COVID-19 and hypogonadism: secondary immune responses rule-over endocrine mechanisms.

Men show higher vulnerability to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection (COVID-19) and present with depleted testosterone levels. Reports pertaining to high luteinizing hormone (LH), while diminished levels of in COVID-19 patients negate the hypothalamic-pituitary-testicular (HPT) axis mediated lowering of testosterone. Although not evidenced, high testicular expression of angiotensin-converting enzymes-2 (ACE2), that aids viral entry into cells, may suggest direct viral-testicular invasion. However, secondary inflammation and oxidative stress (OS), owing to SARS-CoV-2 infection, are more likely to impair steroidogenesis. Moreover, blockage of ACE2 aided angiotensin II into angiotensin (1-7) conversion may also affect testosterone synthesis. SARS-CoV-2, by mimicking adrenocorticotrophic (ACTH) hormones, may trigger host antibodies against the ACTH molecules to suppress host stress response. This commentary concisely presents the possible mechanisms by which SARS-CoV-2 infection may affect testosterone levels, which possibly result in compromised male reproductive health.

Vulnerability of The Male Reproductive System to SARS-CoV-2 Invasion: Potential Role for The Endoplasmic Reticulum Chaperone Grp78/HSPA5/BiP.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may adversely affect male reproductive tissues and male
fertility. This concern is elicited by the higher susceptibility and mortality rate of men to the SARS-CoV-2 mediated coronavirus disease-19 (COVID-19), compared to the women. SARS-CoV-2 enters host cells after binding to a functional receptor named angiotensin-converting enzyme-2 (ACE2) and then replicates in the host cells and gets released into the plasma. SARS-CoVs use the endoplasmic reticulum (ER) as a site for viral protein synthesis and processing, as well as glucose-regulated protein 78 (Grp78) is a key ER chaperone involved in protein folding by preventing newly synthesized proteins from aggregation.
Therefore, we analyzed Grp78 expression in various human organs, particularly male reproductive organs, using Broad
Institute Cancer Cell Line Encyclopedia (CCLE), the Genotype-Tissue Expression (GTEx), and Human Protein Atlas online
datasets. Grp78 is expressed in male reproductive tissues such as the testis, epididymis, prostate, and seminal vesicle. It can facilitate the coronavirus entry into the male reproductive tract, providing an opportunity for its replication. This link between the SARS-CoV-2 and the Grp78 protein could become a therapeutic target to mitigate its harmful effects on male fertility.

N-acetyl cysteine as a potential regulator of SARS-CoV-2-induced male reproductive disruptions.

Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), has shown its persistent pandemic strength. This viral infectivity, kinetics, and the mechanisms of its actions in human body are still not completely understood. In addition, the infectivity and COVID-19 severity reportedly differ with patient's gender with men being more susceptible to the disease. Thus, different studies have also suggested the adverse impact of COVID-19 on male reproductive functions, mainly emphasizing on high expressions of angiotensin-converting enzyme 2 (ACE2) in the testes that allows the viral entry into the cells. Main body: The N-acetylcysteine (NAC), a potent therapeutic agent of COVID-19, may be effective in reducing the impairing impacts of this disease on male reproductive functions. NAC acts as mucolytic agent by reducing sulfide bonds in the cross-linked glycoprotein matrix in mucus owing to its free sulfhydryl group. Since NAC also breaks the viral disulfide bonds required for the host cell invasion, it may help to prevent direct SARS-CoV-2 invasion into the testicular cells as well. NAC also acts as a potent anti-inflammatory and antioxidant, directly scavenging reactive oxygen species (ROS) and regulating the redox state by maintaining the thiol pool being a precursor of cysteine (an essential substrate for glutathione synthesis). Since it is suggested that male reproductive impairment in COVID-19 patient may be caused by secondary immune responses owing to systemic inflammation and OS, the anti-inflammatory and antioxidant properties of NAC explained above may attribute in protecting the male reproduction functions from these COVID-19-mediated damages. Conclusion: This article explains the mechanisms how NAC treatment for COVID-19 may prevent the infection-mediated disruptions in male reproduction.

COVID-19, Oxidative Stress and Male Reproduction: Possible Role of Antioxidants.

Coronavirus disease 2019 (COVID-19) involves a complex pathogenesis and with the evolving novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the long-term impacts of the unceasing COVID-19 pandemic are mostly uncertain. Evidence indicates deleterious impact of this disease upon male reproductive health. It is concerning that COVID-19 may contribute to the already global declining trend of male fertility. The adverse impacts of COVID-19 on male reproduction may primarily be attributed to the induction of systemic inflammatory responses and oxidative stress (OS), which operate as a vicious loop. Bringing the systemic inflammation to a halt is critical for 'putting out' the 'cytokine storm' induced by excessive reactive oxygen species (ROS) generation. The possibility of OS playing a prime role in COVID-19-mediated male reproductive dysfunctions has led to the advocacy of antioxidant therapy. An array of antioxidant defense medications has shown to be effective in experimental and clinical studies of COVID-19. The present review thus discusses the possibilities as to whether antioxidant drugs would contribute to combating the SARS-CoV-2 infection-induced male reproductive disruptions, thereby aiming at kindling research ideas that are needed for identification and treatment of COVID-19-mediated male reproductive impairments.

The impact of COVID-19 on the male reproductive tract and fertility: A systematic review.

