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Hypothalamicpituitaryadrenal axis perturbations in patients with fibromyalgia.

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Number 11, November 1994, pp 1583-1592
0 1994, American College of Rheumatology
Objective. To examine basal and stimulated
hypothalamic-pituitary-adrenal (HPA) axis and related
hormone levels, including adrenocorticotropin (ACTH),
cortisol, arginine vasopressin (AVP), and neuropeptide
Y (NPY), in patients with fibromyalgia (FM).
Methods. Basal and ovine corticotropin-releasing
hormone (oCRH)-stimulated HPA axis function were
assessed in 12 patients with FM and in age- and sexmatched normal subjects. Basal plasma AVP levels and
AVP release after postural change were assessed, and
plasma NPY levels were measured in the same samples.
Results. Patients with FM had low 24-hour urinary free cortisol, but normal peak and elevated trough
plasma cortisol levels, compared with normal subjects.
The net integrated ACTH response to oCRH in FM was
not significantly different from that in normal subjects,
but tended toward an exaggerated response. There was
a significant decrease in net integrated cortisol response
to oCRH in FM patients, indicating adrenal hyporesponsiveness. AVP levels were not significantly different
between FM patients and control subjects, but variability was greater among the FM patients. Plasma NPY
levels were significantly lower in FM patients than in
normal subjects.
Leslie J. Crofford, MD: National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda,
Maryland (current address: University of Michigan, Ann Arbor);
Stanley R. Pillemer, MD: NIAMS, NIH; Konstantine T. Kalogeras,
MD: NIAMS, NIH; Joseph M. Cash, MD: NIAMS, NIH (current
address: Cleveland Clinic Foundation, Cleveland, Ohio); David
Michelson, MD: National Institute of Mental Health (NIMH), NIH;
Mitchel A. Kling, MD: NIMH, NIH; Esther M. Sternberg, MD:
NIMH, NIH; Philip W. Gold, MD: NIMH, NIH; George P. Chrousos, MD, PhD: National Institute of Child Health and Human
Development, NIH; Ronald L. Wilder, MD, PhD: NIAMS, NIH.
Address reprint requests to Leslie J. Crofford, MD, Department of Internal Medicine, Division of Rheumatology, University of
Michigan, 200 Zina Pitcher Place, R4570 Kresge I, Ann Arbor, MI
Submitted for publication February 28, 1994; accepted in
revised form June 12, 1994.
Conclusion. These data support the view that
HPA axis function is perturbed in patients with FM.
Further study is required to ascertain the cause of HPA
axis perturbations and their relationship to symptoms in
patients with FM.
Fibromyalgia (FM; fibrositis) is a syndrome of
widespread chronic pain that affects the musculoskeletal system. The American College of Rheumatology
(ACR) has developed diagnostic criteria for FM based
on identification of defined musculoskeletal tender
points (1). While pain is the hallmark of FM, there are
other common symptoms, including fatigue, morning
stiffness, sleep disturbance, headache, and paresthesias (2). Additionally, there are associated clinical
syndromes, particularly irritable bowel syndrome (1).
The high frequency of fatigue in patients with FM
suggests overlap with the chronic fatigue syndrome
(CFS) (3). Patients with CFS often have musculoskeletal discomfort, and recent studies have shown a high
prevalence of tender points in these patients (43).
Another clinical feature of FM is the association with stress. Several studies have found that
patients with FM have a greater frequency of psychological symptoms than do patients with rheumatoid
arthritis (6,7). Additionally, FM is associated with
stressful major life events or daily hassles (7,8). Dysregulation of the stress response can lead to abnormalities in both physical and behavioral adaptation that
may mimic the clinical symptoms of FM (9,lO).
The hypothalamic-pituitary-adrenal (HPA)
axis is central to the stress response. Regulation of the
HPA axis occurs primarily through modulation of
corticotropin-releasing hormone (CRH) synthesis and
release in the paraventricular nucleus of the hypothalamus (9). However, arginine vasopressin (AVP), the
other major adrenocorticotropin (ACTH) secretagogue, becomes an important modulator of HPA axis
function during conditions of chronic stress (11-13).
