Abstract
Copper intrauterine devices (IUDs) are commonly presented as non-hormonal contraceptives with purely local mechanical action, reinforcing a perception of inertness. However, the observed increase in menstrual blood loss associated with copper IUDs, combined with copper’s potential as an endocrine disruptor, raises concerns about a possible link to iatrogenic endometriosis, a hypothesis that remains insufficiently investigated. This narrative review, based on recent literature, explores the plausibility of a link between copper IUD use and endometriosis. Drawing on environmental, toxicological, endocrine, and historical perspectives, we explore how copper’s classification as a non-biodegradable heavy metal and metalloestrogen challenges the assumption of inertness. Copper can accumulate in endometrial tissue, interfere with hormonal signaling, induce oxidative stress, and trigger cuproptosis, mechanisms increasingly associated with endometriosis and other reproductive pathologies. Furthermore, copper IUDs have historically been promoted without adequate attention to dosage transparency, long-term safety, or informed consent, particularly in marginalized populations. Our findings underscore the need for rigorous, gender-sensitive research and greater transparency in contraceptive risk communication. Reassessing the copper IUD is not only a scientific imperative but a question of long-standing underestimation of gender-specific risks in medicine.
References
Farinet S. Réticence des praticiens à la pose du dispositif intra-utérin au cuivre, chez les femmes nullipares. Médecine Humaine et Pathologie. 2015.
Viganò P, Parazzini F, Somigliana E, Vercellini P. Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):177–200.
Allaire C, Bedaiwy MA, Yong PJ. Diagnosis and management of endometriosis. CMAJ. 2023;195(10):E363–E371.
Andrade AT, Orchard EP. Quantitative studies on menstrual blood loss in IUD users. Contraception. 1987;36(1):129–141.
Milsom I, Andersson K, Jonasson K, Lindstedt G, Rybo G. The influence of the Gyne-T 380S IUD on menstrual blood loss and iron status. Contraception. 1995;52(3):175–9.
Hefnawi F, Askalani H, Zaki K. Menstrual blood loss with copper intrauterine devices. Contraception. 1974;9(2):133-139.
El-Badrawi HH, Hafez ES. IUD-induced uterine bleeding. Contracept Deliv Syst. 1980;1(4):307–313.
Gao J, Li Y, Liu JP, Gu X. Releasing of cupric ion of three types of copper-bearing intrauterine contraceptive device in simulated uterine fluid. J Reprod Contracept. 2007;18(1):33–40.
Jomova K, Alomar SY, Nepovimova E, Kuca K, Valko M. Heavy metals: toxicity and human health effects. Arch Toxicol. 2025;99(1):153-209.
Theophanides T, Anastassopoulou J. Copper and carcinogenesis. Crit Rev Oncol Hematol. 2002;42(1):57-64.
Choucroun D. Refusal of medical contraception in hypermodern age: does sexuality want to emancipate itself from science? Eur Gynecol Obstet. 2024;6(2):50-53.
Kiaune L, Singhasemanon N. Pesticidal copper (I) oxide: environmental fate and aquatic toxicity. Rev Environ Contam Toxicol. 2011;213:1-26.
European Commission. Strategies to reduce copper in pesticides. CO-FREE Project. Results in Brief. FP7. June 2024. Available at: https://cordis.europa.eu/article/id/151480-strategies-to-reduce-copper-in-pesticides
Tamaya T, Nakata Y, Ohno Y, Nioka S, Furuta N. The mechanism of action of the copper intrauterine device. Fertil Steril. 1976;27(7):767-72.
Silva N, Peiris-John R, Wickremasinghe R, Senanayake H, Sathiakumar N. Cadmium a metalloestrogen: are we convinced? J Appl Toxicol. 2012;32(5):318-332.
Darbre PD. Metalloestrogens: an emerging class of inorganic xenoestrogens with potential to add to the oestrogenic burden of the human breast. J Appl Toxicol. 2006;26(3):191-197.
Aquino NB, Sevigny MB, Sabangan J, Louie MC. The role of cadmium and nickel in estrogen receptor signaling and breast cancer: metalloestrogens or not? J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2012;30(3):189-224.
Wallace DR. Nanotoxicology and metalloestrogens: possible involvement in breast cancer. Toxics. 2015;3(4):390-413.
