Neuroendocrine Abnormalities in Fibromyalgia and Related Disorders

Neuroendocrine Abnormalities in Fibromyalgia and Related Disorders LESLIE

J.

CROFFORD, MD

ABSTRACT: Fibromyalgia (FM) and related syndromes are poorly understood disorders that share symptoms such as pain, fatigue, sleep disturbances, and psychological distress. These syndromes are more common in women, and they are associated with psychological or physical stressors. The neuroendocrine axes are essential physiologic systems that allow for communication between the brain and the body. Interconnections among the neuroendocrine axes lead to coordinate regulation of these systems in both a positive and negative fashion. Several neuroendocrine axes have been shown to be dysfunctional in patients with FM. Although we do not yet understand the relationship between the reported disturbances of neuroendocrine function and the development or maintenance of FM and related syndromes, the authors have proposed that these abnormalities are important in symptomatic manifestations. This article reviews data showing disturbances of the neuroendocrine axes in FM and proposes a hypothesis of the development and maintenance of FM related to neuroendocrine disturbances. KEY INDEXING TERMS: Fibromyalgia; Hypothalamic-pituitary-adrenal axis; Neuroendocrine abnormalities. [Am J Med Sci 1998;315(6):359366.]

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itary gland act to stimulate synthesis of the endhormones that have direct effects on target tissues. Interconnections among the neuroendocrine axes lead to coordinate regulation of these systems in both positive and negative fashion. Fibromyalgia (FM) falls into the spectrum of what might be termed "stress-related syndromes," because of the increase in symptoms associated with physical or emotional stress. Dysregulation of the normal stress response can lead to abnormalities in both physical and behavioral adaptation that may mimic some of the clinical symptoms of FM. Other conditions that share substantial symptomatic overlap with FM (chronic fatigue syndrome, irritable bowel syndrome, chronic headaches, dysmenorrhea, irritable bladder syndrome, and temporomandibular disorder) are also thought to be associated with stress. 1 The hypothalamic-pituitary-adrenal (HPA) axis is generally considered to playa pivotal role in the coordinated physiologic response to physical and emotional stress. We and others have described disturbances in basal and stimulated function of the HPA axis in patients with FM. 1 ,3 In addition, there are clinical clues available suggesting the potential importance of the hypothalamic-pituitary-gonadal (HPG) axis, most important, the preponderance of these stress-related syndromes in women. Several groups have investigated the growth hormone axis in FM and have found disturbances that may also be relevant to the clinical symptoms of FM. We will summarize the physiology of the major neuroendocrine axes that may be important in FM and other related disorders. We will also review the primary research findings of perturbed neuroendocrine function in FM. Finally, a hypothesis of the development and maintenance ofFM related to neuroendocrine disturbances will be advanced.

he neuroendocrine axes are essential physiologic systems that allow communication between the brain and the body. Input from higher cortical centers and information from the periphery is integrated at the level of the hypothalamus, which produces releasing hormones that act on the pituitary gland (Fig. 1). Hormones of the anterior pitu-

The Hypothalamic-Pituitary-Adrenal Axis

From the Department of Internal Medicine, Division ofRheumatology, University of Michigan, Ann Arbor, Michigan. Correspondence: Leslie J. Crofford, MD, Division of Rheumatology, University of Michigan, Room 5510E MSRB I, 1150 West Medical Center Drive, Ann Arbor, MI48109-0680.

Regulation of the HPA axis involves a complex array of biochemical events occurring principally among the hypothalamus, anterior pituitary, and the cortex of the adrenal gland. 2 Key among these biochemical signals are corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), which

THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

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Neuroendocrine Abnormalities in Fibromyalgia

Neuroendocrine Axes Input from brain centers

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Figure 1. Neuroendocrine axes. Input from peripheral and brain pathways are integrated in the hypothalamus, which secretes releasing hormones into the hypophyseal-portal circulation. Releasing hormones act on responsive cells in the anterior pituitary. The hormones secreted from the pituitary act both on their target organ and in some instances on other target tissues. Final products have multiple physiologic effects on target tissues in the peripherally and centrally.

