- Confusion exists regarding the Female Athlete Triad (Triad) and Relative Energy Deficiency in Sport (RED-S). Although the syndromes overlap, they differ in the scope of outcomes and populations targeted.
- Position stands and consensus statements for both syndromes should reflect the highest level of scientific rigor and quality of evidence possible.
- Triad research has defined its components, their inter-relatedness, its clinical relevance, and the causal role of low energy availability.
- Future Triad research should develop the male athlete triad model, determine the long-term health effects of the Triad, and demonstrate the validity and effectiveness of other strategies to measure energy availability.
- To date, research on RED-S does not support the current conceptual model.
- Future research on RED-S should establish its clinical relevance, clearly define the components RED-S, and test whether relative energy deficiency is causally related to both the health and performance RED-S outcomes proposed.
It is well established that regular exercise and physical activity promote numerous health benefits for girls and women (1,2). However, under some conditions and in some girls and women, participation in sports and exercise can be associated with negative health outcomes. There are currently two schools of thought and corresponding conceptual models regarding the potential for negative health outcomes of participating in sports and exercise: the Female Athlete Triad (Triad; (2–4)) and Relative Energy Deficiency in Sport (RED-S; (5–7)). The Triad is referred to in position stands from 1997 (8) and 2007 (2), and a recent consensus statement in 2014 (3,4), and RED-S is the topic of a consensus statement from 2014 (5) and a recent update (6).
Both the Triad and RED-S statements call attention to the importance of adequate energy intake to prevent negative health outcomes associated with the participation in sport and exercise. They both include point system algorithms for risk stratification and decision-making on clearance and return to play. However, the Triad and RED-S models differ in several ways, including the target audience and scope of outcomes. The Triad refers to girls and women and is focused on low energy availability and associated clinically relevant outcomes, for example, disordered eating, menstrual dysfunction, and bone loss (2–4). RED-S covers a broader array of both physiological and performance outcomes in both women and men and calls for more research on the impact of race, ethnicity, and disability (5,6). The two statements also differ in the way supporting evidence and scientific rigor are interpreted and incorporated into the models representing each syndrome. The authors of the more recent RED-S consensus statement consider the RED-S model to be more comprehensive than the Triad model and have, therefore, called for the “replacement” of the Triad with RED-S (5). An alternative view is that replacing the Triad with RED-S will a) dilute the emphasis on girls and women when it is they who experience the most severe medical consequences and, thus, need the most attention, b) downplay the clinical relevance of eating disorders, menstrual disturbances, and low bone mass as the primary medical outcomes associated with low energy availability, and c) distort the understanding of the physiological underpinnings of the Triad (9).
At this time, controversy (9) and a lack of clarity exist regarding the existence of the two models. There has been no attempt to directly contrast or compare the two perspectives, or to explore where they may be complementary. This lack of clarity may lead to inconsistencies in knowledge translation and policy development without rigorous supporting data. The existence of two different point system algorithms to assist with decision-making regarding clearance and return to play (3,4,7) is confusing. Sports medicine personnel benefit from clarity from researchers and clinicians, particularly when evidenced-based position stands and consensus statements are published. Shedding light on similarities and differences and reviewing supporting evidence for each model should help consumers of this literature make evidence-based decisions. To this end, we highlight key differences in the Triad and RED-S models with a focus on scientific rigor and quality of evidence.
Position stands and consensus statements are critical for knowledge translation. Developed using a systematic review of peer-reviewed scientific literature, they are utilized for developing a) educational tools and metrics, b) clinical decision-making tools, c) reports of clinical practice guidelines, d) an understanding of gaps in the literature, and e) short- and long-term research agendas (10). A discussion of evidence-based publications raises the issue of scientific rigor, which has been the topic of a large number of recently published editorials and articles (11–13). The use of evidence-based grading systems in the writing of position stands has become increasingly common and assures that scientific rigor is upheld. The quality of scientific evidence is graded depending on the nature of the experimental design, the size of the sample studied, the validity and reliability of the measures, and the importance and robustness of the hypothesis addressed (14,15). As the scientific community considers the advancement of our understanding of the Triad and RED-S, careful attention should be given to scientific rigor, quality of the evidence, and clinical relevance. Specifically, the key role of low energy availability (Triad model) and relative energy deficiency (RED-S model) in each model is discussed.
