Review Article: Can coronavirus disease 2019 effect on human reproduction?


1 Department of Emergency Medicine, Khatam‑Al‑Anbia Hospital, Clinical Immunology Research Center at Zahedan University of Medical Sciences, Zahedan University of Medical Sciences, Zahedan

2 Department of Obstetrics and Gynecology, Nekouei‑Hedayati‑Forghani Hospital, Qom University of Medical Sciences, Qom, Iran


Background: Since the main role in the pathogenesis of the coronavirus is attributed to the angiotensin-converting enzyme (ACE) receptor, it could possibly be a hypothesis in the differential sex-based pathogenesis of the coronavirus. The virus inserts its genetic material into the cell through its ACE2 receptors and replicates it by intracellular proteins. ACE2 receptors are highly expressed in cell membranes of various tissues in the body, including cardiovascular, gastrointestinal, renal, macrophage cells, and especially on the surface of type 2 pneumocytes in the lungs, ovaries, uterus, vagina, placenta, and testes. Therefore, cells having a higher expression of the ACE2 may be a specific target for coronavirus binding and infectivity. Due to the increase of infections in males, concerns have been appeared about the potential impact of coronavirus disease 2019 (COVID-19) on their fertility and reproductive organs. Thus, it is necessary to investigate if COVID-19 disturbs female and male fertility, so this review aimed to study the comprehensive evidences on the association of COVID-19 with human reproduction.


Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020;395:565-74.  Back to cited text no. 1
Yang Z, Wang M, Zhu Z, Liu Y. Coronavirus disease 2019 (COVID-19) and pregnancy: A systematic review. J Matern Fetal Neonatal Med 2020;33:1-4.  Back to cited text no. 2
Di Mascio D, Khalil A, Saccone G, Rizzo G, Buca D, Liberati M, et al. Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: A systematic review and meta-analysis. Am J Obstet Gynecol MFM 2020;2:100107.  Back to cited text no. 3
Petersen E, Koopmans M, Go U, Hamer DH, Petrosillo N, Castelli F, et al. Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. Lancet Infect Dis 2020;20:e238-44.  Back to cited text no. 4
Ding Y, He L, Zhang Q, Huang Z, Che X, Hou J, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: Implications for pathogenesis and virus transmission pathways. J Pathol 2004;203:622-30.  Back to cited text no. 5
Wang Y, Wang Y, Chen Y, Qin Q. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med Virol 2020;92:568-76.  Back to cited text no. 6
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.  Back to cited text no. 7
Zhang H, Li HB, Lyu JR, Lei XM, Li W, Wu G, et al. Specific ACE2 expression in small intestinal enterocytes may cause gastrointestinal symptoms and injury after 2019-nCoV infection. Int J Infect Dis 2020;96:19-24.  Back to cited text no. 8
Sriram K, Insel PA. A hypothesis for pathobiology and treatment of COVID-19: The centrality of ACE1/ACE2 imbalance. Br J Pharmacol 2020;177:4825-44.  Back to cited text no. 9
Li Y, Zhou W, Yang L, You R. Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor. Pharmacol Res 2020;157:104833.  Back to cited text no. 10
Bourgonje AR, Abdulle AE, Timens W, Hillebrands JL, Navis GJ, Gordijn SJ, et al. Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol 2020;251:228-48.  Back to cited text no. 11
Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med 2020;76:14-20.  Back to cited text no. 12
Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005;11:875-9.  Back to cited text no. 13
Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 2020;323:1843-4.  Back to cited text no. 14
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;47:4383-92.  Back to cited text no. 15
Domińska K. Involvement of ACE2/Ang-(1-7)/MAS1 axis in the regulation of ovarian function in mammals. Int J Mol Sci 2020;21:4572.  Back to cited text no. 16
Palumbo A, Ávila J, Naftolin F. The Ovarian Renin-Angiotensin system (OVRAS): A major factor in ovarian function and disease. Reprod Sci 2016;23:1644-55.  Back to cited text no. 17
Vinson GP, Saridogan E, Puddefoot JR, Djahanbakhch O. Tissue renin-angiotensin systems and reproduction. Hum Reprod 1997;12:651-62.  Back to cited text no. 18