Saint-Martin F, Marques C, Ren X, Lequy E, Mancini FR, Frénoy P. Associations between dietary exposure to profiles of metalloestrogens and estrogen-receptor positive breast cancer risk in the French E3N cohort. Environ Health. 2025;24(1):22.
Dutta S, Banu SK, Arosh JA. Endocrine disruptors and endometriosis. Reprod Toxicol. 2023;115:56–73.
Habert R, Chevalier N. Les perturbateurs endocriniens: définitions, sources et enjeux. Actualité et Dossier en Santé Publique. 2021. Available from: https://stm.cairn.info/revue-actualite-et-dossier-en-sante-publique
Markey CM, Rubin BS, Soto AM, Sonnenschein C. Endocrine disruptors: from Wingspread to environmental developmental biology. J Steroid Biochem Mol Biol. 2002;83(1–5):235-244.
United States Environmental Protection Agency (EPA). Research on endocrine disruptors. Available from: https://www.epa.gov/chemical-research/research-endocrine-disruptors
Sultan C, Gaspari L, Kalfa N, Paris F. Perturbateurs endocriniens environnementaux et maladies endocriniennes de l’enfant. Méd Longévité. 2011;3(3):108–110.
Lavogina D, Visser N, Samuel K, et a. Endocrine disrupting chemicals interfere with decidualization of human primary endometrial stromal cells in vitro. Front Endocrinol (Lausanne). 2022;13:903505.
Mallozzi M, Bordi G, Garo C, Caserta D. The effect of maternal exposure to endocrine disrupting chemicals on fetal and neonatal development: A review on the major concerns. Birth Defects Res C Embryo Today. 2016;108(3):224–242.
Wang Y, Yan Q, Shi Y, Long M. Copper Toxicity in Animals: A Review. Biol Trace Elem Res. 2025;203(5):2675-2686.
Pardo C, Bellati A, Polverino G, Canestrelli D. The dark side of organic farming: Copper sulphate compromises the life history and behaviour of the walking stick insect, Bacillus rossius. Sci Total Environ. 2024;942:173626.
Pelosi C, Gavinelli F, Petit-Dit-Grezeriat L, et al. Copper toxicity to earthworms: A comprehensive review and meta-analysis. Chemosphere. 2024;362:142765.
Ameh T, Gibb M, Stevens D, Pradhan SH, Braswell E, Sayes CM. Silver and Copper Nanoparticles Induce Oxidative Stress in Bacteria and Mammalian Cells. Nanomaterials (Basel). 2022;12(14):2402.
Valko M, Jomova K, Rhodes CJ, Kuča K, Musílek K. Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch Toxicol. 2016;90(1):1–37.
Luo J, Zhang M, Deng Y, et al. Copper nanoparticles lead to reproductive dysfunction by affecting key enzymes of ovarian hormone synthesis and metabolism in female rats. Ecotoxicol Environ Saf. 2023;254:114704.
Lin J, Wang L, Huang M, Xu G, Yang M. Metabolic changes induced by heavy metal copper exposure in human ovarian granulosa cells. Ecotoxicol Environ Saf. 2024;285:117078.
Cao J, Wang G, Wang T, et al. Copper caused reproductive endocrine disruption in zebrafish (Danio rerio). Aquat Toxicol. 2019;212:124–136.
Wang C, Liang G, Chai L, Wang H. Effects of copper on growth, metamorphosis and endocrine disruption of Bufo gargarizans larvae. Aquat Toxicol. 2016;170:24-30.
Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 2009;30(4):293-342.
Handy RD. Chronic effects of copper exposure versus endocrine toxicity: two sides of the same toxicological process? Comp Biochem Physiol A Mol Integr Physiol. 2003;135(1):25-38.
Suvi R, Giovanna M, Katja A. Experimental copper exposure, but not heat stress, leads to elevated intraovarian thyroid hormone levels in three-spined sticklebacks (Gasterosteus aculeatus). Ecotoxicology. 2020;29(9):1431-1440.
De Olivera JV, Boufleur LA, Dos Santos CE, et al. Occupational genotoxicity among copper smelters. Toxicol Ind Health. 2012;28(9):789-795.
Santacruz-Márquez R, González-De Los Santos M, Hernández-Ochoa I. Ovarian toxicity of nanoparticles. Reprod Toxicol. 2021;103:79-95.
