Longitudinal plasma proteomics along a menstrual cycle highlights the regulatory effect of sex hormones on inflammatory and cardiometabolic circuits.

Longitudinal plasma proteomics along a menstrual cycle highlights the regulatory effect of sex hormones on inflammatory and cardiometabolic circuits. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Longitudinal plasma proteomics along a menstrual cycle highlights the regulatory effect of sex hormones on inflammatory and cardiometabolic circuits. Serena Sanna, Daria Zhernakova, Federica Grosso, Fabio Chillotti, and 28 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9148671/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Sex hormones exert widespread effects on immune, metabolic, and cardiovascular physiology, yet their systemic impact in healthy women remains poorly characterised due to the scarcity of longitudinal molecular data across the menstrual cycle. Here, we carried out the first longitudinal, high-throughput plasma proteomics analysis of the menstrual cycle. We profiled 159 naturally cycling women from the Women4Health cohort, integrating plasma levels of 2,453 circulating proteins, 5 sex hormones, and 10 serum cardiometabolic phenotypes across four menstrual phases, enabling high-resolution mapping of dynamic proteomic changes. We identified 43 proteins differentially abundant across phases and hundreds associated with sex hormones and cardiometabolic phenotypes. These included proteins involved in extracellular matrix remodelling, immune regulation and hormone metabolism, such as beta-glucuronidase, previously described mainly as part of the microbial estrobolome and here for the first time identified in plasma. To investigate directional relationships, leveraging longitudinal measurements, we applied a cross-lagged structural equation modelling framework and validated its robustness through extensive simulations. With this approach we recovered expected links such as progesterone-mediated regulation of PROK1, as well as novel connections, including those linking IGFBP1 to both hormone and lipid levels. Many of the identified proteins have established causal roles in complex diseases. Our study provides the first proteomic atlas of the menstrual cycle and reveals mechanistic pathways underlying sex-hormone-driven regulation of inflammatory and cardiometabolic circuits. Biological sciences/Computational biology and bioinformatics/Proteome informatics Health sciences/Endocrinology Health sciences/Risk factors Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryNoteTable.xlsx Supplementary Note Tables SupplementaryNote20260113.pdf Supplementary Note supplementarytablesv4.xlsx Supplementary Tables SupplementaryFiguresv4.pdf Supplementary Figures Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Here, we carried out the first longitudinal, high-throughput plasma proteomics analysis of the menstrual cycle. We profiled 159 naturally cycling women from the Women4Health cohort, integrating plasma levels of 2,453 circulating proteins, 5 sex hormones, and 10 serum cardiometabolic phenotypes across four menstrual phases, enabling high-resolution mapping of dynamic proteomic changes. We identified 43 proteins differentially abundant across phases and hundreds associated with sex hormones and cardiometabolic phenotypes. These included proteins involved in extracellular matrix remodelling, immune regulation and hormone metabolism, such as beta-glucuronidase, previously described mainly as part of the microbial estrobolome and here for the first time identified in plasma. To investigate directional relationships, leveraging longitudinal measurements, we applied a cross-lagged structural equation modelling framework and validated its robustness through extensive simulations. With this approach we recovered expected links such as progesterone-mediated regulation of PROK1, as well as novel connections, including those linking IGFBP1 to both hormone and lipid levels. Many of the identified proteins have established causal roles in complex diseases. 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