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Integrity of the Growth Hormone/Insulin-Like Growth Factor System Is Maintained in Patients with Chronic Fatigue Syndrome¹

Departments of Psychological Medicine (A.J.C.) and Medicine (S.S.S., J.J., J.P.M.), Guy’s King’s and St. Thomas’ School of Medicine, and the Institute of Psychiatry (A.J.C.), London, United Kingdom SE5 8AF; and Addenbrooke’s National Health Service Trust (V.O.), Cambridge CB2 2QQ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Anthony Cleare, Department of Psychological Medicine, Kings College School of Medicine and Dentistry and the Institute of Psychiatry, 103 Denmark Hill, London, United Kingdom SE5 8AF. E-mail: a.cleare{at}iop.kcl.ac.uk

	Abstract

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GH deficiency states and chronic fatigue syndrome (CFS) share several characteristics, and preliminary studies have revealed aspects of GH dysfunction in CFS. This study assessed indexes of GH function in 37 medication-free CFS patients without comorbid psychiatric illness and 37 matched healthy controls. We also assessed GH function before and after treatment with low dose hydrocortisone, which has been shown recently to reduce fatigue in CFS. We measured basal levels of serum insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2 and IGFBP-3 together with 24-h urinary GH excretion. We also performed 2 dynamic tests of GH function: a 100-µg GHRH test and an insulin stress test using 0.15 U/kg BW insulin. There were no differences between patients and controls in basal levels of IGF/IGFBP or in urinary GH excretion. GH responses to both the GHRH test and the insulin stress test were no different in patients and controls. CFS patients did have a marginally reduced suppression of IGFBP-1 during the insulin stress test. Hydrocortisone treatment had no significant effect on any of these parameters. There is no evidence of GH deficiency in CFS. At the doses used, hydrocortisone treatment appears to have little impact on GH function.

	Introduction

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CHRONIC FATIGUE syndrome (CFS) represents a major public health issue. It is a debilitating and disabling condition, with a prevalence of approximately 1% (1, 2). Research into the etiology of CFS suggests that it is multifactorial, with important contributions from several biological, psychological, and social factors (3). One model of CFS suggests that in predisposed individuals, including those with a history of past psychiatric illness, fatigue, or medically unexplained symptoms, certain insults, such as severe viral infections or life events, may precipitate the onset of severe fatigue. Many perpetuating factors can then be identified that are important in prolonging fatigue and associated disability. Although psychiatric comorbidity, principally depression, anxiety, and somatoform disorders, is certainly one of these, about one third of patients are free of any psychiatric illness. Cognitive-behavioral factors are also important; illness beliefs, coping strategies, and exercise patterns are powerful determinants of illness and of recovery.

Many attempts have been made to try to unravel the biological components of symptoms in CFS. Although biological factors may be important as both predisposing factors and precipitating factors (4), patients usually present to medical attention after several years of illness. Thus, the contribution of biological factors to illness perpetuation is potentially a more accessible area of study. Several important biological correlates of CFS have been found to date. In particular, neuroendocrine studies have revealed an increased hypothalamic response to serotonergic challenge (5, 6, 7, 8) and abnormal function of the hypothalamo-pituitary-adrenal axis with reduced circulating cortisol levels (5, 9, 10). This latter abnormality appears to contribute to the symptomatology, because randomized controlled trials report that some patients report an amelioration of fatigue with replacement doses of hydrocortisone (11, 12).

There have been few such studies of GH function in CFS. GH is a fruitful area for study given the known link between GH deficiency states and fatigue (13, 14, 15). Furthermore, the fatigue syndrome that characteristically occurs after major surgery can be markedly reduced by the use of human GH treatment (16). On a theoretical level, it is known that severe viral infections can precipitate CFS (17) and that some viruses can directly interfere with GH production (18). In a previous small study of 10 patients, we found some evidence of relative GH deficiency in CFS, with a reduced GH response to insulin-induced hypoglycemia and lowered basal insulin-like growth factor I (IGF-I), IGF-II, and IGF-binding protein-1 (IGFBP-1) levels compared to those in healthy controls (19). In contrast, two other studies found that basal IGF-I levels were normal (20) or increased (21) in CFS.