The Female Athlete Triad Model
The Female Athlete Triad was first described in 1993 (16) and again by the American College of Sports Medicine (ACSM) in 1997 (8) as a clinical syndrome involving disordered eating, amenorrhea, and osteoporosis, which was frequently observed in physically active girls and women and female athletes. ACSM updated the new knowledge about the Triad in 2007 and revised its model components to consist of low energy availability with or without disordered eating, menstrual cycle disturbances, and low bone mineral density (BMD) (2). More recently, the Female Athlete Triad Coalition, an organization of researchers, clinicians, and practitioners dedicated to research and education on the Triad, published guidelines on the treatment and risk-management strategies for clearance and return to play in 2014 (3,4). The current Triad model illustrates the three clinical issues on continua from healthy to disease (Fig. 1). The subclinical manifestations of each condition are illustrated along each continuum (2). The directions of the arrows that link each of the three conditions illustrate how they are related to one another. The bi-directional arrows along each continuum illustrate the reversibility of the conditions such that each condition can improve or become worse. The unidirectional arrows from energy availability to menstrual function and bone health, and from menstrual function to bone health, represent the causal roles of low energy availability and hypoestrogenism in bone loss (2). The Triad model specifically identifies low energy availability and disordered eating by indicating that low energy availability can occur with, or in the absence of, disordered eating.
The RED-S Model
RED-S was proposed to be an update of a previously published International Olympic Committee (IOC) Position Stand and an expansion of the Female Athlete Triad model (5,6). Since 2014 (5), there has been one update (6). The RED-S model uses the new terminology, relative energy deficiency, defined as “an energy deficiency relative to the balance between dietary energy intake and the energy expenditure required to support homoeostasis, health and the activities of daily living, growth and sporting activities” (5). Broader in scope than the Triad, the RED-S model illustrates direct relations between relative energy deficiency as a center hub, and the physiological outcomes stemming from this hub (Fig. 2; (5,6)). In all but one case (psychological), the direction of arrows is from relative energy deficiency outward to each of these physiological systems, indicative of proposed direct relations of relative energy deficiency on all of the health and performance outcomes listed. It is purported that “the syndrome of RED-S refers to impaired physiological function including, but not limited to, metabolic rate, menstrual function, bone health, immunity, protein synthesis, and cardiovascular health directly caused by relative energy deficiency” (5,6). A second spoke and wheel figure (Fig. 3) illustrates the potential effects of relative energy deficiency on performance and conditions that can impact performance (5,6). Uni-directional and direct relations between relative energy deficiency and aspects of performance are represented such as decreased glycogen stores, decreased endurance performance, increased injury risk, decreased training response, impaired judgment, decreased coordination, decreased concentration, irritability, and depression. Notably, the RED-S consensus statements include males and female athletes as target audiences (5). The RED-S model holds that the clinical phenomenon is not a “triad” of the three entities of energy availability, menstrual function, and bone health, but rather a syndrome that affects many aspects of physiological function, health, and athletic performance (5).
CLINICAL RELEVANCE VERSUS PHYSIOLOGICAL “IMPAIRMENT”
Each physiological “impairment” in RED-S is considered to threaten one’s health and warrant treatment. An example where physiological versus clinical relevance can be questioned is the inclusion of “cardiovascular” as a health consequence of RED-S. It is stated that “low EA [energy availability] causes unfavorable lipid profiles and endothelial dysfunction, thereby increasing cardiovascular risk” (5). Although unfavorable lipid profiles and decreased endothelial function have been documented in exercising women with functional hypothalamic amenorrhea (17), the long-term cardiovascular consequences of these changes in this population are unknown (18) and it would seem prudent to weigh any such risks against the protective effects of exercise (19).
