Hormonal Pathways and Regulatory Factors That Lead to Endometrial Disease

doi:10.12280/gjfckx.20240269

Abstract

Abstract:

The development and function of the endometrium are highly dependent on the cyclic secretion of steroid hormones and the expression of their homologous receptors, the most important of which are estrogen and progesterone and their receptors. Estrogen and progesterone enable the endometrium to have a proliferative and secretory phase, maintain a normal menstrual cycle, and prepare for pregnancy. Dysregulation of estrogen and progesterone can lead to a series of diseases such as endometrial cancer, endometrial hyperplasia, and endometriosis, causing serious health problems. Under pathological conditions, estrogen interacts with estrogen receptors to promote excessive proliferation of the endometrium, which is closely related to the increased risk of endometrial lesions. However, progesterone can effectively inhibit the proliferative effect of estrogen, but when the expression of progesterone receptors is abnormal or when progesterone resistance occurs, it can lead to progesterone dysfunction. Effective treatment of endometrial-related diseases depends on the understanding of hormone pathways. This article reviews the hormone pathways and regulatory factors that cause endometrial diseases, with a view to providing reference for the clinical development of new drugs that can effectively prevent and improve treatment outcomes of endometrial diseases.

Key words: Endometrial neoplasms, Endometrial hyperplasia, Endometriosis, Gonadal steroid hormones, Signal transduction, Molecular targeted therapy

GUO Xi, WEI Jia, YANG Yong-xiu. Hormonal Pathways and Regulatory Factors That Lead to Endometrial Disease[J]. Journal of International Obstetrics and Gynecology, 2024, 51(4): 395-400.

