Melatonin Secretion and Increased Daytime Sleepiness in Childhood ...

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The Journal of Clinical Endocrinology & Metabolism 87(8):3993–3996 Copyright © 2002 by The Endocrine Society

Melatonin Secretion and Increased Daytime Sleepiness in Childhood Craniopharyngioma Patients ¨ LLER, GEORG HANDWERKER, BRIGITTE WOLLNY, ANDREAS FALDUM, HERMANN L. MU ¨ NIELS SORENSEN

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Department of Pediatrics, Zentrum fu¨r Kinder- und Jugendmedizin, Klinikum Oldenburg gGmbH (H.L.M.), 26133 Oldenburg, Germany; Children’s Hospital Passau (G.H.), 94032 Passau, Germany; Departments of Pediatrics (B.W.) and Pediatric Neurosurgery (N.S.), University of Wurzburg, 97080 Wurzburg, Germany; and Institute for Medical Biometry, Epidemiology, and Informatics, University of Mainz (A.F.), 55101 Mainz, Germany Craniopharyngioma is a rare dysontogenetic benign tumor. Patients frequently suffer from endocrine deficiencies, sleep disturbances, and obesity due to pituitary and hypothalamic lesions. A self-assessment daytime sleepiness questionnaire (German version of the Epworth Sleepiness Scale) was used to evaluate 79 patients with childhood craniopharyngioma. Because hypothalamic lesions may explain daytime sleepiness in craniopharyngioma patients, salivary melatonin and cortisol concentrations were examined in obese and nonobese craniopharyngioma patients (n ⴝ 79), patients with hypothalamic pilocytic astrocytoma (n ⴝ 19), and control subjects (n ⴝ 30). Using a general linear model procedure analyzing the influence of body mass index (BMI) and tumor diagnosis on diurnal salivary melatonin, we found that morning salivary melatonin levels were related to BMI (by F test, P ⴝ 0.004) and tumor diagnosis (by F test, P ⴝ 0.032). Also for nighttime salivary melatonin levels significant relations with BMI (by F test, P < 0.001) and tumor diagnosis (by F test, P ⴝ 0.025) were

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RANIOPHARYNGIOMAS are benign tumorous embryogenic malformations that arise from ectoblastic remnants of Rathke’s pouch and can be found anywhere along the path of development of Rathke’s pouch in hypothalamic and pituitary regions, which are important in endocrine regulation and satiety modulation (1). Craniopharyngiomas are the most common intracranial tumors of nonglial origin in the pediatric population, constituting between 1.2– 4% of all brain tumors and 6 –9% of pediatric brain tumors. Overall, there are 0.5–2 new cases/million population occurring each year, 30 –50% of whom are children and adolescents (1). The peak incidence is at age 5–10 yr, but they can occur at any age, including infancy and the pre- and neonatal periods (2). Although the tumor itself is benign, and the overall survival rate of patients is high (3), there is considerable morbidity even when the tumor can be completely resected. Childhood craniopharyngioma patients often suffer sequelae of severe obesity and increased daytime sleepiness. Despite hormonal substitution, the management of hypothalamic injury-induced hyperphagia is difficult, and severe obesity occurs postoperatively in up to 52% of patients, with at least half of these patients having extreme difficulty controlling their desire to eat (3). Conventional strategies for weight control are less efficient because of impaired physical activity due to attendant neurological and visual deficits and Abbreviations: BMI, Body mass index; ESS, Epworth Sleepiness Scale.

detectable. Melatonin concentrations in saliva of craniopharyngioma patients collected at night or in the morning showed a negative correlation (night: Spearman’s ␳ ⴝ ⴚ0.42; P ⴝ 0.001; morning: Spearman’s ␳ ⴝ ⴚ0.31; P ⴝ 0.020) with the patient’s Epworth Sleepiness Scale score. Severely obese craniopharyngioma patients and severely obese hypothalamic tumor patients had similar patterns of melatonin secretion. Differences in terms of diurnal salivary cortisol concentrations were not detectable when patient groups and controls were compared. We speculate that hypothalamic lesions might be responsible for both obesity and daytime sleepiness. As decreased nocturnal melatonin levels were associated with increased daytime sleepiness, BMI, and hypothalamic tumor diagnosis, further studies on the beneficial effects of melatonin substitution on daytime sleepiness and weight control in these patients are warranted. (J Clin Endocrinol Metab 87: 3993–3996, 2002)