The purpose of this series of experiments was to undertake a thorough assessment of GH function in a group of carefully selected patients suffering from CFS without comorbid psychiatric disorder. We hypothesized that if abnormalities of GH function are important in the pathophysiology of CFS, then we would detect abnormalities in these tests.

	Materials and Methods

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Subjects

A total of 37 patients with CFS were recruited into the study from 218 consecutive referrals to CFS clinics at King’s College Hospital (London, UK) and Addenbrooke’s National Health Service Trust (Cambridge, UK). All patients had undergone thorough medical screening to exclude a detectable organic cause for their fatigue, including physical examination and relevant investigation, with a minimum of urinalysis; full blood count, urea, and electrolytes; thyroid function tests; liver function tests; 0900 h cortisol; and erythrocyte sedimentation rate. All patients were interviewed using a semistructured interview (22) for CFS and psychological disorder by a psychiatrist (A.J.C.). Included subjects had to fulfil both international consensus criteria for CFS (23, 24) and be free from comorbid psychiatric disorder as defined in the DSM-IV (25). Patients with an illness duration of more than 100 months were also excluded, as were those who also fulfilled criteria for fibromyalgia as defined by the American College of Rheumatology (26). These exclusions were intended to obtain as uniform and heterogeneous a sample as possible, minimizing comorbidity. All subjects were drug free for a minimum of 2 months before endocrine testing, with the exception of 3 patients using oral contraception or hormone replacement. Because of these stringent criteria, the sample represented less than 1 in 5 of our clinic attenders. Female patients were tested during days 1–7 of their menstrual cycle. The mean length of illness was 42 ± 35 months. Nine reported a past psychiatric history, and 22 had an infective onset of their symptoms.

A group of 37 control subjects was recruited from volunteers and staff members at our institutions. Patients and controls were carefully matched for sex, age, weight, body mass index (BMI), and menstrual status. Three of the female controls were selected to be using the same dose of estrogen as the patients. None of the controls had a history of significant medical problems, CFS, or DSM-IV psychiatric disorder. All procedures were approved by the institutional ethics committee. All patients and controls gave written informed consent.

Procedures

We measured baseline unstimulated serum levels of IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3 in all 37 subjects and controls. In addition, subgroups of subjects (those attending King’s College Hospital) underwent dynamic endocrine tests of GH function using 1) a GHRH stimulation test (15 patients and 15 controls), 2) an insulin stress test (IST; 16 patients and 16 controls), and 3) 24-h urinary GH output (15 patients and 15 controls). Ten subjects underwent both the IST and the GHRH test. Urine collection was carried out before any dynamic testing; the dynamic tests were undertaken at least 2 days apart. All patients were also taking part in a randomized controlled trial of hydrocortisone as a therapy for CFS, reported previously (11). We also report here the effects of hydrocortisone treatment on the different indexes of GH function.

Test protocols

Unstimulated serum samples. On their first visit to the laboratory, subjects were cannulated in a forearm vein, and after a 30-min relaxation period, blood was taken into plain tubes. These were allowed to clot before being spun down at 3000 x g for 10 min and then frozen at -20 C.

IST. Patients were fasted from midnight of the preceding day. On the day of testing, all subjects attended the hospital programmed investigation unit at 0900 h. An electrocardiogram was obtained to exclude significant cardiac abnormality. After this, an iv cannula was inserted into a forearm vein and sealed with a rubber bung. The cannula was kept patent throughout by the use of heparinized saline (1-mL bolus of 10 U heparin after each sample was drawn). After cannulation, subjects remained relaxed and semirecumbent throughout the procedure. After a rest period of 15 min, a -30 min sample was obtained, followed 0.5 h later by a 0 min sample. Insulin in a dose of 0.15 U/kg was given in a bolus via the cannula. Additional samples were drawn at 30, 60, 90, and 120 min for serum GH and IGFBP-1. Samples for IGF-I and IGF-II were taken at 0, 60, and 120 min, and samples for IGFBP-2 and IGFBP-3 were taken at 0 and 120 min. Serum was allowed to clot before separation and then was frozen at -20 C.

