Andrological aspects of new coronavirus infection Covid-19


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

COVID-19 is a new highly contagious infectious disease caused by the SARS-CoV-2. The World Health Organization (WHO) on March 11, 2020, has declared the novel coronavirus (COVID-19) outbreak a global pandemic. More attention is currently paid to the fact that men are more at risk for worse outcomes. In addition, SARS-CoV-2 can infect the testes, potentially affecting testosterone production, as well as having a negative influence on the reproductive potential. Our aim was to review the current concepts of the possible influence of testosterone levels on the pathogenesis of COVID-19 in men and to present the available data on the impact of COVID-19 on the structure and function of the testis. Based on the analysis of 72 articles using the MEDLINE database (PubMed), it can be concluded that testosterone is involved in the co-regulation of the synthesis of angiotensin-converting enzyme-2 and transmembrane serine protease-2, facilitating the penetration of SARS-CoV-2 into target cells and promoting easier infection in men. On the other hand, low testosterone levels increase the risk of cardiopulmonary complications. Hypogonadism appears to be an important unfavorable prognostic factor for the disease. Orchitis is a reported complication of COVID-19. Damage to testicular tissue is possible due to direct invasion by a virus, a secondary autoimmune reaction, hyperthermia and thrombosis of testicular microvessels. Prophylaxis of possible vertical and sexual transmission of infection is recommended. Despite the available data, further studies are required to assess the definite role of androgens in the course of infection and the influence of SARS-CoV-2 on male reproductive potential.

Full Text

Restricted Access

About the authors

N. D. Akhvlediani

A.I. Evdokimov Moscow State University of Medicine and Dentistry

Email: nikandro@mail.ru
Ph.D., MD, professor at the Department of Urology Moscow, Russia

I. A Reva

A.I. Evdokimov Moscow State University of Medicine and Dentistry

Email: rewa-igor@rambler.ru
Ph.D., urologist, acting Head of the Urologic Department of University Clinic Moscow, Russia

A. S Chernushenko

A.I. Evdokimov Moscow State University of Medicine and Dentistry

Email: artemchemushenko@gmail.com
urologist at the Urologic Department of University Clinic Moscow, Russia

D. Yu Pushkar

A.I. Evdokimov Moscow State University of Medicine and Dentistry

Email: pushkardm@mail.ru
Ph.D., MD, professor, academician of RAS, Head of the Department of Urology Moscow, Russia

