Lin Nan, Zeleznik Oana A, Vitonis Allison F, Laliberte Ashley, Shafrir Amy L, Avila-Pacheco Julian, Clish Clary, Terry Kathryn L, Missmer Stacey A, Sasamoto Naoko
Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Hum Reprod. 2025 May 1;40(5):843-854. doi: 10.1093/humrep/deaf040.
What are the plasma metabolomics profiles associated with endometriosis in adolescents and young adults?
Our findings show dysregulation of plasma metabolomic profiles in adolescents and young adults with endometriosis, revealing systemic elevation of fatty acyls and ceramides in endometriosis cases compared to controls.
Endometriosis is a gynecologic disease often presenting with severe pelvic pain impacting around 200 million reproductive-aged women worldwide. However, little is known about the pathophysiology and molecular features of endometriosis diagnosed during adolescence and young adulthood.
STUDY DESIGN, SIZE, DURATION: We conducted a cross-sectional analysis including 190 laparoscopically confirmed endometriosis cases and 120 controls who participated in The Women's Health Study: From Adolescence to Adulthood, which enrolled participants from 2012 to 2018. Control participants were females without a diagnosis of endometriosis enrolled from the same clinics as the cases or recruited from the general population. Among the cases, 81 had blood samples collected before and after surgery.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Plasma metabolites were measured in blood collected at enrollment using liquid chromatography-tandem mass spectrometry, and a total of 430 known metabolites were evaluated in our analysis. We used linear regression adjusting for age at blood draw, BMI, hormone use, and fasting status at blood draw. Metabolite set enrichment analysis (MSEA) was used to identify metabolite classes. Number of effective tests (NEF) and false discovery rate (FDR) were used for multiple testing correction.
The median age was 17 years for endometriosis cases and 22 years for controls. The majority of endometriosis cases had rASRM stage I or II (>95%). We identified 63 plasma metabolites associated with endometriosis (NEF < 0.05). Endometriosis cases had higher levels of plasma metabolites associated with proinflammatory response [e.g. eicosatrienoic acid (β = 0.61, 95% CI = 0.37, 0.86)], increased oxidative stress response [e.g. xanthine (β = 0.64, 95% CI = 0.39, 0.88)], and downregulation of metabolites related to apoptosis [glycocholic acid (β = -0.80, 95% CI = -1.04, -0.56)]. MSEA revealed increased fatty acyls (FDR = 2.3e-4) and ceramides (FDR = 6.0e-3) and decreased steroids and steroid derivatives (FDR = 1.3e-4) in endometriosis cases compared to controls. When we examined the changes in plasma metabolite profiles before and after surgery among endometriosis cases, 55 endometriosis-associated metabolites significantly changed from before to after surgery. MSEA revealed steroids and steroid derivatives (FDR = 8.1e-4) significantly increased after surgery, while fatty acyls (FDR = 1.2e-4) significantly decreased after surgery. Ceramides did not change from pre- to post-surgery and were elevated in post-surgical blood compared to controls (FDR = 3.9e-3).
LIMITATIONS, REASONS FOR CAUTION: Our study population mainly consists of self-reported non-Hispanic, white individuals and endometriosis cases with superficial peritoneal lesions only, so the generalizability may be limited. Furthermore, despite our large study population of adolescents and young adults with endometriosis, sample size was limited to conduct detailed stratified analyses of plasma metabolomic profiles, especially by post-surgical pelvic pain outcomes.
Our study includes the utilization of state-of-the-art metabolomics technology with high reproducibility to comprehensively investigate the metabolites that were associated with endometriosis diagnosed in adolescents and young adults. Our results suggest a positive impact of endometriosis-related surgery for some, but not all, on systemic metabolic dysregulation in young patients with endometriosis. These results warrant further investigation on whether and how persistent systemic changes despite treatment may lead to long-term chronic disease risk among those diagnosed with endometriosis.
STUDY FUNDING/COMPETING INTEREST(S): Financial support for establishment of and data collection within the A2A cohort was provided by the J. Willard and Alice S. Marriott Foundation, and support for assay costs was in part provided by the Peery family. This project was funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development R21HD107266. S.A.M., A.L.S., and K.L.T. were supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development R01HD094842. S.A.M. received grant funding from AbbVie, National Institutes of Health, Department of Defense, and Marriott Family Foundation; received honoraria from WERF, Huilun Shanghai, and University of Kansas Medical Center; travel support from SRI, ESHRE, FWGBD, University of Michigan, MIT, ASRM, LIDEA Registry, Taiwan Endometriosis Society, SEUD, Japan Endometriosis Society, NASEM, Endometriosis Foundation of America, Gedeon Richter Symposium at ESHRE; Board member receiving financial remuneration from AbbVie, Roche, LIDEA Registry, Editor of Frontiers in Reproductive Health, Roundtable participation for Abbott; Board member without financial remuneration from NextGen Jane and Statistical Advisory Board member of Human Reproduction; leadership role in Society for Women's Health Research, World Endometriosis Society, World Endometriosis Research Foundation, ASRM, ESHRE. N.S. and K.L.T. receive grant funding from Aspira Women's Health unrelated to this project. The remaining authors have no disclosures relevant to this manuscript.
