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A Randomized, Double-Blind, Placebo-controlled Study of Growth Hormone in the Treatment of Fibromyalgia 1

      Abstract

      PURPOSE: The cause of fibromyalgia (FM) is not known. Low levels of insulin-like growth factor 1 (IGF-1), a surrogate marker for low growth hormone (GH) secretion, occur in about one third of patients who have many clinical features of growth hormone deficiency, such as diminished energy, dysphoria, impaired cognition, poor general health, reduced exercise capacity, muscle weakness, and cold intolerance. To determine whether suboptimal growth hormone production could be relevant to the symptomatology of fibromyalgia, we assessed the clinical effects of treatment with growth hormone.
      METHODS: Fifty women with fibromyalgia and low IGF-1 levels were enrolled in a randomized, placebo-controlled, double-blind study of 9 months’ duration. They gave themselves daily subcutaneous injections of growth hormone or placebo. Two outcome measures—the Fibromyalgia Impact Questionnaire and the number of fibromyalgia tender points—were evaluated at 3-monthly intervals by a blinded investigator. An unblinded investigator reviewed the IGF-1 results monthly and adjusted the growth hormone dose to achieve an IGF-1 level of about 250 ng/mL.
      RESULTS: Daily growth hormone injections resulted in a prompt and sustained increase in IGF-1 levels. The treatment (n = 22) group showed a significant improvement over the placebo group (n = 23) at 9 months in both the Fibromyalgia Impact Questionnaire score (P <0.04) and the tender point score (P <0.03). Fifteen subjects in the growth hormone group and 6 subjects in the control group experienced a global improvement (P <0.02). There was a delayed response to therapy, with most patients experiencing improvement at the 6-month mark. After discontinuing growth hormone, patients experienced a worsening of symptoms. Carpal tunnel symptoms were more prevalent in the growth hormone group (7 versus 1); no other adverse events were more common in this group.
      CONCLUSIONS: Women with fibromyalgia and low IGF-1 levels experienced an improvement in their overall symptomatology and number of tender points after 9 months of daily growth hormone therapy. This suggests that a secondary growth hormone deficiency may be responsible for some of the symptoms of fibromyalgia.
      Fibromyalgia is a common syndrome of widespread musculoskeletal discomfort that is readily differentiated from other causes of rheumatic pain [
      • Wolfe F
      • Smythe HA
      • Yunus MB
      • et al.
      The American College of Rheumatology 1990 criteria for the classification of fibromyalgia report of the Multicenter Criteria Committee.
      ]. Individuals with fibromyalgia probably represent one end of the spectrum of widespread pain that has been reported in 12% to 16% of subjects responding to population surveys [
      • Croft P
      • Schollum J
      • Silman A
      Population study of tender point counts and pain as evidence of fibromyalgia.
      ]. There is increasing evidence that fibromyalgia is an example of a central pain state [
      • Cohen ML
      • Quintner JL
      Fibromyalgia syndrome, a problem of tautology.
      ]. Two well-studied pathophysiological correlates of this phenomenon are an upregulation of NMDA (N-methyl-D-aspartate) receptors at spinal synapses and a dysregulation of substance P production [
      • Dubner R
      Hyperalgesia and expanded receptive fields.
      ]. The central pain sensitization state causes amplification of normally innocuous sensations [
      • Arroyo JF
      • Cohen ML
      Abnormal responses to electrocutaneous stimulation in fibromyalgia.
      ]. Thus the aches and pains of everyday existence become magnified and adversely affect the quality of life [
      • Burckhardt CS
      • Clark SR
      • Bennett RM
      The fibromyalgia impact questionnaire development and validation.
      ]. In some patients the resulting psychological distress causes changes in sleep, endocrine rhythms, psyche, and behavior [
      • Aaron LA
      • Bradley LA
      • Alarcon GS
      • et al.
      Psychiatric diagnoses in patients with fibromyalgia are related to health care-seeking behavior rather than to illness.
      ,
      • Moldofsky H
      Sleep, neuroimmune and neuroendocrine functions in fibromyalgia and chronic fatigue syndrome.
      ]. It has been known for 20 years that patients with fibromyalgia have an abnormal sleep pattern involving stages 3 and 4 of non-REM sleep [
      • Moldofsky H
      • Scarisbrick P
      • England R
      • Smythe H
      Musculosketal symptoms and non-REM sleep disturbance in patients with “fibrositis syndrome” and healthy subjects.
      ]. As growth hormone is secreted predominantly during stages 3 and 4 of non-REM sleep, it was hypothesized that fibromyalgia may be associated with impaired secretion of growth hormones [
      • Bennett RM
      Beyond fibromyalgia ideas on etiology and treatment.
      ]. About one third of patients with fibromyalgia have low IGF-1 levels [
      • 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.
      ].
      Growth hormone deficiency in adults has been associated with symptoms that are similar to those described by patients with fibromyalgia: low energy [
      • Cuneo RC
      • Salomon F
      • McGauley GA
      • Sönksen PH
      The growth hormone deficiency syndrome in adults.
      ], poor general health [
      • Wallymahmed ME
      • Baker GA
      • Humphris G
      • et al.
      The development, reliability and validity of a disease specific quality of life model for adults with growth hormone deficiency.
      ], reduced exercise capacity [
      • Cuneo RC
      • Salomon F
      • Wiles CM
      • et al.
      Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance.
      ], muscle weakness [
      • Rutherford OM
      • Beshyah SA
      • Schott J
      • et al.
      Contractile properties of the quadriceps muscle in growth hormone-deficient hypopituitary adults.
      ], cold intolerance [
      • Cuneo RC
      • Salomon F
      • McGauley GA
      • Sönksen PH
      The growth hormone deficiency syndrome in adults.
      ], impaired cognition [
      • McGauley GA
      • Cuneo RC
      • Salomon F
      • Sönksen PH
      Psychological well-being before and after growth hormone treatment in adults with growth hormone deficiency.
      ], dysthymia [
      • Cuneo RC
      • Salomon F
      • McGauley GA
      • Sönksen PH
      The growth hormone deficiency syndrome in adults.
      ], and decreased lean body mass [
      • Salomon F
      • Cuneo RC
      • Hesp R
      • Sonksen PH
      The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency.
      ]. Furthermore, growth hormone is important in maintaining muscle homeostasis [
      • Florini JR
      Hormonal control of muscle growth.
      ], and it was theorized that suboptimal levels may be a factor in the impaired resolution of muscle microtrauma in fibromyalgia [
      • Bennett RM
      The contribution of muscle to the generation of fibromyalgia symptomatology.
      ]. To test the hypothesis that impaired growth hormone secretion contributes to symptoms of fibromyalgia, we studied the effects of administering growth hormone to patients with fibromyalgia who have low levels of IGF-1.

