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Published online before print December 24, 2007, 10.1097/PSY.0b013e31815ff3ce
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Psychosomatic Medicine 70:65-72 (2008)
© 2008 American Psychosomatic Society

ORIGINAL ARTICLES

HPA Axis Reactivity and Lymphocyte Glucocorticoid Sensitivity in Fibromyalgia Syndrome and Chronic Pelvic Pain

Katja Wingenfeld, PhD, Christine Heim, PhD, Iris Schmidt, PhD, Dieter Wagner, PhD, Gunther Meinlschmidt, PhD and Dirk H. Hellhammer, PhD

From the Department of Psychobiology, University of Trier, Trier, Germany (K.W., C.H., I.S., D.W., G.M., D.H.H.); Department of Psychiatry and Psychotherapy Bethel, Bielefeld, Germany (K.W.); Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA (C.H.); and Institute of Psychology, University of Basel, Switzerland (G.M.).

Address correspondence and reprint requests to Katja Wingenfeld, PhD, Department of Psychiatry and Psychotherapy, Bethel, Remterweg 69–71, 33617 Bielefeld, Germany. E-mail: katja.wingenfeld{at}evkb.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: Chronic pelvic pain (CPP) and fibromyalgia syndrome (FMS) have been associated with hypothalamic-pituitary-adrenal (HPA) axis alterations, i.e., mild hypocortisolism and enhanced feedback sensitivity. We tested the hypothesis of reduced cortisol release in response to a psychosocial stressor and pharmacological stimulation. Furthermore, glucocorticoid (GC) sensitivity was evaluated.

Methods: Plasma total and salivary-free cortisol concentrations were measured in response to a standardized social laboratory stressor, the Trier Social Stress Test, and to adrenocorticotropin (ACTH)1–24 stimulation. In the Trier Social Stress Test, we additionally measured ACTH. GC sensitivity was measured by dexamethasone inhibition of lipopolysaccharide-induced interleukin-6 and tumor necrosis factor-alpha production in whole blood.

Results: There were no HPA axis alterations in women with CPP (N = 18) in these tests. Patients with FMS (N = 17) showed lower total cortisol release in response to the social stressor and exogenous ACTH, but normal free cortisol and ACTH levels compared with controls (N = 24). GC sensitivity was similar in all groups.

Conclusions: Our results suggest normal HPA responses to stress and ACTH stimulation in patients with CPP but reduced adrenal reactivity in patients with FMS, namely in total cortisol release. Free cortisol on the other hand was unaltered, possibly reflecting an adaptation to reduced circulating total cortisol.

Key Words: chronic pelvic pain • fibromyalgia syndrome • hypothalamic-pituitary-adrenal axis • cortisol • glucocorticoid sensitivity

Abbreviations: FMS = fibromyalgia syndrome; CPP = chronic pelvic pain; HPA = hypothalamic-pituitary-adrenal; TSST = Trier Social Stress Test; ACTH = adrenocorticotropin; GC = glucocorticoid; GR = glucocorticoid receptor; BMI = body mass index; LPS = lipopolysaccharide; IL-6 = interleukin-6; TNF-{alpha} = tumor necrosis factor-alpha.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Chronic pelvic pain (CPP) and fibromyalgia syndrome (FMS) are common disorders among women with a prevalence of 12% to 39% (1,2) and 3.4%, respectively (3). The main symptom of CPP is persistent or recurrent lower abdominal, pelvic, and/or back pain (4). Patients typically report additional symptoms, such as headache, fatigue, sleep disturbances, gastrointestinal disorders, and sexual dysfunction (5,6). They also frequently present depressive mood, anxiety, psychosocial distress, and physical and cognitive disability (5,7). FMS is characterized by widespread and chronic musculoskeletal pain, increased sensitivity to palpation, fatigue, sleep disturbances, and morning stiffness (8). Similar to women with CPP, patients with FMS also report elevated levels of depression, anxiety, and psychosocial stress (3,9). The etiology of FMS remains unknown and studies regarding potential pathophysiological mechanisms are inconsistent. Although many organic conditions may cause CPP, many studies failed to identify any physical correlate for the pain. The prevalence of an organic pathology varies between 8% and 91% (see Ref. 10 for review). Interestingly, several studies did not find a relationship between the intensity of CPP symptoms and the severity of the physical correlate (11–13). Therefore, a causal relationship between organic pathology and the development of CPP remains controversial.

