Papers by Flavio A. Cadegiani
Cureus, 2022
Background: Ivermectin has demonstrated different mechanisms of action that potentially protect f... more Background: Ivermectin has demonstrated different mechanisms of action that potentially protect from both coronavirus disease 2019 (COVID-19) infection and COVID-19-related comorbidities. Based on the studies suggesting efficacy in prophylaxis combined with the known safety profile of ivermectin, a citywide prevention program using ivermectin for COVID-19 was implemented in Itajaí, a southern city in Brazil in the state of Santa Catarina. The objective of this study was to evaluate the impact of regular ivermectin use on subsequent COVID-19 infection and mortality rates. Materials and methods: We analyzed data from a prospective, observational study of the citywide COVID-19 prevention with ivermectin program, which was conducted between July 2020 and December 2020 in Itajaí, Brazil. Study design, institutional review board approval, and analysis of registry data occurred after completion of the program. The program consisted of inviting the entire population of Itajaí to a medical visit to enroll in the program and to compile baseline, personal, demographic, and medical information. In the absence of contraindications, ivermectin was offered as an optional treatment to be taken for two consecutive days every 15 days at a dose of 0.2 mg/kg/day. In cases where a participating citizen of Itajaí became ill with COVID-19, they were recommended not to use ivermectin or any other medication in early outpatient treatment. Clinical outcomes of infection, hospitalization, and death were automatically reported and entered into the registry in real time. Study analysis consisted of comparing ivermectin users with non-users using cohorts of infected patients propensity score-matched by age, sex, and comorbidities. COVID-19 infection and mortality rates were analyzed with and without the use of propensity score matching (PSM). Results: Of the 223,128 citizens of Itajaí considered for the study, a total of 159,561 subjects were included in the analysis: 113,845 (71.3%) regular ivermectin users and 45,716 (23.3%) non-users. Of these, 4,311 ivermectin users were infected, among which 4,197 were from the city of Itajaí (3.7% infection rate), and 3,034 non-users (from Itajaí) were infected (6.6% infection rate), with a 44% reduction in COVID-19 infection rate (risk ratio [RR], 0.56; 95% confidence interval (95% CI), 0.53-0.58; p < 0.0001). Using PSM, two cohorts of 3,034 subjects suffering from COVID-19 infection were compared. The regular use of ivermectin led to a 68% reduction in COVID-19 mortality (25 [0.8%] versus 79 [2.6%] among ivermectin non-users; RR, 0.32; 95% CI, 0.20-0.49; p < 0.0001). When adjusted for residual variables, reduction in mortality rate was 70% (RR, 0.30; 95% CI, 0.19-0.46; p < 0.0001). There was a 56% reduction in hospitalization rate (44 versus 99 hospitalizations among ivermectin users and non-users, respectively; RR, 0.44; 95% CI, 0.31-0.63; p < 0.0001). After adjustment for residual variables, reduction in hospitalization rate was 67% (RR, 0.33; 95% CI, 023-0.66; p < 0.0001). Conclusion: In this large PSM study, regular use of ivermectin as a prophylactic agent was associated with significantly reduced COVID-19 infection, hospitalization, and mortality rates.
Journal of Clinical Medicine Research, 2022
In December 2019, coronavirus disease 2019 (COVID-19), a severe respiratory illness caused by the... more In December 2019, coronavirus disease 2019 (COVID-19), a severe respiratory illness caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies recommended "supportive care only" avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of "what was working and what wasn't working", the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and non-antiviral co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically.
Title: Enhancement of hypothalamic-pituitary activity in male athletes: evidence of a novel hormo... more Title: Enhancement of hypothalamic-pituitary activity in male athletes: evidence of a novel hormonal mechanism of physical conditioning. Shortened title: Novel mechanism of hormonal conditioning Authors: Flavio Cadegiani ([email protected]) Claudio Kater ([email protected]) Version: 2 Date: 21 Aug 2019 Author’s response to reviews: Enhancement of hypothalamic-pituitary activity in male athletes: evidence of a novel hormonal mechanism of physical conditioning.
The AndroCoV Clinical Scoring for COVID-19 Diagnosis: A Prompt, Feasible, Costless, and Highly Sensitive Diagnostic Tool for COVID-19 Based on a 1757-Patient Cohort
Cureus
BMC Endocrine Disorders
Background Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel ... more 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 inhere...
