A recently published review on the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), describes the state of current knowledge regarding the impact of this virus on the male reproductive system.
Study: Impact of the SARS-CoV-2 Virus on Male Reproductive Health. Image Credit: aslysun/Shutterstock
Despite an equivalent number of infections in both sexes, the striking male predilection shown by the virus in terms of severe disease and death has garnered much scientific attention since the outbreak of SARS-CoV-2. Many have considered this to be due to androgens, the male sex hormones.
The reasoning for such a hypothesis is that androgen receptors increase the expression level of the cell surface angiotensin-converting enzyme 2 (ACE2) receptors for the virus to gain entry to the host cell.
However, androgen deprivation therapy (ADT), used in the androgen-dependent condition of metastatic prostate cancer, has not been approved for the treatment of COVID-19 due to limited data and adverse side effects.
Mechanism of viral entry
The spike protein of SARS-CoV-2 has two subunits, the S1 and S2, for receptor attachment and membrane fusion, respectively. The S1 subunit contains the receptor-binding domain (RBD), which binds the ACE2 receptor. This cell surface receptor is present in the testicular Leydig and Sertoli cells.
Following virus-ACE2 binding at the RBD, the host serine protease type II transmembrane serine protease (TMPRSS2) cleaves the viral spike to activate fusion. It also enhances ACE2 cleavage and thus promotes viral uptake via the endosomal cysteine proteases cathepsin B and L pathway.
TMPRSS2 is found in multiple cell types, including the prostate and many parts of the gut. In men, TMPRSS2 expression is higher in both type I and type II alveolar cells. In the testis, TMPRSS2 expression is widespread, including in sperm precursor cells. Which indicates it is present in seminal fluid as well.
COVID-19 differences in Men
Sex-differential expression of proteins such as TMPRSS2, which are key to increased viral entry, may explain why males are more severely affected by COVID-19. Another reason is the increased occurrence of health risk factors in men, which have been independently linked to a greater risk of hospitalization with COVID-19.
The protective effect of estrogen has been noted since it modulates ACE2 expression within differentiated airway epithelium and enhances the immune response.
Androgens in COVID-19
Even though obesity and old age are associated with more severe disease, these are also linked to low serum testosterone levels. One study has shown that COVID-19 patients have lower testosterone levels than others, with testosterone deficiency levels being detected in over three-quarters.
The lower the testosterone, the higher the duration of hospitalization and the greater the severity of the disease. Inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP) are also associated with low testosterone levels. This study also showed high serum luteinizing hormone (LH) levels, which would support the occurrence of primary hypogonadism and testicular failure.
Testosterone is produced by Leydig cells in the testis, which express ACE2 at high levels, though TMPRSS2 expression is uncertain. It could be possible that the virus invades the Leydig cells and either destroys or inactivates them, resulting in testicular hypofunction in severe COVID-19. Post-mortem analysis has shown reduced numbers of Leydig cells in patients who succumbed to the virus, supporting this hypothesis.
Testosterone replacement therapy is not considered a valuable option due to the theoretical risk of venous thromboembolic events (VTE), already elevated in severe COVID-19. Overall, testosterone use to modulate COVID-19 outcomes cannot be recommended at present on the weight of available evidence.
Male reproductive organs in COVID-19
Some researchers have reported the occurrence of erectile dysfunction (ED) in patients who have recovered from COVID-19. It is thought to be the effect of endothelial dysfunction, a hallmark of severe COVID-19 disease since endothelial cells carry both ACE2 and TMPRSS2 receptors.
Following the viral entry into endothelial cells, replication and the resulting cell injury leads to vasculopathy. The result is microvascular damage, which is the fundamental lesion in vasculogenic ED. ED prevalence is higher among COVID-19 survivors, though other causes may contribute.
SARS-CoV-2 has been identified in penile and endothelial cells of the corpora cavernosum up to seven months after infection, suggesting that direct damage may also be a factor in ED post-COVID. Testicular inflammation has been described in up to 22% of infected men, and about 17% of post-mortem testicular biopsies tested positive for SARS-CoV-2 by RT-PCR. However, this could be due to blood contamination.
Widespread destruction of germ cells was also found. In severe COVID-19, the virus may reach these organs via the blood, aided by the abundance of ACE2 and TMPRSS2 receptors on them. However, prostate and seminal vesicle ACE2 and TMPRSS2 expression are not associated with injury due to COVID-19. This may be due to low levels of ACE2 expression, with low-to-medium TMPRSS2 levels, in the prostate.
Male fertility and sexual transmission
Researchers have explored the possibility of the virus entering the testis, disrupting the testis-blood barrier, impacting sperm generation, and spreading via sexual contact. Only one study showed viral particles in a sizable minority of semen samples during acute COVID-19, in a group of men with severe infection.
The consensus is that semen testing in andrology technicians is not a probable source of transmission given the low presence of the virus. Sexual transmission is also unlikely, given the timing of the observation during severe acute illness. In convalescent patients, there is no evidence to suggest a risk.
Germ cell loss may cause impaired semen parameters in those with moderate to severe disease. Several studies have shown a reduction in total sperm counts, with some recovery at three months, the time required for a new sperm generation cycle to be completed.
Despite the short-term adverse impact of SARS-CoV-2 on semen quality and the unknown long-term effects, experts believe that cryopreservation of sperm for assisted reproductive techniques remains safe. Fertility tests may be required for men who wish to father children following a bout of COVID-19.