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: Endometriosis is defined as the presence of endometrial glands and stroma in ectopic locations and may be associated with local and systemic inflammatory processes. Copeptin is elevated in acute and chronic inflammation conditions. The aim of the present study was to determine whether serum copeptin levels were altered in women with endometriosis and played a role in the pathophysiology of the disease. A total of 86 women were recruited for this case-control study. 50 patients with surgically proven endometriosis were included, while 36 patients without endometriosis comprised the control group. Patients were classified as having minimal, mild, moderate and severe disease in accordance with American Society of Reproductive Medicine revised classification. Two subgroups were formed by combining patients with minimal and mild disease and with moderate and severe disease (Stage 1-2, stage 3-4; respectively). Levels of copeptin, tumor markers (CA-125, CA-19-9, CA-15-3) and C-reactive protein in serum were measured. Serum copeptin, CA-125, CA-15-3 and CA-19-9 levels were higher in the endometriosis group (p: 0.002; 0.001; 0.017; 0.015; respectively). Copeptin and CA-19-9 levels were significantly higher in stage 3-4 group as compared to stage 1-2 group (p: 0.004; 0.036 respectively). Serum copeptin levels were positively correlated with stage of the disease and size of endometriomas. ROC analysis revealed that CA-125 had the highest AUC for predicting endometriosis (0.938; 95 % confidence interval 0.882-0.993; p: 0.001). Serum copeptin levels were significantly higher in patients with endometriosis as compared to healthy controls. Moreover, severity of the disease was correlated with serum copeptin levels.Archives of Gynecology 02/2014; DOI:10.1007/s00404-014-3163-2 · 1.28 Impact Factor
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ABSTRACT: We studied the effect of lipopolysaccharide (LPS), proinflammatory cytokines (tumor necrosis factor a [TNF-a] and interleukin [IL]-1b), and anti-inflammatory cytokines (IL-4 and IL-10) on leukotriene (LT) A4 hydrolase and LTC4 synthase (LTCS) protein expression in, and LTB4 and LTC4 secretion from, an inflamed porcine endometrium. On day 3 of the estrous cycle (day 0 of the study), 50 mL of either saline or Escherichia coli suspension (109 CFU/mL) was injected into each uterine horn of gilts (n ¼ 12 per group). Endometrial explants, obtained 8 and 16 days later, were incubated for 24 h with LPS (10 or 100 ng/mL of medium), TNF-a, IL-1b, IL-4, and IL-10 (each cytokine: 1 or 10 ng/mL of medium). Although acute endometritis developed in all bacteria-inoculated gilts, a severe form of acute endometritis was diagnosed more often on day 8 of the study than on day 16. The amount of the LTA4 hydrolase (LTAH) protein in the inflamed endometrium on day 8 was greater after applying the lower dose of TNF-a (P < 0.001) and both doses of IL-1b (P < 0.001) and IL-4 (1 ng, P < 0.01 and 10 ng, P < 0.001) than in the saline-treated uteri. A similar situation was observed in the case of the inflamed tissue on day 16 in response to LPS (100 ng, P < 0.01), TNF-a (10 ng, P < 0.05), and IL-4 (1 ng, P < 0.001). The content of LTC4 synthase in the inflamed endometrium on day 8 was reduced by LPS (100 ng, P < 0.05), IL-1b (10 ng, P < 0.05), IL-4 (1 and 10 ng, P < 0.05), and IL-10 (1 ng, P < 0.01) but increased after the application of LPS (100 ng, P < 0.05) and TNF-a (1 and 10 ng, P < 0.001), IL-1b, and IL-4 (1 ng, P < 0.05 and 10 ng, P < 0.001) on day 16. On day 8, endometrial secretion of LTB4 from the saline-injected and E coli-injected organs was similar in response to all of the used mediators. On the other hand, the contents of LTB4 in the medium decreased after incubating the inflamed tissues from day 16 with TNF-a (1 ng, P < 0.05 and 10 ng, P < 0.01), IL-1b (1 ng, P < 0.01), and IL-10 (10 ng, P < 0.05) compared with the saline-treated ones. Secretion of LTC4 from the inflamed uteri on day 8 was elevated by the lower doses of TNF-a (P < 0.01) and IL-10 (P < 0.05), whereas on day 16, such an effect occurred in response to the higher doses of IL-4 (P < 0.01) and IL-10 (P < 0.05). The obtained results show that pro- and anti-inflammatory mediators participate in the synthesis/ secretion of LTs from an inflamed porcine endometrium. Our data suggest that inflammatory mediators may indirectly affect the processes regulated by LTs by influencing LT production.Domestic Animal Endocrinology 09/2014; 49(49):49-59. DOI:10.1016/j.domaniend.2014.05.001 · 1.78 Impact Factor