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NEUROENDOCRINE PERTURBATIONS IN FIBROMYALGIA AND CHRONIC FATIGUE SYNDROME
NEUROENDOCRINE MECHANISMS IN RHEUMATIC DISEASE
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NEUROENDOCRINE PERTURBATIONS IN FIBROMYALGIA AND CHRONIC FATIGUE SYNDROME Gunther Neeck, MD, and Leslie J. Crofford, MD
Because fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) share symptoms, it may be asked whether FMS and CFS are two entities or only two syndromes of a spectrum of similar disorders of common etiology and pathogenesis. The leading symptom of FMS is widespread pain of the locomotor system, but it affects two other systems, the autonomic nervous system and the psyche. The main symptom of CFS is fatigue, but pain in the locomotor system and other symptoms overlapping with FMS may also exist. An increasing amount of literature dealing with endocrine and neuroendocrine data has been published in the last several years on FMS and CFS. The central stress axis, the hypothalamic-pituitary-adrenal (HPA) axis, seems to play an important role in both conditions. Early investigations postulated hypofunction of the HPA axis in FMS and CFS based on the finding of low urine free cortisol and suggested the hypothesis of a common etiopathogenesis. It is increasingly clear that hyperactivity of the HPA axis is present in
Dr. Croffords work is supported by the University of Michigan Multipurpose Arthritis and Musculoskeletal Diseases Center P60-AR20557, the University of Michigan General Clinical Research Center, and ROI-AR43148.
From the Department of Rheumatology University of Giessen, Bad Nauheim, Germany (GN); and the Department of Internal Medicine, University of Michigan, AM Arbor, Michigan (LJC)
RHEUMATIC DISEASE CLINICS OF NORTH AMERICA VOLUME 26 * NUMBER 4 * NOVEMBER 2000
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FMS, whereas hypofunction of the HPA axis is typical, in CFS. One reason for confusion in endocrinologic research on FMS and CFS is the imprecise definition of both conditions, frequent overlap of FMS and CFS, and confounding psychiatric diagnoses that may also affect neuroendocrine axes. The results are strongly dependent on the patients selected for investigation. STRESS AND FIBROMYALGIA SYNDROME In attempting to summarize the current literature, there is a tendency to localize the primary disorder underlying FMS to the central nervous system (CNS)42A reduced pain threshold at the level of the CNS37seems to be the primary cause of a whole cascade of further abnormalities, including autonomic dysfunction, psychologic changes,65 and painful unrelaxed musculaturez0with changes that can be demonstrated ultrastructurally.46The early stages of the disease often involve a biomechanically caused local pain syndrome chiefly in the area of the axial ~ k e l e t o n If. ~this ~ local problem occurs against the background of altered sensitivity of the CNS’s processing of peripheral pain stimuli, potentially because of genetic causes,l early traumatization with severely stressful events,61 or both, the pain may spread beyond the original localization to encompass increasingly widespread areas of the locomotor system. The mechanisms underlying the development of widespread musculoskeletal pain are still unknown. Changes in the neurotransmitter systems, particularly substance P and serotonin, at centers at the level of the spinal cord level or higher have been proposed.50Overall, it is becoming increasing clear that the deficiency of a single neurochemical substance is not the cause of fibromyalgic symptomatology. Rather, a whole series of alterations in the set points of the CNS are the correlate with altered reactivity of the neuroendocrine axes in FMS.48FMS patients, show not only a reduced threshold for pain stimuli but a generally heightened sensitivity to stressful influences of various kinds. The term stress is complex and poorly defined to date. Since its initial description by Hans S e l ~ e it, ~has ~ become increasingly evident that the HPA axis plays a central role in the stress response. Activation of neurons that produce corticotropin-releasing hormone (CRH) in the hypothalamus has direct effects on CRH receptors in the brain. Stress, not only stimulates the pituitary-adrenal axis but, by way of secondary mediators, (e.g., somatostatin), a whole concert of further hypothalamichypophyseal interactions with a permanent effect on the regulation of peripheral glands (Fig. l)?z A wide range of different stimuli can activate the CRH-producing neurons. In addition to pain and emotional distress, various cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor stimulate CRH secretion. In postraumatic stress disorders, the change in the reactivity of the HPA axis seems to play an important role. The acute
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Higher Centers Stress (Pain, Cytokines,etc.)
ACTH
Cortisol
Gfl
IGF- 1
)
,/ T-4
TSH
PRL
T-3
LH
FSH
Estr
Figure 1. Model of CRH-driven hypothalamic hypophyseal interactions (incomplete) in fibromyalgia syndrome patients. CRH = corticotropin-releasinghormone; TRH = thyrotropinreleasing hormone; LHRH = luteinizing hormone-releasing hormone; ACTH = adrenocorticotropic hormone; GH =growth hormone; SOM =somatostatin; TSH = thyro-stimulating hormone; PRL= prolactin; LH = luteinizing hormone; FSH = follicle-stimulating hormone; IGF-1= insulin-like growth factor; Estr= estrogen. Solid arrows = plus, open arrow = minus.
stress event has long passed, but the CRH-producing neurons of the hypothalamus respond to comparatively banal stimuli of everyday life with a stress reaction. These individuals are, not only more prone to stress in a psychologic sense but also in a biologic sense. Fibromyalgia patients who have suffered sexual abuse or been the victims of torture could be subject to such mechanisms. In his theory on diseases of Adaptation, Hans Selye5*describes disease as caused either by hyperfunction or hypofunction of the hypophysis-adrenal cortex axis. Whereas FMS has been characterized primarily by hyperreactivity of the HPA axis, CFS, a syndrome with overlapping clinical features, is characterized more by hyporeactivity (Tables 1 and 2).11 STRESS AND CHRONIC FATIGUE SYNDROME
In one of the earliest descriptions of chronic fatigue, Sir Richard Manningham wrote in 1750 of "febricula" or "little fever", an illness characterized by profound lassitude accompanied by a large variety of constitutional complaints but few objective physical findings.15 Manningham noted the association of this condition with stressful circumstance~.'~ In the next century the appellation neurasfhenia was coined by Beard,6 referring to a lack of strength of the nervous system in patients with similar symptoms. In his initial description, he emphasized that neurasthenia arose from special exciting causes, including "the pressure of bereavement, business and family cares, parturition and abortion, sexual excesses, the abuse of stimulants and narcotics, and civilized
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Table 1. HYPOTHALAMIC-PITUITARY-ADRENALAXIS PERTUBATIONS IN FIBROMYALGIA SYNDROME ~~~~~
~
Basal cortisol Cortisol (blood) Cortisol 800 A.M. (plasma) Cortisol 8:00 A.M. (plasma) Cortisol (24-hour urinary excretion) Cortisol (saliva) Provocative testing cortisol Cortisol (CRH test)
High (McCain and Tilbe, 1989) Normal (Crofford et al, 1994) High (Crofford et al, 1994) Low (Crofford et al, 1994) Elevated (Catley et al, 2000)
Cortisol (corticotropin test) Cortisol (dexamethasone suppression test) Provocative testing corticotropin Corticotrapin (CRH test) Corticotropin (interleukin-6 injection)
Low (Griep et al, 1993) Normal to low (Crofford et al, 1994) Normal (Riedel et al, 1998) Normal (Griep et al, 1993) Normal to high (McCain and Tilbe, 1989) Normal to high (Ferraccioli et al, 1990) Normal to high (Crofford et al, 1994) High (Griep et al, 1993) High (Riedel et al, 1998) Peak delayed (Torpy et al, 2000)
Table 2. HYPOTHALAMIC-PITUITARY-ADRENALAXIS PERTUBATIONS IN CHRONIC FATIGUE SYNDROME ~~
~
Basal hormone levels CRH (cerebrospinal fluid) Corticotropin (plasma) Arginine vasopressin (plasma) Cortisol (24 hour urine free cortisol) Cortisol (plasma) Provocative testing Corticotropin (CRH stimulation)
Cortisol (CRH stimulation) Cortisol (insulin hypoglycemia) Cortisol (corticotropin stimulation) Corticotropin (fenfluramine stimulation) Cortisol (fenfluramine stimulation) Corticotropin (ipsapirone stimulation) Cortisol (ipsapirone stimulation)
t
= Increases;
.1
= Decreases.
