The
Medical Evidence for
Low Cortisol
in Chronic
Fatigue Syndrome!
MEDICAL
ABSTRACTS
J
Clin Endocrinol Metab. 2001 Aug;86(8):3545-54.
Hypothalamo-pituitary-adrenal
axis dysfunction in chronic fatigue syndrome, and the effects
of low-dose hydrocortisone therapy.
Cleare
AJ, Miell J, Heap E, Sookdeo S, Young L, Malhi GS, O'Keane V.
Department
of Psychological Medicine, Institute of Psychiatry and Guy's, King's
and St Thomas' School of Medicine, London SE5 8AZ, United Kingdom.
a.cleare@iop.kcl.ac.uk
These
neuroendocrine studies were part of a series of studies testing
the hypotheses that 1) there may be reduced activity of the hypothalamic-pituitary-adrenal
axis in chronic fatigue syndrome and 2) low-dose augmentation with
hydrocortisone therapy would improve the core symptoms. We measured
ACTH and cortisol responses to human CRH, the insulin stress test,
and D-fenfluramine in 37 medication-free patients with CDC-defined
chronic fatigue syndrome but no comorbid psychiatric disorders and
28 healthy controls. We also measured 24-h urinary free cortisol
in both groups. All patients (n = 37) had a pituitary challenge
test (human CRH) and a hypothalamic challenge test [either the insulin
stress test (n = 16) or D-fenfluramine (n = 21)]. Baseline cortisol
concentrations were significantly raised in the chronic fatigue
syndrome group for the human CRH test only. Baseline ACTH concentrations
did not differ between groups for any test. ACTH responses to human
CRH, the insulin stress test, and D- fenfluramine were similar for
patient and control groups. Cortisol responses to the insulin stress
test did not differ between groups, but there was a trend for cortisol
responses both to human CRH and D-fenfluramine to be lower in the
chronic fatigue syndrome group. These differences were significant
when ACTH responses were controlled. Urinary free cortisol levels
were lower in the chronic fatigue syndrome group compared with the
healthy group. These results indicate that ACTH responses to pituitary
and hypothalamic challenges are intact in chronic fatigue syndrome
and do not support previous findings of reduced central responses
in hypothalamic-pituitary-adrenal axis function or the hypothesis
of abnormal CRH secretion in chronic fatigue syndrome. These data
further suggest that the hypocortisolism found in chronic fatigue
syndrome may be secondary to reduced adrenal gland output. Thirty-two
patients were treated with a low-dose hydrocortisone regime in a
double-blind, placebo-controlled cross-over design, with 28 days
on each treatment. They underwent repeated 24-h urinary free cortisol
collections, a human CRH test, and an insulin stress test after
both active and placebo arms of treatment. Looking at all subjects,
24-h urinary free cortisol was higher after active compared with
placebo treatments, but 0900-h cortisol levels and the ACTH and
cortisol responses to human CRH and the insulin stress test did
not differ. However, a differential effect was seen in those patients
who responded to active treatment (defined as a reduction in fatigue
score to the median population level or less). In this group, there
was a significant increase in the cortisol response to human CRH,
which reversed the previously observed blunted responses seen in
these patients. We conclude that the improvement in fatigue seen
in some patients with chronic fatigue syndrome during hydrocortisone
treatment is accompanied by a reversal of the blunted cortisol responses
to human CRH.
PMID:
11502777 [PubMed - indexed for MEDLINE]
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Psychosom
Med. 2002 Mar-Apr;64(2):311-8
Low-dose
dexamethasone suppression test in chronic fatigue syndrome and health.
Gaab
J, Huster D, Peisen R, Engert V, Schad T, Schurmeyer TH, Ehlert
U.