are neurohormones with cell bodies in the medial parvocellular division of the paraventricular nucleus (PVN) of the hypothalamus. From there, neuronal projections transport CRH and AVP to the external layer of the median eminence. CRH is also widely distributed in other, extrahypothalamic locations, including the limbic system, cerebral cortex, midbrain areas, pons, and medulla. Acute stress results in the release of these peptides into the hypophyseal portal plexus. Stimulation of specific receptors for CRH and AVP on the corticotroph cells of the anterior pituitary results in the release of adrenocorticotropic hormone (AC'1'H) into the systemic circulation, primarily affecting glucocorticoid release from the adrenal cortex. CRH and AVP act synergistically, with AVP causing a tremendous amplification of CRH-induced release of ACTH. Indeed, evidence supports a role for AVP in sustaining the activation of the HPA axis during chronic stress. 3 Complex short and long negative feedback circuits, primarily mediated by specific glucocorticoid receptors (the so-called Type I and Type II receptors), converge to terminate activation of the HPA axis. Fast, or rate-sensitive, feedback is responsive to the rate of rise of circulating glucocorticoids, and

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occurs within minutes of activation of the axis. Delayed, or genomic, feedback is mediated via specific types of glucocorticoid receptors that inhibit transcription of critical genes such as those for the ACTH propeptide, and parvocellular CRH and Avp.3 The specific mechanisms underlying these and other modes of feedback inhibition remain ill defined. The particular suprahypothalamic biochemical signals that affect activation of hypothalamic CRH and AVP in response to stress are equally complex, involving both peptide and catecholamine-containing neural pathways.2 Such pathways are usually redundant circuits, and are often composed of neuronal terminals which co-localize several peptide and nonpeptide elements. Less well studied than these biochemical signals, but of equal importance, are several specific neural circuits that have regulatory effects on the HPA axis. These areas include the amygdala, hippocampus, septal area, cingulate cortex, and certain brainstem regions. 4 In addition to its stress-dependent activation, the HPA axis exhibits a pronounced spontaneous near 24-hour, or circadian, rhythm. In humans, this circadian rhythm is entrained to the light-dark and sleepwake cycles, 5 with the trough in activity occurring in the evening and early night and the peak in activity occurring just before waking. Stress-induced secretion is superimposed on this basal circadian rhythm. There is evidence that the stress responsiveness and negative feedback regulation of the HPA axis varies across the day, and hence specific alterations in the timing, intensity, and duration of any stressor may result in widely varying patterns ofHPA axis perturbation. It is thought, however, that under normal conditions the HPA axis may be a "closed loop" system, such that activation of cortisol secretion by stress will result in a compensatory decrease in circadian drive for cortisol secretion with maintenance of 24-hour integrated cortisol levels in the "normal" range. HPA Axis Dysregulation in FM and Other Stress-Related Syndromes

Our group has proposed that the phenomenologic overlap between FM and a variety of "stress-related" somatic and psychiatric syndromes reflects the involvement of a shared final pathway, the HPA axis, that may be perturbed as the result of a disparate variety of antecedent events. l ,3 However, the pattern of HPA axis response appears to diverge among these conditions, with exaggerated activity (physiologic hyperarousal) in FM and blunted activity in chronic fatigue syndrome (CFS). We have focused on the central component of the HPA axis as a particularly useful area of study for establishing and integrating the underlying pathophysiology of these syndromes. The earliest studies of stress-response systems in June 1998 Volume 315 Number 6

