

2. Satyanath RK, Sorout J, Jayachandra S, Gandhi A, Kacker S. Physiological and clinical aspects in COVID 19. RUDN Journal of Medicine. 2020;24(3):201–206. (In Russ.). https://doi.org/10.22363/2313-0245-2020-24-3-201-206

3. Aitken RJ. COVID-19 and human spermatozoa-Potential risks for infertility and sexual transmission? Andrology. 2021 Jan;9(1):48– 52. https://doi.org/10.1111/andr.12859

4. Kuzmenko AV, Kuzmenko VV, Gyaurgiev TA. Treatment characteristics of patients with male factor infertility in COVID-19. Russian Medical Journal. 2020;13:10–12. (In Russ.).

5. Sapozhkova ZhYu. Viral Effect of SARS-Cov-2 on male infertility. Laboratory and Clinical Medicine. Pharmacy. 2021;1(1):8–13. (In Russ.). https://doi.org/10.14489/lcmp.2021.01.pp.008-013

6. Patel DP, Punjani N, Guo J, Alukal JP, Li PS, Hotaling JM. The impact of SARS-CoV-2 and COVID-19 on male reproduction and men’s health. Fertil Steril. 2021 Apr;115(4):813–823. https://doi.org/10.1016/j.fertnstert.2020.12.033

7. Nassau DE, Best JC, Kresch E, Gonzalez DC, Khodamoradi K, Ramasamy R. Impact of the SARS-CoV-2 virus on male reproductive health. BJU Int. 2022 Feb;129(2):143–150. https://doi.org/10.1111/bju.15573

8. Castañeda-Babarro A, Arbillaga-Etxarri A, Gutiérrez-Santamaría B, Coca A. Physical Activity Change during COVID-19 Confinement. Int J Environ Res Public Health. 2020 Sep 21;17(18):6878. https://doi.org/10.3390/ijerph17186878

9. Grasselli G, Greco M, Zanella A, Albano G, Antonelli M, Bellani G, et al. COVID-19 Lombardy ICU Network. Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy. JAMA Intern Med. 2020 Oct 1;180(10):1345– 1355. https://doi.org/10.1001/jamainternmed.2020.3539

10. Suba Z. Prevention and therapy of COVID-19 via exogenous estrogen treatment for both male and female patients. J Pharm Pharm Sci. 2020;23(1):75–85. https://doi.org/10.18433/jpps31069

11. Lanser L, Burkert FR, Thommes L, Egger A, Hoermann G, Kaser S, et al. Testosterone Deficiency Is a Risk Factor for Severe COVID-19. Front Endocrinol (Lausanne). 2021 Jun 18;12:694083. https://doi.org/10.3389/fendo.2021.694083

12. Gebhard C, Regitz-Zagrosek V, Neuhauser HK, Morgan R, Klein SL. Impact of Sex and Gender on COVID-19 Outcomes in Europe. Biol Sex Differ. 2020;11(1):29. https://doi.org/10.1186/s13293-020-00304-9

13. Kachkovskii MA. Rehabilitation in severe COVID-19 and prevention of the development of post-COVID-19 syndrome. Bulletin of the Medical Institute “REAVIZ” (Rehabilitation, Doctor and Health). 2021;11(6):5–12. (In Russ.). https://doi.org/10.20340/vmi-rvz.2021.6.covid.1

14. Malki MI. COVID-19 and male infertility: An overview of the disease. Medicine (Baltimore). 2022 Jul 8;101(27):e29401. https://doi.org/10.1097/md.0000000000029401

15. Generalova LV, Burgasova OA, Gushchin VA, Kolobukhina LV, Bakalin VV, Tetova VB, et al. The features of a humoral response in patients with COVID-19. The Doctor. 2021;32(12):5–11. (In Russ.). https://doi.org/10.29296/25877305-2021-12-01

