Activated glucocorticoid and eicosanoid pathways in endometriosis
ABSTRACT To define altered gene expression networks in endometriosis.
Experiments using endometriotic tissues and primary cells.
Division of Reproductive Biology Research, Northwestern University.
Matched samples of eutopic endometrium and ovarian endometriosis (n = 8 patients) were analyzed by microarray and verified in a separate set of tissues (n = 6 patients). Experiments to define signaling pathways were performed in primary endometriotic stromal cells (n = 12 patients).
Using a genome-wide in vivo approach, we identified 1,366 differentially expressed genes and a new gene network favoring increased glucocorticoid levels and action in endometriosis.
Transcript and protein levels of 11β-hydroxysteroid dehydrogenase (HSD11B1), which produces cortisol, the biologically active glucocorticoid, were strikingly higher, whereas messenger RNA (mRNA) levels of the cortisol-degrading HSD11B2 enzyme were significantly lower in endometriotic tissue. Glucocorticoid receptor mRNA and protein levels were significantly higher in endometriosis. The inflammatory cytokine tumor necrosis factor robustly induced mRNA and protein levels of HSD11B1 and glucocorticoid receptor but suppressed HSD11B2 mRNA in primary endometriotic stromal cells, suggesting that tumor necrosis factor stimulates cortisol production and action. We also uncovered a subset of genes critical for prostaglandin synthesis and degradation, which favor high eicosanoid levels and activity in endometriosis.
The proinflammatory milieu of the endometriotic lesion stimulates cortisol synthesis and action in endometriotic lesions.
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ABSTRACT: During early pregnancy in sheep, the elongating conceptus secretes interferon-τ (IFNT) and the conceptus as well as endometrial epithelia produce prostaglandins (PG) via PG synthase 2 (PTGS2) and cortisol via hydroxysteroid (11-β) dehydrogenase 1 (HSD11B1). Ovarian progesterone induces and PG and IFNT stimulates endometrial HSD11B1 expression and keto-reductase activity as well as many epithelial genes that govern trophectoderm proliferation, migration, and attachment during elongation. The primary aim of these studies was to test the hypothesis that HSD11B1-derived cortisol has a biological role in endometrial function and conceptus development during early pregnancy in sheep. In study 1, cyclic ewes received vehicle, cortisol, PF 915275 (PF; a selective inhibitor of HSD11B1), cortisol and PF, meloxicam (a selective inhibitor of PTGS2), cortisol and meloxicam, recombinant ovine IFNT, or IFNT and PF into the uterus from day 10 to day14 after estrus. Cortisol and IFNT stimulated endometrial HSD11B1 expression and activity, increased endometrial PTGS2 activity and the amount of PG in the uterine lumen, and up-regulated many conceptus elongation-related genes in the endometrium. Some effects of cortisol and IFNT were mediated by PTGS2-derived PG. In study 2, bred ewes received PF 915275 or recombinant ovine IFNT and into the uterus from day 10 to day 14 after mating. Inhibition of HSD11B1 activity in utero prevented conceptus elongation, whereas IFNT rescued conceptus elongation in PF-infused ewes. These results suggest that HSD11B1-derived cortisol mediates, in part, actions of ovarian progesterone and the conceptus on endometrial function and support the hypothesis that IFNT, PG, and cortisol coordinately regulate endometrial functions important for conceptus elongation and implantation during early pregnancy in sheep.Endocrinology 12/2012; 154(2). DOI:10.1210/en.2012-1909 · 4.64 Impact Factor
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ABSTRACT: In this study, we sought to determine whether resveratrol (RSV), a nonhormonal compound, would suppress the myometrial infiltration, improve pain behavior, lower stress level, improve the expression of some proteins known to be involved in adenomyosis, 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, serving as a blank control. Starting from 4 weeks after birth, hotplate test was administrated to all mice every 4 weeks. At the 16th week, all mice with induced adenomyosis were randomly divided into 3 groups: low-dose RSV (2 mg/kg), high-dose RSV (3 mg/kg), and untreated. Group C received no treatment. After 3 weeks of treatment, they were hotplate tested again, their uterine horns and brains were harvested, and a blood sample was taken to measure the plasma corticosterone (CORT) level by enzyme-linked immunosorbent assay. The left uterine horn was used for immunohistochemistry analysis. The brain stem nucleus raphe magnus (NRM) sections were subjected to immunofluorescence staining for glutamic acid decarboxylase isoform 65 (GAD65). The depth of myometrial infiltration and uterine contractility was evaluated. We found that RSV is well tolerated and that it dose dependently suppressed myometrial infiltration, improved generalized hyperalgesia, reduced uterine contractility and lowered plasma CORT levels, and improved the expression of some proteins known to be involved in adenomyosis. It also elevated the number of GAD65-expressing neurons in the brain stem NRM, possibly boosting the GABAergic inhibition of pain due to adenomyosis. Therefore, RSV appears to be a promising compound for treating adenomyosis. © The Author(s) 2015.Reproductive sciences (Thousand Oaks, Calif.) 05/2013; 20(12). DOI:10.1177/1933719113488455 · 2.18 Impact Factor
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ABSTRACT: PURPOSE OF REVIEW: Endometriosis is a common gynecologic disorder characterized by the displacement of endometrial tissue to ectopic locations. Although predisposition to endometriosis is likely multifactorial, a genetic component is evident. The biochemistry of the disorder is an area of active investigation with translational potential. This review synopsizes recent developments regarding the molecular underpinnings of endometriosis. RECENT FINDINGS: Significant advancements in understanding the molecular hallmarks of endometriosis have occurred in recent years. Inflammation, attenuated progesterone action, and neuroangiogenesis constitute emerging themes in the pathophysiology of endometriosis. SUMMARY: Delineation of the biochemical processes involved in endometriosis has important implications for clinical care. The discovery of a sufficiently sensitive and specific biomarker for the nonsurgical detection of endometriosis promises earlier diagnosis and prevention of deleterious sequelae. Understanding the inflammatory cause, attenuated progesterone action at the level of the endometrium, and neuronal sensitization of endometriotic lesions has facilitated development of novel therapeutic approaches for associated pain and infertility.Current opinion in obstetrics & gynecology 06/2013; DOI:10.1097/GCO.0b013e3283630d56 · 2.37 Impact Factor