Despite the identification of multiple markers among clinical, metabolic, and biochemical parameters in OTS athletes in the EROS study [9,10,11,12,13], we were unable to identify specific patterns or a standard group of biomarkers for OTS, as each affected athlete exhibited a unique combination of altered markers. In the absence of a unique accurate biomarker for the diagnosis of OTS, we observed that combinations of markers that were significantly different between the OTS and ATL groups could potentially lead to a precise diagnosis of OTS, with an accuracy of 100% to distinguish OTS athletes from healthy athletes. Despite the successful ability to identify affected athletes, we were unable to identify independent triggers of OTS, as our previous analyses did not identify the influences on or causes of OTS at the individual level. Moreover, the analyses did not enhance our understanding of how each of the modifiable patterns and the occurrence of OTS independently induced changes in the behaviors of multiple clinical and biochemical markers (i.e., inherent changes caused by each modifiable factor, and changes that were independently modified by OTS itself, not by its triggers).
The post-hoc use of multivariate linear regression and logistic regression, which were not used in the previous EROS studies on OTS [9,10,11,12,13], identified the factors that independently led to OTS, and the parameters that were inherently modulated by the presence of OTS. To understand the correlations between OTS and its triggers, and OTS and its consequences, we investigated which modifiable factors could be independent causes of OTS, (i.e., whether a specific modifiable factor was solely responsible for the occurrence of some cases of OTS). We also examined which parameters might be independently modified by the presence of OTS, irrespective of other characteristics (i.e., even with the same caloric, protein, and carbohydrate intake, the same sleep quality and duration, the same amount of additional sports-related activity, and the same training intensity, volume, frequency, and duration). Our aim was to identify whether and how the mere presence of OTS modified the behaviors of the tested parameters. Specifically, among the intrinsic mechanisms of OTS, which were inherently responsible for at least some of the dysfunctional changes found in OTS, as consequences, not causes, of OTS. The dysfunctional adaptations in the clinical and biochemical aspects induced by the modifiable factors, plus the changes in these parameters were inherently due the occurrence of OTS, which was triggered by the same modifiable factors that also led to changes in the behaviors of multiple parameters. In a negative synergistic process, in which dysfunctions were enhanced by the concurrent insufficient carbohydrate, protein, and/or caloric intake, or poor sleep quality, and the presence of OTS, they were also induced by these factors, whereby both changeable factors and the presence of OTS increased the dysfunctions induced by both factors. This vicious cycle probably plays an important role in the challenging recovery process of OTS, as these factors can have a “snowball effect,” which precludes the healing process.
The use of both healthy and OTS-affected athletes for the logistic regression analyses was important to predict behavior patterns prior to OTS, as the development of OTS may be understood as a process on a continuum (i.e., the end of an unresolved mixture of attempts to adapt to chronic energy depletion and the mechanisms underlying a recovery-deprived environment) [1,2,3, 8, 9, 14, 15]. The significant differences in clinical, hormonal, metabolic, psychological, and biochemical behaviors between the ATL and OTS groups, when all variables were perfectly adjusted for baseline characteristics, and training, eating, social, and sleep patterns, supported the conclusion that these changes in behaviors were inherently due to the presence of OTS, as the occurrence of OTS was shown to independently increase tension levels and blunt vigor levels, while may independently enhance fatigue, as a sort of a vicious cycle, since fatigue is also one of the features of OTS. Given the data generated in the present study, the relationship between physiological and pathological behavior patterns suggest these are early signs of future dysfunction (OTS), and therefore, should be used as a warning signal in clinical practice. These differentiations and the pathophysiological paths have provided us with a more comprehensive understanding of OTS.
Independent triggers of overtraining syndrome: beyond excessive training
Excessive training has traditionally been viewed as the major cause of unexplained reductions in sports performance, and therefore, referred to as “overtraining syndrome.” However, given advances in knowledge about the importance of periodized training, excessive training is now considered a minor factor in the development of OTS.
Unexpectedly, the incidence of OTS did not decrease with the improvements in training patterns, nor did it show a paradoxical increase; perhaps this finding is due to the growing number of athletes. Given this context, despite the clear existence of OTS triggers other than excessive training, these findings had not been reported prior to the EROS study.
