Arthritis & Rheumatism Official Journal of the American College of Rheumatology
LOW LEVELS OF SOMATOMEDIN C IN PATIENTS WITH THE FIBROMYALGIA SYNDROME A Possible Link Between Sleep and Muscle Pain ROBERT M. BENNETT, SHARON R. CLARK, STEPHEN M. CAMPBELL, and CAROL S. BURCKHARDT Objective. Fibromyalgia is a common syndrome of musculoskeletal pain and fatigue. Lacking distinctive tissue or laboratory correlations, it has often been considered a form of “psychogenic rheumatism.’’ In the present study, the notion that the stage4 sleep anomaly typically seen in the fibromyalgia syndrome may disrupt growth hormone secretion was tested. Because growth hormone has a very short half-life, serum levels of somatomedin C were measured; somatomedin C is the major mediator of growth hormone’s anabolic actions and is a prerequisite for normal muscle homeostasis. Methods. Serum levels of somatomedin C were measured in 70 female fibromyalgia patients and 55 healthy controls, using a peptide-specific radioimmunoassay. Results. Significantly lower levels of somatomedin C were observed in the fibromyalgia patients compared with controls (mean 2 SD 124.7 f 47 ng/ml versus 175.2 2 60 ng/ml; P = 0.OoooOl). These results could not be explained by concomitant therapy or by weight, and in a subset of 21 patients in whom this was From the Division of Arthritis and Rheumatic Diseases, Oregon Health Sciences University, Portland, Oregon. Robert M. Bennett, MD, FRCP, FACP: Professor of Medicine and Chairman, Division of Arthritis and Rheumatic Diseases; Sharon R. Clark, PhD: Assistant Professor of Medicine and Research; Stephen M. Campbell, MD: Associate Professor of Medicine; Carol S. Burckhardt, PhD: Assistant Professor of Medicine and Research. Address correspondence to Robert M. Bennett, MD, FRCP, FACP, Department of Medicine, L329A, Oregon Health Sciences University, Portland, OR 97201. Submitted for publication January 14, 1992; accepted in revised form June 2, 1992.
investigated, there was no correlation with various indices of disease activity. Conclusion. These findings indicate that there is a distinctive disruption of the growth hormonmmatomedin C neuroendocrine axis in a majority of fibromyalgia patients. It is hypothesized that this abnormality may explain the link between disturbed sleep and predisposition to muscle pain.
The fibromyalgia syndrome is a common cause of difEuse musculoskeletal pain (1). Its pathogenesis is obscure; distinctive tissue changes have not been described, and laboratory findings are usually normal. In the past, the term “psychogenic rheumatism” was often used to describe these patients, because of the confusing history of multiple somatic complaints, absence of physical findings, and normal results on laboratory tests. Over the last decade, rheumatologists have become increasingly aware of the large number of such patients, characterizedby the consistent features of the medical history, as well as the finding of tender areas in specific locations and absence of tenderness in other locations (2,3). In 1990, the American College of Rheumatology published guidelines for establishing a diagnosis of fibromyalgia (4), and a recent assessment of rheumatology manpower needs cited fibromyalgia as being second only to rheumatoid arthritis as a reason for office visits to rheumatologists (5). A seminal finding in the study of fibromyalgia was reported by Moldofsky et al in 1975, when they described a distinctive disturbance of stage-4 sleep characterized by alpha-wave intrusion into the normal
Arthritis and Rheumatism, Vol. 35, No. 10 (October 1992)
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BENNETT ET AL
Table 1. Demographic characteristics of the fibromyalgia patients and controls* Patients Female/male Mean 2 SD age, years Mean f SD weight, lb Mean f SD duration of fibromyalgia, years No. taking HCAs No. taking NSAIDs
* HCAs
(n = 70)
Controls (n = 55)t
7010 47.6 k 10 160 f 37.6 11.6 f 6.9
5510 45.6 % 13 NA NA
27 36
NA NA
= heterocyclic antidepressants; NSAIDs antiinflammatory drugs. t NA = not available.
