Microbiology and immune mechanisms associated with male infertility.

Up to 50% of infertility is caused by the male side. Varicocele, orchitis, prostatitis, oligospermia, asthenospermia, and azoospermia are common causes of impaired male reproductive function and male infertility. In recent years, more and more studies have shown that microorganisms play an increasingly important role in the occurrence of these diseases. This review will discuss the microbiological changes associated with male infertility from the perspective of etiology, and how microorganisms affect the normal function of the male reproductive system through immune mechanisms. Linking male infertility with microbiome and immunomics can help us recognize the immune response under different disease states, providing more targeted immune target therapy for these diseases, and even the possibility of combined immunotherapy and microbial therapy for male infertility.

COVID-19 and Male Reproduction: A Thorny Problem.

With the global epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the increasing number of infections, little is known about how SARS-CoV-2 affects the male reproductive system during infection or after recovery. Based on the existing research data, we reviewed the effects of SARS-CoV-2 on the male reproductive system and discussed its possible mechanism of action. SARS-CoV-2 enters host cells through the angiotensin-converting enzyme 2 (ACE2)/transmembrane serine protease 2 (TMPRSS2) pathway, and males are more susceptible than females. After infection, immunopathological damage is noticed in the testicles, and the semen index is significantly reduced. Second, abnormalities of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) levels were also observed, suggesting that there may be dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis. Even after recovery, the effect of SARS-CoV-2 on the male reproductive system can last for at least a period. There are still many unresolved questions about the effect of SARS-CoV-2 infection on the male reproductive tract. Other receptors involved during the invasion of human cells by SARS-CoV-2 remain to be identified. Will the mutation of SARS-CoV-2 increase the diversity of receptors? How does SARS-CoV-2 affect the HPG axis? The long-term effects of SARS-CoV-2 on the male reproductive system remain to be evaluated. SARS-CoV-2 infection can affect male reproductive function. Standard treatment strategies should be developed in time to protect the fertility of infected patients. For recovered patients with fertility requirements, fertility assessments should be performed and professional fertility guidance should be provided at the same time.

Update on COVID-19 and histophysiology of the male reproductive system / Actualización sobre COVID-19 e histofisiología del sistema reproductor masculino

RESUMEN: La reciente pandemia de la COVID-19 ha sacudido a la sociedad teniendo una importante repercusión en el campo de la salud y de la investigación. Dada su relevancia, se han llevado a cabo estudios sobre los efectos del SARS-CoV-2 en la fisiología humana. En concreto, sobre la posible presencia y transmisión del virus a través del sistema reproductor masculino y su posible efecto en el éxito reproductivo. Conocer si la presencia del virus altera los órganos responsables del desarrollo y maduración de las células de la serie espermatogénica podría revelarnos su implicación en la calidad seminal. Por ello, nos planteamos esta revisión, con el fin de analizar las principales evidencias científicas sobre los efectos del SARS-CoV-2 en la histofisiología del sistema reproductor masculino y sobre la capacidad fecundante de los espermatozoides.

SUMMARY: The recent COVID-19 pandemic has shaken up society, having a significant impact on the field of health and research. Given its relevance, studies have been performed on the effects of SARS-CoV-2 on human physiology. In particular, the possible presence and transmission of the virus through the male reproductive system could affect reproductive success. Knowing if the presence of the virus disrupts the organs responsible for the development and maturation of the cell lines involved in spermatogenesis could reveal its implications in sperm quality. For that reason, we proposed this review, in order to analyze the main scientific evidence on the effects of SARS-CoV-2 on the histophysiology of the male reproductive system and sperm fertilizing capacity.

Male reproductive system inflammation after healing from coronavirus disease 2019.

