association between skin tolerance in cfs insulin

7/27/2019 Association Between Skin Tolerance in CFS Insulin

1/6

Associations between neuroendocrine responses to the Insulin Tolerance

Test and patient characteristics in chronic fatigue syndrome

Jens Gaab*, Veronika Engert, Vera Heitz, Tanja Schad,Thomas H. Schurmeyer, Ulrike Ehlert1

Center for Psychobiological and Psychosomatic Research, University of Trier, Germany

Received 9 April 2002; accepted 11 September 2002

Abstract

Objective: Subtle dysregulations of the hypothalamic pitui-

tary adrenal (HPA) axis have been proposed as an underlying

pathophysiological mechanism in chronic fatigue syndrome (CFS).

This study attempted to assess the relationship between patient

characteristics and HPA axis functioning using a neuroendocrine

challenge test. Method: A test battery designed to assess different

dimensions of CFS was given to 18 CFS patients and 17 controls. To

evaluate the integrity of the HPA axis, the Insulin Tolerance Test

(ITT), a centrally acting neuroendocrine challenge test, was

performed on patients and controls. ACTH, salivary free cortisol

and total plasma cortisol levels were assessed as a measure of the

HPA axis stress response. Correlations of patient characteristics

were calculated with integrated responses for all endocrineparameters. Results: CFS patients had a significantly reduced area

under the ACTH response curve (AUC) in the ITT. The AUC was

significantly associated with the duration of CFS symptoms

(r=.592, P= .005) and the severity of fatigue symptomatology

(r=.41, P= .045). In addition, duration of CFS was correlated

with the severity of fatigue symptoms (r= .38, P= .045). Similar

associations were not observed for cortisol parameters.Conclusion:

It has been postulated that neuroendocrine dysregulations observed

in CFS are of an acquired nature. The results of a strong association

between the integrated ACTH response and the duration of CFS

emphasizes the need to consider factors known to be risk factors for

the chronicity of CFS symptoms, such as profound inactivity,

deconditioning and sleep abnormalities, as possible candidates for

secondary causes of neuroendocrine dysregulations in CFS.

D 2004 Elsevier Inc. All rights reserved.

Keywords: Chronic Fatigue Syndrome; HPA axis; Cortisol; ACTH, CRH, Symptoms; Inactivity; Duration; Depression; Anxiety

Introduction

Chronic fatigue syndrome (CFS) is characterized by

severe and disabling fatigue and fatigability, and an array

of accompanying symptoms [1]. Its etiology is still subject

to controversy, but given the multitude of conspicuousphysiological and psychological findings that have been

reported, it seems unlikely that CFS represents a unidimen-

sional disease entity. For this reason, the need for an

integrative approach to CFS has been articulated [2]. Sev-

eral multidimensional illness models have been proposed,

linking psychological factors, such as stress and psychiatric

illness, with immune [3,4] and endocrine [5] abnormalities

frequently described in CFS patients.

As it is highly adaptive to internal and external circum-

stances and is also of great importance for the regulation of

several physiological systems, the hypothalamus pitui-

tary adrenal (HPA) axis offers the possibility to linkpsychological and physiological findings in CFS. Subtle

HPA axis dysregulations, probably of central origin, have

been repeatedly reported (for review, see Ref. [6]). Further-

more, a diminished secretion of HPA axis hormones, such as

cortisol and corticotropin releasing hormone (CRH), has

been linked to CFS symptomatology [7].

According to a recent multidimensional illness model of

CFS [8], cumulative life stress and psychiatric morbidity

might result in an inability to mount an adequate HPA axis

response to a stressor (i.e. an infection), and subsequently to

an attenuation of regulatory or counter-regulatory effects of

HPA axis hormones. These assumptions are substantiated by

0022-3999/04/$ see front matterD 2004 Elsevier Inc. All rights reserved.

doi:10.1016/S0022-3999(03)00625-1

* Corresponding author. Current address: Institute for Psychology,

Clinical Psychology and Psychotherapy, University of Zurich, Zurich-

bergstr. 43, CH-8044 Zurich, Switzerland. Tel.: +41-1-6343096; fax: +41-

1-6343696.

