Growth Hormone Deficiency in Fibromyalgia
Introduction to Fibromyalgia and Growth Hormone
Robert Bennett, MD, FRCP
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 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 . 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 . 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 Deficiency
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 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 . 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 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 . 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; .
It is simple, scientific logic...
As your growth hormone DECREASES,
the rate at which you age
Consider that for a moment...
There is a solution...
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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.
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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.
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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.
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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. 1997, 24:1384-1389.
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 deficiency.
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 1999, 84:3378-3381.
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.
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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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A study documenting more cardiovascular risk factors, higher mortality, worse quality of life and higher absolute health costs than the general population in Spain.
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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.
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A comprehensive review of neuroendocrine disorders in fibromyalgia.
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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 as well
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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.
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