June 26, 2021
OVERTRAINING SYNDROME – REFRAMING THE MOST COMMON SPORTS-DERIVED, SPORTS-RELATED DISEASE
By addressing methodological issues on hormonal research, allowing the detection of causality relationship, rather than purely association, and aiming to answer the major questions on overtraining syndrome, Dr. Cadegiani conducted as the principal investigator amongst the largest clinical studies on the field of Endocrinology of Physical Activity, the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study. Together with the answers to the gaps in the understanding of Overtraining Syndrome, the EROS study was also designed to determine potential difference between healthy athletes and healthy sedentary, in order to detect potential hormonal and metabolic physiological adaptative processes that athletes undergo that hadn’t been described until then. This could be done by comparing athletes affected by OTS with healthy athletes and healthy non-physically active subjects, simultaneously.
In total, the EROS study evaluated more than 100 parameters in more than 50 participants in three groups, that revealed more than 45 novel biomarkers and mechanisms not only in overtraining, but also in healthy athletes, has created the first validated scores for the diagnosis of Overtraining Syndrome, which have been published in more than 10 papers.
OVERTRAINING SYMDROME – THE PARADOXICAL DECONDITIONING SYNDROME (PDS)
Since both overtrained and healthy athletes were training exactly the same amount of volume, intensity, frequency, and type of training, excessive training was clearly not the cause of overtraining syndrome in these athletes, which is contra-intuitive since the name of this condition naturally makes us think that excessive training is the major cause of it. Instead, it was a combination of insufficient amount of caloric, carbohydrate, or protein intake, bad sleep quality, and/or relatively large amount of cognitive demands (too much stress in work, too many concurrent demands, etc) that was the main determinant of overtraining syndrome. Of course that the excessive training may be part of this combination, but alone was not able to cause overtraining syndrome.
Because of these novel findings, Dr. Cadegiani proposed a new model of understanding underperformance-related syndromes, coining the term 'Paradoxical Deconditioning Syndrome (PDS)'. The term PDS is based on the hallmark characteristic that Dr. Cadegiani identified in athletes that lost performance, which was the loss of the multiple hormonal and metabolic conditioning processes that typically occur in athletes, and help them to have progressive improvements in sports performance.
NOVEL HORMONAL MARKERS
Among his multiple discoveries, he found out that the testosterone-to-estradiol ratio, rather than testosterone or estradiol alone, may be a better predictor of many clinical and biochemical behaviors, opening doors to the hormonal balance era, instead of isolated analyzes of each hormone, just like what has been recently proposed by researchers of the steroid metabolomics.
He also unraveled that prompt hormonal responses to stimulations predict the ability for explosive physical responses, which means that the more an athlete release hormone in response to a stimulation, more likely will be the ability to have an explosive ability. Conversely, prolonged hormonal responses predict longer time-to-fatigue in sports, which means that the ability to maintain releasing hormones for a more prolonged period of time likely helps the athlete to maintain the sports performed even after longer periods of training or playing.
June 26, 2021
Corpometria Institute offers treatments for all endocrine diseases, sports-related non-orthopaedic states, and a comprehensive and intensive approach to obesity, since the founder has published the first scientific-based protocol for prevention of bariatric surgery. The whole team of the Institute haas been systematically studying and improving their protocols to keep providing the best in terms of treatments and outcomes to their patients.
June 26, 2021
The founder of Corpometria Institute, Dr. Flavio Cadegiani, MD, MsC, PhD is a board certified Endocrinologist, with MsC and PhD degrees in Clinical Endocrinology at Federal University of São Paulo, and focused on investigations in the fields of hormonal physiology of athletic training, pathophysiology of Overtraining Syndrome, etiologies of fatigue, obesity, and androgens. Dr. Cadegiani has two concurrent careers, in the research and in private practice.