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human disease states led to the observation that patients with major depression demonstrate a characteristic disruption of the normal circadian rhythmicity of the pituitary-adrenal axis. 6 This disturbance involves an elevation of adrenal glucocorticoid output, usually seen as an earlier onset of the morning surge of the axis, in conjunction with enhanced cortisol secretion in the late afternoon. Aberrant feedback regulation of the axis was suggested by studies employing the synthetic glucocorticoid, dexamethasone. 7 On the basis of this work, a model of HPA axis dysregulation was developed which suggests that there is an excessive central release of CRH in some cases of major depression. In recent years, however, it has become increasingly apparent that depression is a heterogeneous condition from both a psychological and a physiologic perspective. The initial investigations of the neuroendocrine correlates of depression largely concerned the more classical, melancholic form of depression, which is characterized by increased agitation, loss of sleep, loss of interest in all activities, persistent suicidal thoughts, and reduced appetite and libido. More recently, several alternate forms of depressive illness have been characterized that lack these melancholic features. These depressive subtypes are of particular interest because oftheir overlap with the symptoms of FM and CFS. They are usually dominated by reduced energy, a reactive mood, and a reversal ofthe typical pattern ofvegetative features seen in classical depression. Recent evidence suggests a pattern of HPA function in some of these syndromes reflecting inappropriately normal or frankly reduced activation of the axis. 2 It has been hypothesized that one of the principal features ofthe HPA axis disturbance in these conditions may be a functional deficit in the release of hypothalamic CRH. This is of interest because CRH serves not only as a principal stimulus to the HPA axis, but also is a behaviorally active neurohormone whose central administration to animals and nonhuman primates induces signs of physiologic and behavioral arousal, including activation ofthe sympathetic nervous system, hyperresponsiveness to sensory stimuli, and increased 10comotion. 2 However, posttraumatic stress disorder (PTSD) is also characterized by low levels of cortisol which were shown to be due to enhanced glucocorticoid negative feedback rather than low levels of CRH. S The clinical similarity of FM and CFS to some forms of depression, and the increased lifetime incidence of psychiatric conditions, provoked further interest in examining the specific neuroendocrine characteristics of patients with FM and CFS. In 1981, Poteliakhoff reported that subjects with both acute and chronic fatigue states showed reductions in plasma cortisol compared to nonfatigued individuals, along with altered circadian variation in capilTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

lary resistance and eosinophil counts. 9 These results are of interest because they suggest that even quite mild decrements in circulating glucocorticoids may be associated with measurable physiologic changes. In a report of benign myalgic encephalomyelitis (an illness essentially identical to CFS), only one of 16 subjects showed evidence of glucocorticoid nonsuppression after dexamethasone. 1o Demitrack et al reported reduced urine free cortisol in association with inappropriately low concentrations of CRH and ACTH in the cerebrospinal fluid, low evening plasma cortisol, elevated evening plasma ACTH with blunted response to exogenous administration of ovine CRH, and altered responsiveness of the adrenal cortex to graded doses of ACTH.11 Bearn et al reported that patients with CFS did not differ from controls in response to insulin challenge, but displayed exaggerated ACTH, but not cortisol, response to d-fenfluramine, which causes presynaptic release of serotonin. 12 In a related study, this group compared the response to d-fenfluramine in patients with CFS and those with major depressive disorder, demonstrating a reduced cortisol profile relative to depressed patients, while healthy controls fell between the two patient groupS.13 In contrast, Yatham et al reported no difference in the cortisol response between CFS and normal subjects after administration of d-fenfluramine. 14 In contrast to patients with CFS, up to 35% of patients with FM showed abnormal suppression after dexamethasone. 15,16 McCain and Tilbe reported that patients with FM had reduced 24-hour urine free cortisol excretion, but a loss of the circadian fluctuation of glucocorticoid levels with elevated levels during the circadian nadirY Griep et al reported exaggerated ACTH, but blunted cortisol response to exogenous administration of human CRH and to insulin-induced hypoglycemia. 1s We also found a loss of circadian fluctuation of plasma cortisol in patients with FM because of elevated evening levels, with reduced overall 24-hour urine free cortisol excretion that could not be explained by excess cortisol binding globulin. 19 On provocative challenge with ovine CRH, there was a trend toward increased ACTH, but blunted cortisol response to exogenous CRH, similar to the findings of Griep. 19 In a paradigm employing a different kind of hypoglycemic challenge where the rate of decline in blood glucose is carefully titrated or clamped, Adler et al reported reduced ACTH secretion with a cortisol response that was not different from control subjects. 2o Despite some similarities in overall adrenocortical function, closer observation reveals distinct HPA axis profiles in FM and CFS (Table 1). One possibility that could explain differential ACTH responses to stimulation is a difference in the levels of the ACTH co-secretagogue, AVP . We reported that there was no significant difference in plasma AVP levels between patients with 361

