Function of the hypothalamic-pituitary-adrenal axis in patients with fibromyalgia and low back pain.

OBJECTIVE: We suggested fibromyalgia (FM) is a disorder associated with an altered functioning of the stress-response system. This was concluded from hyperreactive pituitary adrenocorticotropic hormone (ACTH) release in response to corticotropin-releasing hormone (CRH) and to insulin induced hypoglycemia in patients with FM. In this study, we tested the validity and specificity of this observation compared to another painful condition, low back pain. METHODS: We recruited 40 patients with primary FM (F:M 36:4), 28 patients (25:3) with chronic noninflammatory low back pain (LBP), and 14 (12:2) healthy, sedentary controls. A standard 100 microg CRH challenge test was performed with measurement of ACTH and cortisol levels at 9 time points. They were also subjected to an overnight dexamethasone suppression test, followed by injection of synthetic ACTH1-24. At 9 AM, the patients divided in 2 groups, received either 0.025 or 0.100 microg ACTH/kg body weight to test for adrenocortical sensitivity. Basal adrenocortical function was assessed mainly by measurement of 24 h urinary excretion of free cortisol. RESULTS: Compared to the controls, the patients with FM displayed a hyperreactive ACTH release in response to CRH challenge (ANOVA interaction effect p = 0.001). The mean ACTH response of the patients with low back pain appeared enhanced also, but to a significantly lesser extent (p = 0.02 at maximum level) than observed in the patients with FM. The cortisol response was the same in the 3 groups. Following dexamethasone intake there were 2 and 4 nonsuppressors in the FM and LBP groups, respectively. The very low and low dose of exogenous ACTH1-24 evoked a dose and time dependent cortisol response, which, however, was not significantly different between the 3 groups. The 24 h urinary free cortisol levels were significantly lower (p = 0.02) than controls in both patient groups; patients with FM also displayed significantly lower (p < 0.05) basal total plasma cortisol than controls. CONCLUSION: The present data validate and substantiate our preliminary evidence for a dysregulation of the HPA axis in patients with FM, marked by mild hypocortisolemia, hyperreactivity of pituitary ACTH release to CRH, and glucocorticoid feedback resistance. Patients with LBP also display hypocortisolemia, but only a tendency toward the disrupted HPA features observed in the patients with FM. We propose that a reduced containment of the stress-response system by corticosteroid hormones is associated with the symptoms of FM.

Glucocorticoid receptors, fibromyalgia and low back pain.

Recently, fibromyalgia (FMS) was shown to be a disorder associated with an altered functioning of the stress response system. FMS patients display a hyperreactive pituitary adrenocorticotropic hormone (ACTH) release in response to corticotropin-releasing hormone (CRH) and to insulin-induced hypoglycemia. We suggested that negative feedback of cortisol could be deranged. Therefore we investigated the properties and function of the glucocorticoid receptors (GR) in FMS patients and compared the results with those of healthy persons and patients with chronic low back pain (LBP a localized pain condition). Forty primary FMS patients (F:M = 36:4), 28 LBP patients (25:3) and 14 (12:2) healthy, sedentary control persons were recruited for the study. Urinary free cortisol excretion in FMS and LBP patients was lower compared to controls. Only FMS patients displayed lower CBG and basal serum cortisol concentrations when compared to controls. However, plasma free cortisol concentrations were similar in the three groups. There was no difference in the number of GR per cell among the three groups (FMS: 6498 +/- 252, LBP: 6625 +/- 284, controls: 6576 +/- 304), but the dissociation constant (Kd) of the FMS (14.5 +/- 0.9 nmol/l) and LBP (14.7 +/- 1.3 nmol/l) subjects was significantly higher than that of the controls (10.9 +/- 0.8 nmol/l) (p < .05). The maximal stimulation of the lymphocytes, as measured by the maximal thymidine incorporation (in the absence of cortisol) in the FMS group was approximately 1.5 times higher (p < .05) than in the control or LBP group. The ED50 (the cortisol concentration giving 50% inhibition of the thymidine incorporation), however, was identical in all three groups. We conclude that FMS patients have a mild hypocortisolemia, increased cortisol feedback resistance in combination probably with a reduced CRH synthesis or release in the hypothalamus. The role of the GR and mineralocorticoid receptor (MR) in the CRH regulation in the FMS patients remains to be solved.

Lack of correlation between the mean tender point score and self-reported pain in fibromyalgia.