Currently Dr. Cadegiani has a position of CEO of Corpometria Institute and Clinical Director at Applied Biology. He obtained his medical degree in University of Brasilia in 2008, finished his residency in internal medicine in the same university in 2010 and fellowship in Endocrinology and Metabolism in HBDF, Brasilia, Brazil, in 2012. He obtained both master degree (MSc) and PhD in Clinical Endocrinology at Federal University of São Paulo (Unifesp/EPM), mentored by Prof. Dr. Cláudio Elias Kater
Dr. Cadegiani has become a worldwide expert in both Endocrinology and Sports Medicine fields, providing a unique endocrinological perspective from Physical Activity, in addition to a deeper understanding of the underlying mechanisms of fatigue. However, Dr. Cadegiani research fields go beyond fatigue and related conditions. He is a worldwide known expert for obesity management, perhaps amongst the largest experts in actual multidrug pharmacological weight loss management, and the creator and of the first protocol of a combination between pharmacological and non-pharmacological treat patients with moderate and severe obesity clinically and avoid bariatric surgery, and that has been scientifically demonstrated to be effective in the short and long terms.
Dr. Cadegiani contributions to the obesity field also include the first chapter fully dedicated to describe the dysfunctions of the liver in obesity and responses to bariatric surgery. He also described scientifically the first drug to reduce both early and late Dumping's syndrome that typically occurs after bariatric surgery, and he has now demonstrated paradoxical weight loss markers, including increase of homocysteine and triglycerides, which usually are considered as being negative parameters, but that was positivetely associated with fat loss.
Besides fatigue-related conditions, overtraining syndrome, endocrinology of physical activity, and obesity, Dr. Cadegiani believes that there is much to discover in the world of androgens and skin-related diseases, and how skin and hair can provide a deeper and more precise steroidal and metabolic mapping, particularly in the long term, in contrast to the snapchat sort of analysis of blood samples. He wants to expand the understanding of the multiple crosstalks between skin and hormones, and describe a thorough characterization of the peculiarities of the steroidal steroidogenesis in the hair and skin, as well as the implications for diagnoses and therapeutics.
The story on COVID-19
June 26, 2021
THE FOUNDER AND THE STORY ON COVID-19
Since the beginning of the COVID-19 pandemic, in early 2020, Dr. Cadegiani started to notice that several aspects of the infection by SARS-CoV-2, the virus that causes COVID-19, were direct- or indirectly related to endocrine mechanisms, particularly the renin-angiotensin-aldosterone system (RAAS) and the androgen activity, that regulated the angiotensin converting enzyme-2 (ECA-2) and the TMPRSS-2, respectively, the two major proteins involved in the SARS-CoV-2 infectivity. ECA-2 is the protein through which SARS-CoV-2 entries in the cell. TMPRSS-2 ‘prepares’ the virus for its entry in the cell.
Patients with hypertension were amongst the first risk factors detected for severe COVID-19. A hypothesis was that the two most used anti-hypertensive classes, the ECA inhibitors (ECAi) and the angiotensin receptor blocker (ARBs), would be the cause by increasing the ECA-2 attached to the cells. Dr. Cadegiani then proposed that spironolactone, a molecule used as an antihypertensive that has protective effects in the heart, lungs, and kidneys, could hamper the theoretical risk of these two antihypertensive drug classes. The spironolactone action would be to counterbalance the ECA-2 attached to the cell by leading to an increase of the ECA-2 circulating in the blood. As demonstrated by the use of recombinant ECA-2, the ECA-2 that circulates may neutralize the SARS-CoV-2 virus and prevent its entry and infectivity. In addition, spironolactone may modulate the RAAS by antagonizing the action of the harmful hormone called aldosterone. Other risk factors for severe COVID-19, including obesity and type 2 diabetes, are risk factors likely because of the dysfunctions they cause in the RAAS, which could also be corrected by the use of spironolactone.
The first paper hypothesizing spironolactone as a promising drug against COVID-19 was published in the American Journal of Physiology – Endocrinology and Metabolism (AJP-ENDO) in April of 2020.
Right after this first publication, a great group of researchers from the USA and Spain proposed that androgenetic alopecia (AGA) was an independent risk factor for COVID-19 severity, by the observation that the intensive care units (UCIs) were plenty of males with AGA. This could be explained by the fact that AGA is a clinical sign of enhanced androgen activity, and androgens (which are hormones that act like ‘testosterone’, the ‘masculine’ hormone) are the only molecules known to stimulate the expression of TMPRSS-2. For this reason, it has been hypothesized that males had more severe COVID-19 than females, and that males with AGA had more severe COVID-19 than males without AGA because of the overexpression of TMPRSS-2 induced by the high androgen activity. By April of 2020, the team published a series of papers on the antiandrogen hypothesis for COVID-19.