As all the training patterns were similar between the healthy and OTS-affected athletes in the EROS study, excessive training was not found to be a trigger for all of the affected athletes, which allowed us to identify novel etiologies of OTS. In the EROS-PROFILE arm [11], dietary (i.e., carbohydrate, protein, and total caloric intake), social (i.e., the number of hours spent working or studying), and sleep (e.g., sleep quality) patterns were found to have a role in the development of OTS, as these parameters were significantly different between OTS and ATL group. However, whether any of these triggers were independent or dependent upon a combination of triggers was not examined in this arm of the EROS study.
The combination of OTS triggers identified in the EROS study using logistic regression explained all cases of OTS among the participants (i.e., the combination was shown to be “the perfect predictor”). Even without the independent variable of number of hours worked, the combination of dietary and sleep patterns was still found in all of the OTS cases. Conversely, dietary patterns alone, or the combination of two of the three dietary characteristics with other factors did not explain OTS in any of the affected athletes. Therefore, all dietary patterns plus sleep quality need to be assessed in order to identify athletes at risk for OTS. However, not all possible triggers are needed to develop OTS. In addition, it is important to mention that a very high odds ratio is likely to be a statistical overestimation of an association of different variables when one variable is the sole predictor of an outcome (in this case, OTS) without controlling for other variables.
Carbohydrate, protein, or overall caloric intake may each, independently disrupt physiological responses to a sport; hence, OTS can be induced without the presence of any of the other risk factors. Noteworthy, OTS is more likely to occur after changes in eating, sleeping and/or social patterns. In clinical practice, dietary characteristics should be assessed prior to other triggers, and whenever they do not indicate the presence of OTS, sleep and social patterns should be investigated. However, there is not a specific threshold for each activity or habit, as each the influence of them will highly depend on the combination with other potential triggers of OTS.
Overtraining syndrome as an independent predictor of clinical, metabolic, and biochemical behaviors
Our findings help provide novel tools to identify athletes at risk for developing OTS and for its prevention; this approach is more efficient than the management of the challenges associated with recovery from OTS. Specific outcomes related to these findings are described below.
Although early hormonal responses to the ITT were predicted independently and positively by carbohydrate intake, the presence of OTS predicted their late responses (except for prolactin). Indeed, the commencement of a physical activity at maximum capacity for a short period, which is represented by early responses to stimulation and unaffected by OTS, is not typically observed in athletes with OTS. Conversely, reduced time-to-fatigue, a hallmark of OTS, can be explained by the blunted late hormonal responses independently predicted by the presence of OTS. This indicates an inability to maintain hormonal responses for longer periods in the presence of OTS, which probably explains the reduced pace and impaired performance of athletes during training sessions and competitions.
Among the basal hormones, the T:E ratio [12], but not any single hormone, was disrupted by the presence of OTS. The T:E ratio was found to be a better predictor of metabolic and psychological parameters than testosterone or estradiol alone [12, 16,17,18,19,20,21,22], as the benefits of increased estradiol in males were apparent only with a concurrent increase in testosterone [18, 19, 22]. Testosterone alone did not have the same benefits as the simultaneous increase of both testosterone and estradiol [16,17,18]. The benefits of an increase in estradiol accompanied by an increase in testosterone contrasted with the harmful effects of increased estradiol without an increase in testosterone, which is explained by whether the underlying mechanisms that raise estradiol levels are physiological or pathological. Estradiol physiologically increases in response to increased testosterone, and therefore, both levels are higher; however, a rise in estradiol may be a pathological increase due to an exacerbation of aromatase activity, which is present in metabolic and inflammatory dysfunctions, such as obesity and diabetes. The best way to discern whether an estradiol increase has a physiological or pathological cause, using a single marker, is through the T:E ratio, which is unaffected by physiological situations and reduced by aromatase exacerbations, as in the case of an estradiol increase, leading to a testosterone decrease. A reduced T:E ratio might be additional evidence that OTS, regardless of its triggers, induces an anti-anabolic, dysfunctional, and energy-saving environment to reduce testosterone as a protective mechanism against energy expenditure and anabolic activity by its conversion into estradiol by the enzyme aromatase. However, the underlying mechanisms that lead to a reduced T:E ratio in OTS are unknown. The EROS study showed that a T:E ratio should be greater than 13.7:1.0 (for total testosterone and estradiol are expressed in ng/mL and pg/dL, respectively) [12].
