Augsburger Philipp, Niskanen Oili, Jääskeläinen Jarmo, Flück Christa E, Liimatta Jani
Pediatric Endocrinology, Diabetology, and Metabolism, Inselspital, Bern University Hospital, Bern, Switzerland.
Department of BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
Horm Res Paediatr. 2025 Jul 29:1-12. doi: 10.1159/000547606.
Adrenarche is a prepubertal developmental phase in humans characterized by increasing levels of adrenal androgens in circulation. While its regulation and biological significance remain poorly understood, the earlier onset of adrenarche - referred to as premature adrenarche (PA) - raises concerns about potential long-term health risks, including metabolic syndrome and polycystic ovary syndrome. Our study aimed to elucidate the regulatory mechanisms underlying adrenarche and PA, specifically investigating whether PA represents a benign variation of normal development, or a disorder associated with increased risks of unfavorable metabolic and reproductive outcomes in adulthood.
This study employs a longitudinal design to track a well-characterized cohort of children with PA alongside age-matched healthy controls, following them from adrenarche through puberty into early adulthood. Conducted across two independent research centers in Kuopio, Finland, and Bern, Switzerland, the study involves detailed phenotypic assessments, including comprehensive medical histories and body composition analyses. Biological samples undergo multi-omics profiling - encompassing transcriptomics and metabolomics - using advanced techniques such as liquid and gas chromatography tandem-mass spectrometry and RNA sequencing. This integrated approach aims to identify biomarkers predictive of adverse health outcomes in PA, with candidate biomarkers and regulatory factors further validated through in vitro adrenal cell model studies.
This study provides the first comprehensive, longitudinal comparison of PA and healthy controls across critical developmental milestones. By elucidating the molecular factors that regulate the maturation of the zona reticularis, it seeks to resolve the longstanding mystery of adrenarche. Furthermore, by differentiating benign developmental variations from PA cases linked with long-term health risks, the findings could refine current diagnostic criteria and enable early identification of children at risk. Ultimately, this research paves the way for more accurate diagnoses, targeted interventions, and improved long-term health outcomes.
肾上腺初现是人类青春期前的一个发育阶段，其特征是循环中肾上腺雄激素水平升高。尽管其调节机制和生物学意义仍知之甚少，但肾上腺初现提前——即所谓的早熟肾上腺初现（PA）——引发了人们对潜在长期健康风险的担忧，包括代谢综合征和多囊卵巢综合征。我们的研究旨在阐明肾上腺初现和PA背后的调节机制，特别研究PA是正常发育的良性变异，还是与成年期不良代谢和生殖结局风险增加相关的疾病。
本研究采用纵向设计，追踪一组特征明确的PA儿童以及年龄匹配的健康对照，从肾上腺初现开始，跟踪他们直至青春期并进入成年早期。该研究在芬兰库奥皮奥和瑞士伯尔尼的两个独立研究中心进行，涉及详细的表型评估，包括全面的病史和身体成分分析。生物样本使用液相和气相色谱串联质谱以及RNA测序等先进技术进行多组学分析——包括转录组学和代谢组学。这种综合方法旨在识别预测PA不良健康结局的生物标志物，并通过体外肾上腺细胞模型研究进一步验证候选生物标志物和调节因子。
本研究首次对PA和健康对照在关键发育里程碑进行了全面的纵向比较。通过阐明调节网状带成熟的分子因素，旨在解开肾上腺初现这一长期谜团。此外，通过区分与长期健康风险相关的PA病例和良性发育变异，研究结果可能会完善当前的诊断标准，并能够早期识别有风险的儿童。最终，这项研究为更准确的诊断、有针对性的干预以及改善长期健康结局铺平了道路。