Yang Y, Wu J, Wang L, Ji G, Dang Y. Copper homeostasis and cuproptosis in health and disease. MedComm (2020). 2024;5(10):e724.
Kahlson MA, Dixon SJ. Copper-induced cell death. Science. 2022;375(6586):1231–1232.
Lin Y, Yuan M, Wang G. Copper homeostasis and cuproptosis in gynecological disorders: pathogenic insights and therapeutic implications. J Trace Elem Med Biol. 2024;84:127436.
Ge EJ, Bush AI, Casini A, et al. Connecting copper and cancer: from transition metal signalling to metalloplasia. Nat Rev Cancer. 2022;22(2):102–113.
Lu Z, Sun C, Chen D, Fu H. In vitro carcinogenicity test of a copper-containing intrauterine device. Tissue Eng Part C Methods. 2022;28(4):184–190.
Serfaty D. Dispositif intra-utérin au cuivre. In: Gynécologie médicale. CNGOF. 2006. Available at: https://cngof.fr/cngof/lassociation/
Médecins Sans Frontières. Dispositif intra-utérin TCu380A. Available at: https://unicat.msf.org/fr/cat/product/19047
De la Cruz D, Cruz A, Arteaga M, Castillo L, Tovalin H. Blood copper levels in Mexican users of the T380A IUD. Contraception. 2005;72(2):122–125.
Crandell L, Mohler N. A literature review of the effects of copper intrauterine devices on blood copper levels in humans. Nurs Womens Health. 2021;25(1):71-80.
Thomas ML, Xu X, Norfleet AM, Watson CS. The presence of functional estrogen receptors in intestinal epithelial cells. Endocrinology. 1993;132(1):426–430.
Pérez-Debén S, Gonzalez-Martin R, Palomar A, Quiñonero A, Salsano S, Dominguez F. Copper and lead exposures disturb reproductive features of primary endometrial stromal and epithelial cells. Reprod Toxicol. 2020;96:106-117.
He H, Zou Z, Wang B, et al. Copper oxide nanoparticles induce oxidative DNA damage and cell death via copper ion-mediated P38 MAPK activation in vascular endothelial cells. Int J Nanomedicine. 2020;15:3291–3302.
Benagiano G, Brosens I. Who identified endometriosis? Fertil Steril. 2011;95(1):13–16.
Brosens I, Benagiano G. Endometriosis, a modern syndrome. Indian J Med Res. 2011;133(6):581–593.
Vallée A, Ceccaldi PF, Carbonnel M, Feki A, Ayoubi JM. Pollution and endometriosis: a deep dive into the environmental impacts on women’s health. BJOG. 2024;131(4):401–414.
Sampson JA. The development of the implantation theory for the origin of peritoneal endometriosis. Am J Obstet Gynecol. 1940;40(4):549–557.
Surrey ES, Soliman AM, Johnson SJ, Davis M, Castelli-Haley J, Snabes MC. Risk of developing comorbidities among women with endometriosis: a retrospective matched cohort study. J Womens Health (Larchmt). 2018;27(9):1114–1123.
Choi EJ, Cho SB, Lee SR, et al. Comorbidity of gynecological and non-gynecological diseases with adenomyosis and endometriosis. Obstet Gynecol Sci. 2017;60(6):579–586.
Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021;397(10276):839–852.
Yovich JL, Rowlands PK, Lingham S, Sillender M, Srinivasan S. Pathogenesis of endometriosis: Look no further than John Sampson. Reprod Biomed Online. 2020;41(1):7-11.
Moulin AM. De l’analyse au système: le développement de l’immunologie. Rev Hist Sci. 1983;36(1):49-67.
Porpora MG, Scaramuzzino S, Sangiuliano C, et al. High prevalence of autoimmune diseases in women with endometriosis: a case-control study. Gynecol Endocrinol. 2020;36(4):356–359.
Hamburger N, Chang C. Endometriosis as an autoimmune disease. In: Gershwin ME, Tsokos GC, Diamond B, editors. The Rose and Mackay Textbook of Autoimmune Diseases. 7th ed. Academic Press; 2024. p. 687–698.
Dürig J, Calcagni M, Buschmann J. Transition metals in angiogenesis–a narrative review. Mater Today Bio. 2023;22:100757.