=
nonsteroidal
delta rhythm (6). Induction of this sleep abnormality in healthy volunteers produced a transient syndrome similar to fibromyalgia (7). Many metabolic, endocrine, and immune functions follow distinctive diurnal rhythms. Stage-4 sleep is closely related to the pulsatile secretion of growth hormone; -80% of the total daily production of growth hormone is secreted during this stage of sleep (8). Since growth hormone plays a critical role in muscle homeostasis and repair, it was of interest to investigate whether its secretion in patients with the fibromyalgia syndrome is compromised by the stage-4 sleep disturbance. The present study compared serum levels of somatomedin C, a growth hormone-related peptide, in female fibromyalgia patients and age-matched controls.
PATIENTS AND METHODS Seventy female patients with the fibromyalgia syndrome were compared with 55 age-matched female controls. The diagnosis of fibromyalgia was made in accordance with the American College of Rheumatology criteria (4). The 55 controls comprised 43 blood donors from the Portland Red Cross and 12 laboratory employees. All of the controls were reportedly in good health and not taking any medications. Blood samples were obtained between 1O:OO A M and 4:OO PM, from consecutive patients attending the Oregon Health Sciences University Fibromyalgia Treatment Program. The blood was allowed to clot and the serum was harvested and frozen; samples were kept frozen during shipment. Serum somatomedin C levels were assayed by Endocrine Sciences (Calabasas Hills, CA), using a radioimmunoassay that employs a rabbit antiserum directed against a synthetic segment of the protein (amino acids 57-70). Prior to assay, each sample was acid extracted from serum to minimize errors due to the presence of somatomedin binding proteins: 1 part of serum was extracted once with 87.5% ethanol plus 2N formic acid. The resulting supernatant (100 pl) was diluted in 900 pl of buffer (30 mM phosphate, 10 mM EDTA, 0.25% bovine serum albumin, pH 7.3, and 200 pl was incubated with lZSI-labeled synthetic peptide encompassing amino acids 53-70, as previously described (9). The interassay coefficient of variation was 7.3%, and
the intraassay coefficient of variation was 5.4%. Statistical analysis of the differences between fibromyalgia patients and controls was performed using Student’s 2-tailed t-test. The contribution of age, weight, and duration of illness to somatomedin C levels was assessed by multiple regression analysis.
RESULTS Characteristics of the fibromyalgia patients and controls are shown in Table 1, and somatomedin C values for patients and controls are shown in Figure 1. The mean ? SD somatomedin C levels in fibromyalgia patients and controls were 124.7 ? 47 ng/ml and 175.2 ? 60 ng/ml, respectively; this difference was highly significant (P = 0.000001, by Student’s t-test). Regression analysis indicated that age accounted for 14% of the variance in somatomedin C levels in the control group, whereas in the fibromyalgia group, age accounted for 7% of the variance. The duration of fibromyalgia accounted for 80% of patients with fibromyalgia were found to be anaerobically unfit, as assessed by their maximum oxygen uptake upon exercising to volitional exhaustion (13). A lack of regular physical exercise may be a factor contributing to the low levels of somatomedin C observed in some fibromyalgia patients. The observation that fibromyalgia patients have an alphddelta sleep anomaly and that the induction of this sleep anomaly causes a fibromyalgia-like syndrome in healthy volunteers has been a major stimulus for renewed interest in the relationship between sleep disorders and fibromyalgia (1 1). The physiologic link between disrupted stage-4 sleep and musculoskeletal pain has been obscure, but the findings reported herein suggest one plausible hypothesis. Growth hormone is an anabolic peptide which stimulates increased synthesis of DNA, RNA, and proteins; this effect is mediated via its stimulation of somatomedin C secretion by the liver. In adults, the growth hormonesomatomedin C axis has been