Hypothalamicpituitaryadrenal axis dysregulation in healthy subjects undergoing mud-bath applications.
код для вставкиСкачатьLETTERS published reports further highlight the highly complex nature of the defects in the neuroendocrine immunology of RA. Clearly, further systematic evaluation is necessary before we can fully understand the underlying mechanisms. I. C. Chikanza, MB, ChB, MRCP, MD The Royal London Hospital London, UK 1 . Hall J, Morand EF, Medbak S , Zaman M, Perry L, Goulding NJ, Maddison PJ, O’Hare JP: Abnormal hypothalamic-pituitaryadrenal axis function in rheumatoid arthritis: effects of nonsteroidal antiinflammatory drugs and water immersion. Arthritis Rheum 37:1132-1137, 1994 2. Chikanza IC, Petrou P, Kingsley G, Chrousos G, Panayi GS: Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis. Arthritis 35: 12811288, 1992 3. Neek G , Federlin K, Graef V, Rusch D, Schmidt KL: Adrenal secretion of cortisol in patients with rheumatoid arthritis. J Rheumatol 17:24-29, 1990 4. Zacharieva S, Borissova AM, Andonova K, Stoeva I, Matorozov P: Role of prostaglandins E2 on the CRH-induced ACTH in man. Horm Metab Res 24:336-338, 1992 5. Brooks AN, Gibson F: Prostaglandin E2 enhances AVP secretion and not CRH-stimulated ACTH secretion from cultured fetal sheep pituitary cells. J Endocrinol 132:33-38, 1992 6 . Cambronero JC, Rivas FJ, Borelli Guava C: Role of arachidonic acid metabolism on CRH release induced by interleukin-I from superfused rat hypothalami. J Neurimmunol 3957-66, 1992 Hypothalamic-pituitary-adrenal axis dysregulation in healthy subjects undergoing mud-bath applications To the Editor: We read with interest the article by Hall and colleagues, concerning the abnormal HPA axis function observed in untreated RA patients (1). The 8 patients studied showed high levels of plasma ACTH without increase of serum cortisol. However, the significance of this dysregulation remains unclear. The authors also pointed out that immersion in thermoneutral water (34.5-35°C) did not have any effect on the HPA axis function, whereas others have previously disputed this finding (2). In the Euganean Spa resort (Padova, Italy), hot mud-packs and baths in thermal water have been employed since pre-Roman ages to relieve pain and disability in different rheumatic diseases, mostly OA and noninflammatory soft tissue disorders. Hot mud and thermal water are naturally available in this resort, and their application is referred to as thermal treatment. In 6 healthy subjects, ages 20-39, who received thermal treatment, we observed a dysregulation of the HPA axis similar to that reported by Hall et al. During a single mud-bath application (application of 4042°C mud for 15 minutes [head out], followed by immersion in 37-38°C thermal water for 10 minutes [head out]), a transient but significant rise in plasma ACTH and a concurrent reduction in serum cortisol were detected (Figure 1). Moreover, urinary cortisol decreased and urinary 11-hydroxycorticoids slightly increased in the 2 hours after thermal treatment (compared with the 2 hours before). In all 10 0 - +mud+ 20 30 Math &ENDORPHIN 40 4 +CORTISOL - PO mln ACTH Figure 1. Plasma adrenocorticotropic hormone (ACTH), pendorphin (B-END.), and serum cortisol (CORT.) levels during a mud-bath application in 6 healthy subjects. subjects, the same variations of plasma ACTH and serum cortisol were observed during repeated treatments in the course of 11 daily mud-bath applications in 2 weeks. Treatments were performed according to the traditional schedule used in this Spa resort. The HPA axis dysregulation induced by thermal treatment seems to be related to the effect of P-endorphin on the adrenal cortex. In fact, under the same conditions, we have previously demonstrated a significant increase in plasma levels of this opioid peptide (3). Our findings are also consistent with previous reports by other authors, who found that in healthy subjects, high plasma levels of p endorphin reduce the adrenocortical response to ACTH by decreasing the cortisol output (4). We believe that the increase in circulating levels of pendorphin and ACTH observed in our healthy subjects is a result of stress induced by the thermal mud-bath application (5). High plasma levels of &endorphin have also been reported in patients with active RA (6), and this could explain the alterations seen by Hall et al. Moreover, it has been shown that in RA, P-endorphin and leu-enkephalin levels are higher in synovial fluid than in peripheral blood. This suggests that the synovial membrane might release opioid peptides (7). In conclusion, we found that healthy subjects who received thermal treatment demonstrated HPA axis dysregulation. Our observations demonstrate that thermal mudbath applications, as used in the Euganean Spa resort for more than two thousand years for the treatment of various rheumatic complaints, exert neuroendocrine effects. Whether such an effect is the mechanism by which this traditional and empirical treatment is frequently useful in relieving pain and disability, as a lot of rheumatic disease patients currently acknowledge, has yet to be proven. 