In contrast to RED-S, the focus in the Triad model is on three clinically relevant conditions associated with low energy availability: eating disorders or disordered eating, menstrual dysfunction, and bone loss (2–4). Studies documenting the underlying metabolic and endocrine changes associated with low energy availability are cited in the Triad literature. For example, the modest elevation in hypothalamic pituitary adrenal axis activity and the decrease in circulating triiodothyronine (T3) concentrations are described, but in the context that these changes illustrate physiological plasticity, not threats to health or medically concerning changes in and of themselves (2,8). That is, when the availability of oxidizable metabolic fuel is low, the body repartitions energy away from reproduction and growth to maintain basic physiological processes such as cellular maintenance, thermoregulation, locomotion, and immune function (20). In exercising women who chronically experience low energy availability, this repartitioning of metabolic fuel is characterized by decreases in resting metabolic rate and shifts in key metabolic hormones, such as suppression of T3, insulin-like growth factor-1, and leptin, and upregulation of growth hormone and cortisol (21–23) in an effort to conserve fuel. The repartitioning of metabolic fuel results in the suppression of reproductive function and growth, with the concomitant emergence of the clinical outcomes of menstrual cycle dysfunction and low bone mass. Accompanying endocrine and metabolic changes, such as a modest increase in cortisol, are not outside normal physiological ranges (23–27), and, thus, they do not represent unhealthy outcomes in and of themselves, but rather, physiological plasticity. In contrast, by asserting that all physiological effects of relative energy deficiency are equally associated with poor health across a long list of systems, the RED-S model dilutes the clinical relevance of the effects on bone and menstrual function.
SCIENTIFIC RIGOR IN THE TRIAD AND RED-S MODELS
A focus on scientific rigor is essential when interpreting consensus statements and position stands. Scientific rigor and reproducibility are the cornerstones of scientific advancement (13) and scientific rigor is a strong focus of National Institutes of Health (NIH; (28)). Scientific rigor is the stringent adherence to the scientific method in all aspects of experimental design, methodologies, analyses interpretation, and reporting of results. It is a means to uncover scientific truth and minimize the premature adoption of unfounded hypotheses (11–13,29). The “plausibility” of a concept is rarely used as the basis for a consensus statement or position stand (12,29). Rather, the results and interpretation of numerous scientific experiments are used to build evidence-based knowledge and are essential components of the rigorous testing of a hypothesis (11–13). Accordingly, consensus statements should reflect the quality and preponderance of evidence from published studies at the time of their writing. The quality of evidence is enhanced by the extent to which the model illustrates key features such as specificity, causality, differentiation between normal physiologic variation and pathological outcomes, and reversibility of the condition. Hence, a comparison of the Triad and RED-S models from this perspective is warranted.
Scientific rigor also is enhanced by peer review and debate. The evolution of the Triad literature has included varied perspectives and debate (30–35). One of the earliest debates centered on whether normal menstrual cyclicity was dependent on a critical level of body fat (34–38). Later, criticisms focused on the sociological implications of drawing attention to health concerns associated with exercise (30) and the lack of data on the prevalence and interrelatedness of the Triad (32). These challenges spurred useful discussion and research to address identified gaps. Advances include studies that demonstrate the causal role of energy availability/energy deficiency on menstrual function and bone health (21,23,39–43), document the prevalence of Triad conditions (44–46), and examine recovery from the Triad (47). Current debates include the utility of particular definitions of energy availability in nonlaboratory settings (48), and the role of psychogenic factors in the modulation of reproductive function (49). Thus, controversy and debate in research can be viewed as a positive force for advancing scientific rigor and reproducibility (50).
Specificity and Scope of Components in the Triad and RED-S Models
The Triad Model
The degree to which elements of a biomedical condition are clearly defined and quantified improves our understanding and enhances the potential for verifying reproducibility with confirmatory research. The three main components of the Triad have been defined and the units of measurement quantified (2). For example, the variable of low energy availability has a particular conceptual definition and standard units of measure that arose from a set of experiments by Loucks et al. (23,25,51,52) on the effects of various levels of energy availability on luteinizing hormone pulsatility and other endocrine end points. As defined by Loucks (23,25), energy availability represents the energy left over for vital bodily processes after accounting for the energy expenditure associated with purposeful exercise. This definition and the utility of this metric are being tested and debated (48,53–55) and given our advancement in understanding energy availability in exercising women since 2007, future position stands and consensus statements likely will reflect revisions to this concept, particularly around the use of an absolute energy availability threshold. Other work has subsequently identified the magnitude of energy deficiency associated with the initial induction of menstrual disturbances with exercise combined with caloric restriction in untrained women (43). Regarding the eating behaviors described as the “with or without disordered eating” component of the Triad, particular definitions and criteria for diagnosis are referred to in the 2007 ACSM position stand (2) and expanded in the 2014 Female Athlete Triad Coalition Consensus Statement (3,4). The bone health component of the Triad also has evolved as the science of the Triad has progressed to its current definition of low bone mineral content, BMD, or areal BMD Z-score that is less than or equal to −2.0, adjusted for age, sex, and body size, as appropriate (3,4). These specific definitions of the components of the Triad allow the measurements to be assessed consistently and accurately, maximizing application and permitting its outcomes to be diagnosable.