shown to be important in muscle homeostasis (14,15); therapeutic administration of growth hormone has recently been shown to reverse muscle loss associated with the aging process (16). Most fibromyalgia patients locate the site of their pain to muscle and typically report having increased pain after exertion. There is a large body of evidence that links postexertional pain to muscle microtrauma (17-19), and it has been hypothesized that the musculoskeletal pain in fibromyalgia has a similar origin (1 1,20). This paradigm predicts that patients with the fibromyalgia syndrome are either peculiarly susceptible to muscle microtrauma at very low levels of exertion, or have a defect in the repair processes that normally lead to resolution of muscle microtrauma (21). It is proposed that in some fibromyalgia patients, persistent disruption of growth hormone secretion either predisposes to muscle microtrauma and/or impairs the normal healing of muscle microtrauma, as a result of reduced anabolic stimulation due to chronically low levels of somatomedin C. Such a hypothesis is in accord with Jacobsen et al’s finding of somewhat lower levels of serum type I11 procollagen in fibromyalgia patients (22) and the dependence of procollagen I11 synthesis on adequate growth hormone production (23). The recent report of fibromyalgia occurring after hypophysectomy (24) may also reflect such a mechanism. Fibromyalgia causes much distress to the affected patients and often frustrates physicians, who are unable to base therapy on any logical disease pathology. Although the old designation of “psychogenic rheumatism” has been abandoned by most practitioners, it is commonly believed that a maladapt-
DISCUSSION A conspicuous feature of the fibromyalgia syndrome has been the absence of any consistent pathophysiologic picture. The results reported herein indicate that, as a group, fibromyalgia patients have significantly lower serum levels of somatomedin C than do healthy controls. The low values found in some of the controls may be due to their having fibromyalgia, assuming a commonly estimated prevalence of between 3% and 15% in the general population. The rationale for measuring somatomedin C levels was based on theoretical considerations: -80% of growth hormone is produced during stage-4 sleep, and it was hypothesized that the alpha/delta sleep anomaly, which occurs during -60% of stage-4 sleep in patients with fibromyalgia, would disrupt the nocturnal secretion of growth hormone (11). The low levels of somatomedin C reported here may indeed result from such a mechanism; however, further studies measuring the continuous secretion of growth hormone in relation to sleep stages would be needed in order to confirm this. A previous study measured growth hormone levels in fibromyalgia patients, with samples taken at 8:OO AM and 4:OO PM; no differences were found between patients with fibromyalgia and patients with rheumatoid arthritis (12). Since growth hormone has a half-life of only 30 minutes, that study would not have detected reduced nocturnal secretion. Somatomedin C has a half-life of -20 hours, and its serum level is considered to reflect the integrated secretion of growth hormone (8). The other major stimuli for growth hormone release are hypoglycemia, starvation, consumption of large amounts of protein, elevated levels of circulating amino acids, surgical trauma, and other acute stresses, such as exercise. A progressive diminution of regular exercise is commonly encountered in patients with the fibromyalgia syndrome, due to post-
1116
BENNETT ET AL
ive response to stress plays some poorly defined role in pathogenesis of the disease. The findings in this study provide some preliminary insight into a psychoneuro-endocrine dysfunction which may be relevant to understanding the mind-body relationship in this enigmatic disorder.
ACKNOWLEDGMENTS We thank Dr. Mark Stene of Endocrine Sciences for his counsel during the preparation of this manuscript. We are indebted to P. Gierke and the nursing staff of the Portland Red Cross for providing serum samples from blood donors.