Jing Y, Run-Qian L, Hao-Ran W, Hao-Ran C, Ya-Bin L, Yang G, et al. Potential influence of COVID-19/ACE2 on the female reproductive system. Mol Hum Reprod 2020;26:367-73.  Back to cited text no. 19
Li R, Yin T, Fang F, Li Q, Chen J, Wang Y, et al. Potential risks of SARS-CoV-2 infection on reproductive health. Reprod Biomed Online 2020;41:89-95.  Back to cited text no. 20
Mahdian S, Shahhoseini M, Moini A. COVID-19 mediated by Basigin can affect male and female fertility. Int J Fertil Steril 2020;14:262-3.  Back to cited text no. 21
Henarejos-Castillo I, Sebastian-Leon P, Devesa-Peiro A, Pellicer A, Diaz-Gimeno P. SARS-CoV-2 infection risk assessment in the endometrium: Viral infection-related gene expression across the menstrual cycle. Fertil Steril 2020;114:223-32.  Back to cited text no. 22
Abhari S, Kawwass JF. Endometrial susceptibility to SARS CoV-2: Explained by gene expression across the menstrual cycle? Fertil Steril 2020;114:255-6.  Back to cited text no. 23
Segars J, Katler Q, McQueen DB, Kotlyar A, Glenn T, Knight Z, et al. Prior and novel coronaviruses, Coronavirus Disease 2019 (COVID-19), and human reproduction: What is known? Fertil Steril 2020;113:1140-9.  Back to cited text no. 24
Pozzilli P, Lenzi A. Commentary: Testosterone, a key hormone in the context of COVID-19 pandemic. Metabolism 2020;108:154252.  Back to cited text no. 25
Dutta S, Sengupta P. SARS-CoV-2 and male infertility: possible multifaceted pathology. Reprod Sci 2021;28:23-6.  Back to cited text no. 26
Huang C, Ji X, Zhou W, Huang Z, Peng X, Fan L, et al. Coronavirus: A possible cause of reduced male fertility. Andrology 2021;9:80-7.  Back to cited text no. 27
Bridwell RE, Merrill DR, Griffith SA, Wray J, Oliver JJ. A coronavirus disease 2019 (COVID-19) patient with bilateral orchitis. Am J Emerg Med 2021;42:260.e3-5.  Back to cited text no. 28
Delle Fave RF, Polisini G, Giglioni G, Parlavecchio A, Dell'Atti L, Galosi AB. COVID-19 and male fertility: Taking stock of one year after the outbreak began. Arch Ital Urol Androl 2021;93:115-9.  Back to cited text no. 29
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.  Back to cited text no. 30
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.  Back to cited text no. 31
Schroeder M, Tuku B, Jarczak D, Nierhaus A, Bai T, Jacobsen H, et al. The majority of male patients with COVID-19 present low testosterone levels on admission to Intensive Care in Hamburg, Germany: A retrospective cohort study. medRxiv 2020;2020:1-23.  Back to cited text no. 32
Illiano E, Trama F, Costantini E. Could COVID-19 have an impact on male fertility? Andrologia 2020;52:e13654.  Back to cited text no. 33
Mills IG. Maintaining and reprogramming genomic androgen receptor activity in prostate cancer. Nat Rev Cancer 2014;14:187-98.  Back to cited text no. 34
Li K, Chen G, Hou H, Liao Q, Chen J, Bai H, et al. Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age. Reprod Biomed Online 2021;42:260-7.  Back to cited text no. 35
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.  Back to cited text no. 36
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.  Back to cited text no. 37
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.  Back to cited text no. 38
Oncel MY, Akın IM, Kanburoglu MK, Tayman C, Coskun S, Narter F, et al. A multicenter study on epidemiological and clinical characteristics of 125 newborns born to women infected with COVID-19 by Turkish Neonatal Society. Eur J Pediatr 2021;180:733-42.  Back to cited text no. 39
Elshafeey F, Magdi R, Hindi N, Elshebiny M, Farrag N, Mahdy S, et al. A systematic scoping review of COVID-19 during pregnancy and childbirth. Int J Gynaecol Obstet 2020;150:47-52.  Back to cited text no. 40
Danza Á, Ruiz-Irastorza G, Khamashta M. Pregnancy in systemic autoimmune diseases: Myths, certainties and doubts. Med Clin (Barc) 2016;147:306-12.  Back to cited text no. 41
Zoller AL, Schnell FJ, Kersh GJ. Murine pregnancy leads to reduced proliferation of maternal thymocytes and decreased thymic emigration. Immunology 2007;121:207-15.  Back to cited text no. 42
Kraus TA, Engel SM, Sperling RS, Kellerman L, Lo Y, Wallenstein S, et al. Characterizing the pregnancy immune phenotype: Results of the viral immunity and pregnancy (VIP) study. J Clin Immunol 2012;32:300-11.  Back to cited text no. 43
