Neuromediator and hormonal perturbations in fibromyalgia syndrome: results of chronic stress?

4 Neuromediator and hormonal perturbations in fibromyalgia syndrome: results of chronic stress? G U N T H E R NEECK WALTER RIEDEL

Primary fibromyalgia syndrome (FMS) is a non-inflammatory rheumatic disorder with diffuse musculoskeletal pain, fatigue and multiple fibromyalgic tender points. FMS is predominantly found in women and is often associated with various neurovegetative disorders, such as constipation, chilliness, low blood pressure, dermatographia, headaches and sleep disturbances, often combined with depression (Ahles et al, 1987; Miiller, 1987; Neeck and Schmidt, 1990). The complex symptomatology characterizing FMS involves mainly three areas: the musculoskeletal system, the neuroendocrine system and the psyche. Although many studies have described the symptoms of fibromyalgia as an entity of its own, it is still unknown in which of these three areas the disorder primarily originates. In this chapter the profile of neuromediator and hormonal abnormalities found in FMS (Table 1) is reviewed, with the aim of finding evidence of FMS being elicited by an intrinsic disturbance within the neuroendocrine system or being secondarily evoked by a malfunction in one of the two other systems. A leading symptom of nearly .all rheumatic diseases is pain. Patients suffering from FMS experience painful episodes in the onset period of this condition, which as the illness progresses turn into continuous pain, which becomes one of the stress factors perpetuating the disease. BIOGENIC AMINES Catecholamines

Abnormalities in catecholamine secretion or metabolism have been found in recent investigations, but with discrepant results. Van Denderen et al (1992) reported lower plasma concentrations of noradrenaline and adrenaline in FMS patients immediately following cessation of physical exercise and interpreted this, together with a consistently lower heart rate during exercise, as being due to diminished reactivity of the sympathetic system. A Bailli~re's Clinical Rheumatology-Vol. 8, No. 4, November 1994 ISBN 0-7020-1867-8

763 Copyright 9 1994, by Bailli6re TindaU All rights of reproduction in any form reserved

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G. NEECK AND W. RIEDEL Table 1. Neuromediator and hormonal perturbations in FMS.

Neuromediators, hormones or related metabolites

Findings

Biogenic amines

Noradrenaline (blood) Noradrenaline (urinary excretion) Adrenaline (blood) Dopamine (blood) Prostaglandin E2 Serotonin (blood) Tryptophan (blood) Tryptophan (cerebrospinal fluid) 3-Hydroxykyurenine (cerebrospinal fluid)

Low (van Denderen et al, 1992) Normal to high (Hamaty et al, 1989) High (Russell, 1989) Low (van Denderen et al, 1992) Low to normal (Hamaty et al, 1989) High (Hamaty et al, t989) High (Hamaty et al, 1989) Low (Moldofsky, 1982) Low (Russell et al, 1987) Low (Russell et al, 1993) Low (Moldofsky, 1982) Low (Russell et al, 1989) Low (Russell et al, 1992) Low (Russell et al, 1993) High (Russell et al, 1993)

Hypothalamic-pituitary-adrenal axis

Cortisol (blood) Cortisol (dexamethasone suppression test) Cortisol (CRH test) Cortisol (ACTH test) Cortisol 8 a.m. (blood) Cortisol 8 p.m. (blood) Cortisol (urinary excretion) ACTH (CRH test) Arginine vasopressin

High (McCain and Tilbe, 1989) Normal to high (McCain and Tilbe, 1989) Normal to high (Ferraccioli et al, 1990) Low (Griep et al, 1993) Normal to low (Crofford et al, 1993) Normal (Griep et al, 1993) Normal (Crofford et al, 1993) High (Crofford et al, 1993) Low (Crofford et al, 1993) Normal to high (Crofford et al, 1993) High (Griep et al, 1993) Normal (Crofford et al, 1993)

Hypothalamic-pituitary-thyroid axis

Hypothyroidism in FMS FMS in Hashimoto thyroiditis T3, basal (blood) T4, basal (blood) Free T3, basal (blood) Free T4, basal (blood) Free T3 (TRH test) Free T4 (TRH test) TSH, basal (blood) TSH (TRH test)

