Oxytocin in survivors of childhood-onset craniopharyngioma

Anna M. M. Daubenbüchel, Anika Hoffmann, Maria Eveslage, Jale Özyurt, Kristin Lohle, Julia Reichel, Christiane M. Thiel, et al.

Endocrine International Journal of Basic and Clinical

ISSN 1355-008X Volume 54 Number 2

Endocrine (2016) 54:524-531 DOI 10.1007/s12020-016-1084-5

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1 23 Author's personal copy

Endocrine (2016) 54:524–531 DOI 10.1007/s12020-016-1084-5

ORIGINAL ARTICLE

Oxytocin in survivors of childhood-onset craniopharyngioma

1,2 1 3 4 Anna M. M. Daubenbüchel ● Anika Hoffmann ● Maria Eveslage ● Jale Özyurt ● 1 1 4,5 6 Kristin Lohle ● Julia Reichel ● Christiane M. Thiel ● Henri Martens ● 6 1 Vincent Geenen ● Hermann L. Müller

Received: 19 July 2016 / Accepted: 9 August 2016 / Published online: 1 September 2016 © Springer Science+Business Media New York 2016

Abstract Quality of survival of childhood-onset cranio- irradiation were analyzed. Patients with preoperative pharyngioma patients is frequently impaired by hypotha- hypothalamic involvement showed similar oxytocin levels lamic involvement or surgical lesions sequelae such as compared to patients without hypothalamic involvement obesity and neuropsychological deficits. Oxytocin, a pep- and controls. However, patients with surgical hypotha- tide hormone produced in the and secreted lamic lesions grade 1 (anterior hypothalamic area) pre- by posterior , plays a major role in regula- sented with lower levels (p = 0.017) of oxytocin under tion of behavior and body composition. In a cross- fasting condition compared to patients with surgical lesion sectional study, oxytocin saliva concentrations were ana- of posterior hypothalamic areas (grade 2) and patients lyzed in 34 long-term craniopharyngioma survivors with without hypothalamic lesions (grade 0). Craniophar- and without hypothalamic involvement or treatment- yngioma patients’ changes in oxytocin levels before and related damage, recruited in the German Childhood Cra- after breakfast correlated (p = 0.02) with their body mass niopharyngioma Registry, and in 73 healthy controls, index. Craniopharyngioma patients continue to secrete attending the Craniopharyngioma Support Group Meeting oxytocin, especially when anterior hypothalamic areas are 2014. Oxytocin was measured in saliva of craniophar- not involved or damaged, but oxytocin shows less varia- yngioma patients and controls before and after standar- tion due to nutrition. Oxytocin supplementation should be dized breakfast and associations with gender, body mass explored as a therapeutic option in craniopharyngioma index, hypothalamic involvement, diabetes insipidus, and patients with hypothalamic obesity and/or behavioral pathologies due to lesions of specific anterior hypotha- lamic areas. Clinical trial number: KRANIOPHAR- * Hermann L. Müller YNGEOM 2000/2007(NCT00258453; NCT01272622). [email protected]

Keywords Craniopharyngioma ● Hypothalamus ● Obesity ● 1 Department of Pediatrics, Klinikum Oldenburg AöR, Medical Oxytocin ● Behavior Campus University Oldenburg, 26133 Oldenburg, Germany 2 University Medical Centre Groningen (UMCG), University of Groningen, 9712 Groningen, The Netherlands 3 Institute of Biostatistics and Clinical Research, University of Münster, 48149 Münster, Germany Introduction 4 Biological Psychology Lab, Department of Psychology, Faculty of Medicine and Health Sciences, Carl von Ossietzky University, 26129 Oldenburg, Germany Childhood-onset craniopharyngioma (CP) are rare intra- 5 cranial embryonal malformations of the sellar region arising Research Center Neurosensory Science and Cluster of Excellence ’ “Hearing4all”, Carl von Ossietzky University, 26129 Oldenburg, from remnants of Rathke s pouch [1]. CP show low-grade Germany histological malignancy (WHO °I) and frequently effect 6 GIGA-I3 Center of Immunoendocrinology, University of Liege hypothalamic and pituitary regions due to their location [2]. Liege-Sart Tilman, 4000 Liege, Belgium This hypothalamic involvement (HI) of CP and/or Author's personal copy

