Retinoic acid receptor alpha expression in endometrioid heterotopias and the endometrium of patients with endometriosis

BACKGROUND: Vitamin A is a fat-soluble compound, which is a biologically inactive food form and undergoes transformation by cytosolic alcohol dehydrogenases and microsomal retinol dehydrogenases into retinaldehyde, followed by oxidation by retinaldehyde dehydrogenases 1, 2 and 3 into retinoic acid. All-trans-retinoic acid has been identified as an active metabolite of retinoic acid, indirectly participating in various processes: differentiation, proliferation and apoptosis. Based on a number of studies, the role of retinoic acid and its receptors in various diseases has been proven. For example, the destruction of the RAR-β gene by the integration of the hepatitis B virus into its loci can be a factor in the development of human hepatocellular carcinoma. Subsequently, it was described that the characteristic point of interruption of translocation t(15:17), observed in acute promyelocytic leukemia, was located at the locus encoding retinoic acid receptor-α. As a result, in patients with acute promyelocytic leukemia, complete remission of the disease could often be achieved by treatment with high doses of all-trans-retinoic acid. Existing data on the ability of retinol to influence the processes of differentiation, proliferation, and apoptosis indicate that retinol may be involved in the pathogenesis of endometriosis, but the mechanisms of its effect on the disease are subject to further study. AIM: The aim of this study was to evaluate the retinoic acid receptor alpha expression in endometrioid heterotopias and the endometrium of patients with different endometriosis stages according to the Revised American Society for Reproductive Medicine classification.

This was a prospective study to determine the retinoic acid receptor alpha expression in the endometrium and endometrioid heterotopias of patients with endometriosis (n = 28) and of the control group (n = 10).

The retinoic acid receptor alpha expression in endometrioid heterotopias was lower compared to the eutopic endometrium of patients with endometriosis and the endometrium of patients in the control group by 3.4 and two times, respectively (p < 0.001; the Kruskal – Wallis method).