Dysfunction in hypothalamic-pituitary-adrenal (HPA) axis regulation has been reported for various stress-related functional somatic disorders, i.e., chronic fatigue syndrome, gastrointestinal disorder, autoimmune diseases, FMS and CPP (14). Although several neuroendocrine studies investigated alterations of the HPA axis in patients with FMS, studies assessing HPA axis functioning in CPP are rare.

Results on HPA axis function in FMS are heterogeneous. Both hyperactivity and hypoactivity of the HPA axis have been reported. Increased basal plasma cortisol levels have been observed (15), whereas other studies reported decreased 24-hour urinary-free cortisol and low morning cortisol release in patients with FMS (16–19). Normal 24-hour cortisol and diurnal patterns of adrenocorticotropin (ACTH) and cortisol secretion have been reported as well (20–23). Findings regarding alterations in diurnal variation of cortisol secretion are also inconsistent (15,16,24–26). Of note, reduced cortisol release in FMS is associated with depressive symptoms (18,19) and experiences of childhood trauma (26).

In line with studies suggesting reduced adrenal output in FMS, reduced cortisol secretion has been observed in response to ACTH1–24 stimulation (27,28), although negative results have been reported as well (17). In the corticotropin-releasing hormone (CRH) stimulation test, patients with FMS exhibit increased ACTH but normal cortisol responses, suggesting sensitization of the pituitary in combination with adrenal insufficiency (17,29,30). One study measured plasma CRH levels following its injection and found higher values among patients with FMS. ACTH and cortisol remained comparable with healthy controls, which has been interpreted as an possible elevation of CRH-binding globulin in response to enhanced CRH release, resulting in normal pituitary and adrenal output (31). Additionally, lower cortisol release in response to the insulin tolerance test has also been found (28). However, another study reported reduced ACTH release in response to hypoglycemia, suggesting an impaired ability to activate HPA axis (20). In this study, cortisol release was comparable in women with FMS and healthy controls.

We previously found reduced cortisol levels in the low-dose (0.5 mg) dexamethasone suppression test, but unaltered ACTH suppression, also suggesting reduced adrenal output (32). Many of these findings are consistent with relative hypocortisolism in FMS. Interestingly, lower total cortisol, but normal free cortisol concentrations in FMS, has been reported (23). In this study, lower glucocorticoid binding globulin (CBG) and lower affinity for the binding of dexamethasone to the receptor in these patients were found but no differences in the number of glucocorticoid receptor (GR) were reported. Therefore, bioavailability of cortisol was similar to that of controls, but it seems that higher cortisol concentrations are needed to obtain the same effect.

In patients with CPP with no organic correlate as verified using diagnostic laparoscopy, Heim et al. observed markedly reduced salivary cortisol secretion after intake of a low dose (0.5 mg) of dexamethasone (33). The authors discussed that this result might reflect enhanced feedback sensitivity of the HPA axis in these patients, although it could not be excluded that reduced adrenal reactivity to endogenous ACTH might have contributed to the result. Indeed, the cortisol response after administration of CRH was reduced, whereas the ACTH response was normal (33). These findings suggest adrenocortical hyporesponsiveness. Evidence for reduced glucocorticoid (GC) receptor binding in lymphocytes was also provided (34). GC sensitivity has not been evaluated in women with CPP.

In sum FMS and CPP have been associated with HPA axis dysregulation. There is evidence for reduced adrenocortical responsiveness in both disorders, although there are inconsistent findings. To our knowledge neither in FMS nor in CPP have HPA axis responses to a standardized social stressor been examined. Despite the fact that both disorders share some endocrine and psychological features, such as hypocortisolism and high levels of psychosocial distress these disorders have not been compared directly with regard to HPA axis functioning.

