Dr. Yehuda is professor of psychiatry in the Department of Psychiatry at Mount Sinai School of Medicine in New York City.
Acknowledgments: This work was supported in part by National Institute of Mental Health Grant #R02-MH49555 and Veterans Administration Merit Review funding.
Posttraumatic stress disorder (PTSD) is associated with a somewhat unique and paradoxical neuroendocrine profile in that corticotropin-releasing factor (CRF) levels appear to be increased in this disorder even though ambient cortisol levels have generally been found to be low. This set of findings distinguishes the hypothalamic-pituitary-adrenal (HPA) axis alterations in PTSD from those observed in studies of acute and chronic stress and major depressive disorder (MDD), as the latter conditions are associated with increase in both CRF and cortisol levels. A consistent observation in PTSD has been that of a hypersuppression of cortisol in response to dexamethasone administration. In contrast, MDD studies have observed nonsuppression following dexamethosone administration. These findings have led to the idea that PTSD may be characterized by an enhanced negative feedback inhibition of the HPA axis. This review summarizes the evidence for the enhanced negative feedback model in PTSD and discusses some of the implications of this alteration for understanding the phenomenology of PTSD.
Hypothalamic-pituitary-adrenal (HPA) axis alterations in posttraumatic stress disorder (PTSD) are different from those observed in studies of acute and chronic stress and major depressive disorder; the latter conditions are associated with increase in both corticotropin-releasing factor (CRF) and cortisol levels, whereas in PTSD, CRF levels have been shown to be increased while cortisol levels have often been found to be lowered.1
There is converging evidence to support the idea that the HPA axis is particularly sensitive to negative feedback inhibition in PTSD subjects. The increased sensitivity to negative feedback inhibition is reflected by a hypersuppression of cortisol in response to dexamethasone administration,2-7 an increased concentration and sensitivity of lymphocyte glucocorticoid receptors (GRs),2,8 and an augmented adrenocorticotropin hormone (ACTH) response to metyrapone test administration.9 The enhanced negative feedback of cortisol is also accompanied by a more dynamic circadian release of cortisol under basal conditions.10 This review will summarize the evidence for the enhanced negative feedback model in PTSD and discuss some of the implications of this alteration.
The Neuroendocrine Response to Stress
One of the immediate neuroendocrine responses to stress involves the coordinated sympathetic discharge that causes increases in heart rate and blood pressure, initially described as the “fight or flight” reaction. This response allows a greater perfusion of blood glucose to muscles and vital organs and results in increased energy to skeletal muscles, allowing the organism to better fight or flee adverse situations. The HPA axis response to stress involves a more complex set of chemical reactions, in which brain neuropeptides stimulate the release of CRF, or corticotropin-releasing hormone (CRH) vasopressin, and other regulatory neuropeptides from the hypothalamus that stimulate the pituitary to release ACTH. In turn, ACTH stimulates the release of cortisol from the adrenal glands. This is the basic HPA-axis stress-response cascade.11
Typically, the greater the severity of the stressor, the higher the levels of both catecholamines and cortisol. However, whereas catecholamines facilitate the availability of energy to the body’s vital organs, cortisol’s role in stress is to help contain or dampen sympathetic activation and other neuronal defensive reactions that have been initiated by stress.12 As these stress-activated biological reactions begin to shut down, cortisol levels also suppress the HPA axis via the negative feedback inhibition of cortisol on the pituitary, hypothalamus, hippocampus, and amygdala.13
In classic stress theory, stressors that result in the activation of CRF release from the hypothalamus also result in elevated cortisol levels, whereas lower levels of cortisol are thought to result directly from a cessation of activation by CRF. Thus, one paradox in PTSD—which is clearly a disorder in which exposure to stress is a critical feature—is the presence of low cortisol levels.