Neuroendocrine Abnormalities in Fibromyalgia

Table 1. Comparison ofHPA Axis Parameters in Fibromyalgia and Chronic Fatigue Syndrome Fibromyalgia Brain

Pituitary Adrenal

Diurnal rhythm Cerebrospinal fiuidlCRH PlasmaAVP (magnocellular) Insulin-induced hypoglycemia (acute) Hypoglycemic clamp (gradual) Serotonergic challenge Basal ACTH CRH challenge Basal cortisol 24-h urine free cortisol ACTH challenge

Normal Exaggerated ACTH Normal AM, elevated Decreased Normal

CRH challenge

Blunted cortisol

Chronic Fatigue Syndrome

Blunted Normal or elevated

Reduced Reduced

Exaggerated ACTH, blunted cortisol

Normal

Blunted ACTH, NI cortisol

PM

Exaggerated ACTH, blunted cortisol Elevated PM Blunted ACTH Decreased PM Decreased Increased sensitivity, decreased capacity Normal

HPA = hypothalamic-pituitary-adrenal; CRH = corticotropin-releasing hormone; AVP = arginine vasopressin; ACTH = adrenocorticotropic hormone.

FM and healthy controls, but five of 12 subjects had levels that were two standard deviations higher than control subjects. 19 On the other hand, Bakheit et al reported reduced AVP levels in response to fluid restriction in patients with CFS.21 It must be noted than these measurements of circulating AVP reflect activity of magnocellular, not parvicellular, hormone levels; however, central and peripheral compartments are often similarly dysregulated. Certainly, multiple other pathways and mediators impact the activity of the HPA axis. These modulators originate both peripherally (glucocorticoid negative feedback mechanisms) and centrally (interactions with adrenergic, serotonergic, or other neuronal pathways). Differences and similarities between FM, CFS, and other stress-related syndromes could be due to "upstream" modulators of HPA axis activity. The Hypothalamic-Pituitary-Gonadal Axis

FM is far more common in women than in men. This striking epidemiologic observation supports examination of the reproductive axis and its effects on other neuroendocrine systems. The secretion of the principal gonadal steroids in women, estrogen and progesterone, is controlled by cyclic changes in ovarian follicular and corpus luteum development over the course ofthe menstrual cycle. The hypothalamic peptide, gonadotropin-releasing hormone (GnRH), is critical to the proper functioning and timing of the monthly hormonal cycle. GnRH secretion drives production of luteinizing hormone (LH) and folliclestimulating hormone (FSH) from pituitary gonadotrophs. FSH plays the major role in maturing ovarian follicles during the follicular phase of the menstrual cycle. As the follicle develops, estradiol exerts negative feedback on FSH, and negative and de-

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layed-positive feedback on LH. The change in estradiol feedback from negative to positive late in the follicular phase is complemented by rising progesterone, and results in the mid-cycle surge in LH necessary for ovulation. Progesterone levels continue to rise as a result of active secretion from the corpus luteum. LH secretion is necessary for the maintenance of the corpus luteum. In the absence offertilization, the corpus luteum regresses, with subsequent decrease in the production of estrogen and progesterone. The secretion of GnRH is driven by a pulse generator in the arcuate nucleus of the hypothalamus. The time series pattern of individual GnRH pulses controls the frequency and amplitude of LH pulses. Gonadal steroids exert negative feedback effects on the amplitude and frequency of GnRH pulses. The pulsatile pattern of GnRH secretion is critical; indeed, continuous administration of GnRH in a non puIs atile pattern results in the suppression of ovulation. In fact, studies in primates have shown that administration of GnRH in pulses that are too fast or too slow result in low serum concentration ofLH. Additionally, different frequencies of GnRH pulses differentially regulate mRNA for the noncommon subunit of LH and FSH, demonstrating that pulse frequency carries substantial information. In humans, the follicular phase of the menstrual cycle is characterized by a reasonably constant amplitude of LH pulses every 1 to 2 hours, while in the luteal phase, pulse amplitude becomes much more variable and pulse frequency decreases to one pulse every 2 to 6 hours. Reciprocal Interactions Between the HPA and HPG Axes