E-mail address: [email protected] (J. Gaab).1

Current address: Institute for Psychology, Clinical Psychology II,

Journal of Psychosomatic Research 56 (2004) 419424


2/6

empirical studies [9,10] and qualitative observations [11].

However, little is known about how possible HPA axis

dysregulations persist. Several risk factors for chronicity of

the syndrome have been identified, such as psychiatric

illness, a somatic subjective illness model and avoidance

of exercise and activity [12,13]. In addition, sleep dysregu-

lations are common in CFS patients and may contribute tothe symptoms reported [14]. All of these risk factors have

been related to HPA axis dysregulations in CFS patients [8].

However, very few studies have examined the association

between patient characteristics and hormonal variables in

CFS patients. For example, Demitrack et al. [15] observed a

significant positive correlation between evening basal adre-

nocorticotropic hormone (ACTH) levels and patients self-

assessed fatigue in CFS patients.

Based on the assumptions that these risk factors con-

tribute to the chronicity of the syndrome and that HPA

axis dysregulations are associated with CFS symptomatol-

ogy and regarding the fact that little is known aboutwhether observed HPA axis dysregulations in CFS patients

are related on the one hand to patient characteristics and

on the other hand to CFS symptoms, we assessed the

associations between psychological morbidity, symptom

severity, CFS duration and the extent of neuroendocrine

dysregulations in CFS patients using a centrally acting

stress paradigm.

Methods

Subjects

The study was approved by the Ethical Committee of

the Medical Council of Rheinland-Pfalz, Germany. Patients

were contacted through a German self-help organization.

Interested parties received a postal screening questionnaire,

containing all symptoms required by the US and UK

definitions of CFS [1,16]. Patients fulfilling the symptom

requirements in this screening questionnaire were inter-

viewed over the telephone and asked to disclose any

diagnosed medical illnesses and psychiatric disorders.

Prospective participants were only excluded from the study

if they had received a medical or psychiatric diagnosisdefined as an exclusion criterion by the US definition [1].

Selection criteria for participation in the study were

fulfillment of CFS symptom criteria in the postal screening

questionnaire, new or definite onset of CFS, age between

30 and 50, no current antidepressant, anxiolytic, antibiotic,

antihypertensive and steroid medication and no medical

cause for the chronic fatigue in routine laboratory testing.

All patients were medically examined by the same physi-

cian (THS), according to recommendation [1]. They were

also interviewed by a trained psychologist (JG). This

consisted of a computer-aided standardized and structured

diagnostic interview in accordance with the Diagnostical

and Statistical Manual of Mental Health Disorders, 4th

edition [17] and a semistructured CFS interview, which

concerned the severity and course of all symptoms re-

quired by the US and UK definitions [1,16]. All patients

fulfilled US and UK consensus criteria for the diagnosis of

CFS [1,16]. Patients were matched for age and gender

with healthy volunteer controls, randomly recruited viatelephone calls. Controls were medication-free and under-

went comprehensive medical examination for past and

current health problems. Control subjects were screened

for any current or lifetime psychiatric symptoms or dis-

orders by a clinical psychologist (JG). After subjects were

provided with complete written and oral descriptions of

the study, written informed consent was obtained. The

study sample is part of a larger CFS patient cohort. The

previous results of this cohort have been published else-

where [18,19].

Procedure

The Insulin Tolerance Test (ITT) is considered the gold

standard for testing the integrity of the entire HPA axis [20].

Subjects were asked to fast overnight and the ITT began at

9 a.m. All subjects arrived 60 min before the ITT. They were

taken into a separate room where a venous catheter was

inserted and kept patent with a lock. After a 45-min resting

period, a basal sample of blood glucose and endocrine

parameters was taken and an intravenous bolus injection

of 0.15 U/kg soluble insulin (H-Insulin Hoechst) was given.

Blood glucose, ACTH, plasma total cortisol (PC) and

salivary free cortisol (SC) samples were collected 20, 30,

45, 60, 90 and 120 min after the injection.

