Cortisol and PTSD, Part 3

Last week, I shared part 2 of my interview with Dr. Rachel Yehuda, a neuroscientist and the director of the traumatic stress studies division at Mount Sinai School of Medicine in New York. Dr. Yehuda 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. Here is part 3 of our interview.

Source: Pexels

Dr. Jain: Transitioning to this concept of this intergenerational transmission of stress: Your 2005 study with the women who were pregnant in the World Trade Center, it was fascinating to read that study. I thought that it was an elegant demonstration of this concept of intergenerational transmission of stress. It would be great if you could talk a little bit about that study. One question that came to mind was a question about the pre-trauma cortisol level in the women. I wondered if that was measured, and did you gather data on their earlier experiences with trauma? That was just one particular question I had, but if you could just discuss the study in general, because I think it was really a fantastic contribution to the literature.

Dr. Yehuda: We did not have a lot of information on the women. In fact, this whole study was post-hoc in a sense that the study was designed for a completely different reason. It was to monitor pregnant women to make sure they gave birth to healthy babies. Everyone was really concerned about the level of environmental toxins after 9/11. Somebody from the environmental medicine group reached out to me because they noticed that a lot of women were really not doing very well emotionally and psychologically.

So by the time I was involved, some of the women had already given birth, but there had been a lot of information about what trimester they were in, about any pregnancy complications, exposure to toxins, etc. etc. So we added to that an evaluation of PTSD. Then when they came in for their 7 month to 1 year wellness baby evaluation, we were able to get salivary samples from the mother and the child. By then it did not surprise us to see that mothers with PTSD had lower cortisol levels than mothers without PTSD. But what did fascinate us was that in the mothers that had lower cortisol, the babies also had lower cortisol, but that this was a trimester dependent effect and that it seemed to split out in the second and third trimester in mothers who had been exposed in the middle of the second trimester or exposed in the third trimester.

When we had those findings, a lot of possibilities opened up in terms of how cortisol levels might be transmitted from parents to child or from mother to child. We were not the first people to make this observation. There has been a literature that that has demonstrated that mothers who are exposed to under feeding before puberty have children and grandchildren that have metabolic problems. Since we knew that the women exposed to starvation during pregnancy also tend to give birth to children who were more prone to hypertension as adults, we knew that there was the possibility of in utero effects.

But what seemed to happen here was an example of glucocorticoid programming. In the middle of the second trimester of pregnancy, there is an enzyme that becomes expressed in the placenta. It is an enzyme that blocks the conversion of cortisol to its inactive metabolite, cortisone. The induction of this enzyme really helps protect the fetus from detrimental effects of maternal glucocorticoids, because the cortisol is broken down into its inactive metabolite, cortisone. The enzyme is called 11β-Hydroxysteroid dehydrogenase type 2. We had already been interested in studying this enzyme just because we were interested in cortisol metabolism. But it turns out that in mothers who are under stress, it is very possible that their enzyme levels and the amount of glucocorticoids they have could overwhelm the body’s ability to metabolize cortisol into cortisone and affect the fetus. That was one idea that we had, that there might be a transmission based on offspring response in utero to maternal levels of stress hormones.

The message is straightforward: mothers who are stressed during pregnancy can program the stress response of their offspring, in utero, and the offspring accommodates somehow to the level of stress hormone. That has become a very important issue also in our intergenerational studies. It has become one viable mechanism through which mothers may “transmit” different vulnerabilities (or resilience) to their offspring. One does not need to have actual trauma experiences post-natally in order to have some of the neuroendocrine features associated with PTSD and PTSD risk. And this means that pregnancy is an important time with great social implications for our society. I do not think that we think about pregnancy as the very important developmental event that it really is. Otherwise, we would be really taking much better care of traumatized pregnant women than we do.

Dr. Jain: Obstetrics care involves screening for gestational diabetes, congenital defects in the baby, and even screening for postpartum depression……

Dr. Yehuda: Yes, and we should screen for trauma, too.

Dr. Jain: Given how high the rates of trauma exposure are in the population, it is worthwhile screening for trauma in pregnant women.

Dr. Yehuda: Exactly.

Dr. Jain: The other thing I wanted to ask about was early data indicating that exposure to trauma can impact the psychosocial functioning of second, maybe third generation offspring. I think there were some studies done with holocaust survivors. If you could speak a little bit to that, because obviously that has very widespread societal implications, too.

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Dr. Yehuda: Yes, we have found that in the adult children of holocaust survivors, they are more vulnerable to psychopathology and this is true of offspring who have parents with psychiatric symptoms. In one study we were able to measure biological and epigenetic markers showing that there are effects on holocaust offspring, based on either maternal and in utero developmental factors, maternal exposure, or maternal and paternal PTSD.