References 29

[1]	Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3):209-249. doi: 10.3322/caac.21660.
[2]	Abdul Hamid F, Abu MA, Abdul Karim AK, et al. Sex Steroid Receptors in Polycystic Ovary Syndrome and Endometriosis: Insights from Laboratory Studies to Clinical Trials[J]. Biomedicines, 2022, 10(7):1705. doi: 10.3390/biomedicines10071705.
[3]	Yu K, Huang ZY, Xu XL, et al. Estrogen Receptor Function: Impact on the Human Endometrium[J]. Front Endocrinol(Lausanne), 2022, 13:827724. doi: 10.3389/fendo.2022.827724.
[4]	Hojnik M, Sinreih M, Anko M, et al. The Co-Expression of Estrogen Receptors ERα, ERβ, and GPER in Endometrial Cancer[J]. Int J Mol Sci, 2023, 24(3):3009. doi: 10.3390/ijms24033009.
[5]	Pu H, Wen X, Luo D, et al. Regulation of progesterone receptor expression in endometriosis, endometrial cancer, and breast cancer by estrogen, polymorphisms, transcription factors, epigenetic alterations, and ubiquitin-proteasome system[J]. J Steroid Biochem Mol Biol, 2023,227:106199. doi: 10.1016/j.jsbmb.2022.106199.
[6]	Wu J, Xue Y, Lin L, et al. Expression and correlation of Bcl-2, ER and PR in endometrial hyperplasia[J]. Minerva Med, 2023, 114(2):269-271. doi: 10.23736/S0026-4806.22.08015-6.
[7]	Wang L, Lv Q, Wu P, et al. RNA-seq and ATAC-seq analysis of CD163+ macrophage-induced progestin-insensitive endometrial cancer cells[J]. Cancer Med, 2023, 12(5):5964-5978. doi: 10.1002/cam4.5396.
[8]	Ruan GY, Ye LX, Lin JS, et al. An integrated approach of network pharmacology, molecular docking, and experimental verification uncovers kaempferol as the effective modulator of HSD17B1 for treatment of endometrial cancer[J]. J Transl Med, 2023, 21(1):204. doi: 10.1186/s12967-023-04048-z.
[9]	Michalczyk K, Kapczuk P, Witczak G, et al. The Associations between Metalloestrogens, GSTP1, and SLC11A2 Polymorphism and the Risk of Endometrial Cancer[J]. Nutrients, 2022, 14(15):3079. doi: 10.3390/nu14153079.
[10]	Costas L, Frias-Gomez J, Peinado FM, et al. Total Effective Xenoestrogen Burden in Serum Samples and Risk of Endometrial Cancer in the Spanish Screenwide Case-Control Study[J]. Environ Health Perspect, 2024, 132(2):27012. doi: 10.1289/EHP13202.
[11]	Hoang LN, Lee SJ. Casein kinase 1 controls the shuttling of epidermal growth factor receptor and estrogen receptor in endometrial carcinoma induced by breast cancer hormonal therapy: Relevance of GPER1/Src[J]. Cell Signal, 2023,108:110733. doi: 10.1016/j.cellsig.2023.110733.
[12]	Chen H, Li L, Liu H, et al. PAX2 is regulated by estrogen/progesterone through promoter methylation in endometrioid adenocarcinoma and has an important role in carcinogenesis via the AKT/mTOR signaling pathway[J]. J Pathol, 2024, 262(4):467-479. doi: 10.1002/path.6249.
[13]	华腾, 吴婷婷, 汪宏波. 雌激素受体及其变异体与子宫内膜癌的关系[J]. 国际妇产科学杂志, 2014, 41(6):599-602.
[14]	Wu MH, Hsieh YH, Lin CL, et al. Licochalcone A induces endoplasmic reticulum stress-mediated apoptosis of endometrial cancer cells via upregulation of GRP78 expression[J]. Environ Toxicol, 2024, 39(5):2961-2969. doi: 10.1002/tox.24156.
[15]	Wang H, Ma X, Jiang Z, et al. Estrogen promotes the proliferation and migration of endometrial cancer cells by upregulating the expression of lncRNA HOTAIR[J]. Gynecol Endocrinol, 2023, 39(1):2269248. doi: 10.1080/09513590.2023.2269248.
[16]	Hernández-Silva CD, Villegas-Pineda JC, Pereira-Suárez AL. Expression and Role of the G Protein-Coupled Estrogen Receptor (GPR30/GPER) in the Development and Immune Response in Female Reproductive Cancers[J]. Front Endocrinol(Lausanne), 2020,11:544. doi: 10.3389/fendo.2020.00544.
[17]	Li Y, Jia Y, Bian Y, et al. Autocrine motility factor promotes endometrial cancer progression by targeting GPER-1[J]. Cell Commun Signal, 2019, 17(1):22. doi: 10.1186/s12964-019-0336-4. pmid: 30836961
[18]	Deng J, Wang W, Yu G, et al. MicroRNA-195 inhibits epithelial-mesenchymal transition by targeting G protein-coupled estrogen receptor 1 in endometrial carcinoma[J]. Mol Med Rep, 2019, 20(5):4023-4032. doi: 10.3892/mmr.2019.10652.
[19]	Xing B, Zhang X, Gu X, et al. Explore the alterations of downstream molecular pathways caused by ARID1A mutation/knockout in human endometrial cancer cells[J]. J Cancer Res Clin Oncol, 2023, 149(19):17529-17541. doi: 10.1007/s00432-023-05471-x. pmid: 37906351
[20]	Sun Y, Zhang S, Zhang X, et al. AURKA Enhances the Glycolysis and Development of Ovarian Endometriosis Through ERβ[J]. Endocrinology, 2024, 165(4):bqae018. doi: 10.1210/endocr/bqae018.
[21]	Lin X, Dai Y, Tong X, et al. Excessive oxidative stress in cumulus granulosa cells induced cell senescence contributes to endometriosis-associated infertility[J]. Redox Biol, 2020,30:101431. doi: 10.1016/j.redox.2020.101431.
[22]	Xue W, Yao X, Ting G, et al. BPA modulates the WDR5/TET2 complex to regulate ERβ expression in eutopic endometrium and drives the development of endometriosis[J]. Environ Pollut, 2021, 268(Pt B):115748. doi: 10.1016/j.envpol.2020.115748.
[23]	Szukiewicz D. Insight into the Potential Mechanisms of Endocrine Disruption by Dietary Phytoestrogens in the Context of the Etiopathogenesis of Endometriosis[J]. Int J Mol Sci, 2023, 24(15):12195. doi: 10.3390/ijms241512195.
[24]	Zhang J, Yang Y, Zhang Z, et al. Gankyrin plays an essential role in estrogen-driven and GPR30-mediated endometrial carcinoma cell proliferation via the PTEN/PI3K/AKT signaling pathway[J]. Cancer Lett, 2013, 339(2):279-287. doi: 10.1016/j.canlet.2012.10.037. pmid: 23142288
[25]	Zhang C, Yuan X, Zhang Y. The co-expression of GPER and Gankyrin in ovarian endometriosis and its correlation with the rASRM stages[J]. Arch Gynecol Obstet, 2016, 293(1):133-141. doi: 10.1007/s00404-015-3807-x. pmid: 26193952
[26]	Rouhimoghadam M, Lu AS, Salem AK, et al. Therapeutic Perspectives on the Modulation of G-Protein Coupled Estrogen Receptor, GPER, Function[J]. Front Endocrinol(Lausanne), 2020,11:591217. doi: 10.3389/fendo.2020.591217.
[27]	Wu L, Huang X, Wang R, et al. Increased Expression of TGF-β1 Contributes to the Downregulation of Progesterone Receptor Expression in the Eutopic Endometrium of Infertile Women with Minimal/Mild Endometriosis[J]. Reprod Sci, 2023, 30(12):3578-3589. doi: 10.1007/s43032-023-01315-8. pmid: 37531067
[28]	Huang Y, Wang Z, Li B, et al. Loss of KLF15 impairs endometrial receptivity by inhibiting EMT in endometriosis[J]. J Endocrinol, 2024, 261(2):e230319. doi: 10.1530/JOE-23-0319.
[29]	Park Y, Choo SP, Jung GS, et al. Formononetin Inhibits Progression of Endometriosis via Regulation of p27, pSTAT3, and Progesterone Receptor: In Vitro and In Vivo Studies[J]. Nutrients, 2023, 15(13):3001. doi: 10.3390/nu15133001.