Diagnostic reliability of a single IGF-I measurement in 237 adults with total anterior hypopituitarism and severe GH deficiency

Diagnostic reliability of a single IGF-I measurement in 237 adults with
total anterior hypopituitarism and severe GH deficiency.
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Bron : Clin Endocrinol (Oxf)
Datum: 2003 Jul;59(1):56-61.


Aimaretti G, Corneli G, Baldelli R, Di Somma C, Gasco V, Durante C,
Ausiello L, Rovere S, Grottoli S, Tamburrano G, Ghigo E.

Division of Endocrinology and Metabolism, Department of Internal
Medicine, University of Turin, Italy.

OBJECTIVE: Within an appropriate clinical context, GH deficiency (GHD)
in adults must be demonstrated biochemically by a single provocative
test. Insulin-induced hypoglycaemia (ITT) and GH-releasing hormone
(GHRH) + arginine (ARG) are indicated as the tests of choice, provided
that appropriate cut-off limits are defined. Although IGF-I is the best
marker of GH secretory status, its measurement is not considered a
reliable diagnostic tool. In fact, considerable overlap between GHD and
normal subjects is present, at least when patients with suspected GHD
are considered independently of the existence of other anterior
pituitary defects. Considering the time and cost associated with
provocative testing procedures, we aimed to re-evaluate the diagnostic
power of IGF-I measurement. DESIGN: To this goal, in a large population
[n = 237, 139 men, 98 women, age range 20-80 years, body mass index
(BMI) range 26.4 +/- 4.3 kg/m2] of well-nourished adults with total
anterior pituitary deficit including severe GHD (as shown by a GH peak
below the 1st centile limit of normal response to GHRH + ARG tests
and/or ITT) we evaluated the diagnostic value of a single total IGF-I
measurement. IGF-I levels in hypopituitary patients were evaluated based
on age-related normative values in a large population of normal subjects
(423 ns, 144 men and 279 women, age range 20-80 years, BMI range
18.2-24.9 kg/m2). RESULTS: Mean IGF-I levels in GHD were lower than
those in normal subjects in each decade, but not the oldest one (74.4
+/- 48.9 vs. 243.9 +/- 86.7 micro g/l for 20-30 years; 81.8 +/- 46.5 vs.
217.2 +/- 56.9 micro g/l for 31-40 years; 85.8 +/- 42.1 vs. 168.5 +/-
69.9 micro g/l for 41-50 years; 82.3 +/- 39.3 vs. 164.3 +/- 60.3 micro
g/l for 51-60 years; 67.5 +/- 31.8 vs. 123.9 +/- 50.0 micro g/l for
61-70 years; P < 0.0001; 54.3 +/- 33.6 vs. 91.6 +/- 53.5 micro g/l for
71-80 years, P = ns). Individual IGF-I levels in GHD were below the
age-related 3rd and 25th centile limits in 70.6% and 97.63% of patients
below 40 years and in 34.9% and 77.8% of the remaining patients up to
the 8th decade, respectively. CONCLUSIONS: Total IGF-I levels are often
normal even in patients with total anterior hypopituitarism but this
does not rule out severe GHD that therefore ought to be verified by
provocative testing of GH secretion. However, despite the low diagnostic
sensitivity of this parameter, very low levels of total IGF-I can be
considered definitive evidence of severe GHD in a remarkable percentage
of total anterior hypopituitary patients who could therefore skip
provocative testing of GH secretion.


