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Glucocorticoid Feedback Sensitivity and Adrenocortical

Responsiveness in Posttraumatic Stress Disorder


Evan D. Kanter, Charles W. Wilkinson, Allen D. Radant, Eric C. Petrie,
Dorcas J. Dobie, Miles E. McFall, Elaine R. Peskind, and Murray A. Raskind

Background: Decreased basal cortisol levels have been Key Words: PTSD, adrenal cortex, ACTH, cortisol,
reported in individuals with posttraumatic stress disorder metyrapone, DHEA
(PTSD). There is evidence for enhanced negative feedback
sensitivity of the hypothalamic-pituitary-adrenal (HPA)
axis in PTSD, which could account for this, but other
possible mechanisms have not been ruled out. We exam- Introduction
ined the HPA axis employing a metyrapone-cortisol infu-
sion protocol designed to study negative feedback sensi-
tivity. P osttraumatic stress disorder (PTSD) is associated with
abnormalities in neuroendocrine systems (Yehuda
1998), including alterations in the hypothalamic-pituitary-
Methods: Vietnam combat trauma– exposed subjects met
adrenal (HPA) axis. Given the long-established role of the
DSM-IV criteria for PTSD. Exclusion criteria included
HPA axis in the acute response to stress, it is not surprising
substance abuse and most medications. Endogenous feed-
back inhibition was removed by blocking cortisol synthesis that HPA axis abnormalities appear to be present in PTSD.
with oral metyrapone and reintroduced by intravenous The nature and direction of these abnormalities are coun-
infusion of cortisol. In a placebo condition, subjects terintuitive, however. The increase in plasma cortisol seen
received oral placebo and normal saline infusion. Serial in response to acute stress is well documented (Chrousos
blood samples drawn over 4 hours were assayed for and Gold 1992; Selye 1956), and increased basal cortisol
adrenocorticotrophic hormone (ACTH), cortisol, and 11- levels are consistently found in patients with major de-
deoxycortisol. Selected samples were assayed for cortisol pression (Sachar 1975). In contrast, most studies have
binding globulin (CBG) and dehydroepiandrosterone shown decreased basal cortisol levels in PTSD (for review,
(DHEA). see Yehuda 1997). Intensity of combat exposure is corre-
Results: Basal plasma cortisol was significantly de- lated with PTSD symptom severity (Buydens-Branchey et
creased in PTSD subjects (n ⫽ 13) compared with control al 1990) and negatively correlated with plasma cortisol
subjects (n ⫽ 16). No significant difference in the ACTH concentration (Boscarino 1996), suggesting a pathophysi-
response to cortisol infusion following metyrapone was ologic relationship between HPA axis function and PTSD
observed; however 11-deoxycortisol was significantly de- symptoms.
creased in PTSD subjects. In addition, CBG was signifi-
One possible mechanism that could account for low
cantly increased in PTSD subjects, and DHEA was signif-
icantly decreased in both PTSD and combat-exposed cortisol concentrations in PTSD is increased sensitivity of
control subjects. the HPA axis to feedback inhibition by cortisol (Yehuda
1997). Although patients with major depression often fail
Conclusions: These observations suggest decreased ad-
renocortical responsiveness may be an additional or to suppress cortisol concentrations following dexametha-
alternative mechanism accounting for low cortisol in sone (DEX), patients with PTSD hypersuppress cortisol
PTSD. Biol Psychiatry 2001;50:238 –245 © 2001 Soci- concentrations in response to DEX (Goenjian et al 1996;
ety of Biological Psychiatry Heim et al 1998; Stein et al 1997; Yehuda et al 1993).
Demonstration of a decrease in the number of glucocorti-
coid receptors on peripheral lymphocytes in response to
From the Mental Illness Research, Education, and Clinical Center (EDK, DJD, DEX in combat veterans with PTSD, but not in control
MEM, ERP, MAR) and Geriatric Research, Education, and Clinical Center
(CWW), Veterans Affairs Puget Sound Health Care System; and the Depart-
subjects (Yehuda et al 1995), provides additional evidence
ment of Psychiatry and Behavioral Sciences, University of Washington School of an enhanced sensitivity to cortisol in PTSD. This is
of Medicine (EDK, CWW, ADR, ECP, DJD, MEM, ERP, MAR), Seattle,
Washington.
again opposite of the pattern seen in major depression, in
Address reprint requests to Dr. Evan Kanter, VA Puget Sound Health Care System, which decreased sensitivity of lymphocyte glucocorticoid
Mental Illness Research, Education, and Clinical Center (116 MIRECC), 1660
South Columbian Way, Seattle, WA 98108.
receptors is observed (Gormley et al 1985; Whalley et al
Received September 29, 2000; revised March 19, 2001; accepted March 22, 2001. 1986).