Here we tested the hypothesis of reduced adrenocortical responsiveness in CPP and FMS by using a standardized psychosocial laboratory stressor, the Trier Social Stress Test (TSST), and a pharmacological challenge test, the ACTH1–24 stimulation test. Additionally, in vitro GC sensitivity was evaluated to test the hypotheses whether reduced adrenal output might be counter-regulated by an upregulation of GR at target cells.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Subjects
We recruited 18 female patients with CPP and 17 female patients with FMS from local support groups, general practitioners’ offices, and the gynecological department of a general hospital (Mutterhaus der Borromäerinnen, Trier, Germany). Twenty-four female controls were recruited through of local advertising. There were significant differences between study groups in mean age and body mass index (BMI) (Table 1). Eleven patients with FMS, 1 with CPP, and 1 control woman were postmenopausal ({chi}2 = 25.3, p < .001). Eight control women and five women with CPP but none of the patients with FMS took oral contraceptives ({chi}2 = 6.9, p = .026). There were no differences between study groups regarding education, family status, smoker status, or number of cigarettes smoked per day. All participants were free of medication other than oral contraceptives.


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  		TABLE 1. Mean (SD) Clinical Symptom Ratings of Women With Chronic Pelvic Pain (CPP) Fibromyalgia Syndrome (FMS) and Healthy Female Controls

 

All were outpatients. Patients with FMS were diagnosed by their physician according to the American College of Rheumatology criteria (8). All patients with FMS were diagnosed with widespread chronic musculoskeletal pain and increased sensitivity to palpation with no medical causes identified. Patients with CPP were also diagnosed by their physician fulfilling the following criteria: a) acyclic CPP, b) of at least 4 months duration, and c) without any medical explanation. Exclusion criteria were current eating disorders, alcohol or drug dependence, current or lifetime psychosis and bipolar disorder. Women with additional medical illnesses that could explain pain symptoms were excluded. Included controls had never sought psychiatric or psychotherapeutic treatment and did not suffer from any current or lifetime DSM-IV Axis I disorder or medical illness.

Several participants underwent only part of the tests, resulting in different group sizes. In the TSST, complete data were obtained for plasma ACTH and cortisol concentrations, but only 21 controls, 15 patients with CPP, and 16 patients with FMS provided complete saliva samples for free salivary cortisol concentrations. Six participants (3 controls, 2 CPP, 1 FMS) did not perform the ACTH test and three controls did not provide saliva samples for salivary cortisol concentrations. Blood samples for analyses of GC sensitivity were drawn from 21 controls, 12 patients with CPP, and 16 patients with FMS.

Data collection was conducted from October 2000 until July 2003. The Ethics Committee of the University of Trier and the state of Rhineland-Palatine approved the study.

Procedure
Psychiatric disorders were diagnosed using the German version of the Structured Clinical Interview for DSM-IV (SCID-I) (35). Depression and anxiety were further measured using standard rating scales (36,37). For perceived depressive symptoms we used the German version of the Self-Rating Depression Scale (36) and for self-rated trait anxiety, the State-Trait-Angstinventar (37). To evaluate impairment associated with pain, we used the German version of the Pain Disability Index (38). The German version of the Fatigue Scale was used to measure the severity of physical, mental, and total fatigue (39,40). Somatic symptoms were measured using the Freiburger Beschwerdeliste-Revised (41).

We performed the TSST (42), a standardized psychosocial stress task that reliably induces activation of the HPA axis. The TSST consists of a preparation phase (10 minutes) followed by a speech in front of a trained audience (5 minutes) and an arithmetic task (5 minutes). Subjects received an intravenous catheter 1 hour before the test. ACTH and cortisol concentrations were measured in 15-minute intervals before (–15 and 0 minutes), during (15 minutes), and after (30, 45, 60, 75, and 90 minutes) the stress test.

