Journal of Psychiatric Research 40 (2006) 550–567

JOURNAL OF PSYCHIATRIC RESEARCH
www.elsevier.com/locate/jpsychires

Review

Assessment of HPA-axis function in posttraumatic stress disorder: Pharmacological and non-pharmacological challenge tests, a review
C.S. de Kloet
a

a,b,*

, E. Vermetten a,b, E. Geuze a,b, A. Kavelaars c, C.J. Heijnen c, H.G.M. Westenberg b

Department of Military Psychiatry, Central Military Hospital, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands b Rudolf Magnus Institute of Neurosciences, Division Psychiatry, Utrecht, The Netherlands c Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, Utrecht, The Netherlands Received 3 June 2005; received in revised form 15 July 2005

Abstract Posttraumatic stress disorder (PTSD) is typically accompanied by acute and chronic alterations in the stress response. These alterations have mostly been described in individuals under baseline conditions, but several studies have also used a challenge model to further assess the role of the hypothalamic–pituitary–adrenal (HPA) axis in the stress response. This paper reviews common methodology and research findings on HPA function in PTSD, and discusses the pathophysiological mechanisms underlying these findings. We reviewed the literature and selected all English-language, human subject, data driven, pharmacological and non-pharmacological challenge studies pertaining to the HPA axis, and in vitro leukocyte glucocorticoid receptor studies in adult PTSD subjects. Studies using a non-pharmacological stress paradigm (cognitive stress, trauma reminders) to stimulate the HPA axis showed an exaggerated cortisol response in PTSD. The most widely used pharmacological challenge with consistent results was the low dose dexamethasone-suppression test (DST). These DST studies showed enhanced cortisol suppression in subjects with PTSD. Different hypotheses have been purported to explain the alterations in HPA axis functioning in PTSD. The results of the reviewed challenge tests, however, did not exclusively support one of the hypothesized mechanisms. Further research assessing hormones at all levels of the HPA axis at both baseline and at challenge conditions with a proper stratification of study population, will be necessary for a better understanding of stress-responsivity on the level of the HPA axis in PTSD. Ó 2005 Elsevier Ltd. All rights reserved.
Keywords: PTSD; HPA; Glucocorticoid; Cortisol; DST; Review

Contents 1. 2. 3. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methodology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Non-Pharmacological stress challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. CRH challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Naloxone challenge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. ACTH challenge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551 551 552 552 553 553 553

*

Corresponding author. Tel.: +3130 2502 590/124; fax: +3130 250 2586. E-mail address: C.S.deKloet@azu.nl (C.S. de Kloet).

0022-3956/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2005.08.002

. . . Recommendations for future research . . . . and naloxone challenges. . . . . . . . 1995. Glucocorticoid receptor studies. . . . . . . Thaller et al. . 3. 4. including the dexamethasone suppression test (DST). . . . . . . . . . Methodology We performed a Medline Indexed search with the keywords ‘‘PTSD’’ in combination with ‘‘HPA axis’’. . .3. we selected all pharmacological and non-pharmacological challenge studies pertaining to the HPA-axis. Yehuda et al. . . . . dexamethasone CRH test and metyrapone challenge designs is provided. ‘‘cortisol’’. . . . . . . . . . . . . since in vitro leukocyte GR studies have been used as a surrogate measure for central HPA axis feedback regulation. . References . . . . . . Single point plasma and 24 h urine cortisol measurements. . . . Lemieux and Coe. . . . . . . . . .1. . . . . . Rohleder et al. . . . . Yehuda et al. . . . Since PTSD develops after exposure to a stressor and symptoms include hyperarousal. . . . . . . . . . . . . . . 1986. . . . an overview of the findings on non-pharmacological challenges and different pharmacological challenges. . . . . . . . . . . . . The stress response refers to the bodyÕs immediate and long-term reaction to a physical or psychological stressor that endangers homeostasis. . . . . . . 1990. . . . . Dexamethasone suppression test . . . . . . . To further investigate the stress response in PTSD patients. . . . . . . . HPA axis reactivity especially has been thoroughly investigated. . . . . . . Confounding factors and limitations . . . . . . . . ACTH-. . . . . . . 2. . however. . . . . . . . . . . . . . . 1999. . . . . The findings in preclinical literature has led to a rapid expansion of studies pertaining to these systems in patients with PTSD in the past decade. . . have been applied. 1999). . . . . . . . 2004) but not in other studies (Pitman and Orr. . . Other factors involved in HPA-axis regulation .. . . . . . . ‘‘ACTH’’. . .2. . 554 558 559 560 562 562 563 564 564 565 1. . . . . . . . . . . dexamethasone’’. . . . . . . . Although in some of the studies results of other patient . . . . . Bremner et al. . . . . . . . . . Thirty-four studies performed in PTSD patients have been reviewed (only papers published before April 2005 were included). . . . or fear (McEwen. . . . . ‘‘CRH’’. . . . . 1990. .and the hypothalamic–pituitary–adrenal (HPA) axis to the regulation of the stress response. . . . . . . . and sympathetic-adrenal-medullary system are critical in promoting adaptive responses to stress. . 1990). . . Dexamethasone–CRH challenge .. . . . . From these studies. Hypothesized mechanism for altered HPA-axis function in PTSD . . human subject. . .7. . . . ’’metyrapone’’. . . . . .6. . . The combination of high CRH in CSF and lower baseline or diurnal plasma cortisol levels have often been attributed to an enhanced HPA-axis feedback reg- ulation in PTSD. or ‘‘glucocorticoid receptor’’. . . A special paragraph is devoted to leukocyte glucocorticoid receptor studies. . . . .. . . .. . . CRH-. 2001. . . . . . . . and hormone receptor function. . The work in animal models of stress has shown that coordinated functional interactions between the HPA axis. . . . . 1994). . . . . .S. . . . . . . . . . . . . . . . . . . . 2002. . . . . . . . . . alterations in hormone bioavailability. . . . . . . . . From this database English-language. . . . Metyrapone challenges. . . 4. 1998. . . . . .. . . . . . data driven papers were selected. . several challenge paradigms. . . . . . . . . . . .. .. . . . . and might thereby contribute to an understanding of the findings of the reviewed challenge studies in this review. . . . . For review (Bremner et al. . . . . . and glucocorticoid receptors in adult PTSD populations. . . . . . . . . . . . . . . . 1997). .5. . . . . . .C. . .. 2003a. . . . . Baseline studies in adult PTSD patients report high levels of corticotrophin releasing hormone (CRH) in cerebrospinal fluid (CSF) (Baker et al. . . . . .. . . . . . de Kloet et al. . it seems likely that PTSD is accompanied by or will lead to alterations in the biological stress response. .. . In this paper. . . . . . . . . . . . . . . . . . . . 3.4. . . . . . . Glover and Poland. . . 4. . . . 1994). . . . . Yehuda et al. . . . Kanter et al. . . . . . . . . . . . . . . . . . . alterations in activity of the central nervous system (CNS). . . . . . . 1995a. . . . . Other mechanisms that might be involved are an altered perception of stressors. . Maes et al. . . . . . . . Preclinical studies have given insight in the relative contribution of the sympathetic-adrenal-medullary. . 3. .. . . . 2002). targeting at different levels of the axis. .. . . . reveal mixed results. studies that exclusively assessed baseline levels were excluded from this review. . . . . .b. . . Lower plasma and 24 h urine cortisol levels have been reported in some (Mason et al. . .. 1979. 3. . . As the outcome of studies in PTSD assessing baseline levels of hormones involved in HPA axis regulation have already been reviewed. . . . . . 1996 and Vermetten and Bremner. . . . . . . . . . . . while diurnal plasma cortisol levels on average are decreased. . Introduction Posttraumatic stress disorder (PTSD) is a chronic psychiatric disorder that can occur in subjects who have been exposed to or have witnessed a traumatic experience of an extreme nature (APA. . . . Discussion. . . . . . . . . .8. . . . . . . . . . . . . . . . . . . . . . . . . . 4. In the discussion the reported alterations will be discussed in view of clinical and preclinical findings. . . . anxiety. . . . Sapolsky et al. . (Bremner et al. . . / Journal of Psychiatric Research 40 (2006) 550–567 551 4. . . . . . . . .