The other major stress axis, the sympathetic axis,
tends generally to act in conjunction with the HPA
axis, with activation of one leading to activation of the
other (9). Neuropeptide Y (NPY) co-localizes with
norepinephrine and is stimulated peripherally during
stress (14). Many other central nervous system centers
have neural connections with the hypothalamus, thus
contributing to the complexity of the regulation of
CRH synthesis and release (9). Additionally, CRH can
be regulated in response to peripheral substances,
including glucocorticoid-negative feedback and upregulation by cytokines such as interleukin-1,
interleukin-6, and tumor necrosis factor a (for review,
see ref. 9).
There are previous studies suggesting HPA axis
abnormalities in FM, including loss of diurnal variation of plasma cortisol (15), nonsuppression of cortisol
in response to dexamethasone (15,16), and hyperresponsiveness of ACTH to CRH or insulin stress,
with a relatively lower cortisol response (17). Other
neuroendocrinologic abnormalities have also been
described in patients with FM. In particular, Moldofsky and Warsh hypothesized that serotonin (5hydroxytryptamine), a neurotransmitter important in
the regulation of sleep and interpretation of pain, could
be low in the central nervous system of patients with
FM (18,19). Interestingly, serotonin is involved in both
the circadian pattern of CRH secretion and the stressinduced activation of the HPA axis (20-22).
In this study, we evaluated HPA axis function
in female patients with FM compared with agematched normal subjects. Twenty-four-hour urinary
free cortisol studies were done to assess the overall
function of the HPA axis. Blood samples for total and
free plasma cortisol were collected in the morning
and evening. Additionally, we evaluated the ACTH
and cortisol response to evening administration of
ovine CRH (oCRH). We also obtained plasma AVP
and NPY levels at baseline and in response to postural
Patients and controls. Twenty-one female patients
were screened for FM at the Clinical Center of the National
Institutes of Health (NIH) using the ACR criteria of widespread pain for at least 3 months and pain in 11 of 18 tender
point sites. Tender points were also quantitated by dolorimetry. The dolorimeter (pressure algometer; Chatillon, New
York, NY) scale measured 0-6.5kg of pressure; pain at 54.0
kg of pressure was considered tender (23).
Six patients did not meet ACR criteria at the time of
evaluation; 3 patients met criteria, but either had comorbid
illness requiring continued medication or could not complete
the study. Thus 12 patients with FM agreed to participate
and completed the study. No patient or control took medications within 2 weeks of the time of the study. Age-matched
normal female volunteers were recruited to participate in the
study. All normal subjects denied having musculoskeletal
pain, had few tender points, and were taking no medications.
The study protocol was approved by the NIH institutional review board for the study of human subjects. The
clinical characteristics of the patients and controls are listed
in Table 1.
At the initial screening, 11 of the 12 FM patients were
seen by a board-certified psychiatrist (DM or MAK) in a
psychiatric diagnostic interview to evaluate the presence or
absence of depression. Of these, 3 met the Diagnostic and
Statistical Manual of Mental Disorders, Third edition, Revised criteria for major depression. All analyses were performed including or excluding the depressed patients, and
there were no significant differences in the results. Therefore, the results reported include these patients.
Baseline and provocative neuroendocrine testing. Patients (n = 12) and normal subjects (n = 10) collected 3
consecutive 24-hour urine specimens to be analyzed for free
cortisol. On the day of provocative testing, all study subjects
fasted after 1400 hours. Subjects amved 2-3 hours prior to
the test, were placed in a reclining chair, and an intravenous
catheter was placed for serial blood sampling. Basal blood
sampling was performed at -120, -60, -30, -15, and 0
minutes. At 2000 hours, patients received 1 pglkg oCRH
intravenously. Blood was then collected at 5, 15, 30, 60,90,
120, 150,and 180 minutes after injection of oCRH.
