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  1. Article: Catecholamines Are the Key Trigger of COVID-19 mRNA Vaccine-Induced Myocarditis: A Compelling Hypothesis Supported by Epidemiological, Anatomopathological, Molecular, and Physiological Findings.

    Cadegiani, Flavio A

    Cureus

    2022  Volume 14, Issue 8, Page(s) e27883

    Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine-induced myocarditis is a rare but well-documented complication in young males. The increased incidence of sudden death among athletes following vaccination has been reported and ... ...

    Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine-induced myocarditis is a rare but well-documented complication in young males. The increased incidence of sudden death among athletes following vaccination has been reported and requires further investigation. Whether the risk of myocarditis, a known major cause of sudden death in young male athletes, also increases after coronavirus disease 2019 (COVID-19) infection is unknown. The severity and implications of these critical adverse effects require a thorough analysis to elucidate their key triggering mechanisms. The present review aimed to evaluate whether there is a justification to hypothesize that catecholamines in a "hypercatecholaminergic" state are the key trigger of SARS-CoV-2 mRNA vaccine-induced myocarditis and related outcomes and whether similar risks are also present following COVID-19 infection. A thorough, structured scoping review of the literature was performed to build the hypothesis through three pillars: detection of myocarditis risk, potential alterations and abnormalities identified after SARS-CoV-2 mRNA vaccination or COVID-19 infection and consequent events, and physiological characteristics of the most affected population. The following terms were searched in indexed and non-indexed peer review articles and recent preprints (<12 months): agent, "SARS-CoV-2" or "COVID-19"; event, "myocarditis" or "sudden death(s)" or "myocarditis+sudden death(s)" or "cardiac event(s)"; underlying cause, "mRNA" or "spike protein" or "infection" or "vaccine"; proposed trigger, "catecholamine(s)" or "adrenaline" or "epinephrine" or "noradrenaline" or "norepinephrine" or "testosterone"; and affected population, "young male(s)" or "athlete(s)." The rationale and data that supported the hypothesis were as follows: SARS-CoV-2 mRNA vaccine-induced myocarditis primarily affected young males, while the risk was not observed following COVID-19 infection; independent autopsies or biopsies of patients who presented post-SARS-CoV-2 mRNA vaccine myocarditis in different geographical regions enabled the conclusion that a primary hypercatecholaminergic state was the key trigger of these events; SARS-CoV-2 mRNA was densely present, and SARS-CoV-2 spike protein was progressively produced in adrenal medulla chromaffin cells, which are responsible for catecholamine production; the dihydroxyphenylalanine decarboxylase enzyme that converts dopamine into noradrenaline was overexpressed in the presence of SARS-CoV-2 mRNA, leading to enhanced noradrenaline activity; catecholamine responses were physiologically higher in young adults and males than in other populations; catecholamine responses and resting catecholamine production were higher in male athletes than in non-athletes; catecholamine responses to stress and its sensitivity were enhanced in the presence of androgens; and catecholamine expressions in young male athletes were already high at baseline, were higher following vaccination, and were higher than those in non-vaccinated athletes. The epidemiological, autopsy, molecular, and physiological findings unanimously and strongly suggest that a hypercatecholaminergic state is the critical trigger of the rare cases of myocarditis due to components from SARS-CoV-2, potentially increasing sudden deaths among elite male athletes.
    Language English
    Publishing date 2022-08-11
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2747273-5
    ISSN 2168-8184
    ISSN 2168-8184
    DOI 10.7759/cureus.27883
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Can spironolactone be used to prevent COVID-19-induced acute respiratory distress syndrome in patients with hypertension?

    Cadegiani, Flávio A

    American journal of physiology. Endocrinology and metabolism

    2020  Volume 318, Issue 5, Page(s) E587–E588

    MeSH term(s) Angiotensin-Converting Enzyme 2 ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Betacoronavirus ; COVID-19 ; Coronavirus Infections/complications ; Coronavirus Infections/drug therapy ; Humans ; Hypertension/complications ; Pandemics ; Peptidyl-Dipeptidase A/blood ; Pneumonia, Viral/complications ; Pneumonia, Viral/drug therapy ; Respiratory Distress Syndrome/drug therapy ; Respiratory Distress Syndrome/virology ; SARS-CoV-2 ; Spironolactone/therapeutic use
    Chemical Substances Angiotensin-Converting Enzyme Inhibitors ; Spironolactone (27O7W4T232) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Keywords covid19
    Language English
    Publishing date 2020-04-28
    Publishing country United States
    Document type Letter
    ZDB-ID 603841-4
    ISSN 1522-1555 ; 0193-1849
    ISSN (online) 1522-1555
    ISSN 0193-1849
    DOI 10.1152/ajpendo.00136.2020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Repurposing existing drugs for COVID-19: an endocrinology perspective.

    Cadegiani, Flavio A

    BMC endocrine disorders

    2020  Volume 20, Issue 1, Page(s) 149

    Abstract: Background: Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry ... ...