COVID‐19, androgens, and androgenic alopecia
Dermatological Reviews
Journal of the Endocrine Society
Background: The importance of physical activity has achieved levels that has been recognized by a... more Background: The importance of physical activity has achieved levels that has been recognized by as a major world public health game changer, which positively engaged a growing number of subjects to become physically active. While effects of exercise on cardiovascular and musculoskeletal systems are well described, little is known regarding hormonal adapted physiology in athletes, as well as how to detect and manage endocrine abnormalities in physically active subjects. Methodological issues and inconsistent findings precluded from a structured understanding of the endocrinology physiology of physical activity and sport. The objective of the present guideline is to uniformize the design and assessment methods of further studies in the field, based on standardized hormonal and metabolic parameters, and dynamic testings. Methods: Guidelines were actively searched within endocrinology, sports medicine, and cardiology societies. Systematic search on PubMed and Cochrane databases for the ...
Spironolactone: An Anti-androgenic and Anti-hypertensive Drug That May Provide Protection Against the Novel Coronavirus (SARS-CoV-2) Induced Acute Respiratory Distress Syndrome (ARDS) in COVID-19
Frontiers in Medicine
Spironolactone may provide protection from SARS-CoV-2: Targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS)
Medical Hypotheses
Eating, Sleep, and Social Patterns as Independent Predictors of Clinical, Metabolic, and Biochemical Behaviors Among Elite Male Athletes: The EROS-PREDICTORS Study
Frontiers in Endocrinology
Journal of Sports Medicine
Objectives. Overtraining syndrome (OTS), a common dysfunction among elite athletes, causes decrea... more Objectives. Overtraining syndrome (OTS), a common dysfunction among elite athletes, causes decreased performance and fatigue and has no standardized diagnostic criteria. The Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study identified more than 45 potential biomarkers of OTS. In the present study, we hypothesized that combinations of these biomarkers could be an accurate diagnostic tool for OTS. Methods. We selected parameters with largest difference and fewest overlapping results compared to healthy athletes and highest feasibility and reproducibility. Among the multiple combinations attempted, we chose those that did not show overlapping results, according to the objective. Results. We included 11 clinical parameters, 4 basal hormones, and 5 hormonal responses in Insulin Tolerance Test (ITT). The three selected diagnostic tools were the (i) EROS-CLINICAL, with only clinical parameters, which was suitable as an initial assessment for athletes suspected of OTS;...
American Journal of Physiology-Endocrinology and Metabolism
TO THE EDITOR: Coronavirus disease (COVID-19) is an emerging pandemic. Clinical manifestations of... more TO THE EDITOR: Coronavirus disease (COVID-19) is an emerging pandemic. Clinical manifestations of COVID-19 range from asymptomatic to acute respiratory distress syndrome (ARDS) (6, 11, 12, 20, 23). Preliminary data on COVID-19 suggest hypertension to be correlated with worse outcomes (23.2%) compared with that of other metabolic disorders. This observation has been postulated to be correlated with use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) rather than hypertension. This alleged correlation has been disseminated among medical communities and media and has encouraged physicians to withdraw use of these drugs from COVID-19 patients. The potential harm from inappropriate discontinuation of ACEIs/ARBs has led to communication (1, 5) recommending against withdrawal. Two recent reports (17, 18) have stated there are insufficient data to support speculations on the consequences of ACEIs/ARBs use in COVID-19. The hypothesized rationale for the possible (but controversial) correlation between ACEIs and ARBs and progression to ARDS in COVID-19 is based on reports that the receptorbinding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a strong interaction with the angiotensin-converting enzyme-2 receptor (ACE-2R) (7, 10, 13, 22). Hence, an increase in expression of ACE-2Rs attached to cell surfaces in lung endothelia could amplify the capacity of SARS-CoV-2 to enter pulmonary cells. The only study to evaluate ACEI use for long periods demonstrated an increase in levels of angiotensin 1-7 (an indirect marker of ACE-2 action in the lung), which better reflects typical chronic use of ACEIs/ARBs (14). Although attached ACE-2 may allow SARS-CoV-2 to enter cells, its free circulating forms may inactivate SARS-CoV-2 by stopping coupling to membrane ACE-2Rs and consequent entry into pulmonary endothelial cells (1, 10, 21). Recombinant human soluble ACE-2 has been proposed to protect against ARDS and death in COVID-19 (2, 21). Soluble ACE-2 is commercially unavailable, unaffordable, produced at insufficient scales, and lacks definitive data (4). The circulating plasma level of ACE-2 may be insufficient to protect membrane-attached ACE-2Rs from coupling with SARS-CoV-2 (2), but, under particular conditions (e.g., soluble ACE-2), the protective actions of ACE-2 may become relevant. In addition to soluble ACE-2, potassium-sparing diuretics [another class of antihypertensive drug that also acts