a stressfull challenge was able to invoke a sympathetic response. but not ACTH and cortisol.5 mg dexamethasone challenge and one study using a 0. Elzinga et al.S. Bremner et al. Arithmetic cognitive tasks with negative feedback. Bremner et al. we divided the studies based on the methodology used. . Outcome measures Subjective distress. salivary cortisol at several time points before and after challenge. PTSD displayed elevated cortisol levels in anticipation phase and during challenge. seven studies using a 0. In these three studies.m. heart rate. PTSD patients displayed elevated cortisol levels in anticipation phase. In addition one study using a dexamethasone/CRH test is described in patients with a borderline personality disorder with or without a comorbid PTSD. / Journal of Psychiatric Research 40 (2006) 550–567 groups are also described. Cortisol elevated in anticipation phase and in response to challenge in both groups. heartrate. As noradrenergic neurons stimulate CRH release and preclinical and clinical studies show an increased noradrenergic activity and noradrenergic stress responsivity in PTSD patients. memory for neutral and emotional material. (1999) used trauma related acoustic stimuli in combat veterans with and without PTSD and in healthy controls. this review is confined to the results pertaining to the changes in HPA axis reactivity in PTSD patients. healthy controls (n = 18) 2 p. (1999) Population Combat related PTSD (n = 17). 3. Conclusions and remarks PTSD displayed exaggerated response in skin conductance. de Kloet et al. and cortisol. (2003) Civilian PTSD (n = 23).25 mg dexamethasone challenge.m. Cortisol remained significantly elevated for one hour after the challenge in PTSD patients but not in controls. (2003) assessed cortisol responsivity to traumatic reminders using a personalized traumatic script in abused women with and without current PTSD. during exposure to the script. In PTSD populations three studies used a non-pharmacological paradigm.0 mg dexamethasone challenge. PTSD patients had elevated plasma cortisol levels in comparison to controls at baseline and in both noise conditions. Salivary cortisol at several time points before and after challenge. including one cognitive challenge test and two studies using traumatic reminders to assess HPA axis function. Subjects were studied in two sessions in randomized order.552 C. Four studies used a design with administration of metyrapone and eight in vitro studies assessing lymphocyte GR function or intracellular GR density were included. Non-Pharmacological stress challenges Researchers have been especially interested in the way the HPA axis is involved in the management of stress in stress related disorders. In two of the three Time of challenge 9 a. Results In our database of 34 papers. and blood sampling before and after challenge for plasma catecholamines. Heartrate. heartrate. skin conductance. Liberzon et al. ACTH. Although there was an enhanced autonomic and adrenergic response in PTSD patients compared to controls there was no difference in plasma ACTH or cortisol response to combat sounds between groups (see Table 1). thus paradigms have been designed to provoke a stress response. plasma Table 1 Non-pharmacological challenge paradigms Reference Liberzon et al. combat controls (n = 11). and blood pressure. one ACTH challenge. Three studies assessing HPA axis responsivity to non-pharmacological stress challenges in patients with PTSD have been reported. an increased ACTH and cortisol response to stressful challenges was hypothesized in all studies. one naloxone challenge. 3. Patients with PTSD had higher salivary cortisol levels in the period leading up to the script exposure. Elzinga et al. (2003) Abuse related PTSD (n = 12). trauma controls (n = 12) Personalized traumatic script. Different outcome measures have been assessed including cortisol in plasma or saliva. ACTH.1. healthy controls (n = 14) Challenge paradigm Exposure to nonspecific arousing stimuli compared with exposure to trauma-related stimuli. blood pressure. 2 p. Pharmacological challenges included three CRH challenges.m. One session consisted of exposure to non-specific arousing stimuli (white noise) and the other of exposure to trauma-related stimuli (combat sounds). during and after challenge. five studies using a 1. plasma epinephrine and norepinephrine. and throughout the recovery phase. In a mixed gender group. PTSD patients demonstrated significant more elevation of salivary cortisol levels in anticipation of and during the test as compared to controls. (2003b) used an arithmetic task with negative feedback to elicit a stress reaction.

Since baseline studies have shown higher levels of CRH in CSF of PTSD patients. ANP has been hypothesized to play a regulatory role in the ACTH response and it is known to decrease basal and stimulated pituitary–adrenal activity. The main finding of this paradigm is the presence of augmented salivary cortisol levels in response to a stressful test in PTSD patients. and the time at which blood sampling was performed. (2001) used a similar approach in pre-menopausal women with PTSD and healthy controls (Rasmusson et al. 2001). described plasma ACTH and cortisol following administration of 1 lg/kg of CRH in inpatient combat veterans with PTSD and healthy controls (Smith et al. as well as alterations in feedback inhibition by cortisol. CRH challenges Intravenous CRH administration is commonly used to assess the responsivity of the pituitary to CRH. 3. an increase in ACTH can be observed between 5 and 15 min after CRH administration. However. The contrasting results may be due to factors in the realm of methodology and population factors as the design in these studies differs with respect to the time of CRH infusion. 3. Naloxone is an opioid receptor antagonist which ultimately leads to increases in endogenous CRH release. Alterations in pituitary responsivity to CRH. but there was a trend for an increased ACTH response in PTSD patients. cortisol and atrial natriuretic peptide (ANP) levels after CRH stimulation in PTSD patients and healthy controls. with a maximum response between 10 and 15 min.3.2. baseline cortisol levels were higher in PTSD subjects compared to controls. there was no significant difference between PTSD patients without comorbid MDD and the healthy control group. duration of the disorder. The first CRH challenge in PTSD patients performed in 1989. Hockings et al. Plasma cortisol and ACTH levels were measured at baseline and after each dosage. de Kloet et al. ACTH challenge The rapid ACTH stimulation test (RST) was developed to measure the acute adrenal response to ACTH. As in all three studies baseline measurements were within 1 h prior to the test. (1993) administered naloxone in three dosages in patients with combat related PTSD and in healthy volunteers. In this challenge test 1 lg/kg or 100 lg of CRH is given intravenously as a bolus injection. Naloxone challenge Since it is known that centrally mediated opioid response to traumatic stimuli is an important feature in PTSD and that re-exposure to a traumatic stressor will precipitate opioid-mediated stress induced analgesia in people with PTSD. In the study by Liberzon et al. Plasma ACTH increased significantly after CRH administration in both groups..C. in a subgroup of six PTSD patients the ACTH response to naloxone in the lowest dosage was significantly higher than in the other PTSD patients and controls.S. no group difference was found in ACTH and cortisol response. there was a delay in onset of the cortisol response in the PTSD group. . (2000) no CRH response was found after naloxone administration in normal volunteers. Differences in population factors include trauma type. the number of blood samples taken. such as alterations in pituitary function. In healthy individuals. by measuring ACTH levels. and age when traumatized. However. No difference was found between PTSD patients and controls for all of the measurements. some studies have been conducted that apply naloxone. which could be due to the fact that samples were taken immediately after the stressor. Blood samples for ACTH and cortisol assays are taken at regular time points during 1 or 2 h after administration of the bolus. This larger response could not be explained by other comorbid psychiatric disorders or medication. Comparing patients with PTSD and healthy controls they found significantly lower basal ANP levels in PTSD patients and reported no significant differences in the area under the curve (AUC) of the cortisol and ACTH values between PTSD patients and controls. The CRH-induced increase in plasma cortisol was significantly higher in PTSD subjects than in controls. it cannot be excluded that these findings are due to anticipation stress. Rasmusson et al. Moreover. In healthy individuals. Except for the male subjects in the study by Bremner. may be due to a number of factors. 1989). (2003) investigated ACTH. Assessment of the ratio between ACTH.. a down regulation of CRH receptors resulting in a blunted ACTH response was hypothesized in all studies. 3. The three described studies show contrasting results making it impossible to draw any conclusion on pituitary or adrenal reactivity in PTSD. / Journal of Psychiatric Research 40 (2006) 550–567 553 PTSD studies an exaggerated salivary cortisol response to stressful or trauma related stimuli was found.4. the peak cortisol response typically occurs at 30– 60 min after administration. alterations in vasopressin levels. CRH binding peptides or other regulatory peptides such as atrial natriuretic peptide (ANP). The total group of PTSD patients (with and without comorbid MDD) exhibited a significantly smaller ACTH response to CRH than the healthy control group. pituitary CRH receptor number and binding affinity. The two groups did not differ in mean baseline ACTH level. Kellner et al. In a later study by Vythilingam et al. To date three CRH challenge studies in PTSD patients have been reported. and cortisol response in response to CRH administration can provide more information about adrenal responsivity.