BACKGROUND: There is evidence that, after severe acute respiratory syndrome coronavirus 2 infection, male reproductive function and semen quality may be damaged OBJECTIVES: To evaluate a panel of inflammatory mediators in semen in patients recovered from coronavirus disease 2019. MATERIAL AND METHODS: Sexually active men with previous severe acute respiratory syndrome coronavirus 2 infection and proven recovery from coronavirus disease 2019 were enrolled in a prospective cohort study. Clinical, uro-andrological data and semen specimens were prospectively collected. For previously hospitalized coronavirus disease 2019 patients, data on serum inflammatory markers were retrospectively collected. RESULTS: A total of 43 men were enrolled in the study. Of these, 32 men were normozoospermic, three were oligozoospermic, and eight were crypto-azoospermic. Serum inflammatory markers (procalcitonin and C-reactive protein) were analyzed in previously hospitalized patients both at admission and at peak of infection. Levels at admission were statistically significantly higher in patients resulting in crypto-azoospermic with respect to those resulting in normozoospermic (p = 0.05; p = 0.03 and p = 0.02, respectively) after healing. Seminal cytokine levels were similar among all groups. Interleukin-1ß and tumor necrosis factor-α levels were significantly negatively related to sperm total number and concentration, whereas interleukin-4 was correlated with sperm motility. DISCUSSION AND CONCLUSION: Negative correlations between interleukin-1ß and tumor necrosis factor-α and sperm number and the overall high levels of semen cytokines indicate a potential detrimental role of severe acute respiratory syndrome coronavirus 2 driven inflammation on spermatogenesis. Overall, our results indicate that male patients recovering from coronavirus disease 2019 deserve accurate follow-up for their fertility status.

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.

Effect of COVID-19 on Male Reproductive System - A Systematic Review.

Background: Angiotensin-converting enzyme II (ACE2), a receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) to enter host cells, is widely expressed in testes and prostate tissues. The testis and prostate produce semen. At present, there are contradictory reports about whether SARS-CoV-2 can exist in the semen of infected men. Objective: To provide a comprehensive overview of the topic of whether COVID-19 can impact on male reproductive system. Methods: We reviewed the relevant publications on the possible impact of Coronavirus Disease 2019 (COVID-19) on male reproductive system and summarized the latest and most important research results so far. Literature published in English from December 2019 to January 31, 2021 regarding the existence of SARS-CoV-2 in semen, testis, and prostatic fluid and the effects of COVID-19 on male reproductive were included. Results: We identified 28 related studies, only one of which reported the presence of SARS-CoV-2 in semen. The study found that the semen quality of patients with moderate infection was lower than that of patients with mild infection and healthy controls. The impaired semen quality may be related to fever and inflammation. Pathological analysis of the testis/epididymis showed that SARS-CoV-2 viral particles were positive in 10 testicular samples, and the spermatogenic function of the testis was impaired. All 94 expressed prostatic secretion (EPS) samples were negative for SARS-CoV-2 RNA. Conclusion: The likelihood of SARS-CoV-2 in the semen of COVID-19 patients is very small, and semen should rarely be regarded as a carrier of SARS-CoV-2 genetic material. However, COVID-19 may cause testicular spermatogenic dysfunction via immune or inflammatory reactions. Long-term follow-up is needed for COVID-19 male patients and fetuses conceived during the father's infection period.

Current status of the COVID-19 and male reproduction: A review of the literature.

BACKGROUND: Coronavirus disease 2019 (COVID-19), which causes serious respiratory illnesses such as pneumonia and lung failure, was first reported in mid-December 2019 in China and has spread around the world. In addition to causing serious respiratory illnesses such as pneumonia and lung failure, there have been conflicting reports about the presence of SARS-CoV-2 in the semen of patients who were previously diagnosed with COVID-19 and possible implications for the male reproductive tract. OBJECTIVE: The goal for the present study was to review the current status of the literature concerning COVID-19 and male reproduction. MATERIAL AND METHODS: An electronic literature search was done by using PubMed and Google Scholar databases. Relevant papers, concerning SARS-COV-2 and COVID-19 and male reproduction, published between January 2020 and December 2020 were selected, analyzed and eventually included in the present literature review. RESULTS: SARS-CoV-2 may infect any cell type expressing angiotensin-converting enzyme 2 (ACE2), including reproductive cells. Besides the presence of the SARS-CoV-2 receptor, the expression of host proteases, such as transmembrane serine protease 2 (TMPRSS2), is needed to cleave the viral S protein, allowing permanent fusion of the viral and host cell membranes. Here, we aimed to review the current status of the literature concerning COVID-19 and male reproduction. The lack of co-expression of ACE2 and TMPRSS2 in the testis suggests that sperm cells may not be at increased risk of viral entry and spread. However, the presence of orchitis in COVID-19-confirmed patients and compromised sex-related hormonal balance among these patients intrigues reproductive medicine. DISCUSSION: SARS-CoV-2 may use alternate receptors to enter certain cell types, or the expression of ACE2 and TMPRSS2 may not be detected in healthy individuals. CONCLUSION: COVID-19 challenges all medical areas, including reproductive medicine. It is not yet clear what effects, if any, the COVID-19 pandemic will have on male reproduction. Further research is needed to understand the long-term impact of SARS-CoV-2 on male reproductive function.

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.

SARS-CoV-2 infection affects the lower urinary tract and male genital system: A systematic review.

PubMed, Scopus, and ISI Web of Knowledge databases were searched to identify studies published up to December 2020 on the involvement of urinary and male genital systems in COVID-19. Sixteen studies involving a total of 575 patients (538 males and 37 females) were included in this systematic review. The COVID-19 phase was available for 479 patients: 426 in the acute and 53 in the recovery phase. De novo lower urinary tract symptoms (LUTS) were observed in 43 patients and deterioration of pre-existing LUTS in 7. Bladder hemorrhage was observed in three patients and acute urinary retention in one. Regarding the male genital system, scrotal discomfort was observed in 8 patients, swelling in 14, pain in 16, and erythema in 1; low flow priapism was observed in 2 patients. Ultrasound examination identified acute orchitis in 10 patients, acute epididymitis in 7, and acute epididymo-orchitis in 16. A case-control study reported that patients with moderate COVID-19 show a significant reduction in sperm concertation, the total number of sperms per ejaculate, progressive motility, and complete motility. In contrast to what is known from the first studies on the subject, this review also includes subsequent studies that give evidence of the involvement of the lower urinary tract and male genital system in COVID-19.

The other side of COVID-19 pandemic: Effects on male fertility.

The outbreak of novel coronavirus disease 2019 (COVID-19) has become a major pandemic threat worldwide. According to the existing clinical data, this virus not only causes respiratory diseases and affects the lungs but also induces histopathological or functional changes in various organs like the testis and also the male genital tract. The renin-angiotensin system (RAS), also ACE 2 and TMPRSS2 play an important role in the cellular entry for SARS-CoV-2. Because the male genital system presents high ACE 2 expression, the importance of this pathway increases in COVID-19 cases. As the COVID-19 pandemic has affected the male genital system in direct or indirect ways and showed a negative impact on male reproduction, this paper focuses on the possible mechanisms underlying the damage caused by COVID-19 to the testis and also other components of the male genital tract.

Physiological implications of COVID-19 in reproduction: angiotensin-converting enzyme 2 a key player.

The COVID-19 outbreak, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was first identified in China, and it has quickly become a global threat to public health due to its rapid rate of transmission and fatalities. Angiotensin-converting enzyme 2 (ACE2) has been identified as a receptor that mediates the entry of SARS-CoV-2 into human cells, as in the case of severe acute respiratory syndrome coronavirus (SARS-CoV). Several studies have reported that ACE2 expression is higher in Leydig, Sertoli and seminiferous ductal cells of males, as well as in ovarian follicle cells of females, suggesting possible potential pathogenicity of the coronavirus in the reproductive system. Higher ACE2 expression in the human placenta and reports of vertical transmission of SARS-CoV-2 among clinical cases have increased the relevance of further studies in this area. This review focuses on the interaction between SARS-CoV-2 and the ACE2 receptor and speculates on the mechanistic interplay in association with male and female reproductive physiology. In addition, based on the available literature, we discuss the alleged sex differences in terms of the infectivity of SARS-CoV-2, which is claimed greater among males, and further explore the physiological role of ACE2 and 17ß-oestradiol for the same.

COVID-19 and male fertility: Taking stock of one year after the outbreak began.

OBJECTIVES: The aim of this review is to summarize, following a timeline, the current knowledge regarding the effects of the Sars-cov2 virus on male fertility, researching the pathological and clinical results of the studies published in the last year. METHODS: A systematic research was performed on the major international online databases; Thirty-five articles were selected. RESULTS: A statistically significant reduction in testosterone levels and sperm quality in subjects with COVID-19 has been highlighted in several papers; however, in many cases the tests have been conducted in patients with active disease and long-term consequences are still not known. Some studies have confirmed the presence of the virus in the testis in a low percentage of patients; viral presence in sperm has only been found in one study. Testicular discomfort, which could indicate viral orchitis, was highlighted in several works, with an incidence of up to 19% percent of patients. The presence of inflammatory lymphocytic infiltrates, IgG and inflammatory cytokines have been documented in several works; pathological signs of inflammation were found in 60.9% of testicular biopsies performed in one study. The entry of the virus into the testis cells, both stromal and seminal cells appeared to be Angiotensin Converting Enzyme-2 (ACE2) mediated, as it also occurs in other tissues. DNA fragmentation, reactive oxygen species (ROS) formation, autoantibody production and ACE2 mediated effect have all been hypothesized as cause of cellular damage. CONCLUSIONS: The results on effects of COVID-19 infection on the male reproductive system are currently insufficient as they are based on a small number of patients and therefore are often contradictory.Certain mechanisms of testicular damage are still to be assessed, as any risk categories like age, ethnicity, or others. As for the transmission of the virus through sperm, there is insufficient evidence to ensure that this cannot happen.

