Adrenal Fatigue PART II: Cortisol and the Hypothalamic-Pituitary-Adrenal (HPA) Axis – A Dip Into Physiology

by Camille Charlier

“Adrenal fatigue” proponents are right about one thing: the stress of life can definitely be too much for the body to handle. It’s just not the adrenals that are the problem.

Changes in cortisol production aren’t caused by a deficiency in the adrenal glands, but by regulatory mechanisms of the nervous system that protect against the detrimental effects of cortisol. To make sense of it, we need to take a look at the hypothalamic-pituitary-adrenal (HPA) axis, and how it functions in the stress response.

The Stress Response

The stress response is the body’s adaptive strategy for rising to a challenge. These challenges may be internal (infection, for example) or external, physical or psychological. In response to stress, cortisol is released to help the body redirect energy resources to meet a real or anticipated need.

Three inter-communicating parts of the body team up to control cortisol secretion: the hypothalamus, the pituitary gland, and the adrenal glands. This coalition of organs is known as the hypothalamic-pituitary-adrenal axis (HPA axis).

The adrenal glands are like little hats that sit atop the kidneys and produce cortisol (and other hormones) in response to stress. Cortisol is a steroid hormone synthesized from cholesterol in the adrenal cortex. It is released into the blood and transported throughout the body, where it binds to receptors on target tissues to elicit a physiological response. Receptors for cortisol are found in virtually all tissues and organ systems, including the nervous, immune, cardiovascular, respiratory, generative (reproductive), musculoskeletal, and integumentary systems.

How does the body know when to secrete cortisol? If a stressor is interpreted as a threat (this involves various brain structures, especially the amygdala), the hypothalamus produces corticotropin-releasing hormone (CRH), which induces the anterior pituitary to release adrenocorticotropic hormone (ACTH), which triggers the adrenal cortex to release cortisol.

Cortisol mediates the stress response, regulates metabolism, and influences inflammation and immune function. This hormone makes “fight or flight” possible by increasing the availability of blood glucose to the brain, and acting on the liver, muscle, adipose tissue, and pancreas to release energy fast. Cortisol also enhances the activity of glucagon (a pancreatic hormone that promotes the conversion of glycogen to glucose in the liver) and catecholamines (adrenal hormones, including dopamine, norepinephrine, and epinephrine) (Thau, Gandhi, & Sharma, 2021).

HPA activation is adaptive in cases of acute stress, but the body needs a way to return to baseline after the threat has passed. “Fight or flight” is unsustainable for an organism.

So how do we get back to “rest/digest/grow/reproduce” after a dangerous upset? Enter: the negative feedback loop.

Negative Feedback Loops and the Maintenance of Homeostasis

Negative feedback loops are common in physiological signaling pathways, and they’re essential for the maintenance of homeostasis in the body. Cortisol enhances glucose availability and increases attention, which is helpful when confronting an acute threat, but the hormone also inhibits the immune system, sexual motivation, and growth. Blocking these essential functions for too long is a problem.

Healthy stress responses are characterized by rapid cortisol increase, followed by a gradual decline back to basal or “resting” levels. It’s a classic “what goes up must come down” situation; you need a way to return to baseline after the threat has passed.

The body “turns down” cortisol production via a negative feedback loop. In this case, as blood levels of cortisol rise the hormone binds to glucocorticoid receptors in the hypothalamus and pituitary, which signals to these regions to reduce CRH and ACTH production, which leads to reduced cortisol secretion by the adrenals.

It’s a good thing there’s a dimmer switch for cortisol production, because bad things happen when there’s too much of it. We know what that looks like — it’s called Cushing’s syndrome. Cushing’s syndrome is typically caused by a tumor that wantonly produces ACTH. This hormone triggers cortisol production in the adrenals that is unrestricted by regulatory mechanisms. Symptoms include:

  • Rapid weight gain (mostly in the face, chest, and abdomen), contrasted with slender arms and legs
  • Flushed, round face
  • High blood pressure
  • Osteoporosis
  • Skin changes (bruises, purple stretch marks)
  • Muscle weakness
  • Mood swings (anxiety, depression, irritability)
  • Increased thirst and frequency of urination
  • Lack of sex drive
  • Amenorrhea (The Society for Endocrinology, 2019)

Fortunately, in most cases negative feedback loops keep our hormone levels in the sweet spot — not too much or too little. The body intelligently makes continuous micro-adjustments to maintain homeostasis.

But what happens in the case of chronic stress?

Chronic Stress and HPA Axis Dysregulation

The dynamic responsiveness of the HPA axis to stress is crucial for stress adaptation. That being said, if cortisol is secreted excessively, insufficiently, repeatedly, or in response to non-threatening stimuli, it may cause problems. Higher HPA axis reactivity has been extensively documented in cases of early-life stress, and has been shown to increase the risk of depression. In adulthood, people with a history of childhood abuse or chronic stress have demonstrated lower cortisol responses, or a “blunted response” to acute stressors. Chronic exposures to adverse life conditions are known to cause HPA axis dysregulation (Ouellet-Morin et al., 2011).