Blood for AVP and NPY determinations in response
to postural change was collected after the patient had been
supine for 20 minutes (at - 100 minutes). Patients were then
asked to stand, and blood was drawn after 5 and 10 minutes.
Basal AVP levels were determined at -30 minutes and - 15
Seven of the 12 FM patients agreed to have morning
blood samples drawn, and 7 age-matched normal female
subjects were recruited. Subjects arrived at the clinical
center at 0700 hours, were placed in reclining chairs for 1
hour, and blood was collected at 0800 hours. Total and free
plasma cortisol levels were measured at 1900 hours (-60
Determination of cortisol and neuropeptide levels.
Urinary free cortisol levels were determined at the Clinical
Center Laboratory (NIH). Plasma total cortisol, free cortisol, and ACTH levels were measured by radioimmunoassay
as previously described (24).
For measurement of plasma AVP and NPY levels,
frozen plasma samples (1.8ml each) were thawed on ice and
acidified with 10 ml of 0.1N HC1. The acidified plasma
samples were centrifuged and applied to Sep-Pak C18 cartridges (Waters, Milford, MA), which had been activated
with 10 ml of acetonitrile (CH,CN) followed by 10 ml of 0.1N
HC1. The cartridges were then washed with 10 ml of 0.1%
trifluoroacetic acid (TFA) and 3 ml of 10% CH,CN in
0.1% TFA. The absorbed peptides were eluted with 4 ml of
80% CHJN in 0.1% TFA. The eluant was collected and the
Table 1. Clinical characteristics of study patients and controls*
Duration of
No. of tender
points (18
1 .o
6.2 f 3.1
Average dolorimetry
score (kg)
4.5 f 0.4t
2.4 f 0.2t
Fibromyalgia patients
Control subjects (n = 12)
Mean f SEM
39.5 ? 3.0
f 3.0
1.2 f 0.5
* Three control subjects without symptoms did not have dolorimetry performed.
t P < 0.001 versus controls.
solvent removed by means of a speed vacuum concentrator
(Savant, Farmingdale, NY).
The samples were reconstituted in 0.6 ml of assay
buffer, consisting of 10 mM monobasic and 81 mM dibasic
sodium phosphate (pH 7.4), 0.05M NaCl, 0.01% NaN,, 0.1%
bovine serum albumin, and 0.1% Triton X-100, and were
allowed to sit overnight at 4°C. The radioimmunoassay was
performed in polystyrene tubes by mixing 100 pl of sample in
duplicate (or standard in triplicate) and 100 pl of antiserum.
Synthetic (Arg')-vasopressin and NPY standards were purchased from Peninsula Laboratories (Belmont, CA). AntiAVP rabbit serum was obtained from Mitsubishi Petrochemical (Tokyo, Japan), and NPY antiserum was purchased
from Peninsula. The antiserum titers were 1:90,OOO and
1:12O,OOO for AVP and NPY, respectively. The standard
curve concentration range was 0.20-25 pg/ml for AVP and
39-10,OOO pglml for NPY.
After incubation for 48 hours at 4"C, 100 pl of
'251-labeled AVP (3,000 counts per minute) or NPY (5,OOO
cpm) (both from Amersham, Arlington Heights, IL) was
added to each tube, and the incubation continued for another
48 hours at 4°C. Bound and free fractions were then separated by adding 100 pl of goat anti-rabbit IgG serum and 100
pl of normal rabbit serum (Peninsula). The precipitates were
allowed to form overnight at 4"C, then 0.5 ml of assay buffer
was added. The precipitate was collected by centrifugation
at 1,700g for 20 minutes, and the supernatant was removed
by aspiration. The tubes were counted for Iz5I in a scintillation well gamma counter.
