Abstract
Sensitivity and specificity of non-invasive diagnostic methods for endometriosis, especially at early stage, is not optimal. Clinical diagnostic indicator of cancer antigen 125 (CA125) performs poorly in diagnosing minimal endometriosis with a sensitivity of 24%. Therefore, it is urgent to explore novel diagnostic biomarkers. We evaluated metabolomic profile variation of eutopic endometrium between minimal-mild endometriosis patients and healthy women by ultra high performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS). Our study comprised 29 patients with laparoscopically confirmed endometriosis at stage I-II and 37 infertile women who underwent diagnostic laparoscopy combined with hysteroscopy from January 2014 to January 2015. Eutopic endometrium was collected by pipelle endometrial biopsy. The metabolites were quantified by UHPLC-ESI-HRMS. The best combination of biomarkers was then selected by performing step-wise logistic regression analysis with backward elimination. 12 metabolites were identified as endometriosis-associated biomarkers. The eutopic endometrium metabolomic profile of endometriosis patients was characterized by significant increase in concentration of hypoxanthine, L-arginine, L-tyrosine, leucine, lysine, inosine, omega-3 arachidonic acid, guanosine, xanthosine, lysophosphatidylethanolamine and asparagine. In contrast, concentration of uric acid was decreased. Metabolites were filtered by step-wise logistic regression with backward elimination and a model containing uric acid, hypoxanthine, and lysophosphatidylethanolamine were constructed. Receiver-operating characteristic (ROC) analysis confirmed the prognostic value of these parameters in diagnosing minimal/mild endometriosis with a sensitivity of 66.7%, a specificity of 90.0%. Metabolomics analysis of eutopic endometrium in endometriosis was effectively characterized by UHPLC-ESI-HRMS based metabolomics. Our study supports the importance of purine and amino acids metabolites in the pathophysiology of endometriosis and provides the potential biomarkers for semi-invasive diagnose of endometriosis at early stage.
Highlights
DESIGN: We evaluated metabolomic profile variation of eutopic endometrium between minimal-mild endometriosis patients and healthy women by ultra high performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS)
The eutopic endometrium metabolomic profile of endometriosis patients was characterized by significant increase in concentration of hypoxanthine, L-arginine, L-tyrosine, leucine, lysine, inosine, omega-3 arachidonic acid, guanosine, xanthosine, lysophosphatidylethanolamine and asparagine
Receiver-operating characteristic (ROC) analysis confirmed the prognostic value of these parameters in diagnosing minimal/ mild endometriosis with a sensitivity of 66.7%, a specificity of 90.0%
Summary
Endometriosis requires estrogen for development and growth. Levels of estrogen receptor beta (ERb) in endometriosis are reported to be 100 times higher than normal endometrial tissue and inhibition of ERb activity by an ERb selective antagonist suppresses endometriotic lesion growth in mice. Here, we assessed the role of ERb in the development of the early endometriotic lesion by examining the effect of ERb knock down on endometrial stromal cell (ESC) cell attachment and invasion. Levels of estrogen receptor beta (ERb) in endometriosis are reported to be 100 times higher than normal endometrial tissue and inhibition of ERb activity by an ERb selective antagonist suppresses endometriotic lesion growth in mice.. We assessed the role of ERb in the development of the early endometriotic lesion by examining the effect of ERb knock down on endometrial stromal cell (ESC) cell attachment and invasion. Established in vitro assays were used to assess WT and ERbKD tHESC attachment to peritoneal mesothelial cells (PMCs) and invasion through a monolayer of PMCs. Results were analyzed with unpaired t-tests. RESULTS: tHESCs with ERbKD demonstrated decreased protein expression by Western blot and densitometric analysis. CONCLUSIONS: ERbKD decreases tHESCs adhesion to and invasion through PMCs. ERb may serve as a future therapeutic target to decrease early endometriotic lesion formation. Reproductive Endocrinology and Infertility, Caracas Fertility Center, C.A., Caracas, Venezuela, Bolivarian Republic of
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