key: cord-0783776-efktouh9
authors: Hsu, Albert L.; Finlinson, Alex; Warncke, Kristen
title: Mechanisms by Which SARS-CoV-2 May Impact Male Fertility
date: 2020-10-06
journal: Reprod Sci
DOI: 10.1007/s43032-020-00304-5
sha: af2d549f30c16ffd3b7d845dbe71d10b316b373f
doc_id: 783776
cord_uid: efktouh9

The COVID-19 pandemic is unlike anything we have experienced in over a century. In the USA, waves of COVID-19 have migrated from the Northeast to the Sun Belt to the Midwest over the past year. Compared with females, males are more susceptible to SARS-CoV-2 infection, have more severe COVID-19 disease, and have higher death rates. In many countries, men are consistently more likely to die by a factor of almost 2. This article describes some of the mechanisms by which COVID-19 may be associated with male infertility, as discussed by Dutta and Sengupta.

The global number of COVID-19 cases is inexorably rising, with over 33 million worldwide cases reported by the Johns Hopkins Coronavirus Resource Center (as of 9/30/20). There are also marked sex differences in the incidence and severity of COVID-19 cases; in humans, males are more susceptible to SARS-CoV-2 infection compared with agematched females. Men are also more likely to be managed in intensive care or even die from COVID-19. Dutta and Sengupta have detailed the potential impact of COVID-19 on male reproductive function as well as some mechanisms by which COVID-19 may potentially be associated with male infertility [1] .

Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and is differentially regulated in males and females. Cells with high levels of ACE2 expression have the potential to be targeted and damaged by SARS-CoV-2. Single-cell transcriptome studies have revealed abundant ACE2 expression in Sertoli cells, Leydig cells, and spermatogonia, rendering all three categories of testicular cells potentially vulnerable to cellular damage by SARS-CoV-2 [2] .

Cellular entry of SARS-CoV-2 is mediated by its spike glycoproteins (S proteins), which need priming by cellular proteases to facilitate viral fusion to cellular membranes. TMPRSS2 (transmembrane protease serine 2) is utilized for S protein priming and is found in prostate epithelial cells [3, 4] ; androgen receptor activation is needed to trigger TMPRSS2 expression [1] . In addition, brain cells (neurons and glial cells) also express ACE2 receptors, raising the question of whether viral damage by SARS-CoV-2 may also disrupt the hypothalamic-pituitary-testicular axis and thereby disrupt normal male pubertal development and/or contribute to male infertility [2] .

There is some evidence correlating high ACE2 expression with infertility, suggesting that "an overactivation of ACE2 might affect spermatogenesis." [2] Of note, the highest number of ACE2-positive cells was found in a 30-year-old man (compared with a 20-year-old and 60-year-old man) [1] . As the COVID-19 pandemic evolves to strike younger populations of reproductive age globally, it remains an outstanding question whether there will be a rise in male factor infertility (or overall infertility) in general, as a result of this pandemic.

Dutta and Sengupta discuss oxidative stress, inflammation, and the immunologic response to a high testicular viral load in the testes, as parts of a cascade that could lead to COVID-19-related male factor infertility [1] . Evidence of localized testicular damage also suggests the potential for adverse reproductive consequences at the anatomical, cellular, and molecular levels. With evidence that worldwide sperm counts have already declined 50-60% among men in North America, Europe, Australia, and New Zealand between 1973 and 2011 [5] , the potential impact of COVID-19 on sperm and sperm function is an area that requires urgent further study.

SARS-CoV-2 and male infertility: possible multifaceted pathology

Could SARS-CoV-2 affect male fertility?

SARS-CoV-2 presence in seminal fluid: myth or reality

SARS-CoV-2 infection, male fertility and sperm cryopreservation: a position statement of the Italian Society of Andrology and Sexual Medicine (SIAMS) (Società Italiana di Andrologia e Medicina della Sessualità)

Temporal trends in sperm count: a systematic review and meta-regression analysis

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