REFERENCES 1. Goldenberg DL: Fibromyalgia syndrome: an emerging but controversial condition. JAMA 257:2782-2787, 1987 2. Yunus M, Masi AT, Calabro JJ, Miller KA, Feigenbaum SL: Primary fibromyalgia (fibrositis): clinical study of 50 patients with matched normal controls. Semin Arthritis Rheum 11:151-171, 1981 3. Campbell SM, Clark S, Tindall EA, Forehand ME, Bennett RM: Clinical characteristics of fibrositis. I. A “blinded,” controlled study of symptoms and tender points. Arthritis Rheum 26:817-824, 1983 4. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, Fam AG, Farber SJ, Fiechtner JJ, Franklin CM, Gatter RA, Hamaty D, Lessard J, Lichtbroun AS, Masi AT, McCain GA, Reynolds WJ, Romano TJ, Russell IJ, Sheon RP: The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the multicenter criteria committee. Arthritis Rheum 33: 160-172, 1990 5. Marder WD, Meenan RF, Felson DT, Reichlin M, Birnbaum NS, Croft JD, Dore RK, Kaplan H , Kaufman RL, Stobo JD: The present and future adequacy of rheumatology manpower: a study of health care needs and physician supply (editorial). Arthritis Rheum 34: 1209-1217, 1991 6. Moldofsky H , Scarisbrick P, England R, Smythe H: Musculoskeletal symptoms and non-REM sleep disturbance in patients with “fibrositis syndrome” and healthy subjects. Psychosom Med 37:341-351, 1975 7. Moldofsky H, Scarisbrick P: Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosom Med 38:3544, 1976 8. Florini JR, Prinz PN, Vitiello ML: Somatomedin-C levels in healthy young and old men: relationship to peak and 24-hour integrated levels of growth hormone. J Gerontol 40:2-7, 1985 9. Hintz RL, Liu F, Chang D, Seegan G: A sensitive radioimmunoassay for somatomedin-Chnsulin-like growth factor I: based on synthetic insulin-like growth factor 57-70. Horm Metab Res 20:344-347, 1988
10. Burckhardt CS, Clark SR, Bennett RM: The Fibromyalgia Impact Questionnaire: development and validation. J Rheumatol 18:728-733, 1991 11. Bennett RM: Beyond fibromyalgia: ideas on etiology and treatment. J Rheumatol Suppl 19:185-191, 1989 12. McCain GA, Tilbe KS: Diurnal hormone variation in fibromyalgia syndrome: a comparison with rheumatoid arthritis. J Rheumatol Suppl 19:154157, 1989 13. Bennett RM, Clark SR, Goldberg L , Nelson D, Bonafede RP, Porter J, Specht D: Aerobic fitness in patients with fibrositis: a controlled study of respiratory gas exchange and ‘33xenonclearance from exercising muscle. Arthritis Rheum 32:454-460, 1989 14. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH: Growth hormone treatment in growth hormonedeficient adults. 11. Effects on exercise performance. J Appl Physiol 70:695-700, 1991 15. Crist DM, Peake GT, Loftfield RB, Kraner JC, Egan PA: Supplemental growth hormone alters body composition, muscle protein metabolism and serum lipids in fit adults: characterization of dose-dependent and response-recovery effects. Mech Ageing Dev 58: 191-205, 1991 16. Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE: Effects of human growth hormone in men over 60 years old. N Engl J Med 323:l-5, 1990 17. Edwards RHT: Hypotheses of peripheral and central mechanisms underlying occupational muscle pain and injury. Eur J Appl Physiol 57:275-281, 1988 18. Newham DJ, McPhail G , Mills KR, Edwards RH: Ultrastructural changes after concentric and eccentric contractions of human muscle. J Neurol Sci 61: 109-122, 1983 19. Newham DJ, Jones DA, Tolfree SE, Edwards RH: Skeletal muscle damage: a study of isotope uptake, enzyme efflux and pain after stepping. Eur J Appl Physiol 55:106-112, 1986 20. Jacobsen S, Bartels EM, Danneskiold-Samsoe B: Single cell morphology of muscle in patients with chronic muscle pain. Scand J Rheumatol 20:336-343, 1991 21. Bennett RM: Etiology of the fibromyalgia syndrome: a contemporary hypothesis. Intern Med Specialist 11:4861, 1990 22. Jacobsen S, Jensen LT, Foldager M, DanneskioldSamsoe B: Primary fibromyalgia: clinical parameters in relation to serum procollagen type I11 aminoterminal peptide. Br J Rheumatol 29:174-177, 1990 23. Jensen LT, Jorgensen OL, Risteli J, Christiansen JS, Lorenzen I: Type I and I11 procollagen in growth hormone-deficient patients: effects of increasing doses of GH. Acta Endocrinol (Copenh) 124:278-282, 1991 24. Disdier P, Harle J-R, Brue T, Jaquet P, Chambourlier P, Grisoli F, Weiller P-J: Severe fibromyalgia after hypophysectomy for Cushing’s disease. Arthritis Rheum 34: 493-495, 1991