Rare (Carette and Lefrancois, 1988) Often (Becker et al, 1963) Low normal (Simons and Travell, 1989) Low normal (Neeck and Riedel, 1992) Low normal (Simons and Travell, 1989) Low normal (Neeck and Riedel, 1992) Low normal (Neeck and Riedel, 1992) Low normal (Neeck and Riedel, 1992) Reduced (Neeck and Riedel, 1992) Reduced (Neeck and Riedel, 1992) Low normal (Simons and Travell, 1989) Low normal (Neeck and Riedel, 1992) Reduced (Ferraccioli et al, 1990) Reduced (Neeck and Riedel, 1992)

Parathyroid hormone, calcitonin and calcium

Parathyroid hormone (blood) Calcitonin (blood) Calcium, total (blood) Calcium, free (blood)

High normal (Neeck and Riedel, 1992) Low (Neeck and Riedel, 1992) Low (Neeek and Riedel, 1992) Low (Neeek and Riedel, 1992)

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Growth hormone and prolactin FMS in hyperprolactinaemia

SomatomedinC (blood) Growth hormone(urinaryexcretion) Prolactin (TRH test) Prolactin (blood)

Often (Buskila et al, 1992) Low (Bennett et al, 1992) Normal (Jacobsen et al, 1992) High (Neeck and Riedel, 1992) High normal (Russell et al, 1993)

Endorphins and enkephalins

Endorphins (blood) Enkephalins (blood) Endorphins (cerebrospinalfluid) Enkephalins (cerebrospinalfluid)

High normal (Hamatyet al, 1989) High normal (Hamatyet al, 1989) High normal (V~er0yet al, 1991) High normal (V~er0yet al, 1991)

For abbreviations,see text. similar observation was made by V~erCyet al (1989), who found a decreased hand vasoconstrictory response to a cold pressure test and auditive stimulation in FMS patients. In a double-blind study, Hamaty et al (1989) detected high dopamine, variable high to normal noradrenaline, and low to normal adrenaline levels in FMS patients, but also elevated levels of prostaglandin E2. The authors explained their findings by suggesting that FMS patients have a reduced capability to convert noradrenaline to adrenaline. Russell (1989) observed an increased urinary excretion of noradrenaline in some FMS patients. The peripheral catecholamine response to stress has been shown to be reversible and to diminish with time, while the stressinduced changes in the central nervous system may be more permanent (Kopin, 1980). Adrenal cortical steroids or adrenocorticotrophic hormone (ACTH) have been shown to restore depressed levels of key enzymes for synthesizing dopamine, noradrenaline and adrenaline in the adrenal medulla (Wurtman and Axelrod, 1965). Hypercorticalism, a typical response to chronic stress, may therefore considerably modulate adrenal medullary catecholamine secretion, but will probably not influence sympathetic nervous reactivity. Serotonin

Studies on serotonin (5-hydroxytryptamine; 5-HT) metabolism reveal significantly lower serum levels of 5-HT in FMS patients (Moldofsky, 1982; Russell et al, 1987). By comparing 5-HT levels with the intensity of musculoskeletal pain, a highly significant inverse relationship was found. To compensate for this deficit, the number of binding sites for 5-HT in platelets is increased, implying that other structures, including those in the central nervous system, might also increase their 5-HT receptor density. A plausible explanation for the low 5-HT levels of FMS patients was suggested by the concomitant low plasma levels of the essential amino acid tryptophan, the precursor for 5-HT (Moldofsky, 1982; Russell et al, 1989, 1992). These authors explained the low 5-HT levels in terms of an abnormality in tryptophan uptake. The low levels of tryptophan might also lead to a lower transmitter content in the central serotenergic system, which, besides