Center
for Psychobiological and Psychosomatic Research, University of Trier,
Trier, Germany. jgaab@klipsy.unizh.ch
OBJECTIVE:
Subtle dysregulations of the hypothalamus-pituitary-adrenal axis
in chronic fatigue syndrome have been described. The aim of this
study was to examine the negative feedback regulations of the hypothalamus-pituitary-adrenal
axis in chronic fatigue syndrome. METHODS: In 21 patients with chronic
fatigue syndrome and 21 healthy control subjects, awakening and
circadian salivary free cortisol profiles were assessed over 2 consecutive
days and compared with awakening and circadian salivary free cortisol
profiles after administration of 0.5 mg of dexamethasone at 11:00
PM the previous day. RESULTS: Patients with chronic fatigue syndrome
had normal salivary free cortisol profiles but showed enhanced and
prolonged suppression of salivary free cortisol after the administration
of 0.5 mg of dexamethasone in comparison to the control subjects.
CONCLUSIONS: Enhanced negative feedback of the hypothalamus-pituitary-adrenal
axis could be a plausible explanation for the previously described
alterations in hypothalamus-pituitary-adrenal axis functioning in
chronic fatigue syndrome. Because similar changes have been described
in stress-related disorders, a putative role of stress in the pathogenesis
of the enhanced feedback is possible.
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Am J Psychiatry 2001 Apr;158(4):641-3
Urinary
free cortisol in chronic fatigue syndrome
Cleare
AJ, Blair D, Chambers S, Wessely S.
OBJECTIVE:
The authors measured 24-hour urinary free cortisol in a group of
well-characterized patients with chronic fatigue syndrome. METHOD:
They obtained 24-hour urine collections from 121 consecutive clinic
patients with chronic fatigue syndrome and 64 comparison subjects
without the syndrome. RESULTS: Urinary free cortisol was significantly
lower in the subjects with chronic fatigue syndrome regardless of
the presence or absence of current or past comorbid psychiatric
illness. Lower levels of urinary free cortisol were not related
to medication use, sleep disturbance, or disability levels. CONCLUSIONS:
There is mild hypocortisolism in chronic fatigue syndrome. Whether
a primary feature or secondary to other factors, hypocortisolism
may be one factor contributing to the symptoms of chronic fatigue
syndrome.
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Psychoneuroendocrinology
2001 Feb 1;26(2):175-188
Abnormalities
in response to vasopressin infusion in chronic fatigue syndrome.
Altemus
M, Dale JK, Michelson D, Demitrack MA, Gold PW, Straus SE
Weill
Medical College, Cornell University, Box 244, 1300 York Avenue,
10021, New York, NY, USA
Several
neuroendocrine studies have suggested hypoactivation of the hypothalamic-pituitary-adrenal
axis in chronic fatigue syndrome. One possible determinant of this
neuroendocrine abnormality, as well as the primary symptom of fatigue,
is reduced hypothalamic secretion of corticotropin-releasing hormone
(CRH). Because CRH and vasopressin secreted from the hypothalamus
act synergistically at the pituitary to activate ACTH secretion,
the ACTH response to peripheral infusion of vasopressin can provide
an indirect measure of hypothalamic CRH secretion. We measured the
ACTH and cortisol response to a one hour infusion of arginine vasopressin
in 19 patients with chronic fatigue syndrome and 19 age and sex
matched healthy volunteers. Patients with chronic fatigue syndrome
had a reduced ACTH response to the vasopressin infusion and a more
rapid cortisol response to the infusion. These results provide further
evidence of reduced hypothalamic CRH secretion in patients with
chronic fatigue syndrome.
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Psychiatry
Res 2000 Dec 4;97(1):21-28
A
preliminary study of dehydroepiandrosterone response to low-dose
ACTH in chronic fatigue syndrome and in healthy subjects.
Scott
LV, Svec F, Dinan T
Department
of Psychiatry, Trinity College Medical School, St. James' Hospital,
8, Dublin, Ireland
Abnormalities
of the production of dehydroepiandrosterone (DHEA), the adrenal
androgen, have been linked with disorders such as obesity and psychological
disorders such as major depression. Adrenocorticotropin (ACTH) is
the primary stimulant of DHEA, and cortisol, from the adrenal. We
chose to examine the DHEA and DHEA/cortisol response to the novel
low-dose ACTH test in healthy subjects and a cohort with chronic
fatigue syndrome (CFS): this test is useful in assessing subtle
irregularities of pituitary-adrenal activity. Nineteen CFS subjects
(diagnosed by CDC criteria) and 10 healthy subjects were examined.
