Multiple Organ Phenotype of Fatigue, 2025, Xiaohua Liu et al

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Abstract
Fatigue is not only a widespread subjective experience but also a complex physiological and pathological state involving multiple organs and systems. Currently, there is no consensus on the definition and classification of fatigue. Based on its causes, this paper categorizes fatigue into sports fatigue, occupational fatigue, and pathological fatigue. It elaborates on the specific manifestations and underlying mechanisms of fatigue in the motor, nervous, cardiovascular, digestive, urinary, endocrine, and reproductive systems, aiming to uncover the intrinsic connections of fatigue phenotypes across different systems.

These findings may provide key targets for gene-assisted therapy of fatigue-related complications, thereby establishing a new theoretical foundation for the clinical management of fatigue and related research.
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Influence of Fatigue on the Endocrine System

Overtraining syndrome (OTS) is described as a form of chronic fatigue and burnout due to an imbalance between training/competition and recovery. This exercise-induced fatigue can upset the balance of the endocrine system, which in turn affects the function of the adrenal glands and gonads.

First, exercise can affect the size and function of the adrenal glands. The adrenal gland size is increased by 31.04% in the mice with high-intensity exercise, and by 10.08% in the low-intensity exercise mice, and the adrenal medulla is significantly increased with high intensity. A certain intensity of exercise is beneficial for adrenal function, but when exercise is performed excessively, sports fatigue occurs, and OST occurs. Adrenocorticotropic hormone (ACTH) and cortisol are two essential hormones required to maintain performance and speed during any exercise .

Corticotropin-releasing hormone (CRH) overactivity is thought to be associated with overtraining syndrome. Overtrained long-distance runners have a significantly reduced pituitary ACTH response, reflecting reduced hypothalamic and/or pituitary responsiveness and adrenal responsiveness to adrenocorticotropic hormone . Cortisol, a hormone secreted by cortisol-producing cells in the adrenal cortex, is also affected. In overtrained long-distance runners, the maximum exercise-related cortisol levels decreased compared with baseline. In addition, the OTS group had lower cortisol levels during and 30 min after hypoglycemia compared to the exercise-healthy group, and the mean cortisol rose slowly. In the insulin tolerance test, the ACTH/cortisol ratio was significantly lower in the OTS group compared with the healthy inactive group. These suggest that athletes affected by OTS have intrinsic dysfunction of the hypothalamic–pituitary–adrenal gland (HPA) in stressful situations].

In addition, patients with chronic fatigue syndrome have decreased adrenal secretion of cortisol, including basal cortisol and post-activity cortisol