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青少年和青年子宫内膜异位症患者的血浆代谢组学特征是什么？
我们的研究结果显示，青少年和青年子宫内膜异位症患者的血浆代谢组学特征失调，与对照组相比，子宫内膜异位症患者的血浆中脂肪酰基和神经酰胺系统性升高。
子宫内膜异位症是一种妇科疾病，常伴有严重的盆腔疼痛，全球约有2亿育龄妇女受其影响。然而，对于青少年和青年期诊断出的子宫内膜异位症的病理生理学和分子特征知之甚少。
研究设计、规模、持续时间：我们进行了一项横断面分析，纳入了190例经腹腔镜确诊的子宫内膜异位症患者和120名对照，这些患者参与了“从青春期到成年期的女性健康研究”，该研究于2012年至2018年招募参与者。对照参与者为未诊断出子宫内膜异位症的女性，她们与病例组来自同一诊所或从普通人群中招募。在病例组中，81例患者在手术前后采集了血样。
参与者/材料、设置、方法：使用液相色谱 - 串联质谱法测量入组时采集血液中的血浆代谢物，我们的分析共评估了430种已知代谢物。我们使用线性回归对采血时的年龄、体重指数、激素使用情况和空腹状态进行校正。代谢物集富集分析（MSEA）用于识别代谢物类别。有效测试次数（NEF）和错误发现率（FDR）用于多重测试校正。
子宫内膜异位症患者的中位年龄为17岁，对照组为22岁。大多数子宫内膜异位症患者处于rASRM I期或II期（>95%）。我们鉴定出63种与子宫内膜异位症相关的血浆代谢物（NEF < 0.05）。子宫内膜异位症患者血浆中与促炎反应相关的代谢物水平较高[例如，二十碳三烯酸（β = 0.61，95% CI = 0.37，0.86）]，氧化应激反应增强[例如，黄嘌呤（β = 0.64，95% CI = ......（此处原文未完整给出）
局限性、注意事项：我们的研究人群主要由自我报告的非西班牙裔白人个体和仅患有浅表腹膜病变的子宫内膜异位症患者组成，因此普遍性可能有限。此外，尽管我们有大量的青少年和青年子宫内膜异位症患者研究人群，但样本量有限，无法对血浆代谢组学特征进行详细的分层分析，尤其是按术后盆腔疼痛结果进行分析。
我们的研究利用了具有高重现性的先进代谢组学技术，全面研究了与青少年和青年期诊断出的子宫内膜异位症相关的代谢物。我们的结果表明，子宫内膜异位症相关手术对部分（但不是全部）年轻子宫内膜异位症患者的全身代谢失调有积极影响。这些结果值得进一步研究，以确定治疗后持续的全身变化是否以及如何导致子宫内膜异位症患者患长期慢性疾病的风险增加。
研究资金/利益冲突：A2A队列的建立和数据收集的资金支持由J. Willard和Alice S. Marriott基金会提供，检测费用部分由Peery家族提供。该项目由尤妮斯·肯尼迪·施莱佛国家儿童健康与人类发展研究所R21HD107266资助。S.A.M.、A.L.S.和K.L.T.由尤妮斯·肯尼迪·施莱佛国家儿童健康与人类发展研究所R01HD094842资助。S.A.M.获得了艾伯维、美国国立卫生研究院、国防部和万豪家族基金会的资助；获得了WERF、上海惠伦和堪萨斯大学医学中心的酬金；获得了SRI、ESHRE、FWGBD、密歇根大学、麻省理工学院、ASRM、LIDEA注册中心、台湾子宫内膜异位症协会、SEUD、日本子宫内膜异位症协会、NAS、美国子宫内膜异位症基金会、ESHRE的吉迪恩·里希特研讨会的差旅支持；担任艾伯维、罗氏、LIDEA注册中心的董事会成员，《生殖健康前沿》编辑，雅培圆桌会议参与者；担任NextGen Jane董事会成员且无经济报酬，以及人类生殖统计咨询委员会成员；在女性健康研究协会、世界子宫内膜异位症协会、世界子宫内膜异位症研究基金会、ASRM、ESHRE担任领导职务。N.S.和K.L.T.获得了与本项目无关的Aspira Women's Health的资助。其余作者无与此稿件相关的披露信息。
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