The RED-S Model
Relative energy deficiency is the cornerstone of the RED-S model, but no definition and no units of measure are provided (5,6). The definition of relative energy deficiency as published reads “an energy deficiency relative to the balance of dietary energy intake and the energy expenditure required to support homeostasis, health and the activities of daily living, growth and sporting activities” (5,6). There are no specific guidelines on how to measure relative energy deficiency presented in the RED-S IOC Consensus Statement, and the concept is not experimentally derived. Thus, it is unclear how the concept can be applied to assess energy status in the exercising female or male. Notably, in the RED-S consensus statement, and subsequent RED-S publications (5–7), the term relative energy deficiency is used interchangeably with low energy availability, and the evidence provided in support of relative energy deficiency derives from that originally presented by Dr. Loucks in defining energy availability and that used in the Triad model. As such, it is difficult to define which variable represents the cornerstone of RED-S: the measurement representative of the definition described in RED-S publications or that of low energy availability as proposed in the Triad literature.
The physiological and performance-related outcomes that are depicted in RED-S as outcomes of relative energy deficiency are not specifically defined (5,6). For example, “immune function,” “hematological,” and “cardiovascular” are direct outcomes of RED-S, but these outcomes refer to physiological systems rather than quantifiable and reproducible outcomes, making it difficult to confirm or refute these components of RED-S through scientific studies. The magnitude of relative energy deficiency that might be related to various physiological performance or psychological outcomes is not described. Defining what degree of energy deficiency can cause mental impairment, cardiovascular impairment, or declines in muscle strength needs to be demonstrated. Future studies that are designed to test the effects of varying levels of relative energy deficiency on these particular outcomes are necessary to address these questions. Overall, the lack of specificity of the RED-S model invites confusion regarding clarity and prompts important questions with respect to the quality of the evidence supporting the model.
The inclusion of male athletes, athletes across racial and ethnic groups, and disabled athletes in the RED-S model has led to a heightened awareness of the effects of low energy availability in these populations (56). However, effects of sex, race, and ethnicity are a focus of NIH as many physiological systems function uniquely in men and women, and across racial groups, and this literature has evolved in recent decades (57,58). Targeted research is necessary to specifically define the role of low energy availability/energy deficiency on health effects in these groups before the supposition that RED-S affects men, women, and all racial and ethnic groups similarly can be supported. To this end, a roundtable discussion of evidence supporting a “Male Athlete Triad Model” occurred at the ACSM meeting in 2017, and a Female and Male Athlete Triad Coalition sponsored consensus statement is forthcoming.
Identifying Causality in the Triad and RED-S Models
Although scientific progress relies on all types of studies such as observational, association, prospective, randomized controlled trials, and those in animal models, actual experiments that successfully isolate causal factors are required for significant advances in our understanding (11–13,28). The use of arrows in the Triad model depicts not only the direction, but also the causal nature of the association (2). Experiments demonstrating the causal role of low energy availability/energy deficiency on the induction of menstrual disorders (21,43,59) and on poor bone health (39,41,52) support the concepts depicted in the Triad model. Ongoing work is identifying the causal role of energy availability in the reversal of menstrual disturbances and bone loss (47), and there is still much to learn regarding the long-term health effects of the Triad. In the RED-S model, relative energy deficiency is associated, via uni-directional arrows, to 10 different physiological systems and 10 performance outcomes (5,6). The assumption implied by these uni-directional arrows is that these associations are causal and direct, but the evidence to support these direct associations for many of the outcomes is not included in the RED-S 2014 IOC Consensus Statement and update (5,6). Relative energy deficiency does not exert direct and equal effects on all physiological systems as the RED-S model suggests, but rather exerts some of its outcomes indirectly via intermediate physiological changes.