Frontiers in Endocrinology
Objectives: The Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study identifie... more Objectives: The Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study identified multiple hormonal and metabolic conditioning processes in athletes, and underlying mechanisms and biomarkers of overtraining syndrome (OTS). The present study's objective was to reveal independent predictors and linear correlations among the parameters evaluated in the EROS study to predict clinical, metabolic, and biochemical behaviors in healthy and OTS-affected male athletes. Methods: We used multivariate linear regression and linear correlation to analyze possible combinations of the 38 parameters evaluated in the EROS study that revealed significant differences between healthy and OTS-affected athletes. Results: The testosterone-to-estradiol (T:E) ratio predicted the measured-to-predicted basal metabolic rate (BMR) ratio; the T:E ratio and total testosterone level were inversely predicted by fat mass and estradiol was not predicted by any of the non-modifiable parameters. Early and late growth hormone, cortisol, and prolactin responses to an insulin tolerance test (ITT) were strongly correlated. Hormonal responses to the ITT were positively correlated with fat oxidation, predicted-to-measured BMR ratio, muscle mass, and vigor, and inversely correlated with fat mass and fatigue. Salivary cortisol 30 min after awakening and the T:E ratio were inversely correlated with fatigue. Tension was inversely correlated with libido and directly correlated with body fat. The predicted-to-measured BMR ratio was correlated with muscle mass and body water, while fat oxidation was directly correlated with muscle mass and inversely correlated with fat mass. Muscle mass was directly correlated with body water, and extracellular water was directly correlated with body fat and inversely correlated with body water and muscle mass. Conclusions: Hypothalamic-pituitary responses to stimulation were diffuse and indistinguishable between the different axes. A late hormonal response to stimulation, increased cortisol after awakening, and the T:E ratio were correlated with vigor and Cadegiani and Kater The EROS-CORRELATIONS Study fatigue. The T:E ratio was also correlated with body metabolism and composition, testosterone was predicted by fat mass, and estradiol predicted anger. Hydration status was inversely correlated with edema, and inter-correlations were found among fat oxidation, hydration, and body fat.
BMC Endocrine Disorders
Background Exercise is known to induce multiple beneficial conditioning processes. Conversely, al... more 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/m2, with similar baseline characteristics, who underwent gold-standard exercise-independent tests: cosyntropin stimulation test (CST) and insulin tolerance test (ITT), to evaluate cortisol response to CST, and ACTH, cortisol, GH, and prolactin responses to an ITT. Results Responses to ITT wer...
BMC Sports Science, Medicine and Rehabilitation
Background: Hormonal physiology in athletes, dysfunctional paths leading to overtraining syndrome... more Background: Hormonal physiology in athletes, dysfunctional paths leading to overtraining syndrome (OTS), and clinical and biochemical behaviors that are independently modified by the presence of OTS remain unclear. Although multiple markers of OTS have recently been identified, the independent influence of OTS on hormones and metabolism have not been assessed. Hence, the objective of the present study was to uncover the previously unrecognized independent predictors of OTS and understand how OTS independently modifies the behaviors of clinical and biochemical parameters. Methods: In a total of 39 athletes (OTS-affected athletes (OTS) = 14 and healthy athletes (ATL) = 25), we performed two clusters of statistical analyses using the full data of the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study, in a total of 117 markers. We first used logistic regression to analyze five modifiable parameters (carbohydrate, protein, and overall caloric intake, sleep quality, and concurrent cognitive effort) as potential additional independent risk factors for OTS, and OTS as the outcome. We then used multivariate linear regression to analyze OTS as the independent variable and 38 dependent variables. Training patterns were found to be similar between OTS and ATL, and therefore excessive training was not a risk, and consequently not a predictor, for OTS. Results: Each of the three dietary patterns (daily carbohydrate, daily protein, and daily overall calorie intake) were found to be the independent triggers of OTS, while sleeping, social, and training characteristics depended on other factors to induce OTS. Once triggered, OTS independently induced multiple changes, including reductions of cortisol, late growth hormone and adrenocorticotropic hormone responses to stimulations, testosterone-to-estradiol ratio, neutrophils, neutrophil-to-lymphocyte ratio, vigor levels, hydration status, and muscle mass, while increase of tension levels and visceral fat. Conclusions: OTS can be independently triggered by eating patterns, regardless of training patterns, while the occurrence of OTS reduced late hormonal responses and the testosterone-to-estradiol ratio, worsened mood, and affected the immunology panel. These novel findings may explain underperformance, which is the key characteristic of OTS.
