Cortisol and Adrenal Fatigue in Our Patients: Part I

Question:

"Should we be measuring cortisol levels in our patients? What are your thoughts about the concept of adrenal fatigue?"

Charles Raison, MD:
Interestingly, if I had only a sentence to answer both these related questions, it would be a short one: “No.” No, I do not think we should be measuring cortisol levels on a routine basis in any psychiatric condition. And no, I do not believe in the existence of adrenal fatigue as that term is commonly understood (ie, a widespread condition of subclinical adrenal insufficiency that gives rise to a collection of nonspecific, and medically-unexplained symptoms, such as body aches, fatigue, nervousness, sleep disturbances, and digestive problems).

Why did I suggest that my negative answers to these questions might be interesting? Because if you had — for some esoteric reason — followed my research and academic writings you would know that I am part of a research group that has spent over a decade working to establish the centrality of cortisol to a variety of psychiatric conditions. In this role I have consistently maintained that psychiatric pathology is far more often the result of too little, not too much, cortisol signaling. Said differently, I am one of the rare folks in psychiatry who believes that cortisol is a good guy, not a bad guy.

This topic is so large and so important that I am going to devote this blog and my next blog to it. Even this “extended coverage” will be inadequate, so let me start by referring you to a number of review articles on the topic (see references). ^1-6

To place the current discussion in context, we need to remember that in the early days of biological psychiatry, many studies showed that people with depression had very high levels of cortisol. In fact, the dexamethasone suppression test was initially employed, at least to some degree, as a means of separating out depression from Cushing’s disease. These findings — combined with neurobiological understandings of the time — gave birth to an idea still current in many psychiatric circles known as the “glucocorticoid cascade hypothesis.” This hypothesis proposes that an inability to cope with chronic stress causes a vicious cycle of excess glucocorticoid (ie, cortisol) release and a subsequent compensatory downregulation of glucocorticoid receptors (GR) in the hippocampus, which further increases cortisol production, resulting in a feed-forward cascade of degeneration and disease. ⁷  In this model, cortisol is a major “bad guy” responsible for many of the pathological findings seen in major depression, especially loss of cortical volume in the hippocampus.

It is my read of the world’s literature that 25 years of subsequent studies have mostly disconfirmed this hypothesis, and have done so by turning the “glucocorticoid cascade hypothesis” on its head. Instead of too much cortisol leading to donwregulation of the GR, we and many others increasingly believe that the primary problem is downregulation or insensitivity of the GR, which then subsequently drives increased cortisol production as a compensatory — but ineffectual — means of attempting to get the “message through.” ¹ Note that a similar phenomenon is often observed in the early stages of type II diabetes when reduced sensitivity of insulin receptors leads to compensatory increases in plasma insulin levels, which nonetheless are unable to adequately lower blood glucose levels.

From this perspective the high levels of cortisol sometimes seen in depressed individuals reflect not too much cortisol, but too little! It is for this reason that we have argued strongly for the importance of not conflating hormone levels with hormone adequacy. Hormone levels are always only half the story, because they are always in a dynamic equilibrium with the amount and sensitivity of their receptors. Rather than thinking of hormones in isolation therefore, we would do well to think about “hormonal signaling,” which basically asks how well the biological signal for a given hormone is getting through given the current needs of body and brain.

A huge literature shows that environmental factors that increase the risk for depression also reduce the functional capacity of GR in both the brain and the immune system. In animal studies of early life stress, reduced GR functioning plays a central role in the development of adult behavior that resembles human depression. Michael Meaney and colleagues demonstrated that — in rats at least — the lifelong stress protective effects of “good mothering” were physiologically conferred by epigenetic processes that made the GR more sensitive — and hence more functional. More recently, epigenetic patterns consistent with reduced GR functioning in the hippocampus have been demonstrated in the postmortem brains of individuals who experienced documented child abuse, ⁸  consistent with the possibility that early adversity promotes depression — at least in part — not by causing too much glucocorticoid signaling — but by causing too little. Consonant with these findings, a recent study demonstrated that the ability of antidepressants to induce neurogenesis in the hippocampus was abolished when GR were blocked with RU486, ⁹ consistent with other studies suggesting that antidepressants work, at least in part, by making the brain more sensitive to cortisol. ^{10, 11}

Having warned against the dangers of equating hormone concentrations with signaling adequacy, it is nonetheless impossible to ignore the growing number of studies suggesting that many conditions associated with stress and symptoms caused by stress (such as exhaustion and bodily pain) are characterized by reduced levels of circulating cortisol. ^12-14 These conditions include posttraumatic stress disorder (PTSD), chronic fatigue syndrome (CFS), and fibromyalgia. Even more convincing are studies showing that low levels of cortisol at the time of a traumatic incident predict the later development of PTSD. ¹⁵  A recent study that has been reported in the media, but is not yet published, followed up on these observations by showing that people treated with corticosterone immediately after a traumatic incident were less likely to later develop PTSD compared to people receiving placebo. Similarly, glucocorticoid administration has been shown to reduce chronic stress symptoms following prolonged stays in an intensive care unit ¹⁶  and to increase people’s ability to cope with stressful experiences (in this case a standardized laboratory psychosocial stress test). ¹⁷  Finally, a recent animal study found that chronic corticosterone administration through adolescence led to increased hippocampal neurogenesis into early adulthood and reduced depressive-like behavior in response to stress. ¹⁸