the complaint of increased daytime sleepiness by some of these some patients. In a cross-sectional study we analyzed 79 patients with childhood craniopharyngioma for selfassessment of daytime sleepiness using the German version of the Epworth Sleepiness Scale (ESS) (4) to obtain more information about the prevalence of increased daytime sleepiness in these patients. Melatonin, a pineal indoleamine, is postulated to be important in hypothalamic and pituitary regulatory functions (5). Melatonin secretion occurs during the hours of darkness, and because it affects sleep patterns it has been tried in treating jet lag and other disorders caused by delay of sleep because of its possible role in influencing circadian rhythm. Because destruction or dysfunction of the suprachiasmatic nucleus seems likely in many craniopharyngioma patients with suprasellar tumor extension, we compared melatonin secretion in severely obese, obese, and nonobese craniopharyngioma patients. To analyze the influence of obesity and hypothalamic lesions on melatonin secretion, patients with hypothalamic tumors (pilocytic astrocytomas) and obese and normal weight control subjects were also analyzed. Subjects and Methods Patients Seventy-nine patients with childhood craniopharyngioma, 19 children with hypothalamic pilocytic astrocytoma, and 30 controls were analyzed for daytime sleepiness and circadian rhythms of salivary mel-

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4 (1– 6) 0 3 (0 –5) 0 2 (0 –5) 0 11 (8 –17) 50a Shown are medians and ranges.

a

P ⬍ 0.05, c P ⬍ 0.001. n.d., Not determined.

7/9 0 4 (1–15) 8 7 (1–17) 24 3 (0 –19) 11

10.0 (1–19) 42c

7.3 (5.7–9.0) 3.0 (2.1–3.7) 0.4 (⫺0.9 –1.9) 8.6 (4.1–13.3) 2.6 (2.1–3.5) 0.7 (⫺1.3–2.8)

a c

2.7 (2.1–3.8)

6.3 (4.0 –13.9)

14 3/11 14.9 (7.4 –15.5) n.d. n.d.

⬎4 2– 4

4 1/3 9.0 (7.3–10.7) n.d. n.d. 12 7/5 10.9 (4.4 –24.0) n.d. n.d. 4 1/3 7.4 (6.3– 8.5) 5.6 (5.2– 6.1) 0 2 1/1 9.1 (5.0 –16.0) 8.6/5.3 1

Controls

⬍2 ⬎4 2– 4

Hypothalamic pilocytic astrocytoma

31 13 15/16 4/9 16.6 (5.8 –33.0) 10.5 (4.8 –25.6) 7.6 (0.1–18.0) 10.2 (3.2–16.3) 9 4

0.3 (⫺1.6 –1.8)

Samples were obtained by centrifugation and then were frozen and stored at –20 C until analysis. Salivary melatonin concentrations (Fig. 1, A and B) were measured by a commercially available direct saliva melatonin RIA (Bu¨ hlmann Laboratories AG, Allschwil, Switzerland) using the Kennaway G280 antimelatonin antibody (7). The minimum detectable concentration of melatonin in 400 ␮l incubation buffer was 0.2 pg/ml (0.9 pmol/liter). The intraassay precision varied from 10.8% for daytime samples to 2.6% for early morning samples. The interassay precision varied from 16.5% for daytime samples to 6.5% for early morning samples. Salivary melatonin concentrations correlate with melatonin concentrations in plasma (8). Salivary cortisol concentrations were measured by a commercial RIA (Diagnostic Products, Bad Nauheim, Germany). The lower limit of detection for cortisol in saliva was 0.2 ␮g/dl. The intraassay precision varied from 4.0 –5.1%. The interassay precision varied from 4.0 – 6.4%.

17 8/9 14.6 (7.9 –30) 7.4 (3.4 –12.4) 5

Salivary melatonin and cortisol measurements

31 15/16 17.3 (3.5–33.2) 10.8 (4.1–19.2) 5

Salivary melatonin and cortisol concentrations were evaluated in 79 childhood craniopharyngioma patients (31 normal weight, 17 nonseverely obese, and 31 severely obese patients), 19 patients with hypothalamic pilocytic astrocytoma (13 normal weight, 2 nonseverely obese, and 4 severely obese patients), and 30 controls (12 normal weight, 4 nonseverely obese, and 14 severely obese controls; Table 1). Saliva was collected at different time points (morning, 0600 – 0800 h; midday, 1100 – 1400 h; evening, 1800 –2100 h; night, 2300 – 0300 h) using special tubes (Sarstedt, Numbrecht, Germany). All patients received hydrocortisone substitution medication in a daily dosage of approximately 12 mg/m2 body surface area.