LOW LEVELS OF SOMATOMEDIN C IN PATIENTS WITH THE FIBROMYALGIA SYNDROME A Possible Link Between Sleep and Muscle Pain ROBERT M. BENNETT, SHARON R. CLARK, STEPHEN M. CAMPBELL, and CAROL S. BURCKHARDT Objective. Fibromyalgia is a common syndrome of musculoskeletal pain and fatigue. Lacking distinctive tissue or laboratory correlations, it has often been considered a form of “psychogenic rheumatism.’’ In the present study, the notion that the stage4 sleep anomaly typically seen in the fibromyalgia syndrome may disrupt growth hormone secretion was tested. Because growth hormone has a very short half-life, serum levels of somatomedin C were measured; somatomedin C is the major mediator of growth hormone’s anabolic actions and is a prerequisite for normal muscle homeostasis. Methods. Serum levels of somatomedin C were measured in 70 female fibromyalgia patients and 55 healthy controls, using a peptide-specific radioimmunoassay. Results. Significantly lower levels of somatomedin C were observed in the fibromyalgia patients compared with controls (mean 2 SD 124.7 f 47 ng/ml versus 175.2 2 60 ng/ml; P = 0.OoooOl). These results could not be explained by concomitant therapy or by weight, and in a subset of 21 patients in whom this was From the Division of Arthritis and Rheumatic Diseases, Oregon Health Sciences University, Portland, Oregon. Robert M. Bennett, MD, FRCP, FACP: Professor of Medicine and Chairman, Division of Arthritis and Rheumatic Diseases; Sharon R. Clark, PhD: Assistant Professor of Medicine and Research; Stephen M. Campbell, MD: Associate Professor of Medicine; Carol S. Burckhardt, PhD: Assistant Professor of Medicine and Research. Address correspondence to Robert M. Bennett, MD, FRCP, FACP, Department of Medicine, L329A, Oregon Health Sciences University, Portland, OR 97201. Submitted for publication January 14, 1992; accepted in revised form June 2, 1992.
investigated, there was no correlation with various indices of disease activity. Conclusion. These findings indicate that there is a distinctive disruption of the growth hormonmmatomedin C neuroendocrine axis in a majority of fibromyalgia patients. It is hypothesized that this abnormality may explain the link between disturbed sleep and predisposition to muscle pain.
The fibromyalgia syndrome is a common cause of difEuse musculoskeletal pain (1). Its pathogenesis is obscure; distinctive tissue changes have not been described, and laboratory findings are usually normal. In the past, the term “psychogenic rheumatism” was often used to describe these patients, because of the confusing history of multiple somatic complaints, absence of physical findings, and normal results on laboratory tests. Over the last decade, rheumatologists have become increasingly aware of the large number of such patients, characterizedby the consistent features of the medical history, as well as the finding of tender areas in specific locations and absence of tenderness in other locations (2,3). In 1990, the American College of Rheumatology published guidelines for establishing a diagnosis of fibromyalgia (4), and a recent assessment of rheumatology manpower needs cited fibromyalgia as being second only to rheumatoid arthritis as a reason for office visits to rheumatologists (5). A seminal finding in the study of fibromyalgia was reported by Moldofsky et al in 1975, when they described a distinctive disturbance of stage-4 sleep characterized by alpha-wave intrusion into the normal
Arthritis and Rheumatism, Vol. 35, No. 10 (October 1992)
1113
1114
BENNETT ET AL
Table 1. Demographic characteristics of the fibromyalgia patients and controls* Patients Female/male Mean 2 SD age, years Mean f SD weight, lb Mean f SD duration of fibromyalgia, years No. taking HCAs No. taking NSAIDs
* HCAs
(n = 70)
Controls (n = 55)t
7010 47.6 k 10 160 f 37.6 11.6 f 6.9
5510 45.6 % 13 NA NA
27 36
NA NA
= heterocyclic antidepressants; NSAIDs antiinflammatory drugs. t NA = not available.