© 2001 Society of Biological Psychiatry 0006-3223/01/$20.00


PII S0006-3223(01)01158-1
HPA Axis in PTSD BIOL PSYCHIATRY 239
2001;50:238 –245

Yehuda et al (1996) have used the metyrapone stimu- System, Seattle Division. Subjects were in good general health as
lation test as a means to examine sensitivity to removal of determined by history, physical exam, and laboratory studies.
glucocorticoid negative feedback of the HPA axis in Complete blood count, electrolytes, glucose, liver, kidney, and
PTSD subjects. The 11␤-hydroxylase inhibitor metyrap- thyroid function tests, and urinalysis were all within normal
limits. Urine toxicology screens were negative. Subjects had no
one blocks the final step in cortisol biosynthesis, decreas-
substance abuse for at least 3 months and were free of all
ing plasma cortisol concentrations and increasing concen-
medications known to affect the HPA axis for at least 30 days,
trations of the precursor compound 11-deoxycortisol, including antidepressants and other psychotropic medications.
which does not have feedback activity. Plasma adrenocor- Diagnosis of PTSD was established using the Clinician Admin-
ticotrophic hormone (ACTH) increases as a result of istered PTSD Scale (CAPS; Blake et al 1995). The Structured
decreased feedback inhibition at the hypothalamus and Clinical Interview for DSM-IV (SCID; First et al 1995) was used
pituitary by cortisol. In Yehuda’s study, combat veterans to assess other Axis I disorders. PTSD subjects also completed
with PTSD exhibited a greater increase in ACTH release the Revised Combat Exposure Scale (RCS; Gallops et al 1981),
from the pituitary and a greater accumulation of the Mississippi Scale for Combat-Related PTSD—Revised (MISS;
cortisol precursor 11-deoxycortisol in response to me- Keane et al 1988), PTSD Checklist (PCL; Weathers et al 1993),
tyrapone than did normal control subjects, suggesting and Hamilton Depression Rating Scale (HAM-D; Hamilton
increased feedback inhibition by cortisol in PTSD. 1960).
An age-comparable group of control subjects without PTSD
The evidence to date, including the DEX suppression
(mean age 50.2 ⫾ 0.8) were community volunteers recruited by
test and the metyrapone stimulation test, supports a model
newspaper advertisement, advertisement to VA employees, and
of enhanced glucocorticoid negative feedback in PTSD. word of mouth. Nine of these were veterans who had histories of
Other possible mechanisms might contribute to the low combat exposure. Control subjects completed a nonpatient ver-
plasma cortisol seen in PTSD, however, and have not been sion of the SCID, the PCL, and the HAM-D. Combat-exposed
ruled out. These include decreased sensitivity of the control subjects also completed the RCS.
pituitary or the adrenal as well as decreased concentrations The PTSD subjects had a mean score on the CAPS (maximum
of corticosteroid binding globulin (CBG). 136) of 84.5 ⫾ 4.0 and the MISS (maximum 195) of 121.4 ⫾ 3.4,
We sought to examine negative feedback sensitivity in reflecting severe PTSD symptoms. Mean scores on the 14-point
