Download Adult Growth Hormone Deficiency in Patients with Fibromyalgia

Adult Growth Hormone Deficiency
in Patients with Fibromyalgia
Robert M. Bennett, MD, FRCP, FACP, FACR
Address
Oregon Health & Science University, Department of Medicine (OP09),
Portland, OR 97201, USA.
E-mail: [email protected]
Current Rheumatology Reports 2002, 4:306–312
Current Science Inc. ISSN 1523–3774
Copyright © 2002 by Current Science Inc.
Adult growth hormone (GH) deficiency is a welldescribed clinical syndrome with many features reminiscent of fibromyalgia. There is evidence that GH deficiency
as defined in terms of a low insulin-like growth factor-1
(IGF-1) level occurs in approximately 30% of patients with
fibromyalgia and is probably the cause of some morbidity.
It seems most likely that impaired GH secretion in fibromyalgia is related to a physiologic dysregulation of the
hypothalamic-pituitary-adrenal axis (HPA) with a resulting
increase in hypothalamic somatostatin tone. It is postulated that impaired GH secretion is secondary to chronic
physical and psychological stressors. It appears that
impaired GH secretion is more common than clinically
significant GH deficiency with low IGF-1 levels. The
severe GH deficiency that occurs in a subset of patients
with fibromyalgia is of clinical relevance because it is a
treatable disorder with demonstrated benefits to patients.
Introduction
It is common for physicians who are unfamiliar with the
complexity of the fibromyalgia syndrome to view the
patients' symptoms as a result of a hormonal deficiency. The
fatigue, mental sluggishness, and muscle pain of hypothyroidism are reminiscent of fibromyalgia complaints. In general, routine endocrine test results 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 because fibromyalgia occurs in teenagers
[3] and postmenopausal women [4]. In addition, estrogen
replacement does not alleviate the symptoms of fibromyalgia
[5]. A 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•,7,8•].
There are close links between the HPA and the HPgrowth hormone (GH) axis. For instance, corticotropinreleasing factor (CRF) stimulates the release of
hypothalamic somatostatin, which acts to restrain the pituitary secretion of GH. This review discusses the evidence
for disturbances in GH secretion and their postulated link
to a disordered HPA axis in patients with fibromyalgia.
Physiology of the Hypothalamic-PituitaryGrowth Hormone/Insulin-like growth
Factor-1 Axis
The GH/insulin-like growth factor-1 (IGF-1) axis is subject to
exquisite regulation by multiple internal physiologic variables and external cues [9] (Table 1). GH is the only pituitary
hormone that is influenced by stimulatory and inhibitory
hypothalamic hormones. The normal pulsatile secretion of
GH depends on the tonic balance of stimulatory GHreleasing hormone (GHRH) and inhibitory somatostatin
[10•,11]. Under normal circumstances, GH is produced only
when GHRH is secreted in the setting of low levels of
somatostatin tone [12]. Therefore, the regulation of GH
secretion depends 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 older age. Furthermore, intentional sleep
deprivation almost totally abolishes GH production [15].
The increased pulsatile GH secretion that occurs during deep
sleep (in stages 3 and 4) is postulated to result from 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 age beyond 18 to 21 years of age 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 daily. Studies using GHRH stimulation and pyridostigmine (to reduce somatostatin tone)
indicate that combined defects in GHRH release and somatostatin excess are 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 IGF-1. Insulin-related
Adult Growth Hormone Deficiency in Patients with Fibromyalgia • Bennett
Table 1. Factors that influence growth
hormone secretion
Stimulators
Inhibitors
Growth hormone-releasing
hormone
Stage 3 and stage 4 sleep
Stressors
Alpha-adrenergic stimuli
Fasting
Melatonin
Estrogens
Dopaminergic stimuli
Exercise
Serotonin
Hypoglycemia
Interleukin-1, -2, and -6
Levodopa
Clonidine
Bromocriptine
Arginine/lysine
Somatostatin
Elevated insulin-like
growth factor-1 levels
Hyperglycemia
Elevated free fatty acid levels
Serotonin antagonists
Corticotropin-releasing
factor
Beta-adrenergic stimuli
Progesterone
Adrenocorticotropic
hormone deficiency
Hyperthyroidism
Hypothyroidism
Obesity
Depression
Corticosteroids
Amitryptiline
Substance P
growth factor-1 is secreted mainly by the liver in response to
GH release. It has a half-life of approximately 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 patients with fibromyalgia, such as 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 [25]. Furthermore, GH is important in maintaining
muscle homeostasis [26]. It was theorized that suboptimal
levels may factor into the impaired resolution of muscle
microtrauma in patients with fibromyalgia [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 low-density lipoprotein levels
[31•], enhance cognitive psychometric performance [32],
augment stroke volume [33], and improve exercise capacity
and muscle strength [22,34].