=
nonsteroidal
delta rhythm (6). Induction of this sleep abnormality in healthy volunteers produced a transient syndrome similar to fibromyalgia (7). Many metabolic, endocrine, and immune functions follow distinctive diurnal rhythms. Stage-4 sleep is closely related to the pulsatile secretion of growth hormone; -80% of the total daily production of growth hormone is secreted during this stage of sleep (8). Since growth hormone plays a critical role in muscle homeostasis and repair, it was of interest to investigate whether its secretion in patients with the fibromyalgia syndrome is compromised by the stage-4 sleep disturbance. The present study compared serum levels of somatomedin C, a growth hormone-related peptide, in female fibromyalgia patients and age-matched controls.
PATIENTS AND METHODS Seventy female patients with the fibromyalgia syndrome were compared with 55 age-matched female controls. The diagnosis of fibromyalgia was made in accordance with the American College of Rheumatology criteria (4). The 55 controls comprised 43 blood donors from the Portland Red Cross and 12 laboratory employees. All of the controls were reportedly in good health and not taking any medications. Blood samples were obtained between 1O:OO A M and 4:OO PM, from consecutive patients attending the Oregon Health Sciences University Fibromyalgia Treatment Program. The blood was allowed to clot and the serum was harvested and frozen; samples were kept frozen during shipment. Serum somatomedin C levels were assayed by Endocrine Sciences (Calabasas Hills, CA), using a radioimmunoassay that employs a rabbit antiserum directed against a synthetic segment of the protein (amino acids 57-70). Prior to assay, each sample was acid extracted from serum to minimize errors due to the presence of somatomedin binding proteins: 1 part of serum was extracted once with 87.5% ethanol plus 2N formic acid. The resulting supernatant (100 pl) was diluted in 900 pl of buffer (30 mM phosphate, 10 mM EDTA, 0.25% bovine serum albumin, pH 7.3, and 200 pl was incubated with lZSI-labeled synthetic peptide encompassing amino acids 53-70, as previously described (9). The interassay coefficient of variation was 7.3%, and
the intraassay coefficient of variation was 5.4%. Statistical analysis of the differences between fibromyalgia patients and controls was performed using Student’s 2-tailed t-test. The contribution of age, weight, and duration of illness to somatomedin C levels was assessed by multiple regression analysis.
RESULTS Characteristics of the fibromyalgia patients and controls are shown in Table 1, and somatomedin C values for patients and controls are shown in Figure 1. The mean ? SD somatomedin C levels in fibromyalgia patients and controls were 124.7 ? 47 ng/ml and 175.2 ? 60 ng/ml, respectively; this difference was highly significant (P = 0.000001, by Student’s t-test). Regression analysis indicated that age accounted for 14% of the variance in somatomedin C levels in the control group, whereas in the fibromyalgia group, age accounted for 7% of the variance. The duration of fibromyalgia accounted for 80% of patients with fibromyalgia were found to be anaerobically unfit, as assessed by their maximum oxygen uptake upon exercising to volitional exhaustion (13). A lack of regular physical exercise may be a factor contributing to the low levels of somatomedin C observed in some fibromyalgia patients. The observation that fibromyalgia patients have an alphddelta sleep anomaly and that the induction of this sleep anomaly causes a fibromyalgia-like syndrome in healthy volunteers has been a major stimulus for renewed interest in the relationship between sleep disorders and fibromyalgia (1 1). The physiologic link between disrupted stage-4 sleep and musculoskeletal pain has been obscure, but the findings reported herein suggest one plausible hypothesis. Growth hormone is an anabolic peptide which stimulates increased synthesis of DNA, RNA, and proteins; this effect is mediated via its stimulation of somatomedin C secretion by the liver. In adults, the growth hormonesomatomedin C axis has been