Does COVID-19 Worsen the Semen Parameters? Early Results of a Tertiary Healthcare Center.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) is a global pandemic which may affect multiple organs and systems including testes and disrupt the gonadal functions. The current study aimed to evaluate the effect of COVID-19 on the semen parameters and sex-related hormone levels in infertile men. METHODS: The study included 21 patients who were evaluated in Ankara City Hospital, Andrology Clinic, for male infertility and have had the diagnosis of COVID-19. All the patients were evaluated in terms of semen parameters. The follicle-stimulating hormone, luteinizing hormone, and testosterone (T) levels were also evaluated in 8 of the patients. The results were presented through 2 dependent group analyses, based on the data of the patients collected before and after the diagnosis of COVID-19. RESULTS: None of the patients needed to be hospitalized at any time through the course of COVID-19. There was a significant decrease in semen volume, percentage of total motility, percentage of progressive motility, and normal sperm morphology after COVID-19 (3 [1-8] vs. 2.5 [1.5-5], p = 0.005; 48.6 ± 22.1 vs. 34.7 ± 20.7, p = 0.001; 35.1 ± 21.7 vs. 21.8 ± 15.9, p < 0.001; 6 [3-24] vs. 5 [3-18], p = 0.015; respectively). There was also a significant decline in T level of the patients after the diagnosis of COVID-19 (350.1 ± 115.5 vs. 289.8 ± 103.3, p = 0.009). CONCLUSION: COVID-19 may have unfavorable effects on the gonadal functions and may lead to further deterioration of the semen parameters in infertile men, which should be considered through the evaluation for infertility.

COVID-19 and male reproductive system: pathogenic features and possible mechanisms.

Multiorgan dysfunction is the main characteristic of severe COVID-19 patients and the involvement of male reproductive system may occur among these patients. Although there is a limited evidence to confirm the orchitis and virus presence in the semen of patients, there are concerns about the transmission of virus through the semen. In addition, reduced fertility or infertility can be seen as consequences of severe COVID-19 in recovered subjects. In this study, we aimed to review articles related to COVID-19 and male reproductive system to find the possible underlying mechanisms of SARS-CoV-2 in affecting male fertility. The following keywords of SARS-CoV-2, COVID-19, testis, orchitis, semen, angiotensin-converting enzyme 2 (ACE2), hypothalamic-pituitary-testicular (HPT) axis, Hypothalamus, etc., were defined to find the related publications from standard search engines, e.g., PUBMED, SCOPUS, Google Scholar. According to studies, COVID-19 occurs in severe patients as respiratory disease, along with multi-organ failure. The most important mechanisms are classified as direct and indirect pathogenesis of SARS-CoV-2. The presence of ACE2 on the cell surface of various cells in testis increases the risk of direct infection by this virus. SARS-CoV-2 also affects the testis through the cytokine storm. In addition, the important role of HPT axis dysregulation through impaired Leydig cells and hypothalamus should be considered. Using antiviral and immunomodulatory therapy can be harmful for testis function. Further investigations are required to investigate potential mechanisms of male infertility in survivals of COVID-19. Since involvement of testis is essential for fertility, increasing the knowledge of health system may improve the outcomes.

The probable destructive mechanisms behind COVID-19 on male reproduction system and fertility.

PURPOSE: The present study aims to summarize the current understanding of probable mechanisms and claims of adverse effects of SARS-CoV-2 on male fertility potential. METHODS: Our search was including original articles, reviews, guidelines, letters to the editor, comments on guidelines, and editorials, regarding the male reproductive system. We used the words SARS-CoV-2, coronavirus, severe acute respiratory syndrome coronavirus 2, "2019 ncov," testis, sperm, male factor infertility, fertility treatment, semen, assisted reproductive technology (ART), sexual transmission, and ACE2. RESULTS: Data showed coronavirus affects men more than women because of more expression of 2019 nCoV receptors (ACE2 and TMPRSS2) in testicular cells. Also, "Bioinformatics Analysis" suggests that sperm production may be damaged, since "Pseudo Time Analysis" has shown disruption in spermatogenesis. "Gene Ontology" (GO) showed an increase in viral reproduction and a decrease in sperm production-related terms. Recently, SARS-COV-2 mRNA and protein were detected in the semen of patients that had recovered from SARS-CoV-2 infection. Therefore, the probable disruption of blood-testis barrier (BTB) in febrile diseases is suspected in the acute phase of the disease enabling viral entry into the testes. Not only is spermatogenesis disturbed, but also disturbs gonadotropin, androgens, and testosterone secretion during SARS-CoV-2 infection. No sexual transmission has been reported yet; however, detection of the virus in semen still makes the sexual transmission an open question. CONCLUSION: There is a concern that male fertility may be disturbed after the SARS-CoV-2 infection. Therefore, follow-up of the reproductive functions and male fertility may be necessary in recovered cases, especially in aged men.

