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Open access

I M A A van Roessel, J P de Graaf, N R Biermasz, E Charmandari, and H M van Santen


Hypothalamic dysfunction is a rare condition and can be encountered in patients who have been diagnosed or treated for a suprasellar brain tumor. Due to its rarity, the signs and symptoms of hypothalamic dysfunction may be difficult to recognize, leading to delayed diagnosis of the suprasellar brain tumor or to difficulties in finding the health-care expertise for hypothalamic dysfunction after tumor treatment. To improve the care and outcome of patients with acquired hypothalamic dysfunction, professionals are required to understand the patient’s needs.


A worldwide online survey was distributed from April 2022 to October 2022 to patients with childhood-onset hypothalamic dysfunction (as reported by the patient) following a brain tumor.


Patients were notified about the survey through patient advocacy groups, the SIOPe craniopharyngioma working group and the Endo-ERN platform.


In total, 353 patients with hypothalamic dysfunction following craniopharyngioma (82.2%), low-grade glioma (3.1%) or a pituitary tumor (8.2%) or caregivers responded to the survey. Sixty-two percent had panhypopituitarism. Obesity (50.7%) and fatigue (48.2%) were considered the most important health problems. Unmet needs were reported for help with diet, exercise and psychosocial issues. Patients’ suggestions for future research include new treatments for hypothalamic obesity and alternative ways for hormone administration.


According to the patient’s perspective, care for acquired hypothalamic dysfunction can be improved if delivered by experts with a holistic view of the patient in a multidisciplinary setting with a focus on quality of life. Future care and research on hypothalamic dysfunction must integrate the patients’ unmet needs.

Significance statement

Patients with hypothalamic dysfunction may experience a variety of symptoms, which are not always adequately recognized or addressed. In previous papers, the perspective of caregivers of children with craniopharyngioma has been reported (Klages et al. 2022, Craven et al. 2022). Now we address the patients’ perspective on acquired hypothalamic dysfunction using an Endo-ERN global survey. According to the patients’ perspective, care can be improved, with needs for improvement in the domains of obesity, fatigue and lifestyle. Research may focus on ways to improve hypothalamic obesity and alternative ways for hormone administration. Ideally, care should be delivered by doctors who have a holistic view of the patient in a multidisciplinary expert team. The results of this study can be used to formulate best practices for clinical care and to design future research proposals.

Open access

Lukas Plachy, Lenka Petruzelkova, Petra Dusatkova, Klara Maratova, Dana Zemkova, Lenka Elblova, Vit Neuman, Stanislava Kolouskova, Barbora Obermannova, Marta Snajderova, Zdenek Sumnik, Jan Lebl, and Stepanka Pruhova

Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤−2 SD in child and his/her shorter parent); secondary short stature and Turner/Prader–Willi syndrome were excluded criteria. Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by American College of Medical Genetics and Genomics (ACMG) guidelines. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 (81%) carried a causative genetic variant affecting the growth plate, 4 (11%) a variant affecting GH–insulin-like growth factor 1 (IGF1) axis and 3 (8%) a variant in miscellaneous genes. Lower shorter parent’s height (P = 0.015) and less delayed bone age (BA) before GH treatment (P = 0.026) predicted monogenic FSS. In children with BA delayed less than 0.4 years and with shorter parent’s heights ≤−2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, in FSS children treated with GH, a monogenic etiology is frequent, and gene variants affecting the growth plate are the most common. Shorter parent’s height and BA are clinical predictors of monogenic FSS.

