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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 7 2993-2996
Copyright © 2001 by The Endocrine Society

Endocrine Care

Evaluation of the Hypothalamic-Pituitary-Adrenal Axis in Children with Leukemia before and after 6 Weeks of High-Dose Glucocorticoid Therapy

Hilton Kuperman, Durval Damiani, George P. Chrousos, Vaê Dichtchekenian, Thais Della Manna, Vicente Odone Filho and Nuvarte Setian

Departments of Pediatric Endocrinology (H.K., D.D., V.D., T.D.M., N.S.) and Oncology (V.O.F.) of the Children’s Hospital, São Paulo University School of Medicine-Brazil; and Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development (G.P.C.), National Institutes of Health, Bethesda, Maryland

Address all correspondence and requests for reprints to: Hilton Kuperman, M.D., University of São Paulo, Department of Pediatric Endocrinology, Children’s Hospital, Faculty of Medicine, Rua Conselheiro Brotero 1182, apt. 182, São Paulo, Brazil 01232-010. E-mail: hkuperman{at}terra com.br.

Abstract

Among the adverse effects arising from chronic high-dose glucocorticoid treatment, adrenal insufficiency secondary to suppression of the hypothalamic-pituitary-adrenal (HPA) axis is a cause for concern. Glucocorticoid-induced adrenal suppression is related to the duration of therapy, type of steroid used and dosage, and schedule of glucocorticoid administration. To evaluate the suppression and recovery time of the HPA axis in children with acute leukemia, we performed the ovine CRH (oCRH) stimulation test in 15 patients, who were given high doses of dexamethasone as part of their induction chemotherapy for 42 days. The oCRH tests were performed before, and 7 and 14 days after, discontinuation of the glucocorticoid. The ACTH levels were not significantly different among the 3 tests. The cortisol levels, however, were significantly (albeit mildly) lower, both basally and after oCRH, 1 and 2 weeks post treatment than before therapy. Six patients had cortisol values that remained suppressed 2 weeks after discontinuation of therapy. One of these patients had manifestations of mild adrenal insufficiency, 6–8 days after discontinuation of therapy, but required no glucocorticoid coverage. We conclude that up to 2 weeks after discontinuation of 6 weeks of high-dose dexamethasone administration, the HPA axis of patients with acute leukemia is mildly suppressed but infrequently associated with clinical manifestations of adrenal insufficiency. This may indicate that major stress, when concurrent with glucocorticoid treatment, may prevent clinically significant adrenal suppression.

THE CHRONIC USE of high doses of glucocorticoids has been associated with many adverse systemic effects. One of the most worrisome and treatable of these effects is the suppression of the hypothalamic-pituitary-adrenal (HPA) axis, especially after abrupt cessation of glucocorticoid therapy. This may lead to various degrees of glucocorticoid deficiency manifestations (1, 2, 3) and inability to react to stress, and is potentially fatal (4, 5, 6). The degree of adrenocortical suppression is influenced by the duration of administration (7, 8, 9, 10), type of steroid employed and dosage (7, 11, 12), as well as by the route and time of the day at which the drug is administered (13, 14, 15, 16, 17). The full recovery of the HPA axis varies from 1 week to several months after discontinuation of therapy (7, 8, 10, 18, 19, 20, 21).

The objective of the present study was to assess the suppression and recovery of the HPA axis in children with acute lymphoid leukemia (ALL) after treatment with dexamethasone given in conjunction with standard chemotherapy for 42 days. These children were subjected to stress caused by the disease, the concurrent chemotherapy, and/or potential infectious processes. We used the ovine CRH (oCRH) test, results of which closely correlate with those of the insulin tolerance test (ITT). Although the latter has been considered the so-called gold-standard for the evaluation of the HPA axis, the oCRH test has equivalent diagnostic value and fewer side effects (22, 23, 24, 25, 26, 27, 28, 29, 30).