Atmaca et al. de Kloet et al. Due to the clinical overlap of MDD in PTSD populations.. Using this procedure.. 1999)..0 mg DST). (1995) measured the effect of treatment on the DST outcome in 21 hospitalized patients with PTSD before and after four weeks of desipramine treatment. while cortisol levels were assessed at 4 p..5 mg DST have been published..5. Dexamethasone suppression test The dexamethasone suppression test (DST) was originally developed as a diagnostic screening instrument for Cushing disease. the following day in four studies (Kudler et al.m. In all reported studies dexamethasone was administered at 11 p.25 mg of dexamethasone in PTSD patients compared to controls (Yehuda et al.5 mg DST in PTSD. Two other studies reported a significant difference in cortisol suppression between PTSD and MDD patients.. In the standard procedure. The challenge revealed a significantly larger increase of plasma cortisol after ACTH administration in PTSD patients compared to controls (see Table 2). Research confirmed this hypothesis because enhanced suppression was found in virtually all studies following 0. 1987). This could be due to differences in study population and inclusion and exclusion criteria. Recently studies assessing both ACTH and cortisol in response to a 0. 1990. 3. In another study higher baseline cortisol levels and a significantly higher rate of non-suppression was found in PTSD patients compared to healthy controls (Atmaca et al.0 mg cortisol was measured (1. The PTSD group varied in age of first trauma and type of trauma.. or feedback inhibition by cortisol. 2002). the focus in these studies was to test the hypothesis of non-suppression or ‘‘early escape’’ in PTSD. Cortisol levels after administration of dexamethasone were not different before and after treatment. A confounding factor in this study was that the test was not conducted at a fixed time. Reist et al. In psychiatric patients.. The study was performed in women with PTSD and in healthy controls (Rasmusson et al.. The results of the 1 mg DST studies are inconclusive. Unfortunately.5 mg or even 0. (2004c) argued that cortisol suppression is positively correlated with the amount of time passed since the occurrence of initial trauma. Yehuda et al. The first 1 mg DST performed in PTSD patients did not reveal a significant difference in plasma cortisol levels after administration of dexamethasone (Kudler et al. 1993)..25 mg of synthetic ACTH (cosyntropin) is delivered intravenously within 30 s. However. The study populations differed in in.or exclusion of comorbid disorders. This test measures the reactivity at the level of the adrenal glands.. the DST was first used in patients with MDD.. 1996. In this test. blood samples for cortisol measurements are drawn just before and 30 and 60 min after ACTH infusion. Halbreich et al. and the presence or absence of a control group (see Table 3). the use of medication. It measures the feedback inhibition of dexamethasone on the HPA-axis. the time passed since traumatization was not mentioned in these studies.m.. although the design was comparable. 2001). 1989. Alterations in response may be due to adrenal functioning. but no significant differences in cortisol suppression between PTSD patients and controls (Halbreich et al. 2002) and at 8 a. Carroll et al. 40% of the MDD patients were reported to have an abnormal HPA feedback inhibition with an early escape from the dexamethasone suppression (Carroll and Curtis. 1987.m. Yehuda et al. Differences in outcome could not be explained by the presence of comorbid MDD or medication use. (1999) performed a 1 mg DST in Croatian subjects who recently served in the war in Yugoslavia and were diagnosed with PTSD without comorbid psychiatric disorders and found higher cortisol levels in PTSD patients compared to controls after dexamethasone suppression. Goenjian et al. Thaller et al. the next day in one study (Thaller et al. the amount of cortisol suppression after administration of 1.. which causes a rapid increase of cortisol within 30 min. Yeh- . The RST has been applied in one published study in PTSD patients. Both groups were premenopausal at the time of measurement. the frequency of non-suppression was substantially lower in PTSD patients without comorbid MDD compared to PTSD patients with comorbid MDD (0% compared to 50%). / Journal of Psychiatric Research 40 (2006) 550–567 Clinically. The 0. 1976. A blunted cortisol response was hypothesized based on the outcome of a previously performed CRH challenge and findings of low baseline cortisol in patients with PTSD. The DST in PTSD patients originally was conducted with 1 mg of dexamethasone.S. The notion that suppression of cortisol production seemed to be enhanced in PTSD patients led to the introduction of the 0..b. 1989. Kosten et al. glucocorticoid receptor number and affinity. 1995a. In this population. 1990). With this design more information on the role of enhanced feedback inhibition and reduced adrenal output in the pathophysiology of PTSD might be provided.5 mg DST has frequently been used in patients with PTSD and uses the same administration and blood or saliva collection time as the 1 mg test. this test is used to test adrenocortical function in patients with Cushing disease during and after steroid hormone replacement therapy. Kosten et al.554 C. (1993) hypothesized more suppression of cortisol in response to dexamethasone in patients with PTSD compared to controls and suggested using a lower dose of dexamethasone. To date no exact cortisol value has been described as cut off value for enhanced cortisol suppression. and thus provides information about adrenal responsivity. 1980). 0. This test induces a more modest suppression enabling differentiation between normal and augmented suppression (Yehuda et al.

30.4 ± 6.1 ± 1.15.30. CSA. 7. 3.38 (B) Only AUC values mentioned Controls (n = 7) 9.30. childhood sexual abuse. de Kloet et al. (B) 8.m.0 (PC) PTSD (n = 17) 11. area under the curve. (2003) Various trauma Rasmusson et al. CRH 100 lg iv at 3 p. posttraumatic diagnostic scale. (1989) Combat ACTH response fl in PTSD versus controls Rasmusson et al.m. 2.4 (PC) Controls (n = 17) 19.m.7 (B) Values in graph PTSD (n = 12) 4.30. 8.15. 4.1 ± 1.45. (B) 30 and 60 min after challenge.30.8 ± 2.8 ± 0. CRH 1 lg/kg iv at 8 p.3 (B) Only AUC values mentioned Conclusions/ Remarks C.84 ± 1.S. B.6 (B) Values in graph PTSD ACTH (pg/ml) ACTH (pg/ml) PTSD (n = 8) 5.70 (B) 19. (2001) Various trauma Cortisol (PC) › and ACTH (PC) › in PTSD No sign. 8. (2001) Various trauma AUC.0 ± 1.9 (B) Values in graph Controls Cortisol (lg/dl) Cortisol (lg/dl) Controls (n = 11) 4.m.45 p.6 (B) Values in graph Controls (n = 11) 7. 3. 8. (B) 3.2 (PC) Controls (n = 17) 10.6 ± 2..Table 2 ACTH and CRH challenges Reference Type of trauma PTSD assessment Medication Diet Durham 1 week medication free No diet CAPS medication free Fasting and no nicotine for 4 hrs. CAPS Medication free Fasting and no nicotine for 4 hrs.6 ± 11. baseline value.45. 3. 9. 10 p.0 ± 2.m.30.3 ± 26. CAPS. / Journal of Psychiatric Research 40 (2006) 550–567 Smith et al.m. (B) 8.m.m.m.m. Cosyntropin 250 lg at different times. PC.45 p.3 (B) 21.1 ± 2.81 ± 1. 9.02 (B) 14.6 ± 0. clinician administered PTSD scale. Method / time of challenge Time of baseline sample(s) Time of post challenge sample(s) CRH 1 lg/kg iv at 8 p. peakchange. PDS 2 weeks medication free Sober after 1 p. 4.8 (B) Values in graph PTSD (n = 12) 7. PTSD Cortisol (lg/dl) Cortisol (lg/dl) PTSD (n = 8) 7.10 ± 1.30.00.45. 555 .38 ± 0. 9.m.15. 5 p. PDS.1 ± 1.0 (PC) PTSD (n = 17) 16.00.5 (B) Values in graph Controls (n = 11) 3.1 (B) Only AUC values mentioned Controls ACTH (pg/ml) ACTH (pg/ml) Controls (n = 11) 7. difference in cortisol (AUC) and ACTH (AUC) after CRH challenge Cortisol increase after cosyntropin in PTSD › Kellner et al. 2.6 (B) 40. 8 p.45 p. 7.8 ± 1. 8.10 (B) Only AUC values mentioned PTSD (n = 10) 12. 9. Just before challenge. 10 p.