Normal inappropriately (Demitrack et al, 1991) Elevated at 8:OO PM (Demitrack et al, 1991) Normal in AM (Scott et al, 1998) Low (Bakheit et al, 1993) Low (Demitrack et al, 1991) Low (Scott et al, 1998) Low at 8:OO PM (Demitrack et al, 1991) Blunted (Demitrack et al, 1991) Blunted (Scott et al, 1998) Blunted by desmopressin (DDAVP) (Scott et al, 1999) Normal (Demitrack et al, 1991) Blunted (Scott et al, 1998) Normal (Bearn et al, 1995) t Sensitivity, Capacity (Demitrack et al, 1991) Blunted (Scott et al, 1998) Exaggerated (Beam et al, 1995) Normal (Bearn et al, 1995) Normal (Yatham et al, 1995) Blunted (Dinan et al, 1997) Normal (Dinan et al, 1997)
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starvation.”(jAn alternate model of chronic fatigue associated with prolonged recovery from infectious illness emerged in the descriptions of chronic brucellosis. It was proposed that chronic infection could be responsible for cases previously labeled as neurasthenic.*I Follow-up studies rejected the hypothesis of ongoing infection, emphasizing the psychologic and emotional symptoms in patients with prolonged sympA study by Imboden et a131prospectively examined a population at risk for epidemic influenza, obtaining preillness psychologic ratings and then correlating persistence of symptoms such as fatigue, insomnia, headache, and depression with premorbid test results. The authors speculated that in patients with an evident preillness propensity to depression, there was a greater tendency for depressive symptoms during acute infection and an intermingling of depressive symptoms with weakness and fatiguability in the convalescent period.31 Demitrack and Abbey15 synthesized these historical considerations into a modem view of chronic fatiguing illnesses by noting that patients should be viewed as a heterogeneous group with a variety of infectious and noninfectious antecedents. As such, it is useful to formulate CFS as analogous to a number of complex medical conditions such as hypertension, where several direct and indirect factors (some of which may be psychologic) lead to the development of the observable clinical syndrome. Such an approach rejects a unitary causative event to explain the condition but allows for the presence of shared pathophysiologic processes and emphasizes the interactive relation among many disparate fa~t0rs.I~ Potential final common pathways in psychologic and somatic symptoms are the stress-response systems. CFS and related syndromes, including FMS, are associated with antecedent stress, and symptoms are exacerbated in response to perceived stress. It should be noted that stress responses are activated in response to heterogeneous exogenous or endogenous stressors. The peptide and hormone products of the stress response systems produce somatic and psychologic symptoms.’* The HPA axis comprises one of the major stress-response systems. Although alteration of HPA axis activity may generally be shared in stressassociated disorders characterized primarily by somatic symptoms (CFS and FMS) and psychiatric symptoms (depression and anxiety spectrum disorders), differences in the dominant symptomatic manifestations of these patient groups may be associated with specific patterns of dysregulation in the separate components of the HPA axis. EVIDENCE OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS HYPERFUNCTION IN FIBROMYALGIA SYNDROME
Nearly all studies that have investigated the function of the HPA axis in FMS patients have described elevated cortisol levels associated with a flattened diurnal pattern (see Table 1).McCain and Tilbe38com-
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pared morning and evening cortisol levels of FMS patients with those of patients suffering from rheumatoid arthritis. FMS patients showed a typical flattened diurnal cortisol secretion pattern, with elevated cortisol levels that could not be suppressed by dexamethasone administration. Similar findings were reported by Ferraccioli et al.24Crofford et al,13 also reported elevated plasma cortisol in the evening with a blunted diurnal rhythm. The finding of decreased urine free cortisol in this study was counter to the plasma results and could have represented altered circadian secretion of cortisol that was elevated during the daytime hours but depressed during the overnight period in this particular group of patients.13 To elucidate the question of whether this hormonal perturbation originates at the hypothaIamic or pituitary level, Griep et tested the HPA axis in patients with FMS and healthy controls by injecting CRH. This resulted in a markedly enhanced corticotropin release in FMS patients, although the cortisol response in the two groups did not differ, suggesting a reduced responsiveness of the adrenal cortex of FMS patients to corticotropin. Crofford et al,13 also reported CRH stimulation testing that revealed a tendency toward exaggerated corticotropin release with a blunted cortisol response. When synthetic corticotropin (1-24) was injected into patients with FMS, the increase in cortisol between FMS patients and controls was not significantly different.29This result points to a different susceptibility of adrenal cortical tissue to exogenous and endogenous corticotropin and does not support intrinsic insufficiency of the adrenal cortex in FMS. Conversely, the increased corticotropin secretion after administration of CRH combined with a blunted cortisol response in FMS might be caused by an adaptive mechanism of the adrenal cortex to chronic stress, possibly caused by downregulation of corticotropin recept0rs.2~. 40 The hyperreactivity of the HPA axis in patients with FMS seems to correlate to a great extent with the severity of mental depression.*,3, 45 Sachar51and Carroll et al,9 described corticotropin hypersecretion, and hypercortisolemia with flattening of the diurnal secretion pattern and resistance to the dexamethasone suppression test in depressed patients, and these hormonal perturbations correlated closely with the severity of depression. A similar cortisol secretion pattern in patients with FMS has been observed!, 24, 38 Depression may be an accompanying symptom in FMS, but it is not clear whether depression develops as a reaction to chronic pain or is a disease on its own within the FMS. Other diseases associated with hyperactivity of the HPA axis also frequently show symptoms of depression. Two thirds of patients with active Cushing's syndrome exhibit psychiatric symptoms resembling those of depressive illness. Patients suffering from extremely active rheumatoid arthritis exhibit a cortisol secretion pattern similar to that of Cushing's syndrome, which is frequently associated with mental depre~sion.~~ Studies of the hormonal profile of FMS patients employing stimulation of the various hormonal axes by way of the concomitant systemic
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injection of the hypothalamic-releasing hormones, CRH, thyrotropinreleasing hormone (TRH), growth hormone-releasing hormone, and luteinizing hormone-releasing releasing hormone have confirmed the findings reported in the literature and, in addition, provided evidence of a disturbed regulation of sex hormone production in female FMS patients, particularly that of The hormonal profile found in FMS provides support for the hypothesis that the syndrome involves alteration in integrated hormonal regulation as a common disorder. From this perspective, it is rather unlikely that disturbances of the individual hormonal axes play a causal role in FMS. Rather, the disturbance of the hormone balance in FMS is more appropriately regarded as the result of a reaction of the CNS to its main symptom, namely, to chronic pain of the musculoskeletal system. Although the site of the transformation of the pain signals in the CNS is not precisely localized, it is nevertheless regarded as established that the stress and pain signals reach the limbic system, which exerts activating and inhibitory effects on CRH neurons. It seems that the activating influences predominate during stress and pain. Besides its classic effect on the pituitary pro-opiomelanocortin-producing cells and the release of corticotropin, CRH functions as a neurotransmitter to stimulate numerous other CNS neurons. For example, it has been demonstrated that CRH increases the secretion of somatostatin in hypothalamic and cortical neur0ns.4~,~ By way of the hypothalamic-pituitary portal system, somatostatin reaches the hypophysis and inhibits the 23, secretion of growth hormone and thyroid-stimulating This physiologic mechanism offers an explanation for the observation of lowered plasma insulin-like growth factor-1 and thyroid hormone levels in FMS patients?, 43, 48 Additionally, numerous peripheral cells possess receptors for CRH, although the significance of this finding for FMS is unclear. The reduced sensitivity to stimulation by thyroid-stimulating hormone in FMS patients after systemic administration of TRH can also be accounted for by an elevated somatostatin level. In contrast, the lactotrophic cells of the hypophysis have no somatostatin receptors. The cause of the increased prolactin secretion resulting from systemic administration of TRH in FMS patients is probably hypothyreosis, which would be expected to increase TRH activity and, thus provide a chronic stimulating effect on the lactotropic cells of the hypophysis by way of the mechanism of negative feedback on the hypothalamus. A model of these hypothalamic-pituitary interactions is shown in Figure. 