Diagnosis of Adult Growth
Hormone Deficiency
Low levels of IGF-1 are usually indicative of significant adult
GH deficiency [35], but are not sensitive test markers and
will miss up to 60% of patients older than 40 years of age
with GH deficiency. The favored test to diagnose adult GH
307
Table 2. Diagnostic tests for adult growth
hormone deficiency
Insulin-like growth factor-1 level (age-related)
Growth hormone stimulation tests
Clonidine (alpha-2 receptor agonist)
Levodopa (dopaminergic agonist)
Arginine (reduces somatostatin tone)
Exercise
deficiency is the stimulated GH response to a combination of
GHRH and an inhibitor of somatostatin tone, such as pyridostigmine, arginine, clonidine, or insulin (Table 2). Endocrinologists generally consider the insulin tolerance test (ITT)
to be the most useful test to evaluate the overall GH secretion
in patients with possible hypopituitary disease. However, ITT
is unsuitable in elderly patients and in patients with cardiovascular disease or seizure disorders. Furthermore, the GH
response to ITT may be normal in physiologic GH deficiency
because it measures the overall capacity of the stress axis
rather than the physiologic secretion of GH. A comparison of
ITT, pyridostigmine plus GHRH test, the clonidine plus
GHRH (CLO + GHRH) test, and IGF-1 in diagnosing GH
deficiency has been reported recently [36•]. The peak GH
response was significantly higher during the pyridostigmine
plus GHRH test than during the ITT. IGF-1 levels were subnormal in only 42% of the patients. It was recommended
that adults with suspected GH deficiency and a normal IGF-1
level should undergo two different stimulation tests. In
patients with a subnormal IGF-1 value, a single stimulation
test would suffice to confirm the presence of GH deficiency.
Growth Hormone Deficiency in
Patients with Fibromyalgia
It has been known for 25 years that patients with fibromyalgia have an abnormal sleep pattern involving stages 3
and 4 of non-rapid eye movement (non-REM) sleep [37].
Because GH is secreted predominantly during stages 3 and
4 of non-REM sleep, it was originally hypothesized that
patients with fibromyalgia may have impaired GH
secretion [38,39]. IGF-1 levels are abnormally low in some
patients with fibromyalgia. In an analysis of IGF-1 levels in
500 female patients with fibromyalgia and 152 agematched patients without fibromyalgia, the mean IGF-1
level in the patients with fibromyalgia was 137 ± 58 ng/mL
versus 216 ± 86 ng/mL in controls (P = 0.00000000001)
[40••] (Fig 1A). Eighty-five percent of the patients with
fibromyalgia had IGF-1 levels below the 50th percentile of
the control population, and 56% below the 20th percentile. Because IGF-1 levels decrease progressively with older
age, the results were plotted as IGF-1 versus age, shown as
the regression plot with the 99% confidence limits of the
mean. However, there was a considerable overlap of the
two populations as shown in the respective Gaussian
distribution curves (Fig. 1B).
308
Fibromyalgia
Figure 1. Fibromyalgia versus control. A, The insulin-like growth factor-1 (IGF-1) levels in 500 patients with fibromyalgia (stippled circles)
plotted against age. The solid line is the regression mean for 152 control patients, comprised of healthy blood donors and patients with other
rheumatic diseases. The two dotted lines represent the 99% confidence limits of the mean. B, The Gaussian distributions for the fibromyalgia
and control populations. (Adapted from Bennett et al.[40••].)