Materials and Methods

Study subjects

We studied 15 prepubertal patients (10 girls, 5 boys), 1 yr, 5 months-12 yr old, who were admitted to the Oncology Department of the Children’s Hospital with a diagnosis of ALL (low or high risk). The patients were given dexamethasone at a dosage of 6 mg/m2·day, orally divided into 3 doses for the first 42 days of chemotherapy treatment. This treatment includes the administration of daunomycin, vincristine, L-asparaginase, and cytosine-arabinoside. The dose and duration of steroid administration were not varied according to the type of ALL. After providing informed consent, the patients had the oCRH stimulation test before, and again on days 7 and 14, after the last dose of dexamethasone. The tests were designated as zero, day 7, and day 14, respectively.

On the days that the tests were performed, data about infection or side effects from the oCRH stimulation test or arising from the dexamethasone therapy were collected. Infection was defined as either a known infectious process or fever or both, with or without an apparent focus, for which specific or broad-spectrum antibiotics were administered.

After an 8-h fast, a small needle was inserted into a peripheral vein, and saline was administered iv. After a 15-min interval, 1.0 µg/kg oCRH (NIH, Bethesda, MD) was administered iv between 0800 and 0900 h on the day of testing. Blood samples were collected at 0, 15, 30, 60, and 90 min for measurement of cortisol and ACTH. The blood samples were placed in appropriate tubes and centrifuged, and the plasma was stored at -20 C until assay.

Cortisol and ACTH measurements

Cortisol was measured using solid-phase fluoroimmunoassay (AutoDELFIA kit, Wallac, Inc., Turku, Finland). The intraassay coefficient of variation was 3.9%; the interassay coefficient of variation was 6.9%. ACTH was measured by solid-phase immunoradiometric assay (CIS-Bio International, Gif-Sur-Yvette Cedex, France). The intraassay coefficient of variation was 6.7%, and the interassay coefficient of variation was 10.3%.

Statistical analysis

Friedman’s two-way nonparametric ANOVA was used to compare peak cortisol and ACTH values at the three times of testing, and Student’s t test was used for paired and nonpaired samples. The time-integrated, area-under-the-curve (AUC) cortisol and ACTH values were compared. P < 0.05 indicates a significant difference. The results were expressed as mean ± SE.

With the objective of analyzing the response of each child to each of the tests, the peak cortisol and ACTH values in each test were also analyzed and compared with values obtained from normal control children. Values above 12.8 µg/dL (353.2 nmol/L) for cortisol and 16.0 pg/mL (3.5 pmol/L) for ACTH were considered normal (26, 27). The patients with peak values above these levels were considered responsive, and those with peak values below were considered nonresponsive.

Results

As shown in Fig. 1Go and Table 1Go, comparison of the basal, peak, and time-integrated AUC values of ACTH showed no statistically significant differences among the zero, day 7, and day 14 tests. However, the patients had significantly lower (P < 0.05) peak and time-integrated cortisol values on day 7 test than in the pretreatment test. This difference was present also on day 14. The basal and peak cortisol levels of the day 7 and day 14 tests did not differ significantly. Figure 2Go shows the peak ACTH and cortisol values.



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  		Figure 1. Plasma cortisol and ACTH levels (top) and AUCs (bottom) at zero, day 7, and day 14; * P < 0.05.

 

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  		Table 1. Basal, peak and AUC cortisol and ACTH values, during an oCRH test

 


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  		Figure 2. Peak plasma cortisol and ACTH levels at zero, day 7, and day 14. {square}, Mean ± SE for cortisol and ACTH for normal children.

 
All patients responded to oCRH stimulation before the therapy. Thirteen of them had an infection at this time. During glucocorticoid treatment, all patients had increases in their appetite and body weight. During the same period, four patients had the following: nausea and vomiting, diarrhea, pneumonia, and/or acute otitis media. Two of them were given antibiotic therapy through the day 7 test. After the cessation of glucocorticoid therapy, four patients were treated with antibiotics for infection through the day 7 test. Three of these four patients continued being treated with antibiotics through the day 14 test. Just after discontinuation of dexamethasone therapy, one patient had nausea and apathy for 2 days. His pulse, respiratory rate, and arterial pressure were normal. This patient had an appropriate response in the day 7 test. Another patient had prostration, nausea, and malaise while he had the day 7 test. His pulse, respiratory rate, and arterial pressure were normal. No infection was detected during this period. Although he did not respond properly to the test, he was not covered with glucocorticoids but was monitored carefully. He responded normally at the day 14 test. The remaining patients who had suboptimal responses in the oCRH test did not show symptoms or signs of adrenal insufficiency, and their vital signs remained stable.

