Heterogeneity of hypothalamic-pituitary-adrenal system response to a combined dexamethasone-CRH test in multiple sclerosis

Abstract

The endocrine system participates in the regulation of the immune and neural systems and therefore hormonal factors probably play an important role in the development and course of multiple sclerosis (MS). Specifically, the hypothalamic-pituitary-adrenal (HPA) system seems crucial because (a) the inflammatory response is accompanied by HPA activation; (b) animal models with an inherited HPA defect are prone to developing experimental autoimmune encephalitis; and (c) most important, corticosteroids are still the most widely used treatment. We administered a recently developed neuroendocrine function test that combines dexamethasone suppression (1.5 mg orally at 2300 h) and corticotropin-releasing hormone (CRH) stimulation (100 micrograms i.v. at 1500 h the following day) and measured the response of plasma cortisol and corticotrophin (ACTH) secretion in 19 patients with an acute exacerbation of MS. These patients had a significantly higher mean plasma cortisol response than age-matched controls (peak minus baseline; 48.1 +/- 10.5 ng/ml [mean +/- SEM] versus 19.8 +/- 4.2 ng/ml; p < 0.05), but the corresponding ACTH values for the two groups were indistinguishable (13.4 +/- 1.4 pg/ml [mean +/- SEM] versus 11.3 +/- 1.4 pg/ml; n.s.). The response range in the patients was broader and we identified six patients with excessive cortisol release (peak minus baseline: 100.5 +/- 14.4 ng/ml [mean +/- SEM]), whereas four patients failed to respond at all. The hormonal response patterns were not related to previous treatments with corticosteroids or other immunosuppressants or to psychopathological features. These results point to a heterogeneity of HPA system function, most likely at the corticosteroid receptor level, which has clinical implications for all those treatments that affect the HPA system and the course of MS.

Cortisol Awakening Response Is Linked to Disease Course and Progression in Multiple Sclerosis

“…Elevated levels of ACTH and cortisol in response to CRH administration in MS patients have frequently been reported [13], [14], [26] and endocrine changes seem to be associated with clinical course as well as disease progression.…”

“…In response to intravenous administration of CRH, cortisol release was increased in MS patients compared to healthy control subjects [12], [13]. HPA axis function also seems to be linked to radiological as well as clinical aspects: increased cortisol response to CRH was associated with gadolinium enhancing lesions, a marker for acute central nervous system inflammation in MS [14].…”

Acute and chronic neuroendocrine effects of interferon‐β 1a in multiple sclerosis

“…Because cortisol, like exogenously administered glucocorticoids, attenuates the immune response, such an endocrine effect might contribute to the therapeutic actions of IFN‐β in multiple sclerosis. Several groups have found disturbances of the hypothalamo‐pituitary‐adrenal (HPA) axis in multiple sclerosis, 7–14 suggesting that the neuroendocrine responses to IFN‐β may be altered or heterogeneous. If such responses were associated with varying therapeutic effects, they could be useful to predict benefit of treatment.…”

Hormonal Influences in Multiple Sclerosis

“…Using the more sensitive combined dexamethasone-corticotropin releasing hormone (CRH) test, Grasser et al found a normal ACTH response but a higher mean plasma cortisol response in 19 MS patients in acute relapse compared to age-matched controls. Six of the 19 had an excessive release of cortisol; four did not respond at all [89]. Wei and Lightman studied 21 patients with definite MS, most within 1 month of clinical relapse [227].…”