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Table of Contents
Year : 2020  |  Volume : 9  |  Issue : 5  |  Page : 211-214

Possible links between COVID-19 and male fertility

1 Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State; Reproductive Biology and Toxicology Research Laboratories, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
2 Reproductive Biology and Toxicology Research Laboratories, Oasis of Grace Hospital, Osogbo, Osun State; Buntai Medical and Diagnostic Laboratories, Osogbo, Nigeria

Date of Submission16-Jul-2020
Date of Decision02-Sep-2020
Date of Acceptance06-Sep-2020
Date of Web Publication12-Sep-2020

Correspondence Address:
Roland Eghoghosoa Akhigbe
Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State; Reproductive Biology and Toxicology Research Laboratories, Oasis of Grace Hospital, Osogbo, Osun State
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2305-0500.294662

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The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have a ripple effect that puts men at a risk of infertility. This article reviews the possible link between SARS-CoV-2 infection and male reproduction following speculations that the single- stranded RNA viruses could directly invade the testes. SARS-CoV-2 enters the human lung cells via angiotensin converting enzyme 2 (ACE2). ACEs, its products, angiotensin-(1-7), and its receptor, MAS receptor, are expressed in the testes. Although the binding of SAR-CoV-2 to ACE2 could lead to excess angiotensin II with possible enhanced inflammation, angiotensin II could also promote sperm motility. In addition, the pathophysiology of SAR-CoV-2, especially in relation to male fertility, is yet to be fully understood; the suppression of androgen observed in COVID-19 infected men calls for the need for andrological assessment in infected male.

Keywords: SARS-CoV-2; COVID-19; Angiotensin converting enzyme; Steroidogenesis; Spermatogenesis

How to cite this article:
Akhigbe RE, Hamed MA. Possible links between COVID-19 and male fertility. Asian Pac J Reprod 2020;9:211-4

How to cite this URL:
Akhigbe RE, Hamed MA. Possible links between COVID-19 and male fertility. Asian Pac J Reprod [serial online] 2020 [cited 2022 Nov 28];9:211-4. Available from: https://www.apjr.net/text.asp?2020/9/5/211/294662

  1. Introduction Top

Coronaviruses (CoV) are single-stranded RNA viruses that primarily target the human respiratory system. Microscopically, CoV has glycoprotein spikes on its envelope which gives it a crownlike appearance. The betacoronaviruses (coronaviridae family) have several genera that affect humans and other vertebrates like mice, bats, cats, dogs, and bats[1]. The α-CoV and β-CoV cause infection of the respiratory, gastrointestinal, and central nervous systems in human and several mammals, while the σ-CoV and γ-CoV primarily affect birds[2],[3].

At the tail of December 2019, there was an outbreak of a pneumonia-like infection, now called coronavirus disease 2019 (COVID-19) caused by a novel coronavirus (2019-nVoV) that was subsequently named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to its similarity to SARS-CoV[4]. This infectious illness was declared a global pandemic by the World Health Organization on the 11th March 2020[5]. Although there are claims that the first case was transmitted from animal to human[6], human- to-human transmission is fast spreading with a high mortality rate. Established mode of transmission is through respiratory droplets from sneezing and coughing with symptomatic and possibly asymptomatic infected persons being the primary source of spread. As on the 2nd September, 2020, 11:35 GMT, (about eight months from the outbreak), 26 149 876 cases of COVID-19 and 866 015 of mortalities from COVID-19 has been reported[7].

  2. Pathogenesis of COVID-19 Top

Studies have shown that similar to SARS-CoV, SARS-CoV-2 enters the human cells by binding to angiotensin-converting enzyme 2 (ACE2)[8],[9]. ACE2 is a zinc-containing transmembrane aminopeptidase that was initially identified as a variant of ACE. It is widely expressed, especially in the lung type II alveolar cells, endothelial cells of the arteries and veins, arterial smooth muscle cells, enterocytes of the small intestine, cortical neurons and glia[10]. Primarily, ACE2 acts as a counterbalance to ACE.

