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Low levels of somatomedin C in patients with the fibromyalgia syndrome. A possible link between sleep and muscle pain

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Arthritis & Rheumatism
Official Journal of the American College of Rheumatology
LOW LEVELS OF SOMATOMEDIN C IN PATIENTS
WITH THE FIBROMYALGIA SYNDROME
A Possible Link Between Sleep and Muscle Pain
ROBERT M. BENNETT, SHARON R. CLARK, STEPHEN M. CAMPBELL,
and CAROL S. BURCKHARDT
Objective. Fibromyalgia is a common syndrome
of musculoskeletal pain and fatigue. Lacking distinctive
tissue or laboratory correlations, it has often been
considered a form of “psychogenic rheumatism.’’ In the
present study, the notion that the stage4 sleep anomaly
typically seen in the fibromyalgia syndrome may disrupt
growth hormone secretion was tested. Because growth
hormone has a very short half-life, serum levels of
somatomedin C were measured; somatomedin C is the
major mediator of growth hormone’s anabolic actions
and is a prerequisite for normal muscle homeostasis.
Methods. Serum levels of somatomedin C were
measured in 70 female fibromyalgia patients and 55
healthy controls, using a peptide-specific radioimmunoassay.
Results. Significantly lower levels of somatomedin C were observed in the fibromyalgia patients compared with controls (mean 2 SD 124.7 f 47 ng/ml
versus 175.2 2 60 ng/ml; P = 0.OoooOl). These results
could not be explained by concomitant therapy or by
weight, and in a subset of 21 patients in whom this was
From the Division of Arthritis and Rheumatic Diseases,
Oregon Health Sciences University, Portland, Oregon.
Robert M. Bennett, MD, FRCP, FACP: Professor of Medicine and Chairman, Division of Arthritis and Rheumatic Diseases;
Sharon R. Clark, PhD: Assistant Professor of Medicine and Research; Stephen M. Campbell, MD: Associate Professor of Medicine; Carol S. Burckhardt, PhD: Assistant Professor of Medicine
and Research.
Address correspondence to Robert M. Bennett, MD,
FRCP, FACP, Department of Medicine, L329A, Oregon Health
Sciences University, Portland, OR 97201.
Submitted for publication January 14, 1992; accepted in
revised form June 2, 1992.
investigated, there was no correlation with various
indices of disease activity.
Conclusion. These findings indicate that there is a
distinctive disruption of the growth hormonmmatomedin C neuroendocrine axis in a majority of fibromyalgia patients. It is hypothesized that this abnormality may explain the link between disturbed sleep and
predisposition to muscle pain.
The fibromyalgia syndrome is a common cause
of difEuse musculoskeletal pain (1). Its pathogenesis is
obscure; distinctive tissue changes have not been
described, and laboratory findings are usually normal.
In the past, the term “psychogenic rheumatism” was
often used to describe these patients, because of the
confusing history of multiple somatic complaints, absence of physical findings, and normal results on
laboratory tests. Over the last decade, rheumatologists
have become increasingly aware of the large number of
such patients, characterizedby the consistent features of
the medical history, as well as the finding of tender areas
in specific locations and absence of tenderness in other
locations (2,3). In 1990, the American College of Rheumatology published guidelines for establishing a diagnosis of fibromyalgia (4), and a recent assessment of
rheumatology manpower needs cited fibromyalgia as
being second only to rheumatoid arthritis as a reason for
office visits to rheumatologists (5).
A seminal finding in the study of fibromyalgia
was reported by Moldofsky et al in 1975, when they
described a distinctive disturbance of stage-4 sleep
characterized by alpha-wave intrusion into the normal
Arthritis and Rheumatism, Vol. 35, No. 10 (October 1992)
1113
1114
BENNETT ET AL
Table 1. Demographic characteristics of the fibromyalgia patients
and controls*
Patients
Female/male
Mean 2 SD age, years
Mean f SD weight, lb
Mean f SD duration of fibromyalgia,
years
No. taking HCAs
No. taking NSAIDs
* HCAs
(n = 70)
Controls
(n = 55)t
7010
47.6 k 10
160 f 37.6
11.6 f 6.9
5510
45.6 % 13
NA
NA
27
36
NA
NA
= heterocyclic antidepressants; NSAIDs
antiinflammatory drugs.
t NA = not available.