Further evidence of defective GH secretion in fibromyalgia is provided by impaired GH stimulation tests
[40••]. In 25 patients with fibromyalgia tested with GH
stimulation tests, only six reached the lower threshold (5
ng/mL) on one of the tests (clonidine or levodopa); in
four of these, the threshold of 5 ng/mL was only just
achieved. Dinser et al. [41•] reported that approximately
30% of patients with fibromyalgia had an abnormally low
GH response to insulin-induced hypoglycemia and arginine stimulation testing, but concluded that severe GH
deficiency was uncommon in fibromyalgia. Leal-Cerro et
al. [42•] have shown that patients with fibromyalgia have
a marked decrease in spontaneous secretion but have a
normal response to GHRH. This observation was considered to be indicative of a disordered hypothalamic regulation of GH release. However, Riedel et al. [43••] have
reported a reduced response to GHRH in patients with
fibromyalgia. Hallegua et al. [44] have reported on a small
cohort of adults with GH deficiency who were participating in a placebo-controlled trial of GH replacement therapy. Forty percent of the placebo group met the 1990
American College of Rheumatology diagnostic criteria for
fibromyalgia compared with 11% of the patients treated
with GH. This study suggests that there may be an etiologic role for GH deficiency in some patients.
Growth Hormone Treatment in
Patients with Fibromyalgia
Only one study has reported on the use of GH replacement
therapy in patients with fibromyalgia and low levels of
IGF-1 [45••] (Fig. 2). In this study, 50 patients with fibro-
myalgia 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 9month trial. The placebo group showed no such increase.
Only the group treated with GH achieved a significant
improvement between baseline and finish. There was a significant improvement of the group treated with GH compared with the placebo group. No unexpected adverse
reactions occurred in the group treated with GH. Carpal
tunnel syndrome symptoms occurred in 28% of the
patients with GH at some time during the treatment period
(only one control patient had such symptoms). Carpal
tunnel syndrome symptoms were managed by reducing the
GH dose. No patients were experiencing carpal tunnel syndrome 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; two “disabled” patients returned to
work. In general, there was a lag of approximately 6
months before patients started to note improvement. All
the 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 and 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 older age have a protective effect
Adult Growth Hormone Deficiency in Patients with Fibromyalgia • Bennett
309
Figure 2. A, The Fibromyalgia Impact Questionnaire (FIQ). B, Number of tender points. Clinical results of a 9-month controlled trial of growth
hormone therapy in patients with fibromyalgia. The FIQ and the number of fibromyalgia tender points improved significantly toward the end of
the study period. The values shown are the means and standard deviations. (Adapted from Bennett et al. [45••].)
on the development of some cancers. If this notion is
correct, then normalization of IGF-1 levels could put
some patients at increased risk of developing cancer.
However, adult GH deficiency is associated with an
increased mortality rate as a result of accelerated atherosclerotic cardiovascular disease [29,51•,52].
Because fibromyalgia affects 2% to 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 rate, and sometimes mortality.
Unfortunately, GH therapy is very expensive (approximately $1000 per month) and beyond the means of most
patients with fibromyalgia and the budgets of most third
party payers. The decision to treat patients with fibromyalgia with GH supplementation must await confirmatory
long-term studies of its efficacy and side effects profile.
Hopefully, a better understanding of the pathophysiologic
basis for GH deficiency in fibromyalgia will yield novel
approaches for treating patients with GH-deficient fibromyalgia that is more physiologic than daily GH injections.
Possible Causes of Growth Hormone
Deficiency in Patients with Fibromyalgia
The complexity of the GH response has been noted (Table 1).
Low IGF-1 levels in patients with fibromyalgia are
unlikely to have an anatomic cause (eg, a pituitary tumor
or infarction). It seems most likely that the problem is a
physiologic GH deficiency. Some evidence for this notion
was provided by a study in which patients with fibromyalgia exercised to volitional exhaustion on a treadmill. This
is a standard test of GH secretion. Unlike healthy controls,
patients with fibromyalgia were unable to mount a GH
response to exercise, despite reaching an anaerobic threshold (an indication of an adequate exercise workload).