Measures

Sampling methods and biochemical analyses

Ethylenediamine tetraacetate blood samples were spun

immediately at 4jC and stored at20jC until assayed.

Saliva was collected by the subjects using Salivette (Sar-

stedt, Rommelsdorf, Germany) collection devices and

stored at room temperature until completion of the session.

It was then stored at20jC until biochemical analysis was

carried out.

ACTH and PC were measured with two-site commercialchemiluminescence assays (CLIA, Nichols Institute Diag-

nostics, Bad Nauheim, Germany). The free cortisol concen-

tration in saliva (SC) was determined using a time-resolved

immunoassay with fluorometric detection, as described in

detail elsewhere [21]. Inter- and intra-assay coefficients of

variance were below 10% for all analytes.

Psychometric measures and patient characteristics

To assess the severity of the most prominent CFS

symptom, subjects completed a German translation of the

Fatigue Scale (FS) [22]. The FS is an 11-item self-report

measure developed to assess fatigue. It consists of two

J. Gaab et al. / Journal of Psychosomatic Research 56 (2004) 419424420


3/6

scales which assess physical and mental fatigue. We used a

0, 1, 2, 3 scoring system and calculated a total score. An

internal consistency (Cronbachs alpha) of a=0.96 for the

total score has been calculated on a larger CFS population

(N= 193) (Gaab et al., unpublished data). Also, all subjectscompleted a battery of questionnaires including the Sickness

Impact Profile (SIP) [23], the Hospital Anxiety and Depres-

sion Scale (HADS), measuring symptoms occurring during

the last week [24] and the Symptom Checklist (SCL-90R),

assessing symptoms experienced during the last 4 weeks

[25]. All latter scales have been evaluated on German

patient populations, with good validity and reliability. Du-

ration of CFS was assessed in months since onset.

Statistical analysis

v

2

analysis was used to test for significant differences indiscrete variables. ANOVAs and ANCOVAs with endocrine

baseline values as covariates were computed to analyze

endocrine parameters between groups. Correlations were

computed as Pearson productmoment correlations. For all

endocrine parameters, areas under the total response curve

(AUC), expressed as area under all samples, were calculat-

ed using the trapezoidal method. Data were tested for

normal distribution and homogeneity of variance using

KolmogorovSmirnov and Levenes test before statistical

procedures were applied. For all analyses, significance

levels were a=5%. Unless indicated all results shown are

meansFstandard error of means (S.E.M.).

Results

Sample characteristics

Gender ratio, number of subjects, mean age, and body

mass index (BMI) did not differ significantly between the

groups (Table 1). Mean duration of patients symptoms was64.0 months, with a range from 17 to 168 months. Fourteen

CFS patients reported an infectious onset of their symptoms.

All patients reported onset of symptoms within 3 months.

Eighteen CFS patients and 17 controls underwent the

ITT. The HADS, SCL-90R, and SIP scores of the CFS

group were significantly higher than those of the control

group and comparable to reported scores in previous stud-

ies. One CFS patient fulfilled the criteria for a current

episode of Major Depression. However, since the exclusion

of this subject did not alter the results of the analysis, the

patient was included in the reported analysis. None of the

controls reported any current or lifetime psychiatric disor-der. CFS patients had significantly higher FS total scores

[CFS 26.0 (1.1) vs. controls: 10.1 (0.6)].

Integrated endocrine responses in the ITT

Groups differed in baseline levels of ACTH [F(1/33) =

5.65, P= .02], but not for plasma [F(1/33) = 0.05, P=.82] or

salivary cortisol [F(1/33) = 0.73, P= .40]. In comparison to

healthy controls matched for age and gender, CFS patients

had a significantly reduced integrated ACTH response in the

ITT [F(1/32)= 4.92, P=.03] (Fig. 1). No significant differ-

ences were found for plasma total [F(1/32) = 0.73, P= .40]

and salivary free cortisol [F(1/32)= 2.12, P= .15].