References

  1. Xie J. Clinical Characteristics of Patients Who Died of Coronavirus Disease 2019 in China/J. Xie, Z. Tong, X. Guan, et al. JAMA Netw Open. 2020;3(4):e205619. doi: 10.1001/jamanetworkopen.2020.5619.
  2. Onder G. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. Onder G., Rezza G., Brusaferro S. JAMA. 2020;323(18):1775-1776. doi: 10.1001/jama.2020.4683.
  3. Chen T. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. Chen Т., Wu D.I., Chen Н., et al. BMJ. 2020;368: m1091. doi: 10.1136/bmj.m1295.
  4. Korean Society of Infectious Diseases; Korean Society of Pediatric Infectious Diseases; Korean Society of Epidemiology; Korean Society for Antimicrobial Therapy; Korean Society for Healthcare-associated Infection Control and Prevention; Korea Centers for Disease Control and Prevention. Report on the Epidemiological Features of Coronavirus Disease 2019 (COVID-19) Outbreak in the Republic of Korea from January 19 to March 2, 2020. J Korean Med Sci. 2020; 35(10):e112. doi: 10.3346/jkms.2020.35.e112.
  5. La Vignera S. Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis La Vignera D.S., Cannarella R., Condorelli R.A., et al.Int J Mol Sci. 2020;21(8):2948. doi: 10.3390/ijms21082948.
  6. Pozzilli P.Commentary: Testosterone, a key hormone in the context of COVID-19 pandemic. P. Pozzilli A. Lenzi Metabolism. 2020;108:154252. doi: 10.1016/j.metabol.2020.154252.
  7. Douglas G.C. The novel angiotensin-converting enzyme (ACE) homolog, ACE2, is selectively expressed by adult Leydig cells of the testis. G.C. Douglas, M.K. O’Bryan, M.P. Hedger, et al. Endocrinology. 2004;145(10):4703-4711. doi: 10.1210/en.2004-0443.
  8. Wang Z. 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. Z. Wang, X. Xu. Cells. 2020;9(4):920. doi: 10.3390/cells9040920.
  9. Walls A.C. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. A.C. Walls, Y.J. Park, M A. Tortorici, et al. Cell. 2020;181(2):281-292.e6. doi: 10.1016/j.cell.2020.02.058.
  10. Hamming I. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. I. Hamming, W. Timens, M. L. Bulthuis, et al. J Pathol. 2004;203(2):631- 637. doi: 10.1002/path.1570.
  11. Nicholls J. Good ACE, bad ACE do battle in lung injury, SARS. Nicholls J., Peiris M. Nat Med. 2005;11(8):821-822. doi: 10.1038/nm0805-821.
  12. Pal R. COVID-19, diabetes mellitus and ACE2: The conundrum. Pal R., Bhansali A. Diabetes Res Clin Pract. 2020;162:108132. Doi: 10.1016/j. diabres.2020.108132.
  13. Fang L. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? / L. Fang, G. Karakiulakis, M. Roth. Lancet Respir Med. 2020;8(4):e21. doi: 10.1016/S2213-2600(20)30116-8.
  14. Fan R. Preliminary analysis of the association between methylation of the ACE2 promoter and essential hypertension. Fan R., Mao S.Q., Gu T.L., et al. Mol Med Rep. 2017;15(6):3905-3911. doi: 10.3892/mmr.2017.6460.
  15. Liu J. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17|3-oestradiol-dependent and sex chromosome-independent. Liu J., Ji H., Zheng W., et al. Biol Sex Differ. 2010. Vol. 1. № 1. Р. 6. doi: 10.1186/2042-6410-1-6.
  16. Wilson S. The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells. S. Wilson, B. Greer, J. Hooper, et al. Biochem J. 2005;388(3):967-972. doi: 10.1042/BJ20041066.
  17. Lucas J.M. The androgen-regulated protease TMPRSS2 activates a proteolytic Cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Lucas J. M., Heinlein C., Kim T., et al. Cancer Discovery. 2014;4(11):1310-1325. doi: 10.1158/2159-8290. CD-13-1010.
  18. Asselta R. ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. Asselta R., Paraboschi E.M., Mantovani A., et al. medRxiv. 2020. doi: 10.1101/2020.03.30.20047878.
