In a well-functioning person, stress produces rapid and pronounced hormonal responses. However, chronic and persistent stress inhibits the effectiveness of the stress response and induces desensitization. PTSD develops following exposure to events that overwhelm the individual's capacity to reestablish homeostasis. Instead of returning to baseline, there is a progressive kindling of the individual's stress response. Initially only intense stress is accompanied by the release of endogenous, stress-responsive neurohormones, such as cortisol, epinephrine, norepinephrine (NE), vasopressin, oxytocin, and endogenous opioids. In PTSD even minor reminders of the trauma may precipitate a full-blown neuroendocrine stress reaction: It permanently alters how an organism deals with its environment on a day-to-day basis, and it interferes with how it copes with subsequent acute stress.
Early stress can alter the development of the hypothalamic-pituitary-adrenal (HPA) axis, hypothalamic and extrahypothalamic corticotropin-releasing hormone, monoamin-ergic, and gamma-aminobutyric acid/benzodiazepine systems. Stress has also been shown to promote structural and functional alterations in brain regions similar to those seen in adults with depression. Emerging data suggest, however, that the long-term effects of early stress can be moderated by genetic factors and the quality of the subsequent caregiving environment (Kaufman et al., 2000).
A review of the neuroendocrine findings in PTSD to date shows very specific abnormalities in this disorder, compared with other psychiatric problems. The most prominent of these abnormalities appear to be in the HPA axis. PTSD patients show evidence of an enhanced negative feedback inhibition characterized by an exaggerated cortisol response to dexamethasone, an increased number of glucocorticoid receptors, and lower basal cortisol levels (Yehuda, 1998). These findings contrast with the blunted cortisol response to dexamethasone, the decreased number of glucocorticoid receptors, and the increased basal cortisol levels described in major depression. Women with a history of childhood abuse and a current major depression diagnosis exhibited a more than six-fold greater adrenocorticotrophic hormone (ACTH) response to stress than age-matched controls (Heim et al., 2000). These results show that cortisol basically functions as an "antistress" hormone: Through negative feedback inhibition, Cortisol acts on the pituitary, hypothalamus, hippocampus, and amygdala sites initially responsible for the stimulation of cortisol release. Once the acute stress is over the HPA axis activates negative feedback inhibition, leading to the restoration of basal hormone levels (Yehuda, 2002). Simultaneous activation of catecholamines and glucocorticoids stimulates active coping behaviors, while increased arousal in the presence of low glucocorticoid levels may provoke undifferentiated fight-or-flight reactions.
Two prospective, longitudinal biological studies of trauma survivors confirm the notion that individuals with a low initial cortisol response to stress are most vulnerable to develop PTSD. Both studies examined the cortisol response to trauma within hours after the trauma occurred. In the first (McFarlane et al., 1993) the cortisol response to motor vehicle accidents was measured in persons appearing in the emergency room in the immediate aftermath (usually within 1 or 2 h) of the trauma. Six months later, subjects were evaluated for the presence or absence of psychiatric disorder. In subjects who had developed PTSD the cortisol response right after the motor vehicle accident was significantly lower than the cortisol response of those who subsequently developed major depression. Resnick et al. (1997) collected blood samples from 20 acute rape victims and measured their cortisol response in the emergency room. Three months later, a prior trauma history was taken, and the subjects were evaluated for the presence of PTSD. Victims with a prior history of sexual abuse were significantly more likely to have developed PTSD by 3 months following the rape than were rape victims who had not developed PTSD. Cortisol levels shortly after the rapes were correlated with histories of prior assaults: The mean initial cortisol level of individuals with a prior assault history was 15 ^g/dL compared to 30 ^g/dL in individuals without. These findings can be interpreted to mean either that prior exposure to traumatic events results in a blunted cortisol response to subsequent trauma or in a quicker return of cortisol to baseline following stress.
Most studies of catecholamine function in PTSD suggest chronic increased activation. There is also evidence for distinct changes in the hypothalamic-pituitary-thyroid and the hypothalamic-pituitary-gonadal systems (Yehuda, 1998), as well as in the endogenous opioid response to reminders of personal trauma (van der Kolk et al., 1989; Pitman et al., 1990). Finally, there is considerable evidence for a host of somatic problems in the wake of PTSD, including alterations in immune function (Wilson et al., 1999).
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