How does COVID-19 and its treatment affect testicular function?

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Oct 23 2022

Over 627 million individuals worldwide have been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing coronavirus disease 2019 (COVID-19).

Study: COVID-19 and its treatments: lights and shadows on testicular function. Image Credit: Chinnapong / Shutterstock.com

Background

Compared to females, males are more susceptible to COVID-19 and its consequences. This is due to multiple factors, such as genetic background, sex-specific hormones, and lifestyle patterns.

As a result, researchers have studied whether SARS-CoV-2 is present in seminal fluid or affects testicular function. Men's reproductive health has also been assessed after SARS-CoV-2 infection based on reproductive outcomes, alteration of semen parameters, and other aspects. 

The long-term effects of COVID-19 on male reproductive health have also been studied due to reported changes in the hormonal axis and gamete impairment. These studies have indicated that both SARS-CoV-2 infection and its treatments can affect men's reproductive health.

In a recent Endocrine study, researchers summarized available information related to the reproductive effects of COVID-19, which could be immensely beneficial to endocrinologists for developing preventive measures. For this mini-review, the authors obtained all relevant articles from Medline/PubMed and Embase.

How does COVID-19 affect testicular function?

SARS-CoV-2 infects the host by binding with the angiotensin-converting enzyme 2 (ACE2) receptor of the host cell. Subsequently, membrane fusion occurs to establish infection. Interestingly, ACE2 was found to be expressed in male reproductive cells, such as spermatogonia, Leydig and Sertoli cells, and seminiferous duct cells. 

Besides ACE2, several other mediators are also required to facilitate the virus-host cell fusion, such as transmembrane protease serine 2 (TMPRSS2). TMPRSS2 is expressed in the human prostate epithelial cell, wherein androgens control its expression in the male reproductive system. 

Theoretically, there is a possibility of testicular COVID-related damage, which has been supported by the post-mortem detection of viral proteins in testicular tissue. To infect testicular cells, the virus must overcome the blood-testis barrier, which can be achieved through cytokine-induced inflammation that modifies tight junctions of the Sertoli cells.

A recent metanalysis has reported the presence of an insignificant amount of SARS-CoV-2 in the semen samples of an infected person. Nevertheless, few studies have reported the association of SARS-CoV-2 infection with testicular discomfort and pain. Histological studies have detected orchitis, which could be due to vasculitis, in patients who died due to multi-organ failure associated with severe COVID-19.

Based on previous studies, there is a possibility that SARS-CoV-2-related testicular endothelial dysfunction might induce the synthesis of CD3+ and CD68+ leukocytes, as well as other inflammatory cells in the interstitial tissue. However, in most COVID-19 cases, direct damage to the seminiferous tubules and spermatogenesis was not observed, particularly in the absence of comorbidities.

Indirect damage to the testes

Various indirect mechanisms, such as fever, inflammation, and gonadotoxic treatments, might cause damage to the testes.

The testicular temperature could be altered due to fever, which might negatively affect germ cell development. In addition, this condition could also adversely impact semen quality and sperm DNA integrity.

Therefore, COVID-19 fever could stimulate changes in sperm parameters, even in the absence of SARS-CoV-2 in the semen. However, one meta-analysis reported that impaired sperm production due to COVID-19 fever or treatment was rectified after the patient's recovery. 

SARS-CoV-2 infection could significantly alter the levels of several pro-inflammatory mediators that induce testicular damage. For example, cytokines are important factors that trigger inflammation in the male genital tract and increase the risk of infertility.

Additionally, pro-inflammatory cytokines can alter the microenvironment of the seminiferous tubule, which might be associated with altered tight junctions on Sertoli cells, thereby affecting the blood-testis barrier permeability. Cytokines also cause oxidative stress and induce germ-cell apoptosis.

Dysregulated cytokines and chemokines may stimulate an autoimmune reaction that might affect testicular tissue and semen quality and reduce the fertilization capacity of spermatozoa and gametic fusion. SARS-CoV-2 infection also impairs gonadal hormone function with low testosterone levels.

The effect of COVID-19 drugs and vaccines on testicular functions

Many drugs have been identified to interfere with spermatogenesis. Hydroxychloroquine is one drug that was initially used for the treatment of COVID-19; however, animal studies revealed that this drug reduced sperm counts, the weight of the testes, and accessory sex organs, as well as testosterone secretion.

Several antiviral drugs, such as darunavir/ritonavir, lopinavir/ritonavir, nirmatrelvir-ritonavir, molpunavir, and remdesivir, have been used for COVID-19 treatment. Although antiviral drugs are associated with causing alterations in semen parameters, there remains a lack of high-quality evidence supporting this effect. Nevertheless, in vivo animal studies have indicated that some antiviral drugs, such as lopinavir/ritonavir, have adverse effects on sperm parameters, possibly due to increased oxidative stress. 

Importantly, COVID-19 messenger ribonucleic acid (mRNA)-based vaccines exhibited no adverse effects on semen volume and sperm concentration motility. More research in the future is needed to determine sperm morphology following COVID-19 vaccination.