ng/mL (µg/L) x 0.13 = nmol/L ref waarden: 101-303 ng/mL

IGF-I AS A THERAPEUTIC AGENT Part of the allure of IGF-I as a
therapeutic agent is the wide range of its biologic effects and its
actions on many different tissues. IGF-I mediates many if not most of
the anabolic effects of circulating growth hormone. It stimulates bone
formation, protein synthesis, glucose uptake in muscle, and neuronal
survival and myelin synthesis. IGF-I also reverses negative nitrogen
balance during underfeeding and inhibits protein  degradation  in
muscle.  For  these  reasons, IGF-I has been proposed as a therapy for
osteoporosis, various catabolic states, diabetes, obesity, neuromuscular
disorders, growth hormone resistance, and insulin resistance. The broad
spectrum of its biologic actions offers much promise for IGF-I therapy
for many conditions, but it also increases the likelihood that IGF-I
will have side effects or unwanted actions.
I NSULIN LIKE  G ROWTH  FACTORS DEREK  LE  ROITH , MD, PHD
Growth Hormone Deficiency in Fibromyalgia
Robert Bennett, MD, FRCP
Introduction
It is not uncommon for physicians who are unfamiliar with the complexity
of the fibromyalgia syndrome to view the patients' symptoms as due to a
hormonal deficiency.  The fatigue, mental sluggishness and muscle pain
of hypothyroidism are reminiscent of fibromyalgia complaints.  In
general routine endocrine tests are normal in fibromyalgia [1].  Perhaps
the most striking "endocrine" finding in fibromyalgia is its
predominance in women [2].  However there is no obvious relation to
life-time changes in estrogen secretion, as FM occurs in teenagers [3]
as well as post-menopausal females [4], and estrogen replacement does
not alleviate the symptoms of FM [5]. A current paradigm to explain the
complexity of fibromyalgia symptomatology proposes that it is a "stress
related syndrome" in which a disordered hypothalamic-pituitary-adrenal
(HPA) axis acts as a final common pathway linking fibromyalgia to other
"stress-related" somatic and psychiatric syndromes [6-8] . There are
close links between the HPA and the HP-growth hormone (GH) axis. For
instance corticotrophin releasing hormone (CRF) stimulates the release
of hypothalamic somatostatin, which in turn, acts to restrain the
pituitary secretion of GH. In this review the evidence for disturbances
in GH secretion and their postulated link to a disordered HPA axis in
fibromyalgia patients are discussed.

 The physiology of the hypothalamic-pituitary-growth hormone-IGF-1 axis
The growth hormone - IGF-1 axis is subject to exquisite regulation by
multiple internal physiological variables and external cues [9]. Growth
hormone is the only pituitary hormone that is under the influence of
both stimulatory and inhibitory hypothalamic hormones. The normal
pulsatile secretion of GH depends on the tonic balance of stimulatory
growth hormone releasing hormone  (GHRH) and inhibitory somatostatin
(SRIF) [10;11] . Under normal circumstances the production of GH occurs
only when the secretion of GHRH takes place in the setting of low levels
of somatostatin tone [12].  Thus the regulation of GH secretion is
dependent on the relative amounts of GHRH and somatostatin that are
released from the hypothalamus into the hypothalamic-hypophyseal portal
venous system.  GH secretion has a diurnal pattern of secretion that is
linked to stages 3 and 4 of the sleep cycle[13;14] , but this
association is less evident with increasing age.

Furthermore intentional sleep deprivation almost totally abolishes GH
production [15].  The increased pulsatile GH secretion that occurs
during deep sleep (stages 3 and 4)  is postulated to

be a result of reduced hypothalamic somatostatin tone combined with
increased GHRH release. There is an exponential decline in the daily
GH-secretion rate as a function of age, such that every 7 years of
advancing age beyond age 18-21 results in an approximately 50% decline.
There are negative correlations between the daily GH-secretion rate and
body mass index (BMI). For each increase in BMI of 1.5 kg/m2, there is a
50% decrease in the amount of GH secreted per day. Studies, using GHRH
stimulation and pyridostigmine( to reduce somatostatin tone), point to
combined defects in GHRH release and somatostatin excess as being
involved in the GH deficiency that often accompanies obesity.  At
puberty, and throughout adulthood, gonadal steroid-hormone
concentrations in blood positively influence the intensity of GH
secretion. The major mediator of most GH related anabolic activity is
insulin related growth factor-1 (IGF-1).

Insulin related growth factor-1 is secreted mainly by the liver in
response to GH release. It has a half-life of about 21 hours and does
not exhibit much diurnal variation, its plasma level is considered to
reflect the integrated pulses of GH hormone secretion over the previous
48 hours[16].