Renin activates angiotensinogen to angiotensin I. This is cleaved by ACE into angiotensin II, which exerts its effect through angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R). In addition, ACE also cleaves the C-terminal dipeptidyl residue to inactivate bradykinin and enkephalins. ACE2 cleaves phenylalanine from angiotensin II and hydrolyzes it into angiotensin-(1-7) which exert their activities through AT2R and MAS receptors[11]. The spike S1 protein of SARS-CoV-2 binds to the enzymatic domain of ACE2, peptidase domain, on the cell surface and results in endocytosis and translocation of both the virus and enzyme into the cells[11]. The viral entry is facilitated by priming of the S protein by the host serine protease, transmembrane protease serine 2[11]. Following viral entry, it replicates, increases the pH of endosomes and lysosome and activates p38 mitogen activated protein kinases and extracellular regulated protein kinases, which causes hyper-inflammatory response. In the incident of COVID-19, ACE2 becomes overwhelmed, causing a rise in the level of angiotensin II that cannot be hydrolyzed to angiotensin-(1-7) due to unavailability of ACE2. This explains the pulmonary manifestations of the viral infection.

  3. Possible links between COVID-19 and male fertility Top

Studies have revealed the presence of SARS-CoV-2 RNA in stool, urine, and blood samples. Although urine and blood reportedly have a low SARS-CoV-2 RNA detection frequency, the detection rate in the stool is relatively high with longer clearance time than in the nasopharyngeal swabs from respiratory secretions[12],[13],[14]. This infers that the virus could be contracted and spread through other means besides respiratory droplets.

Studies have elucidated the roles of ACE, ACE2 and AT2R in male reproduction [Figure 1]. ACE has been reported to be well distributed in human prostate, testis, epididymis, and semen[15]. It has been linked to testicular development in puberty[16], germ cell maturation[17], regulation of epididymal fluid and electrolyte balance[18], and sperm capacitation[19]. On the other hand, ACE2 has been reported to be expressed in adult testicular Leydig cells, and speculated to play a key role in steroidogenesis[20]. A study by Reis et al confirmed the expression of ACE2, angiotensin-(1-7) and MAS receptors in the Leydig and  Sertoli cells More Details, as well as their possible roles in steroidogenesis and spermatogenesis[21]. AT1R, which has been reported to be expressed in developing human spermatids and mature sperm cell[22], has been linked to sperm capacitation and acrosome reaction[23]. AT2R has been documented to be expressed in human testis, epididymis, prostrate and sperm cells[24]. Studies have shown that exposure of human sperm cells to angiotensin I and angiotensin K enhances sperm motility[23].
Figure 1: Possible link between SARS-CoV-2 and male reproduction. ACE: Angiotensin converting enzyme; S: Spike glycoprotein; M: Membrane protein; N: RNA and nucleocapsid protein; E: Envelope.

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There are lots of speculations about the male gender preponderance to COVID-19 infection, and COVID-19-induced male infertility. Although studies of Xu et al[25] reported infiltration of inflammatory cells into the testes of SARS-CoV-infected patients, no similar reports have been documented on SARS-CoV-2 infection. Semen samples from patients who recovered from COVID-19 and testicular biopsies from a dead COVID-19 patient did not detect SARS- CoV-2 RNA[26]. This finding was corroborated by other studies that reported absence of SARS-CoV-2 viral RNA in the semen of male patients with active or resolving infection[27],[28],[29]. On the contrary, COVID-19 confirmed patients had significantly higher serum luteinizing hormone (LH) and prolactin, but normal levels of circulatory testosterone when compared to their healthy counterparts, indicating a likely initial suppression of testosterone biosynthesis which resulted in a negative feedback thus stimulating increased LH release[30]. These findings suggest that the testis is possibly not directly infected and male are not more predisposed to the virus, but the viral infection could impair androgen production. Interestingly, a cohort study revealed that 6 out of 38 (15.8%) COVID-19 confirmed patients expressed SARS-CoV-2 in their semen; 4 out of the 6 COVID-19 confirmed patients (66.7%) were in the acute stage of infection while 2 out of the 6 COVID-19 confirmed patients (33.3%) were recovering[31]. Although it is unclear whether or not the expressed virus was viable, this calls for caution especially in patients who require assisted reproductive technology/in vitro fertilization interventions. A repeat SARS-CoV-2 RNA testing might be necessary in semen donors to reduce the chance of possible spread and increase the success rate of the artificial reproductive technology.

Since ACE2, angiotensin-(1-7), and MAS receptors are expressed in the testis, SARS-CoV-2 could invade the testes and alter testicular functions. Also, the binding of the virus to ACE2 could lead to an excess of angiotensin II which would give rise to a robust inflammatory response with subsequent impairment of the Leydig and Sertoli cell functions. Although there are limited studies with a small sample size that evaluated the presence of the virus in the testes or semen, it is important to note that no study has reported the presence of the virus in the testes or semen. Since angiotensin K is known to promote sperm motility, excess angiotensin K following overwhelmed ACE2 could precipitate inflammation, and may not override its positive effect on sperm motility, especially if the inflammation is not localized in the testes.