In the ACTH1–24 stimulation test, plasma total and salivary-free cortisol were measured. Subjects received an intravenous catheter 1 hour before the test. Cortisol was measured before (–15 and 0 minutes) and after (+10, +20, +30, +45, +60, +90, and +120 minutes) injection of 1 µg ACTH1–24 Both, the ACTH1–24 stimulation test and the TSST were performed in the afternoon, beginning approximately at 4 PM

Saliva was collected using salivette collection devices (Sarstedt, Rommelsdorf, Germany) and stored at room temperature until completion of the session. Salivettes were stored at –20°C until biochemical analysis. Blood was collected in EDTA tubes, immediately centrifuged, and plasma was stored at –80°C until assayed. Plasma samples were assayed by using commercial enzyme immunoassay (DSL ACTIVE; DSL, Sinsheim) for cortisol and chemiluminiscense immunoassay (Nichols Institute Diagnostics, Bad Nauheim) for ACTH. The free cortisol concentrations in saliva were determined using a time-resolved immunoassay with fluorometric detection. Inter- and intraassay coefficients of variance were below 10% for all analyses.

To evaluate the GC sensitivity, dexamethasone inhibition of lipopolysaccharide (LPS)-induced cytokine production was measured. Dexamethasone (DEX) suppression of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-{alpha}) production in peripheral leukocytes was determined as follows. An intravenous catheter was inserted at 8 AM and a venous blood sample was collected in heparinized tubes (Braun, Melsungen, Germany) 35 minutes later. Before analysis, the blood sample was diluted 10:1 with saline (Braun, Melsungen, Germany) and subsequently incubated with LPS (derived from Escherichia coli 055:B5, Difco, Augsburg, Germany) and different concentrations of DEX (Sigma, Deisenhofen, Germany). Four hundred microliters of diluted whole blood was added to 50 µl of LPS and 50 µl of different DEX concentrations with final concentrations of 30 ng/ml (LPS) and 0, 10–10, 10–9, 10–8, 10–7, and 10–6 mol/l (DEX), respectively. After 6 hours of incubation at 37°C in 5% CO2, the plates were centrifuged for 10 minutes at 2000g at 4°C. The supernatant was collected and stored at –80°C until assayed. To account for interindividual variations in monocytes producing IL-6 and TNF-{alpha}, a differential blood cell count was performed with an SE-9000 cell counter (Sysmex, Norderstedt, Germany).

Statistical Analyses
Statistical analyses were performed using SPSS Version 12.0.1 (SPSS Inc., Chicago, IL). Clinical data were analyzed using {chi}2 test for categorical data and Student’s t test for continuous data. ACTH, plasma, and salivary cortisol were analyzed by ANOVA with repeated measurements. All reported results were corrected by the Huynh-Feldt procedure when assumption of sphericity was violated. Bonferroni post hoc analyses were used in case of a significant group effect. In case of a significant group by time interaction effect post hoc analyses were done using multivariate ANOVA to analyze all measurement points simultaneously but to adjust for multiple comparisons. Level of significance was set at p < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Clinical and Stress Features
All patients with CPP and FMS were diagnosed with current somatoform pain disorder according to DSM-IV, consistent with their CPP and FMS diagnoses. Although eight of the patients with CPP did not suffer from comorbid psychiatric disorders, eight with CPP had anxiety disorders (5 phobia, 2 panic disorder, 1 posttraumatic stress disorder (PTSD)), and two reported dysthymia or panic disorder (including 1 with PTSD). Ten subjects with FMS had no comorbid psychiatric disorder, one with FMS reported dysthymia, one with FMS suffered from PTSD, and five met the criteria of phobia (one with additional panic disorder). Thus, depression and anxiety scores were increased in the patient groups compared with controls. Fatigue, pain disability, and somatic complaints were also higher in the patients, those with FMS reporting the highest disability in most scales (Table 1).