Recovery of AVP and NPY added to hormone-free
plasma was >75%. The lower limit of detection for the AVP
and NPY assays was 0.30 pglml and 25 pg/ml, respectively,
and half-maximal displacement of the tracer was 4.14 pglml
and 398 pglml, respectively. The intra- and interassay coefficients of variation of the AVP assay were 6.0% and 7.2% at
1.56pg/ml, 4.5% and 7.6% at 3.13 pglml, and 3.0% and 7.3%
at 6.25 pg/ml. The intra- and interassay coefficients of
variation of the NPY assay were 4.5% and 6.7% at 313 pg/ml,
5.6% and 8.9% at 625 pg/mI, and 4.7% and 9.2% at 1,250pglml.
!ci 250.-s 2005
0 150-
Table 2.
Total integrated response is the area under the curve from 0
to 180 minutes, and the net integrated response is the area
under the curve from 0 to 180 minutes minus the basal
integrated area under the curve.
Baseline cortisol levels in the study subjects
(mean 2
24-hour urinary free cortisol (nmoles) 116.1 2 15.4*
(n = 12)
AM plasma cortisol (nmoleshiter)
276.2 2 26.2
(n = 7)
40.0 2 14.6
(n = 7)
PM plasma cortisol (nmolesfliter)
300.7 60.7t
(n = 12)
22.1 2 7.2t
(n = 12)
Cortisol binding globulin ( d d l )
15.1 f 1.4
(n = 11)
(mean 2
195.9 ? 16.0
(n = 11)
283.3 & 31.7
(n = 7)
38.6 f 2.8
(n = 7)
138.0 2 22.1
(n = 12)
5.5 ? 0.8
(n = 12)
17.1 2 0.9
(n = 11)
* P < 0.002 versus controls.
t P < 0.04 versus controls.
Statistical analysis. Statistical comparisons were
made using Student’s t-test. For analysis of the oCRH
stimulation tests, basal levels were expressed as the mean of
5 time points from - 120 minutes to time 0, and peak levels
were the highest value reached for each individual. Stimulated pituitary and adrenal responses (0-180 minutes) were
integrated over time and expressed as area under the curve.
Basal cortisol levels. FM patients had significantly lower mean (3 collections per subject) 24-hour
urinary free cortisol levels than normal subjects (Figure 1 and Table 2). Total and free cortisol levels in
plasma collected in the evening, during the usual
cortisol trough, were both significantly elevated (P <
0.04) compared with controls; however, morning total
and free plasma cortisol levels, at the usual cortisol
peak, were not appreciably different from those of
normal subjects. Basal evening cortisol binding globulin levels were not different in FM patients compared
with controls (Table 2).
Ovine CRH stimulation test results. The
pituitary-adrenal response to oCRH was determined
at 2000 hours, during the normal diurnal cortisol
trough (Figures 2A and B and Table 3). Pretest sampling revealed significantly higher basal cortisol levels
in FM patients than in normal subjects (P < 0.02), and
nonsignificant elevations of basal ACTH levels. Peak
+ Fibromyalgia
2 500-
ACTH Response
Net Integrated
200 -
Cortisol Rasponst
Time (min)
0 ,
2 3
Time (min)
Figure 2. Ovine corticotropin-releasing hormone (oCRH)-stimulation test in 12 patients with fibromyalgia (FM) and in 12 normal subjects.
Subjects were placed in a reclining chair and an intravenous catheter was inserted for serial blood sampling; oCRH (1 pg/kg) was injected at
time 0. The net integrated response represents the stimulated area under the curve from 0 to 180 minutes minus the basal integrated area under
the curve. A, Adrenocorticotropin (ACTH) levels at baseline and after oCRH stimulation were not significantly different between groups;
however, there was a tendency toward higher ACTH levels in patients with FM. There was no difference in the net integrated ACTH response
between the 2 groups. B, Total cortisol levels were significantly higher in patients with FM at all basal time points. The net integrated cortisol
response was significantly lower in patients with FM. * = P < 0.05.
FM Control
FM Control
FM Control
Figure 3. Comparison of arginine vasopressin (AVP) levels after
postural stimulation in 12 patients with fibromyalgia (FM) and in 12
age- and sex-matched normal subjects. Subjects were supine for 20
minutes, and then stood upright, and blood was drawn after the
supine period and after 5 and 10 minutes upright. There were no
significant differences between the two groups; however, the patients with FM exhibited greater variability. Five FM patients had
stimulated AVP levels that were >2 SD higher than the highest
value attained by a control subject.
