Cortisol and PTSD, Part 1

An interview with Dr. Rachel Yehuda

Posted Jun 15, 2016

Cortisol, a stress hormone, is a key player in the subtle hormonal changes that have come to be associated with PTSD, and Dr. Rachel Yehuda, a neuroscientist and the director of the traumatic stress studies division at Mount Sinai School of Medicine in New York, has played a major role in advancing our scientific understanding of the role of cortisol in PTSD.

More recently, Dr. Yehuda also offered the PTSD scientific community a novel and intriguing idea: that the children of traumatized parents are at risk for similar problems due to changes that occurred in the biology of their parents, as a consequence of their trauma exposure. It is these epigenetic changes that are then transmitted to their children via a process called “intergenerational transmission.”

Recently, I spoke with Dr. Yehuda about cortisol, intergenerational transmission of stress, and the future of PTSD treatment and research.

Dr. Jain: You played a key role in re-conceptualizing the neuro-endocrine basis for PTSD after it became apparent that individuals with PTSD consistently have low cortisol levels. Can you speak a little bit about how robust a finding this is and what this means for clinical settings? How can we use cortisol levels in the diagnosis of PTSD? Can we use it to track if people are getting better?

Dr. Yehuda: The first published observation on cortisol in PTSD was in 1986 by John Mason and colleagues at Yale.  The group was interested to see if tracking stress hormone levels in patients admitted to the psych unit would aid in determining when patients might be safely discharged, so they measured cortisol levels in a wide range of psychiatric patients. Generally, cortisol levels were higher for patients at admission and then were much lower at discharge, which is what one would expect if cortisol is a marker of stress. However there were two groups of patients, one being patients with post-traumatic stress disorder, for whom this did not appear to be the case. The authors were surprised to find that in fact PTSD patients showed significantly lower cortisol levels at admission and discharge compared to patients with other diagnoses. I joined Yale a year after that finding appeared in the literature. Like many others, I found it curious that cortisol levels would be low and thought for sure there had be some mistake, because we would expect, if anything, that cortisol levels would be high in a stress disorder, particularly one in which there was comorbidity of depression. So I attempted a replication with Mason and his colleagues, and of course, we were able to replicate the low cortisol findings in several studies in the early 90’s.

What was so interesting, however, was how long it took the field to accept that the finding may reflect a reality. At the same time, and in the same patients, Mason and I observed elevated catecholamines. Neither Mason nor I had any trouble with the very first publication that catecholamine levels were higher in PTSD.  No one thought to question the finding because it was something expected—that people who are aroused and under stress have high levels of catecholamines, like norepinephrine. Yet the cortisol data from the samples were difficult for people to believe.  I guess when we hear something that makes sense to us, we do not need a lot of data. But we all questioned the low cortisol finding because it didn’t make sense, and then we questioned the methodology and so on. The reason the finding did not make sense, in the early 90s, was because the field of PTSD was new, and we didn’t really understand PTSD yet. There were really no epidemiological studies until the early 90’s, and even this very well accepted idea that PTSD only occurred in a subset of trauma survivors was not yet known. The prevailing concept was that PTSD always occurred following trauma exposure. But once there was a body of literature that showed that a lot of people are trauma exposed and only a smaller subset of those people get PTSD, the field could start speculating that perhaps low cortisol signals an abnormality that helps explain why recovery has not occurred. And when that happened, we began to ask what is cortisol’s role in stress, anyway? In turns out that one of the things that cortisol does in response to stress is that it helps contain the catecholamine system—it helps bring down the high levels of adrenaline that are released during fight or flight. Since we all know that adrenaline and norepinephrine are responsible for memory formation and arousal, not having enough cortisol to completely bring down the sympathetic nervous system, at the time when it is very important for a person to calm down, may partially explain the formation of traumatic memory or generalized triggers.

The second part of your question is what does this mean in a clinical setting and how can we use cortisol levels in the diagnosis of PTSD? At this moment, we cannot use cortisol levels to aid in diagnoses. They are too variable, and although there is a mean difference between PTSD and other groups, in every study that has been performed to date, there are a lot of overlapping data. Furthermore, even the low cortisol levels in PTSD are well within the normal endocrinological range. The reason the low cortisol finding was important was that it led us down a trail of trying to understand why cortisol levels were low. Then it took us into the dynamics of the way that the hypothalamic–pituitary–adrenal (HPA) axis works and is regulated by the brain. Cortisol levels show natural variation during the day, and are affected by environmental perturbations. It is adaptive that cortisol levels vary, because cortisol helps regulate many bodily functions when we are stressed, and when we are not stressed. What we have been doing for the last 25 years is studying the underlying dynamics of cortisol levels. We have examined circadian rhythm changes that may determine how the brain regulates the release of cortisol over a diurnal cycle. We have looked at cortisol metabolism, to try to understand how cortisol is broken down into its various metabolites in the brain, liver, and kidney. But most of our studies have involved the glucocorticoid receptor and all of the genes and proteins that are involved in regulating the activity and sensitivity of that receptor. These studies have begun to give us an understanding that there is something really different about the stress system in PTSD, or in specific subtypes of people with PTSD,, but it is not going to be cortisol levels per se that are going to be useful to a clinician.

Dr. Jain: So the picture is much more complicated than what may have been originally conceptualized?

Dr. Yehuda: When we say low cortisol levels, an endocrinologist would cringe. In PTSD, cortisol levels are not lower than normal range. They are significantly lower on average compared to persons without PTSD, but the levels themselves are not abnormal. The cortisol levels in PTSD do not suggest that the adrenal gland is broken in any way or not releasing cortisol, but rather, given the normal range of cortisol, which is large—between 20 to 90 micrograms per 24 hours of urine—the means we would get in PTSD were in the 40s. Whereas, a straight mean would be more like in the 50s and 60s. We are not talking about an endocrine problem. We are talking about a tendency to be at the lower end which is within normal variability. Why this was newsworthy, again, was that we were expecting that it would be higher in a stress disorder, because cortisol is associated with stress. I personally would not use cortisol levels, not even 24-hour urinary cortisol levels, as a diagnostic marker. I would want to know a lot more about how the glucocorticoid receptor works. Is it more sensitive? What is the circadian rhythm like? What about cortisol metabolism? What about the genes that control cortisol and glucocorticoid functioning? So there is a potential to find biomarkers that relate to cortisol that may be clinically applicable—we have not given up on that idea at all. It’s just important to understand what kind of neuroendocrine or molecular neuroendocrine information is most relevant.

Dr. Jain: But it is not as simplistic as doing a blood test to diagnose PTSD.

Dr. Yehuda: Would that it were!

Dr. Jain: I know! But you offer a very important clarification: the pattern in PTSD is of lowER cortisol levels, not low cortisol.

Dr. Yehuda: Somehow statistically lower became low, but the devil is in the detail.

Dr. Jain: Absolutely, and that is why it is so valuable to talk to people like yourself.

Dr. Yehuda: Furthermore, the effect size of cortisol differences is small, too. In the Boscarino study (1995), he reported that cortisol was lower in PTSD, but there was a very small effect size. So it is not a diagnostic test. It is just a clue, and we used it exactly as a clue to unravel a deeper mystery.

In my next blog post, I'll share part 2 of my interview with Dr. Yehuda.

Copyright: Shaili Jain, MD. For more information, please see PLOS Blogs.