The effect of "stress" on reproduction has long been recognized. Studies of the effects of HPA axis June 1998 Volume 315 Number 6

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hormones on the HPG axis have revealed that CRH inhibits GnRH secretion. 22 Central opioids, particularly ,B-endorphin, exert tonic inhibition of GnRH secretion and CRH can regulate ,B-endorphin release in the arcuate nucleus. 22 Therefore, CRH has both direct and indirect effects on GnRH secretion. In addition to CRH, ACTH administration reduces the increase in serum LH concentrations following gonadectomy.22 This effect is dependent on the presence of the adrenal gland, and may involve adrenal production of gonadal steroids that are regulated by ACTH. Glucocorticoids may also exert inhibitory effects on GnRH secretion or LH responsiveness to GnRH, including direct effects of cortisol on the gonadotroph. 22 Not only do HPA axis stress hormones modulate the function of the HPG axis, but a reciprocal relationship between these two neuroendocrine axes also exists. There is clear sexual dimorphism ofHPA axis activity mediated by gonadal steroids. The glucocorticoid response to stress differs in male and female rats, with female rats demonstrating a faster onset of secretion and a faster rate of rise. A steeper rate of rise is necessary to trigger fast glucocorticoid negative feedback.23 These data have been explained as an accommodation to the higher levels of corticosteroid binding globulin (CBG), the principal binding protein for circulating glucocorticoids whose levels are positively regulated by estrogen and thus is higher in female rats. However, studies also indicate that estrogen interferes with glucocorticoid negative feedback in the hippocampus, leading to increased HPA axis activity.23 The finding of a partial estrogen-responsive transcriptional element in the CRH gene suggests that estrogen could regulate CRH production. 23 Progesterone may also be able to bind to the glucocorticoid receptor, and may therefore also act as a competitive inhibitor for glucocorticoid negative feedback.22 The Reproductive Axis in Patients With Fibromyalgia

As previously noted, FM is far more common in women, occurring at a ration of about 9 : 1. Other stress-related syndromes also occur with increased incidence in women, although the predominance varies. In addition, clinical and epidemiologic data suggest that there is a peak incidence of FM around the time of menopause. Nevertheless, there are scant data regarding HPG axis hormones in patients with FM. In one study by Waxman and Zatzkis, 65% of patients with FM experienced menopause prior to the onset on FM.24 Of those patients, about 32% had undergone bilateral salpingo-oophorectomy, 46% had abdominal hysterectomy and/or unilateral salpingo-oophorectomy, and 21% had natural menopause. In this study, FM patients between the ages of 24 and 45 were found to be prematurely menopausal about 30% ofthe time. Taken together, these THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

observations suggest an influence of sex steroid hormones on the development of FM, but more work must be done to confirm these observations. The Growth Hormone Axis