PTSD directly using the endogenous ligand cortisol. We RCS were 11.5 ⫾ 0.7 for PTSD subjects and 8.4 ⫾ 1.1 for
used a protocol of cortisol infusion following pretreatment combat-exposed control subjects. Mean scores on the PCL (range
with metyrapone, originally developed to examine the 17– 85) were 69.6 ⫾ 2.1 for PTSD subjects, 20.7 ⫾ 1.7 for
combat-exposed control subjects, and 20.4 ⫾ 2.0 for noncombat
effect of human aging on feedback inhibition of the HPA
control subjects. Mean scores on the HAM-D were 18.5 ⫾ 1.8
axis by cortisol (Wilkinson et al 1997, 2001). Following
for PTSD subjects, 1.0 ⫾ 0.4 for combat-exposed control
suppression of endogenous cortisol by oral metyrapone, subjects, and 1.7 ⫾ 0.9 for noncombat control subjects. Of the 13
cortisol was infused intravenously. Serial measurements PTSD subjects, 11 also met SCID criteria for major depression or
were made of plasma ACTH, cortisol, and 11-deoxycor- dysthymia. No other Axis I disorders were diagnosed in the
tisol. The feedback effect of the exogenous cortisol could PTSD subjects, and none were diagnosed in the control subjects.
be determined by measuring the decrease in circulating Six of 13 PTSD subjects were unemployed at the time of the
ACTH concentrations. We hypothesized that circulating study; two of 16 control subjects were unemployed. Body mass
ACTH would decrease more rapidly in response to cortisol index was 27.6 ⫾ 0.9 for PTSD subjects and 28.1 ⫾ 1.4 for
infusion in PTSD subjects than in normal control subjects, control subjects.
a finding that would be consistent with enhanced negative
feedback sensitivity to cortisol in PTSD. Considering Procedures
other hypotheses to account for hypocortisolemia in
Each subject underwent two study conditions in random order at
PTSD, we assayed samples for CBG. We also measured least 4 days apart. In the experimental condition, subjects were
another corticosteroid, dehydroepiandrosterone (DHEA) administered 750 mg of metyrapone (Metopirone, Ciba-Geigy)
as an additional probe of adrenal function. orally at 0600 and again at 0900. Subjects were instructed to take
nothing by mouth after midnight the night before the study.
Except for two PTSD subjects who completed the study as
Methods and Materials inpatients, all subjects drove to the hospital. They were instructed
to awaken at 0600, take the first metyrapone dose, and then call
Subjects the voicemail of the study nurse to confirm that the medication
The study was approved by the Human Subjects Review Com- was taken at the appropriate time and that they were on their way
mittee of the University of Washington, and written informed to the hospital. At 0830, an intravenous catheter was placed in an
consent was obtained from all subjects. Thirteen Vietnam combat antecubital vein of each arm and kept patent with a slow infusion
veterans (mean age 50.5 ⫾ 0.6) were recruited from inpatient and of normal saline. One intravenous catheter was used for blood
outpatient PTSD programs at the VA Puget Sound Health Care sampling and the other for infusion. At 0855 and 0900 baseline
240 BIOL PSYCHIATRY E.D. Kanter et al
2001;50:238 –245