07 8.96 ± 0.m. (baseline) 8 a.90 0.64 ± 5.40 ± 3.38 ± 1.70 1. (1989) Combat Kosten et al.32 ± 17. (baseline) 8 a.m. (post DEX) Dexamethasone 1 mg. (1990) Combat DSM IIIR criteria Various medication Current substance abuse DSM IV criteria 24 h medication free Alcohol fl Post DEX cortisol in PTSD versus MDD.556 Table 3 Dexamethasone suppression tests C.34 0.m.18 Controls (n = 21) 7.m.14 ± 1.00 ± 3.78 4. 11 p. 11 p.78 ± 2. fl Baseline and post DEX cortisollevels in PTSD. Controls Cortisol (lg/dl) Cortisol (lg/dl) Conclusions and remarks No significant difference in cortisol suppression between PTSD with and without MDD. (1993) Combat Yehuda et al. / Journal of Psychiatric Research 40 (2006) 550–567 Reference Type of trauma Kudler et al.41 10.68 ± 4.04 Controls (n = 12) 15. 11 p.00 6.89 ± 1.43 3.83 7.m. (post DEX) 4 p. 11 p.89 Combat controls (n = 12) 15.9 ± 0. 11 p.57 ± 1. (2002) CAPS 2 weeks medication free Other psychiatric disorders CMPS medication free 1 month alcohol-/ drugs free Yehuda et al.97 ± 3. (1987) Combat PTSD assessment Medication Relevant exclusion criteria Structural PTSD interview 1 week medication free Current alcohol abuse DSM IIIR criteriaa 2 weeks medication freeb Method & time of challenge Time of baseline sample(s) Time of post DEX sample I/II Dexamethasone 1 mg. (post DEX) Dexamethasone 1 mg.12 <3.77 ± 0.50 Other Cortisol (lg/dl) Cortisol (lg/dl) PTSD with MDD (n = 10) No baseline 3.8 Psoriasis (n = 19) 14.91 ± 3.8 ± 1. No baseline 4 p.83 ± 0.62 1.56 PTSD (n = 21) 14.36 PTSD (n = 14) 12.68 fl 5 p.73 MDD without (n = 28) No baseline 4.19 ± 1.76 ± 2.09 ± 0. No baseline 4 p.31 ± 3. (post DEX) Dexamethasone 0. Thaller et al.91 ± 2.m. (baseline) 8 a. 8 a.m.45 1.83 MDD (n = 23) 12. (post DEX) Dexamethasone 0.59 5.37 ± 0.m.86 PTSD with MDD (n = 13) 7.12 Controls (n = 14) 10. (post DEX) Dexamethasone 1 mg. (post DEX) Dexamethasone 1 mg.91 ± 2.51 ± 2.20 1.19 3.90 3.89 ± 1. MDD Line missing . (post DEX) 4 p.69 PTSDc (n = 11) PTSD (n = 18) No baseline 1.m. (baseline) 4 p.1 ± 1.m.78 PTSD (n = 14) 12.11 ± 2.22 2.29 ± 3. 8 a. (post DEX) PTSD Cortisol (lg/dl) Cortisol (lg/dl) PTSD without MDD (n = 18) No baseline 1.m.0 PTSD (n = 34) 21.m.S.28 Controls (n = 14) 14.78 ± 1.m.09 ± 4. baseline cortisollevels in PTSD versus controls. › Post DEX cortisol in PTSD versus controls.m. (1995) Combat Figley PTSD scale medication free for 1 month Alcohol and drugs. Halbreich et al. 8 a. 11 p.16 14. 8 a.76 ± 1.m. 11 p. fl Baseline cortisol and more cortisol suppression in PTSD compared to controls (corrected for baseline cortisol and dexamethasone levels).m. (1999) Combat Atmaca et al.69 ± 1.72 ± 3. (baseline) 4 p. More cortisol suppression after correction for dexamethasone plasma level in PTSD.17 4.m.m.0 1.m.m. 1–4 p.95 Controls No baseline 1.5 mg.m. Percentage of nonsuppressors › in PTSD than in controls. (baseline) 5 p.93 4.5 mg.m.78 ± 2.m.5 ± 2.6 Controls (n = 17) 21. de Kloet et al.

7 8. (1997) CSA CAPS Various medications Dexamethasone 0.21 CSA with PTSD (n = 12) 13.8 86% Trauma no PTSD no MDD (n = 11) 12.7 ± 1.11 ± 2.. (2002) Holocaust/combat CAPS 2 months medication free Alcohol/drugs CAPS Dexamethasone 0. ELS.90 70% CAPS Various medications Alcohol/drugs Newport et al. 11 p. (baseline) 8 a.4 ± 12. (1995) Combat Figley PTSD scale medication free for 1 month Alcohol and drugs.5 mg.40 ± 3.25 mg. CSA with and without PTSD were not compared.19 ± 3.81 1. childhood sexual abuse.45 Combat controls (n = 12) 15.23 ± 3.38 Controls (n = 14) 14.3 ± 0.5 ± 4.14 ± 2.2 12.m.5 ± 10. 4 p. (post DEX) Cortisol suppression PTSD (n = 28) 9.m.58 24.5 mg.0 ± 9. 11 p.11 2.8 ± 5. early life stress.50 CSA (n = 19) 14. 10 p. cortisol (post DEX)) 8 a. 8 a.6 ± 3. (2004) Childhood abuse CAPS Dexamethasone 0.87 ± 8. More cortisol and ACTH suppression in PTSD compared to both controlgroups.46 ± 6.49 ± 3. (2004) CAPS More ACTH and cortisol suppression in PTSD. (saliva) 8 a. fl Post DEX cortisol in PTSD versus controls.84 1.4 14.m.00 ± 3.28 4. C.5 mg.m. 10 p. No difference in ACTH / cortisol ratio. (post DEX) Dexamethasone 0. MDD. cortisol (post DEX)) 8 a.m.33 fl Baseline cortisol and more cortisol suppression in PTSD compared to controls (corrected for baseline cortisol and dexamethasone levels).94 ± 3. 11 p. dexamethasone. 11 p.21 ± 4.1 2. HC. 8 a.99 ± 3.32 ± 2.m. cortisol (post DEX) 4 p. ACTH (post DEX) Dexamethasone 0.81 ± 1.6 5.m. Stein et al.5 mg.m.31 ± 5.12 8.m.m.60 2. No sign.4 ± 7. (saliva) Dexamethasone 0.m.90 5.S. (baseline) 8 a. (post DEX) 4 p.38 Yehuda et al.60 ± 4.. (post DEX) PTSD (n = 14) 11. 8 a.41 10.29 25.m ACTH (baseline) 8 a.49 ± 2.difference in post DEX cortisol.99 Trauma no PTSD no MDD (n = 9) 11.m.1 26.m.79 8.00 ± 3.97 ± 1. (2004) Various trauma PTSD (n = 17) Controls (n = 17) only 8 a. b Five patients used TCA during the study.. cortisol (baseline) 8 a.m ACTH (post DEX)) ELS with PTSD (n = 20) 15. cortisol (baseline) 8 a.47 ± 19.m.m.81 ± 1.67 ± 1.6 15.4 ± 2.33 ± 16.m.Yehuda et al. 4 p.9 4. Civilian Mississippi PTSD Scale.5 ± 3.7 ± 8. (post DEX) Yehuda et al.45 ± 1.00 ± 1.68 ± 2. fl post DEX cortisol in CSA versus controls.m.m. 8 a. healthy control.9 25.41 Controls (n = 21) 16. (baseline) 8 a.2 ± 4.9 ± 3.5 mg.9 1.52 ± 3.7 1.67 ± 4. (baseline) 8 a. 8 a.30 ELS without PTSD (n = 15) 14. MDD Dexamethasone 0. 8 a.5 mg..m. CSA.12 4.50 4.0 Controls (n = 19) 11.m ACTH (post DEX)) 4 p.63 2.m. 11 p. de Kloet et al.5 4.4 ± 18.58 ± 3. fl Baseline and post DEX cortisol in PTSD versus controls.6 10.42 79% Controls (n = 10) 17.59 5.m.02 Controls (n = 10) 10.49 ± 2.01 3. and HC. DEX.9 ± 6.m.m.30 ± 3.49 1.70 5.0 33.m ACTH (baseline) 8 a.m.m.40 1.80 3. No difference in post DEX cortisol between trauma exposed and non exposed controls.2 Controls (n = 19) 20.9 4. c Six PTSD patients were diagnosed with a comorbid MDD. 10 p. (2004) Various trauma Yehuda et al. 11 p. 8 a.m.6 ± 3. a Patients with comorbid alcoholabuse/dependence were included in this study.8 ± 14.00 ± 6. › Baseline cortisol in PTSD. 557 .6 ± 16. No difference in ACTH / cortisol ratio before and after DEX. / Journal of Psychiatric Research 40 (2006) 550–567 % Cortisol suppression › in PTSD compared to trauma exposed non PTSD.6 PTSD (n = 19) 12.92 Lindley et al. major depressive disorder.m.9 2.m.5 ± 12.91 ± 2. CMPS. baseline values mentioned in article PTSD (n = 15) 12.m.