OBJECTIVE: The COVID-19 pandemic, caused by the acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), remains an ongoing public health challenge. Although males are affected slightly more than females, the impact of SARS-COV-2 on male reproductive system remains unclear. This systematic review aims to provide a concise update on the effects of COVID-19 on male reproductive health, including the presence of viral RNA in semen, and the impact on semen quality, testicular histology, testicular pain and male reproductive hormones. The global health is fronting an immediate as well as impending threat from the novel coronavirus (SARS-CoV-2) causing coronavirus disease (COVID-19), that inflicts more males than females. Evidence suggest that male reproductive system is susceptible to this viral infection. However, there are still several pertinent queries that remain to be fully explained regarding the mechanism in testicular SARS-CoV-2 dynamics and the exact mode of its actions. Thus, the present systematic review aims to provide a concise update on the effects of coronavirus disease 2019 (COVID-19) on male reproduction.. METHODS: A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines searching the PubMed database. Eligibility for inclusion were original human studies evaluating the impact of COVID-19 on male reproductive health. Specific outcomes required for inclusion were at least one of the following: i) seminal detection of mRNA virus, or evaluation of ii) semen analysis, iii) testicular histology or ultrasonography, iv) testicular clinical symptoms and/or v) male reproductive hormones in COVID-19-positive patients. RESULTS: Of 553 retrieved articles, 25 met the inclusion criteria. This included studies primarily investigating the presence of viral RNA in semen (n = 12), semen quality (n = 2), testicular histology (n = 5), testicular pain (n = 2) and male reproductive hormones (n= 4). Results show little evidence for the presence of viral RNA in semen, although COVID-19 seems to affect seminal parameters, induce orchitis, and cause hypogonadism. Mortality cases suggest severe histological disruption of testicular architecture, probably due to a systemic and local reproductive tract inflammatory response and oxidative stress-induced damage. CONCLUSIONS: Clinical evaluation of the male reproductive tract, seminal parameters and reproductive hormones is recommended in patients with current or a history of COVID-19, particularly in males undergoing fertility treatment. Any long-term negative impact on male reproduction remains unexplored and an important future consideration.

SARS-CoV-2 infection and human semen: possible modes of contamination and transmission.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has turned into a global pandemic with multitudinous health impacts. MAIN BODY: In light of the higher vulnerability of men to COVID-19 than women, there is rising concerns on the impact of SARS-CoV-2 infection on male fertility and possibilities of seminal contamination and transmission. The pandemic has attributed to the brief suspension of many fertility clinics and pathology laboratories, though many remained functional. Few reports reflect that SARS-CoV-2 can contaminate the semen of COVID-19 patients as well as that of recovering patients. The viral invasion into the testis may be due to the disrupted anatomical barriers of the testis by the inflammatory responses, and the persistence of the virus in the semen may be facilitated by the testicular immune privilege. Since SARS-CoV-2 is an enveloped RNA virus, it is also theoretically possible that this virus can remain viable in the semen samples even after cryopreservation with liquid nitrogen. CONCLUSION: The present review emphasizes the possibilities of seminal dissemination of SARS-CoV-2 and thereby the chances of its sexual transmission. These perceptions and predictions are to facilitate immediate necessary actions to improvise the standard precautionary procedures for laboratory practices, including semen analysis or processing the semen sample for fertility treatments.

An online educational model in andrology for student training in the art of scientific writing in the COVID-19 pandemic.

In 2020, the COVID-19 pandemic led to the suspension of the annual Summer Internship at the American Center for Reproductive Medicine (ACRM). To transit it into an online format, an inaugural 6-week 2020 ACRM Online Mentorship Program was developed focusing on five core pillars of andrology research: scientific writing, scientific methodology, plagiarism understanding, soft skills development and mentee basic andrology knowledge. This study aims to determine mentee developmental outcomes based on student surveys and discuss these within the context of the relevant teaching and learning methodology. The mentorship was structured around scientific writing projects established by the team using a student-centred approach, with one-on-one expert mentorship through weekly formative assessments. Furthermore, weekly online meetings were conducted, including expert lectures, formative assessments and social engagement. Data were collected through final assessments and mentee surveys on mentorship outcomes. Results show that mentees (n = 28) reported a significant (p < .0001) improvement in all criteria related to the five core pillars. These results illustrate that the aims of the online mentorship program were achieved through a unique and adaptive online educational model and that our model has demonstrated its effectiveness as an innovative structured educational experience through the COVID-19 crisis.

Viral Pandemics of the Last Four Decades: Pathophysiology, Health Impacts and Perspectives.

The twenty-first century has witnessed some of the deadliest viral pandemics with far-reaching consequences. These include the Human Immunodeficiency Virus (HIV) (1981), Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) (2002), Influenza A virus subtype H1N1 (A/H1N1) (2009), Middle East Respiratory Syndrome Coronavirus (MERS-CoV) (2012) and Ebola virus (2013) and the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) (2019-present). Age- and gender-based characterizations suggest that SARS-CoV-2 resembles SARS-CoV and MERS-CoV with regard tohigher fatality rates in males, and in the older population with comorbidities. The invasion-mechanism of SARS-CoV-2 and SARS-CoV, involves binding of its spike protein with angiotensin-converting enzyme 2 (ACE2) receptors; MERS-CoV utilizes dipeptidyl peptidase 4 (DPP4), whereas H1N1 influenza is equipped with hemagglutinin protein. The viral infections-mediated immunomodulation, and progressive inflammatory state may affect the functions of several other organs. Although no effective commercial vaccine is available for any of the viruses, those against SARS-CoV-2 are being developed at an unprecedented speed. Until now, only Pfizer/BioNTech's vaccine has received temporary authorization from the UK Medicines and Healthcare products Regulatory Agency. Given the frequent emergence of viral pandemics in the 21st century, proper understanding of their characteristics and modes of action are essential to address the immediate and long-term health consequences.

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.