Blood sugar was monitored during the test at 0, 30, 45, 60, 90, and 120 min using a Glucostix monitor (Bayer PLC, Newbury, Berkshire, UK). More accurate analysis was carried out on stored samples in the laboratory. Patients were given 75 g oral glucose if they showed prolonged hypoglycemia on Glucostix testing or symptomatology. Two patients and three controls received glucose for this reason. Patients were given a full meal with a glucose drink after the end of the test.

All subjects completed a number of self-assessment scales. Fatigue was measured using the fatigue scale of Chalder et al. (27, 28), disability was measured using the Medical Outcomes Study short form 36 (29), psychological symptoms were measured using the General Health Questionnaire (30), and somatic symptoms were measured using the symptom checklist of 40 items (31).

GHRH test. Patients were fasted from midnight of the preceding day. On the day of testing, all subjects attended the hospital programmed investigation unit at 0900 h; cannulation was carried out as described for the insulin stress test. Samples for serum GH were taken at -30 and 0 min. GHRH was given in a bolus of 100 µg through the cannula at 0 min. Additional samples for serum GH measurements were taken at 15, 30, 45, 60, and 90 min after injection. Samples for IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3 were taken at 0 and 90 min. Serum was allowed to clot before separation and then was frozen at -20 C.

Urinary GH. Samples were collected into a plastic container with 0.1 g boric acid added as a preservative over 24 h. The times of first and last collections were noted.

Hydrocortisone therapy

Subjects received 28 days of active treatment or placebo before crossing over to receive the other treatment. The protocol was double blind. The dosage used was 5 mg in half the patients and 10 mg in the other half, taken as a single dose at 0900 h. As previously reported, active treatment led to a significant rise in urinary cortisol output, whereas approximately one third of patients derived significant clinical benefit from it (11). On the day of each test, subjects were instructed to omit the tablet until after testing had been completed.

Hormone assays

GH was measured using the NETRIA (North East Thames Region Immunoassay Unit) two-site immunoradiometric assay (IRMA) with an ¹²⁵I label. Intraassay coefficients of variation (CVs) were 2.7% at 0.8 mU/L, 2.4% at 4.5 mU/L, and 2.6% at 86.5 mU/L. Interassay CVs were 3.3% at 7.7 mU/L, 5.2% at 21.7 mU/L, and 5.5% at 45.8 mU/L. Sensitivity was 0.2 mU/L. IGF-I was assayed using an in-house RIA with acid/ethanol extraction. Intraassay CVs were 9.0% at 45 ng/mL, 6.5% at 243 ng/mL, and 4.7% at 698 ng/mL. Interassay CVs were 10.5% at 75 ng/mL, 10.1% at 196 ng/mL, and 5.1% at 698 ng/mL. Sensitivity was 13 ng/mL. IGF-II was assayed using an IRMA (Diagnostics Systems Laboratories, Inc., Webster, TX). Intraassay CVs were 4.3% at 63 ng/mL, 7.2% at 416 ng/mL, and 4.3% at 1585 ng/mL. Interassay CVs were 9.5% at 74 ng/mL, 6.3% at 427 ng/mL, and 10.4% at 1295 ng/mL. Sensitivity was 12 ng/mL. IGFBP-1 was assayed using an IRMA (Diagnostics Systems Laboratories, Inc.). Intraassay CVs were 5.2% at 5.2 ng/mL, 4.6% at 50.2 ng/mL, and 2.7% at 144.6 ng/mL. Interassay CVs were 3.5% at 5.1 ng/mL, 6.0% at 47 ng/mL, and 3.6% at 142 ng/mL. Sensitivity was 0.33 ng/mL. IGFBP-2 was assayed using an IRMA (Diagnostics Systems Laboratories, Inc.). Intraassay CVs were 8.5% at 13.0 ng/mL, 6.2% at 32.2 ng/mL, and 4.7% at 94.4 ng/mL. Interassay CVs were 7.4% at 2.7 ng/mL, 4.5% at 13.2 ng/mL, and 7.2% at 69.7 ng/mL. Sensitivity was 0.5 ng/mL. IGFBP-3 was assayed using an IRMA (Diagnostics Systems Laboratories, Inc.). Intraassay CVs were 1.8% at 82.7 ng/mL, 3.2% at 27.3 ng/mL, and 3.9% at 7.4 ng/mL. Interassay CVs were 1.9% at 76.9 ng/mL, 0.5% at 21.5 ng/mL, and 0.6% at 8.0 ng/mL. Sensitivity was 0.5 ng/mL. Urinary GH was measured using a previously described method (32). All samples from all tests were kept frozen and then assayed in one or two batches to reduce interassay variability.

