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Impaired hypothalamic-pituitary-adrenal axis activity in patients with multiple sclerosis

From the Department of Neurology (M.C.Y., M.I.G., J.C.), Raúl Carrea Institute for Neurological Research, FLENI; and Institute of Clinical Effectiveness and Health Policy (A.S.L.), Buenos Aires, Argentina.

Address correspondence and reprint requests to Dr. Jorge Correale, Raúl Carrea Institute for Neurological Research, FLENI, Montañeses 2325, (1428) Buenos Aires, Argentina jcorreale{at}fleni.org.ar bairesla{at}fibertel.org.ar

Objective: To investigate hypothalamic-pituitary-adrenal axis activity in well-defined multiple sclerosis (MS) patient subgroups.

Methods: A total of 173 patients with clinically definite MS were studied: 40 with primary progressive, 41 with secondary progressive, 58 with relapsing-remitting in remission, and 34 with relapsing-remitting during acute relapse. Sixty healthy subjects served as controls. No patients were receiving steroid or other immunomodulatory therapy. Plasma cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEAS), as well as urine cortisol levels, were measured using commercial radioimmunoassays. Glucocorticoid receptor (GR)–binding assay in peripheral blood mononuclear cells (PBMCs) was performed using [³H]dexamethasone (Dex). PBMC production of the proinflammatory peptide corticotrophin-releasing hormone (CRH), interleukin (IL)-1β, IL-6, interferon (IFN)-, and tumor necrosis factor (TNF)- was evaluated using enzyme-linked immunosorbent spot assay.

Results: All four groups of patients displayed significantly higher cortisol, ACTH, and DHEAS plasma concentrations and urine cortisol values than controls. Although 62% of MS patients did not suppress Dex, suppression test results did not correlate with IL-1β, IL-6, IFN-, or TNF- production. GR-binding assays showed no differences in binding sites between patients and controls; however, all MS groups showed decreased GR affinity and sensitivity compared with controls. The numbers of IL-1β-, IL-6-, and TNF--secreting cells increased significantly in relapsing-remitting MS patients only during exacerbations; in contrast, IFN--secreting cells increased during both exacerbations and remission. Finally, PBMC CRH-secreting cell numbers were considerably greater in all forms of MS.

Conclusions: Patients with multiple sclerosis show hypothalamic-pituitary-adrenal axis hyperactivity, with lymphocytes expressing similar glucocorticoid receptor numbers to controls; however, binding affinity and glucocorticoid sensitivity of these lymphocytes seem to be reduced.

Abbreviations: ACTH = adrenocorticotropic hormone; BDI = Beck Depression Inventory; B_max = maximum binding capacity; CRH = corticotrophin-releasing hormone; Dex = dexamethasone; DHEAS = dehydroepiandrosterone sulfate; DST = dexamethasone suppression test; EAE = experimental allergic encephalomyelitis; EDSS = Expanded Disability Status Scale; ELISPOT = enzyme-linked immunosorbent spot; GC = glucocorticoid; GR = glucocorticoid receptor; HDS = Hamilton Depression Scale; IFN = interferon; IL = interleukin; K_d = dissociation constant; MBP = myelin basic protein; MFIS = Modified Fatigue Impact Scale; MS = multiple sclerosis; PBMC = peripheral blood mononuclear cell; PPMS = primary progressive multiple sclerosis; RIA = radioimmunoassay; RR = relapsing-remitting; RREMS = relapsing-remitting multiple sclerosis during exacerbation; RRRMS = relapsing-remitting multiple sclerosis in remission; SPMS = secondary progressive multiple sclerosis; TNF = tumor necrosis factor.

Supported by FLENI.

Disclosure: M.C.Y., M.I.G., and A.S.L. report no disclosures. J.C. has received compensation from Merck-Serono and Novartis for clinical trials not related with the current investigation.

Received June 20, 2008. Accepted in final form September 11, 2008.

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