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COVID-19 adversely impacts several markers of inflammation and oxidative stress in semen, a new prospective longitudinal study from Iran indicates.
“We provide the first direct experimental evidence that the male reproductive system could be targeted and damaged by the COVID-19 infection,” the authors note in their article published online January 29 in Reproduction.
Led by PhD student Behzad Hajizadeh Maleki, who is currently working at Justus Liebig University Giessen, Germany, researchers say the magnitude of the adverse effects on sperm is related to disease severity, and they acknowledge that the impact does appear to decline over time.
Nevertheless, the results indicate the testes “should be…declared a high-risk organ by the World Health Organization,” Maleki said in a press release.
And based on their findings, he also suggests the reproductive function of younger men recovering from COVID-19 be monitored.
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Experts Say Any Effects May Be Temporary
However, based on other evidence to date, fertility experts have urged that there shouldn’t be an over-reaction to this study.
“I need to raise a strong note of caution in the interpretation of these data,” Allan Pacey, MD, professor of andrology at the University of Sheffield, UK, told Medscape Medical News.
He recently reviewed 14 published primary research articles and came to a very different conclusion to that of Maleki and colleagues. “To date, more has been written raising this as a concern [rather] than actual primary data which seek to confirm or refute the hypothesis,” he said.
“My view is that the data published to date seemed broadly reassuring that any measurable effect of coronavirus on male fertility is probably only slight and temporary.” But he added, “It is of course important that we keep this [subject] under review.”
Channa Jayasena, PhD, a reader in reproductive endocrinology & andrology, Imperial College London, UK, said that because the angiotensin-converting enzyme 2 (ACE2) receptor — used by the SARS CoV-2 virus to enter cells — is found in the testes there has been concern about possible impairment of male fertility following infection.
But he pointed out that illness due to many viruses can lead to a temporary drop in sperm count, sometimes to zero, for a few weeks or months.
“This makes it difficult to work out how much of the reductions observed in this study were specific to COVID-19 rather than just from being ill,” Jayasena told the UK Science Media Centre.
It’s also possible that differences in bodily composition, and in administered therapies, between the men who had COVID-19 and healthy controls could account for the findings, the experts say.
Wide Range of Markers for Male Fertility Studied
The ACE2 receptor is abundant in the testes and in other male reproductive organs like the prostate gland, seminal vesicles, and bulbourethral glands that contribute seminal fluid to the semen, say the study authors.
Prior to this new study, any effects of COVID-19 on male reproductive function were unclear, said Maleki.
“We aimed to study a wide variety of markers related to male reproductive health and reproductive function which can lead to more accurate and precise conclusions in this regard,” he explained.
The researchers examined changes in seminal ACE2 activity, pro- and anti-inflammatory cytokines, oxidative and antioxidative parameters, apoptotic (cell death) variables, and semen quality parameters in 84 men of reproductive age (20-40 years) with laboratory-confirmed COVID-19 admitted to the Masih Daneshvari Hospital, Tehran, Iran, between March and April 2020.
The time between the confirmatory diagnosis of COVID-19 and first semen collection was 15.2 ± 5.9 days, and further semen samples were taken 10, 20, 30, 40, 50, and 60 days later.
They compared these results with those of semen samples from 105 age-matched healthy controls.
All of the men were assumed to be previously fertile based on physical exam and prior history, as assessed by a urologist.
Sperm Concentration, Motility Reduced, but Did Study End Too Soon?
Of those participants who tested positive for COVID-19, 1.2% were diagnosed as mild, 27.4% as moderate, 32.1% as severe, and 39.3% as critical.
ACE2 activity was significantly higher in men in the COVID-19–infected group than among controls (P < .05) and tended to decrease over time, with a significant decline from 30 to 60 days (P < .05).
By comparison, there were no significant changes in ACE2 activity in the control group.
Also, patients with COVID-19 had significantly higher levels of pro-inflammatory markers (IL-1β, IL-6, IL-8, IL-10, TGF-β, INF-α, and INF-γ) than controls (P < .05) across follow-up.
“The blinding array of measurements to look at the effect of inflammatory markers, or markers of oxidative stress, in the semen…[show] interesting differences, but are not a surprise,” Pacey remarked.
Maleki said: “In men with COVID-19, markers of inflammation and oxidative stress in sperm cells were significantly increased by more than 100% compared to age-matched healthy controls.”
“Pathways that facilitate sperm cell death were activated; and sperm concentration was reduced by 516%, motility by 209%, and sperm morphology was altered by 400%,” he explained.
“This state represents oligoasthenoteratozoospermia, which is one of the most common causes of subfertility in men.”
However, Pacey was complimentary about one aspect of the study: the fact that the researchers were “able to repeat these measurements every 10 days over a 60-day period,” which he described as “no mean feat.”
But “since complete sperm production usually takes just under 3 months, in my opinion they ended the study 30 days too soon. It would have been more useful to see whether there was a difference at 90 days between the two groups,” he observed.
Could Obesity, Treatments for COVID-19 Explain Some Findings?
Pacey also pointed out that the study authors claim a causal relationship between COVID-19 infection and significant impairments of male reproductive function, but their results only show an association.
“There are some significant differences in the characteristics of the men who were infected with COVID-19 and those who were not. The body mass index and the waist circumference of the control group were significantly different [for example],” Pacey said.
The authors acknowledge there are limitations to their study. Of note, being unable to conducted an analysis based on a mild disease course due to insufficient patient numbers.
But they add that comparisons among the moderate, severe, and critically infected men show the magnitude of the perturbations in the studied variables were related to disease severity.
Nevertheless, they agree that further studies in bigger cohorts with prolonged follow-up periods are needed.
And they acknowledge that treatment with steroids, antiviral, and antiretroviral therapies can cause testicular damage and may harm semen quality and function, and might “explain the detrimental effects of COVID-19 infection on the male reproductive system.”
Sheena Lewis, PhD, professor of Reproductive Medicine at Queen’s University Belfast, said these are all valid points.
“My concerns are that the men with COVID had substantially higher body weight and were on a number of therapeutic treatments. We know that obesity alone reduces sperm quality. The COVID treatments may also have affected these men’s sperm quality, rather that COVID itself,” she told the UK Science Media Centre.
Reproduction. Published January 29, 2021. Abstract
Maleki has reported no relevant financial relationships. Pacey has reported being chairman of the advisory committee of the UK National External Quality Assurance Schemes in Andrology, Editor in Chief of Human Fertility, Trustee of the Progress Educational Trust, and Trustee of the British Fertility Society (all unpaid). Jayasena has reported holding a National Institute for Healthcare Research (NIHR) Fellowship in male infertility research. He is also a media ambassador for the Society for Endocrinology. Lewis is CEO of Examenlab.