Is further evaluation for growth hormone (GH) deficiency necessary in fibromyalgia patients with low serum insulin-like growth factor (IGF)-I levels?

Growth Hormone & IGF Research 17 (2007) 82–88 www.elsevier.com/locate/ghir

Is further evaluation for growth hormone (GH) deficiency necessary in fibromyalgia patients with low serum insulin-like growth factor (IGF)-I levels? Kevin C.J. Yuen a,*, Robert M. Bennett b, Cheryl A. Hryciw b, Marie B. Cook a, Sharon A. Rhoads a, David M. Cook a a

Department of Endocrinology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Mailcode L607, Portland, OR 97239-3098, USA b Department of Rheumatology, Oregon Health and Science University, Portland, OR 97239-3098, USA Received 9 November 2006; revised 12 December 2006; accepted 15 December 2006 Available online 6 February 2007

Abstract Objective: Fibromyalgia (FM) is characterized by diffuse pain, fatigue, and sleep disturbances; symptoms that resemble the adult growth hormone (GH) deficiency syndrome. Many FM patients have low serum GH levels, with a hypothesized aetiology of dysregulated GH/insulin-like growth factor (IGF)-I axis. The aim of this study was to assess the GH reserve in FM patients with low serum IGF-I levels using the GH-releasing hormone (GHRH)-arginine test. Design: We retrospectively reviewed the GHRH-arginine data of 77 FM patients with low serum IGF-I levels referred to our tertiary unit over a 4-year period. Results: Of the 77 FM patients, 13 patients (17%) failed the GHRH-arginine test. Further evaluation with pituitary imaging revealed normal pituitary glands (n = 7), coincident microadenomas (n = 4), empty sella (n = 1) and pituitary cyst (n = 1), and relevant medical histories such as previous head injury (n = 4), Sheehan’s syndrome (n = 1), and whiplash injury (n = 1). In contrast, the remaining 64 patients (83%) that responded to the GHRH-arginine test demonstrated higher peak GH levels compared to age and BMI-matched controls (n = 24). Conclusion: Our data shows that a subpopulation of FM patients with low serum IGF-I levels will fail the GHRH-arginine test. We, thus, recommend that the GH reserve of these patients should be evaluated further, as GH replacement may potentially improve the symptomatology of those with true GH deficiency. Additionally, the increased GH response rates to GHRH-arginine stimulation in the majority of FM patients with low serum IGF-I levels further supports the hypothesis of a dysregulated GH/IGF-I axis in the pathophysiology of FM. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Fibromyalgia; Growth hormone; Insulin-like growth factor-I; Growth hormone releasing hormone; Arginine

1. Introduction Fibromyalgia (FM) is a painful debilitating clinical syndrome of nonarticular origin, characterized by dif*

Corresponding author. Tel.: +1 503 494 0175; fax: +1 503 494 6990. E-mail address: [email protected] (K.C.J. Yuen). 1096-6374/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ghir.2006.12.006

fuse pain, fatigue and sleep disturbances, without any other objective findings on clinical examination. Using the American College of Rheumatology diagnostic criteria [1], FM has an estimated prevalence in one community of approximately 2% [2], and up to 20% at rheumatology out-patient clinics [3]. This disease predominantly affects women approaching their fifth decade and beyond [1].

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Although the aetiology of FM is unclear, it has been proposed that the low serum GH levels in these patients is due to the impairment in pituitary GH secretion secondary to a state of altered neurosecretory regulation of GH-releasing hormone (GHRH) and somatostatin [4–9]. There is also increasing evidence that serum insulin-like growth factor (IGF)-I levels are reduced in a substantial number of FM patients [5,10–13]. In an analysis of serum IGF-I levels in 500 patients with FM and 152 age-matched patients without FM, we found that 85% of patients with FM had serum IGF-I levels below the 50th percentile of the control population, and 56% below the 20th percentile [12]. Interestingly, some of the symptomatology of FM overlap with those described in the adult GH deficiency syndrome, namely low energy, reduced exercise capacity, muscle weakness, impaired cognition and low mood [14,15]. This, thus, raises the question as to whether the GH reserve of FM patients with low serum IGF-I levels should be further evaluated for the possibility of concomitant GH deficiency. Because there is an increasing number of patients with FM that are being reported to have low serum IGF-I levels [5,10–13], the Rheumatology FM Outpatients Clinic at our institution [Oregon Health and Science University (OHSU) in Portland, OR, USA] has adopted the policy to routinely measure serum IGF-I levels in all FM patients referred to this clinic. Thus, the aim of this report was to review the results of the standardized GHRH-arginine test and clinical histories of FM patients with low serum IGF-I levels that were referred from the OHSU Rheumatology FM Out-patients Clinic to our unit (OHSU Department of Endocrinology) over a 4-year period for the further assessment of their GH reserve.