blood samples were drawn. Beginning at 0900, cortisol (hydro- analysis of variance (ANOVA) for repeated measures. Differ-
cortisone sodium succinate, Pharmacia, Peapack, NJ) was in- ences in hormonal baseline values between groups were com-
fused at 0.03 mg/kg/hour in 300 mL normal saline over 150 min. pared with two-tailed, unpaired t tests. Determination of the time
Blood sampling occurred every 15 min for 240 min following at which ACTH was significantly inhibited by cortisol feedback
baseline. In the placebo condition, subjects received placebo was made by calculating the difference in ACTH concentration
tablets and a normal saline infusion matched for volume. between the postmetyrapone baseline and each subsequent time
point and analyzing the differences at each time by single sample
Assays t tests. We compared DHEA concentrations in the three treatment
subgroups using one-way ANOVA followed by Fisher’s pro-
We measured ACTH by a double antibody “sandwich” radioim- tected least significant difference (PLSD) post hoc test for paired
munometric assay (Nichols Institute Diagnostics, San Juan Cap- comparisons. Area under the curve (AUC) for plasma free
istrano, CA) following a modified version of the commercial cortisol was calculated with the trapezoidal method and group
protocol. In this assay, cross-reactivity of shorter forms of ACTH differences in AUC were analyzed with two-tailed, unpaired t
and melanotropins is negligible. The detection limit is 2 pg/mL. tests.
Intra- and interassay coefficients of variation are 6.3% and
12.8%, respectively.
Cortisol was measured by radioimmunoassay (RIA) in unex-
tracted plasma. Samples were diluted with phosphate buffer and Results
heated for 20 min at 80°C to denature binding globulins. Cortisol Because the ACTH, cortisol, and 11-deoxycortisol re-
antiserum was obtained from ICN Biomedicals (Costa Mesa,
sponses and CBG concentrations of the combat-exposed
CA). The detection limit for cortisol is 0.5 ␮g/dL. Intra- and
interassay coefficients of variation are 4.6% and 10.2%, respec-
and noncombat control subjects did not significantly differ
tively. Cross-reactivity of the antiserum with 11-deoxycortisol is in either placebo or drug condition (all t ⬍ 1.0, p ⬎ .3), the
10%. Assay values for cortisol were corrected by subtracting two groups were combined for analysis of these variables.
10% of the 11-deoxycortisol values for each sample. All results are presented as means ⫾ standard error of the
11-deoxycortisol was measured by RIA in unextracted plasma mean (SEM).
to which steroid binding globulin inhibitor was added. Anti-
serum, standards, and 125I-labeled 11-deoxycortisol were ob-
Placebo Condition Measurements
tained from ICN Biomedicals. Cross-reactivity of the antiserum
with cortisol is 1.7%. Diluted aliquots of 5 ␮L of plasma were In the placebo condition, plasma cortisol (Figure 1B) was
used in assaying samples from metyrapone-treated subjects and significantly lower in PTSD subjects compared with con-
20 ␮L samples from control subjects. The sensitivity of the assay trol subjects throughout the protocol [F(1, 27) ⫽ 12.6, p ⬍
is 0.5 ng/mL. Intra- and interassay coefficients of variation are .005]. During placebo infusion ACTH (Figure 1A) and
5.2% and 14.4%, respectively. 11-deoxycortisol (Figure 1C) concentrations did not
We measured CBG by radial immunodiffusion with Cortisol change over time and did not differ between PTSD and
Binding Globulin-NL Kits from The Binding Site (San Diego,
control groups. Concentrations of 11-deoxycortisol were
CA). Duplicate 5-␮L plasma samples and standards were added
to individual wells in agarose gel plates containing a monospe-
minimal in both groups.
cific antibody (sheep antihuman corticosteroid binding globulin).
Plates were incubated under moist conditions at room tempera- Pituitary and Adrenal Responses to Metyrapone
ture for 96 hours, and the diameter of the precipitin rings was
read with an electronic reader. Minimum sensitivity of the assay
Metyrapone treatment substantially reduced initial plasma
is 0.1 ␮mol/L. Intra- and interassay coefficients of variation are cortisol (Figure 1B) concentrations and increased initial
2.9% and 4.4%, respectively. Free cortisol was calculated from ACTH (Figure 1A) and 11-deoxycortisol (Figure 1C)
assayed values of total plasma cortisol and CBG using the concentrations. Metyrapone treatment induced signifi-
method of Coolens et al (1987). cantly greater decreases in cortisol concentrations (t ⫽ 2.3,
Plasma concentrations of DHEA were measured with the p ⬍ .05) and significantly greater increases in 11-deoxy-
DSL-8900 DHEA Radioimmunoassay Kit from Diagnostic Sys- cortisol concentrations (t ⫽ 2.4, p ⬍ .05) in control
tems Laboratories (Webster, TX) following the manufacturer’s subjects compared with PTSD subjects. The magnitude of
protocol. Cross-reactivity of the antiserum with DHEA-sulfate is the increase in ACTH concentrations did not differ signif-
0.02%, and cross-reactivities with other steroids are all less than icantly between PTSD and control groups (t ⫽ 1.7, p ⫽
1%. Sensitivity of the assay is 0.03 ng/mL. All samples in this
.10).
study were measured in a single assay, and the intraassay
coefficient of variation was 2.8%.
Plasma ACTH, Cortisol, and 11-Deoxycortisol
Statistical Analysis Responses to Exogenous Cortisol Infusion
Hormonal responses of PTSD and control groups during the There was no significant difference in ACTH concentra-
course of experimental sessions were analyzed by two-way tion (Figure 1A) between PTSD subjects and control
HPA Axis in PTSD BIOL PSYCHIATRY 241
2001;50:238 –245

