Male Fertility and the COVID-19 Pandemic: Systematic Review of the Literature – Beyond the Abstract – UroToday

Coronaviruses (CoV) are a group of viruses whose antigens are expressed on their membranes in a characteristic crown like appearance, hence giving them their name (from Latin corona [crown]). Since their initial discovery in 1965,1 about 46 species have been identified in animals and humans with 2 species, namely, severe acute respiratory syndrome (SARS)-CoV-1 and Middle Eastern Respiratory Syndrome (MERS)-CoV receiving a great deal of attention due to their high rate of transmission and mortality.2 In December 2019, a novel strain of CoV emerged in the city of Wuhan, China and was termed SARS-CoV-2 as it had an 80% genetic similarity with the SARS-CoV-1 virus.3 This new infection which was also named COVID-19, based on the year of its appearance, rapidly spread throughout the world and was announced as a global pandemic on 11 March 2020. The SARS-CoV-2 virus is an RNS virus that belongs to the -CoV subgroup and is characterized by having spike (S) proteins which facilitate viral cell entry, membrane (M) proteins and envelope (E) proteins which assist in viral assembly, and nucleocapsid (N) proteins which mediate viral transcription.4 The SARS-CoV-2 S protein undergo proteolytic priming by transmembrane protease, serine 2 (TMPRSS2) and gain access into host cells through the angiotensin-converting enzyme 2 (ACE2) receptor (Figure 1).5

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 syndromecoronavirus 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

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