      1. Methods

      This study was approved by the ethics committee of the Oregon Health Sciences University and performed according to their guidelines. All subjects gave their informed written consent.

      1.1 Patient Population

      Only women with fibromyalgia were studied. All patients fulfilled the 1990 American College of Rheumatology diagnostic criteria [
      • Wolfe F
      • Smythe HA
      • Yunus MB
      • et al.
      The American College of Rheumatology 1990 criteria for the classification of fibromyalgia report of the Multicenter Criteria Committee.
      ]and had an IGF-1 level <160 ng/mL. Other inclusion criteria were duration of fibromyalgia of 5 years or greater, absence of known pituitary disease, no previous growth hormone therapy, and ability and willingness to give written informed consent. Exclusion criteria included any serious medical condition that would require changes in drug therapy during the study, major depression, malignancy or history of malignancy, any other endocrine disorder including diabetes mellitus, and receipt of any other investigational therapy within 3 months of this study. Patients who were pregnant or were contemplating pregnancy during the study period were also excluded.

      1.2 Medication

      Growth hormone in the form of Nutropin was supplied in 5-mg vials containing sterilized lyophilized powder. (Nutropin is a recombinant protein with a 191 amino acid sequence identical to human pituitary derived growth hormone.) Excipients were mannitol, glycerin, USP for isotonicity, and phosphate for pH balance. The vial contents were reconstituted with bacteriostatic water for injection, USP (benzyl alcohol preserved). Placebo was lyophilized exipient having an appearance identical to the active drug. Exipient vials contained mannitol, glycerin, and sodium phosphate; they were reconstituted, stored, and administered in an identical fashion to growth hormone. Patients were taught to give their own subcutaneous injections.

      1.3 Randomization and Blinding

      Patients were randomly assigned to receive growth hormone (n = 25) or placebo (n = 25). Randomization was performed by the biostatistics department at Genentech, Inc., prior to the shipment of the treatment vials. Each treatment vial was assigned to contain either growth hormone or placebo, according to a randomization table, and vials were numbered anonymously in a sequential fashion. The randomization code was made available only to an unblinded investigator.
      The vials containing either growth hormone or placebo were identical in appearance, and the code number was anonymous as to the contents. The investigator who evaluated the patients and recorded the outcome measures was blinded to the treatment group of the patients. The investigator who reviewed the IGF-1 levels and made adjustments to growth hormone doses was unblinded and did not interact with patients. For every dosage change in a treated patient, a placebo patient was instructed to change the injected volume by a similar amount to maintain the simulation of receiving active drug.