Figure 2. Plasma cortisol binding globulin (CBG) concentra-


tions in subjects with posttraumatic stress disorder (n ⫽ 13) and
control subjects (n ⫽ 16). The first sample in the placebo
condition and the first and last samples in the metyrapone-
cortisol (met-cort) condition were assayed for CBG. Vertical
lines indicate SEM. Concentrations of CBG were significantly
increased in PTSD subjects compared with control subjects [F(1,
27) ⫽ 8.6, p ⬍ .01].

difference in plasma cortisol between PTSD and control


subjects over the course of the experiment [F(1, 27) ⫽
0.95, p ⫽ .34]. The maximum levels of plasma cortisol
reached as a result of the infusion did not differ signifi-
cantly between PTSD and control groups (t ⫽ 1.7, p ⫽
.10). Plasma levels of 11-deoxycortisol (Figure 1C) were
significantly lower in PTSD subjects compared with con-
Figure 1. Hypothalamic-pituitary-adrenal axis responses to me- trol subjects throughout the protocol [F(1, 27) ⫽ 10.7, p ⬍
tyrapone-cortisol protocol in subjects with posttraumatic stress .005].
disorder (PTSD; filled circles, n ⫽ 13) and control subjects (open
circles, n ⫽ 16). Graphs in right-hand column represent re-
sponses to infusion of cortisol at 0.03 mg/kg/hour following oral Measurement of Plasma CBG and Calculated Free
administration of 1500 mg metyrapone in divided doses. Graphs Cortisol
in left-hand column represent placebo responses. Vertical lines
indicate SEM. (A) Adrenocorticotrophic hormone (ACTH): Dif- Plasma CBG concentrations (Figure 2) were measured in
ferences between PTSD subjects and control subjects in the the first sample of the placebo condition and the first and
effect of exogenous cortisol on the ACTH response were not last samples from the metyrapone-cortisol condition. We
significant [F(1, 27) ⫽ 3.0, p ⫽ .10]. (B) Cortisol: Drug
found that CBG was significantly increased in PTSD
condition represents accumulation of cortisol from exogenous
infusion. Placebo condition demonstrates significantly decreased subjects compared with control subjects [F(1, 27) ⫽ 8.6,
baseline plasma cortisol in PTSD subjects compared with control
subjects [F(1, 27) ⫽ 12.6, p ⬍ .005]. (C) 11-deoxycortisol:
Plasma concentrations of 11-deoxycortisol were significantly
lower in PTSD subjects than in control subjects [F(1, 27) ⫽ 10.7,
p ⬍ .005].

subjects [F(1, 27) ⫽ 3.0, p ⫽ .10] and no significant group


by time interaction. The ACTH concentration never de-
clined significantly in either the PTSD or control group by Figure 3. Calculated plasma free cortisol concentrations in
single sample t tests of the difference scores at each time subjects with posttraumatic stress disorder (PTSD; filled circles,
point. n ⫽ 13) and control subjects (open circles, n ⫽ 16). Vertical lines
During the 150 min of exogenous cortisol infusion, indicate SEM. In the placebo condition (left) free cortisol
concentrations were significantly decreased in PTSD subjects
plasma cortisol levels (Figure 1B) steadily increased to
compared with control subjects [F(1,27) ⫽ 20.4, p ⫽ .0001]. In
approximately twice the baseline level. After the infusion the metyrapone-cortisol condition (right) the difference in free
was stopped, cortisol levels decreased over 90 min, nearly cortisol concentrations between PTSD subjects and control
returning to baseline levels. There was no significant subjects did not reach significance [F(1, 27) ⫽ 4.0, p ⫽ .055].
242 BIOL PSYCHIATRY E.D. Kanter et al
2001;50:238 –245