    Abstract Background: Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2.
    Main text: While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19. The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed.
    Conclusion: While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.
    MeSH term(s) Anti-Inflammatory Agents/therapeutic use ; Betacoronavirus/drug effects ; Betacoronavirus/isolation & purification ; COVID-19 ; Coronavirus Infections/drug therapy ; Coronavirus Infections/epidemiology ; Coronavirus Infections/virology ; Dexamethasone/therapeutic use ; Drug Repositioning/methods ; Endocrine System ; Humans ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/epidemiology ; Pneumonia, Viral/virology ; Prognosis ; SARS-CoV-2
    Chemical Substances Anti-Inflammatory Agents ; Dexamethasone (7S5I7G3JQL)
    Keywords covid19
    Language English
    Publishing date 2020-09-29
    Publishing country England
    Document type Journal Article
    ZDB-ID 2091323-0
    ISSN 1472-6823 ; 1472-6823
    ISSN (online) 1472-6823
    ISSN 1472-6823
    DOI 10.1186/s12902-020-00626-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Repurposing existing drugs for COVID-19

    Cadegiani, Flavio A.

    BMC Endocrine Disorders

    an endocrinology perspective

    2020  Volume 20, Issue 1

    Abstract: Abstract Background Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, ...

    Abstract Abstract Background Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2. Main text While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19. The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed. Conclusion While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.
    Keywords Endocrinology, Diabetes and Metabolism ; General Medicine ; covid19
    Language English
    Publisher Springer Science and Business Media LLC
    Publishing country us
    Document type Article ; Online
    ISSN 1472-6823
    DOI 10.1186/s12902-020-00626-0
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article: Repurposing existing drugs for COVID-19: an endocrinology perspective

    Cadegiani, Flavio A

    BMC Endocr Disord

    Abstract: BACKGROUND: Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry ... ...

    Abstract BACKGROUND: Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2. MAIN TEXT: While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19. The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed. CONCLUSION: While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #800840
    Database COVID19

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  6. Article ; Online: Nonpharmacological Interventions for the Management of Testosterone and Sperm Parameters: A Scoping Review.

    Santos, Heitor O / Cadegiani, Flávio A / Forbes, Scott C

    Clinical therapeutics

    2022  Volume 44, Issue 8, Page(s) 1129–1149

    Abstract: Purpose: Testosterone replacement and associated pharmacologic agents are effective strategies to treat male hypogonadism; however, nutraceutical agents and lifestyle modification approaches have gained medical interest. The purpose of this scoping ... ...

    Abstract Purpose: Testosterone replacement and associated pharmacologic agents are effective strategies to treat male hypogonadism; however, nutraceutical agents and lifestyle modification approaches have gained medical interest. The purpose of this scoping review is to highlight the evidence (or lack thereof) of nutraceuticals and lifestyle modification approaches in the management of testosterone levels and sperm parameters.
    Methods: A scoping review of nonpharmacologic interventions (supplements, herbal medicines, diets, sleep, and exercise) with the potential to improve male health was undertaken to elucidate changes in testosterone levels and sperm parameters in men with hypogonadism or infertility compared with healthy patients.
    Findings: A multitude of nutraceuticals and functional nutrients are purported to stimulate testosterone production; however, only a select few have had promising results, such as zinc, vitamin D (in case of hypovitaminosis D), l-arginine, mucuna, and ashwagandha, based on well-controlled randomized clinical trials of men with low testosterone levels and related problems. Except for l-arginine, these natural agents, as well as tribulus and ω3 fatty acids, can improve some degree of sperm parameters in infertile men. Before implementing these nutraceutical agents, adequate sleep, exercise, and weight loss in patients with obesity are imperative. The effects of nonpharmacologic interventions on testosterone levels are modest and hence do not directly translate into clinical benefits. Correspondingly, androgen receptor content, but not endogenous androgens, has been regarded as the principal factor in muscle hypertrophy.
    Implications: A limited number of supplements and herbal medicines can be considered as adjunctive approaches in the management of testosterone levels and sperm parameters, primarily in men with low testosterone levels and infertility, whereas most nonpharmacologic supplements appear to lack evidence. Although proper physical exercise, sleep, and diet are indisputable approaches because of the general benefits to health, the use of nutraceuticals, if considered, must be personalized by physicians and/or registered dietitians.
    MeSH term(s) Arginine/therapeutic use ; Fatty Acids/therapeutic use ; Humans ; Hypogonadism/drug therapy ; Infertility/drug therapy ; Male ; Receptors, Androgen ; Semen ; Spermatozoa ; Testosterone/therapeutic use ; Vitamin D/therapeutic use ; Zinc
    Chemical Substances Fatty Acids ; Receptors, Androgen ; Vitamin D (1406-16-2) ; Testosterone (3XMK78S47O) ; Arginine (94ZLA3W45F) ; Zinc (J41CSQ7QDS)
    Language English
    Publishing date 2022-07-07
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 603113-4
    ISSN 1879-114X ; 0149-2918
    ISSN (online) 1879-114X
    ISSN 0149-2918
    DOI 10.1016/j.clinthera.2022.06.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Eating, Sleep, and Social Patterns as Independent Predictors of Clinical, Metabolic, and Biochemical Behaviors Among Elite Male Athletes: The EROS-PREDICTORS Study.