Chronically stressed individuals typically demonstrate two types of responses to a stressor:

1. Blunted cortisol reactivity
2. Prolonged cortisol elevation with little to no recovery to baseline (Miller et al., 2013)

Blunted Cortisol Response to Stress

The body is incredibly complicated, and the behavior of the HPA axis varies across populations with different illnesses. Contrary to the mythology propagated by proponents of “adrenal fatigue,” baseline cortisol levels are often elevated in those who’ve experienced chronic stress and associated pathologies. Importantly, basal cortisol levels are not predictive of reactionary levels. Depressed patients, for example, exhibit high levels of basal cortisol that are resistant to negative feedback mechanisms, but have a blunted reaction to pharmacological challenge (taking a drug that stimulates cortisol production).

This clearly indicates dysfunction of the HPA axis, not the adrenals. If the adrenals themselves were impaired, we would expect basal levels to be low.

There are a few possibilities that might explain high baseline levels of cortisol, but blunted production in response to acute stress:

  • Reduced release of the appropriate hormone or releasing factor at any level of the HPA axis (CRH, ACTH, cortisol)
  • Hypersecretion of one hormone/factor with subsequent downregulation of the receptors
  • Inhibition of the HPA axis via enhanced negative feedback sensitivity
  • Reduced sensitivity of the adrenals to ACTH (Hébert and Lupien, 2007)
  • Cortisol synthesis may be regulated by an auto-feedback loop within the adrenal gland itself (Ciato and Albani, 2020)

High baseline levels of cortisol point to glucocorticoid resistance — a phenomenon where glucocorticoid receptors become less responsive due to constant exposure to high levels of cortisol. This is basically the body’s way of “turning down the volume” on cortisol in order to protect against the hormone’s potentially harmful effects. It’s a necessary response to chronic exposure to high levels of cortisol, but it has consequences.

Clinical studies have demonstrated that pathological conditions are typically associated with HPA axis hyperactivation accompanied by the reduced capacity of glucocorticoids to inhibit ACTH and cortisol production. Indeed, glucocorticoid resistance has been proposed as the primary mechanism by which hyperinflammatory states are induced under stressful conditions. Furthermore, glucocorticoids play a significant role in brain health. A prolonged increase in cortisol levels is detrimental to brain neuroplasticity; deterioration in neuron-to-neuron connections is a standard feature of stress-induced psychiatric disorders (Merkulov, Merkulova, and Bondar, 2017).

Dehydroepiandrosterone (DHEA) — Cortisol’s Counterpart

Considering cortisol in isolation is overly simplistic. Let’s introduce a new player: DHEA. Like cortisol, DHEA is a hormone produced by the adrenal gland. It can be thought of as the anabolic counterpart to catabolic cortisol. This means that DHEA is involved in energy storage, in contrast to cortisol, which is involved in energy release. These hormones work together to regulate the processes of glucose metabolism and innate immune activity in order to address the energetic and injury-related demands of stressors. Cortisol and DHEA regulate each other, and DHEA plays an important role in buffering the potentially damaging effects of cortisol.

HPA axis dysregulation (characterized by abnormal cortisol and/or DHEA responses to stress) is associated with myriad mental and physical health problems. A blunted HPA response may cause insufficient immune suppression in response to stress, leading to a state of chronic low-grade inflammation that increases the risk of inflammatory diseases.

DHEA responses to acute stress are associated with better cognitive function post-stress, and DHEA responses are typically blunted in folks with depression. Functional DHEA responses have thus been proposed as a mechanism for biological resilience to stress.

One study investigated the relationship between cumulative life stress and cortisol/DHEA production in response to an acute stressor. Subjects with a history of greater cumulative stress were found to have a blunted response to cortisol, but DHEA was heightened.

Like cortisol, DHEA is produced in the adrenal cortex from a cholesterol precursor. Even when cortisol production is reduced in people with chronic stress, DHEA is increased. Looks like another piece of evidence indicating that the adrenals are functioning just fine. The pathologies we see arising from chronic stress have more to do with the regulatory mechanisms of the HPA axis, and little to do with the adrenal glands (Lam et al., 2019).

At this point I think we can all agree that the story of “adrenal fatigue” is a fairy tale about how the body works. Indeed, the notion that “more cortisol is better” is based on a gross oversimplification of physiology and lack of appreciation for the elaborate, sensitive, highly adapted feedback loops involved in the stress response.

Now that we understand HPA axis dysfunction to be the real problem arising from chronic stress, what can we do? In the final installment of this series we’ll explore strategies to support the HPA axis and promote resilience.

This blog is part of a series on Adrenal Fatigue, you can read the first part here and the third part here.