m. Patients with early childhood abuse and PTSD had significantly lower baseline plasma cortisol values and revealed significantly more suppression of cortisol at 8 a.5 mg DST. Although assessment in a non-clinical environment reduces stress caused by a hospital visit. In a recent study by Yehuda et al.558 C.5 mg DST studies..m. This combined DEX–CRH test requires administration of 1. PTSD patients were compared with the other groups in their cortisol.94 and 20. assessment at home.5 mg of dexamethasone orally at 11 pm the night before testing.and ACTH response on the 0. In saliva the amount of free cortisol is assessed (biological active).. despite no significant differences in baseline ACTH values. Yehuda et al. PTSD populations show enhanced suppression of cortisol compared to controls. / Journal of Psychiatric Research 40 (2006) 550–567 uda et al. 2002. 1995a. MDD.m.97 (lg/dl)) than in controls (between 2.S.. PTSD and MDD) and healthy controls (Newport et al. there is little control on the sampling time or the time of dexamethasone administration.b) (Yehuda et al. Correlation analysis showed a significant correlation between post dexamethasone cortisol and post dexamethasone ACTH values and symptom severity. The main difference in the study design used by Lindley et al.91 and 14. Patients with early childhood abuse and PTSD revealed significantly more suppression of ACTH at 8 a. post dexamethasone (0. A factor that has not been taken into account in most studies is the amount of time passed since the initial trauma. In all studies except the latter study.7 (lg/dl)). In a population with MDD.m. In contrast to all other 0. By combining dexamethasone administration with CRH infusion the neuroendocrine feedback regulation of the HPA-axis system in psychiatric disorders was further elucidated (Holsboer et al. A nontraumatized group was compared with a traumatized group without PTSD or MDD. The advantage of this procedure is that at the moment of CRH challenge in both patients and controls the HPA-axis is downregulated due to feedback inhibition by dexamethasone.. On the day of testing. showing high CRH in CSF. reported a significant association between the numbers of years passed since the most recent trauma occurrence and the log transformed plasma cortisol ratio (predexamethasone cortisol level – postdexamethasone cortisol level/ predexamethasone cortisol level). de Kloet et al. Yehuda et al. 2004a). Another explanation might be the assessment in a non-clinical environment instead of a clinical environment.. significantly more suppression of the post DST cortisol level was found compared to the nonabused group (Stein et al. PTSD patients showed significantly more reduction of cortisol after administration of 0. Mean 8 a.81 and 4. compared to healthy controls..m. in patients with PTSD (Yehuda et al. it is purported to be the best tool for assessing HPA-axis alterations.5 mg DST an issue for further discussion.78 (lg/dl)). the effect of trauma exposure on the HPA-axis was also measured. and no effect of prior traumatization on the extent of cortisol suppression was found in patients with PTSD. as a refined DST procedure. 2002) (see Table 3). 2004). The different outcome might be due to a higher fraction of bound cortisol in PTSD.5 mg) levels were lower in PTSD patients (between 1. whereas in plasma total cortisol is assessed (biological active and inactive). However. Dexamethasone–CRH challenge The dexamethasone–CRH (DEX–CRH) challenge test was developed by Holsboer et al..m.. a study assessing salivary cortisol levels showed no significant differences in baseline salivary cortisol and cortisol suppression after dexamethasone administration between patients and controls (Lindley et al. is the use of saliva rather than plasma. However. showing significantly more suppression of cortisol when more years had passed (Yehuda et al. In the first study both a 0. and a larger cortisol response after CRH administration. Based on baseline CRH measurements. there was no significant difference in the abused women with and without PTSD. (refined procedure). However. No effect on cortisol levels was found between non-trauma exposed and trauma exposed non-PTSD/non-MDD patients. A correlation between cortisol suppression and symptom severity has only be reported in two studies (Yehuda et al. The findings of enhanced ACTH suppression after dexamethasone administration support the hypothesis of inhibition at the level of the pituitary.5 and 1 mg DST was used in women with childhood abuse (among which were patients with a diagnosis of PTSD. 2004c).. Baseline cortisol values in PTSD subjects were slightly lower in PTSD patients (between 9. and 4 p. 1987). Two studies also assessed ACTH before and after administration of dexamethasone. The second study confirmed increased suppression of ACTH and cortisol at 8 a.09 and 1. Also in adult women with childhood sexual abuse of whom some also met criteria for PTSD. 3.92 (lg/dl)) than in controls (between 10. Blood samples are drawn every 15 min between 2 and 6 p.5 mg of dexamethasone compared to patients without PTSD. It reveals less cortisol suppression after dexamethasone pre-treatment. 100 lg human CRH is administered intravenously as a bolus at 3 p. 2004). (original procedure) or at 5 time points between 3 and 4:15 p. making the clinical relevance of the observed enhanced cortisol suppression on 0. 2004a). Feedback inhibition should not interfere with this outcome as the high .6.m. a down regulation of CRH receptors in a PTSD population would be expected resulting in a blunted ACTH and cortisol response. 1997). and a significant correlation between cortisol and ACTH suppression and symptom severity..m. and the use of more time points before and after dexamethasone administration.

A decrease in cortisol levels due to metyrapone administration will block the hypothesized enhanced feedback inhibition in PTSD patients. and cortisol is measured in plasma at 8 a. or 0. Another study assessed the effect of metyrapone on sleep in PTSD. and metyrapone at 12 p. On the day of testing.m. / Journal of Psychiatric Research 40 (2006) 550–567 559 dose of dexamethasone administrated before CRH infusion will give the same amount of cortisol suppression in patients and controls. Inhibition of this enzyme results among other things in decreased cortisol synthesis with lower cortisol levels and higher deoxycortisol levels.m. Metyrapone inhibits 11-beta-hydroxylase. plasma levels of ACTH were significantly lower in PTSD subjects compared to controls. The authors of the first metyrapone challenge performed in PTSD patients hypothesized that the enhanced feedback inhibition on the level of the pituitary in PTSD will result in more central stimulation of the HPA-axis in PTSD. and blood for the assessment of cortisol. and higher ACTH levels in this study supported the hypothesized enhanced feedback inhibition at the level of the pituitary.m. deoxycortisol. whereas PTSD decreases the exaggerated ACTH response in abused BPD patients. metyrapone is administered at midnight and ACTH. and on the day of testing at 4 time points between 10 a. but a higher response than controls. As the decrease in cortisol levels and subsequent blockage of feedback inhibition did not lead to a more pronounced stimulation of the HPA-axis in PTSD and cortisol infusion did not show more inhibition on ACTH release in the PTSD group compared to controls as well.m. de Kloet et al. between 2000 (<70 kg) and 3000 mg (>90 kg). Metyrapone substantially reduced the initial plasma cortisol concentrations..m. With this design. The decrease in cortisol levels will result in less negative feedback inhibition on the pituitary and subsequent higher plasma levels of ACTH.. Blood samples for cortisol. Metyrapone induced an increase in ACTH and 11deoxycortisol concentrations in both groups. the next day. Plasma levels of 11-deoxycortisol were significantly lower in the PTSD population throughout the whole study. and ACTH measurements were drawn at baseline. Metyrapone challenges The metyrapone test was introduced in 1959 for the diagnosis of adrenal insufficiency. In order to examine negative feedback sensitivity directly cortisol was infused after prior treatment with metyrapone in PTSD patients and controls (Kanter et al.S.7.m. 2003). this study did not support the hypothesized enhanced feedback sensitivity at the pituitary level.. BPD patients with comorbid PTSD showed a significantly lower ACTH AUC than BPD patients without PTSD. Female patients with borderline personality disorder (BPD) with and without a history of sustained childhood abuse were studied using the refined procedure of the DEX–CRH challenge. after metyrapone administration.C. no group differ- ence in cortisol suppression was reported. (day2). This study also could not support the hypothesis of enhanced feedback sensitivity. 3. but a significantly smaller increase in 11-deoxycortisol levels in PTSD patients compared to controls was reported. 2001).m. the enzyme that catalyzes the hydroxylation of steroids and is necessary for the conversion of deoxycortisol to cortisol. the lower level of 11-deoxycortisol suggests a decreased adrenocortical responsiveness. There was a significantly greater increase in the levels of 11-deoxycortisol and ACTH in the PTSD group compared to the controls. This procedure enables the measurements of the inhibition of ACTH release in the pituitary by exogenous cortisol. 2004).m. metyrapone at 12 p. The doses of metyrapone used were proportional to the bodyweight. (day1). Recently. After metyrapone challenge cortisol was almost completely suppressed in both groups. This would result in a relatively greater increase of ACTH release and an augmented accumulation of 11-deoxycortisol in patients with PTSD (Yehuda et al. 11-deoxycortisol and ACTH was collected before and after administration of metyrapone.. However.m. suggesting enhanced stimulation of the adrenal gland. 2500 mg of metyrapone was administered orally at 10 a. Metyrapone was administered in two doses of 750 mg each at 6 and 9 a. but a significant smaller reduce in plasma cortisol was reported in PTSD patients. The combination of higher 11-deoxycortisol levels. Patients with PTSD without childhood abuse had the lowest ACTH AUC.5 mg dexamethasone at 11 p. (day3) was administered on three consecutive days (Kellner et al. 11-deoxycortisol. in which placebo at 12 p. the suppressive effect of cortisol and . Blood samples were drawn every 15 min from baseline until 1 p. but cortisol levels revealed no group differences (Neylan et al. Thus far only one study reports on the effect of this paradigm in a traumatized psychiatric population (Rinne et al. thereby blocking feedback inhibition by cortisol completely. They hypothesized a more rapid decrease of plasma ACTH after the endogenous cortisol administration. a study design with metyrapone was introduced.. 1996). There was no significant difference in ACTH response between groups. Four doses of 750 mg of metyrapone were administered every 4 h in the morning. After DEX– CRH a larger mean AUC for both the ACTH and cortisol response in chronically abused BPD patients compared to none or mildly abused BPD patients was found. The outcome suggests that early childhood abuse is related to an exaggerated ACTH response on stimulation with CRH. 2002). and 3 p.m. In an improved version of this test.