Endocrine (2016) 54:524–531 525 treatment-related lesions of this region usually result in Oxytocin concentrations were analyzed at a median endocrine deficiencies, neuropsychological deficits, patho- patient age of 20 years (range 7–41 years), with a median logical patterns of eating behavior, and obesity with major interval between initial CP diagnosis and this study of 11.0 negative impact on prognosis and quality of life in surviving years (range: 0.5–31.0 years). They were analyzed for patients [3–7]. Substitution therapy for endocrine defi- height, weight, and body mass index (BMI), as well as ciencies—hydrocortisone, sex steroids, , oxytocin concentrations in saliva, for which samples were , and hormones—is an elemental part in taken shortly before and 60 min after breakfast. For the CP treatment for patients with disturbances involving the oxytocin concentration comparisons, a standardized and hypothalamic and pituitary regions [2]. comparable breakfast for all participants was ensured The peptide hormone oxytocin, which is primarily syn- (approx. 10–15 kcal/kg body weight; 8 a.m.). The study was thesized in the paraventricular and supraoptic nuclei of the conducted during the 17thAnnual Meeting of the German hypothalamus and released by the posterior pituitary, has Craniopharyngioma Support Group, Bad Sassendorf, not been analyzed in the context of CP before this study [8]. Germany, 2014. A total of 73 healthy children, adolescents, It can be assumed that oxytocin synthesis and release is and adults, also attending the 17th Annual Craniophar- disturbed in patients with CP, similar to the other hormones yngioma Support Group Meeting, 2014, served as controls. of the pituitary gland. Oxytocin is similar to the peptide Body composition and the degree of obesity were eval- hormone vasopressin, as its structure differs only by two uated by calculating the BMI standard deviation score amino acids [9]. However, in contrast to vasopressin, whose (SDS) according to the references of Rolland-Cachera et al. function is well understood and the clinical symptoms in [17]. The histological diagnosis of anadamantinomatous CP vasopressin-deficient patients are well known [10], little is was confirmed by reference assessment in all cases. HI of known about the role of oxytocin in CP patients. Oxytocin CP was assessed by magnetic resonance imaging (MRI), is involved in metabolism [11] and in the regulation of a computed tomography, and/or microscopic inspection dur- wide variety of social and non-social behaviors such as non- ing surgery. Preoperative HI was defined as involvement of social memory, anxiety, depression, and stress [12–16]. hypothalamic structures either by tumor growth into the To evaluate the role of oxytocin in CP patients, we hypothalamus or displacement of hypothalamic structures conducted a pilot cross-sectional study analyzing a small by the tumor. Surgical hypothalamic lesions were assessed group of patients recruited in the German Craniophar- on postoperative MRI and reference-confirmed by a neu- yngioma Registry to assess oxytocin concentrations in sal- roradiologist blinded for the clinical data based on a pre- iva of patients with childhood-onset CP in comparison to viously published grading system [18, 19]. healthy controls. The study was approved by the local standing committee on ethical practice and written parental and/or patient con- sent was obtained in all cases.