1. Increased CRH activity may additionally be influenced by other factors. Serotonin (5-HT) plays a pivotal role in the regulation of the HPA axis. In particular, 5-HT seems to be involved in the stimulation of corticotropin secretion during stress. CRH-containing neurons projecting from the paraventricular nucleus to the median eminence receive synaptic input from serotonin neurons projecting from the midbrain raphe nuclei. Serotonin stimulates the release of bio- or immunoassayable CRH from isolated rat hypothalamus in vitro.= A variety of drugs, including precursors of 5-HT such as tryptophan (5-HTP), drugs that release 5-HT
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such as fenfluramine, and drugs that act directly on 5-HT receptors such as ipsapirone, increase cortisol and corticotropin concentration^.'^ There is a general assumption that such stimulation occurs at the hypothalamic level. At least two distinct serotonin receptor subtypes can mediate this effect, the 5-HTIAand 5-HT2, receptors. It is also possible that the 5HT,, or other receptors could stimulate HPA axis Short-term effects should be differentiated from long-term effects. Acute administration of citalopram, a selective serotonin reuptake inhibitor, activates the HPA axis. Long-term citalopram treatment desensitizes the HPA axis, however, supporting the hypothesis that reduction of HPA axis responsiveness is caused by the therapeutic effect of long-term antidepressant treatment.32Interestingly, there exist gender differences in the HPA axis responsiveness to stress. For example, testosterone desensitizes HPA axis function and inhibits serotonergic a c t i ~ a t i o n . ~ ~ The physiologic role of the stimulatory serotonergic influence on HPA axis function is still not completely understood, but serotonin may play a role in circadian rhythmicity and HPA axis function by certain types of stress. Measurement of corticotropin or cortisol levels in human patients after administration of direct-or indirect-acting serotonin agonists and antagonists provides one means of probing the functional state of brain serotonergic systems in disease or after drug EVIDENCE OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS HYPOFUNCTION IN CHRONIC FATIGUE SYNDROME
In 1981, PoteliakhofP7reported that subjects with acute and chronic fatigue states showed reductions in plasma cortisol compared with nonfatigued individuals. In addition, he reported altered circadian variation in capillary resistance and eosinophil c0unts.4~A report of benign myalgic encephalomyelitis (an illness essentially identical to CFS) stated that only 1 of 16 subjects with this condition showed evidence of glucocorticoid nonsuppression after administration of dexamethasone which is an unexpectedly low percentage.6O As dexamethasone nonsuppression is thought to indicate increased central drive to cortisol production, these results may indicate reduced activity of the central components of the HPA axis. Patients with atypical depressive subtypes (e.g., atypical major depression, seasonal affective disorder, depressive syndromes associated with endocrinopathies) characterized by symptoms of reduced energy, hypersomnia, and hyperphagia, which overlap with symptoms of CFS, have also been reported to exhibit inappropriately normal or frankly 63 reduced activation of the HPA Early studies of the HPA axis in patients with CFS were performed by Demitrack et a1.I6These investigators reported low 24-hour urine free cortisol compared with that of control subjects. Baseline evening plasma corticotropin levels were elevated, and cortisol levels were depressed. The net integrated corticotropin response to ovine CRH was lower in
NEUROENDOCRINE PERTURBATIONS IN FMS AND CFS
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patients with CFS, and the cortisol levels remained lower throughout the stimulus, with a resulting normal net integrated response. In the same study, a dose response curve for corticotropin revealed increased sensitivity but decreased capacity for cortisol secretion.l6 Finally, the cerebrospinal fluid CRH levels were similar in patients and control subjects but were interpreted as inappropriately normal in light of low cortisol levels.16 A number of studies have subsequently been performed to evaluate the hypothesis that a hypofunctioning HPA axis is present in CFS patients (see Table 2). Scott and Dinan53were able to reproduce the finding of low urine free cortisol in patients with CFS compared with healthy controls. In addition, they reported blunted corticotropin and cortisol in response to administration of ovine CRH without differences in basal levels.54This same group reported blunted cortisol response to administration of 1 bg of corticotropin and that a subset of CFS patients selected for subnormal response to corticotropin stimulation had reduced adrenal size by computed t ~ m o g r a p h yAdditionally, .~~ the adrenal response to corticotropin with regard to dehydroepiandrosterone levels was b1~nted.I~ In studies performed by Bearn and colleague^,^ patients with CFS did not differ from controls in response to insulin-induced hypoglycemia challenge. To address the role of the corticotropin cosecretagogue arginine vasopressin (AVP) in patients with postviral fatigue syndrome (clinically indistinguishable from CFS), Bakheit et aI5measured baseline total body water, potassium, and glomerular filtration rate. Baseline measurements were followed by assessment of AVP secretion in response to serum osmolality changes during water deprivation and water loading testing5 Baseline AVP levels were low in patients compared with control subjects, although total body water was higher than predicted but still in the normal range. In addition, the close relation between serum and urine osmolality in healthy controls was not present in these patients with postviral fatigue syndrome. Of interest, a study in 1946 by Levy et a13'j in patients with chronic nerzlous exhaustion also showed abnormalities in a water loading test. As previously noted, AVP acts as a secretagogue for corticotropin, usually in conjunction with CRH. Scott et a155evaluated the ability of DDAVP to alter the response of CFS patients to ovine CRH. They found reduced CRH-induced corticotropin responses in the patients with CFS, and the cortisol responses were also reduced. Adding desmopressin to ovine CRH resulted in normalization of the corticotropin response in patients with CFS. These results suggest that there may be chronically low AVP with increased vasopressinergic responsivity of the anterior pituitary in CFS. As noted previously, serotonin generally acts to activate the HPA axis in the acute setting. There have been mixed results in tests employing serotonergic challenge in CFS. Bearn et a17 first reported that patients with CFS displayed exaggerated corticotropin but not cortisol in response to d-fenfluramine, which causes presynaptic release of serotonin. In a second study however, this group compared the response of