Adult Growth hormone deficiency
Growth hormone deficiency in adults has been associated with a
miscellany of symptoms that are similar to those described by
fibromyalgia  patients: low energy [17-20]  , poor general health [21],
reduced exercise capacity [22], muscle weakness [23], cold intolerance
[20], impaired cognition [24], dysthymia [20] and decreased lean body
mass

Consequences of adult GH Deficiency

 Furthermore GH is important in maintaining muscle homeostasis [26], and
it was theorized that sub-optimal levels might be a factor in the
impaired resolution of muscle microtrauma in FM patients [27;28] . The
treatment of GH deficiency in adults has been reported to improve
quality of life and energy level [24;29] , reduce pain [30], improve
depression [31], enhance self esteem [17], improve cholesterol and LDL
levels [31], enhance cognitive psychometric performance [32], augment
stroke volume [33], and improve exercise capacity and muscle strength
[22;22;34] .



Diagnosis of adult growth hormone deficiency

Low levels of IGF-1 are usually indicative of significant adult GH
deficiency [35], but it is not a very sensitive test marker and will
miss up to 60% of GH deficient patients aged over 40. The currently
favored test to diagnose adult GH deficiency is the stimulated GH
response to a combination of GHRH and an inhibitor of somatostatin tone
such as pyridostigmine, arginine, clonidine or insulin Endocrinologists
generally consider the insulin tolerance test (ITT) to be the most
useful test to evaluate the overall GH secretion in subjects with
possible hypopituitary disease .   However, ITT is not suitable in
elderly or in patients with cardiovascular disease or seizure disorders.
Furthermore the GH response to ITT maybe normal in "physiologic" GH
deficiency, as it measures the overall capacity of the stress-axis
rather than the physiological secretion of GH. A comparison of  ITT,
pyridostigmine plus GHRH (PD + GHRH) test, the clonidine plus GHRH
(CLO+GHRH) test, and insulin-like growth factor I (IGF-I) in diagnosing
GH deficiency has recently been reported [36]. The peak GH response was
significantly higher during the PD+GHRH test than during the ITT.
IGF-I levels were subnormal in only 42% of the patients. It was
recommended that adults with suspected GH deficiency and a normal IGF-I
level should undergo two different stimulation tests. In patients with a
subnormal IGF-I value, a single stimulation test would suffice to
confirm the presence of GH deficiency.



Growth hormone deficiency in fibromyalgia patients

It has been known for 25 years that FM patients have an abnormal sleep
pattern involving stages 3 and 4 of non REM sleep [37].  As GH is
secreted predominantly during stages 3 and 4 of non-REM sleep, it was
originally hypothesized that FM patients may have impaired GH secretion
[38;39] . IGF-1 levels are abnormally low in some fibromyalgia patients.
In an analysis of IGF-1 levels in 500 female FM patients and 152 age
matched non-FM subjects the mean IGF-1 level in the FM patients was
137±58 ng/ml versus 216±86 ng/ml in controls (P = 0.00000000001) [40].
Eighty-five percent of the FM patients had IGF-1 levels below the 50th
percentile of the control population and 56% fell below the 20th
percentile. As IGF-1 levels fall progressively with age the results were
plotted as an IGF-1 versus age - shown as the regression plot with the
99% confidence limits of the mean.  However there was also a
considerable overlap of the 2 populations as shown in the respective
Gaussian distribution curves.

(From Bennett et al, J.Rheumatol. 24:1384-1389, 1997)


The main graph shows the individual IGF-1 levels in 500 patients with
fibromyalgia (stippled circles) plotted against age.  The solid line is the
regression mean for 152 control patients, comprising both healthy blood
donors and patients with other rheumatic diseases. The 2 dotted lines
represent the 99% confidence limits of the mean.  The inset graph shows
the Gaussian distributions for the fibromyalgia and control populations.

Growth hormone  treatment in fibromyalgia patients

There is only one study to date that has reported on the use of  GH
replacement  therapy in FM patients with low levels of IGF-1 [45].  In
this study 50 fibromyalgia  patients were enrolled in a 9 month, double
blind, placebo controlled trial. There was a  prompt increase in IGF-1
levels within the first month in all patients receiving GH injections
which was sustained throughout the 9 month trial. The placebo group
showed no such increase. Only the GH treated group achieved a
significant improvement between baseline and finish.   There was a
significant improvement of the GH treated group compared to the placebo
group. No unexpected adverse reactions occurred in the GH treated
group.  Carpal tunnel symptoms occurred in 28% GH patients at some time
during the treatment period; only 1 control patient had such symptoms.
Carpal tunnel symptoms were managed by reducing the GH dose.  No
patients were experiencing carpal tunnel symptoms at the end of the
study. Although no patient had a complete remission of symptoms, several
patients on GH experienced an impressive improvement in their functional
ability and 2 "disabled" patients returned to work.  In general there
was a lag of about 6 months before patients started to note
improvement.  All patients who experienced improvement on GH suffered a
reversion of symptoms over a period of 1 to 3 months after stopping GH
treatment.