Trier Social Stress Test
ACTH Response
Regarding plasma ACTH concentrations, a significant main effect of the time factor (F(7,392) = 4.12, p < .001) but no main effect of the group factor (F(2,56) = 0.89, p = .413) or group by time interaction effect (F(14,392) = 1.19, p = .313) were found (Figure 1). When using ANCOVA with the covariates BMI and age, we found a significant effect of the variable BMI (p = .009), a group effect (p = .04), and also a group by time interaction effect (p = .007). However, post hoc ANCOVA revealed only differences between patients with FMS and CPP (p = .017), those with CPP showing the most pronounced ACTH response. There were no differences between controls and each patient group.


Figure 110
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  		Figure 1. ACTH, plasma total, and salivary-free cortisol release to a standardized social stressor (TSST) in women with FMS, CPP, and healthy controls.

 

Plasma Total Cortisol Release
There were significant effects of the time factor (F(7,392) = 31.12, p < .001) and the group factor (F(7,56) = 5.21, p = .008), but no significant group by time interaction effect (F(14,392) = 1.88, p = .114) (Figure 1). Bonferoni post hoc analyses revealed significant differences between controls and patients with FMS (p = .013) and between patients with FMS and CPP (p = .028), whereas patients with CPP did not differ from controls. ANCOVA was used to control for BMI and age, but there were no significant influences of these variables. To estimate the effect size the "area under the curve (AUC)" was calculated for cortisol release using the following formula



Formula 1

, with Ci denoting the individual measurement, and n the total number of measurements. Mean AUC for controls was 861 (343) and for patients with FMS 568 (255). The effect size was computed using the following formula:



Formula 2

. The effect size for the difference between controls and patients with FMS was 0.67.

Salivary-Free Cortisol Release
There was a significant main effect of the time factor (F(7,343) = 18.75, p < .001), but no main effect of the group factor (F(2,49) = 0.91, p = .410) or a group by time interaction effect (F(14,343) = 0.75, p = .573), reflecting nearly identical salivary cortisol release before, during, and after the TSST in all groups (Figure 1). BMI and age did not have a significant effect on salivary cortisol levels using ANCOVA.

ACTH1–24 Stimulation Test
Plasma Total Cortisol Release
There were significant main effects for the time factor (F(8,400) = 177.63, p < .001) and the group factor (F(2,50) = 3.66, p = .033), as well as a time by group interaction effect (F(16,400) = 2.39, p = .045). Groups differed significantly at measurement points –15, 0, +20, +90, and +120 minutes (MANOVA, p < .05). There were trends for differences at measurement points +10, +45, and +60 (p < .1). Bonferoni post hoc analyses revealed significant differences between controls and patients with FMS (p = .052), whereas the patients with CPP did not differ from controls. There was a trend for a difference between patients with FMS and CPP (p = .084) (Figure 2). We also controlled these analyses for BMI and age using ANCOVA, but did not find any significant effects of these covariates. The effect size was calculated as described above using the AUC for cortisol release as mean value. Mean AUC for the control group was 1691 (529) and for the patients with FMS 1318 (211). The estimated effect size for the comparison between controls and patients with FMS was 0.95.


Figure 210
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  		Figure 2. Plasma total and salivary-free cortisol release to ACTH1–24 stimulation in women with FMS, CPP, and healthy control.

 

Salivary-free Cortisol Release
Concerning salivary cortisol, significant main effects of the time factor (F(8,376) = 81.83, p < .001) and the group factor (F(2,47) = 3.42, p = .041) were observed. There was no time by group interaction effect. Bonferoni post hoc analyses showed that there was a trend for a difference in salivary cortisol between patients with CPP and FMS (p = .06). There were no significant differences between controls and patients with FMS or CPP, respectively (Figure 2). Again, BMI and age did not influence the results.