Dr. Jain: In general, what would you feel are the important questions for trauma scientists to answer in the next one to two decades? What would be top on your list to prioritize?

Dr. Yehuda: Many decades ago when the field first conceptualized the diagnosis of PTSD, our response was to emphasize the commonalities in trauma survivors regardless of what their exposures were. But I think it is important now to go back and see in a more clear way whether combat veterans are or are not different than other trauma survivors, or if interpersonal violence leaves a unique biological scar compared to a natural disaster, or whether age at traumatization matters or duration of trauma matters.

We basically have a threshold phenomenon where if you are over the threshold of what constitutes a trauma, you could be in the category depending on if you have the symptoms that are the symptoms of PTSD, but that is not very nuanced. In my experience, although there are similarities between trauma survivors in their mental health profile, there are also really important differences.

Some of the treatments that we have developed may really work better for some groups rather than others. For example, it seems like prolonged exposure is a fantastic treatment for interpersonal violence in women, and then the question becomes, is it as good for combat veterans? Have we studied this carefully enough? Should we be tailoring treatments based on trauma type and not just whether or not a threshold for trauma and symptoms has been met? We have to start customizing this.

The other thing that I think is really important is this idea that the designation of PTSD is a static one, or that it is binary or not dynamic. We have to rethink that. Now that I have the perspective of having years in the field and seeing the same trauma survivors over a period of many years, even decades, I understand that the same person can at sometimes meet diagnostic criteria for PTSD while at other times, that person may not. Do we view the person as always at risk after s/he has recovered? Especially when you have recovered from something and you are asked about having had it in the past, your memory is not so good for how much you have suffered in the past when you are feeling good right now.

Sometimes, I have had the ability to actually do a diagnostic interview of someone, meet them 10 years later, ask them about their worst episode of PTSD, and if they are feeling fine today they won’t remember how bad it was. What does that mean for biological studies, for biomarkers, and for risk? Just the idea of whether the categories are binary or not, I think is something that we really want to look at.

Finally, I think we have been paying a lot of attention to the psychological aspect of trauma and not enough to the physical illness part—the fact that people who are exposed to combat may die at an earlier age, make poor behavioral health choices, and are more prone to hypertension, metabolic syndrome, inflammatory illness, cardiovascular disease, and cancer. These cannot be coincidences, but may either be part of the trauma effects, or part of the PTSD effects. Why are we not more focused on the biomarkers that might help explain and reverse some of these illnesses? When will we start seeing PTSD and trauma exposure as the multisystem condition that it is and really try to integrate care plans that not only assess for nightmares, hyper vigilance, and concentration, but diet and exercise and hemoglobin A1c? These are markers for trauma survivors because they are at greater risk for all these issues, not to mention cognitive decline. What I would like to see is us incorporating a much more holistic approach to understanding the effect of trauma that does not divide the mind and the body into different spheres and really focuses on wellness in a much more broad way.

Dr. Jain: So that integration between the physical and the mental, even in the way we treat them. Right now, it is separated out into mental health and physical health.

Dr. Yehuda: It does not make sense. Many veterans that come for care do not take such good care of themselves. It is not a priority for them. They do not maybe eat as well as they could or they have really disrupted sleep. I would like us to think about trauma as something that really does affect the whole body and our behavioral health choices. We should think broad, because those are the things that are really very important to ward off long-term diseases.

Dr. Jain: Yes, and enhance overall quality of life, too.

Dr. Yehuda: I think patients talk about what we (as healthcare professionals) want to talk about, and we lead the conversation in a symptom focused way. The symptoms of PTSD are impairing, don’t get me wrong, I am just saying there is a greater range of problems than are contained in the PTSD diagnosis.

Dr. Jain: I could not agree with you more. I feel like it is in the air. We are on the verge of embracing it that way. We are just not quite there yet.

Dr. Yehuda: I completely agree with you, and I think that the reason for that is that as we do our research on a genome wide level, we identify that so many of the biomarker pathways that seem to be altered relate to inflammatory immune functions. The pathways that are being identified in people with PTSD are not just those that associate with psychiatric symptoms, but really affect much more bodily functioning. I think that is also a lesson, just to close the loop on this that has been learned from the glucocorticoid story in PTSD. Cortisol is not just about mental health. There are glucocorticoid receptors in almost every cell in the body. Cortisol has a myriad of different functions in different target tissues, mostly in the metabolic systems promoting fuel and energy. It is silly to just think about cortisol's role in traumatic memory when cortisol is a ubiquitous hormone that has so many different roles.

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