Patients and methods Oxytocin analysis in saliva

Patients We compared saliva levels of the 34 CP patients with the saliva of a healthy control group consisting of 41 female This study analyzed patients with adamantinomatous and 32 male participants with a median age of 39 years childhood-onset CP, recruited in the German Craniophar- (range 8–63 years). Oxytocin saliva levels were measured yngioma Registry and prospectively evaluated in the multi- under fasting conditions as well as directly after a standar- center trials HIT Endo and KRANIOPHARYNGEOM 2000/ dized breakfast meal. In addition, we quantified changes in 2007 (Clinical Trial No.: NCT00258453; NCT01272622), oxytocin levels before and after breakfast (Δ oxytocin is who attended the 17th Annual Meeting of the German defined as the difference in oxytocin after breakfast−oxy- Craniopharyngioma Support Group, Bad Sassendorf, Ger- tocin before breakfast). To measure oxytocin saliva levels, many, 2014. Thirty-four of 40 patients (85 %) attending this saliva was collected from each participant (patients and meeting agreed to participate in the study. These 34 CP controls) before and after breakfast using a standardized patients (19 female, 15 male) had been initially diagnosed at method for saliva sampling. A white cylindrical swab was a median age of 10.5 years (range: 0.02–18.0 years). The chewed gently for 15 min by each participant and then study cohort (n = 34) showed similar characteristics in returned with the absorbed saliva into a salivette—a saliva terms of age and gender distribution, degree of surgical collection device. All salivettes were placed immediately on resection, HI, and hypothalamic surgical lesions when ice and kept cool till centrifugation. After centrifugation, compared with the total cohort of CP patients recruited in patient saliva samples were stored frozen until analysis. the German Craniopharyngioma Registry. Oxytocin concentrations in saliva were measured by Author's personal copy

526 Endocrine (2016) 54:524–531 immunoassay [20]. Briefly, a competition between bioti- nylated oxytocin used as tracer and synthetic oxytocin 13.99) 60.00) – 15.33) 18.41) provides a displacement curve after incubation with – – –

streptavidin-horseradish peroxidase and revelation with 6.16 0.40 − (0.06 (0.06 − ( TMB 3,3’,5,5’-Tetramethylbenzidine. Filtration on Amicon (16.04 Ultracel-2, membrane of 3 kDa (cutoff 3000)—both from Merck Millipore—was performed in order to reduce inter- 8.98) – 63.00) 43.00 13.70) 3.23 22.68) 2.78 ferences. Filtration recovery was measured as 68.4 ± 14.4 % – – fi –

(coef cient of variance: 21 %) of 10 pg added to hormone- 11.63 free plasma. Combined intra-assays standard deviations − (SD) for the enzyme immunoassay (EIA) (n = 10 in dupli- NIOPHARYNGEOM 2000/2007) and cates and triplicates) were 1.05 % at 7.2 pg/ml,

1.94 % at 20 pg/ml, and 1.58 % at 200 pg/ml. Detection 13.99) 0.06 ( – 73) 15.33) 3.56 (0.14 22.68) 2.69 (0.06 ± 63.00) 30.03 (8.09 – – limit ( 2 SD from zero) was typically 0.5 pg/ml and always – = n under 1 pg/ml. 11.63 −

Statistical analyses 0.34 ( —— — −

Statistical analysis was performed with SPSS 23® for 2.33)

Windows (IBM Corporation, Somers, NY, USA) and R – 38.00) 39.00 (8.09 9.14) 3.35 (0.06 10.91) 2.78 (0.06 – 15.04) – – version 3.1.0. For metrical variables, the comparison of two – 6.03 and three independent groups was performed with the − Mann–Whitney U test and the Kruskal–Wallis test, 0.96 ( respectively. Post-hoc pairwise comparisons were per- − formed using Dunn’s test. For comparison of groups con- cerning categorical variables, Fisher’s exact test was used. 8.18) 41.00) 18.00 (7.00 – – Correlation was calculated with the Pearson correlation 18.04) 9.03 (0.02 12.45) 3.95 (0.07 11.24) 3.12 (0.16 – 34) Controls ( – fi fi –

coef cient. The local signi cance level was set to 0.05. 3.55 = − Nevertheless, all inferential statistics were intended to be n fi

exploratory (hypotheses generating), not con rmatory, and 0.90 ( were interpreted accordingly. Therefore, no adjustment for − multiple testing was applied. 8.18) – 41.00) 24.00 (13.00 18.04) 13.05 (3.06 12.45) 2.81 (0.17 11.24) 3.72 (0.07 – – – – 6.03

