The impact of coronavirus infection COVID-19 on the development of male infertility

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Introduction. A few years ago, the world faced an unprecedented challenge – the COVID-19 pandemic, caused by a new member of the coronavirus family. This virus can provokevarious pathological phenomena in организмthe human body, including disability and death. There is some evidence, свидетельствующих that влиянии COVID-19COVID-19 affects men'sreproductive functionю, which can lead to reduced or lost fertility.

Purpose of the work. Consider theimpactof COVID-19 coronavirus infection on the human body and the development of male infertility.

МMaterials and research methods. Analysis of scientific publications concerning the structure of SARS-CoV-2, its impact on human anatomophysiological features and pathogenesis of infertility caused by COVID-19 infection.

Architecture of the SARS-CoV-2 virus. Вирионы Coronavirus virions are described as sphericalsupercapsid суперкапсидныеformationsbordered by spikes on their surface, known as S-proteins, under which there is a layer of hemagglutinin-esterase envelope (HE). These elements (HE and S) play a key role in establishing a reliable connection with target cells, and they improve the process of viral RNA transmission. Most of the virus ' genetic information is stored in RNA polymerase, which binds to angiotensinconverting enzyme II (APF-II) through the aforementioned protein structures, leading to activation of the receptor-binding domain (RBD), the target zone for host antibodies. This interaction explains the process of proteolytic cleavage of S-protein [1].

The process of virus replication. When контактеthe membranes of the virus and the target cell come into contact, a complex is formed that begins to act as mRNA for protein synthesis. The presence of open reading frames in the virus genome simplifies this process. Further, viral assembly occurs in the endoplasmic reticulum and Golgi apparatus, after which экзоцитозаnewly formed virions are transported and released into the intercellular space through the exocytosis mechanism [1].

Coronaviruses mainly attack cells of the alveolar epithelium of the lungs, where they actively multiply. They increase the permeability of the membranes, contributing to increased transportation of liquids, which leads to damage to the surfactant layer, vital for normal gas exchange in the lungs. This process can cause the development of acute respiratory distresssyndrome. The reduced effectiveness of the patient's immune system worsens the problem, facilitating the penetration and spread of fungalinfections of the respiratory tract. As presented in the research, the key mechanism of viral entry into the cell is the binding of the viral S-protein to angiotensin-converting enzyme-2 (APF-II), found in various cell types, including type II alveolar cells, cardiomyocytes, nephron elements, gastrointestinal epithelial cells and urothelial cells. It is important to notethat APF-II is also found in spermatogenic epithelium, indicating its high expression in Leydig and Sertolli cells, which underlines its diverse role in the body [2].

Effect of SARS-CoV-2 on testicular structures. Scientific studies show that 16% of testicular tissue samples were found to contain the SARS-CoV-2 virus. This indicates the potential ability of the virus to spread through sexual contact. Detection of SARS-CoV-2 can trigger the development of inflammatory diseases of the reproductive system, such as orchitis (inflammation of the testicle) and epididymitis (inflammation of the epididymis). SARS-CoV-2 is a highly pathogenic form that can provoke the releaseof a large number of cytokines: Interleukin-6, 10, 12 (IL-6, 10, 12), interleukin-like tumor necrosis factor (TNF-α), interferon-γ (IFNy). These substances increase the pathogenic effect of the virus, which leads to the destruction of the hematotesticular, blood-brain and, as a result, the immune barrier. This effect leads to disruption of spermatogenesis and detachment of the basement membrane of the spermatogenic epithelium [2].

As part of a research study conducted at Justus-Liebig University, the effects of the SARS-CoV-2 virus on the male reproductive system were identified. A significant decrease in the concentration of testosterone, a key male fertility hormone, was found from an average of 5.13-30.43 nmol/ L to a level exceeding a twofold decrease in more than half of the study participants. Such a reduction is associated with a violation of the Leydig cells,which are responsible for the synthesis of testosterone. Scientific studies conducted by specialists of the Department of Urology of the First St. Petersburg State Medical University named after Academician I.P. Pavlov have revealed that in COVID-19, the risk of hypogonadism and a decrease in the quality characteristics of sperm may increase due to an increase in the level of reactive oxygen species (oxidative stress). This is directly related to a malfunction in the functioning of the body's antioxidant defense system, which makes it difficult to effectively counteract reactive oxygen species [3].

