Some aspects of the behavior of the hypothalamus–pituitary–adrenal axis in patients with uncomplicated Plasmodium falciparum malaria: Cortisol and dehydroepiandrosterone levels Rosana Maria Feio Libonati , Berenice Bilharinho de Mendonc¸a , Jos´e Antˆonio Mau´es , Juarez Antonio Sim˜oes Quaresma , Jos´e Maria de Souza a N´ucleo de Medicina Tropical, Universidade Federal do Par´a, Av. General´ıssimo Deodoro 92, Umarizal, Bel´em, PA 66055-420, Brazil b Universidade de S˜ao Paulo, S˜ao Paulo, SP, Brazil c Instituto Evandro Chagas, Bel´em, PA, Brazil Received 25 September 2005; received in revised form 2 April 2006; accepted 22 May 2006 Abstract
We studied the behavior of cortisol and dehydroepiandrosterone (DHEA) in 24 patients with uncomplicated Plasmodium falci- parum malaria of the Evandro Chagas Institute, Bel´em, Par´a, Brazil. The patients were evaluated before treatment (Day 0), 24 hafter the beginning of medication (Day 1) and on Day 8 of follow-up (Day 7). Steroid levels were correlated with parasitemia,temperature and time of the disease. The levels of these hormones were found to be significantly higher on Day 0 than on Day 7,showing no correlation with parasitemia or temperature, but temperature had a positive effect on the correlation between cortisol anddehydroepiandrosterone. Cortisol was not correlated with the time of disease, but a significant negative correlation was observedbetween DHEA and time of disease on Day 7, suggesting a decline in the adrenal reserve of this steroid. In conclusion, an increasein cortisol and dehydroepiandrosterone is observed in patients with falciparum malaria, with these levels declining with decreasingparasitemia. The finding that temperature interfered with the correlation between cortisol and dehydroepiandrosterone suggests acommon mechanism for the activation of these hormones in malaria.
2006 Elsevier B.V. All rights reserved.
Keywords: Malaria falciparum; Cortisol; DHEA 1. Introduction
physiopathogenesis of complicated falciparum malariaobserved The physiopathogenesis of malaria caused by Plas- elevated levels of these cytokines in human malaria modium falciparum is not completely understood.
caused by other Plasmodium species.
Cytokines such as tumor necrosis factor-alpha (TNF- It is known that these cytokines are also released ␣) and interleukin-1 (IL-1) have been implicated in the during the acute response to stress, stimulating thehypothalamus–pituitary–adrenal (HPA) axis, whichleads to the release of cortisol and other steroids such as dehydroepiandrosterone (DHEA) from the adrenal Corresponding author. Tel.: +55 91 32414681; E-mail address: (R.M.F. Libonati).
presents an anti-inflammatory and immunosuppressive 0001-706X/$ – see front matter 2006 Elsevier B.V. All rights reserved.
R.M.F. Libonati et al. / Acta Tropica 98 (2006) 270–276 action, whereas DHEA exerts an immunostimulatory patient clinic on Day 7 for a new control. Cortisol action. Considering that malaria is a stress situation since levels were measured on Days 0, 1 and 7 in dupli- it is a microbial infection, stimulation of the HPA axis cate samples using an AutoDELFIA kit (Wallac Oy).
also occurs in this condition as observed by The intra- and interassay coefficients of variation of patients with falciparum malaria.
the method were less than 6%, with the following Therefore, the objective of the present study was to reference values—morning: 8.85–26.4 ␮g/dl, mean of evaluate the HPA axis in patients with falciparum malaria 16 ␮g/dl; afternoon: 4.0–15.2 ␮g/dl, mean of 8.48 ␮g/dl.
in order to determine the behavior of cortisol and DHEA DHEA levels were measured on Days 0 and 7 in before and after treatment and the correlation between duplicate samples using the DSL-9000 Active DHEA the levels of these steroids and temperature, duration of kit (Diagnostic Systems Laboratories, Inc., Webster, the disease and parasitemia, permitting a better under- TX, USA), with intra- and interassay coefficients of standing of the behavior of the HPA axis in P. falciparum variation of less than 10% and the following refer- malaria. This would be of help for studies regarding ence values—men: 1.4–12.5 ng/ml, mean of 4.6 ng/ml; the treatment of this frequent endemic disease, since women: 0.8–10.5 ng/ml, mean of 3.0 ng/ml.
these two hormones exert antagonistic actions within theimmune system.