      1.4 Dose Adjustments

      The dose of growth hormone was 0.0125 mg/kg daily for the first month. This relatively low initial dose was designed to minimize the development of early side effects, as a strategy for keeping the study double blinded. The dose was adjusted by the unblinded investigator at monthly intervals to maintain an IGF-1 level of about 250 ng/mL. If side effects such as edema, arthralgia, or carpal tunnel symptoms occurred, the dose was reduced to 0.0125 mg/kg per day until the problem subsided.

      1.5 Outcome Measures

      Two primary outcome measures were used to evaluate the effectiveness of the treatments. The Fibromyalgia Impact Questionnaire is a 10-item instrument that measures physical functioning, pain, depression, anxiety, fatigue, morning tiredness, stiffness, work record, job difficulty, and overall well-being [
      • Burckhardt CS
      • Clark SR
      • Bennett RM
      The fibromyalgia impact questionnaire development and validation.
      ]. The instrument has been shown to have good reliability and validity [
      • Goldenberg DL
      • Mossey CJ
      • Schmid CH
      A model to assess severity and impact of fibromyalgia.
      ]. A lower score indicates improvement; the maximum possible score is 100. Fibromyalgia tender points were examined using the protocol described by Wolfe et al [
      • Wolfe F
      • Smythe HA
      • Yunus MB
      • et al.
      The American College of Rheumatology 1990 criteria for the classification of fibromyalgia report of the Multicenter Criteria Committee.
      ]employing 18 standardized locations. The number of tender points could range from 11 to 18 at enrollment and from 0 to 18 at follow-up visits. In addition, at the end of the study, patients were asked whether they had experienced a worthwhile global improvement.

      1.6 Follow-Up Evaluations

      Patients were seen monthly for evaluation of weight, heart rate, blood pressure, peripheral edema, carpal tunnel syndrome symptoms, adverse reactions, IGF-1 levels, and antibodies to human growth hormone. At baseline and at months 3, 6, and 9 patients completed the Fibromyalgia Impact Questionnaire, were evaluated for fibromyalgia tender points, and had a complete blood count, chemistry screen, and urinalysis.

      1.7 Serological Tests

      All blood samples were drawn between 10.00 am and 4.00 pm. IGF-1 was measured on serum samples that had been acid/ethanol extracted to remove IGF-1 binding proteins. The assay was performed at Endocrine Sciences (Calabas Hills, California), as previously described [
      • 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.
      ]. The interassay and intraassay coefficients of variation were 7.3% and 5.4%, respectively. Antibodies to growth hormone were measured by a radioimmunoassay performed at Genentech.

      1.8 Statistical Analysis

      Based on the previous work [
      • Bennett RM
      • Burckhardt CS
      • Clark SR
      • et al.
      Group treatment of fibromyalgia description and results of a 6 month out patient program.
      ], it was estimated that a sample size of 40 would be sufficient to detect a change in Fibromyalgia Impact Questionnaire scoring of 10 and tender point scoring of 3, with an alpha of <0.05 and a power of 80%. Fifty subjects were enrolled in the study to allow for drop-outs. Analysis was based on the intention-to-treat principle. Prior to using parametric tests, we tested for normality using a Kolmogorov-Smirnoff test. If this failed, nonparametric distributions were compared with a Wilcoxon rank sum test or Kruskal-Wallis ANOVA on ranks test. Within-group comparisons from baseline to 9 months employed t tests or Wilcoxon rank sum tests. Between-group comparisons used analysis of variance (ANOVA), with Dunnett’s test for assessment of individual differences. A chi-square analysis with Yates’ correction was used to compare categorical variables. All P values were based on a two-tailed distribution, and 95% confidence intervals (CI) were estimated.

