Speaker: Dr Justin Carrard, MD, Head of Sports and Youth Health Unit, Lausanne University Hospital, Lausanne, Switzerland
Associate researcher, University of Basel
Congress: Sport & Exercise Medicine Switzerland and Swiss Sport Physiotherapy Association joint conference: “Structure & Function”, Lausanne, October 30th and 31st 2025
Scan to access presentation on Sportfisio YouTube channel
Introduction
Overtraining syndrome represents a complex pathological state resulting from chronic imbalance between stress and recovery, producing prolonged performance decrements resistant to standard recovery interventions. While acute fatigue and functional overreaching constitute physiological components of training adaptation, progression to nonfunctional overreaching and overtraining syndrome represents maladaptation with substantial career implications. This article synthesizes current understanding of the fatigue-overtraining continuum, diagnostic approaches, and emerging metabolomic research strategies, drawing from presentation by Dr. Justin Carrard, sports medicine physician and researcher at the Swiss Olympic Medical Center, Lausanne.
Structure-function interdependence: Foundational concepts
Biological systems demonstrate bidirectional structure-function relationships. At macroscopic levels, three-dimensional anatomical structure determines function—cardiac conduction patterns reflect myocardial architecture. Reciprocally, functional demands reshape structure—exercise-induced cardiac remodeling exemplifies function modifying structure. This bidirectional relationship extends to molecular levels. Hemoglobin’s oxygen-transport function depends on tertiary protein structure; conversely, functional demands (exercise-induced tissue warming and acidosis) alter hemoglobin conformation, facilitating oxygen release to active tissues. Understanding overtraining syndrome requires examining both functional manifestations and underlying structural/mechanistic alterations.
The fatigue continuum: Physiology to pathology
Acute Fatigue
Normal post-exercise fatigue resolves within 20-30 hours, facilitating progressive adaptation and performance improvement. This represents physiological, expected training response.
Functional Overreaching
Characterized by deliberate fatigue accumulation during intensified training periods (e.g., training camps) with performance decrements during overload, followed by supercompensation after recovery. This intentional strategy produces performance gains and remains physiological.
Nonfunctional Overreaching
Results from excessive training volume or intensity where recovery periods restore only baseline performance capacity without supercompensation. Athletes invest substantial time and energy without adaptation benefits—a maladaptive, inefficient state marking the transition to pathology.
Overtraining Syndrome
Represents severe maladaptation where performance decrements persist despite weeks, months, or occasionally years of recovery. This constitutes frank pathology requiring prevention rather than treatment.
Overtraining Syndrome: Definition and Pathophysiology
Clinical Definition
Overtraining syndrome involves accumulation of training and/or non-training related stress over prolonged periods resulting in performance capacity reduction, potentially accompanied by physiological and psychological maladaptation signs and symptoms. Recovery requires weeks to months, distinguishing it from shorter-duration overreaching states. Minimum symptom duration of four weeks is required for diagnostic consideration.
Central Fatigue Hypothesis
Chronic stress-recovery imbalance produces central nervous system alterations including reduced serotonin, increased dopamine, and decreased norepinephrine levels. These neurotransmitter changes affect hypothalamic-pituitary function, producing blunted prolactin, adrenocorticotropic hormone (ACTH), and growth hormone secretion, particularly in response to exercise. Parasympathetic nervous system dominance over sympathetic activity characterizes this neuroendocrine disruption.
Peripheral Fatigue Hypothesis
Skeletal muscle represents both contractile and endocrine organs, secreting myokines involved in inflammatory processes. Peripheral mechanisms implicated in overtraining syndrome include chronic glycogen depletion, mitochondrial dysfunction in overtrained athletes, and disrupted muscle endocrine signaling. Current understanding encompasses both functional alterations and partial mechanistic/structural insights, though complete pathophysiological elucidation remains incomplete.
Diagnostic approach: the «Olympic Squares» Framework
Performance Assessment
By definition, overtraining syndrome requires documented performance decrement. Absence of performance decline excludes the diagnosis regardless of symptomatology.
