Expert meeting epidemiology and management of acquired hypothalamic obesity

Authors: Hermann L. Müller, Ute K. Bartels, Christian Denzer, Ulrich Dischinger, Jörg Flitsch, Johannes Gojo, Annette Richter-Unruh, Katrin Scheinemann, Katharina Schilbach, Carsten Friedrich

Abstract

Acquired hypothalamic obesity (aHO) is a disease characterized by rapid, clinically significant, and persistent weight gain resulting from damage to hypothalamic structures. aHO is associated with substantial morbidity, increased mortality, and marked impairment in quality of life. Etiologies include craniopharyngioma and other space-occupying lesions of the sellar/parasellar region, neurosurgical procedures, cranial irradiation, and traumatic brain injury. A multidisciplinary panel comprising ten specialists in neuroendocrinology, neurooncology, and neurosurgery from Germany, Austria, and Switzerland convened in Frankfurt am Main, Germany, on November 10, 2025, to discuss contemporary challenges and advances in this field. aHO should be conceptualized and treated within the broader clinical entity of hypothalamic syndrome, a complex disorder involving multiple neuroendocrine deficiencies, disturbances of circadian regulation, impaired control of hunger, satiety, and thirst, altered thermoregulation, and a range of cognitive, sleep-related, and psychosocial dysfunctions. Long-term outcomes for affected individuals are frequently unfavorable, largely due to increased risks of metabolic syndrome, cardiovascular disease, profound reductions in health-related quality of life, and elevated rates of premature mortality. The management of hypothalamic syndrome remains particularly challenging. Pharmacological strategies, including dextroamphetamine and glucagon-like peptide-1 receptor agonists, have demonstrated potential benefits for weight and hyperphagia-related outcomes. Recently, preliminary findings from a prospective, randomized, placebo-controlled clinical trial (TRANSCEND) provided encouraging evidence for the efficacy of setmelanotide, a melanocortin-4 receptor agonist. This perspectives report reviews clinical advances in epidemiology, diagnostics, treatment, and follow-up of patients with aHO and outlines key directions for future research aimed at improving outcomes in this vulnerable population.

Introduction

A scientific workshop addressing the disease of acquired hypothalamic obesity (aHO) was held in Frankfurt am Main, Germany, on November 10, 2025. The meeting convened 10 experts in endocrinology, pediatric endocrinology, pediatric oncology, pediatric neurooncology, and neurosurgery. The objectives 1) to discuss novel insights on epidemiology of aHO, 2) to derive preliminary, practice-oriented recommendations for diagnosis and management across endocrine and non-endocrine sequelae; 3) to identify priorities, unmet needs and requirements for future research. There was no formal consensus process (no delphi or voting, no grading of recommendations).

aHO is a consequence of hypothalamic damage (1), and is characterized by rapid and severe weight gain that is typically resistant to lifestyle-based interventions (2–4). Conventional lifestyle interventions applied to date have generally resulted in only transient reductions in BMI, suggesting that durable weight control is unlikely to be achieved without continuous support and structured behavioral coaching (5). Achieving long-term treatment success requires a stable and supportive home environment, particularly in light of the complex interaction between persistent hyperphagia, pituitary hormone deficiencies, and behavioral disturbances commonly observed in patients with aHO (6).

aHO most frequently develops following diagnosis and surgical treatment of craniopharyngioma (7, 8) or other supra- and parasellar tumors. However, aHO may also arise after traumatic brain injury (TBI) or hypothalamic microinjury (9). aHO represents a core manifestation of hypothalamic syndrome, which is defined by dysregulation of the autonomic nervous system (10), hyperinsulinemia, reduced sympathetic tone (11), leptin resistance, altered energy expenditure, and pituitary dysfunction. These abnormalities are commonly accompanied by sleep–wake disturbances (12, 13), neurological and visual impairments (14), and reduced physical activity (15, 16) (Figure 1). Hypothalamic involvement in craniopharyngioma is a key determinant of long-term outcomes, particularly regarding weight development, quality of life (17) and overall survival (18, 19).

Pharmacological treatment approaches, including central nervous system stimulants (e.g., dextroamphetamine) (20, 21) have shown potential benefits for weight and hyperphagia-related outcomes. Glucagon-like peptide-1 receptor (GLP-1R) agonists – as monotherapy or in combination with other agents - seem also promising in the treatment of aHO by bypassing damaged hypothalamic pathways and reducing appetite via preserved brainstem and peripheral satiety signaling (22). Emerging evidence suggests that GLP-1R agonists modulate the mesocorticolimbic reward circuitry by acting on receptors within the ventral tegmental area (VTA) and the nucleus accumbens (NAc), where they attenuate dopaminergic signaling and reduce the reinforcing value of palatable food (23).

