Download Impaired Growth Hormone Secretion in Fibromyalgia Patients

ARTHRITIS & RHEUMATISM
Vol. 46, No. 5, May 2002, pp 1344–1350
DOI 10.1002/art.10209
© 2002, American College of Rheumatology
Impaired Growth Hormone Secretion in Fibromyalgia Patients
Evidence for Augmented Hypothalamic Somatostatin Tone
Eduardo S. Paiva, Atul Deodhar, Kim D. Jones, and Robert Bennett
Objective. To determine whether female fibromyalgia (FM) patients exhibit a normal growth hormone
(GH) response to an acute exercise stressor, and to
assess the importance of somatostatin tone in the
generation of this GH response.
Methods. Twenty female FM patients were compared with 10 healthy female controls. All subjects
exercised to volitional exhaustion on a treadmill. A
standard metabolic cart was used to monitor pulse,
blood pressure, electrocardiography, oxygen uptake,
carbon dioxide output, anaerobic threshold, and maximal workload. Blood was drawn for GH and cortisol
measurements 1 hour before exercise, immediately before exercise, immediately after exercise, and 1 hour
after exercise. One month later, testing that was exactly
similar was performed, except all subjects were given
pyridostigmine bromide (Mestinon; 30 mg orally) 1
hour before exercise.
Results. Compared with controls, FM patients
failed to exhibit a GH or cortisol response to acute
exercise (P ⴝ 0.003). After administration of pyridostigmine, 1 hour before exercise, the GH levels of FM
patients increased 8-fold (P ⴝ 0.001), to a value comparable with that of controls. Pyridostigmine did not
increase the cortisol response to exercise in FM patients. Pyridostigmine alone did not stimulate GH secretion in FM patients, nor did it improve exerciseinduced GH secretion in controls. FM patients with
normal insulin-like growth factor 1 (IGF-1) levels had
an impaired GH response to exercise.
Conclusion. Three new findings are reported: 1)
FM patients have a reduced GH response to exercise, 2)
pyridostigmine reverses this impaired response, and 3)
defective GH secretion in FM can occur in patients with
normal IGF-1 levels. Because pyridostigmine is known
to reduce somatostatin tone, it is surmised that the
defective GH response to exercise in FM patients probably results from increased levels of somatostatin, a
hypothalamic hormone that inhibits GH secretion.
Fibromyalgia (FM) is a common clinical syndrome characterized by widespread musculoskeletal
pain, with a high prevalence both in the general population and among patients attending rheumatology clinics (1–4). Increasing evidence implicates a perturbation
in the central mechanisms of sensory processing as being
relevant to understanding the pain component of FM
(5–7). Fibromyalgia is more than a state of chronic
musculoskeletal pain, however, because most FM patients also experience fatigue, poor sleep, visceral pain
(e.g., irritable bowel or bladder), exercise intolerance,
and neurologic symptoms (e.g., dizziness, numbness,
tingling) (8).
A theoretical model explaining the complexity of
FM symptoms has been proposed, which links dysregulation of neuroendocrine/stress/pain mechanisms to disordered sleep–wake physiology (5). This evolving paradigm promotes the notion that FM is a stress-related
syndrome, in which a disordered hypothalamic–
pituitary–adrenal (HPA) axis acts as a final common
pathway linking FM to other stress-related somatic and
psychiatric syndromes (7,9,10). The HPA and the HP–
growth hormone (GH) axis are closely linked in terms of
the opposing influences of corticotropin-releasing hormone and somatostatin on GH secretion (11).
Defective GH secretion in FM was initially surmised based on the finding of low levels of insulin-like
growth factor 1 (IGF-1; somatomedin C) in a subset of
Supported by USPHS grant 5-M01-RR-00334.
Eduardo S. Paiva, MD, Atul Deodhar, MD, MRCP, Kim D.
Jones, PhD, RN, Robert Bennett, MD, FRCP: Oregon Health Sciences University, Portland.
Address correspondence and reprint requests to Robert M.
Bennett, MD, Department of Medicine (OP09), Oregon Health
Sciences University, Portland, OR 97201.
Submitted for publication June 5, 2001; accepted in revised
form December 5, 2001.
