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 . Perhaps the most striking
"endocrine" finding in fibromyalgia is its predominance
in women . However there is no obvious relation to life-time
changes in estrogen secretion, as FM occurs in teenagers 
as well as post-menopausal females , and estrogen replacement
does not alleviate the symptoms of FM . 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
The physiology of the hypothalamic-pituitary-growth
The growth hormone - IGF-1 axis is subject to exquisite regulation
by multiple internal physiological variables and external
cues . 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)
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 . 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 . 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.
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 , reduced exercise capacity , muscle weakness
, cold intolerance , impaired cognition , dysthymia
 and decreased lean body mass Consequences of adult GH
Furthermore GH is important in maintaining muscle homeostasis
, 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 , improve depression ,
enhance self esteem , improve cholesterol and LDL levels
, enhance cognitive psychometric performance , augment
stroke volume , 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 , 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 . 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 .
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)
. 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
(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 . 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 .
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 . As pyridostigmine
is known to reduce somatostatin (somatostatin) tone in the
hypothalamus , 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
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 . Cortisol
inhibits GH production through the mechanism of an increased
density of b-adrenergic receptors -- with resulting stimulation
of adenyl cyclase and somatostatin release .
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 . 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 . However, prolonged CRF secretion eventually
down regulates the density of CRF-1 receptors in the paraventricular
nucleus of hypothalamus . Thus in the face of persistent
CRF secretion its physiological effects on cortisol secretion
ultimately become blunted . 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 , chronic fatigue syndrome
, post traumatic stress disorder  and over-training
syndrome . 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 ;[68;72] 40;58; .
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8 · Weigent DA, Bradley LA, Blalock JE, Alarcon GS:
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A good review of the pathophysiology of aberrant pain perception
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human growth hormone (GH)-insulin-like growth factor type
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An uptodate review of the neuro-physiology of GH secretion.
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28 Bennett RM: The contribution of muscle to the generation
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30 ·· Cuneo RC, Judd S, Wallace JD, Perry-Keene
D, Burger H, Lim-Tio S, Strauss B, Stockigt J, Topliss D,
Alford F, Hew L, Bode H, Conway A, Handelsman D, Dunn S, Boyages
S, Cheung NW, Hurley D: The Australian Multicenter Trial of
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Endocrinol.Metab. 1998, 83:107-116.
An Australian multicenter, randomized, double-blind, placebo-controlled
trial of the effects of recombinant human GH treatment in166
adults patients (72 females and 91 males) with GH deficiency.
GH treatment resulted in 1) prominent increases in serum IGF-I
at the doses employed, in some cases to supraphysiological
levels; 2) modest decreases in total- and low- density lipoprotein
cholesterol, together with substantial reductions in total-body
and truncal fat mass; 3) substantial increases in lean tissue
mass; and 4) modest improvements in perceived quality of life.
31 · Giusti M, Meineri I, Malagamba D, Cuttica CM,
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recombinant human growth hormone treatment on psychological
profiles in hypopituitary patients with adult-onset growth
hormone deficiency. Eur.J Clin Invest. 1998, 28:13-19.
A study of the effect of growth hormone (GH) administration
on the psychological capacity and sense of well-being in 25
patients with adult-onset GH-deficiency. There were significantly
improved psychological profiles, but the quality of life was
not significantly improved over the a 6-month period of treatment.
32 Almqvist O, Thoren M, Saaf M, Eriksson O: Effects of growth
hormone substitution on mental performance in adults with
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R: Cardiac function and structure in growth hormone deficiency.
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35 Aimaretti G, Corneli G, Razzore P, Bellone S, Baffoni C,
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36 · Hoeck HC, Vestergaard P, Jakobsen PE, Falhof J,
Laurberg P: Diagnosis of growth hormone (GH) deficiency in
adults with hypothalamic-pituitary disorders: comparison of
test results using pyridostigmine plus GH-releasing hormone
(GHRH), clonidine plus GHRH, and insulin-induced hypoglycemia
as GH secretagogues. J.Clin.Endocrinol.Metab 2000, 85:1467-1472.
A definitive study suggesting that a diagnosis of adult GH
deficiency be based upon an abnormally low IGF-1 level plus
one abnormal GH stimulation tests, or 2 abnormal GH stimulation
tests in patients with normal IGF-1 levels.
37 Moldofsky H, Scarisbrick P, England R, Smythe H: Musculosketal
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treatment. J.Rheumatol.Suppl. 1989, 19:185-191.
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of somatomedin C in patients with the fibromyalgia syndrome.
A possible link between sleep and muscle pain. Arthritis Rheum.
40 ·· Bennett RM, Cook DM, Clark SR, Burckhardt
CS, Campbell SM: Hypothalamic-pituitary-insulin-like growth
factor-I axis dysfunction in patients with fibromyalgia. J.Rheumatol.
A study of 500 fibromyalgia patients with IGF-1 levels and
GH stimulation tests, demonstrating adult GH deficiency in
about one third of patients.
41 · Dinser R, Halama T, Hoffmann A: Stringent endocrinological
testing reveals subnormal growth hormone secretion in some
patients with fibromyalgia syndrome but rarely severe growth
hormone deficiency . J Rheumatol 2000, 27:2482-2488.
Supports finding of GH deficiency in about one third of fibromyalgia
patients, but concludes that this is seldom a clinically severe
42 · Leal-Cerro A, Povedano J, Astorga R, Gonzalez
M, Silva H, Garcia-Pesquera F, Casanueva FF, Dieguez C: The
growth hormone (GH)-releasing hormone-GH-insulin-like growth
factor-1 axis in patients with fibromyalgia syndrome. J Clin.Endocrinol.Metab
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
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.
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treatment in patients with chronic fatigue syndrome: a preliminary
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51 · Sanmarti A, Lucas A, Hawkins F, Webb SM, Ulied
A: Observational study in adult hypopituitary patients with
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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
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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
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55 ·· Neeck G, Crofford LJ: Neuroendocrine perturbations
in fibromyalgia and chronic fatigue syndrome Rheum.Dis.Clin.North
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A comprehensive review of neuroendocrine disorders in fibromyalgia.
56 Crofford LJ, Engleberg NC, Demitrack MA: Neurohormonal
perturbations in fibromyalgia. Baillieres.Clin.Rheumatol.
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edn 8th. Edited by Wilson JD, Foster DW. Philadelphia: W.B.
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59 · Neeck G, Riedel W: Hormonal pertubations in fibromyalgia
syndrome . Ann.N.Y.Acad.Sci. 1999, 876:325-38; discussion
Postlulates a common primary disturbance in fibromyalgia which
is hypothesized to originate within higher levels of the central
nervous 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
60 Katakami H, Arimura A, Frohman LA: Involvement of hypothalamic
somatostatin in the suppression of growth hormone secretion
by central corticotropin-releasing factor in conscious male
rats. Neuroendocrinology 1985, 41:390-393.
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