Results − 0.93 ( Total Male Female Total Male Female − Oxytocin levels in saliva of 34 CP patients were analyzed. 10.55 (0.02 Proven initial HI was detected in 20 of the 34 cases (59 %) before first surgical treatment of CP. Complete surgical 63.00) 20.00 (7.00 – 15.33) 3.61 (0.07 resection was achieved at initial diagnosis in 10 of 28 CP 22.68) 3.18 (0.07 – – 13.99)

patients (36 %), resection data being available for only these – 28 patients. A total 14 of the 34 CP patients (41 %) received 11.63 0.84 irradiation. Based on desmopressin medication, 28 of 34 CP − 28.05 (7.00 3.48 (0.06 2.79 (0.06 − ( Total cohort Craniopharyngioma patients ( — patients (82 %) had presented with diabetes insipidus by the time this study was initiated. Gender related differences in terms of HI, degree of resection, irradiation and diabetes insipidus were not detectable. We compared oxytocin saliva levels in CP patients with concentrations in saliva of healthy controls. Oxytocin saliva levels were measured under fasting conditions as well as Clinical characteristics and oxytocin saliva concentrations of 34 patients with childhood-onset craniopharyngioma (recruited in HIT Endo and KRA rst surgery; (year, median

directly after a standardized breakfast meal. In addition, we fi quantified changes in oxytocin levels before and after Δ fi (%) 107 (100) 34 (100) 15 (44.1) 19 (55.9) 73 (100) 32 (43.8) 41 (56.2) n Age at evaluation; (year,(range)) median Saliva oxytocin concentration before breakfast; (pg/ml, median (range)) Saliva oxytocin concentration after breakfast; (pg/ml, median (range)) Delta saliva oxytocin concentration (pg/ml, median (range)) 73 healthy controls participating in the study. Parameters are also shown for the subgroups of female and male patients/controls Age at (range)) breakfast ( oxytocin). No signi cant differences in the Table 1 Author's personal copy