Analysis

The maximal response to the challenges ( response) was calculated as the peak value minus the basal value (taken as the 0 min value). The areas under the curve (AUCs) for the GH responses were also calculated using the trapezoidal method on baseline corrected data. Statistical comparisons were made using independent t tests for parametric data on between-group comparisons and paired t tests on within-group comparisons. Nonparametric data were analyzed using a Mann-Whitney U test on between-group comparisons and a Wilcoxon test on within-group comparisons. Means are given with SDs, except for nonparametric data, where medians are used with interquartile ranges in parentheses. All calculations were made using SPSS for Windows (version 8.0, SPSS, Inc., Chicago, IL).

	Results

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The matching of patients and controls with regard to age, sex, weight, and BMI is shown in Table 1.

Table 2 shows the unstimulated serum measures of the different parameters at baseline in patients compared to matched controls. None of the values differed significantly between patients and controls.

The urinary GH values were skewed and not normally distributed; consequently, we used nonparametric statistics to analyze them. The total 24-h urinary output of GH in patients was 62.9 (33.0–117.9) pg/24 h, and that in controls was 74.8 (52.7–153.5) pg/24 h. This difference was not significant by Mann-Whitney U test (z = -1.22; P = 0.23). The mean volume of urine collected in 24 h did not differ between groups (patients, 1.62 L; controls, 1.69 L; t = 0.28; P = 0.79).

IST

All subjects became hypoglycemic after insulin administration, as defined by a plasma glucose level less than 2.2 mmol/L. The mean glucose at baseline was 4.0 ± 0.53 mmol/L in controls and 3.9 ± 0.43 mmol/L in patients (t = -0.58; P = 0.57), and that at the nadir was 1.0 ± 0.29 mmol/L in controls and 0.9 ± 0.30 mmol/L in patients (t = -1.06; P = 0.30).

Figure 1 shows the GH responses in patients and controls. The GH in patients was 79.1 ± 69.8 IU/L, and that in controls was 78.7 ± 54.9 IU/L, a nonsignificant difference (t = 0.015; P = 0.99). Similarly, the AUC GH did not differ between patients and controls, measuring 85.0 ± 86.7 IU/L·h in patients and 81.2 ± 64.1 IU/L·h in controls (t = 0.14; P = 0.89). No patients or controls met the laboratory cut-off point for a diagnosis of GH deficiency (peak GH response during IST, <10 IU/L).

View larger version (15K): [in this window] [in a new window]   Figure 1. Serum GH response to insulin (0.15 µg/kg BW)-induced hypoglycemia in 16 subjects with CFS (diamonds) and 16 healthy matched controls (circles). SEMs are shown.

View larger version (20K): [in this window] [in a new window]   Figure 2. Change from baseline in serum levels of IGFBP-1 during insulin (0.15 µg/kg BW)-induced hypoglycemia in 16 subjects with CFS (diamonds) and 16 healthy matched controls (circles). The inset box shows the maximal percent suppression from baseline in CFS (open box) and controls (shaded box) together with SEMs.

