abstract & commentary
Source: Adler GK, et al. Reduced hypothalamic-pituitary and sympathoadrenal responses to hypoglycemia in women with fibromyalgia syndrome. Am J Med 1999;106:534-543.
Fifteen premenopausal women, ages 27-49 years, satisfying American College of Rheumatology criteria for fibromyalgia (FM; widespread pain present for at least 3 months), with tenderness on digital palpation at 11 or more of 18 specific sites, including bilateral, suboccipital, low cervical, trapezius, supraspinatus, second rib, lateral epicondyle, gluteal, greater trocanter, and knee) were compared to 13 matched healthy women to assess hypothalamic-pituitary-adrenal axis and sympathoadrenal system function. Exclusionary criteria included ongoing pregnancy or lactation, glucocorticoid or estrogen/progesterone treatment within the previous year, ongoing medical problems other than FM (except for 1 hypothyroid FM patient on levothyroxine), and any abnormality on blood chemistry, urinalysis, or thyroid function. Medication other than acetaminophen (and levothyroxine) was stopped two weeks prior to the study and acetaminophen 48 hours prior. All patients underwent complete medical and psychiatric history and examination, with baseline measurements of 24-hour urinary-free cortisol, and morning and evening adrenocorticotrophic hormone (ACTH) and cortisol levels. Hypothalamic-pituitary-adrenal axis and sympathoadrenal system function were assessed by hypoglycemic challenge using the hyperinsulinemic clamp method (DeFronzo RA, et al. Am J Physiol 1979;237:E213-E223), graded ACTH infusion, and placebo. Statistical analysis included Student’s two-tailed t test and Fisher’s exact test.
Twenty-four-hour urinary-free cortisol excretion and baseline morning and evening ACTH and cortisol levels were normal and not significantly different between groups. Induced hypoglycemia, however, resulted in a blunted pituitary-ACTH response in FM compared to controls, with a 30% less rise in ACTH (P = 0.01). Pituitary function was otherwise intact, with an expected rise in prolactin level following hypoglycemia. Despite the reduced ACTH response, cortisol levels following hypoglycemic challenge were similar in the two groups, indicating a normal adrenocortical response, whereas the adrenomedullary response to hypoglycemia, as measured by epinephrine levels, was significantly reduced by 30%. Responses to graded ACTH and placebo infusions showed normal adrenal sensitivity in both groups. Though eight of the 15 FM women had a past (n = 6) and/or present (n = 3) history of psychiatric illness, urinary-free cortisol, and ACTH and integrated epinephrine responses to insulin, hypoglycemic challenge was similar in FM patients with or without such history. FM patients have impairment of hypothalamic-pituitary and sympathoadrenal function independent of psychopathology, resulting in blunted ACTH and epinephrine responses to hypoglycemia.
FM affects 2% of the population and women seven times more frequently than men (Wolfe F, et al. Arthritis Rheum 1990;33:160-172). Presenting with areas of muscle pain, nodularity, and stiffness, it was initially termed muscular, as opposed to articular, rheumatism by 18th and 19th century German and British physicians. Gowers coined the term "fibrositis," despite the absence of pathological inflammation, and finally FM was created to dispel the misleading and incorrect notion that inflammation was involved (Gowers WR. BMJ 1904;1:117-121; Yunus M, et al. Semin Arthritis Rheum 1981;11:151-171). Given the complex relationship of FM with psychiatric illness, the associated multiple nonspecific somatic complaints, and the absence of any diagnostic laboratory abnormalities, FM holds an uncertain position in current medical thought. Despite conflicting findings in other areas, mounting evidence now suggests that FM may be associated with neuroendocrine dysfunction.
Assessment of heart rate variability and spectral analysis of 24-hour ambulatory cardiac recording among 30 FM patients and 30 age- and sex-matched normal controls examined the circadian variations of sympathetic and vagal activity in FM (Martinez-Lavin M, et al. Arthritis Rheum 1998;41:1966-1971). FM patients showed significantly less heart rate variability compared to controls (P = 0.008) with significantly higher nocturnal values of sympathetic/vagal balance, findings that may underlie the fatigue and sleep disturbances of FM. Polysomnographic sleep study of 11 FM women demonstrated more stage 1 sleep, more sleep-state changes, and more sleep fragmentation than control subjects, with alpha, delta, and nonrapid eye movement sleep comparable between groups (Shaver JL, et al. Res Nurs Health 1997;20:247-257). Conflicting results are reported of growth hormone and insulin-like growth factor (IGF-1, somatomedin-C), but not serotonin, being significantly lower in FM compared to controls, underscoring dysfunction of the hypothalamic-pituitary axis (Bagge E, et al. J Rheumatol 1998;25:145-148; Bennett RM, et al. ibid 1997;24:1384-1389; Wolfe F, et al. ibid 555-559). Earlier studies, however, have shown no such differences in growth hormone secretion (Jacobsen S, et al. J Rheumatol 1996;22:1138-1140). Lastly, three-stage tilt table testing in 20 FM patients and 20 controls documented syncope or presyncope, with a 25 mmHg systolic drop in blood pressure, without compensatory tachycardia, during stage 1 (45 minutes at 70° upright) in 12 of the FM patients but in no controls (Bou-Holaigah I, et al. Clin Exp Rheum 1997;15:239-246).
Much remains to be understood, conflicting data still cloud the horizon, and the primary pathogenic role of these findings is uncertain, but these initial steps may ultimately bring fibromyalgia in from the periphery. Meanwhile, its management requires patience, perseverence, and a multidimensional approach including pharmacotherapy (anti-depressants, nonsteroidal anti-inflammatory agents), physical therapy, sleep habit normalization, and, in individualized cases, cognitive, behavioral, and other psychotherapies (Demitrack MA. Psychiatr Clin North Am 1998;21:671-692). —mr
Which of the following statements about fibromyalgia (FM) is correct?
a. All patients are malingerers and should be treated as such.
b. Polysomnographic sleep study has demonstrated more sleep fragmentation in FM patients than in control subjects.
c. Serotonin levels are significantly lower in FM compared to controls.
d. Insulin-like growth factor (IGF-1, somatomedin-C) is significantly higher in FM than controls.
e. Induced hypoglycemia has been shown to result in an enhanced pituitary ACTH response in FM.