A preliminary study of supplemental GH therapy in patients with chronic
fatigue syndrome has reported somewhat similar encouraging results [46].

There have been concerns about elevated IGF-1 levels being associated
with an increased risk of some cancers [47-50]  . However GH therapy
aims to normalize, not increase IGF-1 levels.  It is possible that the
low IGF-1 levels associated with aging have a protective effect on the
development of some cancers; if this notion is correct normalization of
IGF-1 levels could put some patients at increased risk of developing
cancer. On the other hand adult GH deficiency is associated with an
increased mortality due to accelerated atherosclerotic cardiovascular
disease  [29;51;52] .

As fibromyalgia affects 2-4% of all adults, it must be a major
contributing factor to many cases of adult GH deficiency, with
consequences for an impaired quality of life, increased morbidity and
sometimes mortality. Unfortunately GH therapy is very expensive and is
beyond the means of most fibromyalgia patients and the budgets of most
third party payers. The decision to treat fibromyalgia  patients with GH
supplementation must await confirmatory long-term studies of its
efficacy/side effects profile. Hopefully a better understanding of the
pathophysiological basis for GH deficiency in fibromyalgia will yield
novel approaches for treating GH deficient fibromyalgia patients that is
more physiological than daily GH injections.



Possible causes of GH deficiency in fibromyalgia patients

The complexity  of the GH response has already been noted. Low IGF-1
levels in fibromyalgia patients are unlikely to be due to an anatomical
cause (e.g. a pituitary tumor or infarction). Rather it seems most
likely that the problem is a "physiologic GH deficiency". Some evidence
for this notion was provided by a study in which fibromyalgia patients
were exercised to volitional exhaustion on a treadmill; this is a
standard test of GH secretion.  Unlike healthy controls, fibromyalgia
patients were unable to mount a GH response to exercise - despite
reaching an anaerobic threshold (an indication of an adequate exercise
workload).  However, when fibromyalgia patients were given
pyridostigmine one hour prior to exercising, they were able to mount a
reasonable GH response [53]. As pyridostigmine is known to reduce
somatostatin (somatostatin) tone in the hypothalamus [54], this result
is compatible with the notion that GH deficiency in fibromyalgia is a
potentially reversible problem that has a physiologic basis - i.e.
increased hypothalamic somatostatin tone.

The effects of HPA axis dysregulation secretion are postulated to be
relevant to GH deficiency in fibromyalgia [55;56]   Rheumatologists are
familiar with the growth retardation that occurs in some children with
JRA or SLE, who have been treated with long-term corticosteroids.  This
stunting is due to the inhibitory effect of iatrogenic hypercortisolemia
on GH secretion [57]. Cortisol inhibits GH production through the
mechanism of an increased density of b-adrenergic receptors -- with
resulting stimulation of adenyl cyclase and somatostatin release [58].

CRF is the major mediator of the HPA / sympathetic response to both
physical and psychological stressors. Neeck has hypothesized that a
stress induced increase in CRF is the common denominator linking the
disturbed HPA axis and reduced GH secretion in fibromyalgia [59]. The
critical link being the observation that CRF increases hypothalamic
somatostatin tone [60;61] .