2. Subjects and methods 2.1. Subjects The OHSU Rheumatology FM Out-patients clinic is an academic referral clinic, led by one author (R.M.B.), and ran by a dedicated nurse practitioner (C.A.H.) devoted to the evaluation of patients referred from the primary and secondary care setting for fatigue, and diffuse muscle and joint pains. From January 1st 2002 to December 31st 2005, 523 patients (465 females) were referred to the OHSU Rheumatology FM Out-patients clinic, and 395 patients (378 females) were diagnosed with FM using the American College of Rheumatology diagnostic criteria [1]. The American College of Rheumatology diagnostic criteria defines FM primarily in terms of pain. Namely, they mandate a history of 3 months or more of chronic widespread pain (involving at least three out of four quadrants

83

of the body) accompanied by tenderness in at least 11 out of 18 ‘‘tender points’’ upon digital palpitation [1]. Serum IGF-I levels were measured in all of those patients diagnosed with FM, and 77 patients [74 females; age (mean ± SE) 49.5 ± 1.0 years] were found to have low serum IGF-I levels [mean IGF-I standard deviation score (SDS): 2.4 (range: 1.5 to 3.8)], with 45 patients with IGF-I SDS < 2. Out of the 62 female FM patients with low serum IGF-I levels, 44 were menopausal (19 were taking exogenous estrogens either orally or transdermally) and 18 were pre-menopausal. These patients were subsequently referred from the OHSU Rheumatology FM Out-patients clinic to the OHSU Department of Endocrinology to undergo GHRH-arginine testing for the assessment of the possibility of underlying GH deficiency on the basis of their low serum IGF-I levels. Although the insulin tolerance test is regarded as the gold standard test to assess GH reserve [16], many of the FM patients were unable to tolerate the test. Therefore, the combined GHRH-arginine test was used instead, as this test is considered by many to be the best diagnostic alternative to the insulin tolerance test [17,18]. In addition, this test also allowed us to assess the GH responses to exogenously administered GHRH and arginine, an inhibitor of hypothalamic somatostatin secretion. The lowest limit of GH response to an insulin tolerance test in normal subjects has been reported as 5.0 lg/L by some investigators [19,20]. Nevertheless, for the GHRH-arginine test, we chose a stringent criterion of 4.1 lg/L as the cutoff peak GH response to GHRHarginine because this value has been shown to demonstrate 95% sensitivity and 91% specificity with respect to the insulin tolerance test for diagnosing GH deficiency [21], and to minimize the misclassification of obese FM patients subjects as GH-deficient when this was not the case. We compared the GH responses of the FM patients with 24 control subjects matched for age (±5 years) and BMI (±2 kg/m2) status. The control subjects were subjects that we had previously recruited to participate in a previous study [21]. All of the control subjects were evaluated by one author (D.M.C.) to avoid including any subject with other underlying rheumatic disorders and were not on any other investigational drugs within 6 months of the study. The control subjects were healthy, and had undergone normal growth and development. The nine premenopausal female control subjects had a history of regular menses, whereas the remaining nine female control subjects were menopausal. The male control subjects had normal serum testosterone levels. Serum prolactin levels were normal in all control subjects. Approval of the study was obtained from the committee on human research at the OHSU, and all subjects provided written informed consent to participate in the study.