=
nonsteroidal
delta rhythm (6). Induction of this sleep abnormality in
healthy volunteers produced a transient syndrome
similar to fibromyalgia (7). Many metabolic, endocrine, and immune functions follow distinctive diurnal
rhythms. Stage-4 sleep is closely related to the pulsatile secretion of growth hormone; -80% of the total
daily production of growth hormone is secreted during
this stage of sleep (8). Since growth hormone plays a
critical role in muscle homeostasis and repair, it was of
interest to investigate whether its secretion in patients
with the fibromyalgia syndrome is compromised by the
stage-4 sleep disturbance. The present study compared serum levels of somatomedin C, a growth hormone-related peptide, in female fibromyalgia patients
and age-matched controls.
PATIENTS AND METHODS
Seventy female patients with the fibromyalgia syndrome were compared with 55 age-matched female controls.
The diagnosis of fibromyalgia was made in accordance with
the American College of Rheumatology criteria (4). The 55
controls comprised 43 blood donors from the Portland Red
Cross and 12 laboratory employees. All of the controls were
reportedly in good health and not taking any medications.
Blood samples were obtained between 1O:OO A M and
4:OO PM, from consecutive patients attending the Oregon
Health Sciences University Fibromyalgia Treatment Program. The blood was allowed to clot and the serum was
harvested and frozen; samples were kept frozen during
shipment. Serum somatomedin C levels were assayed by
Endocrine Sciences (Calabasas Hills, CA), using a radioimmunoassay that employs a rabbit antiserum directed against
a synthetic segment of the protein (amino acids 57-70). Prior
to assay, each sample was acid extracted from serum to
minimize errors due to the presence of somatomedin binding
proteins: 1 part of serum was extracted once with 87.5%
ethanol plus 2N formic acid. The resulting supernatant (100
pl) was diluted in 900 pl of buffer (30 mM phosphate, 10 mM
EDTA, 0.25% bovine serum albumin, pH 7.3, and 200 pl
was incubated with lZSI-labeled synthetic peptide encompassing amino acids 53-70, as previously described (9).
The interassay coefficient of variation was 7.3%, and
the intraassay coefficient of variation was 5.4%. Statistical
analysis of the differences between fibromyalgia patients and
controls was performed using Student’s 2-tailed t-test. The
contribution of age, weight, and duration of illness to somatomedin C levels was assessed by multiple regression
analysis.
RESULTS
Characteristics of the fibromyalgia patients and
controls are shown in Table 1, and somatomedin C
values for patients and controls are shown in Figure 1.
The mean ? SD somatomedin C levels in fibromyalgia
patients and controls were 124.7 ? 47 ng/ml and 175.2
? 60 ng/ml, respectively; this difference was highly
significant (P = 0.000001, by Student’s t-test).
Regression analysis indicated that age accounted for 14% of the variance in somatomedin C
levels in the control group, whereas in the fibromyalgia
group, age accounted for 7% of the variance. The
duration of fibromyalgia accounted for <1% of the
variance. Twenty-seven patients were taking low-dose
tricyclic antidepressant medication to improve sleep
and 43 were not; the mean somatomedin C values in
these 2 groups were 129.4 ng/ml and 120.1 ng/ml,
respectively (P = 0.54). Thirty-six patients were tak-
350
n=55
-
n
E
300
5
250
0
\
m
n=70
0
.t
200
i
U
Q)
E
150
0
+
E
100
0
v,
50
0
0
Patients
Controls
Figure 1. Box plot of somatomedin C values in fibromyalgia patients compared with age- and sex-matched controls. Boxes encompass the twenty-fifth through seventy-fifth percentile, with a horizontal line at the mean value. Bars represent the tenth and ninetieth
percentiles; individual dots represent values outside the tenth and
ninetieth percentiles. Somatomedin C values in the patient group
(mean f SD 124.7 4 47 ng/ml) were significantly lower than in the
control group (175.2 f 60 nglml) ( P = 0.000001).
SOMATOMEDIN C IN FIBROMYALGIA
1115
ing nonsteroidal antiinflammatory drugs and 34 were
not; their respective mean somatomedin C levels were
132.1 ng/ml and 117.5 ng/ml (P = 0.47). The average
weight of the fibromyalgia patients was 160 lb (SD
37.6); there was no significant correlation between
somatomedin C levels and weight (r = -0.24). In a
subset of 21 patients who had completed the Fibromyalgia Impact Questionnaire (lo), analog scores for
depression, anxiety, fatigue, impaired sleep, stiffness,
pain, number of tender points, and total myalgic score
were analyzed for possible correlations with somatomedin C levels; no significant correlations were
found.
exertional muscle pain and profound fatigue. In 1
study, >80% of patients with fibromyalgia were found
to be anaerobically unfit, as assessed by their maximum oxygen uptake upon exercising to volitional
exhaustion (13). A lack of regular physical exercise
may be a factor contributing to the low levels of
somatomedin C observed in some fibromyalgia patients.