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d-fenfluramine in patients with CFS and major depressive disorder, demonstrating a reduced cortisol profile relative to depressed patients, although the response of healthy controls fell between that of the two patient groups.1' Yatham et aP7 reported no difference in the cortisol response between CFS and normal subjects after administration of d/lfenfluramine. Finally, Dinan et all8 reported that ipsapirone, a 5-HTIA agonist, challenge resulted in significantly blunted corticotroph but not cortisol release in patients with CFS. Based on the hypothesis that patients with CFS had mild glucocorticoid deficiency, a clinical trial of low-dose hydrocortisone as a treatment for CFS was undertaken by McKenzie and c011eagues.~~ The trial was a randomized, placebo-controlled, double-blind therapeutic trial conducted at a single site and enrolling 56 women and 14 men aged 18 to 55 years. Patients received 13 mg of hydrocortisone per square meter of body surface area in the morning and 3 mg of hydrocortisone per square meter of body surface area in the afternoon or placebo for a duration of 12 weeks. The primary outcome measures were a global wellness scale and other self-rating instruments. The percentage of patients showing improvement on the wellness scale was 66.7% in the treatment group and 54.3% in the placebo group ( P = 0.31); however, the treatment group had a significantly greater degree of improvement than did the controls ( P < 0.001). Statistical evidence of improvement was not seen with other self-rating scales. Additionally, suppression of adrenal glucocorticoid responsiveness was documented in 12 patients receiving hydrocortisone. Based on the minor level of improvement and evidence of toxicity, the treatment was not recommended by the authors.39 SUMMARY
A large body of data from a number of different laboratories worldwide has demonstrated a general tendency for reduced adrenocortical responsiveness in CFS. It is still not clear if this is secondary to CNS abnormalities leading to decreased activity of CRH- or AVP-producing hypothalamic neurons. Primary hypofunction of the CRH neurons has been described on the basis of genetic and environmental influences.'2 Other pathways could secondarily influence HPA axis activity, however. For example, serotonergic and noradrenergic input acts to stimulate HPA axis activity. Deficient serotonergic activity in CFS has been suggested by some of the studies as reviewed here. In addition, hypofunction of sympathetic nervous system function has been described and could contribute to abnormalities of central components of the HPA axis.'&17, One could interpret the clinical trial of glucocorticoid replacement in patients with CFS as confirmation of adrenal insufficiency if one were convinced of a positive therapeutic effect.39If patient symptoms were related to impaired activation of central components of the axis, replacing glucocorticoids would merely exacerbate symptoms caused by enhanced negative feedback. Further study of specific components of the
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HPA axis should ultimately clarify the reproducible abnormalities associated with a clinical picture of CFS. In contrast to CFS, the results of the different hormonal axes in FMS support the assumption that the distortion of the hormonal pattern observed can be attributed to hyperactivity of CRH neurons. This hyperactivity may be driven and sustained by stress exerted by chronic pain originating in the musculoskeletal system or by an alteration of the CNS mechanism of nociception. The elevated activity of CRH neurons also seems to cause alteration of the set point of other hormonal axes. In addition to its control of the adrenal hormones, CRH stimulates somatostatin secretion at the hypothalamic level, which, in turn, causes inhibition of growth hormone and thyroid-stimulating hormone at the pituitary level. The suppression of gonadal function may also be attributed to elevated CRH because of its ability to inhibit hypothalamic luteinizing hormone-releasing hormone release; however, a remote effect on the ovary by the inhibition of follicle-stimulatinghormone-stimulated estrogen production must also be considered. Serotonin (5-HT) precursors such as tryptophan (5-HTP), drugs that release 5-HT, or drugs that act directly on 5-HT receptors stimulate the HPA axis, indicating a stimulatory effect of serotonergic input on HPA axis function. Hyperfunction of the HPA axis could also reflect an elevated serotonergic tonus in the CNS of FMS patients. The authors conclude that the observed pattern of hormonal deviations in patients with FMS is a CNS adjustment to chronic pain and stress, constitutes a specific entity of FMS, and is primarily evoked by activated CRH neurons.4B
References 1. Ackenheil M Genetics and pathophysiology of affective disorders: Relationship to fibromyalgia. Z Rheumatol 57(suppl):5, 1998 2. Ahles TA, Yunus MB, Masi AT Is chronic pain a variant of depressive disease? The fibromyalgia syndrome. Pain 29:105, 1987 3. Ahles TA, Yunus MB, Riley SG, et al: Psychological factors associated with primary fibromyalgia syndrome. Arthritis Rheum 25:1101, 1984 4. Atkinson JH, Jr, Kremer EF, Risch SC, et al: Basal and postdexamethasone cortisol and prolactin concentrations in depressed and non-depressed patients with chronic pain syndromes. Pain 25:23, 1986 5. Bakheit AMO, Behan PO, Watson WA, et al: Abnormal arginine-vasopressin secretion and water metabolism in patients with postviral fatigue syndrome. Acta Neurol Scand 87234, 1993 6. Beard G: Neurasthenia, or nervous exhaustion. Boston Med Surg J 3:217, 1869 7. Beam J, Allain T, Coskeran P, et al: Neuroendocrine responses to d-fenfluramine and insulin-induced hypoglycemia in chronic fatigue syndrome. Biol Psychiatry 37245, 1995 8. Bennett RM, Clark SR, Campbell SM, et a 1 Low levels of somatomedin C in patients with the fibromyalgia syndrome. A possible link between sleep and muscle pain. Arthritis Rheum 35:1113, 1992 9. Carroll BJ, Feinberg M, Greden JF, et al: A specific laboratory test for the diagnosis of melancholia. Arch Gen Psychiatry 140338, 1981 10. Catley D, Kaell AT, Kirschbaum C, et al: A naturalistic evaluation of cortisol secretion
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in persons with fibromyalgia and rheumatoid arthritis. Arthritis Care and Research 13:51, 2000 11. Cleare AJ, Beam J, Allain T, et al: Contrasting neuroendocrine responses in depression and chronic fatigue syndrome. J Affect Disord 34:283, 1995 12. Crofford LJ, Demitrack MA: Evidence that abnormalities of central neurohormonal systems are key to understanding fibromylagia and chronic fatigue syndrome. Rheum Dis Clin North km 22267, 1996 13. Crofford LJ, Pillemer SR, Kalogeras KT, et al: Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia. Arthritis Rheum 371583, 1994 14. De Becher P, De Meirleir K, Joos E, et a1 Dehydroepiandrosterone (DHEA) response to i.v. ACTH in patients with chronic fatigue syndrome. Horm Metab Res 31:18, 1999 15. Demitrack MA, Abbey SE: Historical overview and evolution of contemporary definitions of chronic fatigue states. In Demitrack MA, Abbey SE (eds): Chronic Fatigue Syndrome. An Integrative Approach to Evaluation and Treatment. New York, Guilford Press, 1996, p 5 16. Demitrack MA, Dale JK, Straus SE, et al: Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinal Metab 73:1224, 1991 17. Demitrack MA, Gold PW, Dale JK, et al: Plasma and cerebrospinal fluid monoamine metabolism in patients with chronic fatigue syndrome: Preliminary findings. Biol Psychiatry 32:1065, 1992 18. Dinan TB, Majeed T, Lavelle E, et al: Blunted serotonin-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. Psychoneuroimmunology 22261, 1997 19. Dinan TG: Serotonin and the regulation of hypothalamic-pituitary-adrenal axis function. Life Sci 58:1683, 1996 20. Elert J, Rantapaa-Dahlqvist SB, Henriksson-Lars& K, et al: Muscle performance, electromyography and fibre type composition in fibromyalgia and work-related myalgia. Scand J Rheumatol 21:28, 1992 21. Evans A C Brucellosis in the United States. Am J Public Health 37139, 1947 22. Faria ACS, Veldhuis JD, Thorner MO, et al: Half-time of endogeneous growth hormone (GH) disappearance in normal man after stimulation of GH secretion by GH-releasing hormone and suppression with somatostatin. J Clin Endocrinol Metab 68:535, 1989 23. Ferland L, Labrie F, Jobin M, et al: Physiologic role of somatostatin in the control of growth hormone