Male Fertility and the COVID-19 Pandemic: Systematic Review of the Literature

다국어 초록 (Multilingual Abstract)

Purpose: Since its discovery in December 2019, the novel coronavirus SARS-CoV-2 has spread globally, causing the current COVID-19 (coronavirus disease-19) pandemic. As there is an increase of infections in the male population, concerns have emerged about the potential impact of COVID-19 on male reproductive organs and male fertility. Therefore, this study systematically investigates the current evidence of SARS-CoV-2 impact on male reproduction and pregnancy outcomes, discussing them in light of the evidence published on other coronaviruses.
Materials and Methods: Literature search was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 24 original articles were included for the analysis, investigating the effects of the infection on semen parameters, male reproductive hormones, and pregnancy outcomes. Further, a Strengths-Weaknesses- Opportunities-Threats (SWOT) analysis was conducted based on the available evidence linking the virus with male reproduction and conception.
Results: Although there is limited data, viral mRNA has been identified in semen of infected men, with some evidence of altered seminal parameters. Low testosterone and dihydrotestosterone with raised luteinizing hormone has been reported as well as preterm delivery in pregnant women; however, data regarding vertical transmission remains contradictory and inconclusive.
Conclusions: The recent literature provides evidence that male gonads may be potentially vulnerable to SARS-CoV-2 infection, recommending caution to pregnant women and couples planning natural pregnancy or assisted reproduction.

참고문헌 (Reference)

1 Wang Z, "scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2infection in spermatogonia, Leydig and Sertoli cells" 9 : 920-, 2020

2 Lipworth B, "Weathering the cytokine storm in susceptible patients with severe SARSCoV-2 infection" 8 : 1798-1801, 2020

3 Yangli Liu, "WITHDRAWN: Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy" Elsevier BV 2020

4 Guarner J, "Three emerging coronaviruses in two decades : the story of SARS, MERS, and now COVID-19" 153 : 420-421, 2020

5 Coronaviridae Study Group of the International Committee on Taxonomy of Viruses, "The species severe acute respiratory syndrome-related coronavirus : classifying 2019-nCoV and naming it SARS-CoV-2" 5 : 536-544, 2020

6 Bernstein KE, "The role of tissue angiotensin-converting enzyme(ACE) : studies of ACE mutant mice" 82 : 5S-7S, 1998

7 Verdecchia P, "The pivotal link between ACE2 deficiency and SARS-CoV-2 infection" 76 : 14-20, 2020

8 Guo YR, "The origin, transmission and clinical therapies on coronavirus disease 2019(COVID-19)outbreak-an update on the status" 7 : 11-, 2020

9 Contini C, "The novel zoonotic COVID-19 pandemic : an expected global health concern" 14 : 254-264, 2020

10 Lane TM, "The management of mumps orchitis" 97 : 1-2, 2006

11 Schroeder M, "The majority of male patients with COVID-19 present low testosterone levels on admission to intensive care in Hamburg, Germany: a retrospective cohort study"

12 Lucas JM, "The androgen-regulated protease TMPRSS2activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis" 4 : 1310-1325, 2014

13 Helmy YA, "The COVID-19 pandemic : a comprehensive review of taxonomy, genetics, epidemiology, diagnosis, treatment, and control" 9 : 1225-, 2020

14 Qiaoyan Shen, "The ACE2 expression in Sertoli cells and germ cells may cause male reproductive disorder after SARS‐CoV‐2 infection" Wiley 24 (24): 9472-9477, 2020

15 Stopsack KH, "TMPRSS2 and COVID-19 : serendipity or opportunity for intervention?" 10 : 779-782, 2020

16 Heurich A, "TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein" 88 : 1293-1307, 2014

17 D. Paoli, "Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab" Springer Science and Business Media LLC 43 (43): 1819-1822, 2020

18 Payne DC, "Stillbirth during infection with Middle East respiratory syndrome coronavirus" 209 : 1870-1872, 2014

19 Wei X, "Sex differences in severity and mortality among patients with COVID-19: evidence from pooled literature analysis and insights from integrated bioinformatic analysis"

20 Zamora MJ, "Semen residual viral load and reproductive outcomes in HIV-infected men undergoing ICSI after extended semen preparation" 32 : 584-590, 2016

21 Sandro C. Esteves, "SARS‐CoV‐2 pandemic and repercussions for male infertility patients: A proposal for the individualized provision of andrological services" Wiley 9 (9): 10-18, 2021

22 Lukassen S, "SARS-CoV-2 receptor ACE2 and TMPRSS2are primarily expressed in bronchial transient secretory cells" 39 : e105114-, 2020

23 Cooke WR, "SARS-CoV-2 infection in very preterm pregnancy : experiences from two cases" 250 : 259-260, 2020

24 Hoffmann M, "SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor" 181 : 271-280, 2020

25 Sulagna Dutta, "SARS-CoV-2 and Male Infertility: Possible Multifaceted Pathology" Springer Science and Business Media LLC 28 (28): 23-26, 2021

