Epigallocatechin-3-Gallate Reduces Myometrial Infiltration, Uterine Hyperactivity, and Stress Levels and Alleviates Generalized Hyperalgesia in Mice Induced With Adenomyosis

Abstract

In an effort to search for novel therapeutics for adenomyosis, we sought to determine whether treatment with epigallocatechin-3-gallate (EGCG) would suppress the myometrial infiltration, improve pain behavior, lower stress level, and reduce uterine contractility in a mice model of adenomyosis. Adenomyosis was induced in 28 female ICR mice neonatally dosed with tamoxifen, while another 12 (group C) were dosed with solvent only, which served as a blank control. Starting from 4 weeks after birth, hot plate test was administrated to all mice every 4 weeks. At the 16th week, all mice induced with adenomyosis were randomly divided into 3 groups: low-dose EGCG (5 mg/kg), high-dose EGCG (50 mg/kg), and untreated. Group C received no treatment. After 3 weeks of treatment, the hot plate test was administered again, a blood sample was taken to measure the plasma corticosterone level by enzyme-linked immunosorbent assay, and then all mice were sacrificed. The depth of myometrial infiltration and uterine contractility were also evaluated. We found that the induction of adenomyosis resulted in progressive generalized hyperalgesia, along with elevated amplitude and frequency of uterine contractions as well as elevated plasma corticosterone levels. The EGCG treatment dose dependently suppressed myometrial infiltration, improved generalized hyperalgesia, reduced uterine contractility, and lowered plasma corticosterone levels. These results suggest that induced adenomyosis causes pain and elevates stress levels in mice. Uterine hyperactivity may contribute to dysmenorrhea in women with adenomyosis who might also have elevated stress level due to pain. The EGCG appears to be a promising compound for treating adenomyosis.

Stress Management Affects Outcomes in the Pathophysiology of an Endometriosis Model

“…33,34 Of relevance to our study, high levels of uterine contractility have been shown to be associated with dysmenorrhea in women with symptomatic adenomyosis, in a context of high stress levels and pain. 35 Ongoing studies in our laboratories are investigating the effect of stress on the pain threshold and the influence of the brain-gut axis in these changes.…”

Possible Loss of GABAergic Inhibition in Mice With Induced Adenomyosis and Treatment With Epigallocatechin-3-Gallate Attenuates the Loss With Improved Hyperalgesia

“…18,19 We have previously shown that mice with induced adenomyosis exhibit increased uterine hyperactivity, general hyperalgesia, and elevated plasma corticosterone levels. 9,10,20 We have also shown that treatment with valproic acid, a histone deacetylase (HDAC) inhibitor, is efficacious in improving generalized hyperalgesia resulting from induced adenomyosis in mice. 20 Treatment with levo-tetrahydropalmatine, an analgesia, and andrographolide, an NF-kB inhibitor, can retard myometrial infiltration, reduce uterine contractility, and alleviate generalized hyperalgesia in mice with induced adenomyosis.…”

“…9 In addition, we have recently shown that treatment with epigallocatechin-3-gallate (EGCG), a major component of green tea, dose dependently suppressed myometrial infiltration, improved generalized hyperalgesia, reduced uterine contractility, and lowered plasma corticosterone levels. 10 Based on the same experiment as we reported recently, 10 we sought to determine in this study as whether the induction of adenomyosis would cause any changes in the NRM, and, if so, whether the change would correlate with the documented change in hotplate latency in mice with or without adenomyosis. We also sought to determine, as a sequel to the study previously reported, 10 whether the treatment of EGCG would rectify the change in NRM resulting from adenomyosis induction.…”

“…10 Based on the same experiment as we reported recently, 10 we sought to determine in this study as whether the induction of adenomyosis would cause any changes in the NRM, and, if so, whether the change would correlate with the documented change in hotplate latency in mice with or without adenomyosis. We also sought to determine, as a sequel to the study previously reported, 10 whether the treatment of EGCG would rectify the change in NRM resulting from adenomyosis induction. In addition, we also performed an immunohistochemistry analysis of progesterone receptor isoform B (PR-B), NF-kB, cycloxygenase 2 (COX-2), OTR, transient receptor potential vanilloid type 1 (TRPV1), collagen I, and collagen IV in ectopic/eutopic endometrium/myometrium, counted the number of macrophages infiltrating into the ectopic endometrium, and correlated these measurements with the depth of myometrial infiltration, contractile amplitude and frequency, and posttreatment hotplate latency and plasma corticosterone levels.…”

“…6,7 Uterine hyperactivity has also been reported in women with adenomyosis 8 and mouse with induced adenomyosis. 9,10 In conjunction with hyperinnervation, the uterine hyperactivity, likely mediated mainly through oxytocin receptor (OTR), 8 constitutes afferent sensory signals that are transmitted to the brain and ultimately interpreted as dysmenorrhea or pain in women with adenomyosis.…”