The basic immunology panel was also independently affected by the presence of OTS, which supports the theory of involvement of the immune system in the pathophysiology of OTS. Although altered immunology panels (i.e., altered when compared with healthy athletes, but similar to those of non-athletes) may be linked to blunted hormonal responses to stress [23, 24], the immunology panel and the hormonal responses to stimulation did not exhibit linear correlations or predictions, at least for the immunologic markers analyzed in the present study: neutrophils, lymphocytes, and the neutrophil-to-lymphocyte ratio. Other mechanisms, such as an environment with chronic stressors leading to OTS may directly predict leukocyte composition [25].
The relative dehydration, the decrease in muscle mass, and the increase in visceral fat, which were independently induced by OTS, may have been caused by the multiple dysfunctions associated with this syndrome. The highly oxidative and inflammatory environment that occurs in OTS might have caused increased visceral fat without a concurrent increase in overall body fat.
The impaired mood induced by OTS may contribute to the severe psychological effects of OTS, which are sometimes not fully recoverable. Interestingly, although depression has been reported to be one of the outcomes of OTS [1, 3, 6], this parameter was not predicted by OTS. The harmful changes in both body composition and mood also may have roles in previously unexplained decreases in performance, which is the key and sine-quo-non characteristic of OTS.
Overall, the findings of the various arms of the EROS study led to a new understanding of the underlying mechanisms, risk factors, and diagnosis of OTS, including its pathophysiology, as a mix of failures in the conditioning processes that are typically observed in athletes. Our findings also showed that excessive training results from a combination of different triggers, including insufficient caloric intake, excessive physical and concurrent cognitive effort, and poor sleep quality, instead of the traditional theory centered on overtraining.
We hypothesized that any type of disruption in eating, sleep, social, or training patterns could lead to a spread of dysfunctional reactions through multiple pathways, as a “domino effect,” leading to aberrant changes in hormonal, muscular, immunologic, metabolic, and/or physical behaviors, and ultimately, leading to OTS, if not promptly addressed. Although not demonstrated herein, psychological dysfunctions could also play a role in the pathogenesis of OTS. The key premise of this hypothesis is that any imbalance among psychological, sleep, eating, training, or social characteristics (not only excessive training) may lead to OTS; this has been reported extensively in the different arms of the EROS study [9,10,11,12,13].
Usually, a complex and unique combination of different types of dysfunctions lead to OTS, suggesting that each affected athlete should have an individual combination of parameters that are positive for OTS. Hence, OTS can be diagnosed only by using multiple indices, which was supported by all the study’s cases of OTS, which may be explained only if all possible triggers are assessed, as performed in this study using logistic regression. We suggest that further studies on OTS should always assess at least eating, training, psychological, and social patterns. Although we did not evaluate different sports, the importance of each aspect as part of the pathophysiology of OTS may vary according to the type of sport practiced. However, regardless of the type of sport, the most important aspects of OTS impairment are the rapid reduction in pace during long training sessions and reduced time-to-fatigue, which are both typically found in athletes with OTS. The failure to achieve prolonged optimization of hormonal responses in OTS is likely responsible for athletes’ decreased performance and reduced pace.
The summary of the independent predictors of OTS and its disruptions on clinical and biochemical behaviors is illustrated in Fig. 2.
Limitations
The EROS study only evaluated male athletes that practiced either both endurance and strength modalities, or sports that demand both endurance and strength efforts. As the present study did not analyze athletes of endurance, strength, or explosive (“stop-and-go” sports, such as ball games) modalities, it is uncertain whether the findings on OTS can be replicated to these athletes, as well as female athletes. Further studies with larger samples of athletes are crucial to confirm whether our data are reproducible; longitudinal studies are needed because the present study’s design precludes drawing conclusions from the sequence of events in response to interventions in modifiable patterns, including training, eating, and social aspects.