There was a significantly higher mean GR density in patients with childhood sexual abuse compared to subjects without abuse. Subjects who were diagnosed with PTSD had a higher mean leukocyte GR density than subjects who had not been sexually abused (Table 4). which correlated significantly with PTSD symptoms (Yehuda et al. In PTSD patients binding studies have been used to assess leukocyte GR density. which promotes the translocation of GRs to the nucleus. 1993). a larger increase of ACTH and 11-deoxycortisol in response to metyrapone alone and a larger decrease of ACTH and 11-deoxycortisol level on metyrapone and dexamethasone administration in PTSD patients were expected. which might complicate the interpretation. combat exposed veterans without PTSD. However. In this study. 2004b studied GR sensitivity by measuring the inhibition of lysozyme activity by dexamethasone. Only one study showed the hypothesized increase of ACTH and 11-deoxycortisol after metyrapone administration. this has not been confirmed by the last two studies. After dexamethasone administration only combat veterans with PTSD showed a decrease in leukocyte GR number.8. but the most accessible cells to study these receptors are leukocytes. and healthy controls showed increased baseline GR density in both combat related PTSD patients and combat exposed controls compared to healthy controls (Yehuda et al. Although the first studies repeatedly showed a higher baseline leukocyte GR density in PTSD patients. A binding study. Glucocorticoids passively diffuse through the cellular membrane and bind to intracellular receptors. Rohleder et al.. In a replication of these studies. So far studies using a design with metyrapone to inhibit the regulatory effects of cortisol revealed mixed results. It was hypothesized that PTSD subjects would show increased glucocorticoid responsiveness as evidenced by an inhibition of 50% (IC50) on a lower dose of dexamethasone in PTSD subjects compared to controls. there was no group difference in GR density and plasma cortisol levels at 8 a. However. GRs are expressed everywhere in the human body. using 3 H-RU 28362. resulting in up or down regulation in the expression of various genes. showing higher leukocyte GR numbers in patients who had been traumatized early in life. older PTSD subjects demonstrated significantly more suppression of leukocyte GR numbers in response to dexamethasone. However. There was no significant difference between PTSD subjects and trauma exposed non-PTSD subjects.. these studies will be reviewed as well. With respect to the age of traumatization. In both groups metyrapone administration induced a significant increase in ACTH concentrations which rapidly declined after dexamethasone administration. in holocaust survivors and combat veterans with PTSD (Yehuda et al. Assessment of GR number and function in mononuclear leukocytes has been used by different groups as a surrogate model for central GR functioning. The latter data were confirmed in a second study (Yehuda et al.. (2004) measured the GR sensitivity. in mononuclear leukocytes. More inhibition of the immune system reflects more functional GR. PTSD patients had a significantly higher sensitivity to dexamethasone on the level of IL-6 and TNF-a production by leukocytes compared to healthy controls. IC50 levels and basal GR density correlated with the age of exposure to the first trauma in PTSD subjects.S. and GR number using a radioligand binding assay..m. This same protocol was used in women with severe childhood sexual abuse and women with no history of abuse (Stein et al. 2002). de Kloet et al. 1997). However. we have to bear in mind that GR number and affinity is also influenced by the activation state of the immune system.b). 1991). In a recent study Yehuda et al. several studies applying various study designs .. 1995a. no difference in baseline and post DST leukocyte GR density between PTSD patients and controls was reported. The first binding study in PTSD patients showed a significantly higher density of GRs in leukocytes of PTSD patients. Glucocorticoid receptor studies Since leukocyte glucocorticoid receptor (GR) studies have been applied to the arena of endocrine studies in PTSD and might provide more information on central GR functioning.. no significant differences were found between the groups on any of the other parameters. The amount of suppression was smaller compared to the previously described studies. while leukocyte GR expression was lower in each of the examined leukocyte populations in PTSD patients. In this study in Bosnian war refugees with PTSD and healthy controls. / Journal of Psychiatric Research 40 (2006) 550–567 dexamethasone was determined. between PTSD subjects and non-PTSD subjects.560 C. 2003) revealed significantly higher baseline cortisol levels in PTSD patients compared to healthy controls. GR function can be assessed by measuring the inhibitory effect of dexamethasone on the immune system in vitro. A study in Croatian combat veterans with PTSD (Gotovac et al. The mean dose–response curve indeed showed that a significantly lower dose of dexamethasone leads to 50% reduction of lysozyme activity in PTSD subjects compared to the total group of controls including both trauma exposed and non-trauma exposed controls non-PTSD subjects. According to the theory of enhanced feedback inhibition in PTSD patients. 3. assessing both baseline and post dexamethasone GR density in combat exposed veterans with PTSD.. by measuring dexamethasone inhibition of lipopolysaccharide-induced interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-a) production in whole blood.