studies. Second, no evidence of increased sensitivity of


glucocorticoid negative feedback was observed in this
protocol. Third, a variety of data suggested that adreno-
cortical responsiveness was decreased in subjects with
PTSD. Additional findings were increased concentrations
of CBG in subjects with PTSD and decreased concentra-
tions of DHEA in subjects with combat exposure.
One possible explanation for decreased plasma cortisol
concentrations would be decreased concentrations of
Figure 4. Plasma dehydroepiandrosterone (DHEA) concentra- CBG. Because 95% of plasma cortisol is protein bound
tions in PTSD subjects (n ⫽ 13), combat control subjects (n ⫽ (Dunn et al 1981), a relative deficiency of CBG in the
9), and noncombat control subjects (n ⫽ 7). The first two PTSD subjects might result in a lower concentration of
samples in both placebo and metyrapone-cortisol (met-cort)
conditions were assayed for DHEA. Vertical lines indicate SEM.
bound cortisol, which is inactive. Total cortisol would be
Concentrations of DHEA were significantly decreased in both decreased, but the concentration of physiologically active
PTSD subjects and combat control subjects compared with free cortisol might be the same. In our study, CBG was
noncombat control subjects in both placebo and drug conditions actually increased in the PTSD subjects compared with
(all p ⬍ .05). Concentrations of DHEA did not significantly control subjects. Consequently, differences between PTSD
differ between PTSD subjects and combat control subjects.
subjects and control subjects appear greater for free
cortisol than for total cortisol. The finding of increased
p ⬍ .01]. In the placebo condition, calculated free cortisol CBG in the hypocortisolemic PTSD subjects is consistent
(Figure 3) was significantly lower in PTSD subjects
with observations in the rat that removal of corticosterone
compared with control subjects throughout the protocol
by adrenalectomy increases the production and secretion
[F(1, 27) ⫽ 20.4, p ⫽ .0001]. In the metyrapone-cortisol
of CBG (Feldman et al 1979; Levin et al 1987).
condition, there was a trend for free cortisol to be
No significant difference was seen by ANOVA between
decreased in the PTSD group that did not reach the level
PTSD subjects and control subjects in the effect of
of significance [F(1, 27) ⫽ 4.0, p ⫽ .055]. There was no
exogenous cortisol on circulating ACTH. These data
significant difference between the groups in an area under
therefore do not provide support for enhanced glucocorti-
the curve analysis (t ⫽ 1.4, p ⫽ .16).
coid negative feedback of the HPA axis. It is possible that
a significant difference in ACTH suppression would be
Measurement of Plasma DHEA seen using a higher cortisol infusion dose. Given the a
Plasma DHEA concentrations (Figure 4) were measured in priori hypothesis of enhanced negative feedback in PTSD
the first and second samples of each condition (preinfusion patients, the 0.03 mg/kg/hour dose was chosen because it
baseline). Unlike other parameters, DHEA concentrations would produce only a modest suppression of ACTH and
differed significantly between the combat and noncombat might thereby accentuate the difference between PTSD
control groups in both placebo and metyrapone-cortisol and control subjects. A 0.06 mg/kg/hour dose has pro-
conditions (placebo t ⫽ 2.2, p ⬍ .05; drug t ⫽ 3.4, p ⫽ duced a more robust suppression of ACTH in normal
.005). The two control groups were treated separately for subjects in previous studies in our laboratory (Wilkinson
purposes of analyzing DHEA data. Differences in DHEA et al 1997, 2001). Repeating the experiment using the
concentrations among groups were significant by ANOVA higher dose might produce more conclusive results. An-
[F(2, 24) ⫽ 10.4, p ⬍ .001]. Post hoc comparisons using other possible explanation for the lack of the expected
Fisher’s PLSD showed that in both placebo and metyrap- ACTH response to cortisol is that there may have been less
one-cortisol conditions DHEA concentrations were not of a feedback signal in the PTSD group due to the
significantly different between PTSD subjects and combat observed decrease in free cortisol.
control subjects; DHEA concentrations were significantly Yehuda (1997) has proposed that trauma sensitizes the
decreased in both PTSD subjects and combat control HPA axis so that there is enhanced glucocorticoid feed-
subjects compared with noncombat control subjects (all back inhibition, thus explaining the reported low cortisol
p ⬍ .05). concentrations (Yehuda 1997), hypersuppression of corti-
sol following DEX (Goenjian et al 1996; Heim et al 1998;
Stein et al 1997; Yehuda et al 1993), and increased ACTH
Discussion response to metyrapone-induced removal of cortisol feed-
There were three main findings in the study. First, baseline back (Yehuda et al 1996). It is possible, however, that
plasma cortisol levels were significantly lower in PTSD decreased adrenal secretion of cortisol could also contrib-
subjects than control subjects, consistent with previous ute to this pattern of findings. For example, Wittert et al
HPA Axis in PTSD BIOL PSYCHIATRY 243
2001;50:238 –245