Open access

Yijun Tang, Yao Chen, Jiayi Wang, Qianwen Zhang, Yirou Wang, Yufei Xu, Xin Li, Jian Wang, and Xiumin Wang

Diagnosis and management strategy of disorders of sex development (DSD) are difficult and various due to heterogeneous phenotype and genotype. Under widespread use of genomic sequencing technologies, multiple genes and mechanisms have been identified and proposed as genetic causes of 46,XY DSD. In this study, 178 46,XY DSD patients were enrolled and underwent gene sequencing (either whole-exome sequencing or targeted panel gene sequencing). Detailed clinical phenotype and genotype information were summarized which showed that the most common clinical manifestations were micropenis (56.74%, 101/178), cryptorchidism (34.27%, 61/178), and hypospadias (17.42%, 31/178). Androgen synthesis/action disorders and idiopathic hypogonadotropic hypogonadism were the most frequent clinical diagnoses, accounting, respectively, for 40.90 and 21.59%. From all next-generation sequencing results, 103 candidate variants distributed across 32 genes were identified in 88 patients. The overall molecular detection rate was 49.44% (88/178), including 35.96% (64/178) pathogenic/likely pathogenic variants and 13.48% (24/178) variants of uncertain significance. Of all, 19.42% (20/103) variants were first reported in 46,XY DSD patients. Mutation c.680G>A (p.R227Q) on SRD5A2 (steroid 5-alpha-reductase 2) (36.67%, 11/30) was a hotspot mutation in the Chinese population. Novel candidate genes related to DSD (GHR (growth hormone receptor) and PHIP (pleckstrin homology domain-interacting protein)) were identified. Overall, this was a large cohort of 46,XY DSD patients with a common clinical classification and phenotype spectrum of Chinese patients. Targeted gene panel sequencing covered most of the genes contributing to DSD, whereas whole-exome sequencing detected more candidate genes.

Open access

Yee-Ming M Cheung, Rudolf Hoermann, Karen Van, Damian Wu, Jenny Healy, Bella Halim, Manjri Raval, Maria McGill, Ali Al-Fiadh, Michael Chao, Shane White, Belinda Yeo, Jeffrey D Zajac, and Mathis Grossmann


We previously demonstrated that 12 months of aromatase inhibitor (AI) treatment was not associated with a difference in body composition or other markers of cardiometabolic health when compared to controls. Here we report on the pre-planned extension of the study. The pre-specified primary hypothesis was that AI therapy for 24 months would lead to increased visceral adipose tissue (VAT) area when compared to controls.


We completed a 12-month extension to our prospective 12-month cohort study of 52 women commencing AI treatment (median age 64.5 years) and 52 women with breast pathology not requiring endocrine therapy (63.5 years). Our primary outcome of interest was VAT area. Secondary and exploratory outcomes included other measures of body composition, hepatic steatosis, measures of atherosclerosis and vascular reactivity. Using mixed models and the addition of a fourth time point, we increased the number of study observations by 79 and were able to rigorously determine the treatment effect.


Among study completers (AI = 39, controls = 40), VAT area was comparable between groups over 24 months, the mean-adjusted difference was −1.54 cm2 (95% CI: −14.9; 11.9, P = 0.79). Both groups demonstrated parallel and continuous increases in VAT area over the observation period that did not diverge or change between groups. No statistically significant difference in our secondary and exploratory outcomes was observed between groups.


While these findings provide reassurance that short-to-medium-term exposure to AI therapy is not associated with metabolically adverse changes when compared to controls, risk evolution should be less focussed on the AI-associated effect and more on the general development of cardiovascular risk over time.

Open access

Bjarke R Medici, Birte Nygaard, Jeppe L la Cour, Martin Krakauer, Andreas Brønden, Mette P Sonne, Jens J Holst, Jens F Rehfeld, Tina Vilsbøll, Jens Faber, and Filip K Knop


In individuals with hypothyroidism and overweight, levothyroxine substitution therapy is often expected to cause weight loss due to its effect on resting energy expenditure. However, despite levothyroxine-induced enhancement of resting energy expenditure, fat mass loss is rarely seen after levothyroxine substitution therapy. The mechanism behind this conundrum is unknown.


The aim of the study was to assess the effect of levothyroxine therapy on hunger sensations and ad libitum food intake in individuals with hypothyroidism.

Design and setting

Prospective cohort study of 18 newly diagnosed hypothyroid women (thyroid-stimulating hormone (TSH) >10 mU/L). Participants were investigated at diagnosis, after normalization of TSH (<4.0 mU/L), and after 6 months of successful treatment. Eighteen age and body mass index-matched healthy controls were also included.