Testicular Atrophy and Hypothalamic Pathology in COVID-19: Possibility of the Incidence of Male Infertility and HPG Axis Abnormalities.

Coronavirus disease 2019 (COVID-19), which resulted from the pandemic outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a massive inflammatory cytokine storm leading to multi-organ damage including that of the brain and testes. While the lungs, heart, and brain are identified as the main targets of SARS-CoV-2-mediated pathogenesis, reports on its testicular infections have been a subject of debate. The brain and testes are physiologically synchronized by the action of gonadotropins and sex steroid hormones. Though the evidence for the presence of the viral particles in the testicular biopsies and semen samples from COVID-19 patients are highly limited, the occurrence of testicular pathology due to abrupt inflammatory responses and hyperthermia has incresingly been evident. The reduced level of testosterone production in COVID-19 is associated with altered secretion of gonadotropins. Moreover, hypothalamic pathology which results from SARS-CoV-2 infection of the brain is also evident in COVID-19 cases. This article revisits and supports the key reports on testicular abnormalities and pathological signatures in the hypothalamus of COVID-19 patients and emphasizes that testicular pathology resulting from inflammation and oxidative stress might lead to infertility in a significant portion of COVID-19 survivors. Further investigations are required to monitor the reproductive health parameters and HPG axis abnormalities related to secondary pathological complications in COVID-19 patients and survivors.

SARS-COV-2 (Covid-19) and male fertility: Where are we?

Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), a single-stranded RNA virus, was found to be the causal agent of the disease called coronavirus disease. During December 2019, China informed the World Health Organization (WHO) of an outbreak of cases of pneumonia of unknown etiology, which caused severe-acute respiratory distress. The disease was termed coronavirus disease 2019 (Covid-19). Due to alarming levels of spread and severity, on the 11th of March 2020, the WHO declared the outbreak as a global pandemic. As of September 14, 2020, more than 29 million cases have been reported, with over 900,000 deaths globally. Since the outbreak, although not conclusive, discoveries have been made regarding the understanding of the epidemiology, etiology, clinical features, clinical treatment, and prevention of the disease. SARS-COV-2 has been detected in saliva, respiratory fluids, blood, urine, and faeces. Findings are however controversial regarding its presence in the semen or the testis. Hence, this review aimed to further analyse the literature concerning (i) the effects of previously identified human coronaviruses on male fertility (ii) the impact of Covid-19 on male fertility and (iii) the implication for general health in terms of infection and transmission.

Testis and blood-testis barrier in Covid-19 infestation: role of angiotensin-converting enzyme 2 in male infertility.

Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) that causes COVID-19 infections penetrates body cells by binding to angiotensin-converting enzyme-2 (ACE2) receptors. Evidence shows that SARS-CoV-2 can also affect the urogenital tract. Hence, it should be given serious attention when treating COVID-19-infected male patients of reproductive age group. Other viruses like HIV, mumps, papilloma and Epstein-Barr can induce viral orchitis, germ cell apoptosis, inflammation and germ cell destruction with attending infertility and tumors. The blood-testis barrier (BTB) and blood-epididymis barrier (BEB) are essential physical barricades in the male reproductive tract located between the blood vessel and seminiferous tubules in the testes. Despite the significant role of these barriers in male reproductive function, studies have shown that a wide range of viruses can still penetrate the barriers and induce testicular dysfunctions. Therefore, this mini-review highlights the role of ACE2 receptors in promoting SARS-CoV-2-induced blood-testis/epididymal barrier infiltration and testicular dysfunction.

Impact of COVID-19 and other viruses on reproductive health.