ACTH levels tended to be higher in FM patients, but
peak cortisol levels were not appreciably different
from those in control subjects. Total (ACTH producTable 3. Ovine corticotropin-releasing hormone stimulation test
results in 12 fibromyalgia patients and 12 controls
(mean f SEM)
(mean f SEM)
Plasma ACTH (pmoles/liter)*
3.0 f 1.0
1.4 f 0.2
14.3 f 4.0
8.2 t 1.3
11.3 f 3.0
7.3 2 1.2
Total integrated area
1,842 f 477
1,295 f 170
Net integrated area
892 f 175
885 f 121
Plasma cortisol (nmoleshiter)
221.9 f 5l.Ot
92.2 f 14.4
694.1 f 64.9
702.2 f 35.5
472.2 k 42.71
610.0 t 29.4
Total integrated area
124,120 f 15,768 103,044 f 6,893
Net integrated area
55,619 f 6,114t 74,376 ? 4,259
* ACTH = adrenocorticotropin.
t P < 0.02 versus controls.
< 0.01 versus controls.
tion from 0 to 180 minutes) and net (ACTH production
from 0 to 180 minutes minus basal production times
180 minutes) integrated ACTH responses to oCRH
were not different in FM patients compared with
controls. Total integrated cortisol responses were not
significantly different between the 2 groups, but the net
integrated cortisol responses were significantly lower
in FM patients than normal subjects (P < 0.02).
AVP determinations. Basal AVP levels were not
significantly different between FM patients and control
subjects (mean ? SEM 1.64 2 0.64 versus 1.11 & 0.10;
P = 0.21). Stimulatory testing for postural AVP
change was performed by having subjects remain
supine for 20 minutes, then standing and having blood
drawn after 5 and 10 minutes (Figure 3). There were no
significant differences in mean values between FM
patients and control subjects; however, 5 of the 12 FM
patients had markedly elevated AVP levels (more than
2 SD higher than the highest value attained by a
normal subject) after postural stimulation.
NPY determinations. Basal NPY levels were
significantly lower in patients with FM compared with
controls (mean & SEM 91.5 2 5.0 versus 131.2 5 8.7;
P < 0.001). NPY levels were affected by postural
change only in normal subjects after 10 minutes upright, compared with supine values (P < 0.03). NPY
levels were significantly lower in FM patients at all
determinations (Table 4).
Abnormalities of HPA axis function have been
associated with several clinical syndromes, some of
which have features in common with FM, including
chronic fatigue syndrome and atypical depression
(9,25). Our study shows that patients with FM have
perturbed HPA axis function, as determined by significantly 'lower 24-hour urinary free cortisol levels,
compared with that in controls, but elevated basal
Table 4. Plasma neuropeptide Y levels in 12 fibromyalgia patients
and 12 controls
Supine 20 minutes
Upright 5 minutes
Upright 10 minutes
(mean ? SEM)
(mean 2 SEM)
91.5 f 5.0
89.4 f 8.1
103.7 f 6.1
103.7 f 10.7
131.2 f 8.7
118.6 f 9.5
127.9 f 9.1
148.3 f 8.6
* Values are the mean f SEM pg/ml (n = 2 determinations).
evening (trough) cortisol levels, resulting in a loss of
the normal diurnal cortisol fluctuation. McCain and
Tilbe previously reported that patients with FM had
blunted diurnal variation of cortisol compared with
patients with rheumatoid arthritis (15). Their results,
similar to the results reported in this study, showed
normal peak cortisol levels and elevated trough levels.
Strikingly, those investigators also found low 24-hour
urinary free cortisol levels. They noted that abnormal
cortisol measurements were most prominent in patients with FM of long duration (>2 years). All of our
study patients had a duration of symptoms >1 year,
with a mean 2 SEM duration of 6.2 ? 3.1 years.