16. Liu X, Chen Y, Tang W, Zhang L, Chen W, Yan Z, et al. Single-cell transcriptome analysis of the novel coronavirus (SARS-CoV-2) associated gene ACE2 expression in normal and non-obstructive azoospermia (NOA) human male testes. Sci China Life Sci. 2020 Jul;63(7):1006–1015. https://doi.org/10.1007/s11427-020-1705-0

17. Douglas GC, O’Bryan MK, Hedger MP, Lee DK, Yarski MA, Smith AI, et al. The novel angiotensin-converting enzyme (ACE) homolog, ACE2, is selectively expressed by adult Leydig cells of the testis. Endocrinology. 2004 Oct;145(10):4703–4711. https://doi.org/10.1210/en.2004-0443

18. Illiano E, Trama F, Costantini E. Could COVID-19 have an impact on male fertility? Andrologia. 2020 Jul;52(6):e13654. https://doi.org/10.1111/and.13654

19. Hajizadeh Maleki B, Tartibian B. COVID-19 and male reproductive function: a prospective, longitudinal cohort study. Reproduction. 2021 Mar;161(3):319–331. https://doi.org/10.1530/rep-20-0382

20. Fu J, Zhou B, Zhang L, Balaji KS, Wei C, Liu X, et al. Expressions and significances of the angiotensin-converting enzyme 2 gene, the receptor of SARS-CoV-2 for COVID-19. Mol Biol Rep. 2020 Jun;47(6):4383–4392. https://doi.org/10.1007/s11033-020-05478-4

21. Hikmet F, Méar L, Edvinsson Å, Micke P, Uhlén M, Lindskog C. The protein expression profile of ACE2 in human tissues. Mol Syst Biol. 2020 Jul;16(7):e9610. https://doi.org/10.15252/msb.20209610

22. 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 Jun;113(6):1135–1139. https://doi.org/10.1016/j.fertnstert.2020.04.024

23. Ediz C, Tavukcu HH, Akan S, Kizilkan YE, Alcin A, Oz K, et al. Is there any association of COVID-19 with testicular pain and epididymo-orchitis? Int J Clin Pract. 2021 Mar;75(3):e13753. https://doi.org/10.1111/ijcp.13753

24. Carneiro F, Teixeira TA, Bernardes FS, Pereira MS, Milani G, Duarte-Neto AN, et al. Radiological patterns of incidental epididymitis in mild-to-moderate COVID-19 patients revealed by colour Doppler ultrasound. Andrologia. 2021 May;53(4):e13973. https://doi.org/10.1111/and.13973

25. 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 Sep 15;6(5):1124–1129. https://doi.org/10.1016/j.euf.2020.05.009

26. Duarte-Neto AN, Monteiro RAA, da Silva LFF, Malheiros DMAC, de Oliveira EP, Theodoro-Filho J, et al. Pulmonary and systemic involvement in COVID-19 patients assessed with ultrasound-guided minimally invasive autopsy. Histopathology. 2020 Aug;77(2):186– 197. https://doi.org/10.1111/his.14160

27. Barton LM, Duval EJ, Stroberg E, Ghosh S, Mukhopadhyay S. COVID-19 Autopsies, Oklahoma, USA. Am J Clin Pathol. 2020 May 5;153(6):725–733. https://doi.org/10.1093/ajcp/aqaa062

28. Sheikhzadeh Hesari F, Hosseinzadeh SS, Asl Monadi Sardroud MA. Review of COVID-19 and male genital tract. Andrologia. 2021 Feb;53(1):e13914. https://doi.org/10.1111/and.13914

29. Ivell R. Lifestyle impact and the biology of the human scrotum. Reprod Biol Endocrinol. 2007 Apr 20;5:15. https://doi.org/10.1186/1477-7827-5-15

30. Temiz MZ, Dincer MM, Hacibey I, Yazar RO, Celik C, Kucuk SH, et al. 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. 2021 Mar;53(2):e13912. https://doi.org/10.1111/and.13912

31. Gacci M, Coppi M, Baldi E, Sebastianelli A, Zaccaro C, Morselli S, et al. Semen impairment and occurrence of SARS-CoV-2 virus in semen after recovery from COVID-19. Hum Reprod. 2021 May 17;36(6):1520–1529. https://doi.org/10.1093/humrep/deab026