Hopefully, this quick review gives at least a glimpse of why I am so interested in the role of hypothalamic-pituitary-adrenal axis functioning in mood, anxiety, and pain/fatigue disorders, as well as why I believe that, in general, too little, rather than too much glucocorticoid signaling contributes to this welter of clinical problems. But still we are left with a problem: because GR and cortisol levels exist in a see-saw relationship with each other, we are still left with the question of whether glucocorticoid signaling—considered as the sum of hormone levels plus receptor functionality—is really decreased in these conditions. What we need is some type of integrated read-out of glucocorticoid signaling to tell us how well the “full signal” is getting through.

Here is where inflammation comes to the rescue. Because cortisol is one of the most potent anti-inflammatory chemicals in the body, conditions associated with reduced glucocorticoid signaling should also be associated with increased inflammation, whether the reduced signaling occurs primarily at the level of the hormone (eg, PTSD, CFS) or primarily at the level of the receptor (eg, major depression). So what’s the verdict?

Well, anyone following current scientific developments in psychiatry can hardly be unaware of the exploding database linking a wide range of mental disorders to increased inflammation. ¹⁹  This is a whole topic in itself, for current purposes the point is that increasing data suggest that disorders associated with either low cortisol or reduced GR function tend to also be associated with inflammation, which we feel provides fairly strong evidence for true glucocorticoid inadequacy in these conditions.

So with this extended introduction, in my next blog I’ll discuss why—appearances to the contrary—I do not believe in either routine cortisol measurements or in adrenal fatigue.

References

1. Raison CL, Miller AH.  When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders.  Am J Psychiatry.  2003;160(9):1554-1565.
2. Pace TW, Miller AH.  Cytokines and glucocorticoid receptor signaling. Relevance to major depression.  Ann N Y Acad Sci.  2009;1179:86-105.
3. Pace TW, Hu F, Miller AH.  Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression.  Brain Behav Immun.  2007;21(1):9-19.
4. Pariante CM, Miller AH.  Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment.  Biol Psychiatry.  2001;49(5):391-404.
5. Holsboer F.  The corticosteroid hypothesis of depression.  Neuropsychopharmacology. 2000;23(5):477-501.
6. Yehuda R.  Status of glucocorticoid alterations in post-traumatic stress disorder.  Ann N Y Acad Sci.  2009;1179:56-69.
7. Sapolsky RM, Krey LC, McEwen BS.  The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis.  Endocr Rev.  1986;7(3):284-301.
8. McGowan PO, Sasaki A, D'Alessio AC, et al.  Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.  Nat Neurosci. 2009;12(3):342-348.
9. Anacker C, Zunszain PA, Cattaneo A, et al.  Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor.  Mol Psychiatry. 2011;[Epub ahead of print].
10. Pariante CM, Pearce BD, Pisell TL, Owens MJ, Miller AH.  Steroid-independent translocation of the glucocorticoid receptor by the antidepressant desipramine.  Mol Pharmacol.  1997;52(4):571-581.
11. Pariante CM, Makoff A, Lovestone S, et al.  Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters.  Br J Pharmacol.  2001;134(6):1335-1343.
12. Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ. Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. Neuropsychobiology.  2007;55(2):112-120.
13. Tak LM, Rosmalen JG. Dysfunction of stress responsive systems as a risk factor for functional somatic syndromes. J Psychosom Res. 2010;68(5):461-468.
14. Bauer ME, Wieck A, Lopes RP, Teixeira AL, Grassi-Oliveira R.  Interplay between neuroimmunoendocrine systems during post-traumatic stress disorder: a minireview. Neuroimmunomodulation.  2010;17(3):192-195.
15. Delahanty DL, Raimonde AJ, Spoonster E.  Initial posttraumatic urinary cortisol levels predict subsequent PTSD symptoms in motor vehicle accident victims.  Biol Psychiatry.  2000;48(9):940-947.
16. Schelling G, Kilger E, Roozendaal B, et al.  Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study.  Biol Psychiatry.  2004;55(6):627-633.
17. Het S, Wolf OT.  Mood changes in response to psychosocial stress in healthy young women: effects of pretreatment with cortisol.  Behav Neurosci.  2007;121(1):11-20.
18. Xu Z, Zhang Y, Hou B, et al.  Chronic corticosterone administration from adolescence through early adulthood attenuates depression-like behaviors in mice.  J Affect Disord. 2010;[Epub ahead of print].
19. Miller AH, Maletic V, Raison CL.  Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression.  Biol Psychiatry.  2009;65(9):732-741.