A small study of 26 adults with aHO reported weight loss in all but one participant after semaglutide treatment, with a mean reduction of -13.4 kg and a BMI decrease of -4.4 kg/m² at one year (24). Recent case reports in patients with aHO following craniopharyngioma indicate that semaglutide is a safe therapy associated with sustained long-term improvements in eating behavior, weight regulation, metabolic parameters (25), and quality of life, persisting after weight stabilization (26). Consistent with these observations, a systematic review of 10 studies concluded that GLP-1 receptor agonists may represent a safe and effective strategy for weight management in aHO (27). Nevertheless, their efficacy in adults remains controversial. Some studies reported enhanced glycemic control and reduced food intake (27, 28), whereas Shoemaker et al. (28) described a paradoxical decline in total energy expenditure following weekly exenatide administration, disproportionate to weight loss and unrelated to physical activity or leptin changes. In contrast, Perez et al. (29) found greater adiposity reduction at the same exenatide dose in patients with more extensive hypothalamic injury. Overall, preliminary data suggest that semaglutide and exenatide may offer therapeutic benefit for weight management in aHO (22).

Recently, preliminary findings from a prospective, randomized, placebo-controlled clinical trial (TRANSCEND, NCT05774756) enrolling 120 individuals with aHO provided encouraging evidence for the efficacy of setmelanotide, a melanocortin-4 receptor (MC4R) agonist (30). After 52 weeks of treatment, participants receiving setmelanotide (n = 81) achieved a mean reduction in body mass index (BMI) of 16.5% (p <0.0001), whereas those assigned to placebo (n = 39) experienced a mean BMI increase of 3.3%. Notably, 80% of individuals in the active treatment group attained a BMI reduction of at least 5% by week 52. These results indicate that setmelanotide may constitute a promising therapeutic option for the treatment of aHO (31). Setmlanotide acts on the MC4 receptors in the hypothalamus to re-establish the impaired pathway and activate satiety and leads to weight loss. Given that hypothalamic injury may compromise hypothalamic integrity in aHO, the mechanism by which such treatment could exert benefit warrants careful consideration. Importantly, in many cases of aHO, hypothalamic damage is partial rather than complete, resulting in residual hypothalamic function. Under these circumstances, setmelanotide may activate remaining hypothalamic neurons and partially restore satiety signaling. Siljee et al. could show that the expression of MC4R mRNA in the human hypothalamus is widespread and in close approximation to endogenous MC4R binding partners Agouti-related peptide (AgRP) and alpha-melanocyte-stimulating hormone (α-MSH). Most intense MC4R mRNA expression was present in the paraventricular nucleus (PVN), the supraoptic nucleus (SON), and the nucleus basalis of Meynert. Most MC4R-positive cells in the SON also expressed arginine vasopressin/oxytocin (32). Moreover, MC4R expression has been demonstrated not only within the hypothalamus but also in extra-hypothalamic regions, including the cerebral cortex and spinal cord, suggesting potential sites of action beyond the hypothalamus itself.

Epidemiology and socioeconomic burden

The epidemiology and socioeconomic burden of aHO were evaluated using German statutory health insurance claims data (33, 34). The analysis was based on 5.42 million insured individuals with at least 24 months of continuous data between 2010 and 2020. After applying wash-in periods to exclude individuals with prior tumor-related brain surgery, radiotherapy, obesity, or arginine vasopressin deficiency (AVP-D), a cleaned cohort of 3,976 individuals remained. The index event was defined as hospitalization for a tumor associated with aHO combined with tumor-related neurosurgery or radiotherapy. aHO was identified when incident obesity occurred at the index hospitalization or within 12 months thereafter and was validated by the presence of AVP-D and/or desmopressin treatment. Using these criteria, 37 patients fulfilled the claims-based definition of aHO (Figure 2A). This corresponds to an estimated annual incidence of 0.07 – 0.17 per 100,000 individuals, or approximately 80 new cases per year in Germany, with a prevalence of 1,262 cases in 2019. Age distribution included 203 patients <20 years, 784 patients aged 20–64 years, and 275 patients >65 years of age. Benign sellar tumors, predominantly craniopharyngioma, accounted for approximately half of all cases. Claims-based case definitions may misclassify obesity onset and cannot capture key clinical features such as hyperphagia, resting energy expenditure, or MRI-based hypothalamic involvement, likely leading to a certain under-ascertainment.