1344
GH RESPONSE TO EXERCISE IN FEMALE FM PATIENTS
FM patients (12–14). It was originally hypothesized that
GH production in FM patients would be impaired
because such production occurs predominantly during
stages 3 and 4 of non–rapid eye movement sleep (12),
which is disrupted in many FM patients (15). In the
current study, the hypothesis was that an increased level
of somatostatin is related to impaired GH secretion in
FM patients. To test this hypothesis, the exercisestimulated GH response in female FM patients and
healthy controls was evaluated both before and after
administration of pyridostigmine (a potent cholinergic
agent). The rationale for this pharmacologic manipulation was the observation that increased cholinergic activity stimulates GH release by inhibiting hypothalamic
somatostatin tone (16). Thus, an improvement in
exercise-stimulated GH secretion after administration of
pyridostigmine would suggest that FM patients have
increased hypothalamic somatostatin tone.
SUBJECTS AND METHODS
Twenty women with a diagnosis of FM based on the
1990 American College of Rheumatology criteria (3) were
recruited from a database of FM patients at Oregon Health
Sciences University (OHSU). All patients were 18–60 years of
age and were assessed for the following exclusion criteria:
angina, uncontrolled hypertension, chronic obstructive pulmonary disease, hypothyroidism, severe depression, previous pituitary disease or surgery, and pregnancy. Using the same
exclusion criteria, 10 healthy women were selected as controls.
Other than sex, there were no specific selection criteria for
either group. All subjects gave informed consent, and the
OHSU review board approved the study.
Each subject underwent a treadmill test, using the
modified Balke protocol (17). They exercised to the point of
volitional exhaustion, which was defined when either of 2 goals
was reached: 1) respiratory rate (RR) index (anaerobic threshold) of 1.0, indicative of anaerobic metabolism, or 2) exhaustion (Borg) scale value of 10 (maximum perceived effort).
Electrocardiography and blood pressure monitoring were performed every 5 minutes. All testing was performed between
10:00 AM and 2:00 PM. Blood was collected through an indwelling catheter 1 hour before exercise, immediately before exercise (time 0), immediately after exercise, and 1 hour after the
end of exercise. GH and cortisol levels were measured at each
time point. IGF-1 levels were measured 1 hour before the first
treadmill test. Subjects were given a second treadmill test
within at least 1 month of the first test. This second test was
identical to the first, except all subjects were given 30 mg orally
of pyridostigmine bromide (Mestinon) 1 hour before exercise.
IGF-1 was measured by immunoradiometric assay
(Diagnostic Systems Laboratories, Webster, TX). The sensitivity of this assay is 0.80 ng/ml; the mean intra-assay coefficient
of variation (CV) is 2.6%, and the mean inter-assay CV is
4.5%. Human GH was measured by a noncompetitive chemiluminescence assay (Diagnostic Products, Los Angeles, CA).
Sensitivity of this assay is 0.01 ng/ml; the mean intra-assay CV
1345
Table 1.
Baseline characteristics of the patients and controls*
Age, years
Weight, kg
Body mass index
VO2max, ml/kg/minute
RER at VO2max
Total exercise work, watts
IGF-1, ng/ml
Resting GH, ng/ml
Resting cortisol, ng/ml
% pre/postmenopausal
% taking HRT
Fibromyalgia
(n ⫽ 21)
Controls
(n ⫽ 10)
44.6 ⫾ 8.2
80.8 ⫾ 16†
29.05 ⫾ 5.3
18.6 ⫾ 4.8
1.20 ⫾ 0.11
144 ⫾ 51
189 ⫾ 83
0.66 ⫾ 2.1
7.7 ⫾ 3.3
52/48
30
47.0 ⫾ 47
68.3 ⫾ 13
25.9 ⫾ 4.6
18.7 ⫾ 4.4
1.18 ⫾ 0.06
138 ⫾ 36
170.8 ⫾ 50
0.74 ⫾ 1.49
8.6 ⫾ 3.0
62/38
25
* Unless indicated otherwise, values are the mean ⫾ SD. VO2max ⫽
maximum volume of oxygen utilization; RER ⫽ respiratory exchange
ratio; IGF-1 ⫽ insulin-like growth factor 1; GH ⫽ growth hormone;
HRT ⫽ hormone replacement therapy.
† P ⫽ 0.043 versus controls.
is 6.0%, and the mean inter-assay CV is 5.8%. Cortisol was
measured by a competitive chemiluminescence assay (Nichols
Institute Diagnostics, San Juan Capristano, CA). Sensitivity of
this assay is 0.80 ng/ml; the mean intra-assay CV is 4.2%, and
the mean inter-assay CV is 7.9%.
Statistical analysis was performed with SigmaStat software (1995; Jandel Corporation, San Rafael, CA). Mean
changes were compared using a t-test or Mann-Whitney rank
sum test. Within-group changes were compared with a paired
t-test or Wilcoxon’s signed rank test. Categorical data were
analyzed using a 2 ⫻ 2 contingency table with Fisher’s exact
test (because some values were ⬍5). All analyses of significance used a 2-tail distribution.
