Research report
Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers

https://doi.org/10.1016/S0165-0327(97)00101-8Get rights and content

Abstract

Urinary free cortisol excretion (UFC) was compared in 21 patients with chronic fatigue syndrome (CFS), in 10 melancholic depressives and in 15 healthy controls. Patients with depression had UFC values which were significantly higher than healthy comparison subjects, whereas UFC excretion of CFS patients was significantly lower than the comparison group. These findings are in keeping with currently held hypotheses of hyperactivity and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis in depression and chronic fatigue syndrome respectively. Five of the 21 CFS patients had a co-morbid depressive illness. This sub-group retained the profile of UFC excretion of those with CFS alone, suggesting a different pathophysiological basis for depressive symptoms in CFS.

Introduction

Chronic fatigue syndrome (CFS) is a clinically defined syndrome which has always provoked diagnostic controversy (David et al., 1988). Research in this area has been facilitated by the introduction of a working case definition and operational criteria which were first forwarded by the Centres for Disease Control (CDC) in 1988 (Holmes et al., 1988), with a subsequent review in 1994 (Fukuda et al., 1994). The syndrome consists essentially of persistent or relapsing fatigue for at least 6 months, and for its diagnosis any four of the following eight symptoms must be concurrently present at some time during this period: sore throat, enlarged and tender lymph glands, unrefreshing sleep, arthralgia, myalgia, post-exertional malaise, neuropsychological complaints and recurrent headaches. A co-morbid affective disorder does not preclude the diagnosis.

Many wide-ranging biological theories have been forwarded, most notably that of a viral aetiology (Jones et al., 1985, Dowsett et al., 1990), but these have not withstood the rigour of replication (Shorter, 1993). Recently, attempts have been made to explore the neuroendocrine profile of this condition both at the level of the hypothalamic-pituitary-adrenal axis (HPA) (Demitrack et al., 1991), the core stress axis in man (Selye, 1974), and more centrally at serotonergic (Bakheit et al., 1992, Bearn et al., 1995, Cleare et al., 1995, Dinan et al., 1997) and catecholaminergic functioning (Demitrack et al., 1989). Both of these neurotransmitter systems are also involved in the regulation of HPA activity (Plotsky et al., 1989, Dinan, 1996).

Corticotrophin-releasing hormone (CRH) is released from the paraventricular nucleus of the hypothalamus and impacts at the anterior pituitary bringing about the release of adrenocorticotropic hormone (ACTH), which stimulates the adrenal cortex resulting in cortisol production (Michelson et al., 1995). The HPA study by Demitrack (1991), performed in a group of CDC diagnosed CFS patients, demonstrated amongst other parameters low basal cortisol levels, low 24-h urinary free cortisol (UFC) levels and an elevated basal evening ACTH level.

Since the early 1960s, when the association of high cortisol levels with depression was first demonstrated (Gibbons and McHugh, 1963), there has been detailed exploration of the possible HPA and other neuroendocrine abnormalities in this disorder. Cortisol hypersecretion has since been shown using a number of simple measures including cortisol production rates (Gibbons, 1964), 24-h integrated plasma samples (Sherman et al., 1984) and 24-h urinary “free” cortisol levels (Carroll et al., 1976a). Studies of diurnal activity and pulsatility of the HPA system in depressed patients demonstrate a greater frequency (Deuschle et al., 1997), and magnitude of cortisol pulses (Linkowski et al., 1985) in this group.

That depressive and neuropsychiatric symptoms occur frequently in patients with CFS is well established (David et al., 1988, Straus, 1988), and has led to the suggestion that CFS occurs in individuals with a pre-morbid vulnerability to depression (Taerk et al., 1987), a suggestion that has been refuted by others (Hickie et al., 1990). The prevalence of current depressive disorder in CFS patients has ranged in studies from 14.5% (Hickie et al., 1990) to 67% (Manu et al., 1988), indicating its significance as a co-morbid condition, and raising the question of a possible pathophysiological overlap between the two conditions.

Examination of urinary free cortisol levels (UFC) over a 24-h period is a simple and non-invasive method of estimating overall daily cortisol production. UFC levels are considered to reflect the integrated unbound plasma cortisol levels and were originally used in detecting the hypercortisolism of Cushing's disease (Murphy, 1968, Murphy, 1991). UFC levels in depression have generally shown good agreement with plasma cortisol levels (Murphy, 1968, Stokes et al., 1984), and elevated levels are reduced by electroconvulsive therapy, mirroring clinical improvement (Kling et al., 1994). In addition to major depression and CFS, UFC levels have been examined in a number of other psychiatric disorders including obsessive–compulsive disorder (Gehris et al., 1990), dementia (Maeda et al., 1991) and mania (Swann et al., 1992) which show elevated levels, in post-traumatic stress disorder (Yehuda et al., 1995) which shows low levels and in social phobia (Uhde et al., 1994) in which the levels are normal. Fibromyalgia, a condition which overlaps symptomatically with CFS, is associated with reduced UFC levels (Crofford et al., 1994).

We chose to study the 24-h UFC profiles of a group of patients with CDC CFS and a group of melancholically depressed patients and compare them with healthy subjects in order to explore further the suggestions of a differing endocrinological profile.

