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

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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).

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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

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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

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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, have been highlighted as: • Of importance •• Of major importance 1.

2.

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Bennett RM, Clark SR, Campbell SM, Burckhardt CS: Low levels of somatomedin C in patients with the fibromyalgia syndrome: a possible link between sleep and muscle pain. Arthritis Rheum 1992, 35:1113–1116. 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 fibromyalgia in X growth hormone deficiency adults. J Musculoskeletal Pain 2001, 9:35–42. 45.•• Bennett RM, Clark SR, Walczyk J: A randomized, doubleblind, placebo-controlled study of growth hormone in the treatment of fibromyalgia. Am J Med 1998, 104:227–231. The only controlled study of supplemental growth hormone therapy in fibromyalgia. It found a benefit after approximately 6 months of therapy, and a relapse when therapy was discontinued. 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, 8:131–133. 47. Chan JM, Stampfer MJ, Giovannucci E, et al.: Plasma insulinlike growth factor-I and prostate cancer risk: a prospective study. Science 1998, 279:563–566. 48. Mantzoros CS, Tzonou A, Signorello LB, et al.: 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, et al.: 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 rate, worse quality of life, and higher absolute health costs than the general population in Spain.

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