    Cadegiani, Flavio A / Kater, Claudio E

    Frontiers in endocrinology

    2020  Volume 11, Page(s) 414

    Abstract: Objectives: ...

    Abstract Objectives:
    MeSH term(s) Adaptation, Physiological ; Adolescent ; Adult ; Athletes/psychology ; Body Composition ; Cumulative Trauma Disorders/physiopathology ; Cumulative Trauma Disorders/psychology ; Energy Intake ; Exercise ; Fatigue/physiopathology ; Fatigue/psychology ; Feeding Behavior ; Humans ; Male ; Middle Aged ; Sleep ; Social Behavior ; Sports ; Sports Nutritional Physiological Phenomena ; Young Adult
    Language English
    Publishing date 2020-06-26
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2592084-4
    ISSN 1664-2392
    ISSN 1664-2392
    DOI 10.3389/fendo.2020.00414
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Enhancement of hypothalamic-pituitary activity in male athletes: evidence of a novel hormonal mechanism of physical conditioning.

    Cadegiani, Flavio A / Kater, Claudio E

    BMC endocrine disorders

    2019  Volume 19, Issue 1, Page(s) 117

    Abstract: Background: Exercise is known to induce multiple beneficial conditioning processes. Conversely, although exercise may generate several hormonal effects, an intrinsic hormonal conditioning process has not been reported. In the Endocrine and Metabolic ... ...

    Abstract Background: Exercise is known to induce multiple beneficial conditioning processes. Conversely, although exercise may generate several hormonal effects, an intrinsic hormonal conditioning process has not been reported. In the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study, we observed inherent and independent conditioning processes of the hypothalamic-pituitary axes in athletes. Our objective is to describe the theory of the novel hormonal conditioning mechanism using the findings from the EROS study.
    Methods: In this cross-sectional study, we selected 25 healthy athletes (ATL) and 12 non-physically active healthy controls (NPAC), 18-50 years old, males, with BMI 20-30 kg/m
    Results: Responses to ITT were significantly earlier and higher in ATL than NPAC for cortisol [Mean ± SD: 21.7 ± 3.1 vs 16.9 ± 4.1 μg/dL; p < 0.001], GH [Median (95% CI): 12.73 (1.1-38.1) vs 4.80 (0.33-27.36) μg/L; p = 0.015], and prolactin [24.3 (10.5-67.45) vs 10.50 (6.21-43.44) ng/mL; p = 0.002]. Cortisol response to CST was similar between ATL and NPAC. During ITT, cortisol, GH, and ACTH mean increase in ATL were 52.2, 265.2, and 18.6% higher than NPAC, respectively. Prolactin response was absent in NPAC, while present in ATL.
    Conclusions: We found sufficient evidence to propose the existence of a diffuse enhancement of the hypothalamic-pituitary activity in athletes, not restricted to any axis, showing an intrinsic and independent process of "hormonal conditioning" in athletes, similar to those observed in the cardiovascular and neuromuscular systems. This novel conditioning process may be the missing link for understanding the improved responses observed in athletes to harmful situations, traumas, infections, inflammations, and psychiatric conditions.
    MeSH term(s) Adolescent ; Adult ; Athletes/statistics & numerical data ; Cosyntropin/administration & dosage ; Cross-Sectional Studies ; Exercise ; Exercise Test ; Female ; Hormones/administration & dosage ; Humans ; Hydrocortisone/metabolism ; Hypoglycemic Agents/administration & dosage ; Hypothalamo-Hypophyseal System/drug effects ; Hypothalamo-Hypophyseal System/metabolism ; Insulin/administration & dosage ; Male ; Middle Aged ; Pituitary-Adrenal System/drug effects ; Pituitary-Adrenal System/metabolism ; Prolactin/metabolism ; Young Adult
    Chemical Substances Hormones ; Hypoglycemic Agents ; Insulin ; Cosyntropin (16960-16-0) ; Prolactin (9002-62-4) ; Hydrocortisone (WI4X0X7BPJ)
    Language English
    Publishing date 2019-11-01
    Publishing country England
    Document type Journal Article
    ISSN 1472-6823
    ISSN (online) 1472-6823
    DOI 10.1186/s12902-019-0443-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Inter-correlations Among Clinical, Metabolic, and Biochemical Parameters and Their Predictive Value in Healthy and Overtrained Male Athletes: The EROS-CORRELATIONS Study.

    Cadegiani, Flavio A / Kater, Claudio E

    Frontiers in endocrinology

    2019  Volume 10, Page(s) 858

    Abstract: Objectives: ...

    Abstract Objectives:
    Language English
    Publishing date 2019-12-10
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2592084-4
    ISSN 1664-2392
    ISSN 1664-2392
    DOI 10.3389/fendo.2019.00858
    Database MEDical Literature Analysis and Retrieval System OnLINE

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