We demonstrated that 1 mug ACTH significantly elevates DHEA levels,
with no difference in output between CFS and healthy subjects. The
DHEA/cortisol ratio decreased in response to ACTH stimulation in
healthy subjects but not in the CFS cohort. We suggest this divergence
of response between the two groups represents an imbalance in the
relative synthetic pathways of the CFS group which, if present chronically
and if comparable to daily stressors, may manifest itself as an
inappropriate response to stress. This difference may be important
in either the genesis or propagation of the syndrome.
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Psychoneuroendocrinology
1999 Oct;24(7):759-68
Small
adrenal glands in chronic fatigue syndrome: a preliminary computer
tomography study.
Scott
LV, Teh J, Reznek R, Martin A, Sohaib A, Dinan TG
Department of Psychiatry, Trinity College Dublin Medical School,
St. James's, Hospital, Ireland.
No
inclusive or satisfactory biomedical explanation for chronic fatigue
syndrome (CFS) has as yet been forwarded. Recent research suggests
that a dysregulated hypothalamic-pituitary-adrenal axis (HPA) may
be contributory, and in particular that there may be diminished
forward drive and adrenal under-stimulation. In this preliminary
study we wished to examine a cohort of CFS patients in whom evidence
for such hypofunctioning was found. Our aim was to establish whether
these patients had altered adrenal gland size. Patients were recruited
from a fatigue clinic. Those who fulfilled the Centre for Disease
Control and Prevention (CDC) criteria underwent a 1 microgram adrenocorticotropin
(ACTH) stimulation test, a test of adrenal gland functioning. Eight
subjects (five females, three males) with a subnormal response to
this test underwent a computer tomography (CT) adrenal gland assessment.
Measurements were compared with those from a group of 55 healthy
subjects. The right and left adrenal gland bodies were reduced by
over 50% in the CFS subjects indicative of significant adrenal atrophy
in a group of CFS patients with abnormal endocrine parameters. This
is the first study to use imaging methods to measure adrenal gland
size in CFS. It is a limitation of this study that a selected CFS
sample was employed. A future larger study would optimally employ
an unselected cohort of CFS patients. This study has implications
not only for the elucidation of CFS pathophysiology, but also for
possible therapeutic strategies.
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Psychoneuroendocrinology
2000 Jan;25(1)
The
potential role of hypocortisolism in the pathophysiology of stress-related
bodily disorders.
Heim
C, Ehlert U, Hellhammer DH
Center for Psychobiological and Psychosomatic Research, University
of Trier, Germany.
Representing
a challenge for current concepts of stress research, a number of
studies have now provided convincing evidence that the adrenal gland
is hypoactive in some stress-related states. The phenomenon of hypocortisolism
has mainly been described for patients, who experienced a traumatic
event and subsequently developed post-traumatic stress disorder
(PTSD). However, as presented in this review, hypocortisolism does
not merely represent a specific correlate of PTSD, since similar
findings have been reported for healthy individuals living under
conditions of chronic stress as well as for patients with several
bodily disorders. These include chronic fatigue syndrome, fibromyalgia,
other somatoform disorders, rheumatoid arthritis, and asthma, and
many of these disorders have been related to stress. Although hypocortisolism
appears to be a frequent and widespread phenomenon, the nature of
the underlying mechanisms and the homology of these mechanisms within
and across clinical groups remain speculative. Potential mechanisms
include dysregulations on several levels of the hypothalamic-pituitary
adrenal axis. In addition, factors such as genetic vulnerability,
previous stress experience, coping and personality styles may determine
the manifestation of this neuroendocrine abnormality. Several authors
proposed theoretical concepts on the development or physiological
meaning of hypocortisolism. Based on the reviewed findings, we propose
that a persistent lack of cortisol availability in traumatized or
chronically stressed individuals may promote an increased vulnerability
for the development of stress-related bodily disorders. This pathophysiological
model may have important implications for the prevention, diagnosis
and treatment of the classical psychosomatic disorders.