The observation that fibromyalgia patients have
an alphddelta sleep anomaly and that the induction of
this sleep anomaly causes a fibromyalgia-like syndrome in healthy volunteers has been a major stimulus
for renewed interest in the relationship between sleep
disorders and fibromyalgia (1 1). The physiologic link
between disrupted stage-4 sleep and musculoskeletal
pain has been obscure, but the findings reported herein
suggest one plausible hypothesis. Growth hormone is
an anabolic peptide which stimulates increased synthesis of DNA, RNA, and proteins; this effect is
mediated via its stimulation of somatomedin C secretion by the liver. In adults, the growth hormonesomatomedin C axis has been shown to be important in
muscle homeostasis (14,15); therapeutic administration
of growth hormone has recently been shown to reverse
muscle loss associated with the aging process (16).
Most fibromyalgia patients locate the site of
their pain to muscle and typically report having increased pain after exertion. There is a large body of
evidence that links postexertional pain to muscle microtrauma (17-19), and it has been hypothesized that
the musculoskeletal pain in fibromyalgia has a similar
origin (1 1,20). This paradigm predicts that patients
with the fibromyalgia syndrome are either peculiarly
susceptible to muscle microtrauma at very low levels
of exertion, or have a defect in the repair processes
that normally lead to resolution of muscle microtrauma (21).
It is proposed that in some fibromyalgia patients, persistent disruption of growth hormone secretion either predisposes to muscle microtrauma and/or
impairs the normal healing of muscle microtrauma, as
a result of reduced anabolic stimulation due to chronically low levels of somatomedin C. Such a hypothesis
is in accord with Jacobsen et al’s finding of somewhat
lower levels of serum type I11 procollagen in fibromyalgia patients (22) and the dependence of procollagen I11
synthesis on adequate growth hormone production (23).
The recent report of fibromyalgia occurring after hypophysectomy (24) may also reflect such a mechanism.
Fibromyalgia causes much distress to the affected patients and often frustrates physicians, who
are unable to base therapy on any logical disease
pathology. Although the old designation of “psychogenic rheumatism” has been abandoned by most
practitioners, it is commonly believed that a maladapt-
DISCUSSION
A conspicuous feature of the fibromyalgia syndrome has been the absence of any consistent pathophysiologic picture. The results reported herein indicate that, as a group, fibromyalgia patients have
significantly lower serum levels of somatomedin C
than do healthy controls. The low values found in
some of the controls may be due to their having
fibromyalgia, assuming a commonly estimated prevalence of between 3% and 15% in the general population.
The rationale for measuring somatomedin C
levels was based on theoretical considerations: -80%
of growth hormone is produced during stage-4 sleep,
and it was hypothesized that the alpha/delta sleep
anomaly, which occurs during -60% of stage-4 sleep
in patients with fibromyalgia, would disrupt the nocturnal secretion of growth hormone (11). The low
levels of somatomedin C reported here may indeed
result from such a mechanism; however, further studies measuring the continuous secretion of growth
hormone in relation to sleep stages would be needed in
order to confirm this.
A previous study measured growth hormone
levels in fibromyalgia patients, with samples taken at
8:OO AM and 4:OO PM; no differences were found
between patients with fibromyalgia and patients with
rheumatoid arthritis (12). Since growth hormone has a
half-life of only 30 minutes, that study would not have
detected reduced nocturnal secretion. Somatomedin C
has a half-life of -20 hours, and its serum level is
considered to reflect the integrated secretion of growth
hormone (8). The other major stimuli for growth
hormone release are hypoglycemia, starvation, consumption of large amounts of protein, elevated levels
of circulating amino acids, surgical trauma, and other
acute stresses, such as exercise. A progressive diminution of regular exercise is commonly encountered in
patients with the fibromyalgia syndrome, due to post-
1116
BENNETT ET AL
ive response to stress plays some poorly defined role
in pathogenesis of the disease. The findings in this
study provide some preliminary insight into a psychoneuro-endocrine dysfunction which may be relevant to
understanding the mind-body relationship in this enigmatic disorder.
ACKNOWLEDGMENTS
We thank Dr. Mark Stene of Endocrine Sciences for
his counsel during the preparation of this manuscript. We are
indebted to P. Gierke and the nursing staff of the Portland
Red Cross for providing serum samples from blood donors.
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