Growth, along with reproduction, is a so-called vegetative function whose activity is diminished by stress. The hypothalamic-pituitary-insulin-like growth factor I axis is also profoundly influenced by sleep. The pulsatile secretion of growth hormone is controlled by both positive and negative regulatory peptides. Growth hormone-releasing hormone stimulates secretion, while somatostatin inhibits growth hormone release. The growth hormone axis is influenced by a number of central inputs, with increased secretion by adrenergic stimuli, serotonin, and excitatory amino acids. 25 On the other hand, CRH increases somatostatin levels and thereby inhibits secretion of growth hormone. 2 Growth hormone induces secretion ofIGF-I from the liver, which exerts effects on multiple target tissues. 25 Bennett et al initially measured levels of insulinlike growth factor I (IGF-I) in FM hypothesizing that sleep disruption in patients could lead to hyposecretion of growth hormone. Patients with FM were found to have hypoactivity of the growth hormone axis, as measured by insulinlike growth factor I (IGF-I), an important mediator of growth hormone activity.25,26 In a large series of patients, the cause oflow IGF-I levels could not be explained by medications or clinical features (including level of pain, duration of disease, poor aerobic fitness, obesity, depression).25 In addition, the authors felt it was likely that low IGF-I levels were a secondary consequence, rather that a primary event, because levels tended to fall in patients with an initially normal level of IGF-I. 25 Bennett et al also performed stimulation testing using clonidine and L-dopa to assess the pituitary component of the axis. The majority of patients with FM who had low IGF -I levels had abnormal stimulation testing with markedly reduced stimulation of growth hormone secretion. 25 A study from Griep et al using insulin-induced hypoglycemia to provoke neuroendocrine response showed enhanced secretion of growth hormone. 27 Both clonidine and L-dopa stimulate release of growth hormone by inhibiting somatostatin secretion, the negative regulator for growth hormone release. Hypoglycemia, on the other hand, is a more complex stimulus that increases secretion of several hormones. Other studies confirm differences in IGF-I levels between FM patients and control subjects27,28; however, some authors have been unable to reproduce the finding. 29,30 The study by Buchwald et al did not find significantly low levels of IGF-I, but did demonstrate that 20% of the FM patients had levels of IGF-I below the normal range. 29 As discussed by Bennett et aI, deficient func-

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tion of the growth hormone axis could contribute to symptoms in FM patients, particularly reduced exercise capacity and decreased psychological wellbeing. 25

Variability of Neuroendocrine Responses • • • •

Genetics Gender Childhood stressors Adult stressors

A Neuroendocrine Hypothesis of Vulnerability to FM

The concept that disorders such as FM might be associated with "subtle and undetectable" disturbances in the central nervous system was introduced in the 1869 by Beard in his description ofneurasthenia, a syndrome with marked somatic and constitutional complaints but few physical findings. 31 Progress has been made in recent years toward defining neuroendocrine abnormalities and other abnormalities of neuropeptides. We do not yet understand the relationship between the reported disturbances of neuroendocrine function and the development or maintenance ofFM and related syndromes. Evidence from study of the growth hormone axis suggests that decreased growth hormone release and IGF-I levels may be secondary to the development of FM. Are disturbances of other neuroendocrine axes, particularly the HPA axis, similarly consequent to clinical symptomatology or might altered activity of the HPA axis contribute to vulnerability to development of stressrelated syndromes (Fig. 2)? Although we favor the hypothesis that neuroendocrine disturbances contribute to the primary symptoms of FM, an alternative, or perhaps complementary, hypothesis is that neuroendocrine disturbances are related to the healthcare-seeking behaviors found in FM and related disorders. 32 ,33 Reactivity of the HPA axis is variable among individuals and determined by a number of factors. The importance of genetic variability has been demonstrated in inbred rat strains, which showed blunted HPA axis responses to a variety of stressors in Lewis rats, while Fischer rats demonstrate exaggerated HPA axis responses when compared with outbred rats. 23 Lewis rats also display differences in levels of CRH and AVP peptide hormones, as well as receptors for serotonin, when compared with Fischer rats. 34 Differences in HPA axis reactivity in these inbred strains of rats are associated with vulnerability to disease; for example, Lewis rats are susceptible to induction of severe autoimmune inflammatory disease while Fischer rats are resistant to the same stimuli. 35 In addition, these strains display differences in behaviors, such as vigilance, exploration, and responses to restraint or swim stress that could also be related to differences in the central components of the HPA axis. 36,37 In addition, as previously discussed, activity of the HPA axis is influenced by the sex steroid hormones, which can be both a genetic and an environmental influence. A series of experiments by Meaney et al point out the importance of neonatal environmental influ364

Vulnerability to 'Stress-related' Syndromes • Disturbed responses to acute or ongoing stressors • Somatic • Cognitive/Psychological

Syndrome Trigger FOR EXAMPLE: • Traumatic/Degenerative • Whiplash • Repetitive motion injury (e.g. supraspinatous tendinitis) • Osteoarthritis • Inflammatory • Rheumatoid Arthritis • Systemic Lupus • Infectious • Lyme Disease • Viral Illness • Psychological or Emotional • Hormonal

Fibromyalgia Other stress-related syndromes may develop depending on the specific vulnerability or the specific trigger. Perpetuation of symptoms may be related to HPA axis or growth hormone axis disturbances.