Yehuda et al.S.m. GR density correlated with PTSD symptoms. Baseline: PTSD: 8761 ± 2987 Combat controls: 7783 ± 3048 Controls: 4480 ± 2326 After DEX PTSD: 5034 ± 2462 Combat controls: 6535 ± 3019 Controls: 4431 ± 2804 PTSD: 4638 ± 1515 nCSA: 3475 ± 1634 Baseline GR density in combat exposed PTSD and non-PTSD › compared to controls. 3 H-RU 28362 binding assay. before and after 0. LPS-induced IL-6 & TNF-a inhibited by 1-1000 nM DEX in vitro... (1993) C. difference in GR density. (1991) Population Combat PTSD (n = 15) Controls (n = 11) PTSD (n = 8). (2003) Combat PTSD (n = 25). GR.6 ± 3.m. consistent with GC-sensitivity. NK cells) Whole blood cultures Blood sampling at 8 a.m. (1997) CSA with PTSD (n = 12) CSA without PTSD (n = 7) Controls (n = 21) Holocaust/combat PTSD (n = 28). Rohleder et al. (2004) PTSD (n = 26) TC (n = 8) Controls (n = 10) Mononuclear leukocytes Bloodsampling at 8 a. (2004) CSA. 3 H-RU 28362 or 3H-DEX binding assay.25 mg DEX. no correlation between cortisol and GR expression. Stein et al. and 4 p. IL-6: IC50: PTSD: 18 IL-6: IC50: Controls: 27 TNF-a: IC50: PTSD: 10 TNF-a: IC50: Controls: 16 GR expression fl in PTSD.Table 4 Leukocyte glucocorticoid receptor studies Reference Yehuda et al.m. DEX. IC-50 dex fl in PTSD versus controls. difference in IC-50 dex between PTSD and TC.m. GR density in PTSD › compared to controls (trend). MDD (n = 10) Other psych. 3 H-RU 28362 binding assay.7 ± 2.8 No main effect of diagnosis in pre. More inhibition through DEX of IL-6 and TNF-a release. (1995) Mononuclear leukocytes Blood sampling 8 a. No sign.m. (2002) Mononuclear leukocytes Blood sampling before and after 0. single point 3 H-RU 28362 binding assay. de Kloet et al. consistent with increased GC sensitivity.9 ± 2.. Blood sampling between 9 a. disorders (n = 22) Combat PTSD (n = 14) Combat controls (n = 12) Controls (n = 14) GR receptors Mononuclear leukocytes Mononuclear leukocytes Method Blood sampling at 8 a. Baseline: PTSD: 2538 ± 1211 TC: 2603 ± 590 Controls: 2346 ± 506 After DEX: PTSD: 2235 ± 1253 TC: 2417 ± 792 Controls: 2411 ± 1194 PTSD: 2735 ± 940 TC: 3190 ± 1703 Controls: 2912 ± 1340 IC50: PTSD: 4. Controls (n = 35) PTSD (n = 12). 3 H-DEX binding assay. childhood sexual abuse. and 1 p. Lysozyme activity after 3 days in increasing doses of DEX.and post DEX GR density. GR density in PTSD › Yehuda et al.5/0.5 mg DEX. TC (n = 9) Controls (n = 10) Mononuclear leukocytes Blood sampling at 8 a. After DEX more suppression of GR density in PTSD (44%) compared to controls (14%). / Journal of Psychiatric Research 40 (2006) 550–567 Yehuda et al. Blood sampling at 8 a.m. traumacontrol. Controls (n = 13) Lymphocytes (T.m. B. GR density (rece/cell)/IC50 (nM) PTSD: 3702 Controls: not reported PTSD: 9075 ± 1437 MDD: 2677 ± 386 Conclusions and remarks GR density in PTSD › 8 a. dexamethasone. TC.1 IC50: TC: 5. glucocorticoid receptor.4 IC50: Controls: 8. 561 . Yehuda et al.m. GR antibody staining and FACS.m. Gotovac et al. 3H-dex binding assay. No sign.

due to feedback inhibition.. 2001). 2004.. so pituitary or adrenal insufficiency as the main cause for low cortisol levels in PTSD is unlikely. 2004b. (b) pituitary insufficiency or reduced pituitary sensitivity. which showed enhanced suppression of GR number after administration of a low dose dexamethasone (Yehuda et al. using different methods to asses HPA-axis functioning. the outcome of the cognitive stress challenge paradigm shows that during stress an enhanced release of cortisol is possible.. Several explanations have been purported to explain this phenomenon. The infusion of cortisol after administration of metyrapone. 2004. Administration of dexamethasone leads to low plasma cortisol levels. de Kloet et al. Kanter et al. 2002) and increased sensitivity for glucocorticoids (Yehuda et al. A confounding factor in these studies could be the interaction of metyrapone with other systems. An inadequate . However. (d) enhanced bioavailability of dexamethasone. / Journal of Psychiatric Research 40 (2006) 550–567 repeatedly reported an enhanced sensitivity of GR to dexamethasone in cells of the immune system. 2004). If low cortisol levels are due to enhanced feedback sensitivity. these results do not fully support the hypothesis of an enhanced dexamethasone bioavailability.. 2001). suggesting a decreased adrenocortical responsiveness in PTSD subjects. enhanced ACTH and 11-deoxycortisol levels would be expected in response to metyrapone administration. did not support the hypothesized enhanced feedback sensitivity as well (Kellner et al. 2002. However. abnormalities in hepatic metabolism and medication effects. The results of the dexamethasone–CRH test in MDD revealed a role for other regulatory mechanisms that could also explain the enhanced cortisol suppression in PTSD.5 mg DST studies could also be explained by pituitary insufficiency or reduced pituitary sensitivity (Yehuda et al. (2001) showing lower levels of 11 deoxycortisol..b. Hypothesized mechanism for altered HPA-axis function in PTSD The combination of baseline high levels of CRH in CSF and low plasma cortisol levels in patients with PTSD contrasts with results seen in MDD patients.b. Another hypothesized mechanism for the enhanced cortisol suppression on low dose dexamethasone is an enhanced bioavailability of dexamethasone. Yehuda et al.. resulting in a negative feedback signal and subsequently a decrease in cortisol production (Yehuda et al. For the same reason adrenal insufficiency or reduced sensitivity for ACTH could result in enhanced cortisol suppression (Yehuda et al. used as a model for central GR functioning. Enhanced feedback sensitivity to cortisol. Yehuda et al. 4. The finding of both decreased ACTH and cortisol levels after 0. after correction for dexamethasone level there was still significantly more cortisol suppression in PTSD subjects (Yehuda et al. Low plasma cortisol levels stimulate the release of CRH and vasopressin in an effort to normalize cortisol levels. hypothesizes that a greater availability of GR on pituitary cells leads to enhanced binding of cortisol.. This hypothesis is supported by the outcome of the metyrapone study by Kanter et al. and eight in vitro GR studies. dexamethasone levels were not found to be significant covariates (Yehuda et al. 1995a.. Key findings of the reviewed studies are enhanced salivary cortisol levels in response to cognitive challenge. 2004a). Rohleder et al. 4. the outcome of metyrapone studies is still inconclusive. if this hypothesis would be true.. in leukocyte GR function studies an enhanced GR sensitivity was reported in PTSD patients..5 mg of dexamethasone.b). whereas the ACTH challenge showed an enhanced cortisol response (Rasmusson et al. This hypothesis was supported by the first lymphocyte GR study. including (a) enhanced feedback sensitivity. and the combination of metyrapone administration with dexamethasone to directly measure the inhibitory effect of glucocorticoids... 1995a. 2004a). In addition. the expected outcome after ACTH challenge would be a reduced cortisol response.S. Metyrapone is known to cause severe nausea. Some studies indeed found higher dexamethasone levels in PTSD patients (Yehuda et al. 2000). Suppression of cortisol by dexamethasone leads to stimulation of the HPA-axis by vasopressin in response to the low cortisol level (Holsboer. as well as enhanced plasma cortisol suppression after administration of 0. In other studies.. Enhanced cortisol suppression in PTSD therefore could be caused by an insufficient pituitary response to central stimulation in response to low cortisol levels.. 1996). 1997.562 C.. and (e) alterations in vasopressin release. 1993). which is a powerful stimulator of the HPA-axis (Kanter et al. Therefore. 2004c). Yehuda et al.5 mg DST in PTSD patients compared to controls also supports the hypothesized enhanced feedback sensitivity at the level of the pituitary (Newport et al. 1995a. Yehuda et al. 2001). Similarly.. The combination of baseline high levels of CRH in CSF and low plasma cortisol levels in patients with PTSD and enhanced cortisol suppression in 0.1. In patients with MDD synergistic action of vasopressin on CRH activity is thought to account for the enhanced cortisol response in the DEX–CRH test. This could be caused by different factors including alterations in the interaction with cortisol binding peptides... Discussion This paper reviewed 26 challenge studies. The results of other pharmacological and cognitive challenge paradigms as well as GR density studies on leukocytes are still inconclusive. however. (c) adrenal insufficiency or reduced adrenal sensitivity.. Stein et al. 1996).