shown to be important in muscle homeostasis (14,15); therapeutic administration of growth hormone has recently been shown to reverse muscle loss associated with the aging process (16). Most fibromyalgia patients locate the site of their pain to muscle and typically report having increased pain after exertion. There is a large body of evidence that links postexertional pain to muscle microtrauma (17-19), and it has been hypothesized that the musculoskeletal pain in fibromyalgia has a similar origin (1 1,20). This paradigm predicts that patients with the fibromyalgia syndrome are either peculiarly susceptible to muscle microtrauma at very low levels of exertion, or have a defect in the repair processes that normally lead to resolution of muscle microtrauma (21). It is proposed that in some fibromyalgia patients, persistent disruption of growth hormone secretion either predisposes to muscle microtrauma and/or impairs the normal healing of muscle microtrauma, as a result of reduced anabolic stimulation due to chronically low levels of somatomedin C. Such a hypothesis is in accord with Jacobsen et al’s finding of somewhat lower levels of serum type I11 procollagen in fibromyalgia patients (22) and the dependence of procollagen I11 synthesis on adequate growth hormone production (23). The recent report of fibromyalgia occurring after hypophysectomy (24) may also reflect such a mechanism. Fibromyalgia causes much distress to the affected patients and often frustrates physicians, who are unable to base therapy on any logical disease pathology. Although the old designation of “psychogenic rheumatism” has been abandoned by most practitioners, it is commonly believed that a maladapt-
DISCUSSION A conspicuous feature of the fibromyalgia syndrome has been the absence of any consistent pathophysiologic picture. The results reported herein indicate that, as a group, fibromyalgia patients have significantly lower serum levels of somatomedin C than do healthy controls. The low values found in some of the controls may be due to their having fibromyalgia, assuming a commonly estimated prevalence of between 3% and 15% in the general population. The rationale for measuring somatomedin C levels was based on theoretical considerations: -80% of growth hormone is produced during stage-4 sleep, and it was hypothesized that the alpha/delta sleep anomaly, which occurs during -60% of stage-4 sleep in patients with fibromyalgia, would disrupt the nocturnal secretion of growth hormone (11). The low levels of somatomedin C reported here may indeed result from such a mechanism; however, further studies measuring the continuous secretion of growth hormone in relation to sleep stages would be needed in order to confirm this. A previous study measured growth hormone levels in fibromyalgia patients, with samples taken at 8:OO AM and 4:OO PM; no differences were found between patients with fibromyalgia and patients with rheumatoid arthritis (12). Since growth hormone has a half-life of only 30 minutes, that study would not have detected reduced nocturnal secretion. Somatomedin C has a half-life of -20 hours, and its serum level is considered to reflect the integrated secretion of growth hormone (8). The other major stimuli for growth hormone release are hypoglycemia, starvation, consumption of large amounts of protein, elevated levels of circulating amino acids, surgical trauma, and other acute stresses, such as exercise. A progressive diminution of regular exercise is commonly encountered in patients with the fibromyalgia syndrome, due to post-
1116
BENNETT ET AL
ive response to stress plays some poorly defined role in pathogenesis of the disease. The findings in this study provide some preliminary insight into a psychoneuro-endocrine dysfunction which may be relevant to understanding the mind-body relationship in this enigmatic disorder.
ACKNOWLEDGMENTS We thank Dr. Mark Stene of Endocrine Sciences for his counsel during the preparation of this manuscript. We are indebted to P. Gierke and the nursing staff of the Portland Red Cross for providing serum samples from blood donors.
