Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome

https://doi.org/10.1016/j.bbi.2003.12.011Get rights and content

Abstract

The objective of this study was to evaluate and compare the basal circadian and pulsatile architecture of the HPA axis in groups of patients with FMS, CFS, or both syndromes with individually matched control groups. Forty patients with either FMS (n=13), FMS and CFS (n=12), or CFS (n=15) were matched by age (18–65), sex, and menstrual status to healthy controls. Subjects were excluded if they met criteria for major Axis I psychiatric disorders by structured clinical interview (SCID). Subjects were admitted to the General Clinical Research Center where meals and activities were standardized. Blood was collected from an intravenous line every 10 min over 24 h for analysis of ACTH and cortisol. Samples were evaluable for ACTH in 36 subject pairs and for cortisol in 37 subject pairs. There was a significant delay in the rate of decline from acrophase to nadir for cortisol levels in patients with FMS (P<.01). Elevation of cortisol in the late evening quiescent period was evident in half of the FMS patients compared with their control group, while cortisol levels were numerically, but not significantly, lower in the overnight period in patients with CFS compared with their control group. Pulsatility analyses did not reveal statistically significant differences between patient and control groups. We conclude that the pattern of differences for basal circadian architecture of HPA axis hormones differs between patients with FMS and CFS compared to their matched control groups. The abnormalities in FMS patients are consistent with loss of HPA axis resiliency.

Introduction

An enduring historical literature has described patients who report disabling physical symptoms such as musculoskeletal pain, fatigue, sleep disturbance, difficulties in concentration, and mood disturbances particularly depression and anxiety. Upon examination, these patients show no laboratory or radiographic abnormalities useful in clinical diagnostic assessment. Notable in their clinical presentation is the frequent report of symptom onset or exacerbation during periods of physical or emotional stress. Among these clinical conditions, fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) have generated the most intense investigation. While the hallmark feature of FMS is pain, and of CFS, disabling fatigue, close examination reveals considerable symptom similarity between the two (Buchwald, 1996; Goldenberg et al., 1990). This propensity for symptom overlap has led many to speculate that FMS and CFS may represent clinical variants of the same process. However, some differences exist including an older mean age of patients with FMS compared with CFS (Buchwald, 1996).

We have previously proposed that the stress-responsive nature of both FMS and CFS provides an important clue to their proper understanding (Crofford and Demitrack, 1996). An individual's response to stress, either physical or emotional, includes activation of the hypothalamic–pituitary–adrenal (HPA) axis, which is accomplished via secretion of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from the paraventricular nucleus of the hypothalamus (Chrousos and Gold, 1992). Interaction of these neurohormones with specific receptors on corticotroph cells of the anterior pituitary trigger release of adrenocorticotropin (ACTH) which then stimulates secretion of cortisol from the adrenal cortex. In addition to its stress-dependent activation, the HPA axis exhibits a pronounced spontaneous near 24 h, or circadian, rhythm. In humans, this circadian rhythm is entrained to the light–dark and sleep–wake cycles (Czeisler, 1995). The trough of HPA axis activity occurs in the evening and peak activity normally occurs just before waking. Stress-induced secretion is superimposed on the basal circadian rhythm. There is evidence that the stress responsiveness and negative feedback regulation of the HPA axis varies across the day; hence specific alterations in the timing, intensity, and duration of any stress stimulus may result in widely varying patterns of HPA axis activity (Dallman et al., 1992). It is thought that under normal conditions the HPA axis may be a closed-loop system. Therefore, activation of cortisol secretion by stress results in a homeostatic correction ensuring that 24 h integrated cortisol levels are maintained in the normal range (Dallman et al., 1992).

Although alterations of HPA axis activity have been reported in both FMS and CFS, detailed examination of the studies addressing HPA axis function in these conditions has yielded inconsistent results. Furthermore, when taken in aggregate, previous data suggest differences in the characteristics of altered HPA function with hyperactivity of the axis in FMS and hypofunction in CFS (Crofford and Neeck, 2000). It is important to note that most studies of patients with FMS have not specifically excluded patients with CFS or provided information on the number of subjects with CFS included in the study. Particularly if the specific HPA axis alterations differ between patients that are pain-dominant or fatigue-dominant, these methodological issues may provide explanation for inconsistent findings.

Most, but not all, studies of FMS patients have reported increased daytime plasma or salivary cortisol levels (Adler et al., 1999; Catley et al., 2000; Crofford et al., 1994; Griep et al., 1998; McCain and Tilbe, 1989). Two studies reported low urine free cortisol levels (Crofford et al., 1994; Griep et al., 1998), while another reported normal urinary cortisol levels (Adler et al., 1999). Provocative tests have demonstrated normal or increased ACTH and blunted cortisol responses after injection of exogenous CRH, distinct from the findings in depressed patients (Crofford et al., 1994; Griep et al., 1993, Griep et al., 1998; Reidel et al., 1998). After insulin-induced hypoglycemia, one group reported a similar pattern to that of CRH-stimulation testing (Griep et al., 1993), but another group reported a normal pituitary–adrenal response to hypoglycemia (Adler et al., 1999). Adler et al. (1999) reported a reduced ACTH/cortisol ratio in FM patients, but these same authors and Griep et al. (1998) reported a normal cortisol response to exogenous infusion of ACTH 1–24. There is currently no consensus as to the overall state of HPA axis activity in FMS.