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Biol
Psychiatry 1999 Jun 1;45(11):1447-54
Desmopressin
augments pituitary-adrenal responsivity to corticotropin-releasing
hormone in subjects with chronic fatigue syndrome and in healthy
volunteers.
Scott
LV, Medbak S, Dinan TG
Department of Psychiatry, Trinity College Medical School, St. James'
Hospital, Dublin, Ireland.
BACKGROUND:
Corticotopin-releasing hormone (CRH) and vasopressin (VP) are the
two principal neuropeptide regulators of the hypothalamic-pituitary-adrenal
axis in man, with VP serving to augment CRH-induced adrenocorticotropic
hormone (ACTH) release. Unlike VP, desmopressin (DDAVP), which is
a synthetic analogue of VP, when administered alone, has not been
shown in healthy subjects to have consistent ACTH-releasing properties.
It has been suggested that chronic fatigue syndrome (CFS), characterized
by profound fatigue and a constellation of other symptoms, may be
caused by a central deficiency of CRH. METHODS: We administered
100 micrograms ovine CRH (oCRH) and 10 micrograms DDAVP, both alone
and in combination, to a group of subjects with CFS, and to a group
of healthy volunteers. Our aim was to establish the effect of DDAVP
on CRH-induced ACTH release in these two groups. RESULTS: The delta-ACTH
responses to oCRH were attenuated in the CFS (21.0 +/- 4.5 ng/L)
compared to the control subjects (57.8 +/- 11.0 ng/L; t = 3.2, df
= 21, p < .005). The delta-cortisol responses were also reduced
in the CFS (157.6 +/- 40.7 nmol/L) compared to the healthy subjects
(303.5+/- 20.9 nmol/L; t = 3.1, df = 21, p < .01). The delta-ACTH
and delta-cortisol responses to DDAVP alone did not differ between
the two groups. On administration of both CRH and DDAVP no response
differences between the two groups for either ACTH (p = .3) or cortisol
output (p = .87) were established. Comparing the ACTH and cortisol
responses to CRH and CRH/DDAVP in only those individuals from each
group who had both tests, the cortisol output to the combination
was significantly greater in the CFS compared to the healthy group.
The ACTH output was also increased in the former group, though this
was not significant. CONCLUSIONS: DDAVP augments CRH-mediated pituitary-adrenal
responsivity in healthy subjects and in patients with CFS. That
DDAVP was capable of normalizing the pituitary-adrenal response
to oCRH in the CFS group suggests there may be increased vasopressinergic
responsivity of the anterior pituitary in CFS and/or that DDAVP
may be exerting an effect at an adrenal level.
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Horm
Metab Res 1999 Jan;31(1):18-21
Dehydroepiandrosterone
(DHEA) response to i.v. ACTH in patients with chronic fatigue syndrome.
De
Becker P, De Meirleir K, Joos E, Campine I, Van Steenberge E, Smitz
J, Velkeniers B
Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Belgium.
pdbeck@minf.vub.ac.be
Previous
studies have demonstrated concentrating neuroendocrinological disturbances
in chronic fatigue syndrome (CFS) patients, concentrating in particular
on low cortisol levels and a hypothalamic deficiency. In order to
investigate the dynamic response of the adrenal glands, we measured
dehydroepiandrosterone (DHEA) in serum after adreno-corticotropic
hormone (ACTH) stimulation during 60 minutes in 22 CFS-patients
and 14 healthy controls. We found normal basal DHEA levels, but
a blunted serum DHEA response curve to i.v. ACTH injection. This
observation adds to the large amount of evidence of endocrinological
abnormalities in CFS. Relative glucocorticoid deficiency might contribute
to the overall clinical picture in CFS, and could explain some of
the immunological disturbances observed in this syndrome.
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Z
Rheumatol 1998;57 Suppl 2:67-71
The
hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic
fatigue syndrome.
