Reading Research: Chronic Stress and the HPA Axis

Even though I’ve been reading plenty about stress in a couple of books (see The Stress of Life, by Hans Selye and Status Syndrome, by Michael Marmot), I’ve also managed to find the time to read a few interesting studies.

Some of the studies I picked up were absolutely fascinating but I didn’t have any obvious places to write about them, as my main stress posts cover the basic principles rather than more recent findings (see my posts on what is stress? and how does stress work?).  So I decided to start a reading research series, in which I’ll talk about what studies I’ve been looking at.

One of the most fascinating studies I picked up was If it goes up, must it come down? Chronic stress and the Hypothalamic-Pituitary-Adrenocortical Axis in Humans (Gregory Miller, Edith Chen and Eric Zhou, American Psychological Association).

Here’s a quick summary plus a few thoughts.

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OK, what’s it all about?

Well, the study basically falls into two parts, as follows:

1. A summary of the status of stress research in recent years, with a focus on how many theories have identified the HPA axis as the villain; and
2. A discussion of the areas in which there is uncertainty, specifically the way in which the HPA axis is affected by chronic stress – is it activated more strongly or subdued?  Or is there a third possibility?

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1. Stress and the HPA axis

The review states that at present: “the notion that chronic stress fosters disease by activating the hypothalamic-pituitary-adrenocortical (HPA) axis is featured prominently in many theories”.

The general consensus of how activation of the HPA axis is described as follows: “activation occurs when neurons in the pararventricular nucleus of the hypothalamus secrete corticotropin-releasing hormone (CRH).  This molecule travels through the hypophyseal portal circulation to the anterior pituitary gland, which responds to its presence by secreting a pulse of adrenocorticotropic hormone (ACTH).  The ACTH signal is carried through the peripheral circulation to the adrenal glands, which synthesise and release cortisol in a tissue layer called the zona fasciculata.”

If that makes absolutely no sense to you, read the second half of my article on how stress works and it should become clearer.

The review goes on to explain that cortisol has been heavily studied as the main culprit in making people ill in response to stress and that many studies have monitored cortisol levels in people suffering from chronic stress, with a view to understanding how this creates problems.

Finally, the review notes that in most theories at the moment, it is suggested that: “stress triggers disease by increasing output of cortisol, thereby exposing bodily tissues to elevated concentrations of the hormone.  If sustained, this process is thought to lead to tissue damage and subsequent dysregulation of biological systems.”

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So it’s all sorted then?

Not so fast.  The problem is that there have been other theories based on conflicting evidence, that suggests that stress-induced declines in cortisol are the culprit.  This is termed hypocortisolism, as apposed to hypercortisolism.

An example of this work might be Heim, Ehlert and Hellhammer, The Potential Role of Hypocortisolism in the pathophysiology of stress-related bodily disorders, Psychoneuroendocrinology, 2000

This is actually quite annoying.  So we know that chronic stress make us ill but we don’t really know whether it makes cortisol levels go up or down.

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Confusions reigns

This problem actually caused a lot of confusion in stress research.

At the outset, Selye found that cortisol levels were increased and because of his influence, early work showing that in some circumstances cortisol was subdued were ignored.

Later, specific work on post-traumatic stress disorders (PTSD) found that cortisol was often subdued and this was treated as a specific phenomenon to PTSD.  However, more recently it has been found to occur in a wider range of cases as well as PTSD.

So this brings us to the next part of the review.  How does the HPA axis respond to chronic stress and what does stress research need to look at in the next decade?

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2. How does the HPA axis respond to chronic stress

The authors of the review formulated five hypotheses and used a meta-analysis to perform a sense check on them, as follows:

1. Time since onset

Perhaps chronic stress actually both increases and decreases HPA axis activity but at different lengths of time following a threat being perceived?

The review found that based on studies already performed there is some good evidence to suggest that chronic stress causes an initial significant increase in cortisol levels, followed later by a rebound to significantly lower levels, once the stress has been removed.

2. Nature of threat

Is the nature of the stressor important for understanding what the stress response might be?  Social threats have been shown to create large increases in cortisol, as Michael Marmot has discussed.  Also, there may be a difference between traumatic and non-traumatic threats in the response they illicit.

The review found that both traumatic stress and social threats both caused high levels of cortisol that did not fluctuate during the day.

3. Emotions elicited

Some work has suggested that specific emotions might be implicated in either high or low secretions of cortisol.  In particular, shame and loss have both been implicated in varying cortisol responses.

Shame appears to create a higher level of cortisol in the afternoons and evenings, essentially a complete reversal of a normal healthy profile.  Loss appears to cause a flattened profile, similar to the traumatic stress response described above.

4. Controllability of stressor

Control has emerged as a key issue for both humans and animal subjects in tests of stress-related issues.  Michael Marmot believes that our inability to control our environment is what makes poor status a predictor of stress-related disease and mortality.

However, the cortisol response to levels of control seem to be mixed.  Some studies suggest that it causes increases, some decreases.  Fortunately, it seems to be the prolonged stressors that create decreases, which may make this a timing issue.  The review concluded that the evidence on these matters was poor.

5. Individual psychological differences

It is possible that we may individually be predisposed towards either hypercortisolism or hypocortisolism.

Remember above how people with PTSD tended to get hypocortisolism?  Not everyone exposed to a stressor gets PTSD.  However, those that do develop PTSD tend to get hypocortisolism and those that don’t tend to get hypercortisolism.

Also, the levels of stress people report is proportional to the amount of cortisol secreted.

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Confusion reigns

The study concludes that is still confusion over whether stress makes your cortisol levels go up or down but it seems that the general trend is up, with certain caveats, particularly around personality types (predisposition to PTSD, for example) and certain emotions.

However, the review does note that many studies are still only making one cortisol measurement per day and that this needs to change, as there is evidence to suggest that different daily cortisol profiles are associated with different stressors.

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Afterword – HPA axis inflexibility

The study did not review the work of Per Bjorntorp on stress and cardiovascular disease that Malcolm Kendrick describes in his book.  Bjorntorp, who is referred to in the review but not extensively quoted, believed that the key to good health was the flexibility of the HPA axis (i.e. its ability to move up or down over the course of the day) and not whether it was up or down.

Bjorntorp says: “the perturbed regulation of the HPA axis rather than elevated cortisol secretion might be the crux of the matter in attempts to understand how cortisol secretion is associated with metabolic abnormalities.”

I’ll review an article by Bjorntorp next week and you’ll see how his theory actually fits most of the above data quite well.

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Clearly, there is still a lot of work to be done here.