  19. Guan W. J. Clinical Characteristics of Covid-19 in China. Reply. Guan W.J., Zhong N.S. N. Engl J Med. 2020;382(19):1861-1862. Doi: 10.1056/ NEJMc2005203.
  20. Wambier C.G. Androgen sensitivity gateway to COVID-19 disease severity. Wambier C.G., Goren A., Vano-Galvan S., et al. Drug Dev Res. 2020;81(7):771-776. doi: 10.1002/ddr.21688.
  21. Hoffmann M. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Hoffmann M., Kleine-Weber H., Schroeder S., et al. Cell. 2020;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052.
  22. Montopoli M. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N=4532). Montopoli M., Zumerle S., Vettor R., et al. Ann Oncol. 2020;31(8):1040-1045. doi: 10.1016/j.annonc.2020.04.479.
  23. Shi S. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. Shi S., Qin M., Shen B., et al. JAMA Cardiol. 2020;5(7):802-810. doi: 10.1001/jamacardio.2020.0950.
  24. Deanfield J.E. Endothelial function and dysfunction: testing and clinical relevance. Deanfield J.E, Halcox J.P., Rabelink T.J. Circulation. 2007;115(10):1285-1295. doi: 10.1161/CIRCULATIONAHA.106.652859.
  25. Varga Z. Endothelial cell infection and endotheliitis in COVID-19. Varga Z., Flammer A.J., Steiger P., et al. Lancet. 2020;395(10234):1417-1418. doi: 10.1016/S0140-6736(20)30937-5.
  26. Dal Moro F. Any possible role of phosphodiesterase type 5 inhibitors in the treatment of severe COVID19 infections? A lesson from urology. Dal Moro F., Livi U. Clin Immunol. 2020;214:108414. Doi: 10.1016/j. clim.2020.108414.
  27. Akerstrom S. Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. Akerstrom S., Mousavi-Jazi M., Klingstrom J., et al. J. Virol. 2005;79(3): 1966-1969. Doi: 10.1128/ JVI.79.3.1966-1969.
  28. Hak A.E. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. Hak A.E., Witteman J.C., de Jong F.H., et al. J Clin Endocrinol Metab. 2002;87(8):3632-3639. doi: 10.1210/jcem.87.8.8762.
  29. Haffner S.M. Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. Haffner S.M,, Mykkanen L., Valdez R.A., et al. J Clin Endocrinol Metab. 1993;77(6):1610-1615. Doi: 10.1210/ jcem.77.6.8263149.
  30. Jones T.H. Randomized controlled trials - mechanistic studies of testosterone and the cardiovascular system. Jones T.H., D.M. Kelly. Asian J Androl. 2018;20(2):120-130. doi: 10.4103/aja.aja_6_18.
  31. Khaw K.T. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Khaw K.T., Dowsett M., Folkerd E., et al. Circulation. 2007;116(23):2694- 2701. doi: 10.1161/CIRCULATIONAHA.107.719005.
  32. Vikan T. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromso Study. Vikan T., Schirmer H., Njolstad I., et al. J. Eur J Endocrinol. 2009;161(3):435-442. doi: 10.1530/EJE-09-0284.
  33. Balasubramanian V. Hypogonadism in chronic obstructive pulmonary disease: incidence and effects. Balasubramanian V., Naing S. Curr Opin Pulm Med. 2012;18(2):112-117. doi: 10.1097/MCP.0b013e32834feb37.
  34. Montano L.M. Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm. Montano L.M., Espinoza J., Flores-Soto E., et al. J Endocrinol. 2014. Vol. 222. № 1. Р. 1-13. doi: 10.1530/JOE-14-0074.
  35. Mohan S.S. Higher serum testosterone and dihydrotestosterone, but not oestradiol, are independently associated with favourable indices of lung function in community-dwelling men. Mohan S.S, Knuiman M.W., Divitini M.L., et al. Clin Endocrinol (Oxf). 2015;83(2):268-276. doi: 10.1111/cen.12738.
  36. Caminiti G. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a doubleblind, placebo-controlled, randomized study. Caminiti G., Volterrani M., Iellamo F., et al. J Am Coll Cardiol. 2009; 54(10):919-927. Doi: 10.1016/j. jacc.2009.04.078.
  37. Whyte C.S. Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. Whyte C.S., Morrow G.B., Mitchell J L., et al. J Thromb Haemost. 2020;18(7):1548-1555. doi: 10.1111/jth.14872.