and thyrotropin secretion. Biochem Biophys Res Commun 68:149, 1976 24. Ferraccioli G, Cavalieri G, Salaffi F, et a1 Neuroendocrinologic findings in primary fibromyalgia and in other rheumatic conditions. J Rheumatol 17869, 1990 25. Fuller RW The involvement of serotonin in regulation of pituitary-adrenocortical function. Front Neuroendocrinol 13:250, 1992 26. Fuller RW Serotonin receptors and neuroendocrine responses. Neuropsychopharmacology 3:495, 1990 27. Fuller RW Serotonin receptors involved in regulation of pituitary-adrenocortical function in rats. Behav Brain Res 73215, 1996 28. Freeman R, Komaroff AL: Does the chronic fatigue syndrome involve the autonomic nervous system? Am J Med 102:357, 1997 De Kloet ER Altered reactivity of the hypothalamic-pituitary29. Griep EN, Boersma JW, adrenal axis in the primary fibromyalgia syndrome. J Rheumatol 20:469, 1993 30. Handa RJ, Burgess LH, Kerr JE, et a1 Gonadal steroid hormone receptors and sex differences in the hypothalamo-pituitary-adrenalaxis. Horm Behav 28:464, 1994 31. Imboden JB,Canter A, Cluff LE: Convalescence from influenza. Arch Intern Med 108:393, 1961 32. Jensen JB, Jessop DS, Harbuz MS, et al: Acute and long-term treatments with the selective serotonin reuptake inhibitor citalopram modulate the HPA axis activity at different levels in male rats. J Neuroendocrinol 11:465, 1999 33. Joseph-Vanderpool JR, Rosenthal NE, Chrousos GP, et al: Abnormal pituitary-adrenal responses to oCRH in patients with seasonal affective disorder: Clinical and pathophysiological implications. J Clin Endocrinol Metab 721382, 1991
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34. Kamilaris RC, DeBold CR, Pavlou SN, et al: Effect of altered thyroid hormone levels on hypothalamic-pituitary adrenal function. J Clin Endocrinol Metab 65:994, 1987 35. Kling MA, Roy A, Doran AR, et al: Cerebrospinal fluid immunoreactive CRH and ACTH secretion in Cushing’s disease and major depression: Potential clinical implications. J Clin Endocrinol Metab 72260, 1991 36. Levy LS, Power MH, Kepler EJ: The specificity of the “water test” as a diagnostic procedure in Addison’s disease. J Clin Endocrinol 6607, 1946 37. Lorenz J, Grasedyck K, Bromm B: Middle and long latency somatosensory evoked potentials after painful laser stimulation in patients with fibromyalgia syndrome. Electroencephalogh Clin Neurophysiol 100165, 1996 38. McCain GA, Tilbe K S Diurnal hormone variation in fibromyalgia syndrome: A comparison with rheumatoid arthritis. J Rheumatol 16(suppl):154, 1989 39. McKenzie R, OFallon A, Dale J, et al: Low-dose hydrocortisone for treatment of chronic fatigue syndrome. A randomized controlled trial. JAMA 2801061, 1998 40. Meerson FZ: Role of synthesis of nucleic acids and protein in adaptation to the external evironment. Physiol Rev 55:79, 1975 41. Muller W, Kelemen J, Stratz T Spinal factors in the generation of fibromyalgia syndrome. Z Rheumatol 57(suppl):36, 1998 42. Neeck G: From the fibromyalgia challenge towards a new bio-psycho-social model of rheumatic diseases. Z Rheumatol 57(suppl):A13, 1998 43. Neeck G, Federlin K, Graef V, et al: Adrenal secretion of cortisol in patients with rheumatoid arthritis. J Rheumatol 1724, 1990 44. Payne TC, Leavitt F, Garron DC, et al: Fibrositis and psychologic disturbance. Arthritis Rheum 25:213, 1984 45. Peterfreund RA, Vale WW: Ovine corticotropin-releasing factor stimulates somatostatin secretion from cultured brain cells. Endocrinology 112:1275, 1983 46. Pongratz DE, Spath M. Morphologic aspects of fibromyalgia. Z Rheumatol 57(suppl):47, 1998 47. Poteliakhoff A Adrenocortical activity and some clinical findings in acute and chronic fatigue. J Psychosom Res 25:91, 1981 48. Riedel W, Layka H, Neeck G: Secretory pattern of GH, TSH, thyroid hormones, ACTH, cortisol, FSH and LH in patients with fibromyalgia syndrome (FMS) following systemic injection of the relevant hypothalamic releasing-hormones. Z Rheumatol 57(suppl):81, 1998 49. Roozendaal MM, Swarts JJ, van Maanen JC, et al: Inhibition of the LH surge in cyclic rats by stress is not mediated by opioids. Life Sci 60:735, 1997 50. Russell IJ: Neurochemical pathogenesis of fibromyalgia syndrome. Journal of Musculoskeletal Pain 1:61, 1996 51. Sachar EJ: Neurocrine abnormalities in depressive illness. In Topics in Psychoendocrinology. New York, Grune & Stratton, 1975, p 135 52. Selye H: The Physiology and Pathology of Exposure to Stress. Montreal, Acta Medical Publishers, 1950 53. Scott LV, Dinan TG: Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers. J Affec Disord 4749, 1998 54. Scott LV, Medback S, Dinan T G Blunted adrenocorticotropin and cortisol responses to corticotropin-releasing hormone stimulation in chronic fatigue syndrome. Acta Psychiat Scand 97450, 1998 55. Scott LV, Medbak S, Dinan TG: Desmopressin augments pituitary-adrenal responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers. Bio Psychiatry 45:1447, 1999 56. Scott LV, Medbak S, Dinan TG: The low dose ACTH test in chronic fatigue syndrome and in health. Clin Endocrinol48:733, 1998 57. Scott LV, Teh J, Reznek R, et al: Small adrenal glands in chronic fatigue syndrome: A preliminary computer tomography study. Psychoneuroendocrinology24:759, 1999 58. Spink WW: What is chronic brucellosis? Ann Intern Med 35:358, 1951 59. Starkman MN, Schreingart ED, Schork M A Depressed mood and other psychiatric manifestations of Cushing’s syndrome. Relationship of hormone levels. Psychosom Med 43:3, 1981
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60. Taerk GS, Toner BB, Salit IE, et al: Depression in patients with neuromyasthenia (benign myalgic encephalomyelitis). Int J Psychiatry Med 1749, 1987 61. Taylor ML, Trotter DR, Csuka ME: The prevalence of sexual abuse in women with fibromyalgia. Arthritis Rheum 38229, 1995 62. Terry LC, Willoughby JO, Brazeau P, et aI: Antiserum to somatostatin prevents stress induced inhibition of growth hormone secretion in the rat. Science 192565, 1976 63. Tomori N, Suda S, Tozawa F, et al: Immunoreactive corticotropin-releasing factor concentrations in cerebrospinal fluid from patients with hypothalamic-pituitary-adrenal disorders. J Clin Endocrinol Metab 561305, 1983 64. Torpy DJ, Papanicolaou A, Lotsikas AJ, et al: Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6. Arthritis Rheum 43:872, 2000 65. Walter B, Vaitl D, Frank R: Affective distress in fibromyalgia syndrome is associated with pain severity. Z Rheumatol57(suppI):101, 1998 66. Wehrenberg WB, Janowski B, Piering AW, et al: Glucocorticoids: Potent inhibitors and stimulators of growth hormone secretion. Endocrinology 1263203, 1990 67. Yatham LN, Morehouse RL, Chishorm BT, et al: Neuroendocrine assessment of serotonin (5-HT) function in chronic fatigue syndrome. Can J Psychiatry 4093, 1995
Address reprint requests to Gunther Neeck, MD Kerckhoff Clinic and Foundation Department of Rheumatology Ludwigstrasse 37-39, 61231 Bad Nauheim, Germany e-mail: [email protected]
0889-857>(/00 $15.00
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NEUROENDOCRINE PERTURBATIONS IN FIBROMYALGIA AND CHRONIC FATIGUE SYNDROME Gunther Neeck, MD, and Leslie J. Crofford, MD
Because fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) share symptoms, it may be asked whether FMS and CFS are two entities or only two syndromes of a spectrum of similar disorders of common etiology and pathogenesis. The leading symptom of FMS is widespread pain of the locomotor system, but it affects two other systems, the autonomic nervous system and the psyche. The main symptom of CFS is fatigue, but pain in the locomotor system and other symptoms overlapping with FMS may also exist. An increasing amount of literature dealing with endocrine and neuroendocrine data has been published in the last several years on FMS and CFS. The central stress axis, the hypothalamic-pituitary-adrenal (HPA) axis, seems to play an important role in both conditions. Early investigations postulated hypofunction of the HPA axis in FMS and CFS based on the finding of low urine free cortisol and suggested the hypothesis of a common etiopathogenesis. It is increasingly clear that hyperactivity of the HPA axis is present in
Dr. Croffords work is supported by the University of Michigan Multipurpose Arthritis and Musculoskeletal Diseases Center P60-AR20557, the University of Michigan General Clinical Research Center, and ROI-AR43148.