Associations between endocrine responses and

patient characteristics

To test for significant associations between patient char-

acteristics and the extent of neuroendocrine alterations

Table 1

Demographic and psychometric characteristics of CFS patients and healthy

controls

CFS Controls Test

Sex

(male/female)

10/8 10/7 v2 = 0.04; P= .85

Age (years)a 35.4 (3047) 36.4 (29 44) t(32) =0.63; P=.53

BMIa 22.7

(17.626.8)

24.4

(18.134.6)

t(32) =1.43; P=.16

HADSb F(2/32)= 18.9; P< .001

Depression 7. 3 (0.8) 1.1 (0.3) F(1/33)= 36.4; P< .001

Anxiety 6.3 (0.9) 2.5 (0.4) F(1/33) = 11.65; P= .002

SCL-90Rb F(2/32)= 8.92; P< 0.001

Anxiety 58.8 (2.1) 44.1 (1.5) F(1/33)= 29.3; P< .001

Phobic anxiety 53.7 (2.9) 45.1 (1.4) F(1/33)= 7.2; P=.01

Depression 60.3 (2.3) 43.0 (1.7) F(1/33)= 19.7; P< .001

Somatization 72.5 (2.6) 45.4 (1.5) F(1/33)= 90.1; P< 0.001

SIPb F(6/28)= 9.00; P< .001

Home

management

11.4 (2.5) 0.00 (0.0) F(1/33)= 34.5; P< .001

Ambulation 6.4 (1.3) 0.00 (0.0) F(1/33)= 14.8; P< .001

Mobility 7.8 (2.1) 0.33 (0.2) F(1/33)= 9.7; P< 0.001

Alertness

behavior

33.7 (4.4) 0.00 (0.0) F(1/33)= 41.0; P< .001

Sleep and rest 29.0 (4.2) 0.00 (0.0) F(1/33)= 26.1; P< .001

Social

Interaction

16.7 (2.4) 0.94 (0.4) F(1/33)= 34.5; P< .001

a Mean (range).b Mean (S.E.M.).

Fig. 1. Integrated ACTH of CFS patients (gray) and controls (black) in the

ITT.

J. Gaab et al. / Journal of Psychosomatic Research 56 (2004) 419424 421


4/6

observed in CFS patients, indicated by the AUC of the

ACTH, the plasma total (PC) and salivary free cortisol (SC)

responses in the ITT, Pearson correlation coefficients were

calculated (Table 2).

Integrated responses of ACTH in the ITT were strongly

associated with the duration of CFS (r=.59, P= .005).

Correlations between both cortisol responses in the ITT and

duration of CFS in months since onset were not significant.

A significant negative association also existed between the

severity of fatigue symptoms and the integrated ACTH

response in the ITT (r=.41, P= .045). Similar to previous

results, correlations between the AUCs of cortisol responses

and the FS total score were not significant. Significant

negative correlations were observed between the scores of

the Depression and the Anxiety scale of the HADS and the

integrated ACTH response in the ITT (r=.52, P=.014

and r=.63, P= .003). Cortisol parameters were not sig-

nificantly correlated with the HADS scores. The extent of

the functional impairment, as operationalized by the SIP

total score, was not significantly associated with any endo-crine parameter.

In addition, duration of CFS was positively correlated

with the severity of fatigue symptoms, indicated by the FS

total score (r=.38, P= .045).

Discussion

This study set out to assess the possible associations

between patient characteristics and neuroendocrine dysre-

gulations in CFS.

In comparison to healthy controls matched for age andgender, CFS patients had a clearly reduced integrated

ACTH response to the insulin challenge. However, cortisol

responses were normal in CFS patients. This concurs with a

postulated central origin of HPA axis dysregulations (i.e. a

deficient CRH secretion), and a compensatory up-regulation

of adrenal sensitivity [15].

The extent of the observed neuroendocrine dysregulation

was strongly associated with the duration of CFS symp-

toms. Although the cross-sectional and correlative nature of

this analysis cautions against a causal interpretation, we

assume that the longer the respective patient has CFS, the

more pronounced the attenuation of the ACTH response in

the ITT becomes. Furthermore, fatigue symptom severity

was positively associated with the AUC of the ACTH

response in the ITT and the duration of CFS. Also, we

observed a strong negative correlation between the extent of

depression and anxiety and the AUC of the ACTH response

in the ITT.