He B, Hu Y, Cao Q, et al. Progression of unfolded protein response and ferroptosis in angiogenesis. Biomed Pharmacother. 2024;173:116354.
Liu L, Han F, Du N, et al. New insights into the ferroptosis and immune infiltration in endometriosis: a bioinformatics-based analysis. Front Immunol. 2025;15:1507083.
Li G, Lin Y, Zhang Y, et al. Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis. Cell Death Discov. 2022;8(1):29.
Onuma T, Mizutani T, Fujita Y, Yamada S, Yoshida Y. Copper content in ascitic fluid is associated with angiogenesis and progression in ovarian cancer. J Trace Elem Med Biol. 2021;68:126865.
Carrascosa JP, Cotán D, Jurado I, et al. The effect of copper on endometrial receptivity and induction of apoptosis on decidualized human endometrial stromal cells. Reprod Sci. 2018;25(7):985–999.
Laganà AS, Garzon S, Götte M, et al. The pathogenesis of endometriosis: molecular and cell biology insights. Int J Mol Sci. 2019;20(22):5615.
Carey JL, Nader N, Chai PR, Carreiro S, Griswold MK, Boyle KL. Drugs and medical devices: adverse events and the impact on women’s health. Clin Ther. 2017;39(1):10–22.
Healy B. The Yentl syndrome. N Engl J Med. 1991;325(4):274–276.
McGann KP. Sex bias in the treatment of coronary artery disease: equity and quality of care? J Fam Pract. 1994;39(4):327-329.
Rizzo R, Bortolotti D, Rizzo S, Schiuma G. Endocrine disruptors, epigenetic changes, and transgenerational transmission. In: Marci R, editor. Environment Impact on Reproductive Health. Cham: Springer; 2023. p. 49–74.
Rogers RE, Chai S, Pask AJ, Mattiske DM. Prenatal exposure to diethylstilbestrol has long-lasting, transgenerational impacts on fertility and reproductive development. Toxicol Sci. 2023;195(1):53-60.
Kalfa N, Paris F, Soyer-Gobillard MO, Daures JP, Sultan C. Prevalence of hypospadias in grandsons of women exposed to diethylstilbestrol during pregnancy: a multigenerational national cohort study. Fertil Steril. 2011;95(8):2574–2577.
Paulose T, Speroni L, Sonnenschein C, Soto AM. Estrogens in the wrong place at the wrong time: fetal BPA exposure and mammary cancer. Reprod Toxicol. 2015;54:58–65.
Dhimolea E, Wadia PR, Murray TJ, et al. Prenatal exposure to BPA alters the epigenome of the rat mammary gland and increases the propensity to neoplastic development. PLoS One. 2014;9(7):e99800.
Chen Y, Guan F, Wang P, et al. Copper exposure induces ovarian granulosa cell apoptosis by activating the caspase-dependent apoptosis signaling pathway and corresponding changes in microRNA patterns. Ecotoxicol Environ Saf. 2023;264:115414.
Takeshita C. Biopolitique du stérilet. Travail Genre Sociétés. 2015;32(2):109-127.
Tomczyk KM, Rzymski P, Wilczak M. Canonical analysis of concentrations of toxic metals in endometrium of women with gynecological disorders. Ginekol Pol. 2022;93(10):806–810.
Choucroun D, Kone Groot N. (128). Pelvic pain in Tarlov cyst: pathognomony in gender inequality. J Sex Med. 2023;20(Suppl 2):qdad061.123.
Choucroun D. (046). Postpartum sexuality: gender inequality in scientific research. J Sex Med. 2023;20(Suppl 2): 044.
Liu D, Shi Q, Liu C, Sun Q, Zeng X. Effects of endocrine-disrupting heavy metals on human health. Toxics. 2023;11(4):322.
Wu S, Gan M, Wang Y, et al. Copper mediated follicular atresia: implications for granulosa cell death. J Hazard Mater. 2024;477:135391.
Zhao J, Xu Z, Wang X, et al. Environmental copper exposure, placental cuproptosis, and miscarriage. Environ Pollut. 2024;348:123847.
Closing the gender gap in science: accelerating action. February 2023. Available at: https://www.unesco.org/en/articles/closing-gender-gap-science-accelerating-action
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