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controlling other functions, is involved in the regulation of sleep and nociception. A decrease in forebrain serotonin has been found to cause insomnia which could be totally reversed by the administration of 5-hydroxytryptophan (Hobson and Steriade, 1986). Activation of serotonergic pathways originating from the raphe nuclear complex and projecting to the spinal cord has been found to suppress responses to various noxious stimuli (Basbaum and Fields, 1984), characterizing the function of serotonergic pathways as a 'gain setter' of motorneurone excitability in the brainstem and spinal cord (Davis et al, 1980). Furthermore, tryptophan is not only the precursor of 5-HT, but also of melatonin. The rhythm in melatonin secretion is predominantly entrained by the light-dark cycle and influences pituitary and hypothalamic functions. Low or desynchronized melat0nin levels have been associated with depression (Watson and Maden, 1977; Lerner and Norlund, 1978). Thus, the concept of 5-HT deficiency could explain many of the symptoms seen in FMS. Of interest is the finding that the levels of other essential amino acids, such as histidine, lysine and threonine, are also lowered in FMS patients (Russell et al, 1989; Yunus et al, 1992), which suggests inadequate gastrointestinal absorption as a primary disturbance in FMS. On the other hand, decreased levels of amino acids also occur in physiological situations such as pregnancy and during menstruation, pointing to a hormonal sensitivity of amino acid uptake mechanisms. HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

Nearly all studies which have investigated the function of the hypothalamicpituitary-adrenal (HPA) axis in FMS patients have described elevated cortisol levels associated with a flattened diurnal secretion pattern. McCain and Tilbe (1989) compared morning and evening cortisol levels of FMS patients with those of patients suffering from rheumatoid arthritis (RA). FMS patients showed the typical flattened diurnal cortisol secretion pattern with high cortisol levels, which could not be suppressed following administration of dexamethasone. These findings were fully corroborated by the more expanded study of Ferraccioli et al (1990). To elucidate the question of whether this hormonal abnormality originates at the hypothalamic or hypophyseal level, Griep et al (1993) tested the H P A axis in FMS patients by injecting corticotrophin-releasing hormone (CRH). This test revealed a markedly enhanced ACTH release in FMS patients versus controls, while the cortisol response in both groups did not differ, suggesting a reduced sensitivity of the adrenal gland to ACTH. Identical results were obtained using an insulin-induced hypoglycaemia test. However, when synthetic ACTH (1-24) was injected into FMS patients, the cortisol response was similar in FMS patients and controls. This suggests a difference in sensitivity of the adrenal cortical tissue to exogenous and endogenous ACTH, and points away from the assumption of a relative insufficiency of the adrenal gland in FMS. On the other hand, the increased ACTH secretion after C R H without a higher cortisol response might indi-

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cate an adaptive mechanism of a chronically stimulated adrenal cortex, a phenomenon also seen in other hormonal systems, which has been explained by downregulation of receptor elements (Gavin et al, 1974; Meerson, 1975). The hyperactivity of the H P A axis in FMS patients seems to depend to a great extent on the development of depression. Depression is a prominent symptom in FMS (Ahles et al, 1984; Payne et al, 1984; Wolfe et al, 1984); however, it has yet to be clarified whether depression develops as a reaction to chronic pain, or is a disease of its own within the FMS syndrome. Sachar (1975) and Carroll et al (1981) described ACTH hypersecretion, hypercorticalism with flattening of the diurnal secretion pattern, and resistance to dexamethasone suppression in depressed patients; the hormonal abnormality was closely related to the degree of depression. Interestingly, this endocrine reactivity pattern resembles that found by McCain and Tilbe (1989) and Ferraccioli et al (1990) in FMS patients. The hyperactivity of the H P A axis might, however, be a non-specific reaction. Atkinson et al (1986) found elevated cortisol levels and a flattened diurnal secretion pattern in patients with chronic low back pain, which again was dependent on the degree of depression. Chronic pain, therefore, does not always activate the H P A axis, if not accompanied by the distinct hypothalamic or more general limbic system abnormalities which are apparently hallmarks of depression. Although the above described hyperactivity of the H P A axis seems to be a prominent feature caused by depression, the opposite, that hyperactivity of the HPA axis produces depression, has been also observed. Two thirds of patients with active Cushing syndrome show psychiatric symptoms similar to those of depressive illness (Starkman et al, 1981). RA, the most common inflammatory rheumatic disease, develops in progressing from mild to severe degrees a cortisol secretion pattern closely resembling hyperactivity of the HPA axis (Neeck et al, 1990). In the stage of maximal inflammatory activity, R A patients have a cortisol secretion pattern similar to that of Cushing syndrome, with all the signs of hypothalamic abnormalities including depression. In this particular situation, the HPA axis functions similarly in both the RA and FMS patients.. Interestingly, most patients with FMS show a considerably higher activity of the H P A axis compared with that of RA patients, which may indicate a higher sensitivity of FMS patients to pain. HYPOTHALAMIC-PITUITARY-THYROID AXIS Many autonomic disorders found in FMS patients, such as chilliness with increased sensitivity to cold, low blood pressure and constipation, resemble symptoms of hypothyroidism. Indeed, a certain coincidence of FMS with Hashimoto thyroiditis has been reported (Becker et al, 1963), but out of 100 patients with hypothyroidism only five showed the complete symptomatology of FMS (Carette and Lefrancois, 1988). Simons and Travell (1989) and McCain and Tilbe (1989) found low-normal thyroid hormone concentrations in FMS patients, and the levels of thyroid-stimulating hormone