Endocrine (2016) 54:524–531 527 oxytocin levels were detected in the CP patients compared CP either from tumor involvement or its surgical treatment. to the controls, indicating that CP patients were still able to Therefore, it was suspected that oxytocin synthesis and produce and secrete the hormone oxytocin (Table 1). In release would be disturbed in CP patients. However, we addition, the subgroup of 20 patients with proven initial HI could not detect a lack of oxytocin in CP patients. In did not show any significant differences compared to addition, we detected no difference in oxytocin saliva patients without initial HI and the controls (Fig. 1a–c). concentrations compared to the healthy control group. The Grading of the post-surgical hypothalamic lesion was conservation of oxytocin synthesis in CP patients might be possible in 27 of the 34 patients (79 %). This analysis explained by a residual or preserved function of hypotha- showed seven patients had no treatment-related hypotha- lamic structures and/or a taking over of synthesis function lamic lesion; six patients showed a surgical hypothalamic by other neuronal regions. It has been described that—in lesion grade 1, which is defined as a damage of the anterior addition to the synthesis in the paraventricular and parts of the hypothalamic region, leaving the corpora supraoptic nuclei of the hypothalamus—lesser amounts of mammillaria intact. The grading analysis further revealed oxytocin are generated in the bed nucleus of the stria- 14 patients with hypothalamic lesions grade 2, which is terminalis, medial preoptic area, and lateral amygdala, defined as a damage of the anterior and posterior parts of the depending on the species [21]. The release of oxytocin in hypothalamic region. By comparison of these subgroups, humans is known not to happen exclusively via axonal patients with hypothalamic lesion grade 1 showed a sig- secretion in the posterior pituitary but also from the den- nificant lower level of oxytocin before breakfast, compared drites (opposed to the axons) for intracerebral release [22– to patients without hypothalamic lesion and compared to 24]. By discrete grading and comparisons of CP patients patients with hypothalamic lesion grade 2 of the anterior with grade 1 hypothalamic surgical damage (damage and posterior hypothalamus (p = 0.017). Patients with exclusively to the anterior hypothalamic structures) and hypothalamic lesion grade 2 did not differ in terms of grade 2 (damage of anterior and posterior hypothalamic oxytocin levels before breakfast compared to patients regions), we found that patients with grade 1 damage only without hypothalamic lesion. In the oxytocin measurements to the anterior hypothalamus had a lower oxytocin level after breakfast, again the patients with hypothalamic lesion before breakfast compared to patients with grade 2 damage grade 1 showed a lower oxytocin level compared to hypo- and to patients without any hypothalamic damage. This thalamic lesion grade 2 patients, but without reaching a finding is, however, inconclusive, because only six patients significant level. In the analysis of Δ oxytocin before and were categorized with grade 1 hypothalamic damage. after breakfast, no differences were detectable (Fig. 2a–c). Nevertheless, our comparison of results still lead us to By comparison of changes in oxytocin saliva levels speculate that in some patients, oxytocin production and before and after breakfast (Δ oxytocin), no significant dif- release is diminished by hypothalamic damage due to sur- ferences could be measured in patients having undergone gical treatment. The localization of the paraventricular and radiotherapy (Fig. 3a) or in those with diabetes insipidus supraoptic nuclei of the hypothalamus might be the reason (Fig. 3b). Due to the important role of oxytocin in females, for preservation of oxytocin production since both nuclei we compared oxytocin expression in male and female CP are localized in the anterior superior part of the hypothala- patients and controls. Again, no significant differences mus. Growth of CP, however, typically takes place from an could be detected (Fig. 3c). anterior inferior to an upwards posterior direction. Thus, in However, in our analysis of further clinical parameters, it patients with HI, the anterior inferior (tuberal region) of the turned out that changes in oxytocin levels (Δ oxytocin) hypothalamus is attacked first [25]. Depending on the before and after breakfast correlated significantly (p = 0.02) direction of growth and tumor size, the paraventricular and with BMI in CP patients. CP patients with a high BMI supraoptic nuclei may frequently be spared, resulting in showed smaller oxytocin changes. In controls, no sig- preservation of oxytocin synthesis. nificant correlation between BMI SDS and Δ oxytocin In our small group of 34 CP patients, we were indeed able (before/after breakfast) could be detected (Fig. 4). to detect a negative correlation between BMI and changes in oxytocin levels before and after breakfast. This finding links oxytocin to the main problem of CP survivors with HI, Discussion which is severe hypothalamic obesity and its consequent long-term negative impact on quality of life [1]. It is already The present study reports the first analysis of oxytocin well established that the hypothalamus is the regulatory saliva concentrations in adamantinomatous childhood-onset center for feeding and satiety [26]. Oxytocin has also been CP patients. This is significant, as oxytocin synthesis takes linked to energy homeostasis mechanisms in animals, where place in the hypothalamus and is released mainly via the it acts as a strong inhibitor of food intake and affects energy pituitary gland, and these structures are often damaged by expenditure and glucose homeostasis [27–31]. Oxytocin Author's personal copy

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a) b) c) 15 25 25

10 20 20

5 15 15 0 10 10 Oxytocin (pg/ml) Oxytocin (pg/ml) Oxytocin (pg/ml) −5 5 5 Δ −10 0 0 Control CP, no HI CP, HI Control CP, no HI CP, HIControl CP, no HI CP, HI Fig. 1 Oxytocin saliva concentrations (pg/ml) in childhood-onset without preoperative hypothalamic involvement (HI) and healthy craniopharyngioma (CP) patients recruited in HIT Endo and controls. The horizontal line in the middle of the box depicts the KRANIOPHARYNGEOM 2000/2007 before breakfast (a) and 60 median. The top and bottom edges of the box, respectively, mark the min after standardized breakfast (b) and Δ oxytocin saliva 25th and 75th percentiles. Whiskers indicate the range of values that concentrations (oxytocin concentration after standardized breakfast fall within 1.5 box lengths vs. oxytocin concentration before breakfast) (c) in CP patients with and

a) b) c) 25 Kruskal−Wallis: p = 0.017 25 Kruskal−Wallis: p = 0.28 Kruskal−Wallis: p = 0.51 Grade 0 vs. grade 1: p = 0.025 5 20 Grade 0 vs. grade 2: p = 1 20 Grade 1 vs. grade 2: p = 0.031