Healthcare resource utilization analysis demonstrated that patients with aHO required substantially more healthcare services than BMI-matched controls (35). In the first year following the index event, patients with aHO experienced an average of 4.6 additional hospitalizations, with excess hospital use persisting into the second year. Index-quarter costs were markedly higher in patients with aHO (€25,717) compared with controls (€886), largely driven by tumor-related hospitalizations. Excess annual costs relative to controls were €19,935 in the first year and €10,745 in the second year after the index event, with long-term endocrine replacement therapy constituting a major cost driver.

In a comprehensive aHO cohort (data collected between 2010 and 2022) (36), the role of TBI and hypothalamic microinjury was further analyzed (Figure 2B). Among more than 6.2 million insured individuals, 59,382 incident TBIs were identified, of whom 11% developed obesity within one year. None of the TBI patients presented with intracranial space-occupying lesions. Only a small subset (11 patients) developed confirmed aHO with documented AVP-D or pituitary dysfunction, none of which were tumor-related. Among 7,267 individuals with unspecified hypothalamic microinjury, 10% developed obesity within one year, and 4.6% exhibited incident AVP-D. After excluding tumor-related cases, 20 patients remained, the majority of whom received neuroendocrine treatment around the time of obesity onset.

Overall, an estimated 2,500 cases of aHO were present in 2019/2020. Sixty percent were tumor-related, 22% were associated with unspecified microinjury, and 18% with TBI. Tumor-related aHO predominantly affected females (59%), whereas TBI-associated aHO was more common in males (73%). Participants of the workshop noted that these estimates – calculated with methods, designed to avoid false positive results – likely underestimate the true prevalence of aHO, particularly in adults. In addition, rare conditions such as ROHHAD syndrome (Rapid-onset obesity with hypothalamic dysfunction) may also remain underdiagnosed as cause of aHO (37, 38).

Diagnostics and management

Reduced growth velocity and/or headache and visual disturbances should be regarded as an early warning sign of craniopharyngioma in childhood (39, 40). Despite its clinical severity, aHO remains under-recognized and difficult to diagnose due to the absence of standardized biomarkers, diagnostic tests, and comprehensive clinical guidelines (41, 42). Recently proposed international diagnostic guidelines for aHO require fulfillment of three criteria (43):

• A documented traumatic event or neurooncologic disease (causing hypothalamic damage visible on magnetic resonance imaging (MRI));
• Clinically relevant (≥5% BMI increase in adult; ≥+1.0 SDS BMI increase in pediatric patients), rapid and persistent (for 24 months after surgery) BMI increase beginning within 12 months after the index event, under clinical and anthropometric monitoring at 3 months intervals; and
• Attainment of age- and ethnicity-adjusted overweight or obesity thresholds (BMI SDS ≥+2.0 SD in pediatric patients; BMI ≥25 kg/m^2^ or BMI ≥30 kg/m^2^ in adult patients, depending on racial and ethnic characteristics).

In parallel, a seven-domain scoring system for hypothalamic syndrome has been introduced (10, 44), encompassing BMI changes, hyper-/hypophagia, behavioral disturbances, sleep abnormalities, temperature dysregulation, pituitary deficits, and neuroimaging findings. However, incomplete documentation of sleep, behavioral, and thermoregulatory features in routine care highlights significant gaps in current clinical practice. Earlier diagnosis may be facilitated by standardized post-surgical follow-up protocols that include regular anthropometric assessments, temperature monitoring, and targeted questionnaires addressing eating behavior, fatigue, and sleep disturbances. Rehabilitation programs, particularly in pediatric populations, may provide a structured setting for standardized assessment and intervention. However, long-term effects of rehabilitation programs on weight development are limited (45). A planned research initiative at the University of Oldenburg and the University Hospital Würzburg will evaluate real-world outcomes of different therapeutic strategies for aHO. Ultimately, evidence-based diagnostic tools and criteria are needed to support future guideline development.

aHO - a distinct disease entity

Similar to central hypothyroidism, growth hormone deficiency, central hypogonadism, and central hypocortisolism, and comparable to non-endocrine chronic diseases such as chronic renal failure, aHO should be recognized as a distinct clinical disorder resulting from hypothalamic dysfunction, with consistent clinical features and specific therapeutic needs. Formal recognition as a distinct disease would facilitate standardized coding, access to multidisciplinary care pathways, and eligibility for clinical trials and emerging targeted therapies. Regardless of etiology, participants agreed that treatment goals include improvement of eating behavior, increasing energy expenditure to achieve weight stabilization or loss, improving body composition, reducing cardiovascular risk, optimizing neuroendocrine replacement therapy, improving circadian rhythm disturbances, and enhancing psychosocial functioning. Collectively, these measures are expected to result in meaningful improvements in quality of life.

