The coronavirus disease 2019 (COVID-19) pandemic has adversely impacted the lives of millions of people throughout the world. To date, COVID-19 has claimed the lives of over 6.4 million globally.
Many have suggested that people with chronic urinary disorders are more susceptible to severe COVID-19. Furthermore, men with comorbidities like benign prostatic hyperplasia (BPH), prostate cancer, erectile dysfunction (ED), and infertility are also considered to be more vulnerable to COVID-19.
Study: Impact of COVID-19 on male urogenital health: success of vaccines. Image Credit: Studio Romantic / Shutterstock.com
Background
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses its spike (S) protein to bind to the angiotensin-converting enzyme 2 (ACE2) receptor located on the surface of host cells. The priming of the S protein is carried out by transmembrane serine protease 2 (TMPRSS2), which divides the S protein at the S1/S2 site.
The expression of ACE2 in testicular tissues can increase their risk of being targeted by SARS-CoV-2. Additionally, the association of androgen receptor signaling with COVID-19 severity has also provided evidence as to why men are often at a greater risk of severe disease.
A recent Drug Discovery Today journal study discusses the impact of COVID-19 on the urogenital health of males.
Prostate cancer
Prostate cancer is one of the most prevalent types of cancer and is responsible for most cancer-related deaths in men globally. High levels of TMPRSS2 and ACE2 expression have been observed in the prostate tissue.
Previous studies have reported that downregulation of ACE2 expression, along with an increase in ACE2 activity, is associated with prostate carcinogenesis. The overexpression of TMPRSS2 in prostate cancer further suggests a link between prostate cancer and SARS-CoV-2.
Researchers have postulated that TMPRSS2 and anti-androgen inhibitors can potentially be used as effective treatments for prostate cancer patients who are suffering from COVID-19. Thus, the potential benefit in altering TMPRSS2 expression levels can assist in the development new therapies for treating COVID-19, which might include inhibition of TMPRSS2 and androgen deprivation therapy (ADT).
Benign prostatic hyperplasia
Benign prostatic hyperplasia (BPH), which is defined as increased growth of epithelial and stromal cells in the prostate gland transition zone, is one of the most common conditions reported in older males. BPH can lead to urinary incontinence, urinary retention, as well as many forms of lower urinary tract symptoms (LUTS).
The inhibition of the ACE2/Ang(1-7)/Mas pathway due to SARS-CoV-2 infection can worsen BPH. In fact, several previous studies have reported increased LUTS following COVID-19 in older males.
The international prostate symptom score (IPSS) that evaluates BPH and LUTS has been reported to be higher for male COVID-19 inpatients as compared to their score before their COVID-19 diagnosis.
The class of drugs known as 5-α reductase inhibitors (5-ARIs), when used alone or in combination with α1-adrenergic receptor (α1-AR) antagonists, are most commonly used in the treatment of BPH. Importantly, 5-ARIs are capable of modulating ACE2 levels and reducing TMPRSS2 expression, thereby protecting patients on these drugs against severe COVID-19.
Conversely, α1-AR antagonists reduce hyperinflammation and the release of cytokines. These agents have shown to further reduce mortality rates and hospitalization duration among COVID-19 patients taking these medications.
Bladder disorders
After the urinary bladder senses that it is full, it will modulate its nerves and muscle functions. An overactive bladder, cystitis, and other bladder dysfunctions led by bladder inflammation have been reported to occur following COVID-19.
Male reproductive function
Secretion of androgens by Leydig cells is important for spermatogenesis and secondary sex character maintenance. Leydig cells have also been found to regulate testicular lymphocyte and macrophage levels.
Expression of ACE2 receptors has been observed in Sertoli cells, Leydig cells, and spermatogonia, thus making these testicular tissues potential targets for SARS-CoV-2. Moreover, COVID-19 in males has been reported to increase serum luteinizing hormone (LH) levels and decrease the testosterone: LH ratio.
COVID-19 has been reported to induce testicular spermatogenic dysfunction through immune or inflammatory reactions. High levels of proinflammatory cytokines, epididymitis, autoimmune orchitis, as well as disruption of blood-testis barrier integrity have also been observed due to COVID-19.
COVID-19 is also associated with decreased sperm concentration, increased seminal inflammation, decreased semen volume, and increased seminal apoptotic marker activity. Sperm DNA fragmentation by SARS-CoV-2 is associated with impaired embryo development, an increase in miscarriage rates, and a reduced implantation rate.
Erectile dysfunction
Erectile dysfunction (ED) in COVID-19 patients can arise due to altered pulmonary hemodynamics, non-symptomatic hypogonadism, significant psychological burden, and endothelial dysfunction. Several pre-existing conditions such as diabetes, cardiovascular disease, obesity, and hypertension have been reported to increase the severity of COVID-19 and ED.
Anosmia and ageusia associated with COVID-19 can also lead to the development of ED. Prevalence of ED has also been observed in healthcare workers who were at a higher risk of suffering from COVID-19.
Negative impacts on the sexual and mental health of males can also lead to ED. Cytokine storms in some COVID-19 patients that subsequently lead to vascular endothelial cell apoptosis can also increase the risk of ED.
Following recovery from COVID-19, ED can be used as an indicator of general health in males. Phosphodiesterase-5 (PDE5) inhibitors are reported to be effective in the treatment of COVID-9 and ED.
COVID-19 vaccines
Vaccination against COVID-19 has been found to reduce the number of COVID-19 cases with urological symptoms. Vaccination can also be helpful in prostate cancer patients, as it can inhibit the proliferation of cancer cells. However, further in vivo studies are needed to determine the benefit of COVID-19 vaccines in prostate cancer patients.
Recently, the urological safety of the Moderna and Pfizer-BioNTech COVID-19 vaccines has been reported. To this end, no significant changes in sperm parameters have been observed after the administration of two doses of the Pfizer–BioNTech vaccine.
Conclusions
The current review determines that higher severity and mortality rates are associated with older males suffering from COVID-19. COVID-19 adversely impacts the male reproductive function, thus leading to impaired fertility and prostate pathologies. Expression of ACE2 and TMPRSS2 might lead to an increased risk of severe COVID-19 in males.
The extreme changes in the daily lives of most men due to the pandemic have impacted their overall mental and sexual health, which has most commonly led to the development of ED.
Taken together, further research is needed to ensure urogenital safety during times of continuously changing therapies and vaccine protocols.
Journal reference:
- Kucukyildiz, K., Yilmaz-Oral, D., Turkcan, D., et al. (2022). Impact of COVID-19 on male urogenital health: success of vaccines. Drug Discovery Today. doi:10.1016/j.drudis.2022.07.012.
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