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2.2. GHRH-arginine protocol Following an overnight fast, subjects underwent i.v. GHRH-arginine [GHRH 1–29 (Geref, Serono, Inc., Norwell, MA] testing between 0800 and 0900 h. An indwelling catheter was inserted into a cubital vein and blood was sampled at the time of catheter insertion (0 min). Growth hormone-releasing-hormone (1 lg/kg) was then administered as an i.v. bolus, and i.v. arginine hydrochloride (30 g) was simultaneously infused from 0 to 30 min. Further blood samples were drawn at 30, 60, 90 and 120 min. 2.3. Laboratory methods Serum GH levels were measured by two-site radioimmunoassay with an intra-assay coefficient of variation (CV) of 4.4% (Corning, Inc. Nichols Institute Diagnostics, San Juan Capistrano, CA). The inter-assay CV was 6.6%, and the sensitivity of the assay was 0.05 lg/L. Serum IGF-I levels were measured by a double antibody RIA by Esoterix Laboratory Services, Inc., after ethanol extraction and with the addition of IGF-2 as a blocking agent. The assay sensitivity was 10 ng/ml, and the coefficient of variation was 5.4%. The normal IGF-I ranges provided by Esoterix Laboratory Services, Inc. for males was 281–510 lg/L in 18–20 years, 155–432 lg/L in 21– 30 years, 132–333 lg/L in 31–40 years, 121–237 lg/L in 41–50 years, 68–245 lg/L in 51–60 years, 60–220 lg/ L in 61–70 years and 36–238 lg/L in 71–80 years, whereas for females was 217–475 lg/L in 18–20 years, 87–368 lg/L in 21–30 years, 106–368 lg/L in 31–40 years, 118–298 lg/L in 41–50 years, 53–287 lg/L in 51–60 years, 75–283 lg/L in 61–70 years and 54– 205 lg/L in 71–80 years. 2.4. Calculations The IGF-I SDS was calculated in relation to age-specific values according to the formula: (patient IGF-I value minus mean of control group)/standard deviation of control group [22]. The SDS would be expected to have a mean of 0 and an SD of 1.0; thus, the lower 2.5th percentile would be expected to be 2.0. The GH area under the curve (AUC) was calculated using the trapezoidal method. Body mass index was calculated by dividing a subject’s weight (in kilograms) by the square of their height (in meters). 2.5. Statistical analysis All statistical analyses were performed using SPSS for Windows (version 10.0, SPSS, Chicago, IL). Distributions of residuals were examined for normality by graphical methods. Where the residuals were not normally distributed, logarithmic transformation was

applied, or non-parametric methods such as the Mann–Whitney test were used, where appropriate. For normally distributed residuals, the Student’s unpaired t-test was used. Correlations were sought using Pearson’s test and P-values <0.05 was considered statistically significant.

3. Results 3.1. Characteristics of the FM patients that failed the GHRH-arginine test The rate of failure in response to the combined GHRH-arginine test was 17% (13 out of 77 patients) in the FM group, whereas no subject from the control group failed the GHRH-arginine test using a stringent peak GH cutoff of 4.1 lg/L. There were no significant differences in the serum IGF-I levels and IGF-I SDS values between the FM patients that failed compared to those that responded to the GHRH-arginine test. The FM patients that failed the GHRH-arginine test were subsequently evaluated further and the detailed characteristics, magnetic resonance pituitary imaging, endocrine medications and other relevant historical data are presented in Table 1. 3.2. Characteristics and biochemical parameters of the FM patients responding to the GHRH-arginine test Of the 77 FM patients with low serum IGF-I levels tested, 64 patients (83%) were found to respond to the GHRH-arginine test (evoked peak GH levels > 4.1 lg/ L). The characteristics of these FM patients and control subjects are displayed in Table 2. The two groups of subjects were well-matched for age, weight and BMI. Serum IGF-I levels and IGF-I SDS values were significantly lower in the FM patients compared to the control group (Table 2). Following GHRH-arginine stimulation, significant increases in evoked peak GH levels and the GH AUC response were observed in the FM patients compared to control group (Table 2 and Fig. 1). However, we did not observe any correlation between serum IGF-I levels to the GH responses to GHRH-arginine stimulation.

4. Discussion To our knowledge, this is the first study to evaluate the GH rates of response to a standardized method of GHRH-arginine testing in FM patients with low serum IGF-I levels. Our study had two primary objectives. Firstly, this study was aimed at determining the proportion of FM patients with low serum IGF-I levels that failed the GHRH-arginine stimulation test. Secondly,

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Table 1 Characteristics and further evaluation of the patients with FM and low serum IGF-I levels that failed the GHRH-arginine test Age (years) Gender

BMI (kg/m2)

IGF-I (lg/L)

Peak GH (lg/L)