However, when patients with fibromyalgia were administered pyridostigmine 1 hour before exercising, they were
able to mount a reasonable GH response [53•]. Because
pyridostigmine is known to reduce 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 (ie,
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 juvenile
rheumatoid arthritis or systemic lupus erythematosus who
have been treated with long-term corticosteroids. This
stunting is caused by the inhibitory effect of iatrogenic
hypercortisolemia on GH secretion [57]. Cortisol inhibits
GH production through the mechanism of an increased
density of beta-adrenergic receptors, with resulting stimulation of adenyl cyclase and somatostatin release [58].
Corticotropin-releasing hormone is the major mediator of the HPA/sympathetic response to physical and psychological stressors. Neeck and Riedel [59•] have
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 is the observation that CRF increases hypothalamic
somatostatin tone [60,61].
It seems difficult to reconcile the well-described association of hypercortisolemia and defective GH production
with the HPA defect described in fibromyalgia, namely a
hypocortisolemic response to stressors. This paradox may
be a result of the diverging consequences of acute versus
chronic stressors. Selye envisioned three stages to the stress
response in his description of the “general adaption syndrome.” In the first stage, an alarm reaction originates in
310
Fibromyalgia
the brain and spreads to the pituitary gland with an
increased production of adrenocorticotropic hormone
stimulating the adrenal cortex to secrete cortisol. Then,
after more prolonged exposure to the stressor, a second
stage develops in which there is increasing secretion of corticosteroids. This is a regulatory physiologic response promoting survival processes while inhibiting nonessential
processes. In the third stage, an “exhaustion” occurs characterized by a progressive decline in cortisol production with
increased vulnerability to stress-related illnesses. The first
two 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 the
hypothalamus [63]. Therefore, in the case of persistent CRF
secretion, its physiologic effects on cortisol secretion ultimately become blunted [62]. Maybe the subpopulation of
patients with fibromyalgia 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 stressrelated disorders that exhibit an impaired cortisol secretion, such as chronic pelvic pain syndrome [64], chronic
fatigue syndrome [65], post-traumatic stress disorder [66],
and overtraining syndrome [67]. All these conditions are
characterized by an increase in central HPA function with a
paradoxic blunting of the adrenal cortisol response. It
appears that fibromyalgia is one of several other chronic
disorders that are characterized by a hypoactive stress
response in terms of HPA axis and a reduced sympathetic
response [59,68•,69,70].
Conclusions
It is impossible 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 subpopulation of patients
with fibromyalgia 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 [40••,53•,58,68•,71,72].
References and Recommended Reading
Papers of particular interest, published recently,
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•
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39.
311
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40.•• Bennett RM, Cook DM, Clark SR, et al.: Hypothalamicpituitary-insulin-like growth factor-I axis dysfunction in
patients with fibromyalgia. J Rheumatol 1997, 24:1384–1389.
A study of 500 patients with fibromyalgia with insulin-like growth
factor-1 levels and growth hormone stimulation tests, demonstrating
adult growth hormone deficiency in approximately one-third of
the 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 growth hormone deficiency in approximately
one-third of patients with fibromyalgia, but concludes that this is
seldom a clinically severe deficiency.
42.• Leal-Cerro A, Povedano J, Astorga R, et al.: The growth
hormone (GH)-releasing hormone-GH-insulin-like growth
factor-1 axis in patients with fibromyalgia syndrome.
J Clin Endocrinol Metab 1999, 84:3378–3381.
A report of 24-hour spontaneous growth hormone (GH) secretion,
GH responses to growth hormone-releasing hormone (GHRH),
and insulin-like growth factor-1 (IGF-1) and IGF-binding protein
(BP)-3 levels in fibromyalgia before and after 4 days of treatment
with human GH. It found a marked decrease in spontaneous GH
secretion, but normal pituitary responsiveness to exogenously
administered GHRH and an increase 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, 57:81–87.
An excellent review of pituitary axis perturbations in fibromyalgia
after 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 patients with
fibromyalgia may play a key role in "resetting" the various endocrine
loops and in nociceptive and psychological mechanisms.
44. Hallegua DS, Wallace DJ, Silverman S, et al.: Prevalence of
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