A review recently published in the Journal of Medical Virology has discussed some of the effects that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19) – may have on male fertility.
In the paper, Cemile Seymen from Gazi University Institute of Health Sciences, in Ankara, Turkey, summarizes study findings showing how the infection can negatively affect male reproductive health.
Seymen says further studies are needed to investigate the roles that the host cell proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) may play in infection since both of these proteins, which are involved in viral entry, are highly expressed in the male reproductive system.
Very little data are available on the effects of COVID-19 on male fertility
Since SARS-CoV-2 was first identified in Wuhan, China, late last year (2019), studies have shown that the virus not only causes respiratory disease but can affect various different organs, including those of the male reproductive system.
"There is a very limited number of data about the effects of COVID-19 on male fertility, so it has become an important topic for researchers," says Seymen.
ACE2 is highly expressed in the male genital tract
To gain viral entry, SARS-CoV-2 uses a surface structure called the spike protein to bind to the ACE2 receptor present on host cells.
One study published earlier this year showed that ACE2 messenger RNA was expressed in both germ and somatic cells of the testis. Other studies have found that ACE2 is expressed in spermatogonia, Leydig cells, and Sertoli cells.
One study that used electron microscopy to examine post-mortem tissues from the testes of twelve COVID-19 patients demonstrated swelling, vacuolation, and cytoplasmic dilution in the Sertoli cells and a reduction in the number of Leydig cells, compared with patients who did not have COVID-19.
Some studies have also demonstrated increased levels of the autophagy receptor SQSTM1 in cells infected with SARS-CoV-2, indicating a fall in autophagy flux.
"As a result, SARS-CoV-2 may cause male reproductive disorders by regulating the level of autophagy in male germ cells," writes Seymen.
Researchers have also proposed that an increase in testicular temperature as an indirect effect of inflammation has negative impacts on the testes among COVID-19 patients.
What about TMPRSS2?
Seymen also discusses the role that TMPRSS2 may play in SARS-CoV-2 infection of the prostate.
One study found that this enzyme, which cleaves the spike protein in preparation for virus and host membrane fusion, is highly expressed in the prostate's epithelium.
This gland secretes prostate fluid, one of the main components of the seminal fluid. Muscles within the gland are responsible for pushing the seminal fluid through the urethra during ejaculation.
The high expression of TMPRSS2 within the prostate could increase the likelihood of SARS-CoV-2 infection in this gland, which may affect its ability to secrete these fluids, says Seymen.
Effects on the nervous system could affect male fertility
Seymen points out that SARS-CoV-2 could also exert negative impacts on male fertility indirectly, through mechanisms involving the nervous system.
For example, most viruses permeate the blood-brain barrier and reports have shown that glial cells and neurons also express ACE2 receptors, potentially making them a target for neuronal death induced by SARS-CoV-2.
Importantly, the central nervous system plays a critical role in endocrine control and spermatogenesis. Neurons in the hypothalamus secrete gonadotropin-releasing hormone (GnRH), for example, which triggers the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland.
Low levels of GnRH results in decreased FSH and LH, which in turn impacts the function of Sertoli cells and Leydig cells.
Seymen also points out that depression and anxiety (which many people are experiencing during the current pandemic) are associated with increased levels of cortisol and prolactin, as well as a lower sperm count and semen volume, all of which have been shown to contribute to sexual dysfunction.
Further studies are needed
Seymen says that taken together, these study findings suggest that the COVID-19 pandemic affects the male reproductive system in both direct and indirect ways.
"Additional studies are necessary to answer all the questions and further investigations are warranted, but ACE2 and TMPRSS2 play an important role in the cellular entry of SARS-CoV-2. Because the male genital system presents high ACE 2 expression, the importance of this pathway increases in COVID-19 cases," she concludes.
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