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The HPA Axis and its Role in Adrenal Fatigue

Posted Jun 14, 2019

The hypothalamic-pituitary-adrenal (HPA) axis is a primary neuroendocrine regulator that influences many processes in the body, including fertility and immunity as well as the stress response. One of its functions that has the most widespread physiological consequences is adjusting cortisol levels according to the needs of the body in response to stress. Cortisol is responsible for many of the life sustaining functions attributed to the adrenal glands.

Secreted by the zona fasciculata in the adrenal cortex, cortisol is regulated by a complex hormonal feedback loop involving the hypothalamus, pituitary gland and adrenal glands. Under normal and stressed conditions, it does this via corticotropin-releasing hormone (CRH) secreted from the hypothalamus to the pituitary in response to a perceived stressor and adrenocorticotropic hormone (ACTH) secreted from the anterior pituitary to the adrenal cortex.

There ACTH activates receptor cells in the zona fasciculata of the adrenal cortex, stimulating the production and secretion of cortisol. Circulating cortisol then signals the hypothalamus via negative feedback to stop cortisol stimulation. In this way, circulating cortisol levels are continually modulated by the HPA axis to meet the body’s needs.2

The HPA Axis and Adrenal Fatigue

Cortisol, often referred to as the stress hormone, is not secreted uniformly throughout the day, but rather follows a diurnal pattern with the highest levels secreted at approximately 8 AM and the lowest between midnight and 4 AM. It is the rising cortisol level that helps cause morning waking.

After its peak at approximately 8 AM, cortisol downtrends through the rest of the day, often with a small dip in the afternoon between 3 and 5 PM. This dip is not a nice smooth curve, but rather filled with episodic spikes that generally fit into an increasing and decreasing pattern throughout the day and evening. Eating something, even a little snack, causes a small burst in cortisol.



In people with adrenal fatigue, this daily cycle of cortisol secretion may be irregular. Just as there are several long-term patterns of adrenal fatigue, there are circadian variations in adrenal fatigue as well. Some people with adrenal fatigue have an overall low pattern of cortisol secretion with circulating cortisol levels lower than normal at every point of the cycle.

Others spike to the normal level at 8 AM, but by 10 AM their cortisol levels have fallen below normal. Some exhibit the normal pattern and levels through most of the cycle but have a severe drop between 3:00 and 5:00 PM. Others fluctuate throughout the day and can even vary from day to day, making their cortisol levels unpredictable.

Whether these variations are a function of their overall stress level, adrenal health, food or environmental sensitivities, or other factors, it is important to be aware that in some people cortisol levels are very erratic during a 24-hour period. These people may go through part of their day with elevated cortisol levels, part of the day with low levels and part with normal levels.

An intimate association between stress and cortisol is manifested in several ways. No matter what the source of stress, most challenges to homeostasis stimulate the HPA axis, resulting in increased secretion of cortisol. As stress increases, progressively higher levels of cortisol are required. When these higher levels of cortisol cannot be produced, as in adrenal fatigue, the person cannot fully or appropriately respond to stress.

Even at normal levels, cortisol serves the very important function of priming the different mechanisms of the body so they can respond when called into action. During stress, cortisol must simultaneously mobilize fats and proteins for a back-up supply of glucose, as well as modify immune reactions, heartbeat, blood pressure, brain alertness and nervous system responsiveness.

Without cortisol, these mechanisms cannot react adequately to a significant stress. When cortisol levels cannot rise in response to these needs, maintaining the body under stress is nearly impossible. The more extreme the difference between the level of stress and the lack of cortisol, the more significant the consequences.2

Cortisol is so important that when the HPA axis cannot increase cortisol activity in response to stress, these unrestrained mechanisms overshoot and can even damage the body.

Thankfully, adrenal fatigue does not have to be a lifelong struggle. The specific supplements combined with dietary, exercise and stress management recommendations in Dr. Wilson ‘s adrenal fatigue protocol have worked time and again to help thousands of people experiencing adrenal fatigue, even the most severe cases.


  1. DeMorrow, S. Role of the Hypothalamic–Pituitary–Adrenal Axis in Health and Disease. International Journal of Molecular Sciences. https://www.mdpi.com/1422-0067/19/4/986/html
  2. Wilson, J. Adrenal Fatigue The 21st Century Stress Syndrome.