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 May 1;3(5):e208292. https://doi.org/10.1001/jamanetworkopen.2020.8292

33. 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 Jan;93(1):456–462. https://doi.org/10.1002/jmv.26259

34. 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 Aug;114(2):233–238. https://doi.org/10.1016/j.fertnstert.2020.05.028

35. Melnikov IA, Salekhov SA, Gaydukov SN, Bezrukov RV, Dybov YuA. Pathogenetic features of the influence of COVID-19 on sperm fertility. International Journal of Medicine and Psychology. 2020;3(5):146–152. (In Russ.).

36. Best JC, Kuchakulla M, Khodamoradi K, Lima TFN, Frech FS, Achua J, et al. Evaluation of SARS-CoV-2 in Human Semen and Effect on Total Sperm Number: A Prospective Observational Study. World J Mens Health. 2021 Jul;39(3):489–495. https://doi.org/10.5534/wjmh.200192

37. Guo TH, Sang MY, Bai S, Ma H, Wan YY, Jiang XH, et al. Semen parameters in men recovered from COVID-19. Asian J Androl. 2021 Sep-Oct;23(5):479–483. https://doi.org/10.4103/aja.aja_31_21

38. 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(9-10):678–683. https://doi.org/10.1159/000510531

39. Ruan Y, Hu B, Liu Z, Liu K, Jiang H, Li H, et al. 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. 2021 Jan;9(1):99–106. https://doi.org/10.1111/andr.12939

40. Paoli D, Pallotti F, Turriziani O, Mazzuti L, Antonelli G, Lenzi A, Lombardo F. SARS-CoV-2 presence in seminal fluid: Myth or reality. Andrology. 2021 Jan;9(1):23–26. https://doi.org/10.1111/andr.12825

41. Aboelnaga MM, Abdelrazek A, Abdullah N, El Shaer M. Late Impact of COVID-19 Pneumonia on Testosterone Levels in Recovered, Post-Hospitalized Male Patients. Journal of endocrinology and metabolism. 2021;11(3-4):76–82. https://doi.org/10.14740/jem749

42. Okçelik S. COVID-19 pneumonia causes lower testosterone levels. Andrologia. 2021 Feb;53(1):e13909. https://doi.org/10.1111/and.13909

43. Salonia A, Pontillo M, Capogrosso P, Gregori S, Tassara M, Boeri L, et al. Severely low testosterone in males with COVID-19: A case-control study. Andrology. 2021 Jul;9(4):1043–1052. https://doi.org/10.1111/andr.12993

44. van Zeggeren IE, Boelen A, van de Beek D, Heijboer AC, Vlaar APJ, Brouwer MC. Sex steroid hormones are associated with mortality in COVID-19 patients Level of sex hormones in severe COVID-19. Medicine. 2021;100(34):e27072. https://doi.org/10.1097/md.0000000000027072

45. Dhindsa S, Zhang N, McPhaul MJ, Wu Z, Ghoshal AK, Erlich EC, et al. Association of Circulating Sex Hormones with Inflammation and Disease Severity in Patients With COVID-19. JAMA Netw Open. 2021 May 3;4(5):e2111398. https://doi.org/10.1001/jamanetworkopen.2021.11398

46. Toscano-Guerra E, Gallo MM, Arrese-Munoz I, Gine A, Diaz-Troyano N, Gabriel-Medina P, et al. Recovery of serum testosterone levels is an accurate predictor of survival from COVID-19 in male patients. BMC Med. 2022 Mar 29;20(1):129. https://doi.org/10.1186/s12916-022-02345-w

47. Falahieh FM, Zarabadipour M, Mirani M, Abdiyan M, Dinparvar M, Alizadeh H, et al. Effects of moderate COVID-19 infection on semen oxidative status and parameters 14 and 120 days after diagnosis. Reprod Fertil Dev. 2021 Oct;33(12):683–690. https://doi.org/10.1071/rd21153