The Five Domains of Assessment
• Square 1—Performance: Objective documentation of performance capacity reduction
• Square 2—Stressors: Comprehensive history of training and non-training life stressors. «Sufficient» training volume is individual-specific; 10 hours weekly may represent appropriate loading for some athletes but excessive for others.
• Square 3—Recovery: Assessment of rest day frequency, sleep quality and quantity, and recovery strategy implementation
• Square 4—Nutrition: Evaluation for Relative Energy Deficiency in Sport (RED-S), ensuring adequate caloric and protein intake
• Square 5—Mental Health: Systematic screening using International Olympic Committee-published mental health assessment tools
Differential Diagnosis Framework
• Square 1—Deficiencies and Hematology: Iron deficiency, vitamin deficiencies
• Square 2—Infections: Immune system compromise in overtraining increases susceptibility to opportunistic infections (e.g., EBV, HIV, Lyme, toxoplasmosis…)
• Square 3—Metabolic Disease: Thyroid dysfunction (particularly hyperthyroidism screening via TSH in young female athletes), diabetes, hypocortisolism
• Square 4—Immunological Disease: Systemic lupus erythematosus, celiac disease (prevalence 1% in general population, 10% with concurrent iron deficiency), Crohn’s
• Square 5—Sport-Specific Diagnoses: RED-S, musculoskeletal pathology, asthma, EILO, allergies, harassment and abuse
Diagnostic Uncertainty and RED-S Overlap
Overtraining syndrome remains a diagnosis of exclusion. Substantial overlap exists with RED-S—both share symptomatology and may coexist. The conceptual distinction: RED-S reflects caloric input-output imbalance; overtraining syndrome reflects stress-recovery imbalance. However, athletes may simultaneously train excessively, recover inadequately, and fail to meet nutritional requirements.
Emerging Diagnostic Tools: The Training Optimization Test
The Training Optimization Protocol (TOP test) employs two maximal cardiopulmonary exercise tests separated by four hours, with blood sampling before and after each bout. Overtrained athletes demonstrate blunted ACTH, prolactin, and growth hormone responses following the second exercise bout compared to healthy athletes and those with nonfunctional overreaching, providing objective neuroendocrine differentiation.
Metabolomics: Bridging functional and Structural understanding
The Biological Continuum
Biological organization progresses from genome (genes describing potential events) through transcriptome, proteome, to metabolome (small molecules including lipids describing events that actually occurred). The metabolome more closely approximates phenotypic expression than upstream molecular levels, providing clinically relevant biological fingerprints.
Metabolome Characteristics
The metabolome integrates genetic, transcriptomic, and proteomic influences with environmental factors (exercise volume, nutritional intake) and internal microbiome composition. Metabolites demonstrate substantially greater diversity than proteins or genes, enabling individual-specific metabolic fingerprinting. Approximately 70% of blood small molecules are lipids, functioning not only in energy metabolism but as signaling molecules—particularly relevant for overtraining, fatigue, and recovery research.
Targeted Versus Untargeted Approaches
• Untargeted metabolomics: Hypothesis-generation through comprehensive metabolite acquisition
• Targeted metabolomics: Hypothesis-testing of specific molecular families
• Hybrid approaches: Quantification of ~1,000 metabolites with absolute quantification enabling cross-study comparison.
Current research applies metabolomics to the two-bout exercise protocol, acquiring metabolic fingerprints differentiating overtraining syndrome, nonfunctional overreaching, functional overreaching, and healthy athletes through collaboration with Brussels research groups.
Conclusion
Structure shapes function, but function reciprocally reshapes structure—a bidirectional relationship operating across biological organizational levels. Overtraining syndrome is predominantly understood functionally, with substantial gaps in structural and mechanistic knowledge underlying fatigue and maladaptation in sport. Post-genomic approaches, particularly metabolomics, offer powerful strategies for bridging this knowledge gap, potentially enabling earlier detection, mechanistic understanding, and targeted interventions for this athletic career-threatening condition.
References
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