2. Patients and methods
Cortisol levels were compared between Days 0, 1 and 7 by Friedman’s analysis of variance, and DHEA levels were compared between Days 0 and 7 by the Stu-dent t-test. Correlations between parasitemia, cortisol Primoinfected or multi-infected (more than one and DHEA levels, between cortisol and DHEA levels malaria episode) patients of both genders, ranging in age and axillary temperature at the time of collection, and from 15 to 50 years, with a positive diagnosis of P. falci- between cortisol and DHEA levels on Days 0 and 7 and parum malaria who had not used any antimalarial drug the time of evolution of the disease (TED—time from for at least 15 days, except for mefloquine when this the onset of first symptoms to diagnosis and to Day 8 period was extended to 63 days, were studied. Excluded of follow-up, respectively) were determined by Pear- were patients taking glucocorticoids or other immuno- son’s linear correlation coefficient. The multiple linear suppressive drugs, pregnant and breast-feeding women, regression was used to measure associations between women using contraceptives and all patients with severe parasitemia, cortisol, DHEA and temperature. A p-value malaria according to WHO criteria. The sample con- ≤0.05 was considered to be significant. The statistical sisted of patients originating from Amazonian malaria analysis had been made with BioEstat 3,0.
areas who spontaneously sought the Evandro ChagasInstitute because of a suspicion of malaria. Included in 3. Results
the study were patients who fulfilled the inclusion crite-ria and who signed an informed consent form. The study was approved by the Research Ethics Committee of theEvandro Chagas Institute.
Twenty-four patients, 18 men and 6 women ranging in age from 15 to 47 years, including 12 primoinfected and 12 multi-infected subjects, were studied. Of themulti-infected patients, 66.7% had malaria for the sec- Three 10-ml blood samples were collected before ond time The most frequent signs and symp- treatment (Day 0) and on Day 2 (Day 1) and Day 8 of toms were fever, shivering, headache, anorexia, asthenia, follow-up (Day 7). On the 3 days, blood was collected lumbar pain, dizziness, nausea, myalgia, arthralgia, hep- from the same patient always at the same time due to the atomegaly and splenomegaly. All patients were symp- circadian rhythm of cortisol and DHEA. The blood sam- tomatic but none of them presented severe signs. The ples were centrifuged and serum was stored at −20 ◦C.
TED ranged from 1 to 22 days on Day 0 in this sample.
The parasitological exam was performed daily using The geometric mean and range (minimum and max- the thick drop technique until the patient presented imum) of asexual parasitemia are shown in two consecutive negative slides, returning to the out- patients were free of parasites as early as on Day 5.
R.M.F. Libonati et al. / Acta Tropica 98 (2006) 270–276 Table 1Malaria history of the 24 patients with P. falciparum malaria includedin the study on the assessment of serum cortisol and DHEA levels Evandro Chagas Institute, Bel´em, Par´a, Brazil (2003). Source: Primarydata.
a Number of previous malaria episodes.
Fig. 1. Cortisol levels (means ± S.D.) on Days 0, 1 and 7 in the 24patients with falciparum malaria included in the study on the assess- ment of serum cortisol and DHEA levels. Evandro Chagas Institute,Bel´em, Par´a, Brazil (2003).
Eighteen patients received quinine sulfate for 3 days in combination with tetracycline for 7 days. Six of the afternoon and in the morning, which were therefore 24 patients had parasitemia levels above 10,000 asexual pooled in the same group. Mean cortisol levels are shown forms/mm3 blood and received artemisinine derivatives (oral artesunate) instead of quinine in combination withtetracycline for 7 days.
3.5. Mean DHEA levels on Days 0 and 7 3.4. Mean cortisol levels on Days 0, 1 and 7 DHEA levels were measured in only 16 patients, 5 women and 11 men, due to problems with the Day 0 = 22.18 ± 9.26, Day 1 = 17.89 ± 7.2 and Day serum, and the following results were obtained: Day 7 = 10.59 ± 2.8 ␮g/dl. Comparison of these results by the 0 = 6.23 ± 3.02, and Day 7 = 3.94 ± 1.5 ng/ml; compar- Friedman test (Fr = 30.17, p < 0.01) revealed a signifi- ison between means: t = 2.829, p = 0.013. ws cant difference between Days 0 and 1 = 15.5 (p < 0.05), the mean DHEA levels on Days 0 and 7. No signifi- between Days 0 and 7 = 35.5 (p < 0.01) and between cant difference was observed between men and women Days 1 and 7 = 20 (p < 0.01). No significant difference or between collection times, and the data were therefore was observed between patient samples collected in the Table 2Asexual parasitemia on Days 0–4 in the 24 patients with P. falciparum 3.6. Correlation between cortisol levels and malaria included in the study on the assessment of serum cortisol and No significant correlation was observed between cor- tisol on Day 0 and parasitemia on Day 0 (r = 0.0754, p = 0.726). The parasitemia levels had been transformed into Ln, presenting a normal distribution.
