Circulating estradiol and its biologically active metabolites in endometriosis and in relation to pain symptoms

Abstract

ObjectivesEndometriosis (EM) is an estrogen-dominant inflammatory disease linked to infertility that affects women of reproductive age. EM lesions respond to hormonal signals that regulate uterine tissue growth and trigger inflammation and pain. The objective of this study was to evaluate whether estradiol (E2) and its biologically active metabolites are differentially associated with EM given their estrogenic and non-estrogenic actions including proliferative and inflammatory properties.DesignWe performed a retrospective study of 209 EM cases and 115 women without EM.MethodsPain-related outcomes were assessed using surveys with validated scales. Preoperative serum levels of estradiol (E2) and estrone (E1), their 2-, 4- and 16- hydroxylated (OH) and methylated (MeO) derivatives (n=16) were measured by mass spectrometry. We evaluated the associations between estrogen levels and EM anatomic sites, surgical stage, risk of EM, and symptoms reported by women. Spearman correlations established the relationships between circulating steroids.ResultsOf the sixteen estrogens profiled, eleven were detected above quantification limits in most individuals. Steroids were positively correlated, except 2-hydroxy 3MeO-E1 (2OH-3MeO-E1). Higher 2OH-3MeO-E1 was linked to an increased risk of EM (Odd ratio (OR)=1.91 (95%CI 1.09-3.34); P=0.025). Ovarian EM cases displayed enhanced 2-hydroxylation with higher 2MeO-E1 and 2OH-E1 levels (P< 0.009). Abdominal, pelvic and back pain symptoms were also linked to higher 2OH-3MeO-E1 levels (OR=1.86; 95%CI 1.06-3.27; P=0.032).ConclusionsThe 2-hydroxylation pathway emerges as an unfavorable feature of EM, and is associated with ovarian EM and pain related outcomes.

The IL-33-ST2 axis plays a vital role in endometriosis via promoting epithelial–mesenchymal transition by phosphorylating β-catenin

“…Oxidative stress triggers IL-33 secretion during airway inflammation [ 30 ]. Similarly, ectopic endometriotic cells also survive in oxidative stress, hypoxic environments, transforming growth factor-β1 (TGF-β1) [ 31 ], and estradiol (E 2 ) [ 32 ] have been recognized as essential factors in EMs development. Therefore, we explored whether these factors could trigger IL-33 secretion by ESCs.…”

Estrogen Administration Enhances the Adverse Effects of Cigarette Smoking on the Heart in Cycling Female Mice

“…These ndings can be attributed to CS increasing the hepatic metabolism of oral estrogens, thus preventing the body from using drug-derived estrogens by converting them to forms that are less active. In addition, the 2hydroxylation of estradiol results in the production of metabolites that have been associated with endometriosis and pain [25].…”

Epigenetic Regulation Interplays with Endometriosis Pathogenesis in Low-Birth-Weight Patients via the Progesterone Receptor B–VEGF-DNMT1 Axis

“…Estrogen itself stimulates the growth of endometriosis, while progesterone inhibits the occurrence of endometriosis. Therefore, it can be concluded that progesterone resistance in endometriosis leads to increasing growth of endometrial tissue [ 12 , 13 ]. Furthermore, progesterone resistance and the uncontrolled increase of estradiol (E2) levels in endometrial tissue initiate the increase of one angiogenic factor, namely VEGF, that causes angiogenesis and neurogenesis in endometriosis.…”

“…Progesterone resistance and the uncontrolled increase of the estradiol level in endometrial tissue also initiates an increase of vascular endothelial growth factor (VEGF) that causes angiogenesis and neurogenesis in endometriosis. All of the above mechanisms lead to the development and progression of endometriosis [ 4 , 13 , 14 ].…”