Interestingly, there were no associations between cortisolparameters and the described patient characteristics. Hypo-

cortisolism has been discussed to be a possible endocrine

correlate of medically unexplained symptoms, such as

fatigue and pain [26]. Also, the administration of low doses

of hydrocortisone has been shown to have some benefit in

CFS patients [27]. Clearly, the role of cortisol in CFS needs

further study.

Patients for this study were recruited through a self-help

organization. It is possible that this constitutes a selection

bias and that therefore our sample differs from those used in

other studies. Although we have not selected for patients

without psychiatric comorbidity, the observed low psychi-atric comorbidity in our sample could be the result of a

selection bias. Given that self-help groups advocate a

somatic etiology of CFS, it is possible that differences in

the attribution of symptoms experienced partly explains the

low number of psychiatric disorders in our sample, since an

attribution to a biological cause seems to protect against

psychological distress [28,29]. Also, unless our results are

confirmed by studies using different patient samples (e.g.

from primary or secondary care), the representativeness of

our results cannot unrestrictively be assumed.

Our findings confirm the assumptions of a psychoneur-

oendocrine model of CFS, with a central deficit of the HPA

axis being related on the one hand to the severity of clinicalsymptoms and on the other hand to patient characteristics [8].

We observed a medium-sized correlation between symp-

tom severity and the extent of the ACTH response, but no

such association existed for cortisol parameters. Hypotha-

lamic CRH is the principal modulator of the adaptive stress

response, directly and indirectly coordinating adaptive au-

tonomic, endocrine, immune, and behavioral stress

responses. A deficient CRH secretion has been linked to

chronic pain and fatigue syndromes [30,31] and atypical

depressive symptoms, such as hypersomnia and anergia

[32]. A diminished responsivity of pituitary corticotrophs

has been observed after prolonged hypercortisolism [33].However, hypercortisolism does not seem to be respon-

sible for the diminished ACTH response in the ITT, as basal

and reactive cortisol levels have been found to be normal

[19] or reduced [34]. Because the responsivity of pituitary

corticotrophs gradually improves after the normalization of

high cortisol levels [33] and CFS is not characterized by

hypercortisolism, the reduced ACTH response in the ITT

could be explained by a permanent suppression of hypotha-

lamic CRH secretion in CFS, for example, due to perma-

nently enhanced negative feedback [18]. Our finding of a

high correlation between the duration of illness and inte-

grated ACTH response in the ITT is consistent with the

Table 2

Pearsons correlation (P values are in parentheses) between patient

characteristics and integrated endocrine responses

AUC of

ACTH response

AUC of

PC response

AUC of

SC response

Duration of CFS .59 (.005) .10 (.34) .06 (.41)

FS total score .41 (.045) .11 (.34) .12 (.32)

HADS Depression

scale

.53 (.014) .09 (.36) .31 (.11)

HADS Anxiety

scale

.63 (.003) .12 (.32) .15 (.27)

SIP total score .29 (.12) .38 (.32) .32 (.09)



5/6

assumption of a hyporesponsive pituitary due to prolonged

insufficient central priming [15].

It has been postulated that neuroendocrine dysregulations

observed in CFS are of an acquired nature, most likely the

consequences of traumatic and/or chronic stress [26]. While

our finding of a strong association between the integrated

ACTH response and the duration of CFS does not refute thisassumption, it emphasizes the need to consider other factors

known to be risk factors for the chronicity of CFS symp-

toms, such as psychological morbidity, profound inactivity,

deconditioning, and sleep abnormalities.

The finding of a strong negative association between

anxiety and depression levels and observed ACTH response

seems counterintuitive at first, since depressive and certain

anxiety disorders have been associated with hyperrespon-

siveness of central stress systems [7]. However, the HADS

anxiety and depression scores observed in our sample are not

indicative for clinically relevant depression or anxiety and

thus could also be considered as indicators for psychologicaldistress. Given that the HPA axis is highly adaptive to

perceived stressors, it is possible that the observed negative

correlation is a consequence of perceived distress. For exam-

ple, Vedhara et al. [35] observed a clear reduction in basal

HPA axis activity in students undergoing an exam in com-

parison to the same population during a non-exam period.