However it seems difficult to reconcile the well described association
of hyper-cortisolemia  and defective GH production with the HPA defect
described in fibromyalgia - namely  a hypo-cortisolemic response to
stressors. This apparent paradox may be a result of the diverging
consequences of acute versus chronic stressors. Hans Selye envisaged 3
stages to the stress response in his description of the "general
adaption syndrome" : (i) an alarm reaction that originates in the brain
and spreads to the pituitary with an increased production of ACTH
stimulating the adrenal cortex to secrete cortisol, (ii) after more
prolonged exposure to the stressor, a second stage develops in which
there is increasing secretion of corticosteroids; this is a regulatory
physiological response promoting survival processes while inhibiting
non-essential processes, (iii) in the third stage an "exhaustion" occurs
characterized by a progressive decline in cortisol production with
increased vulnerability to stress related illnesses. The first 2 stages
of the general adaption syndrome are mediated by the stress-induced
secretion of CRF [62]. However, prolonged CRF secretion eventually down
regulates the density of CRF-1 receptors in the paraventricular nucleus
of hypothalamus [63]. Thus in the face of persistent CRF secretion its
physiological effects on cortisol secretion ultimately become blunted
[62]. Maybe the sub-population of fibromyalgia patients with defective
neuroendocrine and sympathetic stress responses has reached this "third
stage" of Selye's general adaption syndrome?

There are several other examples of human "stress related" disorders
that exhibit an impaired cortisol secretion, namely: chronic pelvic pain
syndrome[64], chronic fatigue syndrome [65], post traumatic stress
disorder [66] and over-training syndrome [67]. All these conditions are
characterized by an increase in central HPA function with a paradoxical
blunting of the adrenal cortisol response.  Thus it appears that
fibromyalgia is just one of several other chronic disorders, that are
characterized by a hypoactive stress response in terms of HPA axis and a
reduced sympathetic responses [59;68-70]  .

Currently it is not possible to arrive at any definitive conclusions as
to the link between HPA axis dysfunction and GH deficiency in
fibromyalgia. Nevertheless, the presence of a clinically significant GH
deficiency in a sub-population of fibromyalgia patients now seems well
established. Understanding its links with chronic stress may provide
some insights into mechanisms whereby environmental stressors and
developmental factors interact with inherited susceptibility to modify
gene expression and ultimately generate symptoms [71];[68;72] 40;58;
[53].


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A report of 24-h spontaneous GH secretion, GH responses to GHRH, and
IGF-1 and IGF binding protein (BP)-3 levels  in fibromyalgia before and
after 4 days treatment with human (h)GH. Found a marked decrease in
spontaneous GH secretion, but normal pituitary responsiveness to
exogenously administered GHRH and an increased in  IGF-1 and IGFBP-3
levels after GH treatment.

43   ·· Riedel W, Layka H, Neeck G: Secretory pattern of GH, TSH,
thyroid hormones, ACTH, cortisol, FSH, and LH in patients with
fibromyalgia syndrome following systemic injection of the relevant
hypothalamic-releasing hormones. Z.Rheumatol. 1998, 57 Suppl 2:81-87.
An excellent review of pituitary axis perturbations in fibromyalgia
following injections with corticotropin- releasing hormone (CRH),
thyrotropin-releasing hormone, growth hormone- releasing hormone, and
luteinizing hormone-releasing hormone. Concludes that  elevated activity
of  hypothalamic CRH neurons in fibromyalgia patients thus may play a
key role not only in "resetting" the various endocrine loops but also in
nociceptive and psychological mechanisms.

44   Hallegua D.S., Wallace DJ, Silverman S, Bonert V, Mathur R,
Klinenberg JR: Prevalence of fibromyalgia in Xgrowth hormone deficiency
adults. J Musculoskeletal Pain 2001, 9:35-42.

45   ·· Bennett RM, Clark SR, Walczyk J: A randomized, double-blind,
placebo-controlled study of growth hormone in the treatment of
fibromyalgia. Am.J Med 1998, 104:227-231.
The only controlled study of supplemental GH therapy in fibromyalgia to
date. Found a benefit after about 6 months of therapy with a relapse on
discontinuing therapy.

46   Moorkens G, Wynants H, Abs R: Effect of growth hormone treatment in
patients with chronic fatigue syndrome: a preliminary study.Growth
Horm.IGF.Res. 1998, 8 Suppl B:131-133.

47   Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P,
Hennekens CH, Pollak M: Plasma insulin-like growth factor-I and prostate
cancer risk: a prospective study. Science 1998, 279:563-566.

48   Mantzoros CS, Tzonou A, Signorello LB, Stampfer M, Trichopoulos D,
Adami HO: Insulin-like growth factor 1 in relation to prostate cancer
and benign prostatic hyperplasia. Br.J Cancer 1997, 76:1115-1118.