Figure 2. Hypothesis of neuroendocrine vulnerability to fibromyalgia. Responsiveness of the HPA axis (or other neuroendocrine axes) confers vulnerability to "stress-related syndromes," both somatic and psychiatric, in general. A particular syndrome trigger or triggers leads susceptible individuals down a pathway toward a specific set of clinical symptoms. Certain triggers may more powerfully lead to individual syndromes, for example, whiplash or Lyme disease as triggers for FM.

ences in determining lifelong HPA axis responses to stress in rats. 38 Early life stresses lead to changes in the dynamic function of the HPA axis that are detectable throughout life. These experiments demonstrate that changes in HPA axis function can be mediated by differences in levels of regulatory peptides or hormones, and changes in receptor levels or occupancy. Exposure to stressors during adulthood also alters HPA axis hormone levels and function. Rats chronically exposed to cold demonstrate normal basal June 1998 Volume 315 Number 6

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ACTH and corticosterone activity, but HPA responses to novel stimuli are greater than normal, and, after novel stressors, the sensitivity of ACTH secretion to glucocorticoid inhibition is reduced. 39 In contrast to neonatal paradigms where changes in AVP and CRH levels are parallel, in some postnatal stress paradigms, such as adjuvant arthritis and chronic cholestasis, CRH levels decrease while AVP levels increase. 4o,41 Taken together, these data suggest mechanisms by which individual variations in stress-response systems may occur. The idea that vulnerability to stress-related syndromes may be consequent to genetic susceptibility or exposure to stressors, either in childhood or adulthood, has been investigated with variable results. High rates of major depression and alcoholism in first-degree relatives of patients with FM and related disorders have been described,42-44 which could indicate either genetic susceptibility or contribute to high levels of childhood stress. Several studies have shown that abuse history is associated with chronic pain syndromes, including headache, pelvic pain, back or myofascial pain, and irritable bowel syndrome. 45 Additionally, abuse history may have a general effect on increased symptom reporting, poorer adjustment to illness, and increased healthcare seeking. 45 Abuse, in these studies, could consist of sexual abuse, other types of physical abuse, or emotional and verbal abuse. Although the impact of these childhood stresses on the development of neuroendocrine systems is not known in humans, rodent studies show that different types, intensities, and timing of stressors can lead to different, even opposite, effects on adult HPA axis reactivity. It is plausible that genetics and experience may contribute to vulnerability to an illness spectrum encompassing the stress-related syndromes, with their predominance of physical symptoms, as well as to classically psychiatric syndromes (major depressive disorder, posttraumatic stress syndrome) that also exhibit disturbances of HPA axis physiology. We and others have also proposed physical or psychological stress as a triggering factor for the development ofFM and other stress-related syndromes. I ,3 However, the mechanisms that might translate an acute or subacute stress (whiplash injury, viral illness, psychological stressor) to a syndrome of chronic musculoskeletal pain are uncertain and require further research. Interactions between the HPA axis and numerous other neuroendocrine (eg, the growth hormone axis) and neurochemical pathways may playa role in either triggering symptoms or maintaining the syndrome. Further understanding of neuroendocrine axis function in patients with FM and other stress-related syndromes may help to elucidate the underlying causes of these disorders, as well as yield information that may guide the development of new treatment strategies. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