Journal of Athletic Training
Context Overtraining syndrome (OTS) and related conditions cause decreased training performance a... more Context Overtraining syndrome (OTS) and related conditions cause decreased training performance and fatigue through an imbalance among training volume, nutrition, and recovery time. No definitive biochemical markers of OTS currently exist. Objective To compare muscular, hormonal, and inflammatory parameters among OTS-affected athletes, healthy athletes, and sedentary controls. Design Cross-sectional study. Setting Laboratory. Patients or Other Participants Fifty-one men aged 18 to 50 years (14 OTS-affected athletes [OTS group], 25 healthy athletes [ATL group], and 12 healthy sedentary participants [NCS group]), with a body mass index of 20 to 30.0 kg/m2 (sedentary) or 20 to 33.0 kg/m2 (athletes), recruited through social media. All 39 athletes performed both endurance and resistance sports. Main Outcome Measure(s) We measured total testosterone, estradiol, insulin-like growth factor 1, thyroid-stimulating hormone, free thyronine, total and fractioned catecholamines and metanephrines...
BMJ Open Sport & Exercise Medicine
BackgroundExcessive training and inadequate recovery could cause ‘overtraining syndrome’ (OTS), w... more BackgroundExcessive training and inadequate recovery could cause ‘overtraining syndrome’ (OTS), which is characterised by underperformance and fatigue. The pathophysiology of OTS is unclear. We aimed to describe novel mechanisms and risk factors associated with OTS, and thereby facilitate its early identification and prevention, from a comprehensive joint qualitative analysis of the findings from all the four arms of the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study.MethodsWe compared the types and proportions of behavioural patterns of 67 evaluated parameters of OTS from 51 participants—athletes with OTS (OTS, n=14), healthy athletes (n=25) and healthy non-physically active controls (n=12). We performed overall and pairwise comparisons for statistically significant differences between the three groups (p<0.05).ResultsA total of 44 (65.7%) markers exhibited significant differences between the three groups: 32 (72.7%) showed a loss of the conditioning eff...
Clinical and biochemical characteristics of high-intensity functional training (HIFT) and overtraining syndrome: findings from the EROS study (The EROS-HIFT)
Journal of Sports Sciences
Growth hormone (GH) and prolactin responses to a non-exercise stress test in athletes with overtraining syndrome: results from the Endocrine and metabolic Responses on Overtraining Syndrome (EROS) - EROS-STRESS
Journal of science and medicine in sport, Jan 16, 2017
Overtraining syndrome (OTS) leads to worsened sports performance and fatigue. The pathophysiology... more Overtraining syndrome (OTS) leads to worsened sports performance and fatigue. The pathophysiology of OTS has not been entirely elucidated, and there is a lack of accurate markers for its diagnosis. Changes in hormonal responses implicated in OTS were stimulated by exercise, which has limited their interpretation. Hence, we aimed to evaluate growth hormone (GH) and prolactin responses to a gold-standard and exercise-independent stimulation test, the insulin tolerance test (ITT). Volunteers were recruited and divided into OTS-affected athletes (OTS), healthy athletes (ATL), and healthy non-active subjects (NCS) groups, after general and specific inclusion and exclusion criteria. We evaluated the responses of growth hormone (GH) and prolactin to the ITT, and compared between groups. A total of 51 subjects were included (OTS, n=14, ATL, n=25, and NCS, n=12). OTS disclosed significantly lower basal levels of GH (p=0.003) and prolactin (p=0.048), and GH (p=0.001) and prolactin (p<0.001...
Body composition, metabolism, sleep, psychological and eating patterns of overtraining syndrome: Results of the EROS study (EROS-PROFILE)
Journal of sports sciences, Jan 9, 2018
Overtraining syndrome (OTS) is caused by an imbalance between training, nutrition and resting, an... more Overtraining syndrome (OTS) is caused by an imbalance between training, nutrition and resting, and leads to decreased performance and fatigue; however, the precise underlying triggers of OTS remain unclear. This study investigated the body composition, metabolism, eating, sleeping patterns and mood states among participants with OTS. Selected participants were divided into OTS-affected athletes (OTS, n = 14), healthy athletes (ATL, n = 25), and healthy non-physically active controls (NCS, n = 12). Compared to ATL, OTS showed decreased sleep quality (p = 0.004); increased duration of work or study (p < 0.001); decreased libido (p = 0.024); decreased calorie (p < 0.001), carbohydrate (p < 0.001) and protein (p < 0.001) intakes; decreased mood states (p < 0.001); decreased basal metabolic rate (p = 0.013) and fat burning (p < 0.001); increased body fat (p = 0.006); decreased muscle mass (p = 0.008); and decreased hydration (p < 0.001). Levels were similar between O...
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Papers by Flavio A. Cadegiani