{"paper_id":"7c0e3969-2378-4a09-b81b-64a2bb3945c1","body_text":"1 \nTitle: The oxytocin system in patients with craniopharyngioma: A systematic review  \n \nAmy Mann1*, Jennifer Kalitsi1, 2, Khushali Jani3, Daniel Martins1, Ritika R Kapoor3,4†, Yannis \nPaloyelis1†  \n \n† These authors share senior authorship. \n \nAffiliations: \n1Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience,  King’s \nCollege London, London, UK \n2Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, Child and Family \nHealth Nursing, King’s College London,  London, UK \n3Faculty of Life Sciences and Medicine, King’s College London, London, UK \n4Department of Paediatric Endocrinology,  Variety Children ’s Hospital, King's College \nHospital NHS Foundation Trust, London, UK \n \nORCID IDs:  \nAmy Mann: https://orcid.org/0009-0002-1403-9910 \nJennifer Kalitsi: https://orcid.org/0000-0002-7670-1028  \nDaniel Martins: https://orcid.org/0000-0002-0239-8206  \nRitika R Kapoor: https://orcid.org/0000-0002-4335-2159 \nYannis Paloyelis: https://orcid.org/0000-0002-4029-3720 \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n 2 \nCorrespondence: Amy Mann, Department of Neuroimaging (P089), Institute of Psychiatry, \nPsychology and Neuroscience, De Crespigny Park, SE5 8AF, King’s College London, UK . \nEmail: amy.mann@kcl.ac.uk \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 3 \nAbstract \n \nCraniopharyngioma is a benign tumour affecting the hypothalamic and pituitary regions, which \nare involved in the production and secretion of oxytocin. We conducted a systematic review to \nassess dysregulation of the oxytocin system in craniopharyngioma and associations with \nneurobehavioural, eating, and metabolic abnormalities.  Eight studies (n=72 patients ) were \nincluded. Evidence for dysfunction of the endogenous oxytocin system in craniopharyngioma \nis limited and mixed. While no significant differences in baseline salivary oxytocin \nconcentrations were reported between patients with craniopharyngioma and co ntrols, patients \nwith craniopharyngioma were found to have blunted salivary oxytocin response following \nexercise stimulation and this was associated with greater state anxiety and higher BMI. Studies \nadministering exogenous oxytocin are sparse and do not m eet required standards. \nHypothalamic damage may pose an additional mechanism of oxytocin dysregulation. \nImproving understanding of the oxytocin system in craniopharyngioma could be pivotal for \nexploring the potential therapeutic role of exogenous oxytocin in this condition. \n \nKey words:  oxytocin, craniopharyngioma, body mass index, anxiety , neuroendocrinology, \nsystematic review   \n \n \n \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 4 \n1 Introduction \nCraniopharyngioma is a rare benign tumour affecting the hypothalamus and pituitary \ngland, with an incidence of 0.5 to 2 cases per million people per year (Nielsen et al., 2011) . \nPeak onset is between 5-14 years old in children and 50-74 years in adults (Bunin et al., 1998), \nwhere 30-50% of all cases present during childhood or adolescence (Nielsen et al., 2011) . \nAlthough craniopharyngioma is a histologically benign tumour, patients experience significant \nmorbidity related to local infiltration of surrounding structures by the tumour and because of \nthe treatment strategies, which involve resection of the tumour and/ or radiotherapy (Müller, \n2010). The long -term morbidities impairing quality of life of these patients include varying \ndegrees of hypopituitarism, and visual and neurological deficits (Müller, 2020; Zhou et al., \n2021). Cognitive -behavioural, and emotional difficulties (hitherto referred to as \nneurobehavioural impairment) (Özyurt et al., 2015; Zada et al., 2013) , hyperphagia (i.e., \npathological overeating), and obesity (Roth, 2011) are additional prevalent manifestations in \nthese patients. Impairments may persist following treatment of the tumour (Mende et al., 2020), \nand often increase in severity, likely as a consequence of post-operative hypothalamic damage. \nAt present, there is no standard of care for neurobehavioural impairment or hyperphagic eating \nbehaviours experienced by affected patients with craniopharyngioma, despite posing a \nsignificant challenge for both patients and their families.  \nDespite correcting other hormone deficiencies, disruption of the oxytocin system and \nthe potential benefits of the administration of exogenous oxytocin are yet to be assessed, and \nthus not considered in routine care for patients with craniopharyngioma. Oxytocin is a \nhypothalamic neuropeptide primarily synthesised in the magnocellular and parvocellular \nneurons of the paraventricular and supraoptic nuclei of the hypothalamus. Magnocellular \nneurons project to the posterior pituitary for oxytocin release into peripheral circulation, whilst \nboth magnocellular and parvocellular neurons are involved in central oxytocin release \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 5 \n(Althammer & Grinevich, 2017). Oxytocin is known to be implicated in multiple physiological \nand behavioural pathways including the regulation of social-cognitive functioning (Johnson & \nYoung, 2017), the modulation of feeding behaviour (Lawson, 2017), and neuroinflammation \n(Knoop et al., 2022) . As such, oxytocin dysregulation has been suggested in a number of \nneurodevelopmental and psychiatric conditions, including autism spectrum disorder (ASD) \n(John & Jaeggi, 2021) , schizophrenia, and anorexia nervosa (Ferreira & Osório, 2022) . In \naddition, the anorexigenic effects of oxytocin, with reductions in food intake, weight and fat, \nand improvements in glucose homeostasis, have been observed in pre-clinical (e.g., Blevins et \nal. (2015); see also Leslie et al. (2018) and clinical studies (Lawson, 2017) . Interest in \nexogenous oxytocin as a therapeutic for this group is therefore motivated by the potential to \nbenefit patients with craniopharyngioma across key neurobehavioural and metabolic clinical \nfeatures.  \nDamage to the hypothalamo -pituitary region, which is a common feature of \ncraniopharyngioma, poses a likely mechanism of disruption of the homeostatic regulation of \nphysiological concentrations of oxytocin centrally and peripherally, and/or its central and \nperipheral release in response to stimulation. Therefore, hypothalamo -pituitary damage may \nhave considerable implications for metabolic and neurobehavioural functioning in \ncraniopharyngioma. Specifically, there are different degrees of hypothalamic damage, caused \npre-operatively and/or post-operatively, involving the anterior hypothalamic regions (grade I), \nand extending to the posterior hypothalamic regions with or without mammillary body \ninvolvement  (grade II) (Müller et al., 2012; Müller et al., 2019).  