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G. NEECK AND W. RIEDEL

(TSH) were also low. Ferraccioli et al (1990) detected, predominantly in patients with primary FMS but partly also in patients suffering from RA or low back pain, a blunted TSH response upon stimulation of the hypothalamic-pituitary-thyroid (HPT) axis with thyrotrophin-releasing hormone (TRH) which correlated with the degree of depression. A blunted TSH response to TRH in depressed but otherwise healthy patients has been described (Loosen et al, 1983). Comparing the function of the HPT axis of FMS patients with normal volunteers, Neeck and Riedel (1992) also found blunted TSH secretion in response to TR1Llin FMS patients and, in addition, a higher prolactin secretion. The basal TSH and thyroid hormone levels, 20r J 15!

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Figure 1. Changes in TSH, prolactin, flee thyroid horones and total and free calcium in 13 female patients with primary FMS (PFMS) (open circles) compared with 10 age- and sexmatched controls (closed circles) following an intravenous bolus injection of 400 ixg TRH. Values are means + SEta. Asterisks denote statistical significance of comparisons with prestimulation values (* P <0.05; ** P <0.01) or comparisons with healthy control values (* P <0.05; ** P <0.01). From Neeck and Riedel (1992), with permission.

N E U R O M E D I A T O R A N D H O R M O N A L A B N O R M A L I T I E S IN FMS

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with the exception of free thyroxine (T4), were all in the low-normal range, and the secretion of free triiodothyronine (T3) and free T4 in response to T R H was poor (Figure 1). A possible explanation for this thyroid hormone profile might be a failure in the deiodination of T4 to T3, either in peripheral tissues or within the pituitary itself (Maeda and Ingbar, 1984). Such a failure leads to the wellknown 'low T3 syndrome' or the 'sick euthyroid syndrome'. Common to this abnormality in thyroid hormone economy is a decrease in serum T3 levels with mostly normal T4 levels. Characteristically, the fraction of free T4 is greatly increased. This type of thyroidal hormone profile can be elicited by any physiological stress of sufficient intensity in both acute and chronic illness; the more severe the illness, the lower the serum T3 levels. Glucocorticoids have been found not only to inhibit the monodeiodination of T4, but also to decrease the response of TSH to T R H (Otsuki et al, 1973; Visser and Lambert, 1981). A similar profile of thyroid hormones can be experimentally induced in rabbits in warm environments. Inhibition of deiodinase activity by intravenous injection of propylthiouracil was followed by a rapid lowering of free T3 and an increase in free T4, accompanied by the typical vasomotor activity pattern of cold defence as shown by cutaneous vasoconstriction and shivering. The origin of this autonomic response pattern has been explained by the activation of hypothalamic T R H neurones via negative feedback exerted by lowered free T3 levels (Riede!, 1983, 1990). Likewise, in RA patients free T4 levels are elevated and free T3 levels are low, similar to the pattern in the 'sick euthyroid syndrome'. The blunted TSH response to T R H in these patients correlates with the degree of inflammation or increased activity of the H P A axis (Herrmann et al, 1989). A depressed TSH response might, therefore, be caused by a differential feedback action of thyroid hormones, with T4 acting predominantly at the pituitary level and T3 acting predominantly on T R H neurones at the hypothalamic level (Reichlin, 1966). Hypothalamic T R H neurones represent not only the highest control level for the thyroid, but are also involved in eliciting the pattern of cold defence via the autonomic nervous system (Riedel, 1990). At the pontomedullary level T R H has been shown to directly activate the thyroid gland, including thyroid C cells, via autonomic nervous system efferents (Riedel and Burke, 1988). PARATHYROID HORMONE, CALCITONIN AND CALCIUM A prominent part of the symptoms characterizing FMS originate in the musculoskeletal system. Pain and fatigue have directed investigations to muscle energy metabolism, and a reduced content of high-energy phosphates, mitochondrial damage and a disturbed microcirculation have been observed in FMS. Pain may be caused by metabolites released from energydepleted muscles which stimulate nociceptive nerve fibres (Bengtsson and Henriksson, 1989). An inability to relax during repetitive movements has been thought to play an important role both in initiating and in maintaining