GR Sensitivity
There were neither differences in IL-6 nor in TNF-{alpha} production of peripheral leukocytes at baseline and in response to dexamethasone stimulation between the three study groups (all p > .25). However, there were significant main effects of DEX concentration on IL-6 (F(5,230) = 202.09, p < .001) and TNF-{alpha} (F(5,230) = 163.43, p < .001) production. Specifically, the lowest DEX concentrations resulted in the lowest suppression of IL-6 and TNF-{alpha} production, whereas higher DEX concentrations resulted in pronounced suppression of IL-6 and TNF-{alpha} (as would be expected). No influence of these variables could be revealed on using BMI and age as covariates.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
On the basis of the assumption that dysfunctional HPA axis regulation is of pathophysiological relevance in stress-related pain syndromes such as FMS and CPP, the present study aimed to evaluate HPA axis response to a psychosocial stressor and an adrenocortical challenge test compared with healthy controls. We further tested the hypothesis of altered GC sensitivity in these disorders.

We found reduced plasma total cortisol responses in the TSST and ACTH1–24 stimulation test in patients with FMS compared with women with CPP and healthy controls, but no differences in salivary-free cortisol release. In CPP, there was no altered HPA axis response to the TSST or ACTH stimulation. GR sensitivity was unaltered in patients with CPP or FMS.

Our results are in line with studies reporting reduced adrenocortical responsiveness to pharmacological challenge in patients with FMS (27,28). However, normal total cortisol release after ACTH1–24 stimulation in FMS but reduced basal plasma total cortisol has also been reported (17). The latter finding was also reported by Lentjes et al. (23). Interestingly, there were no alterations in basal salivary-free cortisol (22) and in plasma-free cortisol (17,23). On the other hand, in a naturalistic design, elevated salivary-free cortisol was observed when examining the diurnal cycle of cortisol release, but there were no differences in free cortisol responses to stress (15). These results, taken together with the findings presented here, support the assumption of a dissociation between total and free cortisol in FMS. It seems that bioavailability of cortisol might be unaltered in patients with FMS, as suggested by Lentjes et al. (23). However, in urinary-free cortisol most studies reported reduced free cortisol (16,17,24), but one study could not replicate this finding (21). It must be noted that urinary cortisol excretion depends on GC metabolism and may not be comparable with salivary and plasma-free cortisol levels. It has been suggested that a flattened cortisol diurnal rhythm with normal morning peak and higher evening cortisol may be responsible for alterations in 24-hour urinary cortisol (24). Another explanation might be a decreased frequency of cortisol pulses over 24 hours (16). Furthermore, alterations in metabolic clearance of cortisol should be taken into account (43).

Unfortunately, most studies did not measure total and free cortisol simultaneously in response to the same stressor, neither to psychosocial stress nor to pharmacological challenge in patients with FMS, as we did in this study. However, Lentjes et al. (23) and Griep et al. (17) report a dissociation between free and total cortisol in the patients with FMS. The potential mechanisms underlying this dissociation are somewhat speculative and will be discussed below. However, one possible explanation is a reduced concentration of CBG. In fibromyalgia, decreased CBG concentrations have been reported in two studies (17,23).

The present study further explored whether FMS is associated with altered GC sensitivity. We did not find altered GC sensitivity in patients with FMS in our study. However, Lentjes et al. reported that the binding affinity of CGs to the GR was lower in patients with FMS, whereas the number of GR was unaltered compared with healthy controls (23). They suggested that therefore more cortisol is needed to yield the same effects. Lymphocyte sensitivity for the effects of GCs on the other hand was not reduced, which is in line with our results. More research is needed to evaluate the role of GR function and sensitivity of target cells to GCs in FMS.

Although some studies report exaggerated ACTH responses to CRH challenge in FMS (17,30), we observed normal ACTH responses to a psychosocial stressor. Interestingly, ACTH and cortisol concentrations have been reported to be similar in patients with FMS and controls after CRH stimulation, but circulating CRH in plasma was significantly higher in FMS (31). Therefore, ACTH release seems to be rather blunted than enhanced in this study. Furthermore, normal ACTH release to hypoglycemia has been reported (20), which does not support the hypothesis of a hyper-responsive pituitary. We also did not find evidence for altered pituitary (or hypothalamic) functioning in the stress test, but a psychosocial stressor is not directly comparable with pharmacological challenge with CRH, which stimulates HPA axis directly at the pituitary level.

