Figure 1. Cellular entry mechanism
The ACE2 receptors are widely expressed in various tissues including the lungs, cardiovascular system, gastrointestinal system, nervous system, and the testes. The identification of ACE2 receptors in human testes forms the basis of a potential impact for the virus on the male reproductive system. After all, a number of viruses including the Ebola, Zika, herpes simplex, Epstein-Barr, human papilloma, and Mumps have been known to illicit orchitis or to undergo shedding within the seminal fluid. Other CoV, such as the SARS-CoV-1 have been also associated with orchitis.6 While there is a significant increase in the number of publications on COVID-19 infection since the emergence of the disease, the impact of SARS-CoV-2 infection on the male reproductive system and conception has been generally under-investigated. This was the main reason for our systematic review of published literature to understand the potential impact of SARS-CoV-2 infection on male reproduction.
We conducted a literature search using PubMed and Google Scholar as search engines and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The keyword strings included (“severe acute respiratory syndrome–coronavirus 2” OR “severe acute respiratory syndrome coronavirus 2” OR “COVID-19” OR “SARS-CoV-2” OR “2019-nCoV” OR “SARS CoV2” OR “SARS CoV 2”) AND (“semen” OR “sperm*” OR “seminal” OR “testes” OR “testicular” OR “male fertil*” OR “male infertil*” OR “epididymis” OR “prostate” OR “testosterone” OR “LH” OR “FSH” OR “pregnancy” OR “ART” OR “assisted reproduc*” OR “IVF” OR “in vitro fertilization” OR “ICSI” OR “intracytoplasmic sperm injection” OR “cryopreservation”). A total number of 1,171 articles were retrieved and after screening the titles, abstracts, and full texts, 24 articles were considered eligible for inclusion in this study. Six articles investigated the impact of SARS-CoV-2 infections on semen parameters.7-12 while 3 articles addressed male reproductive hormones13-15 and the remaining 15 articles assessed pregnancy outcomes.16-31
Semen samples from 120 patients with active or resolving infections were tested for the presence of SARS-CoV-2 viral RNA. Positive results were identified from 6 patients representing 5% of the tested samples. A single small-sampled study investigated the impact of SARS-CoV-2 infection on semen parameters and reported a significant reduction in sperm concentration, total number of sperm per ejaculate, total number of motile sperm, and total number of progressively motile sperm in patients with moderate infection in comparison to those with mild infection or normal controls.9
With regards to reproductive hormones, there is evidence stating that the androgenic state could be inversely correlated with the severity of COVID-19 infection. Ma et al. observed significantly higher luteinizing hormone (LH) levels and significantly lower testosterone: LH and follicle-stimulating hormone: LH ratios in recovered patients in comparison to healthy counterparts.13 Rastrelli et al. reported a negative association between total testosterone and CRP levels in COVID-19 recovered patients.14 Schroeder et al. observed that the majority of men with active infection had low testosterone and dihydrotestosterone levels.15
As for the effect of COVID-19 infection on pregnancy outcomes, 15 studies including 598 confirmed cases of SARS-CoV-2 assessed the effect of infection on women during their third trimester. While the virus had a minimal influence on maternal mortality (0.8%), intensive care unit admission was observed in 8.5% of women, and preterm delivery was seen in 33.2% of them. 30% of neonates required neonatal intensive care unit (NICU) admission and perinatal mortality was 1.5%. Vertical transmission was reported in 2.3% of cases. Four case-control studies were analyzed. Only Li et al. observed a slightly higher rate of maternal complications and preterm delivery in COVID-19 confirmed cases compared with normal controls.31 The remaining three studies did not report any significant differences.23, 27, 28
We then applied a strengths-weaknesses-opportunities-threats (SWOT) analysis of the available evidence on the topic. While SARS-CoV-2 may be associated with alterations in male and female reproduction, low quality of evidence is noted. Reasons for this finding include a less diligent peer-review process that is practiced on COVID-19 related research, the under-sized and observational designs of the available studies, and the lack of information on the consequences of infection during earlier stages of pregnancy. Taking this into consideration together with the fact that this pandemic will most likely persist for several years, efforts made to propose new standards to reproductive practices may be threatened by the low quality of evidence available so far.
We further elaborated on the current recommendations with regards to the practice of assisted reproduction during the COVID-19 pandemic (AMERICAN SOCIETY FOR REPRODUCTIVE MEDICINE (ASRM) PATIENT MANAGEMENT AND CLINICAL RECOMMENDATIONS DURING THE CORONAVIRUS (COVID-19) PANDEMIC)
In conclusion, the evidence regarding a putative impact of SARS-CoV-2 infection on male reproduction, as well as the potential of SARS-CoV-2 viral transmission through seminal fluids, remains inconclusive. Currently, extra precautions are strongly recommended for natural or ART-related conception, as clear evidence regarding the impact of the SARS-CoV-2 and the possible complications of COVID-19 on reproductive outcomes require additional investigation.