Crofford
LJ
Division of Rheumatology, University of Michigan, Ann Arbor 48109-0680,
USA. crofford@umich.edu
HPA
axis abnormalities in FM, CFS, and other stress-related disorders
must be placed in a broad clinical context. We know that interventions
providing symptomatic improvement in patients with FM and CFS can
directly or indirectly affect the HPA axis. These interventions
include exercise, tricyclic anti-depressants, and serotonin reuptake
inhibitors. There is little direct information as to how the specific
HPA axis perturbations seen in FM can be related to the major symptomatic
manifestations of pain, fatigue, sleep disturbance, and psychological
distress. Since many of these somatic and psychological symptoms
are present in other syndromes that exhibit HPA axis disturbances,
it seems reasonable to suggest that there may be some relationship
between basal and dynamic function of the HPA axis and clinical
manifestations of FM and CFS.
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Int
J Mol Med 1998 Jan;1(1):143-6
Dehydroepiandrosterone
sulfate deficiency in chronic fatigue syndrome.
Kuratsune
H, Yamaguti K, Sawada M, Kodate S, Machii T, Kanakura Y, Kitani
T
Department of Hematology and Oncology, Osaka University Medical
School, Suita city, Osaka 565, Japan.
The
chronic fatigue syndrome (CFS) is a condition of unknown etiology,
characterized by a persistent debilitating fatigue, the muscle-related
symptoms and the neuropsychiatric symptoms. Recently, it has been
reported that the patients with CFS might have impaired activation
of the hypothalamic-pituitary-adrenal axis, and suggested that a
part of the patho-genesis of CFS might be associated with abnormalities
of the endocrine system. Herein, we show that the majority of Japanese
patients with CFS had a serum dehydroepiandrosterone sulfate (DHEA-S)
deficiency. Serum DHEA-S is one of the most abundantly produced
hormones which is secreted from the adrenal glands, and its physiological
function is thought to be a precursor of sex steroids. DHEA-S has
recently been shown to have physiological properties, such as neurosteroids,
which are associated with such psychophysiological phenomena as
memory, stress, anxiety, sleep and depression. Therefore, the deficiency
of DHEA-S might be related to the neuropsychiatric symptoms in patients
with CFS.
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Clin
Endocrinol (Oxf) 1998 Jun;48(6):733-7
The
low dose ACTH test in chronic fatigue syndrome and in health.
Scott
LV, Medbak S, Dinan TG
Department of Psychiatry, Trinity College Medical School, Dublin,
Eire.
OBJECTIVE:
A number of dynamic tests of the hypothalamic-pituitary-adrenal
axis provide evidence for a mild central adrenal insufficiency in
chronic fatigue syndrome (CFS). The 1 microgram adrenocorticotropin
(ACTH) test has been proposed to be more sensitive than the standard
250 micrograms ACTH test in the detection of subtle pituitary-adrenal
hypofunctioning. We aimed to establish whether the 1 microgram ACTH
test would support such a dysregulation in CFS, and also, given
the relative novelty of this test in clinical practice and the uncertainty
with regard to appropriate cut-off values for normality, to compare
our healthy volunteer data with those of previous studies. PATIENTS
AND DESIGN: Twenty subjects with CFS, diagnosed according to Centres
for Disease Control and Prevention criteria, were compared with
20 healthy volunteer subjects. All participants underwent a 1 microgram
ACTH test beginning at 1400 h. Plasma samples for cortisol estimation
were drawn at 0, +30 and +40 min. RESULTS: Baseline cortisol values
did not differ between CFS patients and healthy subjects. The delta
cortisol (maximum increment from baseline) value was significantly
lower in the CFS than the volunteer group (P < 0.05). Comparison
of the +30 min cortisol values revealed no significant differences.
Using an incremental cortisol of > 250 nmol/l as an arbitrary
cutoff point, two (10%) of the healthy subjects and nine (45%) of
the CFS subjects failed the test on this basis (chi 2 = 4.3, df
= 38, P < 0.05). CONCLUSIONS: This study provides further evidence
for a subtle pituitary-adrenal insufficiency in subjects with chronic
fatigue syndrome compared to healthy volunteers. Disparities between
our healthy volunteer data and those of other groups using the 1
microgram ACTH test suggest that the test may not be as reliable
as previously indicated.