With regard to the possible influence of sleep problems

on HPA axis functioning, Leese et al. [36], comparing

endocrine responses to a CRH challenge test after night

shift and day shift work, reported an attenuated integrated

area under the response curve for both ACTH and cortisol

after the night shift work. Similarly, a selective deprivation

of Stage 4 sleep resulted in the experience of musculoskel-etal pain, a symptom frequently experienced in CFS patients

[37]. CFS patients often complain of sleep problems [38]

and are frequently found to have objectively diagnosable

sleep disorders [39].

The duration of CFS is of relevance for the development

of physical deconditioning, which in its own right leads to

many physiological abnormalities seen in CFS patients [40].

Almost all CFS patients report a profound reduction in

activity levels compared to premorbid activity levels

[11,41] and low levels of activity has been shown to be

related to severe fatigue in CFS patients [42]. Prolonged bed

rest and inactivity have been shown to have detrimentaleffects on normal physiological functioning [4345] and

treatments directed against rest and towards moderate and

gradual increase in activity have shown to be of benefit in

CFS [46]. Interestingly, it has been shown that the level of

physical fitness influences the HPA axis activity (i.e. highly

trained runners show HPA axis alterations consistent with

mild hypercortisolism) [47,48]. In comparison to endurance

trained subjects, sedentary men show attenuated absolute

integrated ACTH responses to exercise [49]. Also, over-

trained athletes, experiencing generalized apathy, lethargy

and change of sleep pattern, had attenuated HPA axis

responses to the ITT, which normalized with recovery [50].

Since sleep problems, inactivity and physical decondi-

tioning are considered risk factors for chronicity and also

influence HPA axis functioning, it seems possible that the

observed strong association between the extent of endocrine

dysregulation observed in CFS patients and the duration of

symptoms is a consequence of this interaction.

Given the cross-sectional design of the study, the smallsample size and the correlational analysis, causal interpre-

tations between the reported associations are clearly not

feasible. Furthermore, we have not assessed physical ac-

tivity, sleep problems, and physical fitness in our patients.

Further prospective studies with a larger sample size and

an inclusion of these factors are therefore necessary to

clarify matters.

References

[1] Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A.International Chronic Fatigue Syndrome Study Group. The chronic

fatigue syndrome: a comprehensive approach to its definition and

study. Ann Intern Med 1994;121:9539.

[2] Demitrack MA, Greden JF. Chronic fatigue syndrome: the need for an

integrative approach. Biol Psychiatry 1991;30:747 52.

[3] Glaser R, Kiecolt-Glaser JK. Stress-associated immune modulation:

relevance to viral infections and chronic fatigue syndrome. Am J Med

1998;105:35S42S.

[4] Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG. Cytokine

and other immunologic markers in chronic fatigue syndrome and their

relation to neuropsychological factors. Appl Neuropsychol 2001;8:

5164.

[5] Cleare AJ, Wessely SC. Chronic fatigue syndrome: a stress disorder?

Br J Hosp Med 1996;55:5714.

[6] Parker AJ, Wessely S, Cleare AJ. The neuroendocrinology ofchronic fatigue syndrome and fibromyalgia. Psychol Med 2001;31:

133145.

[7] Ehlert U, Gaab J, Heinrichs M. Psychoneuroendocrinological contri-

butions to the etiology of depression, posttraumatic stress disorder,

and stress-related bodily disorders: the role of the hypothalamus

pituitary adrenal axis. Biol Psychol 2001;57:141 52.

[8] Demitrack MA. The psychobiology of Chronic Fatigue Syndrome:

the central nervous system as a common pathway. In: Demitrack MA,

Abbey SE editors. Chronic Fatigue Syndrome: an integrative ap-

proach to evaluation and treatment. New York: The Guildford Press,

1997. pp. 72112.

[9] Wessely S, Chalder T, Hirsch S, Pawlikowska T, Wallace P, Wright

DJ. Postinfectious fatigue: prospective cohort study in primary care.