15 15 0 10 10

Oxytocin (pg/ml) Oxytocin (pg/ml) Oxytocin Oxytocin (pg/ml) 5 5 Δ −5 0 0 Grade 0 Grade 1 Grade 2 Grade 0 Grade 1 Grade 2Grade 0 Grade 1 Grade 2 Fig. 2 Oxytocin saliva concentrations (pg/ml) in childhood-onset hypothalamic lesions; grade 1 surgical lesions involving anterior craniopharyngioma (CP) patients recruited in HIT Endo and hypothalamic areas, sparing the mammillary bodies; grade 2 surgical KRANIOPHARYNGEOM 2000/2007 before breakfast (a) and 60 lesions involving anterior and posterior hypothalamic areas involving min after standardized breakfast (b) and Δ oxytocin saliva the mammillary bodies. The horizontal line in the middle of the box concentrations (oxytocin concentration after standardized breakfast depicts the median. The top and bottom edges of the box, respectively, vs. oxytocin concentration before breakfast) (c) in CP patients with mark the 25th and 75th percentiles. Whiskers indicate the range of different grades (grade 0–2) of surgical hypothalamic lesions according values that fall within 1.5 box lengths to the grading system of Müller et al. [18, 19]. Grade 0 no

a) b) c)

6 6 6

3 3 3

0 0 0

−3 −3 −3 Oxytocin (pg/ml) Oxytocin (pg/ml) Oxytocin (pg/ml) Δ Δ Δ

−6 −6 −6

male female Irradiation No irradiation Desmopressin No desmopressin Fig. 3 Expression of Δ oxytocin saliva concentrations (oxytocin regarding gender (c). The horizontal line in the middle of the box concentration after standardized breakfast vs. oxytocin concentration depicts the median. The top and bottom edges of the box, respectively, before breakfast; pg/ml) in craniopharyngioma patients recruited in mark the 25th and 75th percentiles. Whiskers indicate the range of HIT Endo and KRANIOPHARYNGEOM 2000/2007 with and without values that fall within 1.5 box-lengths irradiation therapy (a) with and without diabetes insipidus (b) and has also been shown to play an important role in metabo- intake [11] and reward-driven food intake in humans [34]. lism and energy balance in humans [32, 33], such as These findings are in line with our finding that reduced reducing caloric intake with a preferential effect on fat levels of delta oxytocin correlate with a high BMI in CP Author's personal copy

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15 neurobehavioral and pro-social improvement with oxytocin Control, r=–0.006, p=0.96 therapy following surgical resection of their child’sCP[36], CP, r=–0.392, p=0.02 supporting earlier reports on oxytocin effects on social 10 cognition and affiliative behaviour [13–15]. There is a significant amount of extant literature per- 5 taining to the role that oxytocin plays in brain function, and that one of the major mechanisms associated with oxytocin is inhibition of the amygdala, reducing feelings of fear and 0 anxiety [37]. Other studies have found that intranasal oxy-