  38. Kollias A. Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action. Kollias A., Kyriakoulis K.G., Dimakakos E., et al. Br J Haematol. 2020;189(5):846-847. Doi: 10.1111/ bjh.16727.
  39. The Ministry of Health of the Russian Federation. Temporary methodological recommendations. Prevention, diagnosis and treatment of new coronavirus infection (COVID-19). Version 9 / Ministry of Health of the Russian Federation. Moscow, 2020. 236 p.Russian @@Министерство здравоохранения Российской Федерации. Временные методические рекомендации. Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19). Версия 9 / Министерство здравоохранения Российской Федерации. М., 2020. 236 с.
  40. Tang N. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. Tang N., Bai H., Chen X., et al. J Thromb Haemost. 2020;18(5):1094-1099. doi: 10.1111/jth.14817.
  41. Tang N. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. Tang N., Li D., Wang X., et al. J Thromb Haemost. 2020;18(4):844-847. doi: 10.1111/jth.14768.
  42. Ajayi A.A. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Ajayi A.A., Mathur R., Halushka P.V. Circulation. 1995;91(11):2742-2747. doi: 10.1161/01.cir.91.11.2742.
  43. Karolczak K. Testosterone and dihydrotestosterone reduce platelet activation and reactivity in older men and women. Karolczak K., Konieczna L., Kostka T., et al. Aging (Albany NY). 2018;10(5):902-929. doi: 10.18632/aging.101438.
  44. Khetawat G. Human megakaryocytes and platelets contain the estrogen receptor beta and androgen receptor (AR): testosterone regulates AR expression. Khetawat G., Faraday N., Nealen M.L., et al. Blood. 2000;95(7):2289-2296.
  45. Glueck C.J. Endogenous testosterone, fibrinolysis, and coronary heart disease risk in hyperlipidemic men. Glueck C.J., Glueck H.I., Stroop D., et al. J Lab Clin Med. 1993;122(4):412-420.
  46. Giagulli V.A. Worse progression of COVID-19 in men: Is testosterone a key factor? Giagulli V.A., Guastamacchia E., Magrone T., et al. Andrology. 2020. 11:10.1111/andr.12836. doi: 10.1111/andr.12836.
  47. Zeng F. A comparison study of SARS-CoV-2 IgG antibody between male and female COVID-19 patients: A possible reason underlying different outcome between sex. Zeng F., Dai C., Cai P., et al. J Med Virol. 2020;92(10):2050-2054. doi: 10.1002/jmv.25989.
  48. Rastrelli G. Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Rastrelli G., Di Stasi V., Inglese F., et al. Andrology. 2020. 10.1111/andr.12821. doi: 10.1111/andr.12821.
  49. Iglesias P. Hypogonadism in aged hospitalized male patients: prevalence and clinical outcome. P. Iglesias P., Prado F., Macias M.C., et al. J Endocrinol Invest. 2014;37(2):135-141. doi: 10.1007/s40618-013-0009-x.
  50. Nakashima A. Associations Between Low Serum Testosterone and All-Cause Mortality and Infection-Related Hospitalization in Male Hemodialysis Patients: A Prospective Cohort Study. Nakashima A., Ohkido I., Yokoyama K., et al. Kidney Int Rep. 2017;2(6):1160-1168. Doi: 10.1016/j. ekir.2017.07.015.
  51. Rowland S.P. Screening for low testosterone is needed for early identification and treatment of men at high risk of mortality from Covid-19. Rowland S.P., O’Brien Bergin E. Crit Care. 2020;24(1):367. doi: 10.1186/s13054-020-03086-z.
  52. Richardson S. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. Richardson S., Hirsch J.S., Narasimhan M., et al. JAMA. 2020;323(20):2052. doi: 10.1001/jama.2020.6775.
  53. Dietz W. Obesity and its Implications for COVID-19 Mortality / W. Dietz, C. Santos-Burgoa // Obesity (Silver Spring). 2020;28(6):1005. doi: 10.1002/oby.22818.
  54. Ryan D.H. COVID-19 and the Patient with Obesity - The Editors Speak Out. Ryan D.H., Ravussin E., Heymsfield S. Obesity (Silver Spring). 2020;28(5):847. doi: 10.1002/oby.22808.
