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Growth
Hormone Deficiency in Fibromyalgia
Robert Bennett, MD
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].
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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