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Acta
Psychiatr Scand 1998 Jun;97(6):450-457
Blunted
adrenocorticotropin and cortisol responses to corticotropin-releasing
hormone stimulation in chronic fatigue syndrome.
Scott
LV, Medbak S, Dinan TG
Department
of Psychological Medicine, St Bartholomew's and the Royal London
School of Medicine, West Smithfield, UK.
Hypofunctioning
of the pituitary-adrenal axis has been suggested as the pathophysiological
basis for chronic fatigue syndrome (CFS). Blunted adrenocorticotropin
(ACTH) responses but normal cortisol responses to exogenous corticotropin-releasing
hormone (CRH), the main regulator of this axis, have been previously
demonstrated in CFS patients, some of whom had a comorbid psychiatric
disorder. We wished to re-examine CRH activation of this axis in
CFS patients free from concurrent psychiatric illness. A sample
of 14 patients with CDC-diagnosed CFS were compared with 14 healthy
volunteers. ACTH and cortisol responses were measured following
the administration of 100 microg ovine CRH. Basal ACTH and cortisol
values did not differ between the two groups. The release of ACTH
was significantly attenuated in the CFS group (P < 0.005), as
was the release of cortisol (P < 0.05). The blunted response
of ACTH to exogenous CRH stimulation may be due to an abnormality
in CRH levels with a resultant alteration in pituitary CRH receptor
sensitivity, or it may reflect a dysregulation of vasopressin or
other factors involved in HPA regulation. A diminished output of
neurotrophic ACTH, causing a reduced adrenocortical secretory reserve,
inadequately compensated for by adrenoceptor upregulation, may explain
the reduced cortisol production demonstrated in this study.
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J
Affect Disord 1998 Jan;47(1-3):191-194
A
comparison of salivary cortisol in chronic fatigue syndrome, community
depression and healthy controls.
Strickland
P, Morriss R, Wearden A, Deakin B
University
of Manchester and (Guild NHS Trust), Department of Community Psychiatry,
Royal Preston Hospital, Fulwood, UK.
BACKGROUND:
Previous studies reporting cortisol hyposecretion in chronic fatigue
syndrome may have been confounded by venepuncture, fasting and hospitalisation.
METHODS: Morning and evening salivary cortisol were obtained on
consecutive days in the first 3 days of the menstrual cycle and
compared in three samples of women taking no medication and matched
for age: 14 patients with chronic fatigue syndrome, 26 community
cases of ICD-10 current depressive episodes and 131 healthy community
controls. RESULTS: The mean evening cortisol was significantly lower
in the chronic fatigue syndrome patients compared to controls with
depression (P = 0.02) and healthy controls (P = 0.005). Chronic
fatigue syndrome patients without psychiatric disorder had significantly
lower morning salivary cortisols compared to controls (P = 0.009).
CONCLUSION: Chronic fatigue syndrome patients display cortisol hyposecretion
in saliva as well as plasma compared to patients with depression
and healthy controls. LIMITATIONS: Small samples of female patients
with cortisol estimated at only two time points in the day. Cortisol
secretion may be secondary to other neurotransmitter abnormalities
or other physiological or lifestyle factors in chronic fatigue syndrome
patients. CLINICAL RELEVANCE: Chronic fatigue syndrome is biochemically
distinct from community depression.
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A
comparison of salivary cortisol in chronic fatigue syndrome, community
depression and healthy controls.
J
Affect Disord 1998 Jan;47(1-3):191-194
Strickland
P, Morriss R, Wearden A, Deakin B
University
of Manchester and (Guild NHS Trust), Department of Community Psychiatry,
Royal Preston Hospital, Fulwood, UK.
BACKGROUND:
Previous studies reporting cortisol hyposecretion in chronic fatigue
syndrome may have been confounded by venepuncture, fasting and hospitalisation.
