下垂体性成長ホルモン分泌亢進症

Musculoskeletal disease is one of the major determinants of long-term morbidity in acromegaly, yet traditionally its pathophysiology and clinical management have been addressed through separate perspectives on skeletal fragility and arthropathy. Recent advances in skeletal biology, imaging, and biomechanics, as well as longitudinal clinical studies support a broader interpretation of acromegalic osteoarthropathy as a disorder of pathological musculoskeletal remodeling involving coordinated alterations of bone, joints, muscle and body composition. In this review, we propose an integrative conceptual framework that brings together current evidence on the biological mechanisms underlying musculoskeletal remodeling, the clinical phenotype of active disease and the long-term consequences that frequently persist despite successful endocrine treatment. We discuss the strengths and limitations of currently available diagnostic approaches, including assessment of bone quality, vertebral fractures, arthropathy and spinal biomechanics, and examine the clinical determinants of fracture risk beyond conventional bone mineral density evaluation. Particular emphasis is placed on the transition from endocrine-centered care to phenotype-driven management, highlighting current evidence regarding long-term surveillance, disease modification and multidisciplinary management of persistent musculoskeletal disability. Collectively, the available evidence indicates that bone fragility, arthropathy, muscle dysfunction and altered body composition should no longer be considered solely as isolated complications but may be interpreted as biologically related manifestations within a shared framework of pathological musculoskeletal remodeling. This integrated framework provides a biologically coherent interpretation of acromegalic osteoarthropathy and has important implications for individualized patient care, future translational research and the development of disease-modifying therapeutic strategies aimed at preserving lifelong musculoskeletal health.

Familial isolated pituitary adenoma (FIPA) accounts for approximately 2%-5% of all pituitary adenomas, with inactivating variants of the aryl hydrocarbon receptor-interacting protein (AIP) gene representing the most frequent known genetic cause. Clinically, patients with AIP variants often have young-onset macroadenomas with growth hormone hypersecretion, although disease severity and penetrance are variable. Most reported AIP variants are point mutations, whereas large deletions are rare and potentially underdiagnosed. Accurate detection of AIP copy-number variants requires methods such as multiplex ligation-dependent probe amplification or validated copy-number analysis of next-generation sequencing data, as Sanger sequencing alone may fail to identify these alterations. Due to the rarity of the disease, it is unknown whether large deletions in the ubiquitously expressed AIP gene are associated with potentially more severe phenotype. Available data suggest that large deletions may occur in 8%-10% of AIP mutation-positive pedigrees, highlighting the importance of incorporating copy-number variant detection into AIP testing workflows. We analysed data from all published patients with large AIP deletions (n = 25) and report here two novel large AIP deletions (Exons 3-4 and Exons 2-6 deletions) and three additional three families, including an Albanian kindred associated with metastatic Hürthle cell thyroid carcinoma. No major differences compared with other AIP variants were found in age at diagnosis, tumour size, hormonal profile, sex distribution or presence of other tumours. A role for AIP variants in thyroid carcinogenesis is unlikely.

Neuroendocrine tumors (NETs) are rare neoplasms that present significant challenges during pregnancy, particularly in the context of metastatic disease or carcinoid syndrome requiring systemic therapy. Data on the safety of somatostatin analogs during pregnancy remain limited and are primarily derived from studies involving patients with acromegaly. We report the maternal and fetal outcomes in a pregnant patient diagnosed with a metastatic NET of the ileocecal valve, complicated by carcinoid syndrome. The patient had previously undergone treatment with 177Lu-DOTATATE, debulking surgery, and lanreotide therapy. Lanreotide administration was continued throughout the pregnancy under multidisciplinary supervision. Maternal monitoring revealed no complications, and postpartum evaluations confirmed disease stability. The newborn developed transient neonatal hyperbilirubinemia requiring phototherapy but demonstrated normal development at the 18-month follow-up. This case highlights important clinical considerations regarding the continuation of somatostatin analog therapy, biochemical monitoring, peri-delivery planning for a carcinoid crisis, and pregnancy after peptide receptor radionuclide therapy in patients with functioning metastatic NETs. It provides supportive observational evidence that the continuation of lanreotide during pregnancy may be feasible in carefully selected patients under close multidisciplinary supervision, although conclusions regarding safety remain limited by the rarity of available data.

INTRODUCTION: Current long-acting somatostatin analogs control acromegaly and neuroendocrine tumor symptoms, but rely on depot formulations requiring large-bore needle administration, often associated with injection-site pain, nodules, and variable drug release. To address this limitation, we developed TE-8214, a depot-free octreotide analog conjugated to a soluble, dual-fatty-acid albumin-binding module designed to enable prolonged systemic exposure while maintaining a fully aqueous formulation suitable for subcutaneous administration through a fine 30-gauge needle. METHODS: TE-8214's binding to human serum albumin (HSA) and somatostatin receptor 2 (SSTR2), and its receptor-mediated functional activity, were characterized in vitro and compared with octreotide. Pharmacokinetics and pharmacodynamics - suppression of serotonin, growth hormone, and insulin-like growth factor-1 (IGF-1) - were assessed in rodents and dogs following single or repeated dosing of TE-8214 or equimolar octreotide. Safety, tolerability, and pharmacokinetics of TE-8214 were then evaluated in a randomized, double-blind, placebo-controlled Phase 1 single-ascending-dose study in healthy adults (0.6-4.0 mg), with IGF-1 assessed as an exploratory pharmacodynamic biomarker. RESULTS: In vitro, TE-8214 bound HSA while retaining potent SSTR2-mediated activity comparable to octreotide. In rodents and dogs, TE-8214's albumin binding extended its terminal half-life and enabled sustained suppression of serotonin, growth hormone, and IGF-1, exceeding the duration achieved with equimolar octreotide. In the Phase 1 study, TE-8214 was well-tolerated across all doses tested, with no serious or Grade ≥3 treatment-emergent adverse events, and produced sustained, dose-dependent reductions in IGF-1 consistent with systemic exposure; at the highest dose, IGF-1 fell by 22.5% from baseline and remained suppressed through Day 28. DISCUSSION: These findings demonstrate that a depot-free, aqueous-formulated octreotide analog can achieve prolonged systemic exposure and sustained pharmacodynamic activity following a single dose in healthy volunteers. Although this study was not designed to evaluate therapeutic efficacy, the pharmacokinetic and pharmacodynamic profile of TE-8214 supports further clinical evaluation in patients with neuroendocrine tumors or acromegaly. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, identifier NCT06372652.

INTRODUCTION: postoperative hyponatremia is a common complication after endoscopic transsphenoidal surgery, with an incidence of 9-35 % that rises to 41.5 % in patients with acromegaly. CASE REPORT: a 74-year-old woman diagnosed with acromegaly underwent endoscopic transsphenoidal surgery and developed severe symptomatic hyponatremia (sodium 117 mmol/l) due to SIADH on postoperative day 11, after other causes of postoperative hyponatremia were ruled out. Following initial correction with hypertonic saline, treatment with oral urea (15 g/day) was started, achieving a safe increase in serum sodium (133 mmol/l at 48 hours) that allowed hospital discharge. One week later, with normalized sodium levels (137 mmol/l), treatment was withdrawn without subsequent recurrence. DISCUSSION: oral urea is an effective, well-tolerated and cost-effective first-line treatment for SIADH after pituitary surgery, particularly relevant in patients with acromegaly given their higher incidence of late hyponatremia. Systematic sodium monitoring during the highest-risk period could allow earlier treatment initiation and prevent progression to severe cases.