Furthermore, some studies have reported no gender bias in SAR-CoV-2 infection[32], while others observed a slightly higher prevalence in men[33],[34]. In addition, studies have reported that men are at more risk for worse outcomes and mortalities independent on age[32]. The observed higher prevalence, poorer outcome and increased mortality in male are likely not SARS-CoV-2-specific. It has been established that men are more susceptible to infection than women. Estrogen exerts more vigorous immune system response when compared to testosterone, thus suppressing inflammatory cytokine release with resultant increased poor outcome and death in male from viral respiratory infections[35]. In addition, it is not unlikely that the X chromosome which carries the highest number of immune-related genes accounts for the robust immunologic response seen in females[36]. Health-related risky behaviour which impairs immune system response such as smoking and poor utilization of medicare may also explain the higher morbidity and mortality seen in men. When compared with the female counterpart, a higher percentage of men smoke[37] and lower percentage of them utilizes medicare[38].

  4. Conclusion Top

SAR-CoV-2 remains novel and much is yet to be unraveled about this highly contagious virus. The higher prevalence and mortality from COVID-19 observed in men are likely secondary to hormonal factor, genetic makeup, and health-related risky behaviour. Although just a study has demonstrated direct testicular invasion of the virus, the suppression of androgen observed in COVID-19 infected men suggests the need for andrological assessment in infected men. Studies evaluating the direct testicular invasion of SARS-CoV-2 via ACE2 or other mechanisms, and the likely effect of the viral infection on male fertility are necessary to better understand the possible pathophysiology of SARS-CoV-2 on male reproduction and also unravel new preventive strategies and therapeutic opportunities.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Authors’ contributions

Roland Eghoghosoa Akhigbe and Moses Agbomhere Hamed contributed equally to the study.