The fact that androgens could be harmful for COVID-19 allowed the hypothesis that the use of anti-androgens could play a protective role for COVID-19. And spironolactone, when in higher doses, acts as an antiandrogen agent, not only as an antihypertensive drug acting in the RAAS.
For this reason, Dr. Cadegiani got in contact with the research team to talk about the possibility of conducting a clinical trial with spironolactone. From that time on, Dr. Cadegiani joined the team and started to conduct a series of prospective observational studies and randomized clinical trials (RCTs) with different antiandrogens, including spironolactone, dutasteride, and proxalutamide.
Alongside with the RCTs, multiple observations were demonstrating that in fact while hyperandrogenic states were a risk factor for developing severe COVID-19, chronic antiandrogen users seemed to be relatively protected against COVID-19. Together with the research team, Dr. Cadegiani published a few papers showing that women affected by polycystic ovary syndrome and other hyperandrogenic states had more symptoms than women without hyperandrogenism, that men taking dutasteride, a drug that inhibits the conversion of testosterone into dihydrotestosterone (DHT), an androgen approximately five times more potent than testosterone, and that also has a weak effect on the blockage of androgen receptors (ARs), presented fewer and shorter symptoms than both AGA and non-AGA males, that older men hospitalized due to COVID-19 taking dutasteride for prevention and treatment of benign prostate hyperplasia were less likely to progress to the need of ICU compared to non-users, and that the genetic of the androgen receptor was able to predict the severity of COVID-19. Together, this preliminary evidence reinforced the plausibility of the RCTs and other studies that we were starting to conduct.
The preliminary reports of the double-blind, placebo-controlled RCTs with dutasteride and proxalutamide in outpatients infected by the SARS-CoV-2 have been published already, while the main publications are currently under review. The main publication on the double-blind, placebo-controlled RCT conducted in hospitalized patients with proxalutamide is also under review.
Again, bringing the previous knowledge Dr. Cadegiani obtained to COVID-19, it is not testosterone alone that predicts COVID-19 severity. If this was the case, young males would have had the worst outcomes. Instead, it is likely that a combination of: a. The balance between testosterone, DHT, and estradiol, and b. The androgen receptor sensibility to androgens, that more likely predict COVID-19 severity.
June 26, 2021
FATIGUE-RELATED CONDITIONS – WHO CAUSES WHO?
Dr. Cadegiani research on fatigue-related conditions resulted in the article (Adrenal Fatigue Does Not Exist: A Systematic Review”, published in the BMC Endocrine Disorders journal, and has become a world reference to debunk the existence of the pseudo-disease "Adrenal Fatigue", as mentioned by The Washington Post, Yahoo, US News, and other outlets, and four Wikipedia pages.
In his studies, he realized different unrelated states that were markedly affected by fatigue had methodological issues in the assessment of hormones and metabolic parameters, and could have pathophysiological correlations between them. Basically, alleged abnormalities in the cortisol release, the main product of the adrenal glands, were consequence, not cause, of these diseases. Among these states, which include chronic fatigue after chemotherapy for breast cancer, lower back pain and fatigue, and similarities and differences between Chronic Fatigue Syndrome (CFS), a real disease, and ‘adrenal fatigue’, he was called special attention for overtraining syndrome, the most prevailing sport-related disease among amateur and professional athletes, for which endocrinology aspects were claimed to be central for its occurrence, and which fatigue is a major manifestation.
June 26, 2021
Since the beginning of the private practice as a board certified endocrinologist, Dr. Cadegiani believed that obesity is not a mere consequence of bad choices, and that health providers and organizations have always overblamed the patients for their state of obesity, implicitly meaning that they were weak of lacked ‘conscience’ on eating and sports habits. Because of his own history and the familial patterns of obesity, he always believed that obesity was predominantly genetic. The genetics behind obesity, which is now being over and over unveiled, and counts up to 70% of the cause of obesity, are able to make a person be very hard to resist to highly-dense calorie foods due to the enhanced chemistry activated in the brain when the person eats, which makes the person harder to resist, and, once started, harder to stop eating, to be more ‘efficient’ energetically, saving calories and avoid spending calories as much as the body can, in addition to several other mechanisms.