26 de Wit E, "SARS and MERS : recent insights into emerging coronaviruses" 14 : 523-534, 2016

27 Govind A, "Re : novel coronavirus COVID-19 in late pregnancy : outcomes of first nine cases in an inner city London hospital" 251 : 272-274, 2020

28 D. González Romero, "Pronóstico perinatal y de la paciente embarazada con infección por COVID-19" Elsevier BV 220 (220): 533-534, 2020

29 Wong SF, "Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome" 191 : 292-297, 2004

30 Liu D, "Pregnancy and perinatal outcomes of women with coronavirus disease(COVID-19)pneumonia : a preliminary analysis" 215 : 127-132, 2020

31 Trottein F, "Potential causes and consequences of gastrointestinal disorders during a SARS-CoV-2 infection" 32 : 107915-, 2020

32 Wang B, "Potential applications of cryogenic technologies to plant genetic improvement and pathogen eradication" 32 : 583-595, 2014

33 Sissoko D, "Persistence and clearance of Ebola virus RNA from seminal fluid of Ebola virus disease survivors : a longitudinal analysis and modelling study" 5 : e80-e88, 2017

34 American Society for Reproductive Medicine, "Patient management and clinical recommendations during the coronavirus (COVID-19) pandemic" American Society for Reproductive Medicine

35 American Society for Reproductive Medicine, "Patient management and clinical recommendations during the coronavirus (COVID-19) pandemic" American Society for Reproductive Medicine

36 American Society for Reproductive Medicine, "Patient management and clinical recommendations during the coronavirus (COVID-19) pandemic" American Society for Reproductive Medicine

37 Xu J, "Orchitis : a complication of severe acute respiratory syndrome(SARS)" 74 : 410-416, 2006

38 Meo SA, "Novel coronavirus 2019-nCoV : prevalence, biological and clinical characteristics comparison with SARS-CoV and MERS-CoV" 24 : 2012-2019, 2020

39 Pan F, "No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019" 113 : 1135-1139, 2020

40 Masarani M, "Mumps orchitis" 99 : 573-575, 2006

41 Assiri A, "Middle East respiratory syndrome coronavirus infection during pregnancy : a report of 5 cases from Saudi Arabia" 63 : 951-953, 2016

42 Malik A, "Middle East respiratory syndrome coronavirus during pregnancy, Abu Dhabi, United Arab Emirates, 2013" 22 : 515-517, 2016

43 Gould EA, "Methods for long-term virus preservation" 13 : 57-66, 1999

44 Li N, "Maternal and neonatal outcomes of pregnant women with COVID-19pneumonia : a case-control study" 2020

45 정수영, "MERS-CoV Infection in a Pregnant Woman in Korea" 대한의학회 32 (32): 1717-1729, 2017

46 Giulia Rastrelli, "Low testosterone levels predict clinical adverse outcomes in SARS‐CoV‐2 pneumonia patients" Wiley 9 (9): 88-98, 2021

47 Teelin KL, "Introduction to clinical infectious diseases" Springer 191-198, 2019

48 Ashour HM, "Insights into the recent 2019 novel coronavirus(SARS-CoV-2)in light of past human coronavirus outbreaks" 9 : 186-, 2020

49 Lin SY, "Infectious bronchitis virus variants : molecular analysis and pathogenicity investigation" 18 : 2030-, 2017

50 Alserehi H, "Impact of Middle East respiratory syndrome coronavirus(MERS-CoV)on pregnancy and perinatal outcome" 16 : 105-, 2016

51 Khan S, "Impact of COVID-19 infection on pregnancy outcomes and the risk of maternal-to-neonatal intrapartum transmission of COVID-19 during natural birth" 41 : 748-750, 2020

52 Carlsen E, "History of febrile illness and variation in semen quality" 18 : 2089-2092, 2003

53 Lu R, "Genomic characterisation and epidemiology of 2019 novel coronavirus : implications for virus origins and receptor binding" 395 : 565-574, 2020

54 Duggal NK, "Frequent Zika virus sexual transmission and prolonged viral RNA shedding in an immunodeficient mouse model" 18 : 1751-1760, 2017

55 Magrone T, "Focus on receptors for coronaviruses with special reference to angiotensin-converting enzyme 2 as a potential drug target-a perspective" 20 : 807-811, 2020

56 Vignozzi L, "Fat boosts, while androgen receptor activation counteracts, BPH-associated prostate inflammation" 73 : 789-800, 2013

57 Fu J, "Expressions and significances of the angiotensin-converting enzyme 2 gene, the receptor of SARS-CoV-2 for COVID-19" 47 : 4383-4392, 2020

58 Su-Eun Park, "Epidemiology, virology, and clinical features of severe acute respiratory syndrome -coronavirus-2 (SARS-CoV-2; Coronavirus Disease-19)" 대한소아청소년과학회 63 (63): 119-124, 2020