Hypothyroid individuals were treated with levothyroxine according to European Thyroid Association guidelines.

Main outcomes

Changes in hunger sensation were assessed using visual analog scales (cm) before and during a standardized mixed meal test, and food intake was measured during a subsequent ad libitum meal (g).


After 6 months of levothyroxine therapy, mean resting energy expenditure was increased by 144 kcal/day (10%) (P < 0.001). Weight loss was comprised of 0.8 kg fat-free mass while fat mass remained unchanged. Fasting hunger sensation increased from a mean of 4.5 (s.d. 2.2) cm to 5.5 (s.d. 2.2) cm (P = 0.047). The numerical increase in ad libitum meal intake did not reach statistical significance.


Our data suggest that levothyroxine-induced hunger may be a culprit in the lack of fat mass loss from levothyroxine therapy.

Open access

Molly L Tanenbaum and Persis V Commissariat

Diabetes technology continues to advance, with more individuals with type 1 diabetes (T1D) adopting insulin pumps, continuous glucose monitoring (CGM), and automated insulin delivery (AID) systems that integrate real-time glucose data with an algorithm to assist with insulin dosing decisions. These technologies are linked with benefits to glycemic outcomes (e.g. increased time in target range), diabetes management behaviors, and quality of life. However, current devices and systems are not without barriers and hassles for the user. The intent of this review is to describe the personal challenges and reactions that users experience when interacting with current diabetes technologies, which can affect their acceptance and motivation to engage with their devices. This review will discuss user experiences and strategies to address three main areas: (i) the emotional burden of utilizing a wearable device; (ii) the perceived and experienced negative social consequences of device use; and (iii) the practical challenges of wearing devices.

Open access

Alexandra Kiess, Jessica Green, Anja Willenberg, Uta Ceglarek, Ingo Dähnert, Wieland Kiess, and Mandy Vogel

Background and objectives

As part of the LIFE Child study, we previously described the associations between N-terminal-pro-hormone brain natriuretic peptide (NT-proBNP) and hs-troponin T (hs-TnT) levels and an individual’s sex, age and pubertal status, as well as with body mass index (BMI) and serum lipid levels. For NT-proBNP, we found inverse associations with advancing puberty, increasing BMI and serum lipid levels. These findings led us to further question the putative influences of the developing individual’s metabolic and growth status as represented by levels of insulin-like growth factor-1 (IGF-1) and IGF-1-binding protein-3 (IGF-BP3) as well as hemoglobin A1c (HbA1c) and Cystatin C (CysC).

Material and methods

Serum values, medical history and anthropometric data provided by 2522 children aged 0.25–18 years were collected and analyzed as per study protocol.


A strong negative association between NT-proBNP values and IGF-1, IGF-BP3 and HbA1c levels was identified. For IGF-BP3, this interaction was modulated by sex and age, for HbA1c only by age. For hs-TnT, a positive association was found with IGF-BP3, IGF-1 and CysC. The association between hs-TnT and IGF-1 was sex dependent. The association between CysC and hs-TnT was stronger in girls, but the interaction with age was only seen in boys. Between hs-TnT and HbA1c, the association was significantly negative and modulated by age.


Based on our large pediatric cohort, we could identify age- and sex-dependent interactions between the metabolic status represented by IGF-1, IGF-BP3, CysC and HbA1c levels and the cardiac markers NT-proBNP and hs-TnT.

Open access

Nelma Veronica Marques, Luiz Eduardo Armondi Wildemberg, and Monica R Gadelha

Pasireotide long-acting release is effective in achieving biochemical control and reducing tumour volume in patients with acromegaly inadequately controlled by first-line therapy. As part of a long-term, real-world study at our centre, 20 of 50 patients receiving pasireotide benefited from a reduction in pasireotide dose. Pasireotide reduced insulin-like growth factor 1 (IGF1) levels to below the upper limit of the normal range, with some patients responding within 1−3 months of treatment (n = 11) and others after ≥4 months (n = 9). Following pasireotide dose reduction, IGF1 levels showed a mild increase but remained within the normal range after a median of 39 months in the early responders and 17 months in the late responders. Glucose and glycated haemoglobin levels decreased following dose reduction. Identifying patients who may benefit from a reduction in pasireotide dose warrants further research as it may improve the management of pasireotide-associated hyperglycaemia in susceptible patients.