Written by: Ahmad Majzoub, MD1, 2, 3 and Ashok Agarwal, PhD3
- Department of Urology, Hamad Medical Corporation
- Department of Urology, Weill Cornell Medicine - Qatar, Doha, Qatar
- American Center for Reproductive Medicine, Cleveland Clinic, USA
- Tyrrell, D.A. and M.L. Bynoe, CULTIVATION OF A NOVEL TYPE OF COMMON-COLD VIRUS IN ORGAN CULTURES. Br Med J, 1965. 1(5448): p. 1467-70.
- de Wit, E., et al., SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol, 2016. 14(8): p. 523-34.
- Guo, Y.R., et al., The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Mil Med Res, 2020. 7(1): p. 11.
- Lu, R., et al., Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet, 2020. 395(10224): p. 565-574.
- Hoffmann, M., et al., SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 2020. 181(2): p. 271-280.e8.
- Xu, J., et al., Orchitis: a complication of severe acute respiratory syndrome (SARS). Biol Reprod, 2006. 74(2): p. 410-6.
- Pan, F., et al., No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertil Steril, 2020. 113(6): p. 1135-1139.
- Song, C., et al., Absence of 2019 novel coronavirus in semen and testes of COVID-19 patients†. Biol Reprod, 2020. 103(1): p. 4-6.
- Holtmann, N., et al., Assessment of SARS-CoV-2 in human semen-a cohort study. Fertil Steril, 2020. 114(2): p. 233-238.
- Paoli, D., et al., Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab. J Endocrinol Invest, 2020: p. 1-4.
- Ning, J., et al., Effects of 2019 novel coronavirus on male reproductive system: a retrospective study. Preprints, 2020.
- Li, D., et al., Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease 2019. JAMA Netw Open, 2020. 3(5): p. e208292.
- Ma, L., et al., Effect of SARS-CoV-2 infection upon male gonadal function: a single center-based study. medRxiv, 2020.
- Rastrelli, G., et al., Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Andrology, 2020.
- Schroeder, M., 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.
- Sentilhes, L., et al., Coronavirus disease 2019 in pregnancy was associated with maternal morbidity and preterm birth. Am J Obstet Gynecol, 2020.
- Futterman, I., et al., COVID-19 and HELLP: Overlapping Clinical Pictures in Two Gravid Patients. AJP Rep, 2020. 10(2): p. e179-e182.
- Knight, M., et al., Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study. Bmj, 2020. 369: p. m2107.
- Cooke, W.R., et al., SARS-CoV-2 infection in very preterm pregnancy: Experiences from two cases. Eur J Obstet Gynecol Reprod Biol, 2020. 250: p. 259-260.
- Govind, A., et al., Re: Novel Coronavirus COVID-19 in late pregnancy: Outcomes of first nine cases in an inner city London hospital. Eur J Obstet Gynecol Reprod Biol, 2020. 251: p. 272-274.
- Liu, D., et al., Pregnancy and Perinatal Outcomes of Women With Coronavirus Disease (COVID-19) Pneumonia: A Preliminary Analysis. AJR Am J Roentgenol, 2020. 215(1): p. 127-132.
- Zheng, Z., et al., Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis. J Infect, 2020. 81(2): p. e16-e25.
- Yang, H., et al., Clinical features and outcomes of pregnant women suspected of coronavirus disease 2019. J Infect, 2020. 81(1): p. e40-e44.
- Khan, S., et al., Impact of COVID-19 infection on pregnancy outcomes and the risk of maternal-to-neonatal intrapartum transmission of COVID-19 during natural birth. Infect Control Hosp Epidemiol, 2020. 41(6):p. 748-750.
- Khan, S., et al., Association of COVID-19 with pregnancy outcomes in health-care workers and general women. Clin Microbiol Infect, 2020. 26(6): p. 788-790.
- Chen, S., et al., Clinical analysis of pregnant women with 2019 novel coronavirus pneumonia. J Med Virol, 2020.
- Zhang, L., et al., [Analysis of the pregnancy outcomes in pregnant women with COVID-19 in Hubei Province]. Zhonghua Fu Chan Ke Za Zhi, 2020. 55(3): p. 166-171.
- Liao, J., et al., Analysis of vaginal delivery outcomes among pregnant women in Wuhan, China during the COVID-19 pandemic. Int J Gynaecol Obstet, 2020. 150(1): p. 53-57.
- González Romero, D., et al., [Pregnancy and perinatal outcome of a woman with COVID-19 infection]. Rev Clin Esp, 2020.
- Hu, L., et al., Risk Factors Associated with Clinical Outcomes in 323 COVID-19 Hospitalized Patients in Wuhan, China. Clin Infect Dis, 2020.
- Li, N., et al., Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study. Clin Infect Dis, 2020.