{"paper_id":"d611809d-03f6-4962-94f6-419be1926308","body_text":"Abstract\nEndometrial diseases, including uterine fibroids, polyps, intrauterine adhesion, endometritis, etc., are the major causes of infertility among women. However, the association between essential trace element status in women and the risk of endometrial disease is limited and unclear. This study aimed to investigate this association using a case–control study design; a total of 302 women patients with endometrial diseases and 302 healthy women were included. Compared to women in the control group, serum selenium (Se) (p = 0.024) and zinc (Zn) (p = 0.017) levels were significantly lower, while copper (Cu) (p = 0.004) and molybdenum (Mo) (p = 0.005) levels were significantly higher among women with endometrial diseases. In addition, compared to women in the first quartile of the copper/zinc (Cu/Zn) ratio value group, the adjusted ORs (95% CIs) of endometrial diseases were 1.50 (1.05, 2.14), 1.68 (1.18, 2.39), and 1.47 (1.02, 2.10), respectively, in the second, third, and fourth quartile of the Cu/Zn ratio value group (p trend = 0.047). In addition, the results from restricted cubic splines showed that the dose–response relationships of serum levels of these essential elements with the risk of endometrial diseases were nonlinear for Se, Cu, and Zn and relatively linear for Mo and Cu/Zn ratio. The present study showed serum levels of Zn and Se among women with endometrial diseases were significantly lower compared to that among healthy women, while serum levels of Cu and Mo were significantly higher, in addition, the serum Cu/Zn ratio value was also significantly and positively associated with the risk of endometrial diseases.\nSimilar content being viewed by others\nData Availability\nThe data underlying this article will be shared upon reasonable request to the corresponding author.\nCode Availability\nNot applicable.\nReferences\nMunro MG (2019) Uterine polyps, adenomyosis, leiomyomas, and endometrial receptivity. Fertil Steril 111:629–640\nSalim S, Won H, Nesbitt-Hawes E, Campbell N, Abbott J (2011) Diagnosis and management of endometrial polyps: a critical review of the literature. J Minim Invasive Gynecol 18:569–581\nGrimbizis GF, Di Spiezio SA, Campo R (2021) Pregnancy-related intrauterine adhesion treatment: new insights. Fertil Steril 116:1188\nKimura F, Takebayashi A, Ishida M, Nakamura A, Kitazawa J, Morimune A et al (2019) Review: chronic endometritis and its effect on reproduction. J Obstet Gynaecol Res 45:951–960\nGiuliani E, As-Sanie S, Marsh EE (2020) Epidemiology and management of uterine fibroids. Int J Gynaecol Obstet 149:3–9\nRavel J, Moreno I, Simon C (2021) Bacterial vaginosis and its association with infertility, endometritis, and pelvic inflammatory disease. Am J Obstet Gynecol 224:251–257\nHart RJ (2016) Physiological aspects of female fertility: role of the environment, modern lifestyle, and genetics. Physiol Rev 96:873–909\nBicalho ML, Lima FS, Ganda EK, Foditsch C, Meira EB Jr, Machado VS et al (2014) Effect of trace mineral supplementation on selected minerals, energy metabolites, oxidative stress, and immune parameters and its association with uterine diseases in dairy cattle. J Dairy Sci 97:4281–4295\nNayki C, Nayki U, Gunay M, Kulhan M, Cankaya M, HumeyraTaskinKafa A et al (2017) Oxidative and antioxidative status in the endometrium of patients with benign gynecological disorders. J Gynecol Obstet Hum Reprod 46:243–7\nSantulli P, Borghese B, Lemarechal H, Leconte M, Millischer AE, Batteux F et al (2013) Increased serum oxidative stress markers in women with uterine leiomyoma. PLoS ONE 8:e72069\nTok A, Ozer A, Baylan FA, Kurutas EB (2021) Copper/zinc ratio can be a marker to diagnose ectopic pregnancy and is associated with the oxidative stress status of ectopic pregnancy cases. Biol Trace Elem Res 199:2096–2103\nBedwal RSBA (1994) Zinc, copper and selenium in reproduction. Experientia 50:626–640\nRen M, Zhao J, Wang B, An H, Li Y, Jia X et al (2022) Associations between hair levels of trace elements and the risk of preterm birth among pregnant women: a prospective nested case-control study in Beijing Birth Cohort (BBC). China Environ Int 158:106965\nAdeniran SO, Zheng P, Feng R, Adegoke EO, Huang F, Ma M et al (2022) The antioxidant role of selenium via GPx1 and GPx4 in LPS-induced oxidative stress in bovine endometrial cells. Biol Trace Elem 200(3):1140–1155\nCarrascosa JP, Cotan D, Jurado I, Oropesa-Avila M, Sanchez-Martin P, Savaris RF et al (2018) The effect of copper on endometrial receptivity and induction of apoptosis on decidualized human endometrial stromal cells. Reprod Sci 25:985–999\nAtakul T, Altinkaya SO, Abas BI, Yenisey C (2020) Serum copper and zinc levels in patients with endometrial cancer. Biol Trace Elem Res 195:46–54\nSun Y, Wang W, Guo Y, Zheng B, Li H, Chen J et al (2019) High copper levels in follicular fluid affect follicle development in polycystic ovary syndrome patients: population-based and in vitro studies. Toxicol Appl Pharmacol 365:101–111\nOsuchowska-Grochowska I, Blicharska E, Gogacz M, Nogalska A, Winkler I, Szopa A et al (2021) Brief review of endometriosis and the role of trace elements. Int J Mol Sci 22(20):11098\nMalavolta M, Piacenza F, Basso A, Giacconi R, Costarelli L, Mocchegiani E (2015) Serum copper to zinc ratio: relationship with aging and health status. Mech Ageing Dev 151:93–100\nSocha K, Karpinska E, Kochanowicz J, Soroczynska J, Jakoniuk M, Wilkiel M et al (2017) Dietary habits; concentration of copper, zinc, and Cu-to-Zn ratio in serum and ability status of patients with relapsing-remitting multiple sclerosis. Nutrition 39–40:76–81\nNovotny JA, Peterson CA (2018) Molybdenum Adv Nutr 9:272–273\nZhao H, Wu W, Zhang X, Zhu Q, Tang J, He H et al (2021) Associations between molybdenum exposure and ultrasound measures of fetal growth parameters: a pilot study. Chemosphere 269:128709\nLiang C, Wang J, Xia X, Wang Q, Li Z, Tao R et al (2018) Serum cobalt status during pregnancy and the risks of pregnancy-induced hypertension syndrome: a prospective birth cohort study. J Trace Elem Med Biol 46:39–45\nYilmaz BK, Evliyaoglu O, Yorganci A, Ozyer S, Ustun YE (2020) Serum concentrations of heavy metals in women with endometrial polyps. J Obstet Gynaecol 40:541–545\nChoi R, Kim MJ, Sohn I, Kim S, Kim I, Ryu JM et al (2018) Serum trace elements and their associations with breast cancer subgroups in Korean breast cancer patients. Nutrients 11(1):37\nWang N, Tan HY, Li S, Xu Y, Guo W, Feng Y (2017) Supplementation of micronutrient selenium in metabolic diseases: its role as an antioxidant. Oxid Med Cell Longev 2017:7478523\nSharma P, Gupta V, Kumar K, Khetarpal P (2022) Assessment of serum elements concentration and polycystic ovary syndrome (PCOS): systematic review and meta-analysis. Biol Trace Elem Res. https://doi.org/10.1007/s12011-021-03058-6\nMistry HD, Broughton Pipkin F, Redman CW, Poston L (2012) Selenium in reproductive health. Am J Obstet Gynecol 206:21–30\nSami AS, Suat E, Alkis I, Karakus Y, Guler S (2021) The role of trace element, mineral, vitamin and total antioxidant status in women with habitual abortion. J Matern Fetal Neonatal Med 34:1055–1062\nLi Y, Huang P, Gao F, Xiao X, Li L (2021) Selenium ameliorates aflatoxin B1-induced uterine injury in female mice and necrosis of human endometrial microvascular endothelial cells. J Appl Toxicol 41:799–810\nHadrup N, Ravn-Haren G (2020) Acute human toxicity and mortality after selenium ingestion: a review. J Trace Elem Med Biol 58:126435\nKuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N (2004) The role of autophagy during the early neonatal starvation period. Nature 432(7020):1032–1036\nAkhtar MJ, Ahamed M, Alhadlaq HA, Alshamsan A, Khan MA, Alrokayan SA (2015) Antioxidative and cytoprotective response elicited by molybdenum nanoparticles in human cells. J Colloid Interface Sci 457:370–377\nNiehoff NM, O’Brien KM, Keil AP, Levine KE, Liyanapatirana C, Haines LG et al (2021) Metals and breast cancer risk: a prospective study using toenail biomarkers. Am J Epidemiol 190:2360–2373\nZhuang Y, Liu P, Wang L, Luo J, Zhang C, Guo X et al (2016) Mitochondrial oxidative stress-induced hepatocyte apoptosis reflects increased molybdenum intake in caprine. Biol Trace Elem Res 170:106–114\nFeng J, Chen J, Xing C, Huang A, Zhuang Y, Yang F et al (2020) Molybdenum induces mitochondrial oxidative damage in kidney of goats. Biol Trace Elem Res 197:167–174\nRoychoudhury SDL, Sirotkin AV, Toman R, Kolesarova A (2014) In vitro changes