It is difficult to resolve the finding of low
24-hour urinary free cortisol, which reflects the timeintegrated plasma free cortisol concentrations over 24
hours, with the higher cortisol levels in the evening
and no differences in the morning cortisol levels compared with normal subjects. There are, however, possible explanations for these seemingly incongruous
results. The first is that plasma cortisol binding capacity might be higher in patients with FM, leading to low
free-cortisol levels with high total-cortisol levels. We
believe this explanation is unlikely since the comparative levels of free cortisols measured at the circadian
peak and trough times were not different from the total
cortisol levels. Additionally, cortisol binding globulin
measurements were not significantly different between
the 2 groups. Another factor to consider is that the low
24-hour urinary free cortisol level could be due to a
renal abnormality. We believe this is also unlikely
since our patients had normal urinary creatinine levels
and renal function abnormalities affect free cortisol
levels only when creatinine clearance falls below
20-50 muminute (26). Another possible explanation
hinges on the pulsatility of cortisol secretion. There
are normally 8-9 peaks of cortisol over a 24-hour
period, presumably in response to basal surges of
CRH and ACTH. In fibromyalgia, the height of the
cortisol peaks might be normal or even elevated, but
the frequency of the peaks could be decreased, resulting in a low cortisol output when examined over 24
In addition to basal cortisol testing, we performed stimulation testing of the HPA axis by injecting
oCRH and measuring subsequent changes in ACTH
and cortisol. Both ACTH and cortisol increased
briskly in response to oCRH. However, the net change
in cortisol after oCRH injection was significantly decreased compared with that in normal subjects ( P <
0.02). There were no statistically significant differ-
ences in oCRH-stimulated ACTH levels between patients with FM and control subjects in our study.
However, we did note nonsignificant trends toward
higher mean basal and oCRH-stimulated ACTH levels.
Griep and colleagues performed both oCRH
and insulin-induced hypoglycemia stimulation testing
of HPA axis function and found a significantly elevated ACTH response to both stimuli in patients with
FM (17). Their studies were performed in the morning,
at the peak of circadian ACTH levels when there was
no difference in basal peak cortisol levels compared
with controls. The elevated trough cortisol levels in
patients with FM as compared with normal subjects in
our study may have blunted the effect of oCRH on
ACTH. In support of this possibility, it has been
shown that pretreatment with dexamethasone attenuates the release of ACTH in response to CRH infusion
(27). Exaggerated ACTH responses, as shown by
Griep and colleagues (17), might be explained by an
increased pituitary content of proopiomelanocortinderived peptides. This hypothesis is supported by
animal studies of chronic stress paradigms that demonstrate increased anterior pituitary content of ACTH
in chronically stressed animals (28). Alternatively, it
could be due to the presence of increased concentrations of AVP, which is synergistic with CRH at
physiologic concentrations.
The data presented in this study and in the
study by Griep et al show a brisk increase in cortisol
after oCRH stimulation, and no difference in peak
cortisol values between FM patients and matched
controls. Griep et a1 noted that despite higher stimulated ACTH levels, there was no parallel increase in
stimulated cortisol levels (17). Our study showed a
decreased net cortisol response to administration of
oCRH. Both studies suggest relative hyporesponsivenew of the adrenal gland to exogenously stimulated
ACTH secretion. A relatively hyporesponsive adrenal
gland could be due to atrophy from chronic understimulation (for example, fewer than normal daily pulses of
CRH and ACTH).
HPA axis function has been examined in patients with CFS (25). Comparison of HPA axis function in FM patients with that in CFS patients revealed
differences, despite the clinical overlap between these
patients. Demitrack and colleagues showed low 24hour urinary free cortisol levels, similar to the levels
we found in patients with FM; however, in contrast to
FM, evening plasma ACTH levels were elevated and
cortisol levels were depressed in CFS patients compared with control subjects (25). Injection of oCRH
revealed an attenuated ACTH response (decreased net
ACTH stimulation) in CFS patients. Additionally,
stimulation of the adrenal gland revealed that maximal
cortisol responses to ACTH were low, compatible
with secondary adrenal atrophy. Those authors postulated that their findings suggested central CRH insufficiency. Although peripheral measurements of plasma
ACTH and cortisol levels are different in these two
patient groups, both groups have low 24-hour urinary
cortisol levels. These syndromes could represent different forms of insufficient central stimulation of the
HPA axis, with FM characterized by increased exposure of the corticotrophs to AVP or other costimulatory secretagogues.