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G. N E E C K A N D W . R I E D E L

muscle pain (Elert et al, 1992). Electromyographical investigations of FMS patients indeed revealed a pattern of latent tetany and a reduced ability of the muscle to relax (Famaey et al, 1991). Besides disturbed muscle metabolism, muscular pain and stiffness, an exaggerated skin erythematous response (dermographism), cold hands and feet, paraesthesias and a general excitability of peripheral nerves are also classical symptoms of hypocalcaemia. Therefore, Neeck and Piedel (1992), in addition to studying thyroid function, investigated blood levels of calcium and the hormones involved in the regulation of calcium metabolism in FMS patients. A highly consistent finding in FMS patients was substantially lowered levels of total and free calcium (Figure 1), with parathyroid hormone levels not significantly different from the control group of normal volunteers. Calcitonin was either not measurable or near detection level. Vitamin D levels were not assessed in this study. The origin of hypocalcaemia in FMS patients is unknown. Reduction of intestinal calcium uptake and an enhanced urinary secretion caused by elevated glucocorticoid levels may be one mechanism. Interestingly, treatment of hypothyroid patients with thyroid hormones restored not only the plasma calcium, but was also accompanied by a distinct elevation of the parathyroid hormone level. Thus, a combined disturbance of the H P A and the HPT axis might be relevant in the pathophysiology of calcium metabolism in FMS patients. GROWTH HORMONE AND PROLACTIN

Growth hormone (GH) secretion is under the control of two hypothalamic peptides, GH-releasing hormone and somatostatin. GH secretion is regulated by negative feedback and neural control mechanisms. The pulsatile secretion of GH is closely related to stage 4 sleep, with nearly 80% of its daily production released during this stage of sleep. Bennett (1989) hypothesized that sleep anomalies, a main symptom of FMS, could disrupt the nocturnal secretion pattern of GH. Somatomedin C is the major mediator of GH anabolic actions and is a prerequisite for proper amino acid incorporation for the maintainance of normal muscle homeostasis. There is a large body of evidence that postexertional pain derives from muscle microtrauma, and it is assumed that muscular pain in FMS has a similar origin (Newham et al, 1986; Edwards, 1988; Jacobsen et al, 1991). Sleep disorders, especially of stage 4 sleep, may be associated with decreased GH secretion. Indeed, Bennett et al (1992) found a significantly lowered level of somatomedin C in FMS patients, and such a deficit could easily explain the tardiness in muscle repair processes. Interestingly, a decrease in G H secretion has been associated with low thyroid hormone levels or elevated corticosteroids (Daughaday, 1985), two additional factors which might suppress somatomedin C secretion in FMS. Decreased nocturnal G H secretion has also been found in RA patients, but only when very high inflammatory activities were present (Neeck et al, 1988). The differential response of prolactin to T R H between FMS patients and controls as shown in Figure 1 remains an unexplained finding. The higher

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susceptibility of the pituitary mammotrophic cell is a typical response to low thyroid hormone levels and has been explained by an increase in the hypothalamic activity of TRH (Daughaday, 1985). ENDORPHINS AND ENKEPHALINS