METHODS: Morning and evening salivary cortisol were obtained on
consecutive days in the first 3 days of the menstrual cycle and
compared in three samples of women taking no medication and matched
for age: 14 patients with chronic fatigue syndrome, 26 community
cases of ICD-10 current depressive episodes and 131 healthy community
controls. RESULTS: The mean evening cortisol was significantly lower
in the chronic fatigue syndrome patients compared to controls with
depression (P = 0.02) and healthy controls (P = 0.005). Chronic
fatigue syndrome patients without psychiatric disorder had significantly
lower morning salivary cortisols compared to controls (P = 0.009).
CONCLUSION: Chronic fatigue syndrome patients display cortisol hyposecretion
in saliva as well as plasma compared to patients with depression
and healthy controls. LIMITATIONS: Small samples of female patients
with cortisol estimated at only two time points in the day. Cortisol
secretion may be secondary to other neurotransmitter abnormalities
or other physiological or lifestyle factors in chronic fatigue syndrome
patients. CLINICAL RELEVANCE: Chronic fatigue syndrome is biochemically
distinct from community depression.
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Evidence
for impaired activation of the hypothalamic-pituitary-adrenal axis
in patients with chronic fatigue syndrome,
J
Clin Endocrinol Metab, 1991 Dec. Issue: 6, Volume: 73, Page: 1224-34
ISSN: 0021-972X
Demitrack
MA; Dale JK; Straus SE; Laue L; Listwak SJ; Kruesi MJ; Chrousos
GP; Gold PW
Abstract:
Chronic fatigue syndrome is characterized by persistent or relapsing
debilitating fatigue for at least 6 months in the absence of a medical
diagnosis that would explain the clinical presentation. Because
primary glucocorticoid deficiency states and affective disorders
putatively associated with a deficiency of the arousal-producing
neuropeptide CRH can be associated with similar symptoms, we report
here a study of the functional integrity of the various components
of the hypothalamic-pituitary-adrenal axis in patients meeting research
case criteria for chronic fatigue syndrome. Thirty patients and
72 normal volunteers were studied. Basal activity of the hypothalamic-pituitary-adrenal
axis was estimated by determinations of 24-h urinary free cortisol-excretion,
evening basal plasma total and free cortisol concentrations, and
the cortisol binding globulin-binding capacity. The adrenal cortex
was evaluated indirectly by cortisol responses during ovine CRH
(oCRH) stimulation testing and directly by cortisol responses to
graded submaximal doses of ACTH. Plasma ACTH and cortisol responses
to oCRH were employed as a direct measure of the functional integrity
of the pituitary corticotroph cell. Central CRH secretion was assessed
by measuring its level in cerebrospinal fluid. Compared to normal
subjects, patients demonstrated significantly reduced basal evening
glucocorticoid levels (89.0 +/- 8.7 vs. 148.4 +/- 20.3 nmol/L; P
less than 0.01) and low 24-h urinary free cortisol excretion (122.7
+/- 8.9 vs. 203.1 +/- 10.7 nmol/24 h; P less than 0.0002), but elevated
basal evening ACTH concentrations. There was increased adrenocortical
sensitivity to ACTH, but a reduced maximal response [F(3.26, 65.16)
= 5.50; P = 0.0015). Patients showed attenuated net integrated ACTH
responses to oCRH (128.0 +/- 26.4 vs. 225.4 +/- 34.5 pmol/L.min,
P less than 0.04). Cerebrospinal fluid CRH levels in patients were
no different from control values (8.4 +/- 0.6 vs. 7.7 +/- 0.5 pmol/L;
P = NS). Although we cannot definitively account for the etiology
of the mild glucocorticoid deficiency seen in chronic fatigue syndrome
patients, the enhanced adrenocortical sensitivity to exogenous ACTH
and blunted ACTH responses to oCRH are incompatible with a primary
adrenal insufficiency. A pituitary source is also unlikely, since
basal evening plasma ACTH concentrations were elevated. Hence, the
data are most compatible with a mild central adrenal insufficiency
secondary to either a deficiency of CRH or some other central stimulus
to the pituitary-adrenal axis. Whether a mild glucocorticoid deficiency
or a putative deficiency of an arousal-producing neuropeptide such
as CRH is related to the clinical symptomatology of the chronic
fatigue syndrome remains to be determined.
