Lipidome variations in endometrial tissue of women with endometriosis and uterine myoma at different phases of menstrual cycle

• Dinara F. Salimova
• Natalia L. Starodubtseva
• Vitaliy V. Chagovets
• Alisa O. Tokareva
• Narine N. Tonoyan
• Stanislav V. Pavlovich
• Vladimir E. Frankevich

Abstract

Background. Endometriosis and uterine fibroids remain the leading causes of infertility in women of reproductive age. These hyperproliferative, hormone-dependent gynecological diseases are often accompanied by chronic pelvic pain, decreasing the life quality. Clarification of the underlying pathogenetic mechanisms is important to determine their etiology, and thereby to predict recurrence or disease development in various clinical and surgical approaches.

The aim of this study is to improve our understanding about the pathogenesis of these hyperproliferative disorders by comparing eutopic endometrial tissue lipid composition of 40 women with endometriosis and uterine fibroids at different phases of menstrual cycle.

Material and methods. A semi quantitative evaluation of the lipids in eutopic endometrium was carried out using HPLC-MS/MS of tissue organic extracts in positive and negative MS mode. The analysis revealed more than 247 molecular species of lipids, which can be divided into 6 classes: phosphatidylcholines, phosphatidyletha-nolamines, sphingomyelins, triglycerides, plasmalogens and cholesterol esters. The data were analyzed using a discriminant analysis by OPLS-DA method. The OPLS-DA statistical models for myoma (R²=63% and Q²=47%) and endometriosis (R²=80% and Q²=75%) showed good predictive ability for classification of eutopic endometrium at proliferative and secretory phases of menstrual cycle.

Results. The abundance of 16 lipids was significantly different in eutopic endometrium during menstrual cycle in endometriosis case and of 13 lipids in myoma, respectively. These lipids are involved directly in common features of these hyperproliferative disorders, including altered cell proliferation, angiogenesis, changes in the immune response. Further investigation of studied lipids may help elucidate the etiopathogenesis of these pathologies and guide the design of new therapeutics.

Keywords:mass spectrometry, lipidomics, endometriosis, myoma, menstrual cycle, pathogenesis, epithelium

Литература/References

1. Koninckx P.R., Ussia A., Keckstein J.,Adamyan L.V., Zupi E.,Wattiez A., Gomel V. Evidence-Based Medicine: Pandora's Box of Medical and Surgical Treatment of Endometriosis. J Minim Invasive Gynecol. 2018; 25: 360-5.

2. Ozawa Y., Murakami T., Terada Y.,Yaegashi N., Okamura K., Kuriyama S., et al. Management of the pain associated with endometriosis. Tohoku J Exp Med. 2006; 210: 175-88.

3. Li J., Gao Y., Guan L., Zhang H., Sun J., Gong X., et al. Discovery of phosphatidic acid, phosphatidylcholine, and phosphatidylserine as biomarkers for early diagnosis of endometriosis. Front Physiol. 2018; 9: 1-7.

4. Clemenza S., Sorbi F., Noci I., Capezzuoli, T., Turrini, I., Carriero, C.et al. From pathogenesis to clinical practice: Emerging medical treatments for endometriosis. Best Pract. Res Clin Obstet Gynaecol. 2018; 51: 92-101.

5. Prusinski Fernung L.E., Jones K., Mas A., Kleven D., Waller J.L., Al-Hendy A. Expanding upon the Human Myometrial Stem Cell Hypothesis and the Role of Race, Hormones, Age, and Parity in a Profibroid Environment. Am J Pathol. 2018; 188: 2293-2306.

6. Lewis T.D., Malik M., Britten J., San Pablo A.M.A., Catherino W.H. A Comprehensive Review of the Pharmacologic Management of Uterine Leiomyoma. Biomed Res Int. 2018; 2018: 2414609.

7. Patel B.G., Lenk E.E., Lebovic D.I., Shu Y., Yu J., Taylor R.N. Pathogenesis of endometriosis: Interaction between Endocrine and inflammatory pathways. Best Pract Res Clin Obstet Gynaecol. 2018; 50: 50-60.

8. Baranov V.S., Ivaschenko T.E., Yarmolinskaya M.I. Comparative systems genetics view of endometriosis and uterine leiomyoma: Two sides of the same coin? Syst Biol Reprod Med. 2016; 62: 93-105.

9. Lee Y.H., Tan C.W., Venkatratnam A., Tan C.S., Cui L., Loh S.F., et al. Dysregulated sphingolipid metabolism in endometriosis. J Clin Endocrinol Metab. 2014; 99: E1913-21.

10. Vouk K., Ribic-Pucelj M., Adamski J., Rizner T.L. Altered levels of acylcarnitines, phosphatidylcholines, and sphingomyelins in peritoneal fluid from ovarian endometriosis patients. J Steroid Biochem Mol Biol. 2016; 159: 60-9.

11. Doria M.L., McKenzie J.S., Mroz A., Phelps D.L., Speller A., Rosini F. et al. Epithelial ovarian carcinoma diagnosis by desorption electrospray ionization mass spectrometry imaging. Sci Rep. 2016; 6: 1-11.

12. Ctfkova E., Holcapek M., Ltsa M., Vrana D., Gatek J., Melichar B. Determination of lipidomic differences between human breast cancer and surrounding normal tissues using HILIC-HPLC/ESI-MS and multivariate data analysis. Anal Bioanal Chem. 2015; 407: 991-1002.

13. Han X. Lipidomics for studying metabolism. Nat Rev Endocrinol. 2016; 12: 668-79.

14. Noyes R.W., Hertig A.T., Rock J. Dating the endometrial biopsy. Obstet Gynecol Surv. 1950; 5: 561-4.

15. Vilella F., Ramirez L.B., Simon C. Lipidomics as an emerging tool to predict endometrial receptivity. Fertil Steril. 2013; 99: 1100-6.

16. Thevenot E.A., Roux A., Xu Y., Ezan E., Junot C. Analysis of the Human Adult Urinary Metabolome Variations with Age, Body Mass Index, and Gender by Implementing a Comprehensive Workflow for Univariate and OPLS Statistical Analyses. J Proteome Res. 2015; 14: 3322-35.

17. Fagone, P.; Jackowski, S. Phosphatidylcholine and the CDP-choline cycle. Biochim Biophys Acta Mol Cell Biol Lipids. 2013; 183: 523-32.

18. Borghese B., Mondon F., Noel J.-C., Fayt I., Mignot T.-M., Vaiman D. et al. Research Resource: Gene Expression Profile for Ectopic Versus Eutopic Endometrium Provides New Insights into Endometriosis Oncogenic Potential. Mol Endocrinol; 2008, 22: 2557-62.

19. Pradas I., Huynh K., Cabre R., Ayala V., Meikle P.J., Jove M., et al. Lipidomics reveals a tissue-specific fingerprint. Front Physiol. 2018; 9: 1-17.

20. Grandl M., Konovalova T., Id S.W., Orso E., Liebisch G., Schmitz G. Phosphatidylcholine and phosphatidylethanolamine plasmalogens in lipid loaded human macrophages; 2018: 1-21.

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