Contrary to former studies on HPA axis function in CPP, we did not find any HPA dysregulation in our sample; however, we used different tests in this study. It must be noted that in the former studies a different control group has been examined, namely pain-free infertile women. On the other hand, in the Heim study, all patients with CPP and controls were studied as inpatients and their diagnostic status was confirmed using laparoscopy, which might have resulted in more homogenous study groups and standardized testing. Another difference to the former studies is that in the here presented sample all patients with CPP were outpatients, and therefore possibly were less impaired by their pain symptoms compared with women who were treated as inpatients including physical examinations as laparoscopy. In the Heim study none of the patients or controls was menopausal or postmenopausal and none of the women were on medication, including oral contraceptives. All women were in the early follicular phase at the time of the HPA axis challenge tests. Thus the Heim study was more controlled. It should be noted that, in the study of Heim et al., the CRH stimulation test was used, which is, as mentioned before, different from the TSST (33). ACTH challenge did not reveal reduced cortisol release in the present study. One reason for this discrepancy might be the use of only 1 µg ACTH1–24, which is sensitive to estimate adrenal sensitivity rather than capacity. Additionally, the prevalence of comorbid PTSD was about 40% in the study of Heim et al. (33) compared with only two women (11%) in our study. Hypocortisolism and enhanced feedback sensitivity are prominent findings in PTSD (44) and the high comorbidity and CPP and PTSD might in part explain the results of Heim et al. (33).

There are some differences to other studies that should be mentioned: All of our subjects were outpatients, which is unusual. Most studies recruited patients from tertiary care centers. In these populations, usually high rates of comorbid psychiatric disorders were found compared with outpatients (45,46). In our sample, only 1 woman with FMS and 2 with CPP meet criteria of dysthymia and none had current major depressive disorder. Epstein et al., for example, found a prevalence of 22% of major depression disorder and 10% of dysthymia in patients with FMS in a multicenter study (47). We also had only low rates of PTSD in our sample. These low rates of depression disorder and PTSD might be an advantage of our study, because these disorders could have been confounded with HPA axis dysfunction.

In sum, there are two main results of this study that need to be discussed in more detail. First, reduced adrenal responsiveness of patients with FMS and second, dissociation between plasma total and salivary-free cortisol in these patients. There are several potential mechanisms that might contribute to the reduced adrenal output in FMS, but these hypotheses remain speculative:

  1. Our results might reflect a reduced biosynthesis or depletion of cortisol of the adrenal gland. Thus, there may be an adrenal insufficiency in patients with FMS. Findings of low basal cortisol and reduced cortisol release to ACTH as well as findings of low to normal cortisol together with elevated ACTH in the CRH stimulation test support this idea (16–19,27–30).
  2. Reduced adrenal output may be attributed to decreased adrenocortical sensitivity to ACTH via downregulation of adrenal receptors. To our knowledge up to now no study examined the adrenal responsibility for ACTH directly by measuring its receptors in FMS. However, altered ACTH receptor functioning has been reported for several medical conditions such as adrenal tumors or familial GC deficiency (48–50). Furthermore, there is also evidence for genetic contribution of decreased adrenocortical responsiveness (51,52).
  3. Another factor that may contribute to the phenomenon of hypocortisolism is the possibility of morphological changes of the adrenal gland, such as atrophy or decreased volume. Up to now only one study investigated the adrenal size in FMS suggesting it to be unaltered (27). Because only 16 patients with FMS and 12 controls have been examined in this study, further research has to confirm this finding.
  4. A more indirect mechanism, which at first view suffers from face validity, should be considered in the association of hypocortisolism with increased feedback sensitivity. Interestingly, for patients with PTSD increased responsiveness to feedback test together with hypocortisolism has been documented well (44). In contrast to PTSD, where enhanced suppression of cortisol and ACTH have been reported (53,54), we previously showed that patients with FMS exhibited more pronounced suppression of cortisol but not of ACTH (32). Given that there is hypersuppression of cortisol in FMS, reduced adrenal cortisol release might be the consequence of enhanced feedback mechanisms.

