Prospective Two-arm Study of Fertility in Men With COVID-19

In late December 2019, the Chinese city of Wuhan witnessed the emergence of a form of
pneumonia of unknown etiology. By the middle of January 2020, the disease had managed to
spread beyond the country of origin and is now classified by the WHO as the largest pandemic
in modern history.

Rapidly spreading and highly contagious, the infection prompted medical professionals all
over the world to begin research into the virus with the goal of developing early diagnostic
techniques and treatment strategies.

The new pathogen named SARS-Cov-2 belongs to the Coronaviridae family. These viruses cause
severe acute respiratory syndrome (SARS-CoV-1, 2002-2003) and Middle East respiratory
syndrome (MERS, 2012-2013).

The effects of SARS-CoV-2 on the human body stem from its structure. The spike proteins on
the surface of the virus, which are responsible for the name "Coronaviridae," means that it
is able to bind to the host receptor protein, angiotensin-converting enzyme 2 (ACE2). This
makes cells with high quantities of these receptors on the surface susceptible to the virus.

The genome of SARS-Cov-2 responsible for the COVID-19 pandemic contains both human
coronavirus fragments and bat coronavirus fragments (HKU9-1). It is the genetic material of
HKU9-1 that makes SARS-CoV-2 unknown to the immune system of the human body.

As of today, three transmission pathways are recognized: close contact, airborne and fomite.
Moreover, the virus is known to retain its contagious properties on surfaces for up to 72
hours, and the incubation period ranges between 2 and 14 days. Recent reports indicate that
up to 80% of those infected by COVID-19 showed mild or moderate symptoms whereas 20-30%
develop severe forms of the disease characterized by shock as well as respiratory and
multiple organ failure. According to Chinese and Italian healthcare providers, the mortality
rate is between 3.8 and 7.2%.

Zou et al. (2020) reported that non-respiratory symptoms may be explained by the binding of
the virus to ACE-2 in other organs. Shen and Wang (2020) proved that ACE-2 is also expressed
by testicular cells (namely spermatogonia, Leydig cells and Sertoli cells) which makes them
potential targets for the virus. In fact, there are reports of orchitis and epididymitis in
patients diagnosed with COVID-19. This means that SARS-CoV-2 may directly damage testicular
tissue potentially compromising male fertility.

In a number of studies, PCR did not detect the virus in semen samples obtained during both
the acute phase and recovery phase. In another study, postmortem needle and open biopsies of
the testicles performed within an hour after death from COVID-19 revealed that testicular
tissues were free of SARS-CoV-2 in 10 of 11 cases (91%). At the same time, spermograms in
COVID-19 patients showed low ejaculate volume, sperm motility and sperm count. Previously, it
was shown that COVID-19 has a severe effect on vasculature and therefore a microthrombi could
be a possible contributor to fertility impairment. An assessment of testes with a Doppler
enhanced ultrasound was therefore necessary.

Data dedicated to testosterone levels in the blood and inflammatory markers in the semen and
testicular tissues is lacking. Available literature indicates changes in the above-mentioned
parameters in males with verified COVID-19.

There is ultimately too little information to draw reliable conclusions regarding the effects
of the virus on male reproduction. Published reports are limited by small study groups, lack
of the control group and absence of follow-up examinations during recovery warranting further
research and in-depth exploration of the topic.