Oxytocin (pg/ml) tocin may activate reward pathways in the globus pallidus, –5 the striatum, middle frontal gyrus, medial prefrontal cortex, right orbitofrontal cortex, and the left superior temporal sulcus in autistic children [38]. However, in order to –10 recommend intranasal application of oxytocin as a general therapeutic option for CP-induced hypothalamic dysfunc- tion, further research is needed regarding the role oxytocin –2 0 2 4 6 8 10 12 14 BMI (SDS) plays in human metabolism and behavioural functionality. Limitations of our study are related to the small size of Fig. 4 Correlation of Δ oxytocin saliva concentrations (oxytocin our cohort and difficulties of oxytocin measurement. First, it concentration 60 min after standardized breakfast vs. oxytocin con- remains a matter of discussion whether peripherally mea- centration before breakfast; pg/ml) with body mass index (BMI) SDS in childhood-onset craniopharyngioma patients (black dots) recruited sured oxytocin is indicative for central release patterns and in HIT Endo and KRANIOPHARYNGEOM 2000/2007 and controls activities within the brain [39]. Some studies suggest that (grey dots). r = Pearson correlation coefficient certain stimuli lead to coordinated release of central and peripheral oxytocin, whereas other studies indicate that certain stimuli change central levels while leaving periph- patients. We could not demonstrate this delta oxytocin/BMI eral levels unchanged [40]. In addition, the reliability of correlation in the healthy control group, which might be oxytocin measurement is still under debate [39], and issues explained by the lower variability of BMI. In a recent study have been raised regarding the importance of preanalytical with newly diagnosed type 2 diabetic patients, serum oxy- procedures [41]. In this study, we used saliva samples tocin levels were lower compared to the control group with measured with EIA after extraction. To avoid analytical normal glucose tolerance. Serum oxytocin levels were inconsistencies, we measured healthy volunteers as con- negatively correlated with BMI, waist circumference, and trols, also participating at the 17th Annual Craniophar- other parameters of pathological insulin metabolism [35]. yngioma Meeting, 2014, under the same nutrition This correlation of low oxytocin levels and a high BMI in conditions as the CP patients and analyzed all saliva sam- diabetes type 2 patients [35], or minor changes of oxytocin ples using identical laboratory procedures. We were not saliva concentrations in reaction to nutrition (in this study, a able to analyze other metabolic parameters such as glucose, standardized breakfast) and a high BMI, might indicate that lipid and insulin levels and their association with pre- and oxytocin is a potential pharmaceutical agent for obesity post-prandial oxytocin concentrations in saliva. Based on treatment. Indeed, this has been tried in patients with the results of this pilot study, further investigations Prader–Willi syndrome (PWS), a genetic disease with including analyses of these parameters are part of an hypothalamic dysfunction, severe obesity, and hyperphagia upcoming new study in the context of the German Cra- as well as cognitive and behavioral problems. Oxytocin niopharyngioma Registry. supplementation has been tested in a randomized placebo- We conclude that CP patients are able to produce and controlled trial in 24 PWS patients [16]. After a single secrete the hormone oxytocin, even when pituitary and intranasal administration of oxytocin, improved patients’ hypothalamic structures are damaged. However, patients trust in others as well as decreased tendencies towards with hypothalamic damage grade 1, which involves damage depressed moods could be observed. Not surprisingly, no only to the anterior hypothalamic areas, present with a effects on obesity could be detected from this single oxy- significant lower fasting level of oxytocin. In addition, tocin administration [16]. This study demonstrates that changes in oxytocin levels (Δ oxytocin) before and after oxytocin therapy might be an option for diseases with standardized breakfast correlate significantly (p = 0.02) with hypothalamic dysfunction-induced behavioral disturbances BMI in CP patients, demonstrating that patients with and obesity. This therapeutic potential is further reinforced hypothalamic obesity show less variation in oxytocin by a recent case study about a parent having observed secretion due to nutrition. Accordingly, oxytocin Author's personal copy

530 Endocrine (2016) 54:524–531 supplementation might be a therapeutic optionin CP interindividual differences. Psychoneuroendocrinology 38(9), – patients with hypothalamic obesity and/or neurobehavioral 1883 1894 (2013). doi:10.1016/j.psyneuen.2013.06.019 fi fi 13. H.E. Ross, L.J. Young, Oxytocin and the neural mechanisms reg- de cits due to speci c hypothalamic damage in the anterior ulating social cognition and affiliative behavior. Front. Neuroendo- hypothalamic area. crinol. 30(4), 534–547 (2009). doi:10.1016/j.yfrne.2009.05.004 14. T.R. Insel, The challenge of translation in social neuroscience: a fi Acknowledgements We thank all patients who participated in this review of oxytocin, vasopressin, and af liative behavior. Neuron – study. We are grateful for the help of Margarita Neff-Heinrich, Göt- 65(6), 768 779 (2010). doi:10.1016/j.neuron.2010.03.005 tingen, Germany, in proofreading and editing the manuscript. H. L. 15. P.S. Churchland, P. 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