Endogenous opiates, as measured by plasma or spinal fluid levels of betaendorphin, respond to a variety of stressful situations, especially if associated with pain. The question of whether the hyperalgesia of FMS could be explained by lowered endorphin levels has been explored by V~er0y et al (1991) in cerebrospinal fluid samples and by Hamaty et al (1989) using blood samples. Congruently, both investigations reported rather increased or normal endorphin or enkephalin levels. SUMMARY AND CONCLUSIONS Since the first comprehensive description of the symptoms of FMS by Yunus et al (1981), numerous investigations have confirmed that FMS is a clinical entity. However, the aetiology of the syndrome is still not fully elucidated. It seems, however, logical to place the origin of the disorder in the muscle. Muscle pain, especially at the muscle-tendon junctions, fatigue and Stiffness are the first symptoms. A malfunction of energy metabolism has been detected in part of the muscle fibres. However, it has to be considered that the muscle is not an isolated entity. Its activity is controlled by segmentally arranged motor units of the ventral horn of the spinal cord in response to proprioceptive afferent signals arising in the muscle spindles or in other sensory elements including nociceptors. Together with supraspinal descending inputs, the spinal motor neurone pool is the common final pathway for segmental and suprasegmental inputs, making the motor system extremely powerful for adaptive adjustments but also vulnerable if deficits occur in either of these input levels. A second, recently discovered, abnormality seen in FMS is a lowered serotonin level in peripheral and most likely also central structures. The underlying mechanism seems to be defective absorption of the precursor amino acid tryptophan from the gut. Serotonin is involved centrally in the regulation of the sleep pattern, and at the spinal level it acts as a 'gain setter' of motoneurone excitability and suppresses signal transmission of noxious stimuli in dorsal horn neurones. Either of these two disturbances, muscle energy depletion or serotonin deficiency, could by itself evokemany of the symptoms of FMS, and their combined appearance will perpetuate the disease. Depressed levels of somatomedin C, caused by a deficit of stage 4 sleepdependent release of GH, might represent an additional factor in preventing proper development or repair of myoskeletal structures. Malabsorption of certain amino acids, possibly due to a genetic disorder of gut transport mechanisms, may constitute an additional deleterious factor.

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T h e a b n o r m a l i t i e s f o u n d in t h e H P A a n d H P T axis m a y b e s e e n as a n a t t e m p t o f t h e o r g a n i s m to r e s t o r e h o m e o s t a s i s . T h e stimulus eliciting this c o u n t e r - r e g u l a t o r y r e a c t i o n m a y b e p a i n o r o t h e r a f f e r e n t signals w h i c h n o r m a l l y d o n o t r e a c h t h e c e n t r a l n e r v o u s system. It is d o u b t f u l w h e t h e r t h e unspecific a c t i v a t i o n of t h e H P A axis in a n o n - i n f l a m m a t o r y d i s e a s e is beneficial. R a t h e r , o n t h e c o n t r a r y , e l e v a t e d g l u c o c o r t i c o i d levels, v i a t h e i r mostly inhibitory action on various enzymes, may suppress repair of m y o s k e l e t a l s t r u c t u r e s a n d a l t e r f e e d b a c k circuits, as s h o w n p a r a d i g m a tically in t h e r e g u l a t i o n of t h y r o i d h o r m o n e s , with c o n s e q u e n c e s o n t h y r o i d h o r m o n e - d e p e n d e n t m e c h a n i s m s like p a r a t h y r o i d h o r m o n e s e c r e t i o n a n d calcium h o m e o s t a s i s . W h e r e a s such p e r i p h e r a l deficits a r e easily d i s c o v e r e d , t h e i r effects o n c e n t r a l n e r v o u s s y s t e m activities, e s p e c i a l l y as f e e d b a c k signals o n h y p o t h a l a m i c r e l e a s i n g h o r m o n e n e u r o n e s a n d t h e i r specific i n t e r a c t i o n s , n e e d f u r t h e r i n v e s t i g a t i o n to p r o v i d e a r a t i o n a l e for a specific t h e r a p y of F M S .

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