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Mild
adrenocortical deficiency, chronic allergies, autoimmune disorders
and the chronic fatigue syndrome: a continuation of the cortisone
story,
Med
Hypotheses, 1994, Issue: 3, Volume: 42, Page: 183-9, ISSN: 0306-9877
Professor
W. Mck. Jefferies
The
possibility that patients with disorders that improve with administration
of large, pharmacologic dosages of glucocorticoids, such as chronic
allergies and autoimmune disorders, might have mild deficiency of
cortisol production or utilization has received little attention.
Yet evidence that patients with rheumatoid arthritis improved with
small, physiologic dosages of cortisol or cortisone acetate was
reported over 25 years ago, and that patients with chronic allergic
disorders or unexplained chronic fatigue also improved with administration
of such small dosages was reported over 15 years ago, suggesting
that these disorders might be associated with mild adrenocortical
deficiency. The apparent reasons for the failure of these reports
to be confirmed or mentioned in medical textbooks and the facts
needed to restore perspective are reviewed, and the need for further
studies of the possible relationship of a mild deficiency of the
production or utilization of cortisol and possibly other normal
adrenocortical hormones to the development of these disorders is
discussed.
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Contrasting
neuroendocrine responses in depression and chronic fatigue syndrome,
J
Affect Disord, 1995 Aug 18, Issue: 4 Volume: 34 Page: 283-9 ISSN:
0165-0327
Cleare
AJ; Bearn J; Allain T; McGregor A; Wessely S; Murray RM; O'Keane
V.
Hypothalamic-pituitary-adrenal
(HPA) axis and central 5-HT function were compared in chronic fatigue
syndrome (CFS), depression and healthy states. 10 patients with
CFS and 15 patients with major depression were matched for age,
weight, sex and menstrual cycle with 25 healthy controls. Baseline-circulating
cortisol levels were highest in the depressed, lowest in the CFS
and intermediate between the two in the control group (P = 0.01).
Prolactin responses to the selective 5-HT-releasing agent d-fenfluramine
were lowest in the depressed, highest in the CFS and intermediate
between both in the healthy group (P = 0.01). Matched pair analysis
confirmed higher prolactin responses in CFS patients than controls
(P = 0.05) and lower responses in depressed patients than controls
(P = 0.003). There were strong inverse correlations between prolactin
and cortisol responses and baseline cortisol values. These data
confirm that depression is associated with hypercotisolaemia and
reduced central 5-HT neurotransmission and suggest that CFS may
be associated with hypocortisolaemia and increased 5-HT function.
The opposing responses in CFS and depression may be related to reversed
patterns of behavioural dysfunction seen in these conditions. These
findings attest to biological distinctions between these disorders.
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Pathogenic
tracks in fatigue syndromes
Acta
Clin Belg, 1994, Issue: 6 Volume: 49 Pagination: 274-89 ISSN: 0001-5512
Moutschen
M; Triffaux JM; Demonty J; Legros JJ; Lefèbvre PJ;
This
review analyses the recent literature devoted to two related fatigue
syndromes: chronic fatigue syndrome (CFS) and acute onset postviral
fatigue syndrome (PVFS). The articles are grouped into five pathogenic
tracks: infectious agents, immune system, skeletic muscle, hypothalamo-pituitary-adrenal
(HPA) axis and psychiatric factors. Although a particular infectious
agent is unlikely to be responsible for all CFS cases, evidence
is shown that host-parasite relationships are modified in a large
proportion of patients with chronic fatigue. Antibody titres against
infectious agents are often elevated and replication of several
viruses could be increased. Chronic activation of the immune system
is also observed and could be due to the reactivation of persistent
or latent infectious agents such as herpes viruses (i.e. HHV-6)
or enteroviruses. It could also be favorised by an impaired negative
feedback of the HPA axis on the immune system. A model is proposed
where the abnormalities of the HPA axis are primary events and are
mainly responsible for a chronic activation of the immune system
which in turn induces an increased replication of several viruses
under the control of cellular transcription factors. These replicating
viruses together with cytokines such as TNF-alpha would secondarily
induce functional disorders of muscle and several aspects of asthenia
itself.