RESULTS
Baseline characteristics of the FM patients and
controls (Table 1) were comparable, except the mean
weight of FM patients was 12.5 kg greater than that of
controls (P ⫽ 0.043). However, there was no significant
difference in body mass index (BMI) between the 2
groups. All participants were able to reach an anaerobic
threshold at maximal exertion. There was no difference
in the maximal mean values of respiratory exchange
ratio, workload, or oxygen uptake (VO2max) between
FM patients and controls. The mean IGF-1 and resting
GH levels were not significantly different between the 2
groups.
After exercising to volitional exhaustion, the
healthy controls exhibited an increase in GH, from a
mean ⫾ SD of 0.74 ⫾ 1.49 ng/ml before exercise to a
mean ⫾ SD of 6.2 ⫾ 6.1 ng/ml after exercise (P ⫽ 0.003).
This increase was not influenced by pyridostigmine (P ⫽
0.21) (Figure 1). Only 1 control subject did not demonstrate an exercise-induced increase in GH. This subject
1346
had a low IGF-1 level (74 ng/ml), and although she did
not have FM, she was presumed to have physiologic GH
deficiency, because she exhibited a 40-fold increase in
GH after administration of pyridostigmine followed by
exercise.
Eleven of 20 FM patients exhibited no exerciseinduced increase in GH level. Compared with controls,
FM patients had a significantly reduced response to
exercise (P ⫽ 0.017 by Fisher’s exact test) (Figure 1). On
the whole, FM patients had a very modest exerciseinduced change in GH levels, with a mean ⫾ SD
increase of 0.66 ⫾ 2.1 ng/ml at time 0 to a mean ⫾ SD
of 1.66 ⫾ 2.75 ng/ml (P ⫽ 0.20) 1 hour after exercise
(Figure 2). These results cannot be attributed to the
greater mean weight of the FM patients, because there
was no correlation between GH response and weight or
BMI. However, following administration of pyridostigmine, 19 of 20 FM patients exhibited an exerciseinduced increase in GH.
Overall, after administration of pyridostigmine,
GH in FM patients increased from a mean ⫾ SD of
0.57 ⫾ 0.82 ng/ml to a mean ⫾ SD of 4.7 ⫾ 3.8 ng/ml
(P ⫽ 0.001) (Figure 2). This increase in GH was 8-fold
higher than that associated with exercise stimulation
without pyridostigmine and was similar to the increase
seen in healthy controls. This result cannot be explained
by the fact that the FM patients exercised to a greater
intensity with the pyridostigmine protocol, because their
maximal workload was only slightly increased (mean ⫾
Figure 1. Individual peak growth hormone (GH) responses for the 4
study groups. Each pair of symbols connected by a line represents the
values for an individual subject from the immediate preexercise time
and the immediate postexercise time.
PAIVA ET AL
Figure 2. Growth hormone (GH) levels in fibromyalgia (FM) patients
after exercise. Exercise alone failed to stimulate GH secretion in FM
patients, but administration of pyridostigmine bromide (30 mg orally)
1 hour before exercising normalized release of GH in these patients (P
⫽ 0.005). Values are the mean ⫾ SD.
SD 44 ⫾ 51 to 155 ⫾ 33 watts; P ⫽ 0.42), and all
achieved an RR index ⱖ1.0. Pyridostigmine without
exercise did not stimulate GH secretion after 1 hour
(Figure 2).
Backward stepwise regression analysis showed no
relationship between exercise-induced changes in GH
level and weight, BMI, VO2max, age, maximal workload
at volitional exhaustion, or resting GH level, in either
FM patients or controls. The presence of low levels of
IGF-1 at baseline did not predict postexercise levels of
GH in either group; this was true regardless of whether
the cutoff level for IGF-1 deficiency was age-adjusted or
predetermined.
Resting cortisol levels were not significantly different between FM patients and controls (Table 1).
Cortisol secretion was slightly reduced by exercise in FM
patients (mean ⫾ SD 7.7 ⫾ 3.3 ng/ml before and 7.4 ⫾
3.5 ng/ml after exercise; P ⫽ 0.77). Unlike the HP–GH
axis, the HPA axis response to exercise was not influenced by prior administration of pyridostigmine in FM
patients (1-hour postexercise value 6.2 ⫾ 3.3 ng/ml with
pyridostigmine treatment). Cortisol secretion was modestly increased by exercise in healthy controls (mean ⫾
SD 8.6 ⫾ 3.0 ng/ml before and 10.8 ⫾ 3.8 ng/ml after
exercise; P ⫽ 0.17). The postexercise cortisol level was
significantly higher in controls compared with FM patients (P ⫽ 0.02). There was no correlation between
GH RESPONSE TO EXERCISE IN FEMALE FM PATIENTS
postexercise GH levels and cortisol levels, either with or
without pyridostigmine.