OBJECTIVES: To study the validity and nature of self-assessed symptoms among patients with fibromyalgia syndrome (FMS) and to compare our data with findings reported in the US. To determine whether tender point scores correlate with self-reported pain and other symptoms and to study the influence of disease duration. METHODS: Tender point scores were assessed in 113 consecutive patients with FMS. All patients completed 2 self-assessment questionnaires (an extended Campbell list, the Enschede Fibromyalgia Questionnaire, and the Dutch Arthritis Impact Measurement Scales). RESULTS: The self-assessed symptoms of the Dutch FMS patients seem to be valid and are comparable with those of American patients. No association between disease duration and number of self-reported symptoms was found. An association between self-reported pain and mean tender point score was lacking for patients with disease of shorter duration and was weak for patients with disease of longer duration. CONCLUSIONS: The use of a self-report questionnaire for patients with FMS is feasible and appears to be valid. Tender point scores and self-reported pain represent very different aspects of pain in FMS.

Pituitary release of growth hormone and prolactin in the primary fibromyalgia syndrome.

OBJECTIVE: Previously, we demonstrated hyperreactive adrenocorticotropic hormone (ACTH) release in patients with primary fibromyalgia syndrome (primary FMS). We investigated the pituitary release of growth hormone (GH) and prolactin (PRL) in search of further disturbances in neuroendocrine reactivity possibly associated with the pathophysiology of primary FMS. METHODS: Ten female patients with primary FMS fulfilling the 1981 Yunus criteria and 10 matched, healthy and sedentary controls were subjected to an insulin induced hypoglycemia test; samples for measurement of glucose, GH and PRL were taken at intervals. RESULTS: Compared to the controls, the patients with primary FMS displayed significantly lower basal GH levels, whereas their basal PRL levels were slightly, though significantly, higher (respectively p = 0.021 and p = 0.041). Following hypoglycemia, there was a marked, statistically highly significant (p = 0.001), hyperreactivity of the GH response in patients with primary FMS. The PRL response showed wide interindividual variation and did not differ between patients and controls. CONCLUSION: Our findings indicate that fibromyalgia, along with ACTH hyperreactivity, also exhibits a distinct disturbance in the GH-somatomedin C axis. With regard to PRL, the variation in individual responses limits conclusions. The hyperreactive response patterns of GH and ACTH previously suggest a common origin, which might be related to a subtle glucocorticoid deficiency.

Altered reactivity of the hypothalamic-pituitary-adrenal axis in the primary fibromyalgia syndrome.

The reactivity of the hypothalamic-pituitary-adrenal (HPA) axis was investigated in 10 female patients fulfilling the Yunus criteria for the primary fibromyalgia syndrome (PFS) and in 10 matched, healthy and sedentary controls. The 2 groups were subjected to a dexamethasone suppression (DXM) test, a corticotropin-releasing hormone (CRH) test and an insulin induced hypoglycemia (IH) test. In the DXM test there was no escape from suppression in patients or controls. The CRH and the IH tests showed a markedly enhanced, and statistically significant, adrenocorticotropic hormone (ACTH) release in patients with PFS versus controls, while the cortisol response in both groups was not different. Our data suggest that fibromyalgia is related to a neuroendocrine disorder characterized by hyperreactive pituitary ACTH release and a relative adrenal hyporesponsiveness. This HPA response pattern is unique and contrasts to the hypercortisolemic responses observed in affective disorders, e.g., depression, which like PFS, are often thought to be precipitated by chronic stress. Our findings seem to indicate a relative adrenal insufficiency in PFS, which might serve clinically as an explanation for the reduced aerobic capacity and impaired muscle performance these patients display.

Physiological effects of exhaustive physical exercise in primary fibromyalgia syndrome (PFS): is PFS a disorder of neuroendocrine reactivity?

The influence of maximum exercise has been studied in 10 patients with primary fibromyalgia syndrome (PFS) and 10 healthy sedentary control persons. The exercise consisted of a bicycle ergometertest and a steptest, both till exhaustion. In both tests, the mean maximum workload of the PFS patients was lower than that of the controls. Significantly lower values of serum creatinekinase, myoglobin, cortisol, epinephrine and norepinephrine were found in PFS patients. A striking finding was a lower heart rate in PFS patients compared to the controls under the same workload. The lower (nor)epinephrine concentration together with the lower heart rate suggests a disturbance of the sympathetic activity in PFS patients. The preliminary conclusion is that there is a disturbed reactivity of the sympathetic system as well as of the HPA axis in PFS.

Frequency of infections among rheumatoid arthritis patients, before and after disease onset.