Neuroendocrine Alterations in PTSD
Brain CRF concentrations appear to be elevated in PTSD subjects, as indicated by increased concentrations of this peptide in the cerebrospinal fluid.14,15 There is also specific evidence of increased hypothalamic CRF release, as determined by the ACTH response to metyrapone administration.9 However, in several studies, cortisol concentrations have been found to be lower in PTSD subjects than in normal comparison groups, other psychiatric patients, or similarly exposed non-PTSD groups.1,8,16 Some studies of 24-hour urinary cortisol excretion have not replicated the finding that cortisol levels are lower in PTSD subjects17-19 compared to other subject groups. This may reflect differences in the type of subjects studies, the type of methods used in these studies, or may suggest that low cortisol levels are only present in a subgroup of trauma survivors with PTSD.
We have been able to confirm our observations of low urinary cortisol with a 24-hour plasma cortisol study in which blood samples were obtained every 30 minutes around the clock.10 These data demonstrated lower cortisol levels in the evening in combat Vietnam veterans with PTSD, whereas morning levels were comparable to normal groups. Other changes in circadian rhythm were also noted. PTSD subjects showed a greater dynamic range of cortisol over the diurnal cycle compared to normal groups as estimated by the amplitude-to-mesor (“signal-to-noise”) ratio. PTSD subjects also demonstrated evidence of a stronger circadian rhythm, as evidenced by an increased goodness-of-fit of the 24-hour single oscillator cosinor model to the raw cortisol data (Figure).
Studies examining single-point cortisol levels in plasma and salivary samples have also found some evidence of low cortisol. Boscarino20 reported significantly lower cortisol levels in combat veterans with the heaviest combat exposure, including a subset of 293 veterans with PTSD.
In addition, Goenjian and colleagues5 demonstrated that basal salivary cortisol levels were lower in children who had been close to the epicenter of the Armenian earthquake 5 years earlier, and who still had substantial PTSD symptoms, compared to children who had been further away from the epicenter and who, as a group, had fewer symptoms. Furthermore, Heim and colleagues6 found lower basal salivary cortisol in women with chronic pelvic pain who had a high prevalence of sexual trauma and PTSD, compared to women without sexual trauma or PTSD. Finally, Jensen and colleagues21 reported lower basal plasma cortisol levels in combat veterans before and after sodium lactate infusion.22,23 Some investigators reported elevated morning cortisol levels in PTSD.
Other studies have demonstrated low plasma cortisol in trauma survivors who appear to have been symptomatic at the time of assessment, but were not specifically evaluated for PTSD. Low plasma cortisol levels were also observed in a sample of detainees who were studied shortly after being liberated from a prisoner-of-war camp in Bosnia,24 in refugees who had fled from East to West Germany and were still symptomatic 6 weeks after their arrival in West Berlin,25 detainees released from Bosnian concentration camps, displaced persons evacuated from their Croatian town after occupation by the Serbians, and civilians living in Zagreb during the war in Bosnia who were found to “express a severe psychological response.”26
Why Are Cortisol Levels Low in PTSD?
The presence of low cortisol levels in trauma survivors has been intriguing because it is counterintuitive to the idea that stress would be associated with high cortisol levels. One important question that has raised concerns in the course of adaptation to trauma is: when are low basal cortisol levels first observable? In the abovementioned studies, cortisol levels were generally obtained several months, years, or even decades following exposure to the stressor, which leads to the hypothesis that the low basal cortisol levels in PTSD reflect a chronic adaptation of the HPA axis. Implicit in this idea was that if cortisol levels would have been obtained while the individual was undergoing the traumatic event, or at least in the immediate aftermath of it, then they might have been found to be elevated—particularly in individuals who would subsequently develop long-term psychiatric problems and/or PTSD.
