Bando Hironori, Urai Shin, Kanie Keitaro, Yamamoto Masaaki
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Hospital, Kobe 650-0017, Japan.
Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Endocr J. 2025 Jun 2;72(6):649-662. doi: 10.1507/endocrj.EJ25-0035. Epub 2025 Mar 27.
Hypopituitarism, characterized by reduced secretion of pituitary hormones, profoundly impacts systemic metabolic homeostasis and quality of life. Its etiology ranges from congenital anomalies in pituitary development to acquired conditions involving inflammation and autoimmune processes. Despite advances in understanding its pathogenesis, diagnostic challenges persist, particularly in cases with complex extra-pituitary manifestations or novel genetic variations. Congenital hypopituitarism often stems from disruptions in transcription factors and signaling pathways critical for pituitary organogenesis. Emerging studies employing next-generation sequencing and developmental biology techniques have revealed new genetic loci and mechanisms implicated in combined pituitary hormone deficiency. However, the pathogenesis of most congenital cases remains elusive, underscoring the need for functional and phenotypic analyses of novel variants. Acquired hypopituitarism, frequently associated with pituitary tumors or systemic diseases, has also been increasingly linked to autoimmune mechanisms. Notably, the concept of paraneoplastic autoimmune hypophysitis has emerged, highlighting malignancy-driven immune responses as a novel etiological framework. Investigations into immune checkpoint inhibitor-related hypophysitis and anti-PIT-1 hypophysitis exemplify the intricate interplay between tumor immunity and endocrine dysfunction, suggesting shared mechanisms involving ectopic antigen expression and autoimmunity. This review synthesizes recent insights into the genetic, developmental, and immunological underpinnings of hypopituitarism. By exploring both congenital and acquired etiologies, we aim to bridge gaps in the current understanding of this complex disorder and provide a foundation for improved diagnostic and therapeutic strategies. Future perspectives emphasize the integration of advanced genetic tools, deeper exploration of tumor-immunity interactions, and a heightened focus on extra-pituitary phenotypes to refine clinical practice and enhance patient outcomes.
垂体功能减退症，其特征为垂体激素分泌减少，对全身代谢稳态和生活质量产生深远影响。其病因范围从垂体发育的先天性异常到涉及炎症和自身免疫过程的后天性疾病。尽管在理解其发病机制方面取得了进展，但诊断挑战依然存在，尤其是在具有复杂垂体外表现或新的基因变异的病例中。先天性垂体功能减退症通常源于对垂体器官发生至关重要的转录因子和信号通路的破坏。采用下一代测序和发育生物学技术的新兴研究揭示了与联合垂体激素缺乏相关的新基因位点和机制。然而，大多数先天性病例的发病机制仍然难以捉摸，这突出了对新变异进行功能和表型分析的必要性。后天性垂体功能减退症，通常与垂体肿瘤或全身性疾病相关，也越来越多地与自身免疫机制联系在一起。值得注意的是，副肿瘤性自身免疫性垂体炎的概念已经出现，突出了恶性肿瘤驱动的免疫反应作为一种新的病因框架。对免疫检查点抑制剂相关垂体炎和抗PIT-1垂体炎的研究例证了肿瘤免疫与内分泌功能障碍之间复杂的相互作用，表明涉及异位抗原表达和自身免疫的共同机制。本综述综合了对垂体功能减退症的遗传、发育和免疫基础的最新见解。通过探索先天性和后天性病因，我们旨在弥合目前对这种复杂疾病理解上的差距，并为改进诊断和治疗策略提供基础。未来的展望强调整合先进的基因工具、更深入地探索肿瘤-免疫相互作用以及更加关注垂体外表型，以优化临床实践并改善患者预后。