Discussion

Graber et al. (8) reported that chronic use of glucocorticoids leads to adrenal suppression, after abrupt discontinuation of treatment recovery took as long as 9 months. Livanou et al. (31) reported similar results. Healthy volunteers, given a high dose of prednisone for 5 days, started their recovery from suppression after 2 days and had complete recovery after 5 days (19). In a more recent study, Briggel et al. (32) gave healthy volunteers prednisone for 14 days; HPA axis recovery was seen 1 day after discontinuation of therapy, using the oCRH test.

A study similar to ours was performed by Spiegel et al. (18), who analyzed the response of the HPA axis in 14 patients, 6–59 yr of age, who took varying doses of prednisone for a period ranging from 1–4 weeks for the treatment of various neoplasias. Based on the cortisol response by the standard ACTH test, they concluded that the majority of patients had an adequate response as soon as 1 week after the last dose of prednisone. An individual variation in the recovery of the axis was observed, but no clinical signs of adrenal insufficiency were noted. Zora et al. (10), using the ITT, also showed HPA axis suppression in asthmatic children after a 5-day course of prednisone, with full recovery shown, using an ITT after 10 days.

In a recent study, Felner and associates (33) used the ACTH stimulation test to evaluate the recovery the HPA axis in children with acute leukemia, 28 days after discontinuation of dexamethasone therapy. Some of their patients had abnormal cortisol responses, in the standard ACTH test, by the accepted criterion of 18.0 µg/dL. We used the oCRH test to directly evaluate the recovery of the pituitary and adrenal glands. We considered, as normal, a response of cortisol or ACTH, after oCRH administration, that was within the 95% (1.98 SD) confidence limits of values observed in nonstressed normal volunteers (30, 33). Thus, a normal response of cortisol had to be higher than 12.8 µg/dL. The apparently more intense and more symptomatic adrenal suppression of Felner’s patients to dexamethasone therapy was not observed in our children, in whom very few symptoms and no signs of adrenal suppression were noted. If we take into account that our patients’ baseline cortisol levels were higher than in Felner’s patients, we could assume that our patients suffered a higher degree of stress. Ten of our patients reported decreased appetite, four had an infection at the day 7 test; from these, three continued to have an infection at the day 14 test. These patients responded well to oCRH. One patient had nausea and apathy up to 2 days after discontinuation of dexamethasone treatment; and another had nausea, malaise, apathy, and prostration at the day 7 test, but the symptoms were mild. None of our patients needed cortisol coverage.

It is true that we must be suspicious of adrenal suppression when dealing with this kind of patient, who, at times, may need cortisol coverage. Because the symptoms observed in our patients were mild and could be related to the disease itself, to an infectious process, or to the chemotherapy, we did not use stress coverage, but we monitored the patients clinically. On follow-up, all patients did well, having maintained normal vital signs and blood biochemistry.

We suggest that the absence of severe HPA axis suppression by high doses of dexamethasone administration in our patients indicates that the stress of the disease and the chemotherapy and/or a concurrent infectious process may have protected the HPA axis of these children from major chronic suppression.

Acknowledgments

We thank Dr. Berenice Bilarinho de Mendonça and her staff, of the Laboratório de Hormônios e Genética Molecular, LIM 42-Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo, for coordinating and performing assays. We also thank Dr. Maria do Rosário Dias de Oliveira Latorre, from the Faculdade de Saúde Pública da USP, for her contribution in the statistical analysis. We are thankful for the cooperation and contribution of Drs. Lillian Maria Cristófani, Maria Tereza Assis Almeida, and Paulo T. Maluf, and the nursing staff of the Department of Pediatric Oncology of the Children’s Hospital, Faculty of Medicine, University of São Paulo. We thank Elaine Maria Segato Rizzo for constructing the graphics.

Received August 28, 2000.

Revised March 13, 2001.

Accepted March 16, 2001.

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