DISCUSSION
This study provides 3 new pieces of information:
FM patients have a reduced GH response to exercise,
this impaired response is reversed by administration of
pyridostigmine, and defective GH secretion in FM patients can occur in the setting of a normal IGF-1 level.
Studies conducted during the past 10 years have demonstrated conflicting results regarding the serum levels
of IGF-1 in FM patients compared with those in control
subjects. In 4 studies, low levels of IGF-1 were observed
in FM patients (12–14,18), and in 4 other studies, no
difference between FM patients and controls was demonstrated (19–22). Furthermore, the current study
showed no significant difference in IGF-1 levels between
FM patients and controls.
The reasons for these conflicting results most
probably relate to the number of subjects studied. For
instance, Buchwald et al studied 27 FM patients and 15
controls; although there was no significant difference
between the mean IGF-1 levels of the 2 groups, ⬃20%
of the FM patients had low IGF-1 levels (19). In
contrast, investigators at our laboratory compared
IGF-1 levels in 500 FM patients and 152 controls (both
healthy individuals and patients with other rheumatic
diseases) and found a very significant (P ⫽
0.00000000001) reduction of IGF-1 levels in the FM
population (14). Many FM patients studied by the latter
group had normal IGF-1 levels, however, and it was
concluded that about one-third of FM patients have
probable GH deficiency.
The fact that the FM population in the current
study had mean IGF-1 levels similar to those of controls
is not, therefore, surprising, given the fact that we
studied only 20 FM patients and 10 controls. Other
studies have demonstrated low levels of GH in FM
patients (23,24), and reduced GH secretion has been
shown in various types of stimulation studies (13,14,24–
26). On balance, the literature to date supports the
notion that the HP–GH axis is dysfunctional in a subset
of FM patients.
GH is the only pituitary hormone that is under
the influence of both stimulatory and inhibitory hypothalamic hormones. The normal pulsatile secretion of
GH depends on the tonic balance of stimulatory growth
hormone–releasing hormone (GHRH) and inhibitory
somatostatin (27,28). Under normal circumstances, production of GH occurs only when secretion of GHRH
1347
takes place in the setting of low levels of somatostatin
tone. Many studies have shown that cholinergic stimulation with pyridostigmine reduces hypothalamic somatostatin tone, with a resultant up-regulation of GH
release (16,29,30). Both physiologic and pharmacologic
down-regulation of GH secretion is usually the result of
increased somatostatin tone (11). For instance, the
age-related decline in stimulated GH secretion is reversed by pyridostigmine (31,32). Exercise-induced stimulation of GH release is also blunted with aging and can
be reversed by administration of pyridostigmine (31,33).
The low levels of GH found in persons who are morbidly
obese are increased by pyridostigmine (34). The depressed GH secretion that occurs as a result of excessive
endogenous and exogenous corticosteroids is attributable to increased somatostatin tone and can be partially
reversed by pyridostigmine (35).
Thus, the results of the current study suggest that
hypothalamic somatostatin tone in FM patients is increased compared with that in age- and sex-matched
controls. The reason for this is not immediately clear,
but it is reasonable to hypothesize that there is a link
with the perturbations of the HPA axis that have been
reported in FM patients (36–38). According to this
scenario, the pleiotropic actions of corticotropinreleasing factor (CRF) are thought to play a major
controlling role. CRF is the major mediator of the
HPA/sympathetic response to both physical and psychological stressors. Some FM patients have reduced HPA
axis responsiveness to stressors in terms of cortisol
secretion, even though they have enhanced adrenocorticotropic hormone (ACTH) response to CRF
(37,39,40).
Increased GH secretion is the normal response to
an acute stressor (such as exercise). Thus, it might seem
paradoxical that a prolonged stress response could cause
impaired GH secretion. However, in his description of
the “general adaptation syndrome,” Hans Selye (41)
envisaged 3 stages to the stress response: 1) an alarm
reaction originates in the brain and spreads to the
pituitary, where increased production of ACTH stimulates the adrenal cortex to secrete glucocorticoids and
mineralocorticoids; 2) after prolonged exposure to the
stressor, a second stage develops during which there is
increasing secretion of corticosteroids (this is a regulatory physiologic response promoting survival processes
while inhibiting nonessential processes); 3) in the third
stage, an “exhaustion” ensues during which there is a
progressive decline in the adaptive response and an
increasing vulnerability to stress-related pathology. The
first 2 stages of the general adaptation syndrome are
1348
mediated by the stress-induced secretion of CRF (42).
