Water movement across cell membranes through aquaporin water channels creates osmotic equilibrium between extracellular and intracellular fluid compartments. Plasma osmolality is tightly regulated by the kidneys and brain through the process of osmoregulation. The antidiuretic hormone, arginine vasopressin (AVP), is normally released from the posterior pituitary in response to increased osmolality or decreased intravascular volume. Defects in the synthesis or release of AVP result in AVP deficiency (AVP-D) and the syndrome of central diabetes insipidus, characterized by inappropriate aquaresis leading to hyperosmolality and insatiable thirst. While most cases of AVP-D are due to local mechanical, infiltrative, compressive, infectious, or inflammatory processes, some recreational and pharmacological substances can cause AVP-D. In this review, we discuss the history and current knowledge about these substances, including cannabinoids, ethanol, κ opioid receptor agonists, phenytoin, and anesthetic agents.

Acquired hypothalamic obesity (aHO) is characterized by rapid and persistent weight gain resulting from structural or functional damage to the hypothalamus, typically accompanied by neuroendocrine dysfunction. While aHO is well described in the context of hypothalamic or suprasellar tumors, particularly craniopharyngioma, little is known about its epidemiology in non-tumor-related etiologies such as traumatic brain injury (TBI) or subtle, unrecognized hypothalamic injuries. This study estimates the incidence and clinical characteristics of aHO in patients with traumatic brain injury (TBI-aHO) and hypothalamic-pituitary axis dysfunction of unclear origin, referred to as unspecified microinjury (UM-aHO). We conducted a retrospective cohort study using German statutory health insurance claims data (N = 6.3 million, 2010-2022). Patients were included based on either an incident diagnosis of TBI or a diagnostic algorithm indicating hypothalamic-pituitary axis dysfunction without a documented causal event. aHO was defined via incident obesity coding and validated by concomitant arginine vasopressin deficiency (AVP-D) and desmopressin prescription. For UM-aHO, additional validation required at least three concurrent neuroendocrine replacement therapies. Sensitivity analyses assessed the robustness of case definitions. The estimated incidence of TBI-aHO was 1.78 per million persons (mean age: 42 years; 27% female), corresponding to approximately 520 prevalent cases in Germany. UM-aHO showed a slightly higher incidence of 2.12 per million (mean age: 37 years; 55% female), with an estimated 660 prevalent cases. Following the diagnosis of incident obesity, most patients in both cohorts received at least two neuroendocrine therapies in addition to desmopressin, most commonly including hydrocortisone and levothyroxine sodium. This is the first population-based study to characterize aHO following non-tumor-related hypothalamic injury. Both TBI and subtle, nonspecific hypothalamic microinjuries contribute meaningfully to the burden of aHO in clinical practice. These findings underscore the need for increased clinical awareness and early recognition of hypothalamic dysfunction in patients beyond classical tumor etiologies.

Central diabetes insipidus (CDI) can develop as an acquired systemic disease. However, cases of eosinophilic granulomatosis with polyangiitis (EGPA) with concurrent CDI are rare. We herein report a case of EGPA following CDI. A 68-year-old woman with a 30-year history of sinusitis and asthma developed CDI, followed by severe renal dysfunction with eosinophilia and elevated myeloperoxidase-antineutrophil cytoplasmic antibody levels. A renal biopsy confirmed EGPA. Intensive treatment resulted in dialysis discontinuation, while partial improvement in arginine vasopressin secretion suggested a potential link between EGPA and CDI. We also conducted a literature review on concurrent EGPA and CDI. Clinicians should be aware of EGPA in CDI patients with asthma or sinusitis.

Langerhans cell histiocytosis (LCH) is a rare disease involving multiple organs, including the endocrine system. This multicenter study aimed to characterize patients with hypothalamic- pituitary involvement in LCH. The Hypopituitarism European NeuroEndocrine Association (ENEA) Rare Etiologies Observational Study (HEROS) platform invited ENEA members to include patients with rare pituitary diseases like LCH. Demographic data, presenting symptoms, hormonal profile, imaging tests, treatment, and prognosis were retrieved. Forty-eight patients (58% males) were included. Age at diagnosis was 22 ± 16.1 years, with 58% diagnosed as adults (> 18 years). The mean follow-up was 15.8 ± 10.6 years, 46% of the patients initially presented with bone lesions, 42% with lung involvement, and five were incidentally diagnosed. At diagnosis, 69% of the patients had arginine vasopressin deficiency (AVD), 42% had central hypogonadism, 25% hypothyroidism, and 12.5% hypocortisolism. Magnetic resonance imaging (MRI) was available in 41 patients, 73% of whom had pathology of the posterior pituitary/pituitary stalk. Visual disturbances were reported in only one patient. Diagnosis was histopathologically confirmed in all patients, mainly from extra-pituitary lesions. Transcranial biopsy was performed in five patients, and two underwent transsphenoidal intervention. During follow-up, 27% of the patients developed new AVD and five acquired new anterior pituitary hormone deficiency. There was no disease-related mortality during follow-up. Patients with LCH and hypothalamic-pituitary involvement remained clinically stable during long-term follow-up. However, new hormonal deficits may develop years after diagnosis, with most patients ultimately experiencing AVD.

The hypothalamus is the key regulator of human energy balance. Hypothalamic dysfunction leads to (morbid) hypothalamic obesity, but may have many more consequences such as hypopituitarism, adipsia, disruption of the circadian rhythm, decreased energy expenditure, low core body temperature, and behavioral changes. Many patients with hypothalamic dysfunction experience chronic fatigue, increased daytime sleepiness, headaches, inactivity, and mood disorders, all of which may contribute to the development of obesity. Adipsic arginine vasopressin deficiency, severe hypothermia, uncontrollable hyperphagia, and severe mood disorders may require 24/7 management. Signs and symptoms may be severe or mild. Severe hypothalamic dysfunction is usually readily diagnosed, but less severe hypothalamic dysfunction is much harder to recognize because, among other things, of its multifaceted presentation. Through raising awareness and by better categorization of the different clinical signs and symptoms of hypothalamic dysfunction within different domains, the underlying cause for fatigue and obesity observed in patients with hypothalamic dysfunction may be better understood, which in turn, will open new perspectives on successful management options. In this review, the state of the art for diagnostics and management of acquired hypothalamic dysfunction is summarized and a new management algorithm is suggested. The lessons learned from pediatric patients with acquired hypothalamic dysfunction, including hypothalamic obesity management through the different clinical domains, may also prove to be useful for patients with congenital or genetic forms of hypothalamic dysfunction resulting in fatigue and obesity, as well as for children with presumed "common" obesity.