REFERENCES 1. Goldenberg DL: Fibromyalgia syndrome: an emerging but controversial condition. JAMA 257:2782-2787, 1987 2. Yunus M, Masi AT, Calabro JJ, Miller KA, Feigenbaum SL: Primary fibromyalgia (fibrositis): clinical study of 50 patients with matched normal controls. Semin Arthritis Rheum 11:151-171, 1981 3. Campbell SM, Clark S, Tindall EA, Forehand ME, Bennett RM: Clinical characteristics of fibrositis. I. A “blinded,” controlled study of symptoms and tender points. Arthritis Rheum 26:817-824, 1983 4. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, Fam AG, Farber SJ, Fiechtner JJ, Franklin CM, Gatter RA, Hamaty D, Lessard J, Lichtbroun AS, Masi AT, McCain GA, Reynolds WJ, Romano TJ, Russell IJ, Sheon RP: The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the multicenter criteria committee. Arthritis Rheum 33: 160-172, 1990 5. Marder WD, Meenan RF, Felson DT, Reichlin M, Birnbaum NS, Croft JD, Dore RK, Kaplan H , Kaufman RL, Stobo JD: The present and future adequacy of rheumatology manpower: a study of health care needs and physician supply (editorial). Arthritis Rheum 34: 1209-1217, 1991 6. Moldofsky H , Scarisbrick P, England R, Smythe H: Musculoskeletal symptoms and non-REM sleep disturbance in patients with “fibrositis syndrome” and healthy subjects. Psychosom Med 37:341-351, 1975 7. Moldofsky H, Scarisbrick P: Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosom Med 38:3544, 1976 8. Florini JR, Prinz PN, Vitiello ML: Somatomedin-C levels in healthy young and old men: relationship to peak and 24-hour integrated levels of growth hormone. J Gerontol 40:2-7, 1985 9. Hintz RL, Liu F, Chang D, Seegan G: A sensitive radioimmunoassay for somatomedin-Chnsulin-like growth factor I: based on synthetic insulin-like growth factor 57-70. Horm Metab Res 20:344-347, 1988
10. Burckhardt CS, Clark SR, Bennett RM: The Fibromyalgia Impact Questionnaire: development and validation. J Rheumatol 18:728-733, 1991 11. Bennett RM: Beyond fibromyalgia: ideas on etiology and treatment. J Rheumatol Suppl 19:185-191, 1989 12. McCain GA, Tilbe KS: Diurnal hormone variation in fibromyalgia syndrome: a comparison with rheumatoid arthritis. J Rheumatol Suppl 19:154157, 1989 13. Bennett RM, Clark SR, Goldberg L , Nelson D, Bonafede RP, Porter J, Specht D: Aerobic fitness in patients with fibrositis: a controlled study of respiratory gas exchange and ‘33xenonclearance from exercising muscle. Arthritis Rheum 32:454-460, 1989 14. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH: Growth hormone treatment in growth hormonedeficient adults. 11. Effects on exercise performance. J Appl Physiol 70:695-700, 1991 15. Crist DM, Peake GT, Loftfield RB, Kraner JC, Egan PA: Supplemental growth hormone alters body composition, muscle protein metabolism and serum lipids in fit adults: characterization of dose-dependent and response-recovery effects. Mech Ageing Dev 58: 191-205, 1991 16. Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE: Effects of human growth hormone in men over 60 years old. N Engl J Med 323:l-5, 1990 17. Edwards RHT: Hypotheses of peripheral and central mechanisms underlying occupational muscle pain and injury. Eur J Appl Physiol 57:275-281, 1988 18. Newham DJ, McPhail G , Mills KR, Edwards RH: Ultrastructural changes after concentric and eccentric contractions of human muscle. J Neurol Sci 61: 109-122, 1983 19. Newham DJ, Jones DA, Tolfree SE, Edwards RH: Skeletal muscle damage: a study of isotope uptake, enzyme efflux and pain after stepping. Eur J Appl Physiol 55:106-112, 1986 20. Jacobsen S, Bartels EM, Danneskiold-Samsoe B: Single cell morphology of muscle in patients with chronic muscle pain. Scand J Rheumatol 20:336-343, 1991 21. Bennett RM: Etiology of the fibromyalgia syndrome: a contemporary hypothesis. Intern Med Specialist 11:4861, 1990 22. Jacobsen S, Jensen LT, Foldager M, DanneskioldSamsoe B: Primary fibromyalgia: clinical parameters in relation to serum procollagen type I11 aminoterminal peptide. Br J Rheumatol 29:174-177, 1990 23. Jensen LT, Jorgensen OL, Risteli J, Christiansen JS, Lorenzen I: Type I and I11 procollagen in growth hormone-deficient patients: effects of increasing doses of GH. Acta Endocrinol (Copenh) 124:278-282, 1991 24. Disdier P, Harle J-R, Brue T, Jaquet P, Chambourlier P, Grisoli F, Weiller P-J: Severe fibromyalgia after hypophysectomy for Cushing’s disease. Arthritis Rheum 34: 493-495, 1991
