Enhanced UGT1A1 Gene and Protein Expression in Endometriotic Lesions

The cellular function in endometriosis lesions depends on a highly estrogenic milieu. Lately, it is becoming evident that, besides the circulating levels of estrogens, the balance of synthesis versus inactivation (metabolism) of estrogens by intralesion steroid-metabolizing enzymes also determines the local net estrogen availability. In order to extend the knowledge of the role of estrogen-metabolizing enzymes in endometriosis, we investigated the gene and protein expression of a key uridine diphospho-glucuronosyltransferase (UGT) for estrogen glucuronidation, UGT1A1, in eutopic endometrial samples obtained from non-affected and endometriosis-affected women and also from endometriotic lesions. Although UGT1A1 messenger RNA (mRNA) expression was detected at similar frequencies in endometriotic lesions and in eutopic endometrial samples, the levels of mRNA expression were greater in deep-infiltrating endometriotic lesions and in non-deep-infiltrating lesions when compared with either control endometrium or eutopic endometrium from women with endometriosis. Overall, we observed that protein expression of UGT1A1 was significantly more frequent in samples from endometriotic lesions in comparison with endometria. In addition, expression of UGT1A1 protein was greater in deep-infiltrating than in non-deep-infiltrating endometriotic lesions. We suggest that the finding of increased expression of UGT1A1 in lesions versus endometria might be related to impairment of regulatory mechanisms, in response to a highly estrogenic milieu, and that this enzyme may be a new target for therapy. Similar content being viewed by others

Hum DW, Belanger A, Levesque E, et al. Characterization of UDP-glucuronosyltransferases active on steroid hormones. J Steroid Biochem Mol Biol. 1999;69(1–6):413–423. Chung LW, Coffey DS. Androgen glucuronide. II. Differences in its formation by human normal and benign hyperplastic prostates. Invest Urol. 1978;15(5):385–388. Adams JB, Phillips NS, Young CE. Formation of glucuronides of estradiol-17 beta by human mammary cancer cells. J Steroid Biochem. 1989;33(5):1023–1025. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–519. Huhtinen K, Desai R, Stahle M, et al. Endometrial and endometriotic concentrations of estrone and estradiol are determined by local metabolism rather than circulating levels. J Clin Endocrinol Metab. 2012;97(11):4228–4235. Piccinato CA, Neme RM, Torres N, et al. Increased expression of CYP1A1 and CYP1B1 in ovarian/peritoneal endometriotic lesions. Reproduction. 2016;151(6):683–692. Piccinato CA, Neme RM, Torres N, et al. Effects of steroid hormone on estrogen sulfotransferase and on steroid sulfatase expression in endometriosis tissue and stromal cells. J Steroid Biochem Mol Biol. 2016;158:117–126. Hevir N, Ribic-Pucelj M, Lanisnik Rizner T. Disturbed balance between phase I and II metabolizing enzymes in ovarian endome-triosis: a source of excessive hydroxy-estrogens and ROS? Mol Cell Endocrinol. 2013;367(1–2):74–84. Vandesompele J, De Preter K, Pattyn F, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3(7):RESEARCH0034. Stasinopoulos DM, Rigby RA. Generalized additive models for location scale and shape (GAMLSS) in R. J Stat Softw. 2008;23(7). doi:10.18637/jss.v023.i07 Lepine J, Bernard O, Plante M, et al. Specificity and regios-electivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium. J Clin Endocrinol Metab. 2004;89(10):5222–5232. Duguay Y, McGrath M, Lepine J, et al. The functional UGT1A1 promoter polymorphism decreases endometrial cancer risk. Cancer Res. 2004;64(3):1202–1207. Guillemette C, Levesque E, Rouleau M. Pharmacogenomics of human uridine diphospho-glucuronosyltransferases and clinical implications. Clin Pharmacol Ther. 2014;96(3):324–339. Delvoux B, Groothuis P, D’Hooghe T, Kyama C, Dunselman G, Romano A. Increased production of 17beta-estradiol in endometriosis lesions is the result of impaired metabolism. J Clin Endocrinol Metab. 2009;94(3):876–883. Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol. 2000;40:581–616. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Piccinato, C.A., Neme, R.M., Torres, N. et al. Enhanced UGT1A1 Gene and Protein Expression in Endometriotic Lesions. Reprod. Sci. 25, 1371–1375 (2018). https://doi.org/10.1177/1933719118764255 Published: Version of record: Issue date: DOI: https://doi.org/10.1177/1933719118764255