      2. Results

      Fifty patients were enrolled according to the protocol guidelines. Forty-five patients completed all 9 months of study. The two treatment groups were similar in all major demographic features (Table 1). Eighteen subjects in the placebo group and 11 patients in the growth hormone group fulfilled modified criteria for the chronic fatigue syndrome [
      • Fukuda K
      • Straus SE
      • Hickie I
      The chronic fatigue syndrome a comprehensive approach to its definition and study.
      ]. Three patients in the growth hormone group were discontinued, 2 for medical reasons and 1 for noncompliance. Two patients receiving placebo were discontinued, 1 for medical reasons and 1 for noncompliance. There was an abrupt increase in IGF-1 levels within the first month in all 25 patients receiving growth hormone injections; this was sustained throughout the 9-month treatment period. The placebo group showed no increase in IGF-1 levels (Fig. 1). Antibodies to growth hormone were not found at any point during the study.
      Table 1Demographics of Patient Population
      Control GroupGrowth Hormone Group
      Number starting study2525
      Number finishing study2322
      Meeting criteria for CFS1811
      Age47.9 ± 6.646.5 ± 6.4
      Weight (kg)84.8 ± 15.884.0 ± 22
      Height (inches)64.8 ± 2.064.1 ± 2.9
      Initial IGF-1 level (ng/mL)106 ± 35100 ± 31
      Taking NSAIDs812
      Taking tricyclics911
      Taking estrogens1912
      CFS/chronic fatigue syndrome; IGF/insulin-like growth factor; NSAIDs/nonsteroidal antiinflammatory drugs.
      Figure thumbnail gr1
      Fig. 1Mean IGF-1 levels in patients tested with growth hormone or placebo.

      2.1 Between-Group Analysis

      There was a significant improvement in the growth hormone treated group compared with the placebo group (Fig. 2) at the 9-month evaluation for both the Fibromyalgia Impact Questionnaire Score (P <0.04) and the fibromyalgia trigger point score (P <0.03). The mean differences in questionnaire scores (growth hormone - placebo) were −2.7 (95% CI: −10.5 to +5.1) at baseline, −7.8 (95% CI: −16.8 to +1.2) at 3 months, −4.1 (95% CI: −9.8 to +8.4) at 6 months, and −8.5 (95% CI: −18.0 to −1.1) at 9 months. The mean differences in tender point scores were +1.7 (95% CI: +3.0 to −0.34) at baseline, −0.04 (95% CI: −1.8 to −1.7) at 3 months, −1.8 (95% CI: −4.7 to +1.1) at 6 months, and 3.3 (95% CI: −6.1 to −0.4) at 9 months.
      Figure thumbnail gr2
      Fig. 2Mean (SD) scores on the Fibromyalgia Impact Questionnaire (graph A) and the number of fibromyalgia tender points (graph B) in patients treated with growth hormone or placebo. Scores at 9 months are significantly different (P <0.05) in the two groups.

      2.2 Within-Group Analysis

      The growth hormone group achieved a significant improvement between baseline and 9 months in the Fibromyalgia Impact Questionnaire score of −13.8 (95% CI: −5.3 to −22.3); the mean change in the tender point score was −4.5 (95% CI: −0.21 to −6.8). The placebo subjects failed to achieve a significant improvement between baseline and 9 months (Table 2). Fifteen subjects in the growth hormone group and 6 in the control group experienced a worthwhile global improvement at the end of the study (P <0.02).
      Table 2Change in Primary Outcome Measures from Baseline to Finish
      BaselineFinishP value
      Placebo Group
      FIQ52.7 ± 14.346.6 ± 17.80.19
      T. point16.12 ± 3.2316.48 ± 4.760.76
      Growth hormone group
      FIQ50.0 ± 13.136.2 ± 16.60.0025
      T. point17.79 ± 0.8313.26 ± 5.710.0037
      FIQ/fibromyalgia impact questionnaire (range 0–100); T. point/tender point score (range 0–18).
      Eleven patients in the growth hormone group and 18 patients in the placebo group also fulfilled criteria for the chronic fatigue syndrome. The mean change in tender points between baseline and 9 months in the growth hormone group was 5.5 (95% CI: −2.3 to −8.7, P = 0.002). In the placebo group the mean change was −1.8 (95% CI: −4.7 to +1.1, P = 0.222). There was a nonsignificant improvement in the Fibromyalgia Impact Questionnaire score in the growth hormone group (P = 0.08) compared with the placebo group (P = 0.1).

      2.3 Adverse Reactions

      No unexpected adverse reactions that could be attributed to the growth hormone injections were encountered. Two patients in the growth hormone group who had to discontinue the study for serious problems (a sciatic nerve tumor and cardiomyopathy) had early symptoms of these problems prior to entering the study. There were no significant changes in weight, blood pressure, or glucose levels in patients taking growth hormone. Carpal tunnel symptoms occurred in 7 growth hormone patients compared with 1 control. Symptoms were treated by lowering the dose of growth hormone and the provision of night-time wrist splints. They were usually seen in the early stages of therapy; none of the growth hormone treated patients were experiencing carpal tunnel symptoms at the end of the study.