In CFS, plasma and urine cortisol levels were reported as low (Demitrack et al., 1991). The ACTH response to CRH is blunted and cortisol response is normal or blunted (Demitrack et al., 1991; Scott and Dinan, 1998). Furthermore, the peak cortisol response to exogenous ACTH is blunted and adrenal gland size is diminished (Demitrack et al., 1991; Scott and Dinan, 1998; Scott et al., 1999). The majority of studies are consistent with hypoactivity of the HPA axis, though whether this occurs as a result of a central or peripheral abnormality is not known.

We and others have proposed that disruption in the integrity of the HPA axis may be a proximate cause of many of the somatic, cognitive, and emotional symptoms that characterize patients with either FMS or CFS (Chrousos and Gold, 1992; Crofford and Demitrack, 1996; Clauw and Chrousos, 1997; Sternberg, 1993). We hypothesized that analysis of the basal pulsatile and circadian architecture of ACTH and cortisol would clarify abnormalities of the HPA axis in patients with FMS, CFS, or both disorders. In order to characterize the detailed basal function of the HPA axis, we studied patients with either or both conditions, free of concurrent major psychiatric illness, who were individually matched for age, sex, and menstrual status to healthy, sedentary control subjects. Comparisons were made between the three mutually exclusive patient groups and their matched control groups. Comparisons between patient groups could not be made because of demographic differences. Because pituitary–adrenal hormones are secreted in a pulsatile manner with both circadian and ultradian circadian rhythmicity, we employed a technique of intensive, frequent, discrete blood sampling across the 24-h hormonal cycle to characterize fully basal ACTH and cortisol secretion.

Section snippets

Subjects

All patients were recruited from rheumatology, infectious disease or primary care outpatient clinics at the University of Michigan Medical Center. One of three clinicians experienced in the diagnosis of FMS and CFS (LJC, NCE, and MAD) evaluated each patient. History and physical exam data were reviewed and consensus regarding patient diagnoses was reached among all clinicians. Diagnoses of FMS and/or CFS were made using 1990 American College of Rheumatology criteria and 1988 Center for Disease

Subject characteristics

Clinical characteristics of the study groups are reported in Table 1. CFS patients were younger and had a shorter duration of illness than patients with FMS.

Current and past psychiatric diagnoses in the mood and anxiety disorders realm are reported in Table 2. Current diagnoses in the anxiety disorders classification included only specific or social phobias and one patient with sub-threshold panic disorder which were not exclusionary. These anxiety disorders occurred in both patients and

Discussion

This study was designed to examine the hypothesis that patients with FMS, CFS, or both disorders exhibit baseline alterations of pituitary–adrenal function. There have been no previous studies in which patients with FMS, CFS, and FMS/CFS were examined separately using the same experimental design and conditions. We cannot directly compare patients groups, only the manner in which they differ from controls, due to group differences in age, gender, and hormonal status.

An identifiable circadian

Acknowledgments

The authors would like to acknowledge the invaluable assistance of our research assistants Emily Papadopoulos Somers, Lori Masterson, Katherine Spindler, Emily Dawson, and Kathryn Dalbec. We would also like to thank the nurses and staff of the GCRC without whom these studies could not have been completed. This work was supported by NIH RO1AR43148 and the University of Michigan General Clinical Research Center NIH MO1-RR00042.

References (42)

  • D. Catley et al.

    A naturalistic evaluation of cortisol secretion in persons with fibromyalgia and rheumatoid arthritis

    Arthritis Care Res.

    (2000)
  • G.P. Chrousos et al.

    The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis

    JAMA

    (1992)
  • D.J. Clauw et al.

    Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms

    Neuroimmunomodulation

    (1997)
  • L.J. Crofford et al.

    Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome

    Rheum. Dis. Clin. North Am.

    (2000)
  • L.J. Crofford et al.

    Hypothalamic–pituitary–adrenal axis perturbations in patients with fibromyalgia

    Arthritis Rheum.

    (1994)
  • Czeisler, C.A., 1995. The effect of light on the human circadian pacemaker. In: Chadwick, D.J., Ackrill, K. (Eds.),...
  • M.F. Dallman et al.

    Stress, feedback and facilitation in the hypothalamo–pituitary–adrenal axis

    J. Neuroendocrinol.

    (1992)
  • M.A. Demitrack et al.

    Evidence for impaired activation of the hypothalamic–pituitary–adrenal axis in patients with chronic fatigue syndrome

    J. Clin. Endocrinol. Metab.

    (1991)
  • M. Deuschle et al.

    Diurnal activity and pulsatility of the hypothalamus–pituitary–adrenal system in male depressed patients and healthy controls

    J. Clin. Endocrinol. Metab.

    (1997)
  • M. Follenius et al.

    Diurnal cortisol peaks and their relationship to meals

    J. Clin. Endocrinol. Metab.

    (1982)
  • Fukada, K., Straus, S.E., Hickie, I., Sharpe, M.C., Dobbins, J.B., Komaroff, A., group, I.c.f.s.s., 1994. The chronic...
  • Cited by (0)

    View full text