COVID-19 and men’s health: What we know so far

Urology Times Journal, Vol 49 No 08, Volume 49, Issue 08

Studies are beginning to suggest that COVID-19’s impact on men’s health might go beyond the lungs, heart, and kidneys. According to recently published studies, having COVID-19 could have lasting impacts on fertility and sexual function.

Ranjith Ramasamy, MD, associate professor and director of the University of Miami Miller School of Medicine’s Reproductive Urology Program, is uncovering what he says are clear links between COVID-19 infection and men’s sexual health.

“We know the COVID-19 virus can remain inside the testis long after the initial infection in asymptomatic men. We know the COVID-19 virus can decrease sperm count for up to 3 to 6 months. And we know the COVID-19 virus can affect the blood vessels and be present in the penis up to 7 to 9 months after the initial infection and can lead to erectile dysfunction,” Ramasamy said.

Getting the mRNA COVID-19 vaccine does not appear to impact fertility and should be encouraged, according to Ramasamy, who has published several articles on COVID-19 and men’s sexual health, including the research letter, “Sperm parameters before and after COVID-19 mRNA vaccination” published June 17 in JAMA.1

COVID-19 and male infertility

Findings from early studies looking at male infertility post–COVID-19 infection are concerning, reassuring, conflicting, and inconclusive.

COVID-19 does not appear to get into the semen, according to urologist James M. Hotaling, MD, MS, FECSM, medical director of the fertility integrated practice unit and director of the Men’s Health program at the University of Utah, Salt Lake City.

Hotaling and coauthors in China conducted an observational study of 34 adult Chinese males who received a diagnosis of COVID-19 and found severe acute respiratory syndrome (SARS)-CoV-2 was not detected in the men’s semen 1 month after COVID-19 diagnosis.2

Current evidence suggests a low likelihood of SARS-CoV-2 transmission through the seminal fluid. There are limited data characterizing SARS-CoV-2 infection’s impact on male reproductive hormones and semen parameters. And data suggesting SARS-CoV-2 gets into testes are inconclusive, according to Hotaling.

Data regarding the short- and long-term impacts of SARS-CoV-2 on male reproductive health remain largely inconclusive and need further long-term study, Hotaling and colleagues reported in a review of the literature published April 2021 in Fertility and Sterility.3

But Ramasamy and other investigators are finding causes for concern.

A study published earlier this year in the World Journal of Men’s Health by Ramasamy et al looked at testis tissue collected from autopsies of 6 COVID-19 positive and 3 COVID-19 negative men. The investigators found 3 of the 6 COVID-19–positive biopsies had normal spermatogenesis and 3 had impaired spermatogenesis. Electron microscopy showed the COVID-19 virus in testis tissue of 1 COVID-19–positive autopsy case.

The novel COVID-19 virus has an affinity for angiotensin converting enzyme-2 (ACE-2) receptors. Since ACE-2 receptor expression is high in the testes, the study authors hypothesized that COVID-19 can be present in testes tissue of infected patients. This study suggests that the male reproductive tract, specifically the testes, may be the target of COVID-19 infection. They found an inverse association between ACE-2 receptor levels and spermatogenesis, suggesting a possible mechanism of how COVID-19 can cause infertility, according to the study.4

Investigators in China also found evidence that SARS-CoV-2 can infect the testis and germ cells, suggesting a potential impact on spermatogenesis and male fertility.5

“Nevertheless, further study is essential to reveal the underlying mechanism of SARS-CoV-2 infection of testicular cells and the correlation of testis infection with the clinical course of COVID-19,” according to the correspondence published December 14, 2020, in Cellular and Molecular Immunology.

Although more quality research is needed to confirm these results, the findings make sense when one thinks about COVID-19 infection basics, according to Hossein Sadeghi-Nejad, MD, FACS, professor of Surgery/Urology at Rutgers New Jersey Medical School and Hackensack University Medical Center.

Infection from SARS-CoV-2 causes an exaggerated inflammatory response leading to immunosuppression. The body releases cytokines that mainly affect lung tissue but also lead to extrapulmonary effects, he said.

For example, some studies are showing overall testosterone levels can be lower in patients who get COVID-19. Investigators of a single-center cohort study of patients with COVID-19 found lower testosterone concentrations during hospitalization were associated with increased disease severity and inflammation in men.6 Still unclear is whether the decrease in testosterone is an adaptive or maladaptive COVID-19 response.7

The reason for the likelihood of lower testosterone levels in COVID-19 patients is that SARS CoV-2 gets into the system is through ACE-2, which has been expressed in Leydig cells and Sertoli cells, according to Sadeghi-Nejad.

