Repeatedly occurring retrograde menstruation intensifies central sensitization driven by neuroinflammation in endometriosis models
Madeleine E. Harvey, Mingxin Shi, Yeongseok Oh, Taylor M. Page, Debra A. Mitchell, Addie Luo, Ov D. Slayden, James A. MacLean, Anjali Sharma, Kanako Hayashi
Madeleine E. Harvey, Mingxin Shi, Yeongseok Oh, Taylor M. Page, Debra A. Mitchell, Addie Luo, Ov D. Slayden, James A. MacLean, Anjali Sharma, Kanako Hayashi
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Research Article Inflammation Reproductive biology

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

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 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 TIM4hiMHCIIlo residential macrophages and an influx of increased pro-inflammatory TIM4loMHCIIhi 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.

Authors

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

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Figure 10

Evaluation of the effects of dienogest and fingolimod on endometriosis-like lesions and hyperalgesia using a single or multiple lesion induction mouse model of endometriosis.

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Evaluation of the effects of dienogest and fingolimod on endometriosis-l...
(A) Experimental design for study 2 as described in Methods. (B) Comparison of lesion numbers and size in single- or multiple-induction mice at 7 weeks (day 49) after the last lesion induction between the PBS vehicle (drug control in animals with induced disease) and treatment groups (n = 6; animals without lesions in the single-induction group were included for all further analysis in study 2). If >1 lesion was observed, the average lesion size per animal was used for the analysis. (C) Evaluation of the effects of dienogest and fingolimod on endometriosis-associated abdominal and hind paw hyperalgesia by the von Frey test (n = 6/group). The group differences in lesion numbers and sizes were assessed using the Kruskal-Wallis test. For behavioral analysis, time-dependent differences within a group were assessed using the Kruskal-Wallis test comparing thresholds at different time points with those on day –1. To compare the effects of dienogest and fingolimod at each time point, the Kruskal-Wallis test was used to assess the differences among groups. Data are shown as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.