As early as 1968, Bourne and colleagues27 reported surprisingly lower urinary cortisol metabolite 17-hyroxycorticosteroid levels in Vietnam soldiers during a threat of imminent enemy attack while they were stationed in Vietnam. This study raised the possibility that cortisol levels can be low in response to an extremely traumatic experience. These observations were confirmed nearly 30 years later by recent studies.28-30
In one study, McFarlane and colleagues28 measured the cortisol response to motor vehicle accidents in persons appearing in the emergency room in the immediate aftermath (usually within 1–2 hours) of this trauma. Six months later, subjects were evaluated for the presence or absence of psychiatric disorder. In subjects who had developed PTSD, the cortisol response in the immediate aftermath of the motor vehicle accident was significantly lower than the cortisol response of those who subsequently developed major depression. This study suggests that PTSD-like HPA axis alterations are present in the immediate aftermath of a traumatic event. These findings were similar to those reported by Delahanty and colleagues.29
Resnick and colleagues30 demonstrated that women with a prior history of rape or assault had lower cortisol levels immediately after rape than women without such histories.30 Cortisol levels did not predict the subsequent development of PTSD in these women (possibly owing to the small sample size). Thus, there is a possibility that cortisol levels in the immediate aftermath of a traumatic event might be predicted by factors that precede trauma exposure, or by previous exposure.
The prospective longitudinal studies discussed above demonstrate that the acute cortisol responses to trauma in individuals who develop PTSD, or who show characteristic risk factors for PTSD such as prior exposure to trauma, could be different from those of individuals who do not develop PTSD in response to a similar trauma or who do not have a prior history of trauma. These studies raise the provocative question of whether some individuals might have had low cortisol levels even before the traumatic event, or had some abnormality that would account for their aberrant response to the traumatic event they sustained. Evidence for this is currently scant. However, we have recently demonstrated that cortisol levels are low in adult children of Holocaust survivors, who are at increased risk for the development of PTSD.31
Implications of Low Cortisol in the Immediate Aftermath of a Trauma
If cortisol levels are low in the immediate aftermath of a traumatic event, this might result in a failure of cortisol to completely contain the sympathetic nervous system (SNS) response, resulting in an initial problem of a failure of normal memory consolidation. Indeed, there is evidence that catecholamines, particularly epinephrine, enhance memory consolidation in laboratory rats.32 This effect appears to be modulated at least in part by adrenal steroids, since removing the adrenal glands of animals makes them more sensitive to the effects of epinephrine on memory consolidation.32 Furthermore, when such animals are given replacement doses of glucocorticoids, they become less sensitive towards the memory-enhancing effects of epinephrine.32
It has been hypothesized that PTSD results from an exaggerated response of neuropeptides and catecholamines at the time of the trauma,33 and that increased levels of these stress hormones initiate a process in which memories of the traumatic event might be “overconsolidated” or inappropriately remembered due to an exaggerated level of distress. The failure of cortisol to contain other neuropeptides would facilitate this effect. It would also explain why non-PTSD patients do not overconsolidate their traumatic memories and why reminders of the traumatic event are accompanied by distress in individuals with PTSD. However, this process might represent only one of many pathways to the development of PTSD.
Shalev and colleagues34 collected heart rate data from trauma survivors who appeared in the emergency room in the immediate aftermath of a traumatic event, but who did not have significant physical injury. Mean heart rate levels at the time of the trauma were significantly higher in the subjects who developed PTSD, as determined at a 4-month follow-up. The mean heart rate in the PTSD group remained higher at the 1-week follow-up. However, by 1 month and 4 months, there were no group differences. Importantly, subjects who did not develop PTSD also had elevated heart rate in the emergency room because they were expressing a stress response.
It is interesting to consider both the observations of low cortisol and elevated heart rate, particularly in light of the role of SNS-HPA interactions in stress. Under normal stress-activated conditions, cortisol levels would ultimately inhibit the adrenergic system. However, it could be that some trauma survivors have higher heart rates in the immediate aftermath of a traumatic event because cortisol has failed to contain this specific response.
In support of this idea was the observation that cortisol and methoxy-hydroxy-phenylglycol (MHPG) levels—measured from the same blood sample in the aforementioned rape survivors—appeared to be related to different aspects of the traumatic experiences.35 While cortisol levels were related to prior history, MHPG levels in these rape victims were associated with the severity of the trauma. Moreover, in the women who did not subsequently develop PTSD, there was a significant correlation between cortisol and MHPG levels, which is consistent with the normal stress response. In the women who did subsequently develop PTSD, this relationship was lacking. Thus, the HPA and SNS responses to trauma might literally be disassociated in those who subsequently develop PTSD. These preliminary data suggest a possible mechanism for why some individuals would develop PTSD-like responses, whereas others recover.