Although there were no significant differences
in basal AVP levels or AVP levels after postural
stimulation, there was a trend toward increased release of AVP after postural change in patients with
FM. Five of 12 FM patients achieved AVP levels that
were more than 2 SD above the highest control value.
Plasma AVP reflects release of AVP from the magnocellular nucleus of the hypothalamus, not the parvocellular nucleus that releases AVP to the hypophyseal
venous circulation. However, changes in plasma AVP
may parallel parvocellular AVP (29).
AVP becomes a more important ACTH secretagogue during chronic HPA axis stimulation. In a
model of stress due to cholestasis after bile duct
resection, rats developed impaired HPA axis function,
characterized by a reduction of hypothalamic CRH in
conjunction with a dramatic rise in hypothalamic AVP
(30). Rats with adjuvant-induced chronic polyarthritis
exhibit changes in the HPA axis, characterized by loss
of the normal circadian rhythm of ACTH and corticosterone. Rats with chronic polyarthritis also show
decreased hypothalamic CRH messenger RNA production and polypeptide release, and perhaps as compensation for the decrease in CRH, there is also a
dramatic increase in AVP production (3 1,321.
Another animal model of hypothalamic CRH
hypofunction, the Lewis rat, exhibits blunting of the
HPA axis response to inflammatory and noninflammatory stressors (33-35). Blunted HPA axis responses
are associated with deficient hypothalamic CRH expression compared with that in histocompatible
Fischer rats (34,35). Lewis rats also exhibit markedly
elevated plasma and hypothalamic AVP levels compared with Fischer rats (29).
Another possible modulatory influence on HPA
axis function is the sympathetic stress axis. NPY
co-localizes with norepinephrine in the sympathetic
nervous system. Plasma NPY levels in humans represent sympathoadrenal output (14). In human subjects,
elevated NPY levels are seen with heavy physical
exercise or other situations of strong sympathetic
activation (14). Our patients with FM had low plasma
NPY levels. Previous studies have shown that plasma
NPY levels are elevated in patients with depression
and in caregivers of patients with Alzheimer’s disease,
who report a high level of life adversity (36), whereas
cerebrospinal fluid levels of NPY were decreased in
depressed patients with non-endogenous symptoms (37).
NPY is widely distributed and is present in high
concentrations in the mammalian brain, particularly
within the hypothalamus, hippocampus, and cortex
(38,39), but it is not known if plasma NPY levels
parallel NPY expression in any brain region. Central
nervous system NPY has been implicated in the regulation of food intake, cardiovascular function, and
neuroendocrine function (for review, see refs. 40 and
41). NPY is reported to increase the concentration
of CRH in the hypothalamus (40). Additionally, NPY
is present in high concentrations in the portalhypophyseal venous circulation and acts synergistically with CRH to stimulate the release of ACTH (41).
NPY has also been reported to have ACTH-like activities at the level of the adrenal cortex (42).
We can only speculate about the reason for low
plasma NPY levels in our patients with FM. Since
exercise stimulates plasma NPY levels, low levels may
merely reflect deconditioning of patients with FM.
Although norepinephrine levels in FM are reportedly
normal (43), low NPY levels seen in our patients may
represent hypofunction of the sympathetic stress axis.
It is, however, not clear that low NPY levels are
related to the observed HPA axis perturbations in FM.
There was overlap between patients and controls in
urinary free cortisol and plasma NPY levels. In addition, there was no significant correlation between
urinary free cortisol and plasma NPY levels when
examining patients and controls or patients alone.