Surgical strategy and expertise

Surgical approach, institutional case volume, and neuro-oncologic expertise have been identified as key prognostic factors for the development of aHO following craniopharyngioma treatment (46). Iatrogenic hypothalamic injury is associated with increased risk of aHO and reduced quality of life (17). Surgical strategy is strongly influenced by tumor location, patient age, and surgeon experience. Larger centers more frequently employ hypothalamus-sparing techniques, and patient load reflecting center size and expertise has emerged as an independent prognostic factor for aHO risk (47–49). Participants anticipated that mandatory certification of neurosurgical centers and further centralization of craniopharyngioma care over the next decade is expected to be associated with improved patient outcomes. Experience from the Netherlands suggests that centralized treatment in specialized centers is associated with improved outcomes for patients with craniopharyngioma (50).

Bariatric interventions

Bariatric surgical interventions have demonstrated substantial efficacy and acceptable safety profiles in facilitating weight reduction among patients with craniopharyngioma. In an individual patient–level meta-analysis comprising 21 CP cases, Bretault et al. (51) reported significant postoperative weight loss at both 6 and 12 months, with percentage total weight loss of −0.9% and −15.1%, respectively. The greatest degree of weight reduction was observed in patients undergoing Roux-en-Y gastric bypass procedures. In pediatric cohorts, the application of irreversible bariatric techniques, including gastric bypass, remains ethically and legally controversial and should preferably be restricted to controlled clinical trial settings (52). According to the Endocrine Society’s Clinical Practice Guideline for the management of pediatric obesity, bariatric surgery should be considered only in adolescents with severe obesity who have reached advanced pubertal development and near-final or final adult stature, and who have demonstrated sustained adherence to structured dietary and physical activity interventions (53).

Patient cases

Setmelanotide, a MC4R agonist, represents a mechanism-based therapeutic approach targeting satiety pathways downstream of leptin signaling (54). Phase 3 data from the TRANSCEND study (7) along with clinical and real-world case reports from several German centers, illustrated the potential efficacy of setmelanotide in aHO. Treatment effects were primarily described as restoration of physiological satiety. Skin hyperpigmentation, the most common adverse effect, occurred in most patients but was generally well tolerated. Participants emphasized the need for structured safety monitoring and standardized patient-reported outcomes on hunger/satiety and quality of life in real-world use. Discussion suggested that additional patient subgroups with undetected MC4R-related dysfunction may exist, including individuals with TBI, hypothalamic microinjury, or rare inflammatory events such as ROHHAD syndrome (10), who develop rapid weight gain and panhypopituitarism in the absence of tumor surgery (36).

Results and key clinical conclusions

Craniopharyngioma: Hypothalamus-sparing surgical strategies should be prioritized to prevent aHO. Long-term outcomes are largely determined by late sequelae, particularly aHO; therefore, management should be conducted within experienced multidisciplinary teams. There is a critical need for policy-level initiatives aimed at defining and implementing quality criteria for multidisciplinary craniopharyngioma management (e.g., minimum case volume, multidisciplinary tumor boards with neuroendocrinology, standardized postoperative follow-up including hypothalamic syndrome screening). Future investigations should extend beyond radiological endpoints to rigorously assess the impact of evolving surgical and medical therapies on cognitive function, cardiometabolic morbidity, hypothalamic morbidity, and overall patient well-being in the context of national or international registries and trials.

Other brain A range of histological tumor entities, including low-grade glioma and germ-cell tumors, can occur in the sellar region and therefore require different surgical and oncological strategies. Despite this heterogeneity, hypothalamic damage has been reported and may still be underdiagnosed in this patient group. In analogy to ongoing efforts in craniopharyngioma, a structured evaluation of surgical, radiotherapeutic, and oncological approaches—together with a systematic assessment of aHO and the broader hypothalamic syndrome—is essential to better quantify disease burden and to inform future therapeutic strategies in this population.

aHO/Hypothalamic Recognizing aHO as a distinct clinical entity, defined by functional hypothalamic disruption rather than solely by etiology, is essential for advancing research, improving diagnosis and care, and expanding access to emerging therapies. There is a critical need for further research into targeted therapies addressing aHO and its underlying neuroendocrine and behavioral mechanisms (8). Future studies should systematically include patients with non-tumor etiologies, such as TBI, SOD, ROHHAD, and other midline or intracranial pathologies. Standardized diagnostic criteria and outcome measures for aHO (including standardized hunger/satiety metrics, sleep/circadian measures, resting energy expenditure (REE)/physical activity assessments, and health-related quality of life instruments) are essential to enable meaningful comparisons across studies and clinical trials. Determination of the most effective timing (early vs. delayed initiation) and integration of novel targeted therapies with surgery and radiotherapy is warranted.