Read Part one and two of the series.
Epidemiological data from the COVID-19 outbreak showed a higher prevalence and severity of COVID-19 in men, indicating greater susceptibility, a more aggressive course of acute infection, and higher mortality rates. However, Long COVID rates are significantly lower in men. This might be due to differences in the immune system of men and women as we have explained previously.
A recently published meta-analysis summarized the findings of 16 publications about COVID-19 on testicular function. The authors performed a meta-analysis over 1250 patients with active or recent COVID-19 infection and 1232 matched healthy controls. The publications evaluated patients in a period ranging from baseline (acute infection) up to 80 days from infection. This short time period barely includes the transition from acute infection to Long COVID. Which effects last during Long COVID can thus not be determined. However, the short-term information gives hints at what should be researched with a longer timeframe.
The meta-analysis suggests an association between SARS-CoV-2 infection and primary testicular damage, indicated by altered steroidogenesis (formation of steroid hormones) and impaired spermatogenesis (production of sperm cells).
Impaired production of sperm cells
The results show that sperm concentration, total sperm count, and total sperm motility were significantly lower in COVID-19 patients compared to controls. Moreover, fever has been shown to negatively affect sperm quality in any disease. Importantly, none of the studies detected SARS-CoV-2 mRNA directly in the semen of infected patients, suggesting a low risk of sexual transmission of the virus.
Semen Analysis: The amount of sperm cells (sperm count) and movement ability (motility) is determined. (Source: Adobe Stock)
Spermatogenesis is the process of sperm cell development, which takes place in the testes. This process involves several key cell types, such as Leydig cells and Sertoli cells.
Leydig cells produce testosterone. Testosterone is crucial for the development and maintenance of spermatogenesis and promotes the maturation of sperm cells. Sertoli cells provide structural and nutritional support to developing sperm cells. They also form the blood-testis barrier, which protects spermatogenic cells from autoimmune attacks and harmful substances.
One possible explanation for the effect COVID-19 infections have on male reproductive health lies in the enzyme ACE2.
ACE2 is found in cells of the lungs, thyroid, heart and other organs but also in the male testes. SARS-CoV-2 and other corona viruses have a high affinity for ACE2. This interaction ultimately facilitates viral entry into ACE2 expressing cells.
A 2021 publication reviewed the hypothesis that men have higher ACE2 serum activity as a reason why men are prone to more severe acute coronavirus infections. While this hypothesis is not entirely proven, the authors have observed that ACE2 activity is increased in men with hypertension and heart failure which have both been identified as risk factors for adverse outcomes.
Sex hormones also seem to affect ACE2 levels. Removal of the ovaries in women increased ACE2 activity, while removal of the male testes led to a decrease. These observations and the fact that ACE2 is expressed on Leydig and Sertoli cells in the testes suggest the SARS-CoV-2/ACE2 interaction as a potential pathway for the virus into spermatogenesis. If the hypothesis is proven, one could assume a possible disruption of the reproductive system as long as the virus resides in the body.
SARS-CoV-2 can enter into Sertoli and Leydig cells and damage sperm and testosterone production. (Source: Cannarella et al.)
Testosterone levels
Several studies have reported worse outcomes in patients with pre-existing testosterone deficiency, including longer disease duration and extended ICU stays. It remains unclear whether testosterone deficiency is a cause or consequence of COVID-19. However, COVID-19 patients had lower levels of total testosterone and follicle-stimulating hormone. Moreover, male COVID-19 patients showed elevated levels of hormones such as estradiol and prolactin that are usually expressed at higher levels in females.
One publication discovered a high prevalence of erectile dysfunction during the third month of recovery from COVID-19 but did not follow up after a longer time period. Pharmacological interference during acute infection, particularly from anti-inflammatory therapy, may also suppress hormone secretion. This has been observed in men and male rats.
In summary, while there is research on the short-term effects of COVID-19 on male reproductive health, long term studies are lacking. Although Long COVID manifests less often in men, research is desperately needed for all genders.
This was part three of the series. Read part one and two about the impact of Long COVID and associated diseases on female reproductive health. Follow this series to learn more about reproductive health effects in transgender individuals and how testosterone levels could play a role in all genders.