Low energy availability and energy restriction have direct and causal effects on menstrual function (21,43,59–61), and bone health (39,41,52). However, energy deficiency also has indirect effects on bone health through hypoestrogenism secondary to chronic energy deficiency (62,63), which is not illustrated by the RED-S model. In the RED-S model, relative energy deficiency is described to increase cardiovascular risk due to the development of unfavorable lipid profiles and endothelial dysfunction (5). However, it is the hypoestrogenic state that develops secondarily to low energy availability that has been proposed as the mechanism underlying changes in lipoproteins and endothelial function (17). The RED-S model would be improved if it included an arrow connecting “menstrual function” to “cardiovascular” to highlight the indirect relation between these two health outcomes, similarly to how menstrual function is connected to bone health in the Triad model (3,4).
The RED-S Consensus Statement describes an effect of relative energy deficiency on immunity, but no prospective studies are cited to support this. One report is cited in the RED-S 2018 update (6) linking relative energy deficiency to immunity, but it is possible that the physical effects of exercise training or hypoestrogenism are the causes of impaired immune function (64). Shimizu et al. (64) state that intensive exercise training, as opposed to an energy related factor, reduces salivary immunoglobulin A secretion and increases susceptibility to upper respiratory tract infections in athletes, and they fail to link their findings directly to relative energy deficiency. Similarly, a single observational study relating a greater prevalence of viral illnesses to relative energy deficiency in Olympic athletes is based on the response to a question asking whether the individual had been “ill for one week or more during the past [three] months” (65). Although the prevalence of self-reported illness in the previous 3 months was greater in athletes in leanness sports, there is no evidence that the athletes had signs of energy deficiency (65). In a more recent report (66), no definition of “immunological function” was provided, but it was reported that there was no difference in immunological function between athletes divided into low energy availability and adequate energy availability groups based on a conglomerate of self-reported and indirect measures of energy availability.
Gastrointestinal problems are a defined end point of relative energy deficiency in the RED-S Consensus Statement (6,7), but the citation regarding gastrointestinal complications traces back to the eating disorder literature, specifically. It is possible that gastrointestinal symptoms may be secondary to eating disorder behaviors (67–71), including bingeing and purging, rather than being secondary to relative energy deficiency. More recently, Ackerman et al. (66) reported a higher self-reported incidence of gastrointestinal symptoms in athletes who were classified as having low energy availability based on questionnaire data. However, no definition of “gastrointestinal symptoms” was provided. Moreover, interpreting this finding is challenging because there is an established literature documenting gastrointestinal issues in athletes with contributing factors inclusive of mechanical forces and neuroendocrine changes (72), altered gastrointestinal blood flow (73), ischemia (74), and inflammatory bowel disease (75).
A second spoke and wheel diagram in the RED-S model illustrates direct effects of relative energy deficiency on 10 different aspects of athletic performance, ranging from decreased endurance and muscular performance to irritability, decreased concentration and coordination, and impaired judgment (5,6). However, there are few studies cited that support these claims. Many references to performance in the RED-S literature do not include assessments of human performance, but rather, functional limitations such as dehydration, electrolyte imbalances, and gastrointestinal problems such as esophagitis or mucosal atrophy (5,76,77). One study often cited in junior elite female swimmers (78) is one of the few supporting studies that includes biological measures of energy availability and actual performance measures (defined as swim velocity). Another consideration when discussing performance is whether the effects of exercise itself are controlled for. There is much potential for overlap between the overtraining literature and the purported effects of RED-S on performance as decreases in sport-specific performance, emotional/mood changes, lack of motivation, sleep disturbances, overuse injuries, and immune dysfunction are all signs of overtraining syndrome (79–81), and are cited as “health detriments” for RED-S (5,6).
Based on the research cited in the RED-S publications, it can be argued that there is insufficient evidence to date relating relative energy deficiency to the additional physiological and performance outcomes depicted in the model, particularly the purported effects on immune, cardiovascular, gastrointestinal, growth and development, hematological, and performance outcomes. More research must include experiments that establish the direct and causal influence of relative energy deficiency on these end points, and such experiments will need to establish that the effects of relative energy deficiency are independent of the physical effects of exercise. With regard to the Triad, much work needs to be done to address the impact of modifying factors such as gynecological age, genetics, and psychogenic stress on the susceptibility to menstrual disturbances during conditions of low energy availability (82).