References 1. Crofford LJ, Engleberg NC, Demitrack MA. Neurohormonal perturbations in fibromyalgia. Bailliere's Clin Rheumatol. 1996; 10:365-78. 2. Chrousos GP, Gold PW. The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis. JAMA. 1992;267:1244-52. 3. Crofford LJ, Demitrack MA. Evidence that abnormalities of central neurohormonal systems are key to understanding fibromyalgia and chronic fatigue syndrome. Rheum Dis Clin North Am. 1996;22:267-84. 4. DallmanMF,Akana SF, LevinN, WalkerC·D,Bradbury MJ, Suemara S, et al. Corticosteroids and the control of function in the hypothalamo-pituitary-adrenal (HPA) axis. Ann N Y Acad Sci. 1994;746:22-31. 5. Czeisler CA. The effect oflight on the human circadian pacemaker. In: Chadwick DJ, Ackrill K, eds. Circadian Clocks and Their Adjustments. New York: John Wiley & Sons, 1995:254-302. 6. Sachar EJ, Hellman L, Roffwarg HP, Halpern FS, Fu· kush DK, Gallagher TF. Disrupted 24-hour patterns of cortisol secretion in psychotic depressives. Arch Gen Psychiatry. 1973; 18:19-24. 7. Carroll BJ, Feingerg M, Greden JF, Tarika J, Albala AA, Haskett RF, et al. A specific laboratory test for the diagnosis of melancholia: standardization, validation, and clinical utility. Arch Gen Psychiatry. 1981;38:15-22. 8. Yehuda R, Levengood RA, Schmeidler J, Wilson S, Guo LS, Gerber D. Increased pituitary activation following metyrapone administration in post-traumatic stress disorder. Psychoneuroimmunology. 1996; 21:1-16. 9. Poteliakhoff A. Adrenocortical activity and some clinical findings in acute and chronic fatigue. J Psychosom Res. 1981;25:91-5. 10. Taerk GS, Toner BB, Salit IE, Garfinkel PE, Ozersky S. Depression in patients with neurasthenia (benign myalgic encephalomyelitis). Int J Psychiatry Med. 1987; 17:49-56. 11. Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJP, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin End Metab. 1991;73:122434. 12. Beam J, Allain T, Coskeran P, Munro N, Butler J, McGregor A, et al. Neuroendocrine responses to d-fenfluramine and insulin-induced hypoglycemia in chronic fatigue syndrome. BioI Psychiatry. 1995;37:245-52. 13. Cleare AJ, Beam J, McGregor A, Allain T, Wessely S, Murray RM, et al. Contrasting neuroendocrine responses in depression and chronic fatigue syndrome. J Affect Dis. 1995;35:283-9. 14. Yatham LN, Morehouse RL, Chishorm BT, Haase DA, MacDonald DD, Marrle TJ. Neuroendocrine assessment of serotonin (5-HT) function in chronic fatigue syndrome. Can J Psychiatry. 1995;40:93-6. 15. Hudson JI, Pliner LF, Hudson MS, Goldenberg DL, Melby JC. The dexamethasone suppression test in fibrositis. BioI Psychiatry. 1984; 19:1489-93. 16. Ferraccioli G, Cavalieri F, Salaffi F, Fontana S, Scita F, Nolli M, et al. Neuroendocrinologic findings in primary fibromyalgia (soft tissue chronic pain syndrome) and in other chronic rheumatic conditions (rheumatoid arthritis, low back pain). J Rheumatol. 1990;19:869-73. 17. McCain GA, Tilbe KS. Diurnal hormone variation in fibromyalgia syndrome: a comparison with rheumatoid arthritis. J Rheumatol. 1989; 16(suppl 19):154-7. 18. Griep EN, Boersma JW, de Kloet EP. Altered reactivity of the hypothalamic-pituitary-adrenal axis in the primary fibromyalgia syndrome. J Rheumatol. 1993;20:469-74. 19. Crofford LJ, Pillemer SR, Kalogeras KT, Cash JM, Mi· chelson D, Kling MA, et al. Hypothalamic-pituitary-adre-

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20.

21.

22. 23. 24. 25.

26. 27. 28.

29. 30.

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June 1998 Volume 315 Number 6