Background: Current non-invasive diagnostic methods for endometriosis lack sensitivity and specificity. In search for new diagnostic biomarkers for ovarian endometriosis, we used a hypothesis-generating targeted metabolomics approach. Methods: In a case-control study, we collected plasma of study participants and analysed their metabolic profiles. We selected a group of 40 patients with ovarian endometriosis who underwent laparoscopic surgery and a control group of 52 healthy women who underwent sterilization at the University Clinical Centre Ljubljana, Slovenia. Over 140 targeted analytes included glycerophospholipids, sphingolipids and acylcarnitines. The analytes were quantified by electrospray ionization tandem mass spectrometry. For assessing the strength of association between the metabolite or metabolite ratios and the disease, we used crude and adjusted odds ratios. A stepwise logistic regression procedure was used for selecting the best combination of biomarkers. Results: Eight lipid metabolites were identified as endometriosis-associated biomarkers due to elevated levels in patients compared with controls. A model containing hydroxysphingomyelin SMOH C16:1 andthe ratio between phosphatidylcholine PCaa C36:2 to etherphospholipid PCae C34:2, adjusted for the effect of age and the BMI, resulted in a sensitivity of 90.0%, a specificity of 84.3% and a ratio of the positive likelihood ratio to the negative likelihood ratio of 48.3. Conclusions: Our results suggest that endometriosis is associated with elevated levels of sphingomyelins and phosphatidylcholines, which might contribute to the suppression of apoptosis and affect lipid-associated signalling pathways. Our findings suggest novel potential routes for therapy by specifically blocking highly up-regulated isoforms of phosphpolipase A2 and lysophosphatidylcholine acyltransferase 4.
COBISS.SI-ID: 30025945
Oxidative metabolism of estrogens was studied in 31 ovarian endometriosis and 29 normal endometrium samples, by qPCR. Expression was monitored for genes encoding five estrogen hydroxylating, five hydroxy (OH)-estrogen conjugating, and three estrogen quinone detoxifying enzymes. CYP1B1, COMT, NQO1, and GSTP1 protein levels were determined using Western blotting and immunohistochemistry staining. Increased expression of CYP1A1, CYP3A7 and COMT, and higher levels of MB-COMT were seen in endometriosis, as compared to normal endometrium. Expression of CYP1B1, CYP3A5, SULT1A1 and NQO2 was unchanged, with comparable CYP1B1 protein levels. Expression of SULT1E1, SULT2B1, UGT2B7, NQO1, and GSTP1 was decreased. Three NQO1 isoforms were detected; NQO1c appears to be endometriosis-specific. Our data indicate a disturbed balance between phase I and II metabolizing enzymes in endometriosis, potentially leading to excessive OH-estrogen and altered ROS formation, and stimulation of proliferation of ectopic endometrium. This is the first report on disturbed expression of estrogen oxidative metabolism genes in ovarian endometriosis
COBISS.SI-ID: 30367193
Expression levels of genes encoding phases I and II estrogen-metabolizing enzymes: CYP1A1, CYP1A2, CYP1B1, CYP3A5, CYP3A7, SULT1A1, SULT1E1, SULT2B1, COMT, UGT2B7, and GSTP1 were studied by real-time PCR in 38 samples of cancerous and adjacent control endometrium. We found significantly lower levels of CYP1B1 and CYP3A7, higher levels of SULT2B1, UGT2B7 and GSTP1, and no differences in expression of COMT, CYP1A1, CYP3A5, SULT1E1 and SULT2A1 in the endometrial cancers. The CYP1B1 and COMT proteins were also examined by Western blotting and immunohistochemical staining, supporting the real-time PCR analysis. Lower levels of CYP1B1 detected in cancerous endometrium suggestits important role in control, precancerous tissue. Additionally, we showed for the first time higher protein levels of soluble COMT in cancerous endometrium, and higher levels of membrane-bound COMT in control, precancerousendometrium. The importance of the changed ratio between soluble and membrane-bound COMT still needs to be evaluated in further studies.
COBISS.SI-ID: 27490009
Endometrial cancer is the most common gynecological malignancy in the developed World. Based on their histopathology, clinical manifestation, and epidemiology, the majority of endometrial cancer cases can be divided into two groups: the more prevalent type 1 which is associated with unopposed estrogen exposure; and the less common type 2, which is usually not associated with hyper-estrogenic factors. This manuscript overviews the published data on the expression of genes encoding the estrogen biosynthetic enzymes, the phase I and phase II estrogen metabolic enzymes, and the estrogen receptors in endometrial cancer, at the mRNA, protein and enzyme activity levels. The potential role of altered expression of these enzymes and receptors in cancerous versus control endometrial tissue, and the implication of estrogens in tumor initiation and promotion, are discussed. Finally, based on the published data, a model of estrogen metabolism and actions is proposed for pre-cancerous and cancerous endometrial tissue, and the role of the estrogens in the progression of endometrial cancer from endometrial hyperplasia is suggested.
COBISS.SI-ID: 30741465
In the search for novel biomarkers of endometriosis, we selected 152 genes from the GeneLogic database based on results of genome-wide expression analysis of ovarian endometriosis, plus 20 genes related to estrogen metabolism and action. We then performed low-density array analysis of these 172 genes on 11 ovarian endometriosis samples and 9 control endometrium samples. Principal component analysis of the gene expression levels showed clear separation between the endometriosis and control groups. We identified 78 genes as differentially expressed. Based on Ingenuity pathway analysis, these differentially expressed genes were arranged into groups according to biological function. These analyses revealed that 32 differentially expressedgenes are estrogen related, 23 of which have not been reported previously in connection with endometriosis. Functional annotation showed that25 and 22 genes are associated with the biological terms "secreted" and "extracellular region", respectively. Differential expression of 4 out of 5 genes related to estrogen metabolism and action (ESR1, ESR2, PGR and BGN) was also confirmed by immunohistochemistry. Our study thus reveals differential expression of several genes that have not previously been associated with endometriosis and that encode potential novel biomarkers and drug targets.
COBISS.SI-ID: 28170457