Male infertility is linked to some viral infections including human papillomavirus (HPV), herpes simplex viruses (HSV) and human immunodeficiency viruses (HIVs). Almost nothing is known about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) effect on fertility. The possible risk factors of coronavirus disease 2019 (COVID-19) infection on fertility comes from the abundance of angiotensin-Converting Enzyme-2 (ACE2), receptor entry of the virus, on testes, a reduction in important sex hormone ratios and COVID-19-associated fever. Recent studies have shown a gender difference for COVID-19 rates and comorbidity. In this review, we will discuss the potential effect of COVID-19 on male fertility and talk about what needs to be done by the scientific community to tackle our limited understanding of the disease. On the other side, we will focus on what is known so far about the risk of COVID-19 on pregnancy, neonatal health and the vertical transfer of the virus between mothers and their neonates. Finally, because reproduction is a human right and infertility is considered a health disease, we will discuss how assisted reproductive clinics can cope with the pandemic and what guidelines they should follow to minimise the risk of viral transmission.

The hypothesis that SARS-CoV-2 affects male reproductive ability by regulating autophagy.

The outbreak of CoronaVirus Disease19 (COVID19) in December 2019 posed a serious threat to public safety, and its rapid spread caused a global health emergency. Clinical data show that in addition to respiratory system damage, some male patients with COVID-19 are also accompanied by abnormal renal function and even renal damage. As the main receptor of syndrome coronavirus 2 (SARS-CoV-2), angiotensin converting enzyme 2 (ACE2) is also found to be highly expressed not only in respiratory mucosa and alveolar epithelial cells, but also in renal tubule cells, testicular Leydig cells and seminiferous tubule cells. This suggests that SARS-CoV-2 has the possibility of infecting the male reproductive system, and the recent detection of SARS-CoV-2 in the patient's semen further confirms this theory. In previous studies, it has been found that ACE2 has the ability to regulate autophagy. Not only that, recent studies have also found that SARS-CoV-2 infection can also lead to a reduction in autophagy. All of these associate SARS-CoV-2 with autophagy. Furthermore, autophagy has been shown to have an effect on male reproduction in many studies. Based on these, we propose the hypothesis that SARS-CoV-2 affects male reproductive function by regulating autophagy. This hypothesis may provide a new idea for future treatment of COVID-19 male patients with reproductive function injury, and it can also prompt medical staff and patients to consciously check their reproductive function.

SARS-CoV-2 and Male Infertility: Possible Multifaceted Pathology.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease 2019 (COVID-19) has been declared a pandemic by the World Health Organization (WHO) on 11th March 2020. Bulk of research on this virus are carried out to unveil its multivariate pathology. Surprisingly, men are reportedly more vulnerable to COVID-19 even with higher fatality rate compared to women. Thus, it is crucial to determine whether SARS-CoV-2 infection can even affect male fertility as an immediate or long-term consequence of the disease. Among the discrete data available, an important finding is that angiotensin converting enzymes 2 (ACE2) receptor, that aids the SARS-CoV-2 entry into host cells, is profoundly expressed in testicular cells. In addition, the endogenous androgen milieu and its receptors are associated with ACE2 activation reflecting that enhanced testosterone levels may trigger the pathogenesis of COVID-19. In contrary, hypogonadism has also been reported in the acute phase of some COVID-19 cases. Moreover, SARS-CoV-2 infection-induced uncontrolled inflammatory responses may lead to systemic oxidative stress (OS), whose severe disruptive effects on testicular functions are well-documented. This article aims to precisely present the possible impact of COVID-19 on male reproductive functions, and to highlight the speculations that need in-depth research for the exact underlying mechanisms how COVID-19 is associated with men's health and fertility.

Could SARS-CoV-2 affect male fertility?

We performed this systematic review to evaluate the possibility of an impact of SARS-CoV-2 infection on male fertility. SARS-CoV-2 enters the cells with the help of ACE2; therefore, testicular expression of ACE2 was analysed from transcriptome sequencing studies and our unpublished data. Literature suggested that SARS-CoV-1 (2002-2004 SARS) had a significant adverse impact on testicular architecture, suggesting a high possibility of the impact of SARS-CoV-2 as well. Out of two studies on semen samples from COVID-19 affected patients, one reported the presence of SARS-CoV-2 in the semen samples while the other denied it, raising conflict about its presence in the semen samples and the possibility of sexual transmission. Our transcriptome sequencing studies on rat testicular germ cells showed ACE expression in rat testicular germ cells. We also found ACE2 expression in transcriptome sequencing data for human spermatozoa, corroborating its presence in the testicular germ cells. Transcriptome sequencing data from literature search revealed ACE2 expression in the germ, Sertoli and Leydig cells. The presence of ACE2 on almost all testicular cells and the report of a significant impact of previous SARS coronavirus on testes suggest that SARS-CoV-2 is highly likely to affect testicular tissue, semen parameters and male fertility.