From the Department of Rheumatology University of Giessen, Bad Nauheim, Germany (GN); and the Department of Internal Medicine, University of Michigan, AM Arbor, Michigan (LJC)
RHEUMATIC DISEASE CLINICS OF NORTH AMERICA VOLUME 26 * NUMBER 4 * NOVEMBER 2000
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FMS, whereas hypofunction of the HPA axis is typical, in CFS. One reason for confusion in endocrinologic research on FMS and CFS is the imprecise definition of both conditions, frequent overlap of FMS and CFS, and confounding psychiatric diagnoses that may also affect neuroendocrine axes. The results are strongly dependent on the patients selected for investigation. STRESS AND FIBROMYALGIA SYNDROME In attempting to summarize the current literature, there is a tendency to localize the primary disorder underlying FMS to the central nervous system (CNS)42A reduced pain threshold at the level of the CNS37seems to be the primary cause of a whole cascade of further abnormalities, including autonomic dysfunction, psychologic changes,65 and painful unrelaxed musculaturez0with changes that can be demonstrated ultrastructurally.46The early stages of the disease often involve a biomechanically caused local pain syndrome chiefly in the area of the axial ~ k e l e t o n If. ~this ~ local problem occurs against the background of altered sensitivity of the CNS’s processing of peripheral pain stimuli, potentially because of genetic causes,l early traumatization with severely stressful events,61 or both, the pain may spread beyond the original localization to encompass increasingly widespread areas of the locomotor system. The mechanisms underlying the development of widespread musculoskeletal pain are still unknown. Changes in the neurotransmitter systems, particularly substance P and serotonin, at centers at the level of the spinal cord level or higher have been proposed.50Overall, it is becoming increasing clear that the deficiency of a single neurochemical substance is not the cause of fibromyalgic symptomatology. Rather, a whole series of alterations in the set points of the CNS are the correlate with altered reactivity of the neuroendocrine axes in FMS.48FMS patients, show not only a reduced threshold for pain stimuli but a generally heightened sensitivity to stressful influences of various kinds. The term stress is complex and poorly defined to date. Since its initial description by Hans S e l ~ e it, ~has ~ become increasingly evident that the HPA axis plays a central role in the stress response. Activation of neurons that produce corticotropin-releasing hormone (CRH) in the hypothalamus has direct effects on CRH receptors in the brain. Stress, not only stimulates the pituitary-adrenal axis but, by way of secondary mediators, (e.g., somatostatin), a whole concert of further hypothalamichypophyseal interactions with a permanent effect on the regulation of peripheral glands (Fig. l)?z A wide range of different stimuli can activate the CRH-producing neurons. In addition to pain and emotional distress, various cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor stimulate CRH secretion. In postraumatic stress disorders, the change in the reactivity of the HPA axis seems to play an important role. The acute
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Higher Centers Stress (Pain, Cytokines,etc.)
ACTH
Cortisol
Gfl
IGF- 1
)
,/ T-4
TSH
PRL
T-3
LH
FSH
Estr
Figure 1. Model of CRH-driven hypothalamic hypophyseal interactions (incomplete) in fibromyalgia syndrome patients. CRH = corticotropin-releasinghormone; TRH = thyrotropinreleasing hormone; LHRH = luteinizing hormone-releasing hormone; ACTH = adrenocorticotropic hormone; GH =growth hormone; SOM =somatostatin; TSH = thyro-stimulating hormone; PRL= prolactin; LH = luteinizing hormone; FSH = follicle-stimulating hormone; IGF-1= insulin-like growth factor; Estr= estrogen. Solid arrows = plus, open arrow = minus.
stress event has long passed, but the CRH-producing neurons of the hypothalamus respond to comparatively banal stimuli of everyday life with a stress reaction. These individuals are, not only more prone to stress in a psychologic sense but also in a biologic sense. Fibromyalgia patients who have suffered sexual abuse or been the victims of torture could be subject to such mechanisms. In his theory on diseases of Adaptation, Hans Selye5*describes disease as caused either by hyperfunction or hypofunction of the hypophysis-adrenal cortex axis. Whereas FMS has been characterized primarily by hyperreactivity of the HPA axis, CFS, a syndrome with overlapping clinical features, is characterized more by hyporeactivity (Tables 1 and 2).11 STRESS AND CHRONIC FATIGUE SYNDROME
In one of the earliest descriptions of chronic fatigue, Sir Richard Manningham wrote in 1750 of "febricula" or "little fever", an illness characterized by profound lassitude accompanied by a large variety of constitutional complaints but few objective physical findings.15 Manningham noted the association of this condition with stressful circumstance~.'~ In the next century the appellation neurasfhenia was coined by Beard,6 referring to a lack of strength of the nervous system in patients with similar symptoms. In his initial description, he emphasized that neurasthenia arose from special exciting causes, including "the pressure of bereavement, business and family cares, parturition and abortion, sexual excesses, the abuse of stimulants and narcotics, and civilized
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Table 1. HYPOTHALAMIC-PITUITARY-ADRENALAXIS PERTUBATIONS IN FIBROMYALGIA SYNDROME ~~~~~
~
Basal cortisol Cortisol (blood) Cortisol 800 A.M. (plasma) Cortisol 8:00 A.M. (plasma) Cortisol (24-hour urinary excretion) Cortisol (saliva) Provocative testing cortisol Cortisol (CRH test)
High (McCain and Tilbe, 1989) Normal (Crofford et al, 1994) High (Crofford et al, 1994) Low (Crofford et al, 1994) Elevated (Catley et al, 2000)
Cortisol (corticotropin test) Cortisol (dexamethasone suppression test) Provocative testing corticotropin Corticotrapin (CRH test) Corticotropin (interleukin-6 injection)
Low (Griep et al, 1993) Normal to low (Crofford et al, 1994) Normal (Riedel et al, 1998) Normal (Griep et al, 1993) Normal to high (McCain and Tilbe, 1989) Normal to high (Ferraccioli et al, 1990) Normal to high (Crofford et al, 1994) High (Griep et al, 1993) High (Riedel et al, 1998) Peak delayed (Torpy et al, 2000)
Table 2. HYPOTHALAMIC-PITUITARY-ADRENALAXIS PERTUBATIONS IN CHRONIC FATIGUE SYNDROME ~~
~
Basal hormone levels CRH (cerebrospinal fluid) Corticotropin (plasma) Arginine vasopressin (plasma) Cortisol (24 hour urine free cortisol) Cortisol (plasma) Provocative testing Corticotropin (CRH stimulation)
Cortisol (CRH stimulation) Cortisol (insulin hypoglycemia) Cortisol (corticotropin stimulation) Corticotropin (fenfluramine stimulation) Cortisol (fenfluramine stimulation) Corticotropin (ipsapirone stimulation) Cortisol (ipsapirone stimulation)
t
= Increases;
.1
= Decreases.
