Ethyl Pyruvate as a Potential Therapeutic Agent for Endometriosis: A Perspective

Endometriosis is a disease where vascularised tissue similar to endometrium (the lining of the uterus) grows outside of the uterus. Its pathogenesis involves a complex interplay of inflammation, angiogenesis, cellular proliferation, reactive oxygen species (ROS) production, altered energy metabolism, and epithelial-to-mesenchymal transition (EMT).Even though endometriosis was described more than 150 years ago, we have been unable to find its effective therapy. Conservative treatment approaches like non-steroidal anti-inflammatory drugs or hormone therapy are available to date for the treatment of endometriosis. Anti-angiogenic inhibitors and immunomodulators like IFN-α, β, and TNF-α inhibitors are also potential treatment options. These treatments are inadequate as they either affect the symptoms only of endometriosis or target only one pathological pathway involved. Surgical excision of the endometriotic lesion is also possible, however, recurrence of the disease is reported in several cases. A single therapeutic agent targeting several pathological processes in endometriosis would always be a better option. Here we present our perspective on the pharmacological potential of Ethyl pyruvate and also propose it as a promising therapeutic agent for endometriosis as it inhibits inflammation, cell proliferation, angiogenesis, aerobic glycolysis, EMT, and ROS activity together. Similar content being viewed by others

Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10:261–75. https://doi.org/10.1038/nrendo.2013.255. Bulletti C, Coccia M, Battistoni S, Borini A. Endometriosis and infertility. J Assist Reprod Genet. 2010;27:441–7. Deguara CS, Pepas L, Davis C. Does minimally invasive surgery for endometriosis improve pelvic symptoms and quality of life? Curr Opin Obstet Gynecol. 2012;24:241–4. https://doi.org/10.1097/GCO.0b013e328355626f. Bulun SE. Endometriosis. N Engl J Med. 2009;360:268–79. https://doi.org/10.1056/NEJMra0804690. Simoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, Brandes I, et al. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod. 2012;27:1292–9. https://doi.org/10.1093/humrep/des073. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;511–9. https://doi.org/10.1016/j.fertnstert.2012.06.029. Christodoulakos G, Augoulea A, Lambrinoudaki I, Sioulas V, Creatsas G. Pathogenesis of endometriosis: the role of defective immunosurveillance. Eur J Contracept Reproductive Health Care. 2007;12. https://doi.org/10.1080/13625180701387266. Nothnick W, Alali Z. Recent advances in the understanding of endometriosis: the role of inflammatory mediators in disease pathogenesis and treatment. F1000Res. 2016. https://doi.org/10.12688/f1000research.7504.1. Ngô C, Chéreau C, Nicco C, Weill B, Chapron C, Batteux F. Reactive oxygen species controls endometriosis progression. Am J Pathol. 2009;175. https://doi.org/10.2353/ajpath.2009.080804. Groothuis PG. Angiogenesis and endometriosis. In: Giudice LC, Evers JLH, Healy DL, editors. Endometriosis: science and practice. Blackwell. 2012. p.190–9. https://doi.org/10.1002/9781444398519.ch19. Vercellini P, Somigliana E, Viganò P, Abbiati A, Barbara G, Crosignani PG. Surgery for endometriosis-associated infertility: A pragmatic approach. Hum Reprod. 2009. https://doi.org/10.1093/humrep/den379. Kao KK, Fink MP. The biochemical basis for the anti-inflammatory and cytoprotective actions of Ethyl pyruvate and related compounds. Biochem Pharmacol. 2010. https://doi.org/10.1016/j.bcp.2010.03.007. Karaer A, Tuncay G, Mumcu A, Dogan B. Metabolomics analysis of follicular fluid in women with ovarian endometriosis undergoing in vitro fertilization. Syst Biol Reprod Med. 2019;65. https://doi.org/10.1080/19396368.2018.1478469. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15:441–61. https://doi.org/10.1093/humupd/dmp007. Chapron C, Souza C, Borghese B, Lafay-Pillet MC, Santulli P, Bijaoui G, et al. Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Hum Reprod. 2011;26. https://doi.org/10.1093/humrep/der156. Ferrero S, Alessandri F, Racca A, Leone Roberti Maggiore U. Treatment of pain associated with deep endometriosis: alternatives and evidence. Fertil Steril. 2015. https://doi.org/10.1016/j.fertnstert.2015.08.031. Pelch KE, Sharpe-Timms KL, Nagel SC. Mouse model of surgically-induced endometriosis by auto-transplantation of uterine tissue. J Visualized Experiments. 2012. https://doi.org/10.3791/3396. Malvezzi H, Marengo EB, Podgaec S, Piccinato CDA. Endometriosis: Current challenges in modeling a multifactorial disease of unknown etiology. J Translational Med. 2020. https://doi.org/10.1186/s12967-020-02471-0. Arruda MS, Petta CA, Abrão MS, Benetti-Pinto CL. Time elapsed from onset of symptoms to diagnosis of endometriosis in a cohort study of Brazilian women. Hum Reprod. 2003;18. https://doi.org/10.1093/humrep/deg136. Wang X, Perez E, Liu R, Yan LJ, Mallet RT, Yang SH. Pyruvate protects mitochondria from oxidative stress in human neuroblastoma SK-N-SH cells. Brain Res. 2007;1132. https://doi.org/10.1016/j.brainres.2006.11.032. Montgomery CM, Webb JL. Metabolic studies on heart mitochondria. II. The inhibitory action of parapyruvate on the tricarboxylic acid cycle. J Biol Chem. 1956;221. Harada T, Iwabe T, Terakawa N. Role of cytokines in endometriosis. Fertil Steril. 2001. https://doi.org/10.1016/S0015-0282(01)01816-7. Jeung IC, Cheon K, Kim MR. Decreased cytotoxicity of peripheral and peritoneal natural killer cell in endometriosis. Biomed Res Int. 2016. https://doi.org/10.1155/2016/2916070. Králíčková M, Vetvicka V. Immunological aspects of endometriosis: A review. Annals Translational Med. 2015. https://doi.org/10.3978/j.issn.2305-5839.2015.06.08. Santanam N, Murphy AA, Parthasarathy S. Macrophages, oxidation, and endometriosis. Annals of the New York Academy of Sciences. 2002. https://doi.org/10.1111/j.1749-6632.2002.tb02779.x Klune JR, Dhupar R, Cardinal J, Billiar TR, Tsung A. HMGB1: endogenous danger signaling. Mol Med. 2008. https://doi.org/10.2119/2008-00034.Klune. Yun BH, Chon SJ, Choi YS, Cho S, Lee BS, Seo SK. Pathophysiology of endometriosis: role of high mobility group box-1 and toll-like receptor 4 developing inflammation in endometrium. PLoS ONE. 2016;11. https://doi.org/10.1371/journal.pone.0148165. Park SY, Yi EY, Jung M, Lee YM, Kim YJ. Ethyl pyruvate, an anti-inflammatory agent, inhibits tumor angiogenesis through Inhibition of the NF-κB signaling pathway. Cancer Lett. 2011;303. https://doi.org/10.1016/j.canlet.2010.12.024. Mitola S, Belleri M, Urbinati C, Coltrini D, Sparatore B, Pedrazzi M, et al. Cutting edge: extracellular high mobility group Box-1 protein is a proangiogenic cytokine. J Immunol. 2006;176. https://doi.org/10.4049/jimmunol.176.1.12. Ueda T, Yoshida M. HMGB proteins and transcriptional regulation. Biochim Et Biophys Acta - Gene Regul Mech. 2010. https://doi.org/10.1016/j.bbagrm.2009.11.005. Nogueira-Machado A, de Oliveira Volpe JM. HMGB-1 as a target for inflammation controlling. Recent Pat Endocr Metab Immune Drug Discov. 2012;6. https://doi.org/10.2174/187221412802481784. Shimizu K, Kamada Y, Sakamoto A, Matsuda M, Nakatsuka M, Hiramatsu Y. High expression of high-mobility group box 1 in menstrual blood: implications for endometriosis. Reproductive Sci. 2017;24. https://doi.org/10.1177/1933719117692042. Fink MP. Ethyl pyruvate: A novel anti-inflammatory agent. J Intern Med. 2007. https://doi.org/10.1111/j.1365-2796.2007.01789.x. Yang R, Gallo DJ, Baust JJ, Uchiyama T, Watkins SK, Delude RL, et al. Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock. Am J Physiol Gastrointest Liver Physiol. 2002;283. https://doi.org/10.1152/ajpgi.00022.2002. Ulloa L, Ochani M, Yang H, Tanovic M, Halperin D, Yang R, et al. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci U S A. 2002;99. https://doi.org/10.1073/pnas.192222999. Chen B, Na F, Yang H, Li R, Li M, Sun X, et al. Ethyl pyruvate alleviates radiation-induced lung injury in mice. Biomed Pharmacotherapy. 2017;92. https://doi.org/10.1016/j.biopha.2017.05.111. Jung SM, Lee J, Baek SY, Lee J, Jang SG, Hong SM, et al. Ethyl pyruvate ameliorates inflammatory arthritis in mice. Int Immunopharmacol. 2017;52. https://doi.org/10.1016/j.intimp.2017.09.027. Shen M, Lu J, Dai W, Wang F, Xu L, Chen K, et al. Ethyl pyruvate ameliorates hepatic ischemia-reperfusion injury by inhibiting intrinsic pathway of apoptosis and autophagy. Mediators Inflamm. 2013;2013. https://doi.org/10.1155/2013/461536. Sims CA, Wattanasirichaigoon S, Menconi MJ, Ajami AM, Fink MP. Ringer’s ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats. Crit Care Med. 2001;29. https://doi.org/10.1097/00003246-200108000-00003. Su X, Wang H, Zhu L, Zhao J, Pan H, Ji X. Ethyl pyruvate ameliorates intracerebral hemorrhage-induced brain injury through anti-cell death and anti-inflammatory mechanisms. Neuroscience. 2013;245. https://doi.org/10.1016/j.neuroscience.2013.04.032. Tsung A, Kaizu T, Nakao A, Shao L, Bucher B, Fink MP, et al. Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis. Transplantation. 2005;79. https://doi.org/10.1097/01.TP.0000151681.07474.2E. Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A. 2004;101. https://doi.org/10.1073/pnas.2434651100. Yang R, Han X, Delude RL, Fink MP. Ethyl pyruvate ameliorates acute alcohol-induced liver injury and inflammation in mice. J Lab Clin Med. 2003;142. https://doi.org/10.1016/S0022-2143(03)00138-0. Yang R, Uchiyama T, Alber SM, Han X, Watkins SK, Delude RL, et al. Ethyl pyruvate ameliorates distant organ injury in a murine model of acute necrotizing pancreatitis. Crit Care Med. 2004;32. https://doi.org/10.1097/01.CCM.0000130835.65462.06. Yang R, Shaufl AL, Killeen ME, Fink MP. Ethyl pyruvate ameliorates liver injury secondary to severe acute pancreatitis. J Surg Res. 2009;153. https://doi.org/10.1016/j.jss.2008.04.004. Keenan JA, Chen TT, Chadwell NL, Torry DS, Caudle MR. Interferon-gamma (IFN-γ) and interleukin-6 (IL-6) in peritoneal fluid and macrophage-conditioned media of women with endometriosis. Am J Reprod Immunol. 1994;32. https://doi.org/10.1111/j.1600-0897.1994.tb01111.x. Arici A. Local cytokines in endometrial tissue: the role of interleukin-8 in the pathogenesis of endometriosis. Ann N Y Acad Sci. 2002. https://doi.org/10.1111/j.1749-6632.2002.tb02770.x. Koch AE, Volin MV, Woods JM, Kunkel SL, Connors MA, Harlow LA, et al. Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide 78 in the rheumatoid joint. Arthritis Rheum. 2001;44. https://doi.org/10.1002/1529-0131(200101)44:1%3C;31::AID-ANR5%3E;3.0.CO;2-4. Cohen T, Nahari D, Cerem LW, Neufeld G, Levin BZ. Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem. 1996;271. https://doi.org/10.1074/jbc.271.2.736. Lee YM, Kim J, Jo K, Shin SD, Kim CS, Sohn EJ et al. Ethyl pyruvate inhibits retinal pathogenic neovascularization by downregulating HMGB1 expression. J Diabetes Res. 2013;2013. https://doi.org/10.1155/2013/245271 Wingfield M, Macpherson A, Healy DL, Rogers PAW. Cell proliferation is increased in the endometrium of women with endometriosis. Fertil Steril. 1995;64. https://doi.org/10.1016/s0015-0282(16)57733-4. Chen P, Mamillapalli R, Habata S, Taylor HS. Endometriosis cell proliferation induced by bone marrow mesenchymal stem cells. Reproductive Sci. 2021;28. https://doi.org/10.1007/s43032-020-00294-4. Wang X, Zeng W, Xu S, Nie J, Huang L, Lai Y, et al. Up-regulation of DNA2 results in cell proliferation and migration in endometriosis. J Mol Histol. 2021;52. https://doi.org/10.1007/s10735-021-09983-z. Johnson MC, Torres M, Alves A, Bacallao K, Fuentes A, Vega M, et al. Augmented cell survival in eutopic endometrium from women with endometriosis: expression of c-myc, TGF-beta1 and Bax genes. Reproductive Biology Endocrinol. 