GHRH

The GH response to GHRH is shown in Fig. 3. Analysis of the GH and AUC GH values showed no significant difference between patients and controls. Because of a skewed distribution, nonparametric statistics were used. The median GH was 16.4 (11.1–60.5) IU/L in patients and 28.0 (11.3–52.8) IU/L in controls (z = -0.37; P = 0.71). The median AUC GH was 11.8 (6.8–48.4) IU/L·h in patients and 26.7 (9.1–47.3) IU/L·h in controls (z = -0.77; P = 0.46).

View larger version (15K): [in this window] [in a new window]   Figure 3. Serum GH response to GHRH (100 µg) in 15 subjects with CFS (diamonds) and 15 healthy matched controls (circles). SEMs are shown.

There were no observable effects of GHRH on IGFBP-2, IGFBP-3, IGF-I, or IGF-II at the time points studied.

Effect of hydrocortisone replacement therapy

Basal values of serum IGF-I and -II, and IGFBP-1, -2, and -3 are shown in Table 3 together with the effect of treatment with hydrocortisone or placebo. None of the values changed significantly after hydrocortisone therapy.

	Discussion

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As the GH response to IST is usually taken as the gold standard test of GH deficiency, these CFS patients were not GH deficient. This contrasts with our previous study of a totally separate group of patients that showed a reduced GH response to IST (19). There are several advantages of the present study, including a larger number of subjects and very close matching of patients and controls in age, sex, weight, and menstrual cycle phase, which was absent from the previous study. All of these factors could explain differences in the results of these two studies. Furthermore, one other recent study measured the GH response to the IST and found no difference between patients and controls (33). However, in the related syndrome of fibromyalgia, which shares many clinical (34) and endocrine (35) characteristics with CFS, one study has suggested a hyperreactivity of the GH axis, with enhanced GH responses to IST in a group of 10 patients (36).

We conclude from this set of experiments that there is no evidence for GH deficiency in CFS patients free from comorbid psychiatric illness. It may not be surprising, therefore, that recombinant human GH is not an effective treatment for CFS (37).

The GHRH test is a specific test of pituitary GH function and gives an indication of the pituitary reserve of GH. Our finding of an identical response in patients and controls suggests normal pituitary GH reserve and no abnormality of the GHRH receptors on the pituitary. We are not aware of any previous studies that performed the GHRH test in CFS patients. Other GH challenge tests that have been performed in CFS patients are indirect ones. Thus, Sharpe et al. (8) measured the GH response to the serotonergic partial agonist buspirone, which presumably acts at a hypothalamic level via serotonin 1A receptors. They found no difference in the GH response between CFS patients and controls, further evidence that hypothalamus-mediated GH release is normal in CFS. Another study found a reduced GH response to dexamethasone challenge in CFS, but the explanation for this was believed to be in the hypothalamo-pituitary-adrenal axis itself in the form of defective glucocorticoid receptors (38). Finally, Berwaerts et al. (33) did find a marginally reduced nocturnal secretion of GH in a group of 20 CFS patients, but noted that, given the high prevalence of sleep disturbance in CFS, it was not possible to ascribe this reduced nocturnal secretion of GH to a cause or effect of CFS.

Finally, the peripheral markers of GH activity we measured, IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3 levels, were all normal in CFS. This finding is also distinct from the results of our previous study. Again, reasons for this might include the methodological advances, including larger numbers and closer subject matching in the present study. Our findings also support the study of Buchwald et al. (20), which found that there is no alteration in IGF-I level in CFS, but are different from the report by Bennett et al. (21), who found elevated IGF-I in CFS. However, the samples in this latter study were not matched for weight or BMI, and the controls were not well characterized, being drawn from anonymous blood donors. Like us, Buchwald et al. (20) found no changes in IGFBP-3 levels in CFS, but we could not find reference to any other studies that measured IGF-II or the other binding proteins. Our finding of normal urinary GH levels in the subset of patients tested is consistent with the other measures.

