Metabolomic profiling of adolescent endometriosis

摘要 子宫内膜异位症是一种影响全球2亿女性的衰弱疾病，会导致严重的疼痛和 不孕不育。尽管超过50%的患有子宫内膜异位症的成年人报告说在青春期开始疼痛，但大多数 患有子宫内膜异位症的女性由于目前的原因，平均延迟诊断7年 手术可视化的诊断标准，导致疼痛延长，生活质量下降。因此， 迫切需要为子宫内膜异位症寻找新的、非侵入性的生物标志物，这是NICHD的一种 与子宫内膜异位症相关的研究目标。能够在生命过程中早期诊断子宫内膜异位症 青春期和青春期，可能导致更早的干预和改善临床结果。然而， 对青少年子宫内膜异位症的病理生理和分子特征知之甚少。 青少年子宫内膜异位症通常表现为严重的盆腔疼痛和腹膜浅层病变，这是 与成人诊断的子宫内膜异位症不同，后者通常表现为疼痛、不孕不育和深层纤维化 损伤。此外，我们的初步数据显示，大约30%的患有子宫内膜异位症的青少年患有 手术后持续或复发的盆腔疼痛，尽管接受了手术后激素治疗， 导致了复发的手术。最近，我们报道了血CA125在子宫内膜异位症中升高。 在成人中确诊，在患有子宫内膜异位症的青少年中不升高。青少年诊断的子宫内膜异位症 可能与成人诊断的子宫内膜异位症有不同的分子表型，这可能需要 不同的诊断和治疗策略。该应用程序目的是识别新的(1)血液 与青少年子宫内膜异位症相关的代谢组学特征和(2)腹腔液代谢组学标志物 预示着手术后的持续性疼痛。代谢物是细胞活动的下游产物。 受基因组调控，受环境因素修饰，已被证明在生物标志物中具有价值 许多慢性病的发现。根据我们的初步数据，前列腺素合成的上调 鉴于青少年子宫内膜异位症的常见表现，它可能是其重要的病理生理途径 带着痛苦。使用详细的临床信息、疼痛测量以及配对的血液和腹腔液样本 来自女性健康研究的注解充分的纵向队列：从青春期到成年期 我们将应用一个经过验证的代谢组学平台，该平台可以同时测量600多个 代谢物，使我们能够识别青少年子宫内膜异位症特有的代谢物和生物途径。这个 提议的AIMS将识别可能导致青少年子宫内膜异位症的新的代谢生物标记物 子宫内膜异位症早期诊断生物标志物和个体化治疗策略的研究进展。 重要的是，阐明青少年子宫内膜异位症的分子图谱将提供有关 早期病程中的病理生理学轨迹，提示未来R01建议阐明 随着疾病从青春期发展到成年期，代谢谱的变化。

ABSTRACT Endometriosis is a debilitating disease affecting 200 million women worldwide, causing severe pain and infertility. Although over 50% of adults with endometriosis report onset of pain during adolescence, most women with endometriosis experience a delayed diagnosis on average of seven years due to the current diagnostic standard of surgical visualization, resulting in prolonged pain and decreased quality of life. Thus, there is a critical need to identify novel, non-invasive biomarkers for endometriosis, which is one of the NICHD research goals related to endometriosis. Being able to diagnose endometriosis earlier in the life course, during adolescence and young adulthood, may lead to earlier intervention and improved clinical outcome. However, little is known about the pathophysiology and molecular features of endometriosis diagnosed in adolescents. Adolescent endometriosis typically presents with severe pelvic pain and superficial peritoneal lesions, which is distinct from adult-diagnosed endometriosis which typically present with pain, infertility, and deep fibrotic lesions. Furthermore, our preliminary data shows that about 30% of adolescents with endometriosis suffer from persistent or recurring post-surgical pelvic pain despite being treated with post-surgical hormone therapy, leading to recurring surgeries. Recently, we reported that blood CA125, which is elevated in endometriosis diagnosed in adults, was not elevated in adolescents with endometriosis. Adolescent-diagnosed endometriosis may have distinct molecular phenotype compared to adult-diagnosed endometriosis, which may require different strategies for diagnosis and treatment. The objective of this application is to identify novel (1) blood metabolomic profiles associated with adolescent endometriosis and (2) peritoneal fluid metabolomic markers predictive of persistent post-surgical pain. Metabolites are the downstream products of cellular activities regulated by the genome and modified by environmental factors and have proven valuable in biomarker discovery for many chronic diseases. Based on our preliminary data, upregulation of prostaglandin synthesis could be an important pathway for adolescent endometriosis pathophysiology given its common presentation with pain. Using the detailed clinical information, pain measures, plus paired blood and peritoneal fluid samples from the well-annotated longitudinal cohort of the Women’s Health Study: From Adolescence to Adulthood cohort, we will apply a validated metabolomics platform which can simultaneously measure over 600 metabolites, allowing us identify metabolites and biologic pathways unique to adolescent endometriosis. The proposed aims will identify novel metabolomic biomarkers of adolescent endometriosis which may lead to advances in determining early diagnostic biomarkers and personalized treatment strategies for endometriosis. Importantly, elucidating molecular profiles of adolescent endometriosis will provide new information about the pathophysiology during the earlier course the disease trajectory, informing future R01 proposals to elucidate changes in metabolomic profiles as the disease progresses from adolescence to adulthood.