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ResearchIn-Press PreviewInflammationReproductive biology Open Access | 10.1172/JCI194136

Repeatedly occurring retrograde menstruation intensifies central sensitization driven by neuroinflammation in endometriosis models

Madeleine E. Harvey,1 Mingxin Shi,1 Yeongseok Oh,1 Taylor M. Page,1 Debra A. Mitchell,1 Addie Luo,2 Ov D. Slayden,2 James A. MacLean,1 Anjali Sharma,3 and Kanako Hayashi1

1School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, United States of America

2Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

3Department of Chemistry, Washington State University, Pullman, United States of America

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1School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, United States of America

2Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

3Department of Chemistry, Washington State University, Pullman, United States of America

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1School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, United States of America

2Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

3Department of Chemistry, Washington State University, Pullman, United States of America

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1School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, United States of America

2Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

3Department of Chemistry, Washington State University, Pullman, United States of America

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1School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, United States of America

2Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

3Department of Chemistry, Washington State University, Pullman, United States of America

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1School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, United States of America

2Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

3Department of Chemistry, Washington State University, Pullman, United States of America

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1School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, United States of America

2Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

3Department of Chemistry, Washington State University, Pullman, United States of America

Find articles by Slayden, O. in: PubMed | Google Scholar

1School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, United States of America

2Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

3Department of Chemistry, Washington State University, Pullman, United States of America

Find articles by MacLean, J. in: PubMed | Google Scholar

1School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, United States of America

2Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

3Department of Chemistry, Washington State University, Pullman, United States of America

Find articles by Sharma, A. in: PubMed | Google Scholar

1School of Molecular Biosciences, Center for Reproductive Biology, Washington State University, Pullman, United States of America

2Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, United States of America

3Department of Chemistry, Washington State University, Pullman, United States of America

Find articles by Hayashi, K. in: PubMed | Google Scholar

Published March 17, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI194136.
Copyright © 2026, Harvey et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 17, 2026 - Version history
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Abstract

This study investigated how chronic pelvic pain (CPP) develops using rhesus macaques with naturally occurring endometriosis and a multiple-lesion induction mouse model (MIM), as repeated retrograde menstruation is considered an underlying mechanism of endometriosis pathogenesis. MIM increased lesion numbers and elevated hypersensitivity. Elevated persistent glial cell activation was observed across multiple brain regions and/or spinal cords in MIM and rhesus macaques. Elevated TRPV1, SP, and CGRP expressions in the dorsal root ganglia (DRG) were persistent in MIM. MIM induced the severe disappearance of TIM4hi MHCIIlo residential macrophages and an influx of increased pro-inflammatory TIM4lo MHCIIhi macrophages in the peritoneal cavity. Cytokine levels were persistently elevated in MIM. Furthermore, dienogest (a synthetic progestin) and fingolimod (a selective immunosuppressor) reduced hyperalgesia and neuroinflammation. Our results indicate that recurrent retrograde menstruation can be a peripheral stimulus that induces nociceptive pain and creates a composite chronic inflammatory stimulus, leading to neuroinflammation and sensitization of the central nervous system. The circuits of neuroplasticity and stimulation of peripheral organs via a feedback loop of neuroinflammation may mediate widespread endometriosis-associated CPP. These findings in mice were further supported by results from the spontaneously developed advanced endometriosis in rhesus macaques via recurrent retrograde menstruation.

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