We have previously reported a reduction in IGFBP-1 suppression in response to exogenously administered insulin in CFS (19). Normally, IGFBP-1 is regulated by insulin through direct effects on gene transcription (39, 40) and indirect effects on transcapillary movement out of the circulation (41). Although the direct effects of insulin are best seen in states of substrate availability (e.g. during euglycemic clamps) (42) we have previously shown in normal subjects an initial fall in IGFBP-1 followed by a counterregulatory rise in response to hypoglycemia (19). In the current study there was again a trend toward less insulin-mediated suppression of circulating IGFBP-1 (perhaps suggesting a degree of relative insulin resistance), although this did not reach significance.

There are a number of potential confounders in studies of GH function in CFS. First, there have been some studies suggesting that GH responses to GHRH challenge may be reduced in depression (43). For this reason, it was important to study only patients without comorbid depression, although the IST does not appear to be significantly affected in depression (44). It is also known that exercise and sleep exert a physiological effect on GH release (45); as both of these are disrupted in CFS, it remains impossible in cross-sectional studies to rule out any observed abnormalities being a consequence of illness.

Effects of glucocorticoids on GH

Essentially, we found little effect of low dose hydrocortisone on GH function in CFS. Although urinary GH release was significantly lower during hydrocortisone treatment, it was lower still in the placebo condition. The reasons for this fall in GH must therefore remain obscure; part of the reason may be the lower urinary volumes after the treatment period, reflecting less complete collections, although we did not measure creatinine concentrations to confirm this. In contrast to this general lack of effect of glucocorticoid treatment on GH responses, several previous studies have found significant effects of glucocorticoids on GH function in humans. However, these effects differ. For example, Miell et al. (46) explored the effects of 4-day treatment with 4 mg dexamethasone in divided doses. This resulted in a significant attenuation of the GH response to GHRH, a potentiation of the GH response to arginine, and increases in the basal levels of GH and IGF-I. Further work suggested that this dose of dexamethasone also leads to a suppression of IGFBP-1 and IGFBP-2, and an increase in IGFBP-3 (47). Other studies of the effects of intermediate term glucocorticoids on GH responses to various secretogogues suggest an attenuation of responses to arginine (48), insulin-induced hypoglycemia (49, 50, 51), and GHRH (52). Finally, there is much evidence that glucocorticoids can also have permissive effects on GH responses (53).

However, these studies use doses of glucocorticoids well in excess of those used in this study. Furthermore, hydrocortisone crosses the blood-brain barrier easily, whereas dexamethasone does not. There have not been studies using the doses we prescribed in this study. Because there was a small reduction in the GH response to GHRH after hydrocortisone treatment, albeit not significant, it is possible that this represents a type 2 error and that a larger group of patients would show a modest effect of hydrocortisone. Arguing against this, there was no suggestion of any attenuation of the GH response to the IST. We conclude that the doses of hydrocortisone used in this study do not have significant effects on the GH axis.

Conclusions

This series of dynamic and basal measurements of GH function in CFS suggests that there is no evidence of GH deficiency or significant dysregulation of the GH-IGF axis. Low doses of hydrocortisone treatment for 1 month do not appear to have a significant effect on GH function.

	Acknowledgments

 
We gratefully acknowledge the help of Serono Laboratories, Inc. (UK) Ltd., who supplied the GHRH (GEREF) preparations. These studies were carried out in collaboration with the Chronic Fatigue Syndrome Research Unit at King’s College Hospital, directed by Prof. Simon Wessely. We also thank Dorothy Blair, research nurse, Laura Young, endocrine nurse, and Yvonne McKenzie, endocrine nurse, for help in performing dynamic endocrine tests.

	Footnotes

 
¹ This work was supported by the Linbury Trust, who provided a project grant for the study and a Senior Research Fellowship (to A.J.C.), and by a Wellcome Trust fellowship (to J.P.M.).

Received September 20, 1999.

Revised December 8, 1999.

Accepted December 17, 1999.

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