Lancet 1995;345:13338.

[10] Theorell T, Blomkvist V, Lindh G, Evengard B. Critical life events,infections, and symptoms during the year preceding chronic fatigue

syndrome (CFS): an examination of CFS patients and subjects with a

nonspecific life crisis. Psychosom Med 1999;61:30410.

[11] Surawy C, Hackmann A, Hawton K, Sharpe M. Chronic fatigue

syndrome: a cognitive approach. Behav Res Ther 1995;33:53544.

[12] Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue and

chronic fatigue syndrome: a systematic review. Q J Med 1997;90:

22333.

[13] Deale A, Chalder T, Wessely S. Illness beliefs and treatment outcome

in chronic fatigue syndrome. J Psychosom Res 1998;45:7783.

[14] Morriss RK, Wearden AJ, Battersby L. The relation of sleep difficul-

ties to fatigue, mood and disability in chronic fatigue syndrome.

J Psychosom Res 1997;42:597605.

[15] Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ,

J. Gaab et al. / Journal of Psychosomatic Research 56 (2004) 419424 423


6/6

Chrousos GP, Gold PW. Evidence for impaired activation of the hy-

pothalamic pituitary adrenal axis in patients with chronic fatigue

syndrome. J Clin Endocrinol Metab 1991;73:122434.

[16] Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW,

David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, et al. A

reportchronic fatigue syndrome: guidelines for research. J R Soc

Med 1991;84:11821.

[17] Wittchen H-U, Pfister H. DIA-X-Interviews. Frankfurt: Swets andZeitlinger, 1997.

[18] Gaab J, Huster D, Peisen R, Engert V, Schad T, Schurmeyer TH,

Ehlert U. Low-dose dexamethasone suppression test in chronic fa-

tigue syndrome and health. Psychosom Med 2002;64:3118.

[19] Gaab J, Huster D, Peisen R, Engert V, Heitz V, Schad T, Schurmeyer

T, Ehlert U. Hypothamaluspituitaryadrenal axis reactivity in

chronic fatigue syndrome and health under psychological, physiolo-

gial and pharmacological stimuation. Psychosom Med. In press.

[20] Fish HR, Chernow B, OBrian JT. Endocrine and neurophysiologic

responses of the pituitary to insulin-induced hypoglycemia: a review.

Metabolism 1986;35:76380.

[21] Dressendorfer RA, Kirschbaum C, Rohde W, Stahl F, Strasburger CJ.

Synthesis of a cortisolbiotin conjugate and evaluation as a tracer in

an immunoassay for salivary cortisol measurement. J Steroid Bio-

chem Mol Biol 1992;43:683 92.[22] Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright

D, Wallace EP. Development of a fatigue scale. J Psychosom Res

1993;37:14753.

[23] Kessler S, Jaeckel W, Cziske R. Assessing health in musculoskeletal

disordersthe appropriateness of a German version of the Sickness

Impact Profile. Rheumatol Int 1997;17:11925.

[24] Herrmann C, Buss U, Snaith RP. HADS-D Hospital Anxiety and

Depression ScaleEin Fragebogen zur Erfassung von Angst und

Depressivitat in der somatischen Medizin. Hans Huber, 1995.

[25] Franke G. Die Symptom-Checkliste von DerogatisDeutsche Ver-

sion. Gottingen: Beltz Test, 1995.

[26] Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortis-

olism in the pathophysiology of stress-related bodily disorders. Psy-

choneuroendocrinology 2000;25:1 35.

[27] Cleare AJ, Heap E, Malhi GS, Wessely S, OKeane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised cross-

over trial. Lancet 1999;353:4558.

[28] Chalder T, Power MJ, Wessely S. Chronic fatigue in the community:

a question of attribution. Psychol Med 1996;26:791800.

[29] Powell R, Dolan R, Wessely S. Attributions and self-esteem in de-

pression and chronic fatigue syndromes. J Psychosom Res 1990;34:

66573.

[30] Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes: over-

lapping clinical and neuroendocrine features and potential pathogenic

mechanisms. Neuroimmunomodulation 1997;4:134 53.