59 최덕환, "Emergency cesarean section in an epidemic of the middle east respiratory syndrome -a case report-" 대한마취통증의학회 69 (69): 287-291, 2016

60 Ning J, "Effects of 2019novel coronavirus on male reproductive system : a retrospective study"

61 Ma L, "Effect of SARS-CoV-2 infection upon male gonadal function: a single center-based study"

62 Karlberg J, "Do men have a higher case fatality rate of severe acute respiratory syndrome than women do?" 159 : 229-231, 2004

63 Tyrrell DA, "Cultivation of a novel type of common-cold virus in organ cultures" 1 : 1467-1470, 1965

64 Weiss SR, "Coronavirus pathogenesis" 81 : 85-164, 2011

65 Loïc Sentilhes, "Coronavirus disease 2019 in pregnancy was associated with maternal morbidity and preterm birth" Elsevier BV 223 (223): 914.e1-914.e15, 2020

66 European Society of Human Reproduction and Embryology, "Coronavirus covid-19: ESHRE statement on pregnancy and conception" European Society of Human Reproduction and Embryology

67 Esper F, "Coronavirus HKU1 infection in the United States" 12 : 775-779, 2006

68 Siddell SG, "Coronaviridae" 20 : 181-189, 1983

69 Pozzilli P, "Commentary : testosterone, a key hormone in the context of COVID-19 pandemic" 108 : 154252-, 2020

70 Araujo AB, "Clinical review : endogenous testosterone and mortality in men : a systematic review and meta-analysis" 96 : 3007-3019, 2011

71 Yang H, "Clinical features and outcomes of pregnant women suspected of coronavirus disease 2019" 81 : e40-e44, 2020

72 Li D, "Clinical characteristics and results of semen tests among men with coronavirus disease 2019" 3 : e208292-, 2020

73 Siyu Chen, "Clinical analysis of pregnant women with 2019 novel coronavirus pneumonia" Wiley 92 (92): 1556-1561, 2020

74 Zhang JP, "Clinical analysis of pregnancy in second and third trimesters complicated severe acute respiratory syndrome" 38 : 516-520, 2003

75 Guan WJ, "China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China" 382 : 1708-1720, 2020

76 Knight M, "Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK : national population based cohort study" 369 : m2107-, 2020

77 Szczepanski A, "Canine respiratory coronavirus, bovine coronavirus, and human coronavirus OC43 : receptors and attachment factors" 11 : 328-, 2019

78 Anifandis G, "COVID-19and fertility : a virtual reality" 41 : 157-159, 2020

79 Futterman I, "COVID-19 and HELLP : overlapping clinical pictures in two gravid patients" 10 : e179-e182, 2020

80 Zhang J, "Bioinformatic analysis reveals that the reproductive system is potentially at risk from SARS-CoV-2"

81 Khan S, "Association of COVID-19 with pregnancy outcomes in health-care workers and general women" 26 : 788-790, 2020

82 Veiga A, "Assisted reproduction and COVID-19: a joint statement of ASRM, ESHRE and IFFS" European Society of Human Reproduction and Embryology

83 Nora Holtmann, "Assessment of SARS-CoV-2 in human semen—a cohort study" Elsevier BV 114 (114): 233-238, 2020

84 Gheblawi M, "Angiotensin-converting enzyme 2 : SARSCoV-2 receptor and regulator of the renin-angiotensin system : celebrating the 20th anniversary of the discovery of ACE2" 126 : 1456-1474, 2020

85 Liao J, "Analysis of vaginal delivery outcomes among pregnant women in Wuhan, China during the COVID-19 pandemic" 150 : 53-57, 2020

86 Zhang L, "Analysis of the pregnancy outcomes in pregnant women with COVID-19 in Hubei province" 55 : 166-171, 2020

87 Segars J, "American Society for Reproductive Medicine Coronavirus/COVID-19 Task Force. Prior and novel coronaviruses, coronavirus disease 2019(COVID-19), and human reproduction : What is known?" 113 : 1140-1149, 2020

88 Okada H, "Age as a limiting factor for successful sperm retrieval in patients with nonmosaic Klinefelter’s syndrome" 84 : 1662-1664, 2005

89 Song C, "Absence of 2019 novel coronavirus in semen and testes of COVID-19patients" 103 : 4-6, 2020

90 Fan C, "ACE2 expression in kidney and testis may cause kidney and testis damage after 2019-nCoV infection"

91 Corvol P, "ACE sets up fertilization" 11 : 118-119, 2005

92 Arav A, "A recommendation for IVF lab practice in light of the current COVID-19 pandemic" 37 : 1543-, 2020

93 Zhou P, "A pneumonia outbreak associated with a new coronavirus of probable bat origin" 579 : 270-273, 2020

94 Lam CM, "A case-controlled study comparing clinical course and outcomes of pregnant and non-pregnant women with severe acute respiratory syndrome" 111 : 771-774, 2004