725 LETTERS Franco Cozzi, MD Paolo Lazzarin, MD Silvano Todesco, MD Lorenzo Cima, MD University of Padova Padova, Ztaly 1 . Hall J, Morand EF, Medbak S, Zaman M, Perry L, Goulding NJ, Maddison PJ, O’Hare JP: Abnormal hypothalamic-pituitaryadrenal axis function in rheumatoid arthritis: effects of nonsteroidal antiinflammatory drugs and water immersion. Arthritis Rheum 37:1132-1137, 1994 2. Coruzzi P, Ravanetti C, Musiari L, Biggi A, Vescovi PP, Novarini A: Circulating opioid peptides during water immersion in normal man. Clin Sci 74:133-136, 1988 3. Giusti P, Cima L, Tinello A, Cozzi F, Targa L, Lazzarin P, Todesco S: Stresshormone, freigesetzt durch Fangotherapie: ACTH- und Beta-Endorphin-Konzentrationen unter Warmestress. Fortschr Med 108:601403, 1990 4. Beyer HS, Parker L, Li HC, Stuart D, Sharp BM: Betaendorphin attenuates the serum cortisol response to exogenous adrenocorticotropin. J Clin Endocrinol Metab 62:808-81I , 1986 5. Cima L, Cozzi F, Giusti P, Guidetti G, Todesco S: Neuroendocrine effects of a cycle of fangotherapy. Pharmacol Res 26 (suppl 1):302, 1992 6. Ekdahl C, Andersson SI, Ekman R, Svensson B: Dynamic training and circulating neuropeptides in rheumatoid arthritis: a two-year follow-up study. Pain 4 9 : 6 1 4 , 1992 7. Suzuki N , Yoshino S , Nakamura H: A study of opioid peptides in synovial fluid and synovial tissue in patients with rheumatoid arthritis. Arerugi 41:615420, 1992 To the Editor: We thank Dr. Chikanza and Dr. Cozzi and colleagues for their interest in our recent paper on abnormal HPA axis function in RA. These correspondents raise issues which relate to the main findings reported in our paper, which were (i) that individuals with untreated RA had significantly increased levels of ACTH compared with controls, without accompanying elevation of cortisol, suggesting adrenal hyporesponsiveness; (ii) that matched NSAID-treated RA patients and matched healthy controls did not display this elevation in ACTH; and (iii) that water immersion had no effect on peripheral ACTH and cortisol levels in any group. Dr. Chikanza concurs with our conclusion that our findings may be explained by elevations of hypothalamic or extrahypothalamic corticotropin-releasing factor (CRF) production. This would be consistent with animal and in vitro data regarding the stimulation of hypothalamic CRF production by inflammatory mediators. The extremely low concentrations and short circulating half-life of human CRF in peripheral blood make reliable measurement difficult, and may mean that peripheral blood CRF levels do not necessarily reflect levels in the HPA circulation. The inclusion of CRF-induction of HPA axis activity into our study may have yielded additional information, but Dr. Chikanza’s suggestion that our results could be explained by chronic understimulation of the adrenals is not consistent with our finding of elevated levels of ACTH in RA patients. Understanding of the role of prostanoids, and hence of NSAIDs, in HPA axis function is not complete. In Dr. Chikanza’s group’s previous paper, which also demon- strated hyporesponsiveness of the HPA axis to stress in subjects with RA, no separate analysis of the effects of NSAIDs was reported, and would be difficult to interpret given that only 3 of 10 and 2 of 9 RA and OA patients, respectively, were not NSAID-treated (1). Certainly, relying upon similar proportions of subjects being NSAID-treated is poorly informative, given that only mean data were presented. Dr. Chikanza refers to further, unpublished data on ACTH and cortisol levels in NSAID-treated and nonNSAID-treated RA, OM, and OA subjects. The lack of a significant difference in ACTH levels between these groups contrasts with our findings, but is difficult to comment upon further without seeing the data, as the size and comparability of the groups studied is unknown, and factors such as the duration and intensity of previous NSAID therapy may also need to be considered. Dr. Chikanza cites work by Brooks et a1 which showed that pituitary ACTH production induced by AVP is more susceptible to modulation by prostaglandins than that induced by CRF (2). Recent animal studies suggest that AVP may supplant CRF in the regulation of pituitary ACTH production in chronic stress (3’), and while the applicability of this finding to humans is uncertain, it would be consistent with our results of lower ACTH levels in NSAID-treated chronic RA. Other in vitro animal and human studies clearly illustrate the involvement of prostanoids in inflammatorymediator-induced HPA axis activation and the ability of NSAIDs to influence this at many levels (4-7). The chronic elevations of inflammatory cytokines and mediators in subjects with RA may thus result in differential effects of NSAIDs in these subjects. We await a fuller publication of Dr. Chikanza’s new data with interest. In their letter, Dr. Cozzi et a1 report the results of a small, uncontrolled study of the effects of sequential 15minute hot mud and water immersion on HPA axis function in healthy individuals. They conclude that this regimen is associated with HPA axis dysregulation and that this may be explained by elevations in P-endorphin. Unfortunately, only mean data are presented, with no documentation of standard errors or of statistical analysis of their data. The figure they provide shows that mean levels of ACTH and /3-endorphin increased transiently during the first 20 minutes of the immersion regimen, but that these had returned to prestress levels by 60 minutes, and further, that cortisol levels declined somewhat during this period. Taken at face value, these data are in fact broadly consistent with our results, in which hourly sampling during and after prolonged water immersion showed no significant change in ACTH or cortisol. The more frequent sampling in the 60 minutes of observation in the work by Cozzi et a1 may have revealed alterations of ACTH and cortisol not detected by the hourly sampling in our study. However, the lack of sustained alterations of cortisol in both our study and Cozzi’s strongly suggests that immersion does not exert its putative therapeutic effects through alterations in endogenous glucocorticoid production. Nonetheless, Cozzi’s observation that similar results were obtained in serial exposures to mud/water immersion is of value. The conclusion that these data reflect /3-endorphin inhibition of adrenal cortisol production is, however, not supported by the literature. For example, the study by Beyer
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