Normal inappropriately (Demitrack et al, 1991) Elevated at 8:OO PM (Demitrack et al, 1991) Normal in AM (Scott et al, 1998) Low (Bakheit et al, 1993) Low (Demitrack et al, 1991) Low (Scott et al, 1998) Low at 8:OO PM (Demitrack et al, 1991) Blunted (Demitrack et al, 1991) Blunted (Scott et al, 1998) Blunted by desmopressin (DDAVP) (Scott et al, 1999) Normal (Demitrack et al, 1991) Blunted (Scott et al, 1998) Normal (Bearn et al, 1995) t Sensitivity, Capacity (Demitrack et al, 1991) Blunted (Scott et al, 1998) Exaggerated (Beam et al, 1995) Normal (Bearn et al, 1995) Normal (Yatham et al, 1995) Blunted (Dinan et al, 1997) Normal (Dinan et al, 1997)
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starvation.”(jAn alternate model of chronic fatigue associated with prolonged recovery from infectious illness emerged in the descriptions of chronic brucellosis. It was proposed that chronic infection could be responsible for cases previously labeled as neurasthenic.*I Follow-up studies rejected the hypothesis of ongoing infection, emphasizing the psychologic and emotional symptoms in patients with prolonged sympA study by Imboden et a131prospectively examined a population at risk for epidemic influenza, obtaining preillness psychologic ratings and then correlating persistence of symptoms such as fatigue, insomnia, headache, and depression with premorbid test results. The authors speculated that in patients with an evident preillness propensity to depression, there was a greater tendency for depressive symptoms during acute infection and an intermingling of depressive symptoms with weakness and fatiguability in the convalescent period.31 Demitrack and Abbey15 synthesized these historical considerations into a modem view of chronic fatiguing illnesses by noting that patients should be viewed as a heterogeneous group with a variety of infectious and noninfectious antecedents. As such, it is useful to formulate CFS as analogous to a number of complex medical conditions such as hypertension, where several direct and indirect factors (some of which may be psychologic) lead to the development of the observable clinical syndrome. Such an approach rejects a unitary causative event to explain the condition but allows for the presence of shared pathophysiologic processes and emphasizes the interactive relation among many disparate fa~t0rs.I~ Potential final common pathways in psychologic and somatic symptoms are the stress-response systems. CFS and related syndromes, including FMS, are associated with antecedent stress, and symptoms are exacerbated in response to perceived stress. It should be noted that stress responses are activated in response to heterogeneous exogenous or endogenous stressors. The peptide and hormone products of the stress response systems produce somatic and psychologic symptoms.’* The HPA axis comprises one of the major stress-response systems. Although alteration of HPA axis activity may generally be shared in stressassociated disorders characterized primarily by somatic symptoms (CFS and FMS) and psychiatric symptoms (depression and anxiety spectrum disorders), differences in the dominant symptomatic manifestations of these patient groups may be associated with specific patterns of dysregulation in the separate components of the HPA axis. EVIDENCE OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS HYPERFUNCTION IN FIBROMYALGIA SYNDROME
Nearly all studies that have investigated the function of the HPA axis in FMS patients have described elevated cortisol levels associated with a flattened diurnal pattern (see Table 1).McCain and Tilbe38com-
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pared morning and evening cortisol levels of FMS patients with those of patients suffering from rheumatoid arthritis. FMS patients showed a typical flattened diurnal cortisol secretion pattern, with elevated cortisol levels that could not be suppressed by dexamethasone administration. Similar findings were reported by Ferraccioli et al.24Crofford et al,13 also reported elevated plasma cortisol in the evening with a blunted diurnal rhythm. The finding of decreased urine free cortisol in this study was counter to the plasma results and could have represented altered circadian secretion of cortisol that was elevated during the daytime hours but depressed during the overnight period in this particular group of patients.13 To elucidate the question of whether this hormonal perturbation originates at the hypothaIamic or pituitary level, Griep et tested the HPA axis in patients with FMS and healthy controls by injecting CRH. This resulted in a markedly enhanced corticotropin release in FMS patients, although the cortisol response in the two groups did not differ, suggesting a reduced responsiveness of the adrenal cortex of FMS patients to corticotropin. Crofford et al,13 also reported CRH stimulation testing that revealed a tendency toward exaggerated corticotropin release with a blunted cortisol response. When synthetic corticotropin (1-24) was injected into patients with FMS, the increase in cortisol between FMS patients and controls was not significantly different.29This result points to a different susceptibility of adrenal cortical tissue to exogenous and endogenous corticotropin and does not support intrinsic insufficiency of the adrenal cortex in FMS. Conversely, the increased corticotropin secretion after administration of CRH combined with a blunted cortisol response in FMS might be caused by an adaptive mechanism of the adrenal cortex to chronic stress, possibly caused by downregulation of corticotropin recept0rs.2~. 40 The hyperreactivity of the HPA axis in patients with FMS seems to correlate to a great extent with the severity of mental depression.*,3, 45 Sachar51and Carroll et al,9 described corticotropin hypersecretion, and hypercortisolemia with flattening of the diurnal secretion pattern and resistance to the dexamethasone suppression test in depressed patients, and these hormonal perturbations correlated closely with the severity of depression. A similar cortisol secretion pattern in patients with FMS has been observed!, 24, 38 Depression may be an accompanying symptom in FMS, but it is not clear whether depression develops as a reaction to chronic pain or is a disease on its own within the FMS. Other diseases associated with hyperactivity of the HPA axis also frequently show symptoms of depression. Two thirds of patients with active Cushing's syndrome exhibit psychiatric symptoms resembling those of depressive illness. Patients suffering from extremely active rheumatoid arthritis exhibit a cortisol secretion pattern similar to that of Cushing's syndrome, which is frequently associated with mental depre~sion.~~ Studies of the hormonal profile of FMS patients employing stimulation of the various hormonal axes by way of the concomitant systemic
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injection of the hypothalamic-releasing hormones, CRH, thyrotropinreleasing hormone (TRH), growth hormone-releasing hormone, and luteinizing hormone-releasing releasing hormone have confirmed the findings reported in the literature and, in addition, provided evidence of a disturbed regulation of sex hormone production in female FMS patients, particularly that of The hormonal profile found in FMS provides support for the hypothesis that the syndrome involves alteration in integrated hormonal regulation as a common disorder. From this perspective, it is rather unlikely that disturbances of the individual hormonal axes play a causal role in FMS. Rather, the disturbance of the hormone balance in FMS is more appropriately regarded as the result of a reaction of the CNS to its main symptom, namely, to chronic pain of the musculoskeletal system. Although the site of the transformation of the pain signals in the CNS is not precisely localized, it is nevertheless regarded as established that the stress and pain signals reach the limbic system, which exerts activating and inhibitory effects on CRH neurons. It seems that the activating influences predominate during stress and pain. Besides its classic effect on the pituitary pro-opiomelanocortin-producing cells and the release of corticotropin, CRH functions as a neurotransmitter to stimulate numerous other CNS neurons. For example, it has been demonstrated that CRH increases the secretion of somatostatin in hypothalamic and cortical neur0ns.4~,~ By way of the hypothalamic-pituitary portal system, somatostatin reaches the hypophysis and inhibits the 23, secretion of growth hormone and thyroid-stimulating This physiologic mechanism offers an explanation for the observation of lowered plasma insulin-like growth factor-1 and thyroid hormone levels in FMS patients?, 43, 48 Additionally, numerous peripheral cells possess receptors for CRH, although the significance of this finding for FMS is unclear. The reduced sensitivity to stimulation by thyroid-stimulating hormone in FMS patients after systemic administration of TRH can also be accounted for by an elevated somatostatin level. In contrast, the lactotrophic cells of the hypophysis have no somatostatin receptors. The cause of the increased prolactin secretion resulting from systemic administration of TRH in FMS patients is probably hypothyreosis, which would be expected to increase TRH activity and, thus provide a chronic stimulating effect on the lactotropic cells of the hypophysis by way of the mechanism of negative feedback on the hypothalamus. A model of these hypothalamic-pituitary interactions is shown in Figure. 1. Increased CRH activity may additionally be influenced by other factors. Serotonin (5-HT) plays a pivotal role in the regulation of the HPA axis. In particular, 5-HT seems to be involved in the stimulation of corticotropin secretion during stress. CRH-containing neurons projecting from the paraventricular nucleus to the median eminence receive synaptic input from serotonin neurons projecting from the midbrain raphe nuclei. Serotonin stimulates the release of bio- or immunoassayable CRH from isolated rat hypothalamus in vitro.= A variety of drugs, including precursors of 5-HT such as tryptophan (5-HTP), drugs that release 5-HT