Furthermore, the discrepancy between plasma total and salivary-free cortisol needs to be addressed. Again, there are possible underlying mechanisms to be considered, but studies on this topic are rare and the presented hypotheses need further scrutiny. Overall, one may hypothesize that normal free cortisol is an adaptation to reduced total cortisol secretion. However, due to the fact that longitudinal studies are rare, the time course of manifestation of HPA axis alterations is understudied. This would be of particular interest in the case of chronic stress and the development of stress-related disorders. One explanation that could explain the discrepancy between total and free cortisol are lower levels of CBG as supported by the works of Lentjes et al. (23) and Griep et al. (17). The primary role of CBG is to regulate the bioavailability of GCs (55). Interestingly, mutations of the CBG gene that decrease CBG levels do exist, resulting in lower total cortisol levels compared with control subjects but comparable free cortisol levels (55,56). Torpy et al. emphasizes the possible relationship between these findings and fatigue symptoms, which might be of interest in the case of FMS that is strongly correlated with chronic fatigue syndrome (56,57). Not only reduced levels but also changes in the binding affinity of CBG might contribute to the problem (58). Several conditions have been shown to decrease CBG capacity. Of particular interest is the finding that chronic social stress might result in reduced CBG levels (59). Furthermore, immune parameters, such as IL-6 or IL-1β, inhibit the production of CBG (60,61). This has been related to more acute stressors, such as septic shock or injury (61). FMS has not only been associated with chronic stress, but numerous patients report that their symptoms began after specific incidents, such as infections or injuries (62–64). Therefore, viral infection might be a trigger for the onset of FMS. Following this hypothesis, lower plasma total cortisol might be an adaptation to primary enhanced free cortisol, which was related to stress-induced CBG deficiency, for example, caused by infection. However, these remarks remain speculative and mechanisms that might contribute to the discrepancy between total and free cortisol need to be investigated in stress-related bodily disorders.

There are a number of limitations of the current study that should be mentioned. First, there were differences between patients with FMS and controls regarding menopausal status and between those with FMS and CPP regarding intake of oral contraceptives. Both variables might influence HPA axis function. Because of the relatively low number of cases of these variables in each group (only one menopausal woman in the CPP and the control group, and none with oral contraceptive use in the FMS group), we were not able to control for these variables adequately. Unfortunately, we did not control for menstrual cycle phase, which is a major limitation of the study. Second, we did not measure CBG concentrations. Therefore, interpretation of the discrepancy between total and free cortisol remains speculative. Furthermore, it might have been of interest to measure the number of GR in lymphocytes. Another major limitation is the small sample size of the study groups, which makes it difficult to interpret nonsignificant results. Possibly, the statistical power was too low to detect smaller effects. Therefore, the nonsignificant differences between patients with CPP and controls and the results concerning ACTH release have to be interpreted carefully and should be confirmed by other studies.

The results of this study indicate that FMS is associated with relative hypoadrenocortical output, but normal free cortisol circulation in response to a psychosocial stressor and an adrenocortical challenge test. Therefore, it seems that bioavailability of cortisol as well as GC sensitivity are unaltered in patients with FMS. Patients with CPP did not show HPA axis dysfunction in the specific measures, which might be due to sample characteristics, namely outpatients with low rates of depression and PTSD. Future studies should continue investigating HPA axis functioning in chronic pain disorders focusing on subgroups of patients with different comorbid disorders or stress experiences. Furthermore, mechanism of dissociation between total and free cortisol in the same patients within the same HPA axis challenge tests should be clarified.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
Received for publication February 2, 2007; revision received August 28, 2007.

This work was supported by a center grant of the Deutsche Forschungsgemeinschaft FOR 255 (to D.H.H.; clinical subproject D to C.H. and D.H.H.).

DOI:10.1097/PSY.0b013e31815ff3ce


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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