Significance statement

Patients with acromegaly often need medical therapy for extended periods of time, and pasireotide is an effective, long-term treatment option. However, pasireotide may increase blood glucose levels in some patients, such as those with pre-existing diabetes. In this single-centre study, we show that following dose reduction of pasireotide over time, patients with acromegaly maintained their biochemical response (IGF1 < ULN) and had improved glycaemic control. As such, dose reductions may be an effective, personalised treatment approach for managing some patients receiving long-term pasireotide therapy and could allow patients to achieve early and long-term biochemical control while minimising adverse drug effects.

Open access

Yang Yu, Hairong Hao, Linghui Kong, Jie Zhang, Feng Bai, Fei Guo, Pan Wei, Rui Chen, and Wen Hu

Previous studies have shown that the elevated levels of circulating branched-chain amino acids (BCAAs) are associated with the development of insulin resistance and its complications, including obesity, type 2 diabetes, cardiovascular disease and some cancers. However, animal models that can mimic the metabolic state of chronically elevated BCAAs in humans are rare. Therefore, the aim of this study was to establish the above animal model and analyse the metabolic changes associated with high BCAA levels. Sixteen 8-week-old Sprague–Dawley (SD) rats were randomly divided into two groups and given either a high fructose diet or a normal diet. BCAA levels as well as blood glucose and lipid levels were measured at different time points of feeding. The mRNA expression levels of two key enzymes of BCAA catabolism, ACAD (acyl-CoA dehydrogenase) and BCKDH (branched-chain α-keto acid dehydrogenase), were measured by qPCR, and the protein expression levels of these two enzymes were analysed by immunohistochemistry. Finally, the metabolite expression differences between the two groups were analysed by Q300 metabolomics technology. Our study confirms that defects in the catabolic pathways of BCAAs lead to increased levels of circulating BCAAs, resulting in disorders of glucose and lipid metabolism characterized by insulin resistance by affecting metabolic pathways associated with amino acids and bile acids.

Open access

Paweł Komarnicki, Paweł Gut, Jan Musiałkiewicz, Maja Cieślewicz, Adam Maciejewski, Prachi Patel, George Mastorakos, and Marek Ruchała


Neuroendocrine tumors (NETs) are rare neoplasms that occur in various locations throughout the body. Despite their usually benign character, they might manifest with distant metastases. N-terminal prohormone of brain natriuretic peptide (NT-proBNP) has previously been described as a useful biomarker in diagnosing carcinoid heart disease (CHD), a common advanced NETs manifestation. We observed plasma concentrations of NT-proBNP in metastatic midgut NETs over a 4-year period.


We aimed to explore NT-proBNP concentrations in states of varying levels of cell proliferation and disease status. Our goal was to investigate NT-proBNP’s role in predicting disease progression in relation to previous research and up-to-date scientific guidelines.

Patients and methods

We performed a retrospective multivariate analysis of NT-proBNP concentrations in 41 midgut NETs patients treated with somatostatin analogs, all with liver metastases. NT-proBNP concentrations were measured in every patient across 16 evenly distanced time points over a 48-month period and were compared to variables such as sex, age, grading, Ki-67, primary tumor location, and CT findings.


NT-proBNP concentrations correlated positively with higher liver tumor burden, higher grading, high Ki-67 levels, and with progressive disease in CT. There were no differences in NT-proBNP levels with regard to primary location (ileum vs jejunum), sex, and age.


We conclude that NT-proBNP is a useful analyte for monitoring NETs progression, due to its increased concentration in scenarios implying increased cellular proliferation. These long-term follow-up results align with previous findings and suggest an additional role for NT-proBNP in diagnostic algorithms, beyond a CHD biomarker.