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such as fenfluramine, and drugs that act directly on 5-HT receptors such as ipsapirone, increase cortisol and corticotropin concentration^.'^ There is a general assumption that such stimulation occurs at the hypothalamic level. At least two distinct serotonin receptor subtypes can mediate this effect, the 5-HTIAand 5-HT2, receptors. It is also possible that the 5HT,, or other receptors could stimulate HPA axis Short-term effects should be differentiated from long-term effects. Acute administration of citalopram, a selective serotonin reuptake inhibitor, activates the HPA axis. Long-term citalopram treatment desensitizes the HPA axis, however, supporting the hypothesis that reduction of HPA axis responsiveness is caused by the therapeutic effect of long-term antidepressant treatment.32Interestingly, there exist gender differences in the HPA axis responsiveness to stress. For example, testosterone desensitizes HPA axis function and inhibits serotonergic a c t i ~ a t i o n . ~ ~ The physiologic role of the stimulatory serotonergic influence on HPA axis function is still not completely understood, but serotonin may play a role in circadian rhythmicity and HPA axis function by certain types of stress. Measurement of corticotropin or cortisol levels in human patients after administration of direct-or indirect-acting serotonin agonists and antagonists provides one means of probing the functional state of brain serotonergic systems in disease or after drug EVIDENCE OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS HYPOFUNCTION IN CHRONIC FATIGUE SYNDROME
In 1981, PoteliakhofP7reported that subjects with acute and chronic fatigue states showed reductions in plasma cortisol compared with nonfatigued individuals. In addition, he reported altered circadian variation in capillary resistance and eosinophil c0unts.4~A report of benign myalgic encephalomyelitis (an illness essentially identical to CFS) stated that only 1 of 16 subjects with this condition showed evidence of glucocorticoid nonsuppression after administration of dexamethasone which is an unexpectedly low percentage.6O As dexamethasone nonsuppression is thought to indicate increased central drive to cortisol production, these results may indicate reduced activity of the central components of the HPA axis. Patients with atypical depressive subtypes (e.g., atypical major depression, seasonal affective disorder, depressive syndromes associated with endocrinopathies) characterized by symptoms of reduced energy, hypersomnia, and hyperphagia, which overlap with symptoms of CFS, have also been reported to exhibit inappropriately normal or frankly 63 reduced activation of the HPA Early studies of the HPA axis in patients with CFS were performed by Demitrack et a1.I6These investigators reported low 24-hour urine free cortisol compared with that of control subjects. Baseline evening plasma corticotropin levels were elevated, and cortisol levels were depressed. The net integrated corticotropin response to ovine CRH was lower in
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997
patients with CFS, and the cortisol levels remained lower throughout the stimulus, with a resulting normal net integrated response. In the same study, a dose response curve for corticotropin revealed increased sensitivity but decreased capacity for cortisol secretion.l6 Finally, the cerebrospinal fluid CRH levels were similar in patients and control subjects but were interpreted as inappropriately normal in light of low cortisol levels.16 A number of studies have subsequently been performed to evaluate the hypothesis that a hypofunctioning HPA axis is present in CFS patients (see Table 2). Scott and Dinan53were able to reproduce the finding of low urine free cortisol in patients with CFS compared with healthy controls. In addition, they reported blunted corticotropin and cortisol in response to administration of ovine CRH without differences in basal levels.54This same group reported blunted cortisol response to administration of 1 bg of corticotropin and that a subset of CFS patients selected for subnormal response to corticotropin stimulation had reduced adrenal size by computed t ~ m o g r a p h yAdditionally, .~~ the adrenal response to corticotropin with regard to dehydroepiandrosterone levels was b1~nted.I~ In studies performed by Bearn and colleague^,^ patients with CFS did not differ from controls in response to insulin-induced hypoglycemia challenge. To address the role of the corticotropin cosecretagogue arginine vasopressin (AVP) in patients with postviral fatigue syndrome (clinically indistinguishable from CFS), Bakheit et aI5measured baseline total body water, potassium, and glomerular filtration rate. Baseline measurements were followed by assessment of AVP secretion in response to serum osmolality changes during water deprivation and water loading testing5 Baseline AVP levels were low in patients compared with control subjects, although total body water was higher than predicted but still in the normal range. In addition, the close relation between serum and urine osmolality in healthy controls was not present in these patients with postviral fatigue syndrome. Of interest, a study in 1946 by Levy et a13'j in patients with chronic nerzlous exhaustion also showed abnormalities in a water loading test. As previously noted, AVP acts as a secretagogue for corticotropin, usually in conjunction with CRH. Scott et a155evaluated the ability of DDAVP to alter the response of CFS patients to ovine CRH. They found reduced CRH-induced corticotropin responses in the patients with CFS, and the cortisol responses were also reduced. Adding desmopressin to ovine CRH resulted in normalization of the corticotropin response in patients with CFS. These results suggest that there may be chronically low AVP with increased vasopressinergic responsivity of the anterior pituitary in CFS. As noted previously, serotonin generally acts to activate the HPA axis in the acute setting. There have been mixed results in tests employing serotonergic challenge in CFS. Bearn et a17 first reported that patients with CFS displayed exaggerated corticotropin but not cortisol in response to d-fenfluramine, which causes presynaptic release of serotonin. In a second study however, this group compared the response of
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d-fenfluramine in patients with CFS and major depressive disorder, demonstrating a reduced cortisol profile relative to depressed patients, although the response of healthy controls fell between that of the two patient groups.1' Yatham et aP7 reported no difference in the cortisol response between CFS and normal subjects after administration of d/lfenfluramine. Finally, Dinan et all8 reported that ipsapirone, a 5-HTIA agonist, challenge resulted in significantly blunted corticotroph but not cortisol release in patients with CFS. Based on the hypothesis that patients with CFS had mild glucocorticoid deficiency, a clinical trial of low-dose hydrocortisone as a treatment for CFS was undertaken by McKenzie and c011eagues.~~ The trial was a randomized, placebo-controlled, double-blind therapeutic trial conducted at a single site and enrolling 56 women and 14 men aged 18 to 55 years. Patients received 13 mg of hydrocortisone per square meter of body surface area in the morning and 3 mg of hydrocortisone per square meter of body surface area in the afternoon or placebo for a duration of 12 weeks. The primary outcome measures were a global wellness scale and other self-rating instruments. The percentage of patients showing improvement on the wellness scale was 66.7% in the treatment group and 54.3% in the placebo group ( P = 0.31); however, the treatment group had a significantly greater degree of improvement than did the controls ( P < 0.001). Statistical evidence of improvement was not seen with other self-rating scales. Additionally, suppression of adrenal glucocorticoid responsiveness was documented in 12 patients receiving hydrocortisone. Based on the minor level of improvement and evidence of toxicity, the treatment was not recommended by the authors.39 SUMMARY
A large body of data from a number of different laboratories worldwide has demonstrated a general tendency for reduced adrenocortical responsiveness in CFS. It is still not clear if this is secondary to CNS abnormalities leading to decreased activity of CRH- or AVP-producing hypothalamic neurons. Primary hypofunction of the CRH neurons has been described on the basis of genetic and environmental influences.'2 Other pathways could secondarily influence HPA axis activity, however. For example, serotonergic and noradrenergic input acts to stimulate HPA axis activity. Deficient serotonergic activity in CFS has been suggested by some of the studies as reviewed here. In addition, hypofunction of sympathetic nervous system function has been described and could contribute to abnormalities of central components of the HPA axis.'&17, One could interpret the clinical trial of glucocorticoid replacement in patients with CFS as confirmation of adrenal insufficiency if one were convinced of a positive therapeutic effect.39If patient symptoms were related to impaired activation of central components of the axis, replacing glucocorticoids would merely exacerbate symptoms caused by enhanced negative feedback. Further study of specific components of the
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HPA axis should ultimately clarify the reproducible abnormalities associated with a clinical picture of CFS. In contrast to CFS, the results of the different hormonal axes in FMS support the assumption that the distortion of the hormonal pattern observed can be attributed to hyperactivity of CRH neurons. This hyperactivity may be driven and sustained by stress exerted by chronic pain originating in the musculoskeletal system or by an alteration of the CNS mechanism of nociception. The elevated activity of CRH neurons also seems to cause alteration of the set point of other hormonal axes. In addition to its control of the adrenal hormones, CRH stimulates somatostatin secretion at the hypothalamic level, which, in turn, causes inhibition of growth hormone and thyroid-stimulating hormone at the pituitary level. The suppression of gonadal function may also be attributed to elevated CRH because of its ability to inhibit hypothalamic luteinizing hormone-releasing hormone release; however, a remote effect on the ovary by the inhibition of follicle-stimulatinghormone-stimulated estrogen production must also be considered. Serotonin (5-HT) precursors such as tryptophan (5-HTP), drugs that release 5-HT, or drugs that act directly on 5-HT receptors stimulate the HPA axis, indicating a stimulatory effect of serotonergic input on HPA axis function. Hyperfunction of the HPA axis could also reflect an elevated serotonergic tonus in the CNS of FMS patients. The authors conclude that the observed pattern of hormonal deviations in patients with FMS is a CNS adjustment to chronic pain and stress, constitutes a specific entity of FMS, and is primarily evoked by activated CRH neurons.4B
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