Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Boston Center for Endometriosis, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA, USA.
Hum Reprod. 2023 Aug 1;38(8):1509-1519. doi: 10.1093/humrep/dead099.
What are the similarities and differences in the systemic proteomic profiles by endometriosis-associated pain subtypes among adolescents and young adults with endometriosis?
Endometriosis-associated pain subtypes exhibited distinct plasma proteomic profiles.
Endometriosis patients, especially those diagnosed in adolescents and young adults, are often plagued by various pain symptoms. However, it is not clear what biological processes underlie this heterogeneity.
STUDY DESIGN, SIZE, DURATION: We conducted a cross-sectional analysis using data and plasma samples from 142 adolescent or young adult participants of the Women's Health Study: From Adolescence to Adulthood cohort with laparoscopically confirmed endometriosis.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured 1305 plasma protein levels by SomaScan. We classified self-reported endometriosis-associated pain into subtypes of dysmenorrhea, acyclic pelvic pain, life impacting pelvic pain, bladder pain, bowel pain, and widespread pain phenotype. We used logistic regression to calculate the odds ratios and 95% confidence intervals for differentially expressed proteins, adjusting for age, BMI, fasting status, and hormone use at blood draw. Ingenuity Pathway Analysis identified enriched biological pathways.
Our study population consisted mainly of adolescents and young adults (mean age at blood draw = 18 years), with nearly all (97%) scored as rASRM stage I/II at laparoscopic diagnosis of endometriosis, which is a common clinical presentation of endometriosis diagnosed at a younger age. Pain subtypes exhibited distinct plasma proteomic profiles. Multiple cell movement pathways were downregulated in cases with severe dysmenorrhea and life impacting pelvic pain compared to those without (P < 7.5×10-15). Endometriosis cases with acyclic pelvic pain had upregulation of immune cell adhesion pathways (P < 9.0×10-9), while those with bladder pain had upregulation of immune cell migration (P < 3.7×10-8) and those with bowel pain had downregulation (P < 6.5×10-7) of the immune cell migration pathways compared to those without. Having a wide-spread pain phenotype involved downregulation of multiple immune pathways (P < 8.0×10-10).
LIMITATIONS, REASONS FOR CAUTION: Our study was limited by the lack of an independent validation cohort. We were also only able to explore any presence of a pain subtype and could not evaluate multiple combinations by pain subtypes. Further mechanistic studies are warranted to elucidate the differences in pathophysiology by endometriosis-pain subtype.
The observed variation in plasma protein profiles by pain subtypes suggests different underlying molecular mechanisms, highlighting the need for potential consideration of pain subtypes for effectively treating endometriosis patients presenting with various pain symptoms.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Department of Defense W81XWH1910318 and the 2017 Boston Center for Endometriosis Trainee Award. Financial support for establishment of and data collection within the A2A cohort were provided by the J. Willard and Alice S. Marriott Foundation. N.S., A.F.V., S.A.M., and K.L.T. have received funding from the Marriott Family Foundation. C.B.S. is funded by an R35 MIRA Award from NIGMS (5R35GM142676). S.A.M. and K.L.T. are supported by NICHD R01HD094842. S.A.M. reports serving as an advisory board member for AbbVie and Roche, Field Chief Editor for Frontiers in Reproductive Health, personal fees from Abbott for roundtable participation; none of these are related to this study. Other authors report no conflict of interest.
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子宫内膜异位症相关疼痛亚型在青少年和年轻成年子宫内膜异位症患者中的系统蛋白质组学特征有何异同？
子宫内膜异位症相关疼痛亚型表现出明显不同的血浆蛋白质组学特征。
患有子宫内膜异位症的患者，尤其是那些在青少年和年轻成人中诊断出的患者，常常受到各种疼痛症状的困扰。然而，尚不清楚这种异质性背后的生物学过程是什么。
研究设计、大小、持续时间：我们对来自 Women's Health Study：From Adolescence to Adulthood 队列的 142 名腹腔镜确诊为子宫内膜异位症的青少年或年轻成年参与者的数据分析和血浆样本进行了横断面分析。
参与者/材料、设置、方法：我们使用 SomaScan 测量了 1305 种血浆蛋白水平。我们将自我报告的子宫内膜异位症相关疼痛分为痛经、非周期性盆腔疼痛、影响生活的盆腔疼痛、膀胱疼痛、肠道疼痛和广泛疼痛表型等亚型。我们使用逻辑回归计算差异表达蛋白的优势比和 95%置信区间，调整年龄、BMI、禁食状态和采血时激素使用情况。Ingenuity Pathway Analysis 确定了丰富的生物学途径。
我们的研究人群主要由青少年和年轻成年人组成（采血时的平均年龄为 18 岁），几乎所有（97%）患者在腹腔镜诊断为子宫内膜异位症时均被评为 rASRM Ⅰ/Ⅱ期，这是年轻患者中常见的子宫内膜异位症临床表现。疼痛亚型表现出明显不同的血浆蛋白质组学特征。与无疼痛的患者相比，严重痛经和影响生活的盆腔疼痛患者的多种细胞运动途径下调（P<7.5×10-15）。非周期性盆腔疼痛的子宫内膜异位症病例中，免疫细胞黏附途径上调（P<9.0×10-9），而膀胱疼痛的患者中免疫细胞迁移途径上调（P<3.7×10-8），肠道疼痛的患者中免疫细胞迁移途径下调（P<6.5×10-7）与无疼痛的患者相比。具有广泛疼痛表型的患者涉及多个免疫途径的下调（P<8.0×10-10）。
局限性、谨慎的原因：我们的研究受到缺乏独立验证队列的限制。我们还只能探索疼痛亚型的存在，无法评估疼痛亚型的多种组合。需要进一步的机制研究来阐明不同的子宫内膜异位症-疼痛亚型的病理生理学差异。
疼痛亚型的血浆蛋白质组学特征的变化表明不同的潜在分子机制，强调需要考虑疼痛亚型来有效治疗表现出各种疼痛症状的子宫内膜异位症患者。
研究资金/利益冲突：本研究由美国国防部 W81XWH1910318 和 2017 年波士顿子宫内膜异位症培训生奖资助。A2A 队列的建立和数据收集得到了万豪家族基金会的支持。N.S.、A.F.V.、S.A.M.和 K.L.T. 获得了万豪家族基金会的资助。C.B.S. 获得了 NIGMS R35 MIRA 奖（5R35GM142676）的资助。S.A.M. 担任 AbbVie 和 Roche 的顾问委员会成员，担任 Frontiers in Reproductive Health 的现场首席编辑，个人从 Abbott 获得轮值参与费；这些都与本研究无关。其他作者报告没有利益冲突。
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