  55. Simonnet A. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation. Simonnet A., Chetboun, Poissy J., et al. Obesity (Silver Spring). 2020;28(7):1195-1199. doi: 10.1002/oby M.22831.
  56. Kassir R. Risk of COVID-19 for patients with obesity. Kassir R. Obes Rev. 2020;21:13034. doi: 10.1111/obr.13034.
  57. Giagulli V.A. Pathogenesis of the decreased androgen levels in obese men. Giagulli V.A., Kaufman J.M., Vermeulen A. J Clin Endocrinol Metab. 1994;79(4):997-1000. doi: 10.1210/jcem.79.4.7962311.
  58. Garci'a-Alonso V. Prostaglandin E2 exerts multiple regulatory actions on human obese adipose tissue remodeling, inflammation, adaptive thermogenesis and lipolysis. Garcia-Alonso V., Titos E., Alcaraz-Quiles J., et al. PLoS One. 2016;11(4): e0153751. doi: 10.1371/journal.pone.0153751.
  59. Simpson, E.R. Minireview: aromatase and the regulation of estrogen biosynthesi-some new perspectives. Simpson E.R., Davis S.R. Endocrinology. 2001;142(11):4589-4594. doi: 10.1210/endo.142.11.8547.
  60. Mohamad N.V. The relationship between circulating testosterone and inflammatory cytokines in men. Mohamad N.V., Wong S.K., Wan Hasan W.N., et al. Aging Male. 2019;22(2):129-140. doi: 10.1080/13685538.2018.1482487.
  61. Corona G. Hypogonadism as a possible link between metabolic diseases and erectile dysfunction in aging men. Corona G., Bianchini S., Sforza A., et al. Hormones (Athens). 2015;14(4):569-578. doi: 10.14310/horm.2002.1635.
  62. Salonia A. SARS-CoV-2, testosterone and frailty in males (PROTEGGIMI): A multidimensional research project. Salonia A., Corona G., Giwercman A., et al. Andrology. 2020. doi: 10.1111/andr.12811.
  63. Yang M. Pathological Findings in the Testes of COVID-19 Patients: Clinical Implications. Yang M., Chen S., Huang B., et al. Eur Urol Focus. 2020;6(5):1124-1129. doi: 10.1016/j.euf.2020.05.009.
  64. Ma X. Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients. Ma X., Guan C., Chen R., et al. Cell Mol Immunol. 2020. doi: 10.1038/s41423-020-00604-5.
  65. La Marca A. Testicular pain as an unusual presentation of COVID-19: a brief review of SARS-CoV-2 and the testis. La Marca A., Busani S., Donno V., et al. Reprod Biomed Online. 2020;41(5):903-906. Doi: 10.1016/j. rbmo.2020.07.017.
  66. Pan F. No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Pan F., Xiao X., Guo J., et al. Fertil Steril. 2020;113:1135-1139. Doi: 10.1016/j. fertnstert.2020.04.024.
  67. Ma L. Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study. Ma L., Xie W., D. Li, et al. medRxiv 2020. doi: 10.1101/2020.03.21.20037267.
  68. Holtmann N. Assessment of SARS-CoV-2 in human semen - a cohort study. Holtmann N., Edimiris P., Andree M., et al. Fertil Steril. 2020;114:233- 238. doi: 10.1016/j.fertnstert.2020.05.028.
  69. Song C. Absence of 2019 novel coronavirus in semen and testes of COVID-19 patients. Song C. Wang Y., Li W., et al. Biol Reprod. 2020;103(1):4-6. doi: 10.1093/biolre/ioaa050.
  70. Li D. Clinical characteristics and results of semen tests among men with coronavirus disease 2019. D. Li, M. Jin, P. Bao, et al. JAMA Netw Open. 2020. Р. e208292. doi: 10.1001/jamanetworkopen.2020.8292.
  71. He W. Impact of SARS-CoV-2 on Male Reproductive Health: A Review of the Literature on Male Reproductive Involvement in COVID-19. W. He, X. Liu, L. Feng, et al. Front Med (Lausanne). 2020;7:594364. Doi: 10.3389/ fmed.2020.594364.
  72. Cardona Maya W.D. SARS-CoV-2 and the testis: similarity with other viruses and routes of infection / W. D. Cardona Maya, S. S. Du Plessis, P. A. Velilla. Reprod Biomed Online. 2020; 40:763-764. doi: 10.1016/j.rbmo.2020.04.009.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies