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.

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.

Potential mechanisms of SARS-CoV-2 action on male gonadal function and fertility: Current status and future prospects.

The novel coronavirus was recognised in December 2019 and caught humanity off guard. The virus employs the angiotensin-converting enzyme 2 (ACE2) receptor for entry into human cells. ACE2 is expressed on different organs, which is raising concern as to whether these organs can be infected by the virus or not. The testis appears to be an organ enriched with levels of ACE2, while the possible mechanisms of involvement of the male reproductive system by SARS-CoV-2 are not fully elucidated. The major focus of the present studies is on the short-term complications of the coronavirus and gains importance on studying the long-term effects, including the possible effects of the virus on the male reproductive system. The aim of this review was to provide new insights into different possible mechanisms of involvement of male gonads with SARS-CoV-2 including investigating the ACE2 axis in testis, hormonal alterations in patients with COVID-19, possible formation of anti-sperm antibodies (ASA) and subsequently immunological infertility as a complication of SARS-CoV-2 infection. Finally, we suggest measuring the sperm DNA fragmentation index (DFI) as a determiner of male fertility impairment in patients with COVID-19 along with other options such as sex-related hormones and semen analysis. Invasion of SARS-CoV-2 to the spermatogonia, Leydig cells and Sertoli cells can lead to sex hormonal alteration and impaired gonadal function. Once infected, changes in ACE2 signalling pathways followed by oxidative stress and inflammation could cause spermatogenesis failure, abnormal sperm motility, DNA fragmentation and male infertility.

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.

The role of Interleukin-4 in COVID-19 associated male infertility - A hypothesis.

COVID-19 is a present-day complex pandemic infection with unpredictable levels of morbidity and mortality in various global populations. COVID-19 is associated with the different comorbidities with its change in biological function such as causing heart dysfunction via deregulating ACE-2 receptor, gastrointestinal risk via causing vomiting, diarrhea, and abdominal pain, chronic kidney disease via proteinuria and hematuria, diabetes mellitus, liver injury via increasing ALT, AST and bilirubin level, lung injury, CNS risk, ocular risk, and cancer risk. In this, we are focused on the COVID-19 connected with male infertility. Some of the studies show that the patients of COVID-19 are associated with impaired spermatogenesis. Impaired spermatogenesis via COVID-19 decreases the level of testosterone by disturbing cytokines such as TNF-α, IL-4, IL-6, and IL-12 and further, attenuates the sperm count. COVID-19 is causing inflammation via TNF-α and interferons. IL-4 plays an eminent role in the activation of the JAK-STAT pathway and leads to the disturbing pro-inflammatory cytokine as well as further cause's male infertility. Th2 activates the IL-4 through IgG and IgE and mediates apoptosis with the triggering of STAT signaling. The activated STAT signaling augments Batf/Irf4, and the Bach2/Batf pathway. On the other hand, SARS-CoV-2 is activating the level of Th2 cells. So, we hypothesized that the augmented Th2 cells would disturb the level of IL-4, JAK-STAT signaling, Batf/Irf4, and Bach2/Batf pathway. The disturbed IL-4 decreases the level of the ACE-2 with the inflammation. This further leads to male infertility in COVID-19 patients. So, in this hypothesis, we focused on the role of IL-4 in COVID-19 patients associated with male infertility via Th2 cells and JAK-STAT signaling.

Coronavirus: A possible cause of reduced male fertility.

In lately December 2019, a novel coronavirus (SARS-CoV-2) outbreak occurred in Wuhan, PR China. It is a high contagious virus that has threatened human health worldwide. SARS-CoV-2 infection, termed COVID-19, causes rapidly developing lung lesions that can lead to multiple organ failure in a short period. Whenever a novel virus emerges, reproductive risk assessments should be performed after infection. In this review, we show that male fertility might be damaged by coronavirus associated with (i) direct cytopathic effects derived from viral replication and viral dissemination in the testis; and (ii) indirect damage to male fertility derived from immunopathology. In this review, we briefly describe the impaired fertility of humans and animals infected with coronaviruses to deduce the impact of the new coronavirus on male fertility. Together with information related to other coronaviruses, we extrapolate this knowledge to the new coronavirus SARS-CoV-2, which may have a significant impact on our understanding of the pathophysiology of this new virus.

SARS-CoV-2 and its relationship with the genitourinary tract: Implications for male reproductive health in the context of COVID-19 pandemic.

BACKGROUND: The current outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, named coronavirus disease 19 (COVID-19), is not the first well-known spillover of an animal originated virus to infect humans. However, one of the few to make such a fast jump in a powerful evolutionary shortcut. The incredible pattern of aggressiveness worldwide since the beginning of the outbreak is that up to 20% of those infected need hospitalization and 5% evolve to critical conditions, not limited to respiratory-related issues, but rather to systemic involvement. OBJECTIVE: This study aims to summarize the current knowledge about the effects of SARS-CoV-2 infection on the male genitourinary tract. MATERIALS AND METHODS: A narrative review was carried out to identify articles on the SARS-CoV-2 infection on the male genitourinary system. RESULTS: Considerations were made about the molecular characteristics of SARS-CoV-2 and immune response to coronavirus. We discussed the influence of the virus on the urinary system, potential mechanisms of COVID-19- related acute kidney injury (AKI), and the role of cytokine release syndrome on the renal pathophysiology of the disease. In the male reproductive tract, it was discussed the testis' vulnerability to SARS-CoV-2 invasion and the possible adverse effects on its function and the seminal findings of COVID-19. DISCUSSION AND CONCLUSION: During the COVID-19 pandemic, an international coordinated scientific effort must arise to understand the role of the urogenital system in the SARS-CoV-2 infection in the clinical setting.

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.

Prior and novel coronaviruses, Coronavirus Disease 2019 (COVID-19), and human reproduction: what is known?

OBJECTIVE: To summarize current understanding of the effects of novel and prior coronaviruses on human reproduction, specifically male and female gametes, and in pregnancy. DESIGN: Review of English publications in PubMed and Embase to April 6, 2020. METHOD(S): Articles were screened for reports including coronavirus, reproduction, pathophysiology, and pregnancy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Reproductive outcomes, effects on gametes, pregnancy outcomes, and neonatal complications. RESULT(S): Seventy-nine reports formed the basis of the review. Coronavirus binding to cells involves the S1 domain of the spike protein to receptors present in reproductive tissues, including angiotensin-converting enzyme-2 (ACE2), CD26, Ezrin, and cyclophilins. Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) may cause severe orchitis leading to germ cell destruction in males. Reports indicate decreased sperm concentration and motility for 72-90 days following Coronavirus Disease 2019 (COVID-19) infection. Gonadotropin-dependent expression of ACE2 was found in human ovaries, but it is unclear whether SARS-Coronavirus 2 (CoV-2) adversely affects female gametogenesis. Evidence suggests that COVID-19 infection has a lower maternal case fatality rate than SARS or Middle East respiratory syndrome (MERS), but anecdotal reports suggest that infected, asymptomatic women may develop respiratory symptoms postpartum. Coronavirus Disease 2019 infections in pregnancy are associated with preterm delivery. Postpartum neonatal transmission from mother to child has been reported. CONCLUSION(S): Coronavirus Disease 2019 infection may affect adversely some pregnant women and their offspring. Additional studies are needed to assess effects of SARS-CoV-2 infection on male and female fertility.

SARS-CoV-2 pandemic and repercussions for male infertility patients: A proposal for the individualized provision of andrological services.

The prolonged lockdown of health facilities providing non-urgent gamete cryopreservation-as currently recommended by many reproductive medicine entities and regulatory authorities due to the SARS-CoV-2 pandemic will be detrimental for subgroups of male infertility patients. We believe the existing recommendations should be promptly modified and propose that the same permissive approach for sperm banking granted for men with cancer is expanded to other groups of vulnerable patients. These groups include infertility patients (eg, azoospermic and cryptozoospermic) undergoing medical or surgical treatment to improve sperm quantity and quality, as well as males of reproductive age affected by inflammatory and systemic auto-immune diseases who are about to start treatment with gonadotoxic drugs or who are under remission. In both scenarios, the "fertility window" may be transitory; postponing diagnostic semen analysis and sperm banking in these men could compromise the prospects of biological parenthood. Moreover, we provide recommendations on how to continue the provision of andrological services in a considered manner and a safe environment. Our opinion is timely and relevant given the fact that fertility services are currently rated as of low priority in most countries.