Subsequent pituitary imaging

Endocrine medications subsequently started

Comments

1

66F

36.1

46

2.6

1.5

Empty sella

Thyroxine

61

3.3

2.3

Normal

–

29.5

67

3.9

2.5

Normal

Testosterone

47F

33.9

64

3.2

4.0

Normal

–

5

44F

36.4

89

2.6

4.0

Normal

Thyroxine

6

74F

36.9

69

1.6

2.3

Microadenoma

–

7 8

57F 53F

35.5 33.5

57 68

1.9 1.7

4.0 2.6

Microadenoma Microadenoma

– Thyroxine

9 10

53F 61F

31.0 34.1

33 42

2.3 2.6

3.7 0.8

Normal Normal

– –

11

47F

29.5

87

2.7

1.5

Microadenoma

12

38F

30.8

94

2.2

4.0

Pituitary cyst

Thyroxine, progesterone cream –

13

50F

27.2

43

2.6

2.8

Normal

–

Persistent fatigue, 2° hypothyroidism History of Sheehan’s (first child), persistent fatigue, depression Hypogonadotrophic hypogonadism History of head injury, secondary amenorrhoea (aged 39) History of head injury, type 2 diabetes, persistent fatigue, 1° hypothyroidism History of head injury (twice), type 2 diabetes – Type 2 diabetes, 1° hypothyroidism History of head injury History of head injury, type 2 diabetes History of head injury, type 2 diabetes, persistent fatigue, 2° hypothyroidism Oligomenorrhoea (started aged 36), type 2 diabetes, depression History of whiplash injury

2

45F

30.5

3

45M

4

Patient number

IGF-I SDS

1°, primary; 2°, secondary; F, female; M, male; BMI, body mass index; IGF-I, insulin-like growth factor-I; IGF-I SDS, insulin-like growth factor-I standard deviation score; GH, growth hormone.

Table 2 Characteristics of the FM patients that responded to the GHRHarginine test, and control subjects

Gender (males/females) Age (years) Weight (kg) BMI (kg/m2) IGF-I (lg/L) IGF-I SDS Peak GH (lg/L) GH AUC (lg/L/120 min)

FM (n = 64)

Controls (n = 24)

2/62 48.9 ± 1.0 81.2 ± 2.2 29.8 ± 0.8 69.8 ± 3.2* 2.4 ± 0.1* 25.2 ± 2.4a 1758.3 ± 168.8a

6/18 48.5 ± 2.4 85.0 ± 3.1 30.4 ± 1.0 111.5 ± 5.3 1.7 ± 0.1 15.5 ± 1.7 1066.2 ± 127.3

with low serum IGF-I levels who fail the GHRH-arginine test should be considered for further evaluation of their GH reserve, particularly given the close overlap of clinical features of FM with the adult GH deficiency syndrome. The GH Research Society Consensus Guidelines [23] and more recently, the American Endocrine Society Clinical Practice Guidelines [24] have mandated that the diagnosis of adult GH deficiency has to be

30

Data are presented as mean ± SEM, except for gender. * P < 0.01. a P < 0.005 vs. controls subjects. GH (ng/mL)

as the pathogenesis of FM is thought to be related to an altered state of neuroendocrine regulation of pituitary GH secretion, this study simultaneously examined the GH responses of FM patients with low serum IGF-I levels to GHRH-arginine stimulation. Our results demonstrated that approximately 17% of FM patients with low serum IGF-I levels failed the GHRH-arginine test using a stringent cutoff peak GH level of 4.1 lg/L [21], implying that a significant proportion of such subjects may have concomitant GH deficiency. Thus, these findings imply that FM patients

FM Controls 20 GHRH/arginine infusion

10

0 0

30

60

90

120

Time (minutes)

Fig. 1. Plasma GH levels at multiple time points following GHRHarginine stimulation in patients with FM (n = 64) and control subjects (n = 24). Data are presented as mean ± SEM.