Section snippets

Subjects

A total of 46 subjects participated in the study. All gave fully informed consent.The CFS group all of whom fulfilled the CDC criteria consisted of 14 women and 7 men with an age range of 21 to 66 years (mean±SEM, 36.1±2.9 years). Based on a clinical interview five of this group had a co-morbid psychiatric disorder fulfilling the DSM IV criteria for major depressive disorder with a mean±SEM, Hamilton depression score (HAMD; Hamilton, 1960) of 19±1.0. These were compared with ten patients (6

Method

Subjects were provided with a container for urine collection and it was explained that all urine within a 24-h period was to be included in the sample. Urinary free cortisol levels were measured by a specific RIA after extraction with dichloromethane (Diagnostic Product Corporation, Los Angeles, CA., 1991). The sensitivity of the assay is 28 nmol l−1, the lower limit of detection. The intra-assay coefficients variation (CVs) at urinary cortisol concentrations of 76 nmol l−1, 363 nmol l−1 and

Results

The mean±SEM UFC value of the CFS group was 116.1±10.7 nmol/24 h, of the depressives 252.7±33.3 nmol/24 h and of the control group 181.3±42.9 nmol/24 h Fig. 1. A one-way ANOVA yielded a between groups comparison which was highly significant (F=16.2, df=2, p<0.001). Planned comparisons were as follows: CFS vs depressives (p<0.01); CFS vs healthy controls (p<0.01); depressives vs healthy controls (p=0.027). No significant difference was found between UFC values of the depressed CFS, 95.2±17.4

Discussion

This to our knowledge is the first study in which, on a measure of cortisol production, patients with CFS have been directly compared with depressives and healthy controls. The UFC values of the depressed group were significantly greater than the control population, whereas the CFS group values were significantly lower, thus supporting a distinct endocrinology for the two conditions. Failure to find a correlation between UFC levels in the depressed group and HAMD scores is surprising, given

Acknowledgements

L. Scott is supported by a grant from the Linbury Trust.

References (55)

  • Carroll, B.J., Curtis, G.C., Mendels, M., 1976b. Cerebrospinal fluid and plasma free cortisol concentrations in...
  • L.J. Crofford et al.

    Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia

    Arthritis Rheum.

    (1994)
  • A. David et al.

    Myalgic encephalomyelitis or what?

    Lancet

    (1988)
  • M.A. Demitrack et al.

    Plasma and cerebrospinal fluid metabolism in patients with chronic fatigue syndrome: preliminary findings

    Biol. Psychiatry

    (1989)
  • M.A. Demitrack et al.

    Evidence for impaired activiation 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)
  • Diagnostic Product Corporation (DPC), Los Angeles, California,...
  • T.G. Dinan et al.

    Serotonin mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome

    Psychoneuroendocrinology

    (1997)
  • E.J. Dowsett et al.

    Myalgic encepmyelitis-a persistent viral infection?

    Postgrad. Med. J.

    (1990)
  • K. Fukuda et al.

    The chronic fatigue syndrome: a comprehensive approach to it's treatment and study

    Ann. Intern. Med.

    (1994)
  • J.L. Gibbons et al.

    Plasma cortisol in depressive illness

    Psychiatry Res.

    (1963)
  • J.L. Gibbons

    Cortisol secretion rate in depressive illness

    Arch. Gen. Psychiatry

    (1964)
  • P.W. Gold et al.

    Responses to cortciotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease

    New Engl. J. Med.

    (1986)
  • P.W. Gold et al.

    Corticotropin releasing hormone in the pathophysiology of melancholic and atypical depression and in the mechanism of action of antidepressant drugs. (Review)

    Ann. NY Acad. Sci.

    (1995)
  • M. Hamilton

    A rating scale for depression

    J. Neurol. Neurosurg. Psychiatry

    (1960)
  • I. Hickie et al.

    The psychiatric status of patients with chronic fatigue

    Br. J. Psychiatry

    (1990)
  • G.P. Holmes et al.

    Chronic fatigue syndrome-a working case defesnition

    Ann. Intern. Med.

    (1988)
  • Cited by (97)

    • Efficacy of Korean red ginseng (Panax ginseng) for middle-aged and moderate level of chronic fatigue patients: A randomized, double-blind, placebo-controlled trial

      2020, Complementary Therapies in Medicine
      Citation Excerpt :

      Several studies demonstrated the role of oxidative stress in CF and suggested the administration of antioxidants as a potential treatment.6,7 Some study indicated that altered cortisol levels are associated with CF and investigated the relationship by comparing cortisol excretion among CF, depression, and healthy subjects.8 In treatment, several therapies for CF have been introduced and the anti-fatigue effects of ginseng (Panax ginseng Meyer) have been reported by various studies.

    • A systematic review of the psychobiological burden of informal caregiving for patients with dementia: Focus on cognitive and biological markers of chronic stress

      2017, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      Taken together, these findings highlight risks to caregivers, as well as potential for intervention. Chronic excessive secretion of cortisol has been linked with numerous health problems, including hypertension and depression (e.g. Chrousus and Gold, 1998; Scott and Dinan, 1998). If the immune system is subjugated in response to challenge, then caregivers may experience greater adverse health events from infection (Kiecolt-Glaser et al., 1991).

    • Chronic Fatigue Syndrome

      2014, Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases
    • Chronic fatigue syndrome

      2012, Handbook of Clinical Neurology
      Citation Excerpt :

      However, other studies found no difference in salivary cortisol concentrations between CFS and healthy controls (Young et al., 1998; Gaab et al., 2002). A similar pattern of positive and negative studies has emerged in the examination of urinary free cortisol (UFC), with some studies finding no differences between CFS and control groups (Cannon et al., 1998; Hamilos et al., 1998; Young et al., 1998; Crofford et al., 2004; Inder et al., 2005) and others observing lower UFC levels in CFS (Demitrack et al., 1991; Scott and Dinan, 1998; Cleare et al., 2001a, b; Jerjes et al., 2006a). A morrecent study (Jerjes et al., 2006b) reported numerically, but not statistically, lower UFC levels in CFS compared to nonfatigued controls.

    View all citing articles on Scopus
    View full text