No. Sex (f/m) Age at visit (yr) Age at diagnosis (yr) Irradiation (patients) BMI at visit (SD score) ESS score ESS ⬎10 (%)

Salivary melatonin and cortisol concentrations

⬍2

The German version of the ESS was used to assess subjective daytime sleepiness (4). Severe daytime sleepiness was rated with a score above 10 points on the ESS.

⬎4

ESS assessment

2– 4

Body weight was evaluated by calculating the BMI: BMI ⫽ weight (kilograms)/height (meters)2. Expression of the BMI as an sd score was performed using the references of Rolland-Cachera et al. (6). Severe obesity was defined as a BMI of 4 sd or more, nonsevere obesity as a BMI of 2– 4 sd, and nonobesity as a BMI less than 2 sd.

Craniopharyngioma

BMI

⬍2

Statistical analysis was performed using a commercial software program (SPSS 10.0, SPSS, Inc., Chicago, IL) and was supervised by the Institute for Medical Biometry, Epidemiology, and Informatics at University of Mainz (Mainz, Germany). Correlations were estimated by Spearman’s correlation test. All calculated correlation coefficients (␳) are nonparametric due to Spearman. The corresponding P values are given as well. The influence of body mass index (BMI) and tumor diagnosis on salivary melatonin concentrations was estimated by a general linear model procedure model using type IV sums of square and including an intercept in the model. Complete datasets for BMI, tumor diagnosis, and salivary melatonin concentration were analyzed in 120 subjects for morning melatonin, in 113 subjects for midday melatonin, in 118 subjects for evening melatonin, and in 111 subjects for nighttime melatonin. Differences between the groups of patients and controls in terms of salivary cortisol concentrations were estimated using the Kruskal-Wallis test. All statistical procedures were performed as explorative analysis.

score

Statistical methods

SD

atonin and cortisol. Patients with missing data on ESS and melatonin secretion due to noncompliance or technical problems in collecting nocturnal saliva samples were excluded from the study. The study was approved by the local standing committee on ethical practice, and written parental and/or patient consent was obtained in all cases. Patients’ characteristics are included in Table 1.

Mu¨ ller et al. • Melatonin and Sleep in Craniopharyngioma

BMI

J Clin Endocrinol Metab, August 2002, 87(8):3993–3996

TABLE 1. Characteristics in patients with childhood craniopharyngioma and hypothalamic pilocytic astrocytoma and controls who were evaluated for salivary melatonin and cortisol concentrations in relation to BMI SD score according to Rolland-Cachera et al. (6)

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FIG. 1. A and B, Salivary melatonin concentrations at night (A) and in the morning (B) in patients with childhood craniopharyngioma, patients with hypothalamic pilocytic astrocytoma, and controls in relation to the degree of obesity [BMI, ⬍2 SD (f), 2– 4 SD (o), or ⱖ4 SD (䡺)]. The horizontal line in the middle of the box depicts the median. The edges of the box mark the 25th and 75th percentile. Whiskers indicate the range of values that fall within 1.5 box-lengths. Values more than 1.5 box-lengths from the 25th and 75th percentiles are marked with an asterisk.

Results ESS questionnaire

We evaluated the rate of severe diurnal sleepiness in patients with childhood craniopharyngioma using the German standardized version of the ESS questionnaire. Craniopharyngioma patients with severe obesity (BMI ⬎4 sd) had higher (P ⬍ 0.01) scores on ESS than normal weight or less obese craniopharyngioma patients, indicating increased daytime sleepiness (Table 1). Twenty-eight of the 79 craniopharyngioma patients (35%) yielded a score above 10 on the ESS, indicating severe daytime sleepiness. Thirteen of 31 severely obese patients (42%) scored above 10 on the ESS. Salivary melatonin and cortisol measurement comparisons