Review of COVID-19 and male genital tract.

COVID-19 pandemic leads to health challenges globally, and its diverse aspects need to be uncovered. Multi-organ injuries have been reported by describing potential SARS-CoV-2 entrance routes: ACE2 and TMPRSS2. Since these cell surface receptors' expression has been disclosed within the male reproductive system, its susceptibility to being infected by SARS-CoV-2 has been summarised through this literature review. Expression of ACE2 and TMPRSS2 at RNA or protein level has been reported across various investigations indicates that the male genitalia potentially is vulnerable to SARS-CoV-2 infection. Presence of SARS-CoV-2 within semen samples and following direct viral damage, secondary inflammatory response causing orchitis or testicular discomfort and finally the amount of viral load leading testicular damage and immune response activation are among probable underlying mechanisms. Therefore, genital examination and laboratory tests should be considered to address the male reproductive tract complications and fertility issues.

Relationship between COVID-19 and the male reproductive system.

OBJECTIVE: The objective of this review is to provide currently available information on the potential effects of coronavirus disease 2019 (COVID-19) on male fertility. MATERIALS AND METHODS: This is a mini-review. Due to the similarity between the COVID-19 and severe acute respiratory syndrome (SARS) virus, we searched for the following keywords: "SARS-CoV, male reproductive system, infertility, COVID-19, SARS-CoV-2, and orchitis". By reviewing and analyzing the literature, we analyzed the influence of temperature on sperm, the expression of angiotensin-converting enzyme 2 (ACE2) in the testes, and the impact of SARS-CoV-2 on the male reproductive system. RESULTS: SARS-CoV-2 enters the body through the ACE2 receptor. The high expression of ACE2 on the surface of spermatogonia and supporting cells in the testes, as well as the immune response caused by COVID-19, can lead to testicular spermatogenesis dysfunction and reduced sperm count. CONCLUSIONS: COVID-19 infection can affect male reproductive function, and standard treatment strategies should be established in time to help male patients infected with COVID-19.

COVID-19 Infection in the Human Reproductive Tract of Men and Nonpregnant Women.

SARS-CoV-2 is an enveloped non-segmented positive-sense RNA virus, classified as a beta coronavirus, responsible for the COVID-19 pandemic. Angiotensin-converting enzyme 2 (ACE2), reported as a SARS-CoV-2 receptor, is expressed in different human tissues (lung, intestine, and kidney) and in the testis, ovaries, uterus, and vagina. This suggests a potential risk to the human reproductive tract in COVID-19 patients. In addition, SARS-CoV-2 RNA has been detected in the blood, urine, facial/anal swabs, semen, and vaginal secretion, suggesting other potential means of transmission. However, little has been reported about SARS-CoV-2 infection in the male and nonpregnant female reproductive tracts, which may provide direct evidence on sexual transmission and fertility problems. Therefore, we focused this narrative review mainly on the distribution of ACE2 and SARS-CoV-2 positivity in the male and nonpregnant female reproductive tracts, providing an overview of the potential threat of COVID-19 to reproductive health and sexual transmission.

The impact of SARS-CoV-2 and COVID-19 on male reproduction and men's health.

Many couples initially deferred attempts at pregnancy or delayed fertility care due to concerns about coronavirus disease 2019 (COVID-19). One significant fear during the COVID-19 pandemic was the possibility of sexual transmission. Many couples have since resumed fertility care while accepting the various uncertainties associated with severe acute respiratory syndrome coronavirus 2, including the evolving knowledge related to male reproductive health. Significant research has been conducted exploring viral shedding, tropism, sexual transmission, the impact of male reproductive hormones, and possible implications to semen quality. However, to date, limited definitive evidence exists regarding many of these aspects, creating a challenging landscape for both patients and physicians to obtain and provide the best clinical care. This review provides a comprehensive assessment of the evolving literature concerning COVID-19 and male sexual and reproductive health, and guidance for patient counseling.