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defined biochemically first by provocative testing using the insulin tolerance test, or in patients with contraindications to the insulin tolerance test, an alternative test such as the GHRH-arginine test before being eligible for GH replacement. Therefore, if these FM patients are proven to be truly GH-deficient with a second abnormal provocation test, it might then be possible that these patients may benefit from a trial of GH replacement that might improve some, if not all, of the symptoms such as decreased quality of life and energy levels, reduced exercise capacity, muscle weakness, and impaired cognition [14,15]. The GHRH-arginine test has been shown to compare well with the insulin tolerance test in diagnosing GH deficiency [21], and has been considered as a reasonable alternative test [17,18]. The combined GHRH-arginine test has been demonstrated to be a highly reliable and reproducible provocative test in the evaluation of the maximal secretory capacity of somatotrope cells [21] and in distinguishing normal subjects from GH-deficient patients in adulthood [17]. It, however, remains unknown whether the GHRH-arginine is comparable to the insulin tolerance test in patients with FM, but because the GHRH-arginine test poses less risk and discomfort to the patient, and has been shown to be reliable in other populations to detect GH deficiency [17,21], this test was therefore chosen. Nevertheless, further studies are required to determine the best threshold to define the GH response rates to the GHRH-arginine test in the FM population. In keeping with the proposed hypothesis of altered neuroendocrine function of the GH/IGF-I axis in FM patients, we also found that, despite their low serum IGF-I levels, a large proportion of our cohort of patients (83%) demonstrated exuberant GH responses to GHRH-arginine stimulation when compared to healthy control subjects matched for age and BMI. This hypothesis has been put forward by many investigators [4–8] in an attempt to explain the aetiology of the FM syndrome. Some investigators have hypothesised that this neuroendocrine defect is related to the augmentation of the hypothalamic somatostatin tone in reducing pituitary GH secretion [9,13,25–27], while others have suggested abnormalities of other neurotransmitters, namely serotonin, neuropeptide Y and corticotropinreleasing hormone [7]. Nevertheless, the principal finding in many of these studies was of significantly diminished serum GH levels and concomitantly reduced serum IGF-I levels. However, there are also some studies that do not confirm these findings [28–31]. Denko et al. demonstrated elevations of basal serum GH levels, but comparable serum IGF-I levels with the control group implying a degree of hepatic GH resistance in their study cohort [28]. However, the FM patients in that study had other co-morbid complications such as depression and osteoarthritis that may have contributed

to the altered circulating serum GH levels. In addition, that study also reported elevated fasting insulin levels raising the possibility that those patients may have underlying insulin resistance and increased adiposity, which may account for the underlying hepatic GH resistance; all of which are important factors in modulating overall circulating GH and IGF-I levels [32–34]. Further evidence that hepatic GH resistance is an unlikely phenomenon in FM patients is provided by Leal-Cerro et al., where they reported marked increases in serum IGF-I and IGFBP-3 levels after 4 days of treatment with a conventional GH dose of 2 IU/day (0.67 mg/day), suggesting that GH responsiveness at target tissues is preserved in this patient group [4]. Potential limitations of our study design must also be considered. The patients with FM and low serum IGF-I levels were highly selected, as they were recruited from an academic tertiary clinic. As such, we cannot ensure that our sample of patients is representative of the whole population of community-dwelling men and women of all ages who suffer from FM since not every patient is referred to or consults a rheumatologist. In addition, the observation that the control subjects had relatively low serum IGF-I levels may be explained by the fact that many of the controls had low to moderate daily activity levels. Finally, we were unable to obtain data from FM patients with normal serum IGF-I levels for comparison because, given their normal serum IGF-I levels, these patients were not referred to us by the rheumatologists at our institution for further endocrinological evaluation of their GH reserve. In summary, we have found that a subpopulation of FM patients presenting with low serum IGF-I levels will fail the GHRH-arginine test, and that the diagnosis of GH deficiency should be entertained in these patients, especially when accompanied by other hormonal deficiencies, a suggestive history and/or the presence of structural pituitary disease. We therefore recommend that physicians looking after patients with FM routinely measure serum IGF-I levels and to undertake further evaluation of the GH reserve in those found to have low or low/normal serum IGF-I levels (based on the appropriate sex- and age-related IGF-I reference ranges). The opportunity to diagnose GH deficiency in FM patients with low serum IGF-I levels should be addressed so that the patient has a chance of being offered GH replacement, which may potentially improve the overall symptomatology of those with true GH deficiency. By contrast, whether GH treatment can be routinely advocated for those FM patients with low serum IGF-I levels that exhibit exuberant GH responses to GHRH-arginine stimulation is yet to be fully elucidated although to date, there is one published study that has reported positive effects of GH treatment in improving pain and overall symptomatology in this patient group [35]. Furthermore, the exuberant GH responses to

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GHRH-arginine stimulation observed in the majority of the FM patients in our series lends further support to the hypothesis of disordered hypothalamic regulation of the GH/IGF-I axis being involved in the pathogenesis of FM.

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Acknowledgements K.C.J.Y. is supported by research grants from Pfizer Inc. and the Growth Hormone and IGF Research Society Fellowship.

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