However, prolonged CRF secretion eventually downregulates the density of CRF-1 receptors in the paraventricular nucleus of hypothalamus (43). Therefore, notwithstanding persistent CRF secretion, the physiologic
effects on cortisol secretion ultimately become blunted
(42); this is thought to be one mechanism by which the
third stage of the general adaptation syndrome is mediated.
A second mechanism by which chronic stress is
postulated to lead to a dysfunctional endocrine response is
up-regulation of somatostatin tone by increased levels of
CRF (13). A correlation between defective GH secretion
in FM and Selye’s third stage of the general adaptation
syndrome is intriguing but speculative. For instance, Neeck
and Riedel hypothesized that a stress-induced increase in
CRF is the common denominator linking the disturbed
HPA axis and reduced GH secretion in FM (36), the
critical link being the observation that CRF increases
hypothalamic somatostatin tone (44,45). On the other
hand, Torpy et al provided some evidence for a chronically reduced hypothalamic CRF tone and hypothesized
that low IGF-1 levels in FM are a consequence of
reduced GHRH secretion secondary to impaired nonadrenergic input (38). Van Denderen et al reported an
impaired adrenergic response to exhaustive exercise in
FM patients as well as a deficient cortisol response (as
was also shown in this study) (46), thus providing some
support for the reduced GHRH hypothesis.
The notion that an enhanced hypothalamic somatostatin tone results from increased CRF is not supported by the exaggerated response to CRF that has
been reported (37,47). This result would not be expected
in the setting of chronic oversecretion of CRF, because,
in general, there is a reciprocal relationship between
receptor density and the concentration of its cognate
ligand. However, the complexity of endocrine regulation
in terms of long, short, and ultrashort feedback loops,
changes in ligand-binding proteins, induced and inherited changes in receptor density/function, and permissive/
inhibitory effects of interacting hormones (e.g., the
potentiation of CRF-induced release of ACTH by vasopressin) does not permit any definitive conclusions to be
reached without performance of more sophisticated
experiments.
There are several examples of human stressrelated disorders other than FM in which patients
exhibit evidence of impaired cortisol secretion: chronic
pelvic pain syndrome (48), chronic fatigue syndrome
(CFS) (49), posttraumatic stress disorder (50), and
overtraining syndrome (51). All of these conditions are
PAIVA ET AL
characterized by an increase in central HPA function
with a paradoxical blunting of the adrenal cortisol
response. Whether the blunted cortisol response in FM
and these other conditions is a manifestation of central
changes or a primary adrenal insufficiency is not currently clear, but a preliminary report of a 50% reduction
in the size of the adrenal glands in patients with CFS
supports the latter explanation (52).
Thus, the concept has arisen that FM and some
other chronic disorders are characterized by a hypoactive stress response in terms of the HPA axis, GH axis,
gonadal axis, and thyroidal axis, together with reduced
sympathetic responses (13,36,53–55). This neuroendocrine dysfunction is often considered to be an epiphenomenon in the complex pathophysiology of FM
(6,14,36), e.g., a secondary response to the stress of
chronic pain and its association with human suffering.
This introduces a psycho-physiologic dimension into the
understanding of these hormonal perturbations, because
environmental and developmental factors interact with
genetic susceptibility in modulating an individual’s responses to chronic stressors (39,53,56–58).
In the current study, the defective GH secretion
in all FM patients, even those with normal IGF-1 levels,
was an unexpected finding. However, it is now apparent
that although a low level of IGF-1 is usually indicative of
adult GH deficiency (59), it is not a very sensitive
measure and will miss up to 60% of GH-deficient
patients older than age 40 years (60,61). The currently
favored test to diagnose adult GH deficiency is the
stimulated GH response to a combination of GHRH
and an inhibitor of somatostatin tone such as pyridostigmine, arginine, clonidine, or insulin (60). The results of
this study indicate that GH deficiency is probably more
common in FM patients than was originally reported.
Recognition of defective GH secretion in FM patients is
of some practical relevance, because GH replacement
therapy was shown to benefit FM patients in a 9-month
placebo-controlled study (62). It would, therefore, be of
interest to determine whether pyridostigmine could be
used to provide long-term improvement of growth hormone production in FM patients.
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