The self-reported frequency of genitourinary and bronchopulmonary infections in postmenopausal women with rheumatoid arthritis (RA) and in postmenopausal women with osteoarthritis and/or soft tissue rheumatism was compared. Neither before, nor after the onset of joint disease was a higher frequency reported by the RA patients. The previously established increased mortality from infectious disease among RA patients might be due to a more severe infectious disease course, leading to an increased case-fatality rate.

Noncontraceptive hormones and rheumatoid arthritis in perimenopausal and postmenopausal women.

The use of noncontraceptive hormones before onset of joint disease was compared between 490 perimenopausal and postmenopausal women with rheumatoid arthritis and a control group of 659 women with soft-tissue rheumatologic disorders and/or osteoarthritis. Both groups were sampled randomly from the attendees of five rheumatologic clinics. A negative association was found between the onset of rheumatoid arthritis and the previous use of noncontraceptive hormones (odds ratio, 0.32; 95% confidence interval, 0.16 to 0.64). This association persisted on univariate and multivariate control of potentially confounding variables and on subgroup analysis. The protective effect of oral contraceptives on the development of rheumatoid arthritis was confirmed.

The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: a controlled retrospective follow-up.

In a retrospective follow-up we compared the incidence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide with that in another group of patients with rheumatoid arthritis and also with the incidence of malignancies in the general population. Among 81 patients treated with cyclophosphamide in the past decade 15 malignancies occurred. This was 4.1 times the expected number obtained from a closely matched control group of patients with rheumatoid arthritis not treated with cytotoxic drugs (95% confidence interval 1.5 to 19.0), and 3.7 times the expected number calculated from general population rates (95% confidence interval 2.1 to 5.9). The increase in haematological and lymphoreticular malignancies was specially notable. The data also indicate that the development of malignancies after the start of cyclophosphamide therapy necessitates a certain induction time and that it is to some extent dose-dependent.

Oral contraceptives and rheumatoid arthritis: further evidence for a preventive effect.

To investigate a reported negative association between the use of oral contraceptives (OC) and the development of rheumatoid arthritis, a case-control study was undertaken to compare the histories of OC use between 228 women with a diagnosis of probable or definite rheumatoid arthritis and 302 women with the diagnosis of soft-tissue rheumatism and/or osteoarthritis. The use of OCs before the onset of joint complaints was acknowledged by 31.1% of the rheumatoid arthritis patients and by 55.6% of the controls. After adjustment for possible confounding variables, the rate ratio for ever use became 0.42 (95% confidence interval 0.27--0.65), while it was 0.40 (0.22-0.72) for ex-users and 0.45 (0.28-0.75) for current users. These findings confirm the finding from the Royal College of General Practitioners Oral Contraceptive Study that the incidence rate of rheumatoid arthritis among OC users was halved.

PIP: In order to study a reported negative association between the use of oral contraceptives (OCs) and the development of rheumatoid arthritis, a case-control study was undertaken to compare the histories of OC use between 228 women with a diagnosis of probable or definite rheumatoid arthritis and 302 women with the diagnosis of soft-tissue rheumatism and/or osteoarthritis. 31.1% of the rheumatoid arthritis patients and 55.6% of the controls used OCs before the onset of joint complaints. The adjusted rate ratio for ever use is 0.42 while it was 0.40 for ex-users and 0.45 for current users. The results confirm the theory that OC use is associated with a halving of the incidence rate for rheumatoid arthritis in both current and ex-users. It was also found that OC use effects seropositive more than seronegative rheumatoid arthritis. These results call for further elaboration of biological models of hormonal influences on autoimmune phenomena.

Retardation of ossification of the lumbar vertebral column in ankylosing spondylitis by means of phenylbutazone.

Does phenylbutazone exert an inhibitory influence on the progression of ossification of the lumbar vertebral column? In a retrospective study of 40 definite cases of ankylosing spondylitis the case histories were divided into periods demarcated by the radiological examinations. An adequately exact method was used for quantitative assessment of ossification. The periods were divided into three groups: (A) continuous phenylbutazone medication; (B) phenylbutazone medication, but not throughout the period; (C) no phenylbutazone medication. Rapid progression of ossification had occurred in group C. In group A, ossification had either remained absent or, if already in progress, had been arrested or substantially delayed. In early or relatively early stages of ankylosing spondylitis, continuous phenylbutazone medication can completely or largely control ossification of the vertebral column. Possibilities of further improvement of this therapy are discussed.