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Hypothalamicpituitaryadrenal axis dysregulation in healthy subjects undergoing mud-bath applications.

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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
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.
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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axis, hypothalamicpituitaryadrenal, health, application, bath, mud, dysregulation, undergoing, subjects
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