(1996) found that intense physical training leads to de- data show an association between decreased DHEA and
creased adrenal responsiveness to ACTH, consistent with combat exposure, rather than PTSD, the findings are still
an association between physical stress and decreased consistent with adrenal hyporesponsiveness. A precursor
adrenal function. Furthermore, an analogy with the HPA to many other steroids, including testosterone and estro-
axis characteristics of major depression suggests the pos- gen, DHEA is secreted in large concentrations from the
sibility of adrenal hyporesponsiveness. Both decreased adrenal cortex. It possesses weak androgenic activity; its
glucocorticoid negative feedback sensitivity (Young et al intrinsic physiologic function is unknown (Kroboth et al
1991) and increased adrenal sensitivity to ACTH (Jaeckle 1999). Administration of DHEA has been reported to have
et al 1987) have been demonstrated in major depression. If positive effects on mood and memory (Wolkowitz et al
a pattern of HPA axis abnormalities in PTSD is emerging 1997). The finding of decreased DHEA in PTSD subjects
that is opposite that seen in depression, it seems reasonable is intriguing because affective disturbance and difficulty
to hypothesize that decreased adrenal sensitivity would be with memory for nontraumatic events are symptoms com-
observed in PTSD. If adrenal hyporesponsiveness were monly reported in the disorder.
present, one might have expected to see increased ACTH A potential concern about studies that use DEX to
levels in response to low cortisol in PTSD subjects. The evaluate glucocorticoid feedback sensitivity is that DEX
absence of an increase in ACTH might be explained if differs from endogenous glucocorticoids in significant
increased negative feedback sensitivity were also present. ways. First, DEX and the human endogenous glucocorti-
The finding of significantly lower levels of plasma coid cortisol have different affinities for corticosteroid
11-deoxycortisol in PTSD subjects compared with control receptor subtypes (DeKloet et al 1991). Second, the two
subjects lends further support to the possibility of de- ligands differ in the level of the HPA axis at which the
creased adrenocortical responsiveness as an additional or feedback inhibition is recognized (Kovacs and Makara
alternative mechanism to explain observations of low 1988; Miller et al 1992). Because DEX does not penetrate
cortisol in PTSD. After metyrapone treatment, ACTH was well into the brain and exerts feedback effects primarily at
not significantly different between PTSD subjects and the pituitary, using it to test suprapituitary components of
control subjects, but the magnitude of the changes in both the HPA axis may be problematic (De Kloet et al 1998).
cortisol and 11-deoxycortisol was significantly decreased A potentially significant difference between this study
in the PTSD group, again providing evidence of decreased and that of Yehuda (1996) is the dose of metyrapone used.
adrenal responsiveness in PTSD subjects. The observed In Yehuda’s study, 2500 mg of metyrapone was given in
difference in adrenal sensitivity could represent a differ- a single dose. At this dose some of the subjects may have
ential response to ACTH, perhaps at the level of the experienced nausea. Because nausea is one of the most
ACTH receptor, or it could be a function of some other powerful known stimulators of the HPA axis (Eversmann
factor that acts synergistically with or in opposition to et al 1978), this could have been a confounding factor. In
ACTH. An ACTH stimulation test would be a means to our study, metyrapone was given in two doses of 750 mg.
test directly this hypothesis. With administration of metyrapone in this manner, no
Although there has been no report of an ACTH chal- subjects in our study experienced any gastrointestinal side
lenge in the PTSD literature, there have been reports of effects. As a result of the lower metyrapone dose, ACTH
CRF challenges in PTSD. Smith et al (1989) reported a did not increase in response to metyrapone to the same
blunted ACTH response to CRF in subjects with PTSD degree as it did in the Yehuda study. Approximately 50%
compared with control subjects, with normal levels of suppression of endogenous cortisol was achieved in nor-
cortisol. This would be consistent with a model of en- mal subjects. This degree of suppression was sufficient to
hanced negative feedback by cortisol. On the other hand, enable demonstration of differences in glucocorticoid
Heim et al (1998) reported different results in a population feedback sensitivity between young and old subjects in
of women with chronic pelvic pain, many of whom had previous studies (Wilkinson et al 1997, 2001). An addi-
PTSD. In this study, ACTH levels were normal and tional consequence of the study design is that the full
cortisol levels were decreased compared with control effect of the first metyrapone dose and the effect of the
subjects, a pattern that would be consistent with adrenal second dose on ACTH concentrations are masked by the
hyporesponsiveness. cortisol infusion.
Plasma DHEA concentrations were decreased in PTSD The majority of the PTSD subjects in this study also met
subjects and in combat-exposed control subjects compared criteria for major depression or dysthymia. This is to be
with control subjects without combat exposure. These expected because signs and symptoms sufficient to meet
differences were amplified when adrenal stimulation was criteria for a depressive disorder are frequently comorbid
increased by treatment with metyrapone, in a pattern with PTSD (Brady et al 2000). In the National Comorbid-
similar to that observed for 11-deoxycortisol. Although the ity Survey, lifetime prevalence of major depression in
244 BIOL PSYCHIATRY E.D. Kanter et al
2001;50:238 –245