49   Yee D: The insulin-like growth factors and breast
cancer--revisited. Breast Cancer Res.Treat. 1998, 47:197-199.

50   Stoll BA: Breast cancer: further metabolic-endocrine risk markers?
Br.J Cancer 1997, 76:1652-1654.

51   · Sanmarti A, Lucas A, Hawkins F, Webb SM, Ulied A: Observational
study in adult hypopituitary patients with untreated growth hormone
deficiency (ODA study). Socio-economic impact and health status.
Collaborative ODA (Observational GH Deficiency in Adults) Group. Eur.J
Endocrinol. 1999, 141:481-489.
A study documenting more cardiovascular risk factors, higher mortality,
worse quality of life and higher absolute health costs than the general
population in Spain.

52   Bengtsson BA: The consequences of growth hormone deficiency in
adults. Acta Endocrinol. 1993, 128:2-5.

53 ·    Paiva, E.S., Deodhar, A., Jones, K.D., Bennett, R.M.,  Impaired
growth hormone secretion in
      fibromyalgia patients: evidence for augmented hypothalamic
somatostatin tone. Arthritis
      Rheum. (in Press 2002)

       This study shows that GH deficiency in fibromyalgia is probably
more common than previously  reported from the
        measurements of IGF-1 levels. It provides evidence that
perturbed GH  secretion in fibromyalgia is probably, in part,

        a result of increased hypothalamic tone of  somatostatin.



54   Valcavi R, Valente F, Dieguez C, Zini M, Procopio M, Portioli I,
Ghigo E: Evidence against deletion of the growth hormone (GH)-releasable
pool in human primary hypothyroidism: studies with GH-releasing hormone,
pyridostigmine, and arginine. J Clin Endocrinol Metab 1993, 77:616-620.

55   ·· Neeck G, Crofford LJ: Neuroendocrine perturbations in
fibromyalgia and chronic fatigue syndrome  Rheum.Dis.Clin.North Am.
2000, 26:989-1002.
A comprehensive review of neuroendocrine disorders in fibromyalgia.

56   Crofford LJ, Engleberg NC, Demitrack MA: Neurohormonal
perturbations in fibromyalgia. Baillieres.Clin.Rheumatol. 1996,
10:365-378.



57   Thorner O: The anterior pituitary. In Textbook of endocrinology,
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58   Devesa J, Lima L, Tresguerres JAF: Neuroendocrine control of growth
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59   · Neeck G, Riedel W: Hormonal pertubations in fibromyalgia syndrome
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system. Recent studies of the entire endocrine profile of FM patients
following a simultaneous challenge of the hypophysis with corticotropin-
releasing hormone (CRH), thyrotropin-releasing hormone, growth hormone-
releasing hormone, and luteinizing hormone-releasing hormone support the
hypothesis that an elevated activity of CRH neurons determines not only
many symptoms of FM but may also cause the deviations observed in the
other hormonal axes. Hypothalamic CRH neurons thus may play a key role
not only in "resetting" the various endocrine loops but possibly also
nociceptive and psychological mechanisms as well



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61   Rivier C, Vale W: Involvement of corticotropin-releasing factor and
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62   Hauger R.L. DFM: Regulation of the stress response by
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63   Bonaz B, Rivest S: Effect of a chronic stress on CRF neuronal
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64   Heim C, Ehlert U, Hanker JP, Hellhammer DH: Abuse-related
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65   Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJP,
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66   Heim C, Ehlert U, Hanker JP, Hellhammer DH: Psychological and
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67   Wittert GA, Livesey JH, Espiner EA, Donald RA: Adaptation of the
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68   · Clauw DJ, Chrousos GP: Chronic pain and fatigue syndromes:
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Hypothesizes that fibromyalgia and chronic fatigue syndrome may be a
result of genetic and environmental factors that interact to cause the
development of named syndromes. Various components of the central
nervous system are envisaged  to be involved, including the hypothalamic
pituitary axes, pain-processing pathways, and autonomic nervous system.

69   Dessein PH, Shipton EA, Stanwix AE, Joffe BI: Neuroendocrine
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70   Neeck G, Riedel W: Thyroid function in patients with fibromyalgia
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71   Winfield JB: Pain in fibromyalgia. Rheum.Dis.Clin.North Am. 1999,
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72   Dorn LD, Chrousos GP: The neurobiology of stress: understanding
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