Scientists from Миссурийскогоthe University of Missouri studied the relationship between serum testosterone concentrations, interleukin-6 and C-reactive protein and the severity of COVID-19. All indicators were measured on the day of hospitalization, as well as on the 3rd, 7th, 14th and 28th days after admission to the hospital. We also compared the baseline values of hormones in patients with severe and mild course of the disease. The study involved 66 men with severe COVID-19. The median testosterone concentration on the day of hospitalization in these patients was 53 ng/dl, while on the third day it increased to 151 ng/dl (p = 0.01). In addition, the testosterone concentration was inversely proportional to the level of interleukin-6 and C-reactive protein. In patients with severe COVID-19, testosterone levels were restored to baseline values by day 14 of follow-up. The results of the study showed that men with a severe form of COVID-19 disease had 65-85-% lower testosterone levels than men witha mild course of the disease [4].

Spanish studies have also shown that serum testosterone levels are a highly effective predictor of survival among men with COVID-19. This confirms that coronavirus infection can significantly changethe hormonal profile of the patient [5].

The clinical picture of the disease and the patient's age have a significant impact on the degree of damage to Leydig cells under the influence of this virus. This process is caused by the production of transmembrane serine protease (TMPRSS2), which facilitates endocytosis of SARS-CoV-2. As a result, the development of stable erectile dysfunction is observed in approximately у20% of the subjects. In addition, SARS-CoV-2 has the ability to reduce the tone of the vascular wall, which affects the prolongation of the disease. The Institute of Urology and Reproductive Medicine of Sechenov University revealed deterioration of testicular functions and the development of their pathological conditions, in particular: obstruction ofthe basement membrane of the seminal tubules, causing a violationof spermatogenesis due to their obstruction; desquamation ofthe spermatogenic epithelium of the testicle; disruption ofspermatogenesis [3].

Coagulation disorders in SARS-CoV-2 and the effect on GTB. At the moment, the pathogenesis ofCovid-19 includes such an important aspect as disorders in the hemostatic system. Against the background of active cytokine expression and complement activation развивается , hypercoagulation develops, hypoxia induces гиперактивностьplatelet hyperactivity, which is a direct cause of thrombosis. Normally, a healthy endothelium produces anticoagulant factors such as NO, antithrombin, etc. Against the background of SARS-CoV-2, endotheliopathies developэндотелиопатии, whichalso contributes to hypercoagulation [6]. Such a cascade of reactions increases the permeability of blood vessels, including testicular capillaries, a component of the hematotesticular barrier (GTB). GTB consists of capillary endothelium, its continuous basement membrane, pericytes, myoid cells, and tight junctions of sustentocytes. As a result of damage to the endothelium and Sertolli cellsСертолли, hyperpenetrability of GTB develops, which is also an aspect of testicular damageand impaired spermatogenesis [7].

Conclusion. Thus, it can be noted that exposure to the SARS-CoV-2 virus leads to a significant decrease in the function of the male reproductive system. The main impact area is damage to Leydig cells, which are responsible for the production of the hormone testosterone. In situations where the disease is severe, histohematic barriers are destroyed, resulting in inflammation of the testes (orchitis) and epididymis (epididymitis), which are the leading factors in the development of male infertility. Dueto damage to the spermatogenic epithelium, the process of spermatogenesis is disrupted, which leads to the appearance of atypical spermatozoa. In addition, there is a development of hypogonadism and a drop in blood vessel tone, which causes the appearance of persistent erectile dysfunction. In some cases, abnormalities in the structure of the spermatic cords are recorded: there is a detachment of spermatogenic epithelial cells and their basement membrane, which leads to blocking of passages in the spermatic cords.

Also, the condition is significantly complicated by fever and the development of distresssyndrome: fever, decreased saturation, гиперкоагуляцииblood hypercoagulation, etc.. All this has a pronounced gonadotoxic effect and can cause multiple inflammatory processes.

About the authors

Nikita A. Kombarov

Voronezh State Medical University named after N. N. Burdenko

Email: nik_kombarov@mail.ru
ORCID iD: 0009-0007-2712-685X
SPIN-code: 5978-5624
ResearcherId: MIN-7401-2025

Student of the Faculty of Medicine

Russian Federation, 394036, Russia, Voronezh, Studencheskaya str., 10

Olesya V. Lidokhova

Voronezh State Medical University named after N.N. Burdenko

Author for correspondence.
Email: lidokhova@mail.ru
ORCID iD: 0000-0002-7766-066X
SPIN-code: 9211-9344

Candidate of Biological Sciences, Associate Professor of the Department of Pathological Physiology of Voronezh State Medical University named after N.N. Burdenko

394036, Russia, Voronezh, 10 Studencheskaya str.

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