There may be other metabolic abnormalities in
patients with FM that result in HPA axis perturbations. It has been shown that serotonin metabolism is
abnormal in FM patients, evidenced as follows: (a)
The serum concentration of serotonin is lower in
patients with FM than in matched controls (44); (b)
patients with FM have an increased number of serotonin reuptake receptors on platelets (44); (c) there is
an inverse correlation between the level of free serum
tryptophan, a precursor of serotonin, and severity of
pain in FM patients, although the levels were in the
normal range (18); (d) patients may experience clinical
improvement after treatment with tricyclic antidepressants, which probably act to block the reuptake of
biogenic amines, such as serotonin (43); and (e) treatment of FM patients with the serotonin precursor
5-hydroxytryptophan resulted in symptomatic improvement over placebo in a double-blind trial (45).
Serotonin is known to influence the circadian fluctuation of HPA axis products (20,21). It is not yet known
whether the abnormalities of serotonin metabolism
could result in the HPA axis perturbations observed in
FM patients.
Could the observed HPA axis perturbations
play a role in the symptoms of patients with FM? It is
known that low glucocorticoid levels may increase the
perception of pain. FM patients had low 24-hour
cortisol levels compared with normal individuals.
However, no study has suggested that low-dose glucocorticoid treatment improves symptoms in patients
with FM. There are also interconnections between
HPA axis products and other neuroendocrine systems
that could influence symptoms. For example, HPA
axis hormones are involved in the regulation of the
growth hormone axis (9). Bennett and colleagues have
described a 30% decrease in insulin-like growth factor
1 (IGF-1; somatomedin C) levels compared with those
in normal subjects, and this may reflect low growth
hormone levels (46). Those authors postulated that
such abnormalities might explain some FM symptoms,
since the growth hormone-IGF-1 axis is important in
muscle homeostasis (46). Although an acute elevation
of growth hormone is usually observed during the
onset of the stress response in humans, prolonged
activation of the stress system leads to suppression of
growth hormone and IGF-1 secretion, which could
lead to inhibition of their effects on target tissues (46).
Low levels of hypothalamic CRH and/or adrenal glucocorticoids could influence the secretion of growth
hormone-releasing hormone, leading to decreased
growth hormone and IGF-1 levels in FM.
There are also interactions between CRH and
opioid peptides in the central nervous system. Although no abnormalities of pendorphin levels in the
plasma or cerebrospinal fluid of patients with FM have
been demonstrated (47,48), the relationship of opioid
peptides to pain perception continues to make these
substances interesting candidates for continued investigation.
Central nervous system CRH exerts effects on
many centers that may be associated with symptoms
of FM other than musculoskeletal pain. Other disor-
ders that might be characterized by central CRH
hypofunction include atypical depression, Cushing’s
syndrome, seasonal depression, chronic fatigue syndrome, hypothyroidism, hyposerotonergic forms of
obesity, post-traumatic stress disorder, and nicotine
withdrawal (9). These conditions share some symptoms that could be related to CRH actions on central
nervous system centers, including dysphoria, hyperphagia, hypoarousal, and sleep disturbance. Lewis
rats that have deficient hypothalamic CRH expression
manifest associated behavioral phenotypes such as
poor performance in swim stress testing, increased
locomotor activity and decreased grooming behavior
in open field testing, and decreased fecal boli during
restraint stress compared with Fischer rats (35). Open
field behaviors of these two rat strains are consistent
with their differences with respect to CRH secretion,
since previous studies showed that direct intracerebroventricular injection of CRH influences these same
behaviors (49-5 1). These data suggest the possibility
that HPA axis activity could influence the central
nervous system centers that subserve at least some of
the symptoms reported by patients with FM.
In summary, HPA axis function is perturbed in
patients with FM. At this time, neither the cause of the
perturbations, nor their consequences to the pathophysiology of FM are fully understood. Further study
of these stress axis abnormalities could improve our
understanding of this common, and sometimes devastating, illness and give insights to novel therapeutic
approaches to the treatment of FM.
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