Research Blog

February 19, 2022

Stress Biomarkers and Consequences Part 5: Identifying Stress

Welcome to part 5 of the ODX Stress Biomarkers Series. In this post, the ODX Research team reviews the stages of the General Adaptation Syndrome and how the exhaustion phase can contribute to adrenal hypofunction and negative consequences.

The ODX Stress Biomarkers Series

  1. Stress Part 1: A Quick Overview
  2. Stress Part 2: How Do We Get Stressed Out?
  3. Stress Part 3: The Physiology of Stress
  4. Stress Part 4: Hormonal Control of the Stress Response
  5. Stress Part 5: Identifying Stress
  6. Stress Part 6: Disorders Associated with Stress
  7. Stress Part 7: Biomarkers of Stress Overview
  8. Stress Part 8: Biomarkers of Stress, Individual Markers
  9. Stress Part 9: Addressing Stress: Can We Treat It or Beat It?
  10. Stress Part 10: Nutrition and Stress
  11. Stress Part 11: Optimal Takeaway
The response to stress may vary from person to person and will likely be based on the perceived severity of the threat or stressor, or even the emotional state of the stressee.[1]

However, there are some basic internal and external signs of stress that are common. Early investigation and observation of the effects of stress were described as the General Adaptation Syndrome (GAS). The GAS takes into consideration physical and emotional causes and effects of stress.

General Adaptation Syndrome

The theory of a general adaptation syndrome (GAS) was developed in the 1930s by researcher Hans Selye who observed physiological changes that occurred in response to different types of stressors. Animals in the experiments ultimately experienced adrenal gland hypertrophy, lymphatic organ atrophy (i.e., thymus, spleen, and lymph nodes), and bleeding gastric ulcers as a result of prolonged stress.[2]

From Hans Selye’s “The Physiology and Pathology of Exposure to Stress” (1950):[3]

“A variety of "stressors" (such as emotional upsets, exposure to extremes of temperature, and anoxia) set into motion defense reactions mediated through the nervous and the hormonal systems.

These affect blood pressure, body temperature, blood sugar level, blood clotting, osmotic pressure and tissue hydration. During prolonged, severe systemic stress there are 3 phases: "shock," adaptation, and exhaustion. Strong emotions are particularly effective in eliciting the somatic manifestations of the general adaptation-syndrome.

Psychosomatic derangements as well as a variety of neuropsychiatric disturbances are likely to fall into the steadily broadening category of "diseases of (mal)adaptation" to biological stresses.”[4]

The three stages of the stress response are still taken into account today, as researchers observe characteristic signs and symptoms of stress: [5]

Alarm stage “fight or flight”

  • Increased epinephrine, norepinephrine
  • Increased heart rate
  • Increased arterial pressure
  • Increased blood flow to muscles
  • Decreased blood flow to organs not needed for locomotion
  • Increased coagulation
  • Increased cellular metabolism
  • Increased muscle strength
  • Increased mental activity
  • Increased blood glucose
  • Increased glycolysis

Resistance phase

  • Poor concentration
  • Irritability
  • Frustration

Exhaustion phase

  • Anxiety
  • Burnout
  • Depression
  • Fatigue
  • Reduced stress tolerance
  • Decreased immunity

Early in the stress response, both cortisol and DHEA increase but can return to baseline fairly quickly. Symptoms may not be present at this stage. However, if stress continues, the adaption phase will be characterized by persistently high cortisol, declining DHEA, and mood changes including anxiety. In the exhaustion phase, dysfunction progresses toward adrenal hypofunction with low cortisol and low DHEA. Additional consequences can occur at this stage including severe fatigue, hormone imbalance, hair loss, muscle and bone loss, immune dysfunction, arthritis, weight gain, insomnia, anxiety, and depression.[vi]

The General Adaptation Syndrome is basically an observation of the stages of the stress response from acute to exhausted. It is easy to see how a prolonged exhaustion stage can compromise both physical and mental health.


[1] Kemeny, Margaret E. "The psychobiology of stress." Current directions in psychological science 12.4 (2003): 124-129.

[2] Wardle, Jon, and Jerome Sarris. Clinical naturopathy: an evidence-based guide to practice. Elsevier Health Sciences, 2019. 3rd edition.

[3] Selye, Hans. "The physiology and pathology of exposure to stress." (1950).

[4] Selye, Hans. "The physiology and pathology of exposure to stress." (1950).

[5] Chu, Brianna, et al. “Physiology, Stress Reaction.” StatPearls, StatPearls Publishing, 8 June 2021.

[vi] Noland, Diana, Jeanne A. Drisko, and Leigh Wagner, eds. Integrative and functional medical nutrition therapy: principles and practices. Springer Nature, 2020.

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