A real disease like obesity should be approached. Patients should take their own responsibility, the food chemical environment should become more friendly to help patients, not only by avoiding having tasty foods near them, but also by providing pharmacological help to make the weight loss process less painful. Over-efforts tend to lead to overcompensations afterwards, and for this reason the weight loss process should be as easy and should seem as natural as possible.
Recognizing obesity as an actual condition is the best way to beat fatphobia/obesophobia, because it removes the blame from the individual, which is what inherently happens in fatphobic/obesophobic situations. Understanding that treatments for obesity take time and can suffer relapses (which is quite natural and expected), and that patients are not guilty for their obesity opens our eyes to the correct rights they should have for larger seats and other types of priorities.
Endocrinology of Physical Activity
June 26, 2021
HORMONAL CONDITIONING IN ATHLETES – A NOVEL MECHANISM UNVEILED
Dr. Cadegiani conducted the EROS study, the study that discovered the existence of a novel mechanism that occurs in physically active subjects, termed as 'hormonal conditioning', by demonstrating that multiple hormonal axes have optimized responses to any type of stimulation, not only to physical effort, which may finally explain several of the health benefits of physical activity for which the mechanisms could not be fully clarified until these findings.
In conclusion, not only the cardiovascular and musculoskeletal systems become conditioned with training, but also the endocrine system, helping improve performance and reducing multiple risks related to diseases.
HOW ATHLETES HABITS MAY INFLUENCE THEIR PERFORMANCE? DISCOVERY OF NOVEL CORRELATIONS
In the EROS study, Dr. Cadegiani also noticed that good eating and sleeping habits can improve direct- or indirectly sports performance.
Higher protein intake was able to improve body fat, muscles, and hydration. Carbohydrate intake was able to improve sports performance and was not directly correlated with fat gain, except when too much. On the other hand, too few carbohydrate intake led to a paradoxical fat gain and muscle loss. However, athletes with too few carbohydrate intake but that allowed themselves indulge twice a week in a as-much-as-you-can-eat meal were able to prevent this paradoxical reaction, and actually built up more muscles and lost fat.
Too much work led to body composition and metabolism changes for the bad. Bad quality of sleep led to multiple psychological consequences.
The Book on Overtraining Syndrome
June 26, 2021
OVERTRAINING SYNDROME – THE BOOK
Besides being responsible for the majority of the articles published in the field and a reviewer for the majority of the articles in the field that he does not participate as an author, in the last 05 years, Dr. Cadegiani is also the sole author of one of the most comprehensive books in Overtraining Syndrome, published in October of 2020 by Springer Nature, named “Overtraining Syndrome in Athletes – A Comprehensive Review and Novel Perspectives”, first published in October of 2020. In this book, he shows the classical and new theories on overtraining syndrome, the mechanisms that lead to this syndrome, novel clinical and biochemical markers, how to diagnose OTS, practical approaches to the athlete suspected for OTS, among other aspects of OTS. Basically, Dr. Cadegiani proposes a change from the view that excessive training is the major cause of overtraining syndrome to the concept of OTS being a multifactorial disorder, largely influenced by eating, sleeping, and mental patterns. In the book, the author also proposes a standardization and uniformization of the methodological assays of hormonal and metabolic markers for future researches in the field of Sports Endocrinology, in order to improve the quality of the data on this field. It is a must-read for scientists and enthusiasts of sports medicine.
June 26, 2021
The exponential number of publications and citations allowed Dr. Cadegiani not only to become a reviewer of dozens of articles per year, but also to obtain positions as editors of multiple journals. Currently, he is a senior editor of BMC Endocrine Disorders and guest editor of Frontiers in Medicine, Frontiers in Endocrinology, and BMC Sports Science, Medicine, and Rehabilitation.