      3. Discussion

      We assessed the efficacy of recombinant human growth hormone in the treatment of fibromyalgia patients. The treated group experienced significant improvement after 9 months of treatment in symptoms, as measured by the Fibromyalgia Impact Questionnaire, and signs, as measured by the tender point score. No patient had a complete remission of symptoms, although several patients experienced an impressive improvement in their functional ability. In general there was a lag of about 6 months before patients started to note improvement. It is probably pertinent that the reported effects of growth hormone on improving muscle strength and exercise performance describe a benefit at about 3 months, with progressive improvements thereafter [
      • Cuneo RC
      • Salomon F
      • Wiles CM
      • et al.
      Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance.
      ,
      • Cuneo RC
      • Salomon F
      • Wiles CM
      • et al.
      Growth hormone treatment in growth hormone-deficient adults. I. Effects on muscle mass and strength.
      ]. Such a time course would be unusual for a placebo response.
      The beneficial changes that patients remarked upon were not precisely captured by the standard fibromyalgia outcome measures used in this study. A common observation was an initial increased sense of well-being followed by the ability to sustain increased levels of activity without the usual increase in muscle pain. All patients who experienced improvement with growth hormone experienced a reversion of symptoms over a period of 1 to 3 months after stopping growth hormone treatment. However, this observation must be interpreted with caution, as the posttreatment period was not blinded.
      Growth hormone therapy in adults has been reported to improve quality of life and energy level [
      • McGauley GA
      • Cuneo RC
      • Salomon F
      • Sönksen PH
      Psychological well-being before and after growth hormone treatment in adults with growth hormone deficiency.
      ], enhance cognitive psychometric performance [
      • Almqvist O
      • Thoren M
      • Saaf M
      • Eriksson O
      Effects of growth hormone substitution on mental performance in adults with growth hormone deficiency a pilot study.
      ], augment stroke volume [
      • Shahi M
      • Beshyah SA
      • Hackett D
      • et al.
      Cardiac function and structure in growth hormone deficiency.
      ], and improve exercise capacity and muscle strength [
      • Cuneo RC
      • Salomon F
      • Wiles CM
      • et al.
      Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance.
      ,
      • Cuneo RC
      • Salomon F
      • Wiles CM
      • et al.
      Growth hormone treatment in growth hormone-deficient adults. I. Effects on muscle mass and strength.
      ]. Formal testing has shown that the many patients with fibromyalgia have an impaired exercise capacity [
      • Jacobsen S
      • Danneskiold-Samsë B
      Dynamic muscular endurance in primary fibromyalgia compared with chronic myofascial pain syndrome.
      ]and low aerobic fitness [
      • Bennett RM
      • Clark SR
      • Goldberg L
      • et al.
      Aerobic fitness in patients with fibrositis. A controlled study of respiratory gas exchange and 133xenon clearance from exercising muscle.
      ], and thus the beneficial effects on work capacity that were subjectively reported by many patients on growth hormone in the current study may have a physiological explanation. Most patients with fibromyalgia report flares of pain in muscles that have been overused. It has been suggested that this is the result of muscle microtrauma [
      • Bennett RM
      The contribution of muscle to the generation of fibromyalgia symptomatology.
      ]—the usual cause of postexertional pain [
      • Armstrong RB
      • Warren GL
      • Warren JA
      Mechanisms of exercise-induced muscle fibre injury.
      ]. However, this pain is exaggerated in fibromyalgia, both in terms of severity and the period for recovery. We have hypothesized that the prolonged recovery of muscle microtrauma in patients with fibromyalgia would be worsened by growth hormone deficiency [
      • 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.
      ]. The results of this study lend some support to this notion.
      Growth hormone deficiency in fibromyalgia appears to be an epiphenomenon that occurs in a subset of patients secondary to hypothalamic-pituitary secretory dysfunction [
      • Bennett RM
      • Cook D
      • Clark SR
      • et al.
      Hypothalamic-pituitary-insulin-like growth factor-1 axis dysfunction in patients with fibromyalgia.
      ]. An analogous “stress”-related disturbance of growth hormone secretion has recently been described in abused children [
      • Skuse D
      • Albanese A
      • Stanhope R
      • et al.
      A new stress-related syndrome of growth failure and hyperphagia in children, associated with reversibility of growth-hormone insufficiency.
      ]. We hypothesize that suboptimal growth hormone secretion in patients with fibromyalgia adversely affects the symptoms of fatigue, poor exercise tolerance, dysthymia, and postexertional muscle pain. Because 1 month of therapy with growth hormone costs about $1,500, the cost-benefit ratio prohibits its use in the treatment of patients with fibromyalgia and low levels of IGF-1.

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