  References Top

Su S, Wong G, Shi W, Liu J, Lai ACK, Zhou J, et al. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 2016; 24: 490-502.  Back to cited text no. 1
Ashour HM, Elkhatib WF, Rahman MM, Elshabrawy HA. Insights into the recent 2019 novel coronavirus (SARS-CoV-2) in light of past human coronavirus outbreaks. Pathogens (Basel, Switzerland) 2020; 9(3): 186.  Back to cited text no. 2
Peng X, Xu X, Li Y, Cheng L, Zhou X, Ren B. Transmission routes of 2019-nCoV and controls in dental practice. Int J Oral Sci 2020; 12: 9.  Back to cited text no. 3
Guo Y, Cao Q, Hong Z, Tan Y, Chen S, Jin H, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID- 19) outbreak - An update on the Status. Military Med Res 2020; 7: 11.  Back to cited text no. 4
Puliatti S, Eissa A, Eissa R, Amato M, Mazzone E, Dell’Oglio P, et al. COVID-19 and urology: A comprehensive review of the literature. BJU Int 2020; doi: 10.1111/bju.15071.  Back to cited text no. 5
Illiano E, Trama F, Costantini E. Could COVID-19 have an impact on male fertility? Andrologia 2020; 52(6): e13654.  Back to cited text no. 6
Worldometer. COVID-19 coronavirus pandemic. [Online] Available from: https://www.worldometers.info/coronavirus/. [Accessed on 2nd September 2020].  Back to cited text no. 7
Zhou D, Dai S, Tong Q. COVID-19: A recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother 2020; doi:10.1093/jac/dkaa114.  Back to cited text no. 8
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270-273.  Back to cited text no. 9
Kabbani N, James L. “Does COVID19 infect the brain? If so, smokers might be at a higher risk”. Molecul Pharmacol 2020; 97(5): 351-353.  Back to cited text no. 10
Aitken RJ. COVID-19 and human spermatozoa—Potential risks for infertility and sexual transmission? Andrology 2020; doi: 10.1111/ andr.12859.  Back to cited text no. 11
Ling Y, Xu SB, Lin YX. Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients. Chin Med J (Engl) 2020; doi: 10.1097/cm9.0000000000000774.  Back to cited text no. 12
Zheng S, Fan J, Yu F. Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang Province, China, January-March 2020: Retrospective cohort study. BMJ 2020; 369: m1443.  Back to cited text no. 13
Xie C, Jiang L, Huang G. Comparison of different samples for 2019 novel coronavirus detection by nucleic acid amplification tests. Int J Infect Dis 2020; 93: 264-267.  Back to cited text no. 14
Foresta C, Indino M, Manoni F, Scandellari C. Angiotensin converting enzyme content of human spermatozoa and its release during capacitation. Fertil Steril 1987; 47: 1000-1003.  Back to cited text no. 15
Holbrugger G, Schweisfurth H, Dahlheim H. Angiotensin I converting enzyme in rat testis, epididymis and vas deferens under different conditions. JReprod Fertil 1982; 65: 97-103.  Back to cited text no. 16
Velletri PA. Testicular angiotensin-converting enzyme. Life Sci 1985; 36: 1597-1608.  Back to cited text no. 17
Wong PYD, Fu WO, Huang SJ, Law WK. Effect of angiotensins on electrogenic anion transport in monolayer cultures of rat epididymis. J Endocrinol 1990; 125: 449-456.  Back to cited text no. 18
Foresta C, Mioni R, Rossato M, Varotto A, Zorzi M. Evidence for the involvement of sperm angiotensin converting enzyme in fertilization. Int J Androl 1991; 14: 333-339.  Back to cited text no. 19
Douglas GC, O’Bryan MK, Hedger MP, Lee DKL, 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; 145: 4703-4711.  Back to cited text no. 20
Reis AB, Araujo FC, Pereira VM, Dos Reis AM, Santos RA, Reis FM. Angiotensin (1-7) and its receptor Mas are expressed in the human testis: Implications for male infertility. J Molecul Histol 2010; 41: 75-80.  Back to cited text no. 21
Sabeur K, Vo AT, Ball BA. Effects of angiotensin K on the acrosome reaction in equine spermatozoa. J Reprod Fertil 2000; 120: 135-142.  Back to cited text no. 22
Leung PS, Sernia C. The renin-angiotensin system and male reproduction: New functions for old hormones. J Mol Endocrinol 2003; 30: 263-270.  Back to cited text no. 23
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 2020; doi: 10.1101/2020.03.31.20042333.  Back to cited text no. 24
Pan F, Xiao X, Guo J, Song Y, Li H, Patel DP. No evi dence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertil Steril 2020; 113: 1135-1139.  Back to cited text no. 25
Holtmann N, Edimiris P, Andree M, Doehmen C, Baston-Buest D, Adams O. Assessment of SARS-CoV-2 in hu man semen-a cohort study. Fertil Steril 2020; doi: 10.1016/ j.fertnstert.2020.05.028.  Back to cited text no. 26
Paoli D, Pallotti F, Colangelo S, Basilico F, Mazzuti L, Turriziani O. Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab. J Endocrinol Invest 2020; doi: 10.1007/ s40618-020-01261-1.  Back to cited text no. 27
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 2020; doi: 10.1101/2020.03.21.20037267.  Back to cited text no. 28
Li D, Jin M, Bao P, Zhao W, Zhang S. Clinical characteristics and results of semen tests among men with coronavirus dis ease 2019. JAMA Netw Open 2020; 3: e208292.  Back to cited text no. 29
Jin J, Bai P, He W, Wu F, Liu X, Han D, et al. Gender differences in patients with COVID-19: Focus on severity and mortality. Front Public Health 2020; 8: 152.  Back to cited text no. 30
Liu N, Zhang F, Wei C, Jia Y, Shang Z, Sun L, et al. Prevalence and predictors of PTSS during COVID-19 outbreak in China hardest-hit areas: Gender differences matter. Psychiat Res 2020; 287: 112921.  Back to cited text no. 31
Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ. Clinical characteristics of 140 patients infected by SARS-CoV-2 in Wuhan, China. Allergy 2020; doi: 10.1111/all.14238.  Back to cited text no. 32
Gausman J, Langer A. Sex and gender disparities in the COVID-19 pandemic. J Women’s Health 2020; 29: 465-466.  Back to cited text no. 33
Walter LA, McGregor AJ. Sex and gender-specific observations and implications for COVID-19. West J Emerg Med 2020; 21: 507-509.  Back to cited text no. 34
Sue K. The science behind “man flu.” BMJ 2017; 359: j5560.  Back to cited text no. 35
Schurz H, Salie M, Tromp G. The X chromosome and sex-specific effects in infectious disease susceptibility. Hum Genom 2019; 13(1): 2.  Back to cited text no. 36
Cai H. Sex difference and smoking predisposition in patients with COVID-19. Lancet Respir Med 2020; 8(4): e20.  Back to cited text no. 37
Akhigbe RE, Bamidele JO. Prevalence and pattern of utilization of voluntary counseling and testing services and HIV infection in Ogbomoso, southwestern Nigeria. J Nat Sc Biol Med 2013; 4: 163-166.  Back to cited text no. 38


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