3.7. Correlation between DHEA levels and As was the case for cortisol, no significant correlation Source: Primary data. Evandro Chagas Institute, Bel´em, Par´a, Brazil was observed between DHEA on Day 0 and parasitemia on Day 0 (r = 0.162, p = 0.549).
R.M.F. Libonati et al. / Acta Tropica 98 (2006) 270–276 Fig. 2. DHEA levels (means ± S.D.) on Days 0 and 7 in 16 patientswith falciparum malaria included in the study on the assessment of Fig. 3. Correlation between DHEA on Day 7 and time of evolution serum cortisol and DHEA levels. Evandro Chagas Institute, Bel´em, of the disease (TED) on Day 7 in 16 patients with falciparum malaria included in the study on the assessment of serum cortisol and DHEAlevels. Evandro Chagas Institute, Bel´em, Par´a, Brazil (2003).
3.8. Correlation between cortisol and DHEA levels (r = 0.102, p = 0.661). However, there was a significant The following results were obtained: cortisol on Day negative correlation between DHEA on Day 7 and TED 0 and DHEA on Day 0 (r = 0.485, p = 0.057; 16 variable on Day 7 (r = −0.580, p = 0.018). ws the cor- pairs); cortisol on Day 7 and DHEA on Day 7 (r = 0.351, relation between DHEA on Day 7 and TED on Day 7.
p = 0.182; 16 variable pairs).
4. Discussion
3.9. Correlation between cortisol, DHEA andaxillary temperature and parasitemia measured at In Brazil, the Amazon region accounts for more than 95% of malaria cases. Cortisol and DHEA are steroidsthat play an important role in the immune response, first No significant correlation was observed between cor- by repressing this response and second by stimulating tisol and temperature (r = 0.104, p = 0.637), or between it. Therefore, we proposed the present study since data DHEA and temperature (r = 0.312, p = 0.257). However, regarding the behavior of these steroids in malaria are calculation of the partial correlation between cortisol (y), DHEA (z) and temperature (x) showed a positive Serum cortisol levels were measured on Days 0, 1 effect of temperature on the correlation between corti- and 7, with a higher mean concentration being observed sol and DHEA (Rxyz = 0.411, p = 0.147; Rxyz = 0.473, on Day 0 followed by a significant reduction on Day 1 p = 0.087; Ryzx = 0.557, p = 0.038). In the analysis of and a highly significant decline on Day 7. These results multiple linear regression it did not have association demonstrate the presence of increased cortisol levels in between levels of cortisol, temperature and DHEA with patients with P. falciparum malaria, indicating stimula- the parasitemia, however association occurred between tion of the HPA axis in these patients, in agreement with cortisol and DHEA (partial coefficient of correlation who observed intact adrenal function in patients with P.
malaria. Activation of this axis in malaria 3.10. Correlation between cortisol, DHEA and TED is the result of the release of cytokines and, in part, of the stress situation generated by the disease, with theactivation of the HPA axis leading to an interaction of No significant correlation was observed between cor- the neuro–immune–endocrine systems in these patients.
tisol on Day 0 and TED on Day 0 (r = −0.293, p = 0.164), DHEA on Day 0 and TED on Day 0 (r = −0.283, receptor showed stronger associations with basal and p = 0.288), or cortisol on Day 7 and TED on Day 7 peak plasma ACTH. This event has been observed in R.M.F. Libonati et al. / Acta Tropica 98 (2006) 270–276 other infectious states such as severe bacterial infections els of dehidroepiandrosterone sulphate (DHEAS) were significantly associated with decrease parasite density in Cortisol levels will be declining as the clinical condi- adolescents and young adults. Maybe in this present sam- tion improves and parasitemia decreases, probably due ple, the patients’ variable age and the number of patients can have interfered in these results.
studying a population of 11 European and 5 African indi- In our research it was not possible to evaluate the viduals, observed regression of TNF levels to normal levels of DHEA before the patients being infected. In around the eighth day after the beginning of malarial negative parasitemia of the patients and had initially fol- In the present study, mean DHEA levels were signifi- lowed the parasitemia levels and the DHEA. The DHEA cantly higher on Day 0 compared to Day 7. A decline in level was the important factor of the average of the par- the levels of these steroids is found in maintained stress, a fact not observed for the present sample. We cannot make clinical associations between DHEA patients with chronic stress (with infec- and parasitemia therefore we did not know the levels of tious or noninfectious diseases), observed a highly sig- DHEA before the patients being infected. But support- nificant increase in basal cortisol levels compared to nor- ing conclusions of previous works, probably DHEA can mal controls, whereas basal DHEA levels were reduced present protective effect against the malaria.