[31] Lariviere WR, Melzack R. The role of corticotropin-releasing factor

in pain and analgesia. Pain 2000;84:1 12.

[32] Geracioti TD, Loosen PT, Orth DN. Low cerebrospinal fluid cortico-

tropin-releasing hormone concentrations in eucortisolemic depression.

Biol Psychiatry 1997;42:16574.[33] Magiakou MA, Mastorakos G, Rabin D, Dubbert B, Gold PW, Chrou-

sos GP. Hypothalamic corticotropin-releasing hormone suppression

during the postpartum period: implications for the increase in psychi-

atric manifestations at this time. J Clin Endocrinol Metab 1996;81:

19127.

[34] Cleare AJ, Blair D, Chambers S, Wessely S. Urinary free cortisol in

chronic fatigue syndrome. Am J Psychiatry 2001;158:6413.

[35] Vedhara K, Hyde J, Gilchrist ID, Tytherleigh M, Plummer S. Acute

stress, memory, attention and cortisol. Psychoneuroendocrinology2000;25:53549.

[36] Leese G, Chattington P, Fraser W, Vora J, Edwards R, Williams G.

Short-term night-shift working mimics the pituitaryadrenocortical

dysfunction in chronic fatigue syndrome. J Clin Endocrinol Metab

1996;81:186770.

[37] Moldofsky H, Scarisbrick P. Induction of neurasthenic musculoskele-

tal pain syndrome by selective sleep stage deprivation. Psychosom

Med 1976;38:35 44.

[38] Morriss R, Sharpe M, Sharpley AL, Cowen PJ, Hawton K, Morris J.

Abnormalities of sleep in patients with the chronic fatigue syndrome.

BMJ 1993;306:11614.

[39] Buchwald D, Pascualy R, Bombardier C, Kith P. Sleep disorders in

patients with chronic fatigue. Clin Infect Dis 1994;18(Suppl 1):

S6872.

[40] White PD. The role of physical inactivity in the chronic fatigue syn-drome. J Psychosom Res 2000;49:283 4.

[41] Ware NC. Society, mind and body in chronic fatigue syndrome: an

anthropological view. Ciba Found Symp 1993;173:6273.

[42] Vercoulen JH, Bazelmans E, Swanink CM, Fennis JF, Galama JM,

Jongen PJ, Hommes O, Van Der Meer JW, Bleijenberg G. Physical

activity in chronic fatigue syndrome: assessment and its role in fa-

tigue. J Psychiatr Res 1997;31:661 73.

[43] Haines RF. Effect of bed rest and exercise on body balance. J Appl

Physiol 1974;36:323 7.

[44] Greenleaf JE, Kozlowski S. Physiological consequences of reduced

physical activity during bed rest. Exerc Sport Sci Rev 1982;10:

84119.

[45] Natelson BH, DeRoshia C, Levin BE. Physiological effects of bed

rest. Lancet 1982;1:51 (letter).

[46] Fulcher KY, White PD. Randomised controlled trial of graded exer-cise in patients with the chronic fatigue syndrome. BMJ 1997;314:

164752.

[47] Luger A, Deuster PA, Kyle SB, Gallucci WT, Montgomery LC,

Gold PW, Loriaux DL, Chrousos GP. Acute hypothalamic pitui-

tary adrenal responses to the stress of treadmill exercise. Physiologic

adaptations to physical training. N Engl J Med 1987;316:130915.

[48] Heuser IJ, Wark HJ, Keul J, Holsboer F. Hypothalamic pituitary

adrenal axis function in elderly endurance athletes. J Clin Endocrinol

Metab 1991;73:485 8.

[49] Duclos M, Corcuff JB, Rashedi M, Fougere V, Manier G. Trained

versus untrained men: different immediate post-exercise responses of

pituitary adrenal axis. A preliminary study. Eur J Appl Physiol Occup

Physiol 1997;75:34350.

[50] Barron JL, Noakes TD, Levy W, Smith C, Millar RP. Hypothalamic

dysfunction in overtrained athletes. J Clin Endocrinol Metab 1985;60:8036.


association between skin tolerance in cfs insulin

Documents