Damage to Leydig cells may lead to testosterone deficiency, he said.

Evolving science of covid-19 and ed

There are about 2 dozen peer-reviewed articles containing research or findings regarding COVID-19 and erectile dysfunction (ED), according to Martin Gross, MD, assistant professor at Dartmouth-Hitchcock Medical Center and codirector of the Dartmouth-Hitchcock Men’s Health Center.

“They predominantly include case reports, observational studies, survey data, expert opinions, and review articles. These types of articles tend to be on the lower end of scientific rigor,” Gross said. “We don’t know much about the relationship between ED and COVID-19 at this point.”

A study by Ramasamy et al, published in July in the World Journal of Men’s Health analyzing penile tissue from COVID-19 patients who recovered and subsequently developed ED, was novel and interesting, according to Gross.8

It was the first study to demonstrate the presence of the COVID-19 virus in the penis up to 9 months after the initial infection and suggests that endothelial dysfunction from the virus could contribute to ED.

Omer Raheem, MD, MSc, assistant professor of urology and director of men’s health at Tulane University School of Medicine, New Orleans, Louisiana, said he found it interesting that 1 of the 2 men Ramasamy and colleagues studied was hospitalized for COVID-19 infection, whereas the other had only mild COVID-19 symptoms, yet both men developed severe erectile dysfunction.

This study suggests that widespread endothelial cell dysfunction from COVID-19 infection can contribute to erectile dysfunction. Larger prospective studies are warranted to further validate this finding, Raheem said.

“From patient’s perspective, albeit not conclusive, there is some evidence suggesting the potentially negative impact of COVID-19 infection on male reproductive function and overall men’s health. Likewise, COVID-19–infected or COVID-19–recovered men should be aware of the possible risk of developing erectile dysfunction, male infertility, and hypogonadism, owing to the adverse effect of the SARS-CoV-2 virus on testicular Sertoli and Leydig cells via ACE-2 binding. And obviously those symptomatic men should seek urologic consultation to evaluate and treat these conditions,” Raheem said.

Although the link between COVID-19 infection, endothelial damage, and ED is interesting, the finding should be further evaluated in larger studies and viewed cautiously, according Sadeghi-Nejad.

“Endothelial damage is not restricted to COVID-19. Endothelial dysfunction is seen in many of our patients who have erectile dysfunction, which we know to be a neurovascular problem,” Sadeghi-Nejad said.

There are conflicting data about whether sexual activity increased or decreased during the pandemic, according to Sadeghi-Nejad.

Many surveys on sexual activity during quarantining suggest decreased activity, possibly because the studies included younger patients with children living at home. Other studies on older patients showed increased activity.

Interestingly, investigators studying US sales of phosphodiesterase-5 (PDE5) inhibitors show sales of the medications spiked during lockdowns.9

Turkish authors of a paper published earlier this year in Sexual Medicine reported a significant increase in andrological diagnoses during the pandemic, compared with before it.10

“There was a statistically significant increase in the number of patients diagnosed with male reproductive or sexual health problems during the COVID-19 pandemic period,” according to the authors. “The number of patients diagnosed with erectile dysfunction during the pandemic was also significantly higher than [in] the pre–COVID-19 pandemic period.”

The paper’s authors suggest that although these problems are multifactorial, psychogenic factors might be a significant trigger.

In other research, the PDE5 inhibitors men use to treat erectile dysfunction could also treat COVID-19. These medications, the authors wrote, have anti-inflammatory, antioxidant, immune response regulation, and antiapoptotic properties.11

“A lot of the paper was theoretical but solidly grounded in physiology and pharmacology,” Gross said. “These studies are all interesting to some degree, but they are snapshots in time that may lose relevance down the road.”

Putting the information to practice

Counseling patients about COVID-19’s potential impact on sexual health and fertility might start with encouraging patients to get vaccinated.

“I recommend that all couples trying to conceive get the vaccine. And that it is safe,” Hotaling said.

Men who have acute COVID-19 infections and see a decline in spermatogenesis should consider waiting 3 to 6 months before planning fertility treatment so their sperm counts can recover, according to Ramasamy.