individuals with PTSD was 48% (Kessler et al 1995). bidity of psychiatric disorders and posttraumatic stress disor-
Highly symptomatic, treatment-seeking patients with der. J Clin Psychiatry 61(suppl 7):22–32.
PTSD such as those in our sample may have even greater Breslau N, Davis GC, Andreski P, Peterson E (1991): Traumatic
rates of comorbid depression. Chronicity of PTSD further events and posttraumatic stress disorder in an urban popula-
tion of young adults. Arch Gen Psychiatry 48:216 –222.
increases comorbidity (Breslau et al 1991). The comorbid
Buydens-Branchey L, Noumair D, Branchey M (1990): Duration
depression in this study may be unavoidable and does not and intensity of combat exposure and posttraumatic stress
appear to have substantially affected the results. If it had, disorder in Vietnam veterans. J Nerv Ment Dis 178:582–587.
one would expect to observe increased cortisol levels in Chrousos GP, Gold PW (1992): The concepts of stress and stress
the depressed PTSD subjects. system disorders: Overview of physical and behavioral ho-
The veterans in this study suffer from a severe form of meostasis. JAMA 267:1244 –1252.
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for having a lifetime prevalence of alcohol or other drug homeostatic control. Front Neuroendocrinol 12:95–164.
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unknown consequence. Because HPA axis activity is hormones: Binding of endogenous steroids to both testoster-
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possible relevance. Sleep disorders are common in PTSD human plasma J Clin Endocrinol Metab 53:58 – 68.
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the study. Finally, employment status is uncontrolled; prolactin, antidiuretic hormone and cortisol induced by the
stress of motion sickness. Aviat Space Environ Med 49:53–
PTSD subjects were more likely to be unemployed than 57.
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The data in this report provide further support for the cocorticoid and estrogen regulation of corticosteroid-binding
observation of decreased cortisol concentrations in chronic globulin production by rat liver. Am J Physiol 237:E493– 499.
PTSD and suggest that the mechanisms underlying this First, MB, Spitzer RL, Gibbon M, Williams JBW (1995):
observation are complex. Our study does not rule out the Structured Clinical Interview for DSM-IV Axis I Disorders.
possibility that increased sensitivity of the HPA axis to New York: New York State Psychiatric Institute, Biometrics
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related posttraumatic stress disorder and alterations of the
adrenal cortex contributes to the decreased cortisol con- hypothalamic-pituitary-adrenal axis in women with chronic
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This work was supported by the Department of Veterans Affairs and a Legacies of Vietnam: Comparative Adjustments of Veterans
Thomas H. Holmes Research Scholar Award (EDK). We gratefully and their Peers, Vol 3. Washington, DC: U.S. Government
acknowledge the excellent technical assistance of Jill Perander, Hollie Printing Office, 125.
Holmes, Elizabeth Colasurdo, Robert Beckham III, Shannon Boldt, and
Carl Sikkema.
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