2005;3. https://doi.org/10.1186/1477-7827-3-45. Montenegro ML, Bonocher CM, Meola J, Portella RL, Ribeiro-Silva A, Brunaldi MO, et al. Effect of physical exercise on endometriosis experimentally induced in rats. Reproductive Sci. 2019;26. https://doi.org/10.1177/1933719118799205. Worku N, Stich A, Daugschies A, Wenzel I, Kurz R, Thieme R, et al. Ethyl pyruvate emerges as a safe and fast acting agent against trypanosoma brucei by targeting pyruvate kinase activity. PLoS ONE. 2015;10. https://doi.org/10.1371/journal.pone.0137353. Cheng P, Dai W, Wang F, Lu J, Shen M, Chen K, et al. Ethyl pyruvate inhibits proliferation and induces apoptosis of hepatocellular carcinoma via regulation of the HMGB1-RAGE and AKT pathways. Biochem Biophys Res Commun. 2014;443. https://doi.org/10.1016/j.bbrc.2013.12.064. Birkenmeier G, Hemdan NYA, Kurz S, Bigl M, Pieroh P, Debebe T, et al. Ethyl pyruvate combats human leukemia cells but spares normal blood cells. PLoS ONE. 2016;11. https://doi.org/10.1371/journal.pone.0161571. Liang X, Romo de Vivar Chavez A, Schapiro NE, Loughran P, Thorne SH, Amoscato AA, et al. Ethyl pyruvate administration inhibits hepatic tumor growth. J Leukoc Biol. 2009;86. https://doi.org/10.1189/jlb.0908578. Zhang J, Zhu JS, Zhou Z, Chen WX, Chen NW. Inhibitory effects of Ethyl pyruvate administration on human gastric cancer growth via regulation of the HMGB1-RAGE and Akt pathways in vitro and in vivo. Oncol Rep. 2012. https://doi.org/10.3892/or.2012.1623. Yang S, Lian G. ROS and diseases: role in metabolism and energy supply. Mol Cell Biochem. 2020. https://doi.org/10.1007/s11010-019-03667-9. Defrère S, Van Langendonckt A, Vaesen S, Jouret M, Ramos RG, Gonzalez D, et al. Iron overload enhances epithelial cell proliferation in endometriotic lesions induced in a murine model. Hum Reprod. 2006;21. https://doi.org/10.1093/humrep/del261. Van Langendonckt A, Casanas-Roux F, Donnez J. Iron overload in the peritoneal cavity of women with pelvic endometriosis. Fertil Steril. 2002. https://doi.org/10.1016/S0015-0282(02)03346-0. Lousse JC, Van Langendonckt A, Defrere S, Gonzalez Ramos R, Colette S, Donnez J. Peritoneal endometriosis is an inflammatory disease. Frontiers in Bioscience - Elite. 2012;4 E. https://doi.org/10.2741/358 Koprivica I, Djedovic N, Stojanović I, Miljković Đ. Ethyl pyruvate, a versatile protector in inflammation and autoimmunity. Inflamm Res. 2022. https://doi.org/10.1007/s00011-021-01529-z. Wang X, Sun S, Duan Z, Yang C, Chu C, Wang K, et al. Protective effect of Ethyl pyruvate on gut barrier function through regulations of ROS-related NETs formation during sepsis. Mol Immunol. 2021;132. https://doi.org/10.1016/j.molimm.2021.01.012. Kim HS, Cho IH, Kim JE, Shin YJ, Jeon JH, Kim Y, et al. Ethyl pyruvate has an anti-inflammatory effect by inhibiting ROS-dependent STAT signaling in activated microglia. Free Radic Biol Med. 2008;45. https://doi.org/10.1016/j.freeradbiomed.2008.06.009. Kelle I, Akkoc H, Tunik S, Nergiz Y, Erdinc M, Erdinc L. Protective effects of Ethyl pyruvate in cisplatin-induced nephrotoxicity. Biotechnol Biotechnol Equip. 2014;28. https://doi.org/10.1080/13102818.2014.942489. Taylor MD, Grand TJ, Cohen JE, Hsu V, Liao GP, Zentko S, et al. Ethyl pyruvate enhances ATP levels, reduces oxidative stress and preserves cardiac function in a rat model of off-pump coronary bypass. Heart Lung Circ. 2005;14. https://doi.org/10.1016/j.hlc.2004.12.021. Wang P, Gong G, Wei Z, Li Y. Ethyl pyruvate prevents intestinal inflammatory response and oxidative stress in a rat model of extrahepatic cholestasis. J Surg Res. 2010;160. https://doi.org/10.1016/j.jss.2009.03.027. Rossmann C, Nusshold C, Paar M, Ledinski G, Tafeit E, Koestenberger M, et al. Ethyl pyruvate inhibits oxidation of LDL in vitro and