leading to a decrease of CRH receptor binding. the role of these immune alterations and their interaction with the HPAaxis still needs to be evaluated in PTSD populations. It is known to bind CRH with a higher affinity than CRH receptors and in this way antagonizes CRH-induced ACTH release. Corticosteroid binding globulin (CBG) binds cortisol with a high affinity and thereby regulates the bioavailability of. 2002. To date no studies assessing CRH-BP in PTSD patients have been published. 2004). 2003).. This suggests an additional feedback mechanism by an upregulation of CRH-BP in response to stress. 2001. A reduction or increase in leukocyte GR function may also provide an explanation for sickness behavior which is present in numerous stress related disorders such as PTSD (Boscarino.. Raison and Miller. The results of the reviewed challenges do not exclusively support one of the hypothesized mechanisms. and might serve as an explanation for unexplained medical symptoms after deployment (Kang et al. and the immune factors. 1989. Kellner et al. e.. .. free cortisol to target tissues (Breuner and Orchinik. however. Binding of CRH to CRH-BP promotes a rapid clearance of the complex.g. 2002). CBG levels have been assessed in only one study and revealed significantly higher plasma CBG levels in PTSD patients compared to controls (Kanter et al. Leukocyte GR studies might provide a tool in studying this interaction. The higher salivary cortisol levels in response to a cognitive challenge do not seem to support the hypothesis of pituitary-. including the pituitary. enhanced feedback inhibition in PTSD patients. Based on the observations of altered cytokine production in PTSD we stress the need for further exploration of the interaction between the immune system and the HPAaxis in PTSD (Besedovsky and del Rey. When plasma cortisol is assessed total cortisol is measured without an indication of the amount of free (biological active) cortisol. Although a low ACTH response was found by Smith et al. Kanter et al.. Alterations in plasma cortisol baseline or in challenge paradigm do not necessary imply a suppression of biologically active cortisol. biological active.g. 1998). Cellular synthesis of CBG limits the availability of cortisol to intracellular receptors and has been hypothesized to interfere with the negative feedback of cortisol on ACTH secretion (Berdusco et al. 1990). On the other hand cytokines influence the HPA-axis and GR expression.. showed an exaggerated cortisol response which is in contrast with the assumed decrease in ACTH response. and inhibition of the ACTH releasing activity (McClennen et al. Future studies assessing CBG in combination with cortisol in plasma or CSF could provide additional information on the availability of biologically active cortisol in PTSD. 4. 2000.. / Journal of Psychiatric Research 40 (2006) 550–567 563 vasopressin reaction could then account for the enhanced cortisol suppression in patients with PTSD.. suggesting more binding of CRH to CRH-BP to inhibit pituitary activation (Suda et al. de Kloet et al. On the one hand cortisol decreases the production of pro-inflammatoire cytokines and increases the production of anti-inflammatory cytokines. Wong. Rasmusson et al. IL-6 stimulates the production of glucocorticoids. The infusion of cortisol after administration of metyrapone.C.. Other factors involved in HPA-axis regulation Other factors involved in altered stress regulation in PTSD that need to be further explored are hormone binding proteins (e.S. CRH binding protein and corticosteroid binding globulin).. Decreased vasopressin release could also account for the baseline findings of high CRH levels and low cortisol levels.. and has been found to upregulate GR binding and GR expression in leukocytes. 2003). or adrenal insufficiency or an inadequate vasopressin reaction. This hypothesis predicts a low ACTH response after CRH challenges and in cognitive challenge studies. There is also evidence for CBG synthesis in tissues outside of the liver. Preclinical studies show increased CRH-BP mRNA in response to restraint stress and a decrease of CRH-BP mRNA after adrenalectomy. this finding was not replicated in later studies (Smith et al.. 1995). Although in a PTSD population alterations in immune function have been reported frequently (Miller et al.. Although dexamethasone bioavailability has not been found to be a significant covariate. 2002). and the combination of metyrapone administration with dexamethasone to directly measure the inhibitory effect of glucocorticoids did not support the hypothesized enhanced feedback sensitivity (Kellner et al. we should make note of the higher levels of dexamethasone after DST often reported in PTSD patients. The outcome on non-pharmacological stress challenge studies. CRH binding protein is co-localized with CRH at several sites in the brain. 2001). ACTH and CRH.2. 2003). 2004.. Alterations in leukocyte GR function can be hypothesized to play a major role in increased cytokines production in PTSD. Il-2 has been found to induce CRH and ACTH release and anti-inflammatory Il-10 enhances CRH and ACTH production (for review see Wong. 2001). The immune system interfaces with the HPA-axis in a bidirectional way. 2001). CRH-BP therefore might also play a role in the enhanced feedback inhibition on DST in PTSD. del Rey and Besedovsky. 2000. which implies that more studies are necessary before it is possible to accept the most often purported hypothesis: namely. Studies in patients with CushingÕs disease and AddisonÕs disease also suggest that in humans plasma cortisol decreases plasma CRH-BP levels.

the correlation between in vivo dexamethasone suppression and GR sensitivity in mononuclear leukocytes in healthy controls supports the idea that GR expression in leukocytes may reflect central GR expression (Yehuda et al. 1993).g. most pituitary and adrenal hormones have a diurnal rhythm and a pulsatile secretion. The outcome of the non-pharmacological paradigm showed enhanced adrenal responsivity in PTSD subjects.. the time passed since the most recent trauma has been shown to be significantly associated with the amount of cortisol suppression after low dose dexamethasone.. Another problem in the interpretation of the results is whether authors correlated their findings with existing PTSD symptoms or with the experience of a traumatic effect. This concept may be doubted as preclinical studies show tissue specific differences in GR expression between cells and tissues of the immune system (Miller et al. and treatment of psychiatric disorders. preferably perform multicenter research. as has been reached in the dexamethasone–CRH test. However. (2003). whereas PTSD patients showed significantly more cortisol suppression compared to non-PTSD subjects. When leukocyte GR studies are used as a model for central GR function the assumption is that leukocyte GR and brain GR expression are correlated. (2004c). (Yehuda et al. These factors may also play a crucial role for the assessment of HPA-axis function using challenge paradigms. These results confirm the data reported by Grossman et al. no difference in cortisol suppression was found between non-traumatized subjects and traumatized subjects without PTSD or MDD. ACTH and metyrapone tests in this review differed both in time of challenge.S. and mild stressful stimuli may be interpreted as threatening stimuli in patients with PTSD (Engelhard et al. combat experience. However. (1998) have shown that access of the synthetic glucocorticoid dexamethasone to central targets is hampered by MDR1a P-glycoprotein. earlier studies in depressive populations showed comparable cortisol outcome between designs using hydrocortisone and dexamethasone to induce feedback inhibition (Gispen-de Wied et al. but also the frequency and intensity of the traumatic event.. However. course.564 C. A confounding factor might be that when measuring ex vivo GR density after administration of dexamethasone in vivo. Furthermore. the studied populations varied widely. The interpretation of the results of challenges in which dexamethasone is used instead of cortisol. in most studies the time passed since the traumatic event has not been assessed. Confounding factors and limitations For proper interpretation of the results there are factors we should take notice of. However. showing a positive association between the amount of cortisol suppression and the number of years passed since the traumatic event occurred.3. This emphasizes the complexity of baseline assessments in this population. sexual or physical assault. In the earlier described study by Yehuda et al. however. complicating interpretation of single point baseline measurements as well as comparisons between challenge studies at different timepoints during the day. The design of CRH. Another important factor is the experienced stress during assessments. More stimuli are interpreted as stressful. PTSD symptoms could be caused by early childhood abuse. To overcome the problem of variation in population in PTSD research it is necessary to use larger study populations. 1998). In the reviewed studies. the outcome might be influenced by the amount of in vivo bound dexamethasone. / Journal of Psychiatric Research 40 (2006) 550–567 4. 2001). Faced with all the factors influencing the outcome of HPA-axis measurements we should not be surprised by the inconclusiveness of most challenge designs. Recommendations for future research The development of a classified system for psychiatric disorders is necessary to gain insight into etiology. 2004c). Population factors which might have influenced the outcome in the reviewed study designs include gender and age. Preclinical studies by De Kloet et al. to enable proper differentiation in . e. de Kloet et al.. subjects with PTSD revealed significantly more cortisol suppression. at the level of the endothelial cells of the blood–brain barrier. Assessment of leukocyte GR density has the disadvantage that an increase in GR density does not necessarily imply enhanced receptor sensitivity. GR sensitivity resembles the number of functional GR receptors as well as the transduction of the signal from the receptor to the intracellular effector system. These studies make it plausible that at least the altered DST response is correlated with PTSD and not with trauma. is necessary to further develop our understanding of HPA-axis dysfunction in PTSD. should take note of the fact that dexamethasone may not cross the blood brain barrier. Thus not only the moment of trauma in lifespan and the time passed since the event differed between and within studies. and moment. In these studies enhanced cortisol levels in PTSD samples may be caused by more severe conditioning. Other factors that can influence the outcome are the age of the individual at the moment of the traumatic event and the chronicity of the traumatic event. who reported that in a population with a high incidence (88%) of traumatic experiences (as defined by the A criterion of the PTSD diagnosis) neither childhood nor adult history of trauma had a significant effect on cortisol suppression after 0. motor vehicle accidents.4.5 mg DST. Similarly.. The latter may have influenced the outcome on the ACTH challenge and metyrapone challenge designs. consensus in the design of research paradigms. especially in a clinical environment. 4. and number of assessments.. 2004b).

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