Dashraath P, Wong JL, Lim MX, Lim LM, Li S, Biswas A, et al. Coronavirus disease 2019 (COVID-19) pandemic and pregnancy. Am J Obstet Gynecol 2020;222:521-31.  Back to cited text no. 44
Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 2004;136:95-103.  Back to cited text no. 45
Thevarajan I, Nguyen TH, Koutsakos M, Druce J, Caly L, van de Sandt CE, et al. Breadth of concomitant immune responses prior to patient recovery: A case report of non-severe COVID-19. Nat Med 2020;26:453-5.  Back to cited text no. 46
Littauer EQ, Esser ES, Antao OQ, Vassilieva EV, Compans RW, Skountzou I. H1N1 influenza virus infection results in adverse pregnancy outcomes by disrupting tissue-specific hormonal regulation. PLoS Pathog 2017;13:e1006757.  Back to cited text no. 47
Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records. Lancet 2020;395:809-15.  Back to cited text no. 48
Hsu AL, Guan M, Johannesen E, Stephens AJ, Khaleel N, Kagan N, et al. Placental SARS-CoV-2 in a pregnant woman with mild COVID-19 disease. J Med Virol 2021;93:1038-44.  Back to cited text no. 49
Fenizia C, Biasin M, Cetin I, Vergani P, Mileto D, Spinillo A, et al. Analysis of SARS-CoV-2 vertical transmission during pregnancy. Nat Commun 2020;11:5128.  Back to cited text no. 50
Lee WY, Mok A, Chung JPW. Potential effects of COVID-19 on reproductive systems and fertility; assisted reproductive technology guidelines and considerations: A review. Hong Kong Med J 2021;27:118-26.  Back to cited text no. 51
Yart L, Roset Bahmanyar E, Cohen M, Martinez de Tejada B. Role of the uteroplacental renin-angiotensin system in placental development and function, and its implication in the preeclampsia pathogenesis. Biomedicines 2021;9:1332.  Back to cited text no. 52
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;23:479-83.  Back to cited text no. 53
[PUBMED]  [Full text]   54.
He M, Skaria P, Kreutz K, Chen L, Hagemann IS, Carter EB, et al. Histopathology of third trimester placenta from SARS-CoV-2-positive women. Fetal Pediatr Pathol 2020;1:1-10.  Back to cited text no. 54
Penfield CA, Brubaker SG, Limaye MA, Lighter J, Ratner AJ, Thomas KM, et al. Detection of severe acute respiratory syndrome coronavirus 2 in placental and fetal membrane samples. Am J Obstet Gynecol MFM 2020;2:100133.  Back to cited text no. 55
Lumbers ER. The physiological roles of the renin-angiotensin aldosterone system and vasopressin in human pregnancy. In: Maternal-Fetal and Neonatal Endocrinology. Canada: Academic Press; 2020. p. 129-45.  Back to cited text no. 56
Blumenfeld Z. Possible impact of COVID-19 on fertility and assisted reproductive technologies. Fertil Steril 2020;114:56-7.  Back to cited text no. 57
Pinto D, Park Y, Beltramello M, Walls AC, Tortorici MA, Bianchi S, et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature 2020;583:290-295.  Back to cited text no. 58
Blasco Santana L, Miraval Wong E, Álvarez-Troncoso J, Sánchez García L, Bartha JL, Regojo-Zapata RM. Maternal and perinatal outcomes and placental pathologic examination of 29 SARS-CoV-2 infected patients in the third trimester of gestation. J Obstet Gynaecol Res 2021;47:2131-9.  Back to cited text no. 59
Prochaska E, Jang M, Burd I. COVID-19 in pregnancy: Placental and neonatal involvement. Am J Reprod Immunol 2020;84:e13306.  Back to cited text no. 60
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.  Back to cited text no. 61
Vahed SZ, Ghiyasvand S, Tolouian R, Noshad H, Tolouian AC, Shoja MM, et al. The footprint of androgen sensitive serine protease (TMPRSS2) in gender mortality with COVID-19. Immunopathologia Persa 2020;6:3-4.  Back to cited text no. 62
Bhattacharya K, Mukhopadhyay LD, Goswami R, Dutta S, Sengupta P, Irez T, et al. SARS-CoV-2 infection and human semen: Possible modes of contamination and transmission. Middle East Fertil Soc J 2021;26:18.  Back to cited text no. 63
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.  Back to cited text no. 64
Erbay G, Sanli A, Turel H, Yavuz U, Erdogan A, Karabakan M, et al. Short-term effects of COVID-19 on semen parameters: A multicenter study of 69 cases. Andrology 2021;9:1060-5.  Back to cited text no. 65