One could further theorize that the increased dose of distress every time there are traumatic reminders might activate stress responsive hormones and neuromodulations such as CRF. Thus, CRF might be hyper-released due to the anxiety brought about by memories that have been experienced while persons were distressed. We have previously suggested that CRF hypersecretion activates the pituitary to release ACTH. However, because of an increased sensitivity of GRs, the HPA axis may become progressively more sensitive to cortisol (and stress) as it continues to be exposed to CRF.1,2 An increased responsiveness of GRs may facilitate a stronger negative feedback inhibition.
The enhanced negative feedback response contrasts to the well-known cascade in depression, in which chronic CRF release results in an erosion of negative feedback inhibition, resultant hypercortisolism, and GR downregulation.11 This would imply that low cortisol may be a downstream manifestation of a more primary alteration—an enhanced negative feedback inhibition resulting from an increased GR sensitivity. However, this hypothesis has not been adequately tested to date.
GR Responsiveness in PTSD
The binding of cortisol to GRs initiates the transcription of mRNA and the synthesis of proteins that alter the structure and function of cells. Our group has demonstrated that urinary cortisol concentrations and lymphocyte GR numbers are not always inversely correlated,8 which supports the notion that there can be critical individual differences in the number and functional activity of the receptor. In turn, individual differences in GR sensitivity would also potentially explain why individuals do not respond to stress in the same manner.
In major depression, the number and sensitivity of lymphocyte type II GRs in lymphocytes are lower than normal.36 Therefore, although high cortisol levels are present in major depression, the decreased sensitivity of the receptor might actually result in an attenuation of the normal biobehavioral effects of steroids. This phenomenon has been referred to as “glucocorticoid resistance.”1,31 The occurrence of a glucocorticoid resistance explains why depressed patients with very high cortisol levels do not show evidence of endocrinological disorders such as Cushing’s syndrome (a disease characterized by excessively high release of cortisol).
In contrast to the decreased number of GRs observed in major depression and stress, the number of lymphocyte GRs appears to be increased in PTSD subjects compared to normal subjects and other psychiatric groups.3,9,10 That GRs might also be more sensitive is implied by the fact that dexamethasone administration resulted in a significant decrease or downregulation of the lymphocyte GR number in combat veterans with PTSD but not in trauma survivors without PTSD or in normal controls. This suggests that the GRs of PTSD subjects show a greater response to the administration of the synthetic steroid.2
Diminished glucocorticoid sensitivity in major depression is primarily observed by the reduced cortisol negative-feedback inhibition of the HPA axis on the dexamethosone suppression test.11 In contrast, subjects with PTSD show an augmented suppression following dexamethasone compared to both similarly exposed subjects without PTSD and nonexposed subjects.3-7 Further evidence for the idea of an enhanced negative feedback theory has been provided by the results of the metyrapone stimulation test.
Metyrapone administration resulted in an augmented ACTH response in combat veterans with PTSD compared to nontraumatized men who showed ACTH increases in the normal endocrinologic range.8 The increased ACTH response to metyrapone demonstrates that when the pituitary is unconstrained by negative feedback inhibition, there is clearly evidence of suprapituitary activation (increased CRF). Therefore, under basal conditions, the increased negative feedback inhibition at the level of the pituitary results in lower ambient cortisol levels.
Neuroendocrine alterations in PTSD, particularly those relating to the HPA axis, do not typically resemble those that have been described in classic studies of stress or major depression. If one considers these findings in the context of the fact that PTSD is not a universal stress response, the data can be more readily understood. Indeed, PTSD represents a situation where there has been a failure of restitution of the body to its pre-stress baseline. The biological findings appear to mirror this phenomenon; there may be biological risk factors that determine the responses that are most likely to result in a PTSD syndrome. These biological risk factors could be related to the prior stress history of the person experiencing a traumatic event. As our knowledge of the biology of PTSD grows, we will be able to better understand the developmental biological progression of PTSD, as well as its implications for the pathophysiology and treatment of the disorder. PP
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