Sadeghi-Nejad cites American Society of Reproductive Medicine recommendations regarding shared decision-making and detailed discussions, including not withholding the vaccine from patients who are planning to conceive, those who are already undergoing fertility treatment, and pregnant patients. These groups should be encouraged to receive vaccination if there are no other contraindications.12

Gross, however, said he questions the value of further research on the link between ED and COVID-19, and a COVID-19 diagnosis does not change his approach to ED treatment.

“It would be presumptuous to think that our little corner of medicine has any relevance to the bigger COVID-19 picture. And lots of conditions cause ED; let’s try and tackle those first,” Gross said. “I have never found a good reason to wait to treat any patient’s erectile dysfunction. If a patient has a problem, hears his options, and is healthy enough and wants to proceed with some or all of these options, then I’m happy to help. If patients aren’t healthy enough or otherwise prepared to move forward with treatment, then we can wait until they’re ready.”

Ongoing research

Questions remain about how the virus invades the immune system and can stay in organs for such a long time, as well as whether any impact from COVID-19 on male fertility or sexual function is permanent, according to Ramasamy.

More data should be coming out soon, according to Hotaling.

“Some of the big IVF groups are tracking their outcomes where the men or women have had COVID-19. A lot of these big claims databases will release their data from 2020 sometime between now and the end of the year,” Hotaling said. “There are a lot of studies out of Europe that I’ve seen tracking cohorts of patients who had COVID-19.”

Ongoing and long-term studies to evaluate the potential impact of the COVID-19 infection on men’s health are needed as we emerge from COVID-19 pandemic and monitor the novel COVID-19 Delta variant, Raheem said.

References

1. Gonzalez DC, Nassau DE, Khodamoradi K, et al. Sperm parameters before and after COVID-19 mRNA vaccination. JAMA. Published online June 17, 2021. doi:10.1001/jama.2021.9976

2. Pan F, Xiao X, Guo J, 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):1135-1139. doi:10.1016/j.fertnstert.2020.04.024

3. Patel DP, Punjani N, Guo J, Alukal JP, Li PS, Hotaling JM. The impact of SARS-CoV-2 and COVID-19 on male reproduction and men’s health. Fertil Steril. 2021;115(4):813-823. doi:10.1016/j.fertnstert.2020.12.033

4. Achua JK, Chu KY, Ibrahim E, et al. Histopathology and ultrastructural findings of fatal COVID-19 infections on testis. World J Mens Health. 2021;39(1):65-74. doi:10.5534/wjmh.200170

5. Ma X, Guan C, Chen R, et al. Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients. Cell Mol Immunol. 2021;18(2):487-489. doi:10.1038/s41423-020-00604-5

6. Dhindsa S, Zhang N, McPhaul MJ, et al. Association of circulating sex hormones with inflammation and disease severity in patients with COVID-19. JAMA Netw Open. 2021;4(5):e2111398. doi:10.1001/jamanetworkopen.2021.11398

7. Stolk RF, van Leeuwen HJ, Kox M, et al. The chicken or the egg: low testosterone predisposes for COVID-19 or COVID-19 induces a decrease in testosterone? Crit Care. 2021;25(1):237. doi:10.1186/s13054-021-03664-9

8. Kresch E, Achua J, Saltzman R, et al. COVID-19 endothelial dysfunction can cause erectile dysfunction: histopathological, immunohistochemical, and ultrastructural study of the human penis. World J Mens Health. 2021;39(3):466-469. doi:10.5534/wjmh.210055

9. Hernandez I, Gul Z, Gellad WF, Davies BJ. Marked increase in sales of erectile dysfunction medication during COVID-19. J Gen Intern Med. 2021;1-3. doi:10.1007/s11606-021-06968-2

10. Duran MB, Yildirim O, Kizilkan Y, et al. Variations in the number of patients presenting with andrological problems during the coronavirus disease 2019 pandemic and the possible reasons for these variations: a multicenter study. Sex Med. 2021;9(1):100292. doi:10.1016/j.esxm.2020.100292

11. Mostafa T. Could oral phosphodiesterase 5 inhibitors have a potential adjuvant role in combating COVID-19 infection?. Sex Med Rev. 2021;9(1):15-22. doi:10.1016/j.sxmr.2020.08.006

12. ASRM issues statement on COVID-19 vaccines, joins other OB/GYN groups on community-wide statement. News release. American Society for Reproductive Medicine. Dec 16, 2020. Accessed July 13, 2021. https://bit.ly/3BbJ5Bq