Acute stimulation of the HPA axis leads to the release of cortisol and other steroids produced and secreted corticotrophic hormone (ACTH) resulted in increased by the adrenal glands. On the basis of the behavior of cortisol concentrations throughout the stimulus, whereas DHEA during maintained stimulation of the HPA axis, DHEA showed an initial peak followed by a decline 2 h one may suppose the existence of nonsignificant corre- after stimulation. This suppression of DHEA levels was lations between DHEA and cortisol since higher cortisol not observed in the present patients.
and lower DHEA levels would be expected on Day 0 due In the present study, we calculated the correlation between cortisol levels and parasitemia. No significant while on Day 7, with the cessation of HPA axis correlation was observed between cortisol levels on Day stimulation, cortisol and DHEA levels would probably 0 and parasitemia on Day 0; thus, in the present sample return to normal. As expected, no significant correla- cortisol did not seem to interfere with the parasitemia tion between DHEA and cortisol was observed on Day of the patients, although cortisol and dexamethasone 7; however, on Day 0, although DHEA levels tended to act by reducing the adherence of malaria infected ery- follow cortisol levels, although in a nonsignificant man- throcytes to monocytes after monocytes were treated ner (p = 0.057), with both steroids being increased during A positive correlation between cortisol levels and Calculation of the correlation between serum cortisol parasite load has been shown to exist in P. falciparum- levels and axillary temperature measured at the time of collection on Day 0 showed no significant correlation.
Therefore, in the present sample an increase in temper- of cortisol are more important in pregnant woman, where ature was not an acute stimulus for the release of ACTH the immunomodulation is mediated others hormones as estrogen, progesterone and prolactin ( There was also no significant correlation between DHEA and axillary temperature at the time of collection DHEA levels were also correlated with parasitemia to on Day 0, indicating that temperature did not interfere determine the possible existence of a negative correlation with this variable. However, the association between cor- between these two variables due to the antimalarial activ- tisol, DHEA and temperature showed that cortisol levels did not interfere with the correlation between DHEA and temperature, and that DHEA levels did not interfere with the correlation between cortisol and temperature, cant correlation was observed between DHEA on Day 0 but that temperature had a significant positive effect and parasitemia on Day 0. Therefore, DHEA also did not on the correlation between DHEA and cortisol. This interfere with parasitemia levels in the present sample, finding can be explained by the fact that fever reflects a time of blood cell lysis, releasing parasite antigens ducting studies in Kenya have demonstrated that the lev- into the circulation which, in turn, induce the release R.M.F. Libonati et al. / Acta Tropica 98 (2006) 270–276 of cytokines such as TNF-␣ and IL-1. These cytokines was significantly lesser in the patients with serious ill- stimulate the thermoregulatory center in the hypotha- ness indicating a diminished reserve of DHEA to the lamus as well as the HPA axis, and this fact might stimulation with ACTH. The authors suggest that it has explain the higher DHEA levels during pretreatment, in the chronic stimulation of the axis a change in the way with schizogony therefore representing an acute stim- of the pregnenolone metabolism in direction the gluco- ulus of the HPA axis. The correlation between cortisol corticoid way, reflecting an increase of the production of levels and TED and between DHEA and TED were cal- culated to determine the behavior of these steroids in We conclude that: (a) an increase in DHEA and corti- relation to the duration of the disease. A nonsignifi- sol levels occurred in patients with P. falciparum malaria, cant negative correlation was observed between cortisol indicating stimulation of the HPA axis in these patients; and TED on Day 0. However, although not significant, (b) there was no correlation between cortisol or DHEA cortisol tended to decline during the course of the dis- levels and parasitemia; (c) the increase in DHEA levels ease, a finding that might be explained by the fact that on Day 0 followed the increase in cortisol levels; (d) a the patient will acquire a certain resistance to malaria decline in DHEA levels occurred with increasing dura- over time, i.e., an antiparasitic effect mediated by Th1 tion of the disease, suggesting that relative reduction in cells and, more slowly, involving a Th2 cellular response the production of the DHEA for the adrenais occurs; that promotes the formation of antibodies ( was no correlation between cortisol or DHEA levels and temperature, but the latter had a significant in the stimulation of the HPA axis occurs with clinical effect on the correlation between cortisol and DHEA; (f) schizogony represented an acute stimulus of the HPA A nonsignificant negative correlation was observed axis, suggesting that the release of the two hormones between DHEA and TED on Day 0. However, DHEA also tends to decline with increasing TED as reportedby patients with a more than one- Acknowledgments
week history of the disease. It is also important to takeinto account that DHEA levels tended to follow corti- We thank the Evandro Chagas Institute for making sol levels and that temperature had a significant positive this study possible and the Coordenadoria do Curso de effect on the correlation between cortisol and DHEA.
Mestrado em Medicina Tropical, Universidade Federal Since temperature reflects the time of schizogony, lead- do Par´a, for institutional support.
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