The data obtained indicate the involvement of retinol in the pathogenesis of endometriosis. Despite the relative increase in retinol level in the peripheral blood and peritoneal fluid in patients with endometriosis compared to the control group, shown in our previous studies, the reduced retinoic acid receptor alpha expression in endometrioid heterotopias does not allow for full binding of vitamin A to the receptor and is accompanied by its improper metabolism. Full Text About the authors Chimnaz I. kyzy Seyidova The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott Author for correspondence. Email: [email protected] ORCID iD: 0000-0002-6800-8661 MD Russian Federation, Saint PetersburgMaria I. Yarmolinskaya The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott Email: [email protected] ORCID iD: 0000-0002-6551-4147 SPIN-code: 3686-3605 MD, Dr. Sci. (Medicine), Professor, Professor of the Russian Academy of Sciences Russian Federation, Saint PetersburgReferences - Semba RD. On the “discovery” of vitamin A. Ann. Nutr. Metab. 2012;61(3):192–198. doi: 10.1159/000343124. - Niederreither K, Dollé P. Retinoic acid in development: towards an integrated view. Nat Rev Genet. 2008;9(7):541–553. doi: 10.1038/nrg2340 - Osanai M, Takasawa A, Takasawa K, et al. Retinoic acid metabolism in cancer: potential feasibility of retinoic acid metabolism blocking therapy. Med Mol Morphol. 2023;56(1):1–10. doi: 10.1007/s00795-022-00345-6 - Khalil S, Bardawil T, Stephan C, et al. Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects. J Dermatol Treat. 2017;28(8):684–696. doi: 10.1080/09546634.2017.1309349 - Rhinn M, Dollé P. Retinoic acid signalling during development. Development. 2012;139(5):843–858. doi: 10.1242/dev.065938 - Dabrock A, Ernesti N, Will F, et al. RAR-Dependent and RAR-Independent RXR signaling in stem-like glioma cells. Int J Mol Sci. 2023;24(22):16466. doi: 10.3390/ijms242216466 - Ross AC, Zolfaghari R. Cytochrome P450s in the regulation of cellular retinoic acid metabolism. Annu Rev Nutr. 2011;31:65–87. doi: 10.1146/annurev-nutr-072610-145127 - Petkovich M, Chambon P. Retinoic acid receptors at 35 years. J Mol Endocrinol. 2022;69(4):T13–T24. doi: 10.1530/JME-22-0097 - Peinemann F, van Dalen EC, Tushabe DA, et al. Retinoic acid post consolidation therapy for high-risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation. Cochrane Database Syst Rev. 2015;1. doi: 10.1002/14651858.CD010685.pub2 - Yarmolinskaya MI, Seyidova ChI, Tkachenko NN. Retinol and endometriosis – is everything simple in pathogenesis? Farmateka. 2023;30(4–5):60–66. EDN: FYIRZL doi: 10.18565/pharmateca.2023.4-5.60-66 - Aylamazyan EK, Yarmolinskaya MI, Molotkov AS, et al. Classifications of endometriosis. Journal of Obstetrics and Women’s Diseases. 2017;66(2):77–92. EDN: YNBWDV doi: 10.17816/JOWD66277-92 - Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817–821. doi: 10.1016/s0015-0282(97)81391-x - Tanabe K, Utsunomiya H, Tamura M, et al. Expression of retinoic acid receptors in human endometrial carcinoma. Cancer Sci. 2008;99(2):267–271. doi: 10.1111/j.1349-7006.2007.00684.x - Lee JC, Kim SH, Oh YS, et al. Increased expression of retinol-binding protein 4 in ovarian endometrioma and its possible role in the pathogenesis of endometriosis. Int J Mol Sci. 2021;22(11):5827. doi: 10.3390/ijms22115827 - Pierzchalski K, Taylor RN, Nezhat C, et al. Retinoic acid biosynthesis is impaired in human and murine endometriosis. Biol Reprod. 2014;91(4):84. doi: 10.1095/biolreprod.114.119677 - Yoo HS, Cockrum M.A., Napoli J.L. Cyp26a1 supports postnatal retinoic acid homeostasis and glucoregulatory control. J Biol Chem. 2023;299(5):104669. doi: 10.1016/j.jbc.2023.104669 - Casey ML, MacDonald PC, Andersson S. 17 beta-Hydroxysteroid dehydrogenase type 2: chromosomal assignment and progestin regulation of gene expression in human endometrium. J Clin Invest. 1994;94(5):2135–2141. doi: 10.1172/JCI117569 - Cheng YH, Yin P, Xue Q, et al. Retinoic acid (RA) regulates 17beta-hydroxysteroid dehydrogenase type 2 expression in endometrium: interaction of RA receptors with specificity protein (SP) 1/SP3 for estradiol metabolism. J Clin Endocrinol Metab. 2008;93(5):1915–1923. doi: 10.1210/jc.2007-1536 - Çakıroğlu Y, Confino R, Pavone ME. Retinoid metabolism in endometriosis. Journal of Endometriosis and Pelvic Pain Disorders. 2017;9(4):232–238. doi: 10.5301/jeppd.5000309 - Yilmaz BD, Bulun SE. Endometriosis and nuclear receptors. Hum Reprod Update. 2019;25(4):473–485. doi: 10.1093/humupd/dmz005 - Pavone ME, Reierstad S, Sun H, et al. Altered retinoid uptake and action contributes to cell survival in endometriosis. J Clin Endocrinol Metab. 2010;95(11):E300–9. doi: 10.1210/jc.2010-0459 - Pavone ME, Dyson M, Reirstad S, et al. Endometriosis expresses a molecular pattern consistent with decreased retinoid uptake, metabolism and action. Hum Reprod. 2011;26(8):2157–2164. doi: 10.1093/humrep/der172 - Pavone ME, Malpani S, Dyson M, et al. Altered retinoid signaling compromises decidualization in human endometriotic stromal cells. Reproduction. 2017;154(3):207–216. doi: 10.1530/REP-16-0592 - Wang X, Allen C, Ballow M. Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages. J Clin Immunol. 2007;27(2):193–200. doi: 10.1007/s10875-006-9068-5 - Wieser F, Wu J, Shen Z, et al. Retinoic acid suppresses growth of lesions, inhibits peritoneal cytokine secretion, and promotes macrophage differentiation in an immunocompetent mouse model of endometriosis. Fertil Steril. 2012;97(6):1430–1407. doi: 10.1016/j.fertnstert.2012.03.004 - Schug TT, Berry DC, Shaw NS, et al. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell. 2007;129(4):723–33. doi: 10.1016/j.cell.2007.02.050