To ascertain pathogenic relations, we analyzed profiles of salivary melatonin and cortisol concentrations in relation to BMI and tumor diagnosis. We calculated a general linear model procedure analyzing the influence of BMI and tumor diagnosis on diurnal salivary melatonin levels. As the interaction between BMI and tumor diagnosis did not relevantly increase the r2 of the model, but broadened the confidence interval of the parameter estimates, only the main effects were included in the final model. Salivary melatonin concentrations at midday (1100 –1400 h) and in the evening (1800 –2100 h) were similar in patients with craniopharyngioma or hypothalamic astrocytoma and in control patients (data not shown). No significant relation was found between midday (by F test, P ⫽ 0.175 and 0.940, respectively) and evening (by F test, P ⫽ 0.140 and 0.210, respectively) salivary melatonin levels and BMI value and tumor diagnosis, respectively. However, morning salivary

melatonin levels were related to BMI (by F test, P ⫽ 0.004) and tumor diagnosis (by F test, P ⫽ 0.032). Also for nighttime salivary melatonin levels, significant relations with BMI (by F test, P ⬍ 0.001) and tumor diagnosis (by F test, P ⫽ 0.025) were detectable (Fig. 1, A and B). Melatonin concentrations in saliva of craniopharyngioma patients collected at night or in the morning showed a significant (night: Spearman ␳ ⫽ ⫺0.42; P ⫽ 0.001; morning: ␳ ⫽ ⫺0.31; P ⫽ 0.02) negative correlation with the patient’s ESS score. Severely obese craniopharyngioma patients and severely obese hypothalamic tumor patients had similar patterns of melatonin secretion. Differences in terms of morning and nighttime salivary melatonin concentrations were not detectable between normal weight controls and normal weight patients with craniopharyngioma or hypothalamic tumor. All patients received hydrocortisone substitution medication. A Kruskal-Wallis test showed no significant differences in terms of diurnal salivary cortisol levels between the analyzed groups (data not shown). Discussion

Some patients with childhood craniopharyngioma complain of increased daytime sleepiness. In a German multicenter study of childhood craniopharyngioma patients, behavioral and laboratory results suggested a secondary hypothalamic disorder as a reason for the severe obesity (3). In the current study we surveyed a large group of patients with childhood craniopharyngioma and hypothalamic astrocytoma for daytime sleepiness using the ESS. About one third of our patients reported increased daytime sleepiness,

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J Clin Endocrinol Metab, August 2002, 87(8):3993–3996

characterized by an ESS score above 10. The severity of their daytime sleepiness was unexpectedly high, especially in obese patients with a BMI more than 4 sd (Table 1). As sleep regulation and circadian rhythms are at least partially mediated by hypothalamic structures, e.g. the suprachiasmatic nucleus, we compared salivary melatonin concentrations in the morning, midday, evening, and night among severely obese, obese, and nonobese patients and normal controls. Whereas several studies (9 –11) of different patient cohorts found no significant relation between melatonin secretion and obesity, Birketvedt et al. (12) reported on a rare night eating syndrome characterized by frequent awakening at night, higher nocturnal energy intake, and attenuation of nocturnal rise in plasma melatonin. As hypothesized based on hypothalamic disorders in the severely obese craniopharyngioma patients, we found lower melatonin concentrations at night in these patients than in the other groups. We speculate that the diurnal rhythm of melatonin is suppressed in obese patients with hypothalamic tumors as craniopharyngioma or pilocytic astrocytoma. As cortisol may also influence wakefulness, we compared salivary cortisol concentrations in all groups to exclude confounding effects. We found no significant difference among the groups (data not shown). The significant negative correlations between salivary melatonin concentrations in the morning and at night and the ESS scores indicate that reduced nocturnal melatonin secretion may lead to increased daytime sleepiness in patients with childhood craniopharyngioma. In conclusion, our findings suggest that increased daytime sleepiness in patients with childhood craniopharyngioma is related to decreased nocturnal melatonin levels. Nocturnal melatonin levels were related to the degree of obesity (BMI) and the tumor diagnosis. As it has been reported (3) that hypothalamic damage is a risk factor for severe obesity in craniopharyngioma patients, we speculate that hypothalamic damage could have been responsible for disturbances in melatonin secretion. This speculation is supported by our similar findings for patients with hypothalamic tumors of other histology (pilocytic astrocytoma). Further studies of the hypothesis of this study are part of the ongoing German prospective multicenter study of


patients with childhood craniopharyngioma (KRANIOPHARYNGEOM 2000; protocol: www.kraniopharyngeom. com) (13). Acknowledgments Received October 9, 2001. Accepted April 23, 2002. Address all correspondence and requests for reprints to: Hermann L. Mu¨ ller, M.D., Children’s Hospital, Department of Pediatrics, Klinikum Oldenburg gGmbH, Cloppenburgerstrasse 363, 26133 Oldenburg, Germany. E-mail: [email protected]. This work was supported by the Deutsche Kinderkrebsstiftung, Bonn, Germany (www.kinderkrebsstiftung.de).

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