Healthy to Pathological Continuum and Reversibility
The 2007 Triad model is in the form of an expanded, 3-D triangle where each of the three aspects of the Triad exists on a continuum from healthy to pathological (2). The end points at the healthy and pathological ends of each continuum are specifically defined and quantifiable. Both the induction and the reversibility of Triad conditions have been explored, and it has been clarified that individuals can move along the three continua in either direction. Scientific evidence supports this bi-directionality and the fact that subclinical conditions exist “along the way” (2). Subclinical menstrual disturbances have been defined both cross-sectionally (44) and prospectively (42,43,59). Short-term changes in bone turnover markers in response to low energy availability (52,83) and animal models of the Triad (39,41) illustrate prospective changes in bone metabolism and BMD. It also has been clarified that the rates of change along the three continua of the Triad are vastly different. In other words, changes in energy availability can happen across the day, or from day to day, whereas changes in menstrual function may take weeks to months, and changes in bone density, structure, and geometry take months to years (3,4).
Experiments illustrating the reversibility of low energy availability/energy deficiency and its impact on reproductive function have been performed (21,84,85). However, a key gap in the Triad literature is the question of whether bone loss can be recovered with the reversal of low energy availability. Case studies (86,87) and observational studies (88) have been published on this issue, but until recently, no randomized controlled trials have addressed this question. This question is being addressed by a randomized controlled trial (47), but more studies are necessary to address the recovery of bone health. The RED-S model does not depict continua from a healthy state to a pathological state, and it is not known whether the effects of relative energy deficiency on gastrointestinal function, cardiovascular function, immune function, growth and development, and hematological function are reversible. If RED-S is to be understood as a biomedical syndrome, future research should address the reversibility of RED-S outcomes when a correction of relative energy deficiency is achieved.
The benefits of exercise and physical activity to human health and well-being are clear and provide a strong rationale for the current recommendations for the quantity and types of exercise. Thus, there are important public health concerns when recommendations are formulated to warn about negative clinical consequences associated with exercise training. As such, intense scrutiny is warranted when considering the scientific evidence supporting such claims. Removing an athlete from competition, or advising an adolescent girl that her exercise is contributing to low energy availability and that she needs to reduce her training, can have a significant impact on the individual’s quality of life given the positive impact of exercise on health and wellness. Moreover, the potential for over-diagnosing or “false positives” underscores the importance of caution when position stands and consensus statements are developed as these often form the basis for sports medicine policy formation.
We have described the differences in specificity and scope between the Triad and RED-S models, the causal role of low energy availability/energy deficiency, and differences in the approaches used to interpret available evidence. Based on our analysis, there are major concerns regarding the lack of specificity and clarity in the RED-S model that hinder the potential reproducibility of findings and a clear understanding of the etiology and scope of the RED-S syndrome. Features such as clinical relevance, directionality, reversibility, and causality that are illustrated and demonstrated in the Triad model based on supporting literature are absent in the expanded representation of energy-related outcomes of RED-S. The lack of evidence supporting many of the purported physiological, health, and performance outcomes described in RED-S and the potential for the confounding effects of exercise itself and overtraining are problematic. As such, the potential is high for confusion and misdiagnoses in the application of RED-S when managing the syndrome in individual athletes. Caution is warranted regarding the overgeneralized approach applied in RED-S when considering the effects of sex, race, and level of ability. Despite these aforementioned issues, there is evidence using citation analyses and social media metrics that the concept of RED-S has garnered significant attention from the public and sports medicine practitioners. Although consumers of scientific literature benefit from the ability of social media to facilitate the rapid dissemination of original research reports, they are done a disservice if the research is over-interpreted or lacking scientific rigor. Opportunities for peer review, the replication of findings, and the execution of experiments identifying causality take years to accumulate. There are tangible consequences of avoiding these steps in the development and maturation of a scientific theory that will impact the clinical care of athletes across the sporting world.
In summary, based on an analysis of the conceptual representation of RED-S and its supporting literature, significant concerns are warranted regarding the scientific basis of RED-S as a working model of a biomedical syndrome. More research is needed to advance our understanding of the effects of relative energy deficiency on health and human performance, but at this point in time, RED-S should not be regarded as a diagnosable condition or considered an evidence-based syndrome. Rather, it is more appropriate to regard RED-S as a concept, like the Triad was in the 1980s, which will require extensive discussion, debate, and experimentation to determine whether it is a diagnosable and a clinically relevant condition. If the idea of RED-S is to be advanced as an evidence-based syndrome, researchers and clinicians would benefit by proceeding with greater caution and attention to scientific rigor, and clarifying key issues such as causality, clinical relevance, directionality, and reversibility.
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