April 19, 2020

expert reaction to preprint on testes and the COVID-19 virus, SARS-CoV-2

A pre-print, posted on MedRxiv, reports on testes and the COVID-19 virus, SARS-CoV-2.

Dr Rod Mitchell, Research Group Leader and Honorary Consultant Paediatric Endocrinologist, MRC Centre for Reproductive Health, University of Edinburgh, said:

“This is a small study involving a relatively low number of patients.  The main suggestion that the testicles act as a reservoir for the virus is theoretical and is not actually tested.

“Crucially, the study does not determine when each person became infected and therefore it is not possible to accurately determine the duration of infection.

“The study includes patients aged from 3-75 years, which is not accounted for in the analysis.  Given the variation in the behaviour of the virus and differences in the testicles between children and adults, this is an important omission.

“Whilst the ACE2 protein is involved in the transport of the virus into cells, there are other proteins that contribute to this process.  Therefore, additional studies would be needed to prove whether the virus enters and persists in the cells of the testicle.

“Given the limitations of the study, it is important to emphasise that this report has not been peer-reviewed by experts in the field.”

Prof Paolo Madeddu, Professor of Experimental Cardiovascular Medicine, University of Bristol, said:

“While COVID-19 is certainly more frequent and severe in men, the study is pointing at possible association of infection with ACE2 expression in the gonads.  But the evidence is weak for two reasons.

“The sample examined is small and the difference though statistically significant would only have a small biologic effect if any.

“Second, there are many other possible reasons for the difference seen, including viral loads, risk factors, and protection of female hormones.  The article does not provide an explanation of testicular ACE2 as a clearance mechanism.  If their hypothesis was true we should observe clinical symptoms such as testicular inflammation etc. which as far as I know is not a common symptom.  There has been no suggestion that reduced testicular function or reduced fertility is an outcome of this virus – a previous report suggesting that men that had contracted the disease had reduced fertility was then retracted.  Also we already know temporary reduction in number of spermatozoi can be observed with high fever of any cause.

“Importantly, another study has shown that there was no sign of the virus in the semen of infected men.  This, together with observation that the virus does not travel through the bloodstream, makes the possibility of the testis being a reservoir of the virus unlikely.

“In fact this preprint based the hypothesis only on indirect evidence linking a modest difference in the duration of the disease with the observation that the receptor for the virus entry is abundant in testicle.  The authors did not measure the virus in semen, nor did they report other testicular symptoms such as signs of inflammation etc.

“Another article reported changes in sex hormones in 80 men (LH/testosterone levels decreased and associated to the inflammatory marker reactive C protein) compared with 100 male healthy controls – however, again no assessment was done of the virus in semen or testis.  Hormonal changes could be due to general inflammation affecting also the gonad function.

“In summary, there is no evidence testicles can harbour the virus.  A modest increase in the duration of the disease in a small cohort studied by the authors, together with the fact the virus receptor is expressed in testicle, is far from sufficient to say the testicle is a reservoir for the virus.

“This this publication does not provide robust evidence and further studies are needed on large cohorts using stronger endpoints.”

Prof Ian Jones, Professor of Virology, University of Reading, said:

“The main site of virus replication is the respiratory tract and to reach other sites the virus would have to travel in the bloodstream – viraemia.  This has been reported for the virus but it is not generally what coronaviruses do.  Men generally do worse than women in immunological outcomes, possibly the result of only one X chromosome, and I think that this imbalance is more likely behind the differences seen.  This work is not peer-reviewed.”

Prof Jonathan Ball, Professor of Molecular Virology, University of Nottingham, said:

“In a different study*, which again was a preprint and so not peer-reviewed, a small number of males had their semen tested for the presence of the coronavirus whilst they were recovering from the virus.  There was also a sample of testes from another patient that had unfortunately died.  None of the samples tested positive for the presence of the virus, suggesting that the male genital tract wasn’t an important reservoir for the virus.  Obviously understanding the body distribution of the virus at different stages of disease is important, and therefore more studies are needed to understand how COVID develops and why males seem to be more badly affected.”

* https://www.medrxiv.org/content/10.1101/2020.03.31.20042333v2

Preprint (not a paper): ‘Delayed clearance of SARS-CoV2 in male compared to female patients: High ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs’ by Aditi Shastr et al. is on medRxiv.  This work is not peer-reviewed.

https://www.medrxiv.org/content/10.1101/2020.04.16.20060566v1

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www.sciencemediacentre.org/tag/covid-19

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