in secretion activity of rat ovarian fragments induced by molybdenum. Physiol Res 63:807–809\nAshrap P, Sanchez BN, Tellez-Rojo MM, Basu N, Tamayo-Ortiz M, Peterson KE et al (2019) In utero and peripubertal metals exposure in relation to reproductive hormones and sexual maturation and progression among girls in Mexico City. Environ Res 177:108630\nNasiadek M, Stragierowicz J, Klimczak M, Kilanowicz A (2020) The role of zinc in selected female reproductive system disorders. Nutrients 12(8):2464\nLu XZQ, Xu L et al (2020) Zinc is essential for the transcription function of the PGC-1α/Nrf2 signaling pathway in human primary endometrial stromal cells. Am J Physiol Cell Physiol 318:C640–C648\nMartin MB, Reiter R, Pham T, Avellanet YR, Camara J, Lahm M et al (2003) Estrogen-like activity of metals in MCF-7 breast cancer cells. Endocrinology 144:2425–2436\nDA Gibson SI, Collins F, Saunders PTK (2020) Androgens, oestrogens and endometrium: a fine balance between perfection and pathology. J Endocrinol 246:R75–R93\nKossai M, Penault-Llorca F (2020) Role of hormones in common benign uterine lesions: endometrial polyps, leiomyomas, and adenomyosis. Adv Exp Med Biol 1242:37–58\nChou CH, Chen SU, Shun CT, Tsao PN, Yang YS, Yang JH (2015) Divergent endometrial inflammatory cytokine expression at peri-implantation period and after the stimulation by copper intrauterine device. Sci Rep 5:15157\nPerez-Deben S, Gonzalez-Martin R, Palomar A, Quinonero A, Salsano S, Dominguez F (2020) Copper and lead exposures disturb reproductive features of primary endometrial stromal and epithelial cells. Reprod Toxicol 93:106–117\nÇınar M, Eryılmaz ÖG, Özel Ş, Fındık RB, Kansu H, Özakşit G (2016) The role of oxidative stress markers in development of endometrial polyp. J Exp Ther Oncol 11(4):269–273\nMatsubayashi H, Kitaya K, Yamaguchi K, Nishiyama R, Takaya Y, Ishikawa T (2017) Is a high serum copper concentration a risk factor for implantation failure? BMC Res Notes 10:387\nAcknowledgements\nThe authors thank all the medical staff in the First Afflicted Hospital of Anhui Medical University in Anhui, China, for recruiting subjects and collecting specimens. The authors are grateful to the Scientific Research Center in Preventive Medicine, School of Public Health, Anhui Medical University for the technical support in our experiment.\nFunding\nThis work was supported by the National Natural Science Foundation of China (NSFC-U20A20350, NSFC-82173532, NSFC-81971455, NSFC-81871216, and NSFC-81601345), Postdoctoral Research Foundation of China (2021M700181), Excellent Young Talents Fund Program of Higher Education Institutions of Anhui Province (gxyq2021173), and the Provincial Natural Science Foundation of Anhui (1908085MH244).\nAuthor information\nAuthors and Affiliations\nContributions\nD.M.J. and X.F.X. designed the experiments. D.Y.L., T.T.J., and X.W. experimented and wrote the manuscript. Z.K.Z. and L.C.S. analyzed the statistical data. T.Y. collected samples. W.W.Z. and K.Z. collated patients’ data. Y.J.L. and D.L. reviewed the data statistics. Y.X.C. and C.M.L. revised the manuscript.\nCorresponding authors\nEthics declarations\nCompeting interests\nThe authors declare no competing interests.\nEthics Approval\nThis study was approved by the Biomedical Ethics Committee of Anhui Medical University (20160270).\nConsent to Participate\nAll participants signed an informed consent form for the use of the samples.\nConsent for Publication\nThe authors affirm that human research participants provided informed consent for publication.\nConflict of Interest\nThe authors declare no competing interests.\nAdditional information\nPublisher's Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nDanyang Li, Tingting Jiang, and Xin Wang are the equal first authors.\nSupplementary Information\nBelow is the link to the electronic supplementary material.\nRights and permissions\nAbout this article\nCite this article\nLi, D., Jiang, T., Wang, X. et al. Serum Essential Trace Element Status in Women and the Risk of Endometrial Diseases: a Case–Control Study. Biol Trace Elem Res 201, 2151–2161 (2023). https://doi.org/10.1007/s12011-022-03328-x\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s12011-022-03328-x","source_license":"CC0","license_restricted":false}