Studies have shown that the \ncystic and solid components of craniopharyngioma are high in lipids, cholesterol, and pro -\ninflammatory markers (Apps et al., 2018; Whelan et al., 2020), where the cystic fluid has shown \nto initiate an inflammatory activation of the microglia, causing damage to the hypothalamus \n(Ainiwan et al., 2022). This lipid-rich and inflammatory composition is greater than that seen \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 6 \nin other benign tumours (Apps et al., 2018; Donson et al., 2017) , likely accounting for the \nprevalent hypothalamic dysfunction in this specific tumour type (alongside the damage caused \nby surgical excision and/or radiotherapy). The degree of hypothalamic involvement predicts \noutcome type and severity in craniopharyngioma (Müller, 2020). The presence of hypothalamic \ndamage (caused pre-operatively and/or post-operatively) therefore poses a key clinical feature \nin need of consideration in patients with craniop haryngioma as it contributes to clinical \nheterogeneity and heterogeneity in the degree of involvement of the oxytocin system.  \nThis is the first systematic review that aims to assess the extent to which the oxytocin \nsystem is compromised in craniopharyngioma, the relevance of hypothalamic damage, and \nwhether alterations in the function of the oxytocin system may be associated with the \nneurobehavioural and metabolic dysfu nction observed in this condition. It is anticipated that \nimproving understanding of the involvement of the oxytocin system in craniopharyngioma \ncould be pivotal for exploring the potential therapeutic role of exoge nous oxytocin in this \ncondition.   \n \n2 Methods \nThe present systematic review was pre -registered with PROSPERO (ID: \nCRD42023397966) and followed the Preferred Reporting Items for Systematic Reviews and \nMeta-Analyses (PRISMA) guidelines (Moher et al., 2009; Page et al., 2021)  (see \nSupplementary Material Table S1). \n \n2.1  Search strategy  \nPubMed, Embase, and PsycInfo were searched to identify peer -reviewed articles \npublished in English, from inception through January 19, 2024. The following search terms \nwere used and adjusted based on the requirements of each database: (oxytocin OR OT OR OXT \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 7 \nOR OXTR OR CD38) AND (craniopharyngioma). The Cochrane Central Register of \nControlled Trials was also searched using the terms “craniopharyngioma” and “oxytocin”. No \nfilters or limits were applied to the search. Hand -searching of the reference lists of included \nstudies and relevant literature reviews was performed to search for additional studies.  \n \n2.2  Study selection  \n Articles were exported into Rayyan ( http://rayyan.qcri.org) where duplicate articles \nwere removed using the duplicate identification tool. Authors AM and JK/ KJ independently \nreviewed the titles and abstracts against the inclusion and exclusion criteria. Due to the novelty \nof this field, our inclusion criteria were intentionally broad and included original peer-reviewed \narticles with: 1) a sample of humans with craniopharyngioma; and 2) assessment of the \noxytocin system (e.g., baseline, pre - and/ or post -intervention for release of endogenous \noxytocin, pre- and/ or post -exogenous oxytocin intervention, or genetic association); and 3) \nmeasurement of neurobehavioural outcomes (e.g., behavioural, cognitive, social, emotional, \npsychiatric) or eating behaviours (e.g., hype rphagia); or 4) measurement of metabolic \noutcomes (e.g., body mass index; BMI). Clinical trial registrations were included and extracted \nwhere sufficient outcome data had been reported. Non -English articles and those where full -\ntexts could not be obtained were excluded due to the inability to extract re quired data. All \nexcluded articles were documented in an Excel database with justifications for exclusion.  \n \n2.3  Data charting and synthesis  \nData was independently extracted by three authors, AM, JK and KJ, into a data \nextraction spreadsheet generated during protocol development. The following data were \nextracted from included papers: 1) first author, 2) year of publication, 3) study design and  \nsample size, 4) age and gender of participants, 5) participant clinical characteristics (e.g., \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 8 \nendocrine morbidity, visual impairment, grade of hypothalamic damage), 6) treatment status \n(i.e., if pre - or post -operative), 7) comparator group demographics (if applicable), 8) \ninformation on measurement, sampling, and quantification of oxytocin, or oxyt ocin treatment \n9) information on neurobehavioural or metabolic outcomes,  or eating behaviours  10) \nassociations between the oxytocin system and neurobehavioural or metabolic outcomes,  or \neating behaviours, and 11) group differences between craniopharyngioma and comparators in \nthe oxytocin system and neurobehavioural or metabolic outcomes , or eating behaviours . \nInformation on demographic, clinical, and outcome data are detailed in Table 1. A narrative \nsynthesis was used to integrate the key findings of the included articles.  \n  \n2.4  Quality assessment  \nDue to the variance in study designs, appropriate versions of the JBI Critical Appraisal \nchecklists were used to assess individual study quality (see Supplementary Material Figure S1 \nto 3). Adjustments to the JBI checklists were made by the study team for studies administering \nexogenous oxytocin. Two independent reviewer s assessed the quality of each study; any \ndiscrepancies were resolved through discussion or intervention by a third reviewer. No study \nwas excluded due to a poor-quality assessment. \n \n3 Results \nThe study selection process is detailed in Figure 1. The search yielded 67 unique \narticles, of which eight studies were included. Of the eight included studies, data of 72 patients \nare reported on across two case reports (Cook et al., 2016; Hsu et al., 2017), one interventional \nstudy administering a single dose of 24IU intranasal oxytocin (Hoffmann et al., 2017), and five \ncross-sectional, case -control studies (Brandi et al., 2020; Daubenbüchel et al., 2016; \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 9 \nDaubenbüchel et al., 2019; Gebert et al., 2018; Özyurt et al., 2020). No papers assessing genetic \nassociations were found from the search.  \nIt is important to note that oxytocin samples were collected from the same participant \nsample for Daubenbüchel et al. (2016)  and Daubenbüchel et al. (2019) ; Özyurt et al. (2020)  \nreports on a subsample of these studies. Similarly, Brandi et al. (2020)  reports oxytocin data \non a subsample of Gebert et al. (2018) . Therefore, only unique results are discussed in this \nreview and the earliest study will be referenced for studies reporting on the same data.   \n \n[Insert Figure 1 here] \n \n3.1 Methods of assessing the oxytocin system  \nVaried approaches to assessing the oxytocin system in craniopharyngioma were \nadopted in the eight included studies (see Table 1). Two case reports assessed the effects of \nlong-term use of low dose (4IU-6IU/ day) intranasal oxytocin on parent -reported behavioural \nchange and BMI (Cook et al., 2016; Hsu et al., 2017). One study assessed the effects of a single-\ndose of intranasal oxytocin on emotion recognition performance (Hoffmann et al., 2017). Two \nresearch groups assessed concentrations of endogenous oxytocin before (baseline) and after an \nintervention intended to activate the endogenous oxytocin system, in comparison to a healthy \ncontrol group (Daubenbüchel et al., 2016; Gebert et al., 2018) . Özyurt et al. (2020)  reported \nonly on baseline measurements of fasting salivary oxytocin in comparison to healthy controls. \nAll studies assessing endogenous oxytocin concentrations measured salivary oxytocin  \n(Daubenbüchel et al., 2016; Gebert et al., 2018; Hoffmann et al., 2017) , with one study also \nmeasuring oxytocin in urine (Hoffmann et al., 2017). Two research groups quantified oxytocin \nusing radioimmunoassay (RIA) (Gebert et al., 2018; Hoffmann et al., 2017) , and one group \nused enzyme immunoassay (EIA) (Daubenbüchel et al., 2016). \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 10 \n Across the two research groups (Daubenbüchel et al., 2016; Gebert et al., 2018)  \nimplementing a pre - and post -activation paradigm, baseline oxytocin concentrations were \nobtained in fasting state between 08:00 – 08:30 as a single salivary sample (using Salivettes). \nIn terms of activating the oxytocin system, Gebert et al. (2018) used a bicycle ergometer where \nstepwise increasing wattage difficulty was used and participants continued until exertion \n(lactate in capillary blood was measured repeatedly to standa rdise for individual exertion). \nParticipants exercised on the bike for up to 7 minutes and stopped when lactate levels >4 \nmmol/l or if lactate levels were maintained at 4 mmol/l, when participants reached physical \nexhaustion, or after 25 minutes of exercise. A single salivary sample was taken to measure \noxytocin immediately after exhaustion was reached. By contrast, Daubenbüchel et al. (2016)  \nactivated the endogenous oxytocin system by administering a standardised breakfast meal (10 \nto 15 kcal/kg body weigh t) and post-prandial concentrations of oxytocin were measured by a \nsingle salivary sample 60 minutes after consumption of the meal.  \nHoffmann et al. (2017) was the only study to implement an interventional pre-and post-\nintranasal oxytocin paradigm to assess the emotion identification ability in 10 adults before and \nat ~60 minutes after intranasal  oxytocin administration. No placebo arm or blinding was \nimplemented in this study; all participants received a single dose of 24IU intranasal oxytocin \nadministered using a nasal spray . The authors additionally measured baseline and post -\nintranasal concentrations of salivary  (at 45 to 60 after ad ministration) and urinary  (at 90 \nminutes after administration) oxytocin.  \n \n[Insert Table 1 here] \n \n3.1.1 Intranasal oxytocin studies  \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 11 \nAcross three studies administering intranasal oxytocin, consistent improvements were \nfound for  socio-emotional functioning, with unclear evidence for metabolic benefits. One case \nreport of a 6 -year-old female found no improvements in food -related obsessive-compulsive \nfeatures or weight, but did report parent -observed improvements in social and emotional \nbehaviours over approximately 14 months (dosage of 4IU/day) (Cook et al., 2016) . Another \ncase report administering 6IU/day intranasal oxytocin in a 13 -year-old male did report \nimprovements in overall food preoccupation and BMI z-score, which decreased from 1.77 SDS \n(96th percentile) to 0.82 SDS (79th percentile) over 48 weeks (Hsu et al., 2017). The difference \nin effects of oxytocin on BMI/ weight here may be accounted for by the addition of naltrexone \n(100mg/day) over the treatment period in Hsu et al. (2017). Naltrexone is an opioid antagonist \nwith selective preference for μ-opioid receptor binding that has shown to be an effective \ntreatment for adult obesity (Kulak-Bejda et al., 2021); μ-opioid receptor antagonism has shown \nto potentiate the effects of oxytocin (Nisbett et al., 2024)  and increase plasma oxytocin \nconcentrations by disinhibition of central oxytocin release in rodents during late pregnancy \n(Douglas et al., 1993). However, Hsu et al. (2017) did report a decrease in BMI z -score from \n1.77 SDS to 1.49 SDS (93 rd percentile) over the 10 weeks before naltrexone was added. This \nsuggests that, at least in part, the improvements in BMI cannot be explained by naltrexone \nalone. Nevertheless, in both cases, no placebo arm was implemented and the neurobehavioural \nand eating behaviour observations were based on parent opinions, as opposed to measurements \nusing validated scales. \nThe only study investigating the effects of single -dose intranasal oxytocin on social \ncognition observed a numerical improvement in emotion identification (Hoffmann et al., 2017). \nIt reported increased percentage of correct assignment of emotional vocal expressions for \npatients with post -operative grade I hypothalamic damage (anterior lesions; n=4) post -\ntreatment, compared to baseline. By contrast, minimal changes or worsened scor es were \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 12 \nreported in the patients with grade II hypothalamic damage (mammillary bodies, anterior and \nposterior lesions; n=6) (Hoffmann et al., 2017). The authors suggested that supplementation of \noxytocin may therefore only be beneficial for patients with lesions limited to the anterior \nhypothalamus (Hoffmann et al., 2017). Yet, given the small sample size of this study (n=4 to \n6 per group), absence of inferential statistical analysis, and the lack of placebo -controlled \ncondition, no firm conclusions can be drawn on  the differential socio -cognitive effects of \nintranasal oxytocin dependent on grade of hypothalamic damage.  \n \n3.1.2 The endogenous oxytocin system  \nEvidence for dysfunction of the endogenous oxytocin system in craniopharyngioma is \nlimited and mixed, with differential findings depending on the paradigms used to measure \noxytocin concentrations (e.g., single baseline measurements vs. response to intervention) and \nthe stratification of analyses by hypothalamic damage.  \nAcross two research groups comparing patients with craniopharyngioma and healthy \ncontrols, no significant differences in baseline salivary oxytocin concentrations were observed \n(Brandi et al., 2020; Daubenbüchel et al., 2016; Daubenbüchel et al., 2019; Özyurt et al., 2020). \nIn patients  with craniopharyngioma  (n=70), mean/median baseline salivary oxytocin \nconcentrations ranged between 0.32 pg/mL and 1.90 pg/mL for samples quantified using RIA \n(Brandi et al., 2020; Gebert et al., 2018; Hoffmann et al., 2017) , and between 3.3 pg/mL and \n3.6 pg/mL for samples quantified using EIA (Daubenbüchel et al., 2016; Özyurt et al., 2020) . \nIn healthy controls (n=99), mean/median baseline salivary oxytocin concentrations ranged \nbetween  1.24 pg/mL and 1.33 pg/mL for samples quantified using RIA (Brandi et al., 2020; \nGebert et al., 2018), and between 3.4 pg/mL and 4.4 pg/mL for samples quantified using EIA \n(Daubenbüchel et al., 2016; Özyurt et al., 2020) . These values are comparable to the mean \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 13 \noxytocin concentrations of extracted salivary samples (adjusted for quantification assay) \nreported in the literature for healthy adults (e.g., see Engel et al. (2019)).  \nWhen stratifying analyses by hypothalamic damage, mixed findings for differences in \nbaseline salivary oxytocin were observed. Specifically, there was no difference when \ncomparing patients with grade I (n=8) hypothalamic damage and no hypothalamic damage; \nwhile patients with grade II hypothalamic damage (n=7) were found to have significantly lower \nbaseline salivary oxytocin concentrations than patients with no hypothalamic damage (n= 7) \n(Gebert et al., 2018). By contrast, Daubenbüchel et al. (2016) found that patients with grade I \n(n=6) hypothalamic damage had significantly lower baseline salivary oxytocin concentrations \nthan patients with no hypothalamic damage (n=7); yet there was no difference between patients \nwith grade II (n=14) hypothalamic damage and no hypothalamic damage. In the same study \n(Daubenbüchel et al., 2016) , patients with grade I hypothalamic damage were found to have \nlower baseline salivary oxytocin concentrations than grade II patients. A trend towards lower \nbaseline urinary oxytocin concen trations in patients with grade I  (n=4) damage compared to \ngrade II (n=6) hypothalamic damage ( p=0.06) was similarly reported in Hoffman et al. \n(Hoffmann et al., 2017). Given that both grade I and grade II hypothalamic damage involve the \nanterior hypothalamus, differences in oxytocin concentrations between patients with different \ngrades of hypothalamic lesions was not anticipate d; yet these findings were likely due to the \nimpact of the small sample sizes (n=6 to 14 per group) on obtaining a reliable estimat e of \noxytocin concentrations for each grade of hypothalamic damage, and consequent lack of \nstatistical power. \n In studies assessing change in oxytocin concentrations pre -and post -intervention, \nsignificant differences between craniopharyngioma and controls were observed for studies \nimplementing exercise  stimulation, but not those using prandial  intervention. Specifically, \nDaubenbüchel et al. (2016) did not find any significant differences when comparing the change \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 14 \nbetween pre- and post-prandial salivary oxytocin concentrations between craniopharyngioma \nand controls, with both groups showing  similar post -prandial (compared to pre -prandial) \ndecreases in oxytocin concentrations, suggesting that the postprandial oxytocin response is \nintact in craniopharyngioma. This pattern of post -prandial decrease in salivary oxytocin \nconcentrations is consistent with a study that reported a decrease in plasma oxytocin \nconcentrations at 30 and 60 minutes following a standardised mixed meal in healthy females \n(independent of age, calorie intake, and menstru al phase) (Aulinas et al., 2019) . By contrast, \nGebert et al. (2018)  found that in response to exercise all patients with craniopharyngioma \nshowed a decrease in salivary oxytocin concentrations, compared to pre -exercise \nconcentrations (-13.7%), whilst controls showed an increase (+24.8%) as expected. This was \nsimilarly found for the subsample of this study reported in Brandi et al. (2020), with a 7.90% \ndecrease in oxytocin concentrations in patients with craniopharyngioma, compared to a 21.26% \nincrease in controls.  \nOverall, findings from studies focusing on the endogenous oxytocin system suggest that \ndeficits may only be identified when assessing the reactivity of the oxytocin system to \nstimulation (e.g., exercise), as opposed to single measurements of baseline  concentrations \nalone. Therefore stimulation paradigms may pose an appropriate methodology for assessing \nthe integrity of the oxytocin system in craniopharyngioma.  \n \n[Insert Table 2 here] \n \n3.2 Associations between the oxytocin system and key outcomes   \nCurrent e vidence suggests that dysregulated oxytocin in craniopharyngioma is \nassociated with BMI (Daubenbüchel et al., 2016; Daubenbüchel et al., 2019; Gebert et al., \n2018) and affective function (Gebert et al., 2018; Özyurt et al., 2020) , while there are mixed \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 15 \nfindings for a relationship with social cognition (Brandi et al., 2020; Hoffmann et al., 2017; \nÖzyurt et al., 2020).  \n \n3.2.1 Oxytocin, metabolism, and eating behaviours \nConvergent findings from two independent studies suggest a relationship between the \nchange in pre - and post-stimulation concentration of salivary oxytocin and BMI and eating \nbehaviours in craniopharyngioma. Specifically, Daubenbüchel et al. (2016) found that higher \nBMI was associated with smaller pre - vs. post -prandial decrease in salivary oxytocin \nconcentrations in patients, whilst no association was found for controls. It is important to note \nthat the authors did not report descriptive data on BMI, and th erefore it is unknown how the \ndispersion of BMI values within the control group might have accounted for the lack of \nassociation here. It  was additionally found that a smaller change in salivary oxytocin \nconcentration was associated with subjective eating behaviours  in patients with \ncraniopharyngioma, specifically, with increased concerns about eating and weight \n(Daubenbüchel et al., 2019) . Moreover, Gebert et al. (2018)  found that across the whole \nsample, participants with higher BMI showed a smaller incre ase in salivary oxytocin \nconcentrations post-exercise stimulation than those with lower BMI.  \nGiven that higher BMI was associated with blunted changes in salivary oxytocin \nconcentrations following prandial and exercise intervention, BMI may pose a key metabolic \nfeature moderating oxytocin dysregulation in this group.  \n \n3.2.2 Oxytocin and neurobehavioural impairment \nA complex association was observed between salivary oxytocin and anxiety, with \ndifferent relationships found for oxytocin with state anxiety (i.e., the transient response to a \npsychosocial stressor) and trait anxiety (i.e., the tendency to feel anxious acr oss different \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 16 \ncontexts). Specifically, Gebert et al. (2018) found that greater trait anxiety was associated with \nhigher baseline salivary oxytocin, whilst blunted release of oxytocin (i.e., no/ a smaller increase \nbetween pre- and post-exercise salivary oxytocin concentrations) was a significant predictor of \ngreater state anxiety in craniopharyngioma. In addition, Özyurt et al. (2020) found that lower \nbaseline salivary oxytocin concentrations were associated with greater state anxiety and \nseverity of depression symptoms, across the whole sample. Stress-inducing contexts are known \nto increase the secretion of oxytocin (Takayanagi & Onaka, 2021) , which can have an \nanxiolytic effect; when considering trait anxiety, it may be that over time, repeated initiation \nof oxytocin release due to heightened trait anxiety results in the downregulation of oxytocin \nreceptors, and thus, an increase in circulati ng oxytocin concentrations (Uzun et al., 2022) , \npossibly accounting for the positive relationship between baseline oxytocin and trai t anxiety. \nAcross the two studies however, lower concentrations of baseline oxytocin (Özyurt et al., 2020) \nand a blunted oxytocin release in response to exercise  (Gebert et al., 2018)  were associated \nwith higher state anxiety. The association between oxytocin dysregulation and anxiety \ntherefore likely poses a complex relationship that is dependent on the context and type of \nanxiety, and will benefit from advances in standardised tools and protocols, to facilitate meta-\nanalysis and investigation of moderators related to the paradigm or conditions of the studies.   \nLimited evidence for an association between baseline oxytocin and socio -cognitive \nfunctioning emerged. Specifically, no associations between baseline salivary oxytocin \nconcentrations and empathy quotient scores or socio -cognitive tasks, such as the Reading the \nMind in the Eyes Test (Brandi et al., 2020) , Theory of Mind (as measured by the Movie \nAssessment of Social Cognition), and Identification of Emotional Expressions in Voices \n(Özyurt et al., 2020)  were observed , across the whole sample . Patients with hy pothalamic \ndamage, however, were found to have reduced Theory of Mind and reduced accuracy in \nidentifying emotional vocal expressions compared to controls; yet, this difference was not \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 17 \nobserved when comparing all patients (i.e., no hypothalamic damage and hypothalamic \ndamage) with controls (Özyurt et al., 2020). No group differences in baseline salivary oxytocin \nconcentrations were found in this study (Özyurt et al., 2020). This suggests that hypothalamic \ndamage may pose a mechanism underlying socio-cognitive difficulties, independent of effects \nof baseline oxytocin. The mechanisms underlying socio -cognitive difficulties in \ncraniopharyngioma therefore remain to be established, and further research is required in order \nto delineate the specific direct and indirect effects of hypothalamic damage on this relationship.   \nWe should note here a methodological concern regarding the assessment of associations \nbetween oxytocin and neurobehavioural or metabolic outcomes by pooling participants across \npatient and control subgroups, in the presence of mean group differences in the  associated \nvariables (Gebert et al., 2018; Özyurt et al., 2020) , as this practice may result in illusory \ncorrelations (Hassler & Thorsten, 2003) . A more appropriate approach would be to pool \ncorrelation coefficients across samples (Hassler & Thorsten, 2003). \n \n4 Discussion \nThis systematic review provides preliminary evidence that dysregulation of the \noxytocin system may be associated with neurobehavioural functioning and BMI, and therefore, \nmay pose a mechanism underlying these features in craniopharyngioma. While no significant \ndifferences were found between baseline salivary oxytocin concentrations in patients and \ncontrols, the findings of this review suggest that patients with craniopharyngioma may present \na deficit in oxytocin secretion in response to a stressor, and that hypothalamic damage poses a \nlikely moderator of the severity of this dysregulation. However, the methods of measuring \nendogenous oxytocin implemented by these studies (e.g., sampling type, quantification assay; \nsee Tabak et al. (2023) ) may not be sensitive to identifying  differences in baseline \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 18 \nconcentrations between patients and controls, highlighting the need for the utilisation of more \nvalid measurement protocols in future research.  \nA number of limitations in the methods implemented by the studies in the present \nreview may account for the presence or absence of  significant differences in baseline oxytocin \nconcentrations between patients and controls. First, the studies used single salivary samples for \noxytocin collection, yet the physiology (i.e., the diffusion into and clearance from saliva) of \nsalivary oxytoci n has not been established and its association with circulatory plasma and \ncerebrospinal fluid (CSF) oxytocin is unknown, and  therefore may not present a valid trait \nmarker of the central oxytocin system (Martins et al., 2020). Plasma has been identified as the \nfavourable alternative to CSF measures, as the normal physiological range of < 10 pg /mL in \nmammal circulation has been established for extracted samples quantified using RIA (Leng & \nSabatier, 2016) . No studies in this review collected plasma oxytocin highlighting a key \nlimitation of current research in craniopharyngioma in need of implementation. Second, one \nresearch group (Daubenbüchel et al., 2016)  used EIA rather than RIA to quantify oxytocin \nconcentrations, despite EIA having been criticised for having low sensitivity and high inter -\nassay variability (Tabak et al., 2023) . The need for assays of higher sensitivity is especially \nrelevant for patients with craniopharyngioma, since it is anticipated that this condition may \nhave lower concentrations of central and/or peripheral oxytocin. Lastly, irrespective of the \nissues surrounding salivary sampling and quantification assays, single baseline measures of \nperipheral oxytocin concentrations have shown variability in the same individual at the same \ntime, across different days, and therefore it is questionable whether single baseline samples can \nprovide a valid and reliable marker of the integrity or function of the oxytocin system (Martins \net al., 2020) . The absence of studies collecting plasma oxytocin and the inconsistent \nimplementation of RIA quantification methods, limits the validity of existing assessments of \nthe endogenous oxytocin system . Additionally, given the intra -individual variability of \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 19 \noxytocin concentrations (Martins et al., 2020), alternative sampling protocols to single samples \nare necessary to reliably assess the endogenous oxytocin system in this population. At present, \nthese limitations, combined with the lack of a standardised range of baseline values that could \nbe utilised to assess oxytocin deficiency in routine care, emphasise a key area in need of \ninvestigation.  \nRepeated sampling and stimulation paradigms may prove more suitable methods for \nlimiting the effects of intra -individual variability and increase the validity of baseline \nmeasurements (Martins et al., 2020)  when assessing oxytocin concentrations in \ncraniopharyngioma. For example, stimulation paradigms may present a more valid method of \ncharacterising the endogenous oxytocin system than single baseline measurements, with meta-\nanalytic evidence supporting a relationship between peripheral and CSF measurements  in \nresponse to stress stimulation in animals (i.e., pre - and post-stress stimulation measurements \nof oxytocin) (Valstad et al., 2017). In humans, stimulation by exercise, sexual self-stimulation, \nand psychosocial stress have been established to initiate a robust and reliable, fast -acting \nincrease in salivary oxytocin concentrations (Alley et al., 2019; Jong et al., 2015)  and plasma \noxytocin concentrations (Carmichael et al., 1987; Hew-Butler et al., 2008; Pierrehumbert et al., \n2010). Research work has addi tionally suggested 3,4-methylenedioxymethamphetamine \n(MDMA) administration as an effective provocation test for identifying a clinically meaningful \noxytocin deficiency in patients with central diabetes insipidus (i.e., vasopressin deficiency) \n(Atila et al., 2023). In the present review, a difference in endogenous oxytocin concentrations \nbetween patients and controls was only found in one research group (Brandi et al., 2020; Gebert \net al., 2018) assessing the reactivity of the oxytocin system in response to exercise stimulation. \nTherefore, stimulation paradigms provide evidence that the oxytocin system may be \ncompromised in craniopharyngioma. Future research implementing stimulation paradigms \n(Valstad et al., 2017) and/ or repeated sampling of plasma and/or salivary oxytocin (at baseline) \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 20 \n(Martins et al., 2020)  are required in order to sensitively and accurately characterise the \nphysiology of the oxytocin system in craniopharyngioma. In addition, oxytocin has been shown \nto elicit a diurnal rhythm with peak CSF concentrations at 12:00 (Amico et al., 1983), and more \nrecently, to have a pulsatile architecture of secretion during resting state (Baskaran et al., 2017). \nInvestigation into the dynamics of peripheral oxytocin secretion at rest, using repeated \nsampling across a single day/ night, may therefore identify deficits at specific phases of the \ncycle that cannot be captured using measurements at single time points , highlighting another \narea in need of exploration in patients with craniopharyngioma.  \nDifferences in baseline oxytocin concentrations were identified between patients \ndepending on presence of hypothalamic damage, suggesting hypothalamic damage as a \nprobable moderator of oxytocin dysregulation in craniopharyngioma. Specifically, patients \nwith hypothalamic damage were found to have lower salivary oxytocin concentrations than \npatients with no hypothalamic damage (Daubenbüchel et al., 2016; Gebert et al., 2018) . \nHypothalamic damage implicates the anterior hypothalamus , where oxytocin synthesisin g \nneurons of the paraventricular and supraoptic nuclei send axonal projections to the posterior \npituitary for the release of oxytocin in peripheral circulation, as well as axonal projections and \ncollaterals to central targets (Althammer & Grinevich, 2017) . Therefore, patients with \ncraniopharyngioma and hypothalamic damage may present either with an oxytocin -\nsynthesising deficiency, and/or a deficit in oxytocin section if axonal projection routes are \ndisrupted (Gebert et al., 2018) . The effect of hypothalami c damage on the oxytocin system \ntherefore needs to be disentangled before firm conclusions on the mechanisms of oxytocin \ndysregulation in craniopharyngioma may be established. \nHypothalamic damage was assessed by the studies in this review by visual inspection \nof the presence or absence of lesions to the anterior and/or posterior (with or without mamillary \nbody involvement) hypothalamus (Müller et al., 2012) . While the Müller grading system is \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 21 \nclinically well-established, it does not allow for the assessment of parameters such as volume, \nor possible microstructure alterations that may impact the function of the oxytocin system. A \nvolumetric approach to measuring hypothalamic damage in patients with craniopharyngioma \nhas been explored, where lower hypothalamic volume was associated with greater fat mass and \nhigher leptin levels (Fjalldal et al., 2019) , suggesting hypothalamic volume as a quantitative \nmarker of metabolic dysfunction in this condition. Existing methods may also be enhanced by \nimplementing advanced imaging sequences , such as diffusion neurite orientation dispersion \nand density imaging (NODDI)  and automated hypothalamic segmentation tools (Billot et al., \n2020), that may be more sensitive to pathological change and allow for better characterisation \nof hypothalamic involvement . Utilisation of quantitative parameters to assess hypothalamic \ndamage therefore presents an important avenue in need of exploration when investigating the \noxytocin system  and neurobehavioural and metabolic outcomes, in patients with \ncraniopharyngioma.  \nWhile the extent to which the oxytocin system is compromised in craniopharyngioma \nis not yet clear, supplementation with exogenous oxytocin poses a potential therapeutic avenue, \nby restoring the inflammatory activation caused by the cystic and solid components of \ncraniopharyngioma. In vivo evidence has shown that oxytocin pre -treatment reduced the \ninflammatory microenvironment generated by ox -Low Density Lipoprotein (ox -LDL) in the \nhippocampus of mice with craniopharyngioma, which subsequently improved cogn itive \nfunction as measured by faster escape latencies in the Morris Water Maze Test (Wang et al., \n2023). Anti-inflammatory effects have similarly been observed in obese mice where oxytocin \ninfusion was found to reduce inflammation of visceral adipose tissue, reduce peripheral \nmarkers of systemic inflammation such as amyloid A levels, and increase circulating levels of \nadiponectin (an anti -inflammatory marker) (Szeto et al., 2020) . The potential therapeutic \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 22 \nbenefits of the central and peripheral anti -inflammatory effects of exogenous o xytocin in \ncraniopharyngioma need to be investigated in future research.  \nStudies addressing t he direct effects of exogenous oxytocin on behavioural and/or \nmetabolic outcomes in patients  with craniopharyngioma  are sparse, do not adhere to strict \nstandards (e.g., randomization, double blinding, placebo -controlled) and mixed in methods  \n(e.g., the length of treatment, dosage of intranasal oxytocin, and the outcomes measured ) and \nparticipant characteristics, which impedes drawing any firm conclusions. Some promising \nevidence exists from a recent randomised placebo-controlled crossover pilot trial of intranasal \noxytocin  (16 to 24IU, three times per day) over eight weeks in 10 patients aged 10 -35 years \nwith hypothalamic obesity (secondary to a hypothalamo-pituitary tumour) (McCormack et al., \n2023). No improvements in BMI were reported, but benefits for anxiety and impulsive traits \nwere found (McCormack et al., 2023) , suggesting exogenous oxytocin may indeed have \nbenefits for neurobehavioural functioning in conditions affecting the hypothalamic region.  \nRepeated administration (Terenzi & Ingram, 2005)  and long -term use (Du et al., 2017)  of \noxytocin have been suggested to desensitise the oxytocin system (and consequently lead to \nworsened outcomes) (Du et al., 2017), suggesting that dose and administration frequency are \nimportant parameters. It has been shown that intermittent dosing (i.e., every other day) was \nmore effective for attenuation of neural reactivity in subjects with elevated anxiety, compared \nto dosing e very day (Kou et al., 2022) . Studies with larger sample sizes, control condit ions, \ndouble-blinding, and investigating optimal dosage schedules, are therefore required before \nimplementation of exogenous oxytocin or analogues (e.g., Carbetocin; (Roof et al., 2023))  in \nroutine care of craniopharyngioma can be supported.  \n \n4. 1 Limitations  \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 23 \n This systematic review aimed to assess the oxytocin system and its associations with \nneurobehaviour and metabolic parameters in craniopharyngioma. It should however be noted \nthat this review could have been more inclusive of other tumours known to affect the \nhypothalamo-pituitary region such as prolactinoma and pilocytic astrocytoma, as included in  \nthe samples of two other related studies (Daughters et al., 2017; McCormack et al., 2023). To \nmaximise homogeneity and control for the potential confound of add itional clinical features \nassociated with other tumours, only studies assessing patients with craniopharyngioma were \nincluded in the present review. Despite this restriction, high heterogeneity among the studies \nin relation to the sample demographics (e.g. , age distribution) and methods of assessing the \noxytocin system (e.g., sampling type, sampling protocol, quantification assay) was observed. \nAs a result, it was not possible to statistically assess the relative contribution of potential \nconfounding factors such as hypothalamic damage, age, and sex. Moreover, this review only \nincluded five independent samples, with the majority of studies reporting on the same, or a sub-\ngroup of the same, sample; our review is therefore based on the data of a limited number  of \nindependent observations. While the paucity of independent studies is likely contributed to by \nthe rarity of craniopharyngioma (0.5 to 2 cases per million people per year (Nielsen et al., \n2011), further clinical studies with larger sample sizes are needed.   \nAnother important limitation is the broad age range of participants included in this \nreview. A distinct pattern of OXTR expression across the lifespan has been reported with peak \nOXTR expression being identified during childhood; in particular, this increased expression \nwas found in the mediodorsal nucleus of the thalamus, which has been associated with attention \nand memory (Pergola et al., 2018). OXTR expression then decreases during adulthood, until a \nsecond peak in late adulthood (Rokicki et al., 2022). Studies investigating the oxytocin system \nin craniopharyngioma may therefore need to restrict study samples to specific age groups in \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 24 \norder to more sensitively assess any underlying relationships between oxytocin and socio -\ncognitive and behavioural outcomes.   \n \n5 Conclusions  \n Overall, this review suggests that patients  with craniopharyngioma  experience \ndysregulation of the oxytocin system. The presence of hypothalamic damage may constitute a \nkey moderator of oxytocin dysregulation in craniopharyngioma and subsequent affective and \nmetabolic related outcomes. It however remains challenging to draw firm conclusions from the \ncurrent literature, particularly due to the lack of valid and reliable  oxytocin sampling and \nquantification methods , the limited number of studies, and the het erogeneity of the study \ndesigns. Future research implementing appropriate assessments of peripheral oxytocin \nconcentrations are required in order to understand the mechanisms underlying oxytocin \ndysregulation in craniopharyngioma (i.e., is there an oxytocin-synthesising deficiency and/or a \nrelease deficit). Once valid protocols for measurement of oxytocin have been establishe d, \nmulti-centre studies measuring oxytocin concentrations in craniopharyngioma and its \nrelationship with neurobehavioural outcomes, eating behaviours, and metabolic outcomes may \ndelineate which subgroups are at greater risk of presenting oxytocin dysregulation. \nAdditionally, if craniopharyngioma is shown to be associated with oxytocin insufficiency, this \nfinding will lay the foundations for future research into exogenous oxytocin as a therapeutic in \nthis population, once optimal dosing and administration protocols have been established.  \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 25 \nAuthor Contributions: Amy Mann: Conceptualization; Methodology; Writing- original draft; \nWriting – reviewing and editing. Jennifer Kalitsi: Methodology. Khushali Jani: Methodology. \nDaniel Martins: Conceptualization ; Writing- reviewing and editing. Ritika Kapoor: \nConceptualization; Supervision; Writing- reviewing and editing.  Yannis Paloyelis: \nConceptualization; Supervision; Writing- reviewing and editing. \n \nFinancial Disclosure: RRK is supported by MRC grant [MR/V038060/1]. For the purpose of \nopen access, the author has applied a Creative Commons Attribution (CC BY) licence to any \nAuthor Accepted Manuscript version arising. YP and RRK are supported by an unrestricted \nresearch grant from Merck Serono Ltd.  \n \nConflicts of Interest: None. \n \nEthical Considerations: Not applicable.  \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 26 \nReferences \n \nAiniwan, Y., Chen, Y., Mao, C., Peng, J., Chen, S., Wei, S., Qi, S., & Pan, J. 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Prevalence of neurobehavioral, \nsocial, and emotional dysfunction in patients treated for childhood \ncraniopharyngioma: a systematic literature review. PLoS One, 8(11), e76562. \nhttps://doi.org/10.1371/journal.pone.0076562   \nZhou, Z., Zhang, S., & Hu, F. (2021). Endocrine Disorder in Patients With \nCraniopharyngioma. Front Neurol, 12, 737743. \nhttps://doi.org/10.3389/fneur.2021.737743   \n \n \n \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 34 \nFigure 1. PRISMA diagram of search strategy \n \n \n \n \n \n \n \n \n \n  \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nRecords identified through \ndatabase searching \nPubMed (n= 26) \nEMBASE (n= 71) \nPsycInfo (n= 4) \nCochrane (n=3) \n \nTotal (n= 104) \nScreening \n Identification \nAdditional records \nidentified from \nother sources \n(n = 0) \nRecords after duplicates removed \n(n = 67) \nRecords screened \n(n = 67) \nRecords excluded \n(n = 32) \nEligibility \nFull-text articles \nassessed for eligibility \n(n = 35) \nFull-text articles excluded \n (n = 27) \n \nNot in English = 3  \nConference abstract = 8 \nUnable to stratify by tumour = 4 \nReview paper = 8 \nNo outcomes = 3 \nUnidentified duplicate = 1 \n \n \n \nIncluded \nStudies included in \nreview  \n(n = 8) \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 35 \nTable 1. Clinical, demographic, and key outcome data for included studies  \nFirst Author, \nYear \nStudy \nDesign \nSample \nSize \nAge (yrs) Gender Treatment \nStatus \nClinical phenotype Control group \ndemographics \nMeasuremen\nt of oxytocin \nsystem  \nNeurobehavioural \n& Eating measures  \nMetabolic \noutcomes \nAssociations between oxytocin \nsystem and outcomes  \nCook, 2016 Case \nreport  \n1 6 F Post-operative Panhypopituitarism, \nhypothalamic \nobesity, \nhyperphagia, severe \ndamage to pituitary \nstalk and \ninfundibulum \n \nn/a Chronic \nintranasal \noxytocin (2 \nIU twice \ndaily) ~14 \nmonths \nParent opinion   - Improvements in social and \nemotional behaviours, but no \nimprovements in obsessive-\ncompulsive features, food focus or \nhypothalamic obesity.  \n \nHsu, 2018 Case \nreport \n1 13 M Post-operative Panhypopituitarism, \nvisual impairment, \npost-operative \nhypothalamic \nobesity, \nhyperphagia  \nn/a Chronic \nintranasal \noxytocin (6 \nIU/ day) 38 \nweeks, NAL \n(100 mg/day) \nadded at 10 \nweeks.  \nParent opinion BMI SDS Improvements in satiety, decreased \nurgency to eat, overall decreased \nfood preoccupation, but maintained \nsecretive hedonistic food-seeking \noutside of home (palatable foods). \nBMI z-score improved from 1.77 \nSDS (96th percentile) to 0.82 SDS \n(79th percentile). \n \nHoffman, 2017 Cross-\nsectional \n10 Median 27 \n(20.4 – \n41.8) \n5M, 5F Post-operative  \n(3 complete \nresection, 4 \nirradiation) \nGrade 1 HD 4/10 \nGrade 2 HD 6/10 \n \nEndocrinopathies \n(e.g., DI) \nn/a Pre- and post-\nintranasal \noxytocin (24 \nIU) \n  \nGEMEP, MDMQ, \nFMH \nBMI SDS Improved emotion identifications in \npatients with post-operative lesions \nof the anterior hypothalamus \ncompared to those with anterior and \nposterior legions.  \n \nBrandi, 2020* Case-\nControl \n \n13 Mean \n37.15 \n(SD=11.0\n8) \n7M, 6F Post-operative Grade 0 HD 7/13 \nGrade 1 HD 5/13  \n \nEndocrinopathies \n(e.g., GHD, DI) \n23 healthy \ncontrols (11F, \n12M) \nMean=36.83 \nyears (SD=13) \nPre- and post-\nstimulation \nusing bicycle \nergometer \nAQ, ACIPS, RMET - Patients with smaller pre-and post-\nstimulation change in oxytocin had \ngreater autistic traits, reduced levels \nof hedonia for social interactions, \nbut showed no impairments in \nattributing mental states.  \n \nDaubenbüchel, \n2016 ** \nCase-\ncontrol \n \n \n34 Median 20 \n(7-41)  \n15M, \n19F \nPost-operative \n32/34 \nPre-operative \n2/34 \nGrade 0 HD 7/27 \nGrade 1 HD 6/27 \nGrade 2 HD 14/27 \n \nEndocrinopathies \n(e.g., DI) \n73 healthy \ncontrols (41F, \n32M)  \nMedian=39 \nyears (Range: 7-\n63 years) \nPre- and post-\nstimulation \nusing \nstandardised \nbreakfast  \n- BMI SDS Changes in oxytocin pre- and post-\nbreakfast correlated with BMI in \npatients but not in controls; patients \nwith higher BMI showed smaller \nchanges in oxytocin levels.  \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 36 \nDaubenbüchel, \n2019 ** \nCase-\ncontrol \n \n \n34 Median 20 \n(7-41)  \n15M, \n19F \nPost-operative \n32/34 \nPre-operative \n2/34 \nGrade 0 HD 7/27 \nGrade 1 HD 6/27 \nGrade 2 HD 14/27 \n \nEndocrinopathies \n(e.g., DI) \n \n73 healthy \ncontrols (41F, \n32M)  \nMedian=39 \nyears (8-63 \nyears) \nPre- and post-\nstimulation \nusing \nstandardised \nbreakfast \n \nIEG, ESI BMI SDS Smaller changes in pre- and post-\nprandial oxytocin levels were \nassociated with adverse eating \nbehaviour and higher BMI.  \nGebert, 2018* Case-\ncontrol  \n26 39.7 \n(SD=12.1) \n13M, \n13F \nPost-operative Grade 0 HD 7/26 \nGrade 1 HD 8/26 \nGrade 2 HD 7/26 \n4/26 unable to \nclassify \n \nEndocrinopathies \n(e.g., GHD, DI)  \n \n26 healthy age- \nand sex matched \ncontrols \nPre- and post-\nstimulation \nusing bicycle \nergometer \nBDI, STAI, EQ BMI Higher baseline oxytocin was \nassociated with higher trait anxiety \nand blunted oxytocin-release was \nassociated with higher state anxiety, \nbut no associations with empathy \nwere found. \n \nÖzyurt, 2020** Case-\ncontrol \n \n \n31 (29 in \nfinal \nanalysis) \n20 years \n(7-38 \nyears) \n12M, \n17F \nPost-operative Grade 0 HD 7/29 \nGrade 1 HD 5/29 \nGrade 2 HD 17/29  \n34 healthy age- \nand sex-\nmatched \ncontrols \nPre- and post-\nstimulation \nusing \nstandardised \nbreakfast  \nEIVE (using \nGEMEP), TFT, \nMASC, BDI, STAI \n- Lower baseline oxytocin associated \nwith higher state anxiety and \ndepression scores, but no \nassociation between baseline \noxytocin and social-cognitive tasks \n(EIVE, TFT, or MASC) across the \nwhole sample.  \n \n– indicates not assessed; ACIPS, Anticipatory and Consummatory Interpersonal Pleasure Scale; AQ, Autism-Spectrum Quotient; BDI , Beck Depression \nInventory; BMI; body mass index ; BMI SDS, body mass index standard deviation score; DI; diabetes insipidus; EIVE; Emotion Identification in Vocal \nExpressions; ESI, The Inventory for Eating Disorders; EQ, Empathy Quotient; FMH, The German Daily Life Ability Scale (Fertigkeitenskala Mü nster-\nHeidelberg); GEMEP, Geneva Multimodal Emotion Portrayals; GHD, growth hormone deficiency; HD, hypothalamic damage; IEG, The Inventory for Eating \nBehaviour and Weight Problems;  MASC, Movie for Assessment of Social Cognition ; MDMQ, Multidimensional Mood Questionnaire; n/a,  not applicable;  \nNAL, naltrexone; RMET, Reading The Mind in the Eyes Test; STAI, State-Trait Anxiety Inventory; TFT, Trustworthiness of Faces Task. *Same sample; **Same \nsample. Note that not all studies reported detailed data on known endocrine deficiencies within their sample.  \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 37 \nTable 2.  Methods of assessing the endogenous oxytocin system in craniopharyngioma and healthy controls    \nFirst Author, Year Oxytocin \nMeasurement \nSampling Sample \npreparation \nSample Extraction Oxytocin Quantification Basal OT-levels in \npg/mL \nPost-intervention \nOT-levels in pg/mL \nΔOSC (pre- post), \npg/mL \nHoffman, 2017 Basal: \n \nPost- single intranasal  \nadministration of 24 IU \noxytocin  \n(Syntocinon® Spray, \nNovartis, Basel, \nSwitzerland): 3 puffs \nper nostril.  \n \nSaliva: 40 min after \nUrine 90 mins after \n \nSaliva, \nurine  \nNR NR RIA (RIAgnosis, Sinzing, \nGermany) \n \nMedian (Range)  \n \nSaliva = 0.32 (0.25–\n3.60)  \nUrine = 0.90 (0.42–\n1.59) \nPost-Intranasal \nOxytocin:  \n \nMedian (Range) \n \nSaliva = 87.3 (5.21 – \n97.27)  \n \nUrine =  11.13 \n(1.32-105.68) \n-  \nBrandi, 2020* Basal: AM (8:30am \nstart, fasting state, food \n>12 h, water >1 h) \n \nPost-stimulation: \nbicycle ergometer \n \nSaliva \n \n \nCentrifuged at \n3000g for 5min at \n4°C, then stored at \n-20°C. \nYes – all samples \nextracted and assayed \nin same batch at same \ntime to eliminate \ninter-assay variation.  \nRIA (RIAgnosis, Sinzing, \nGermany)  \nMean (SD)  \n \nCP = 1.90 (1.43)  \nHC = 1.24 (1.08)  \np=0.865 \nNR Mean (SD)  \n \nCP = -7.90% (20.6)  \nHC = 21.26% (27.41)  \np<.001 \nDaubenbüchel, \n2016 ** \nBasal: AM  \n \nPost-stimulation: 60 \nmins after standardised \nbreakfast (approx. 10–\n15 kcal/kg body weight; \n8am) \nSaliva Placed \nimmediately on \nice, centrifuged, \nthen stored \nfrozen. A protease \ninhibitor was not \nused in \ncentrifugation. \nYes – all samples \nextracted.  \n \nEIA \n \n \n \n \n \nMedian (Range)  \n \nCP = 3.61 (0.07 – \n12.45)  \nHC = 3.35 (0.06 – \n15.33) \nn.s. \nMedian (Range)  \n \nCP = 3.18 (0.07–\n11.24) \nHC = 2.78 (0.06–\n22.68) \nn.s. \nMedian (Range)  \n \nCP = −0.93 (−6.03‐\n8.2) \nHC = −0.34 (−11.6‐\n13.99) \nn.s \n \n. \nDaubenbüchel, \n2019 ** \nBasal: AM  \n \nPost-stimulation: 60 \nmins after standardised \nbreakfast (approx. 10–\n15 kcal/kg body weight; \n8am) \nSaliva Placed \nimmediately on \nice, centrifuged, \nthen stored \nfrozen. A protease \ninhibitor was not \nused in \ncentrifugation.   \nYes – all samples \nextracted.  \n \n \nEIA \n \n \nMedian (Range) \n \nCP = 3.6 (0.1‐12.5) \nHC = 3.4 (0.1‐15.3) \nMedian (Range) \n \nCP = 3.2 (0.1‐11.2) \nHC = 2.8 (0.1‐22.7) \n \n \nMedian (Range) \n  \nCP = −0.9 (−6.0‐8.2) \nHC = −0.3 (−11.6‐\n14.0) \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint \n\n 38 \nGebert, 2018* Basal: AM (8:30am \nstart, fasting state, food \n>12 h, water >1 h) \n \nPost-stimulation: \nbicycle ergometer  \nSaliva \n \n \nCentrifuged at \n3000g for 5min at \n4°C, then stored at \n-20°C. \nYes – all samples \nextracted and assayed \nin same batch at same \ntime to eliminate \ninter-assay variation.  \nRIA (RIAgnosis, Sinzing, \nGermany)  \nMean (SD)  \n \nCP = 1.46 (1.20)  \nHC = 1.33 (1.13) \np=0.731 \nMean (SD)  \n \nCP = 1.26 (0.87)  \nHC = 1.66 (1.76) \np= 0.391 \nMean \n \nCP = -13.7% \nHC = 24.8% \n \n(GLM time x group)  \np=0.005 \n \nÖzyurt, 2020** Basal Saliva Placed \nimmediately on \nice, centrifuged, \nthen stored frozen \nuntil analysis. A \nprotease inhibitor \nwas not used in \ncentrifugation.  \nYes – all samples \nextracted.  \n \nEIA \n \n \nMedian (IQR)  \n \nCP = 3.3 (3.6) \nHC = 4.42 (7.6) \np=0.329 \n- - \n– indicates, not assessed; EIA, enzyme immunoassay; CP, craniopharyngioma; HC, healthy control; IQR, interquartile range; NR, not reported; n.s., not \nsignificant (no p-value reported by authors); RIA, radioimmunoassay; SD, standard deviation. *Same sample; **Same sample.  \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted August 1, 2024. ; https://doi.org/10.1101/2024.07.31.24311260doi: medRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}