Stress is inevitable, but the consequences are modifiable if the pathophysiologic basis of the effects of stress and fatigue are well understood, and enough education and support is provided to the patient. Fatigue being a subjective feeling is a very difficult diagnosis to establish. This leads to a prolonged period of dilemma and delay in treatment. Stress affects the neuroendocrine axis (hypothalamic-pituitary-adrenal axis; HPA axis), and preventive and supportive measure targeted towards normalising or balancing the neurotransmitters with lifestyle management, sleep hygiene, balanced nutrition, targeted amino acid precursors, and hormones, may significantly reduce distress and improve the quality of life of patients suffering from chronic fatigue. Chronic fatigue syndrome is a complex area, which involves many problems, including mitochondrial involvement with altered ATP production, leaking gut syndrome owing to ongoing immunological impairment, and inflammation. However, this article will discuss the relationship of fatigue, stress, adrenal gland hormones and neurotransmitters.

Fatigue is one of the most challenging diagnoses to confirm. It can be associated with viral flu, hormone imbalances, stress, neurasthenia, Epstein–Barr virus infection, effort syndrome or post‑viral fatigue syndrome. There has been a range of different nomenclature for the health issues associated with fatigue, but the US Centers of Disease Control and Prevention (CDC) has developed diagnostic criteria1:

‘Clinically evaluated, unexplained persistent or relapsing fatigue that is of new or definite onset, not the result of ongoing exertion, not alleviated by rest and results in substantial reduction of previous levels of occupational, educational, social, or personal activities.’

Physicians are therefore advised to examine patients for four or more of the following symptoms that persist or recur during 6 or more consecutive months of illness and do not predate the fatigue:

  • Self-reported impairment in short-term memory or concentration
  • Sore throat
  • Tender cervical or axillary nodes
  • Muscle pain
  • Multiple joint pain without redness or swelling
  • Headaches of new pattern or severity
  • Unrefreshing sleep
  • Post exertional malaise lasting < 24 hours.


Chronic fatigue syndrome (CFS) is four times more commonly seen in women than men. The most commonly affected age group is 25–45 years, and it is more common in developed countries. Fatigue is a common finding, but CFS is not commonly diagnosed. Of the 4 million Americans who have CFS, less than 20% have been diagnosed owing to the lack of sufficient diagnostic laboratory tests or biomarkers2.


Fatigue is commonly attributed to a variety of causes such as immunological, genetic, post-viral and even neuropsychological, but definitive evidence is still lacking. Nutritional deficiency may be another contributing factor to symptoms of fatigue; however, more evidence is needed to determine what nutritional defects can lead to fatigue. According to recent controlled studies3, 4, CFS has been associated with the impairment of the hypothalamic-pituitary-adrenal axis (HPA) that corrects the normalisation of the imbalance. Whether these changes are primary or because of any other underlying aetiology is still under debate.

Clinical manifestations

A previously healthy individual usually notices fatigue. This leads to a medical visit. Usually, the complaints are of vague aches and pains without any known aetiology and are often underestimated until other symptoms such as depression, difficulty sleeping, and lack of concentration manifest, affecting personal, social, and work life. This can eventually lead to isolation, frustration, anger and even the inability to work.

The symptoms of fatigue and burnout can be divided into three categories:

  • Physical symptoms, including difficulty sleeping, fatigue and exhaustion, gastrointestinal problems, headaches, and increased vulnerability to illnesses such as cold or flu
  • Emotional symptoms, including anxiety, depression, guilt, irritability, and a sense of helplessness
  • Behavioural symptoms, including aggression, callousness, cynicism, defensiveness, pessimism, and substance abuse. Continued fatigue can change work‑related behaviour causing decreased or poor work performance, absenteeism, misuse of work breaks, tardiness, or attrition thefts. Interpersonal behaviour changes include dehumanisation, reduced communication with colleagues and friends, and withdrawal.


Fatigue is a subjective phenomenon, but it is the main complaint of burn-out or CFS. There is no diagnostic test to confirm fatigue. A thorough medical history, exclusion of other underlying pathology, physical examination, and the use of CDC criteria is the best way in which to make the diagnosis.


As more evidence correlates the HPA axis with fatigue, this article will discuss the relationship of fatigue, stress, adrenal gland hormones, and neurotransmitters. It will also establish treatments based on evidence-based medicine, focusing on balance of the neuroendocrine system, hormones and neurotransmitters to reduce the consequences of chronic fatigue or burnout.

Acute stress or delayed effects of chronic stress and related conditions are significant reasons for patients ro visit primary care physicians. This can account for up to 75–90% of cases5. Originally, stress was more physical in nature. Without stress man would have turned into food for predators or would have died as a result of starvation. Before the establishment of agrarian societies, stress conferred protection from imminent danger or any situation mimicking it. Now stress is multi-factorial and stems from mental, emotional, psychological, social, and environmental sources. The body does not distinguish between real or perceived stress, thus the consequences of mental strain can be the same as physical strain. In a study of 29 burnt-out, 33 work-engaged, and 26 healthy managers it was noticed that burnt-out and work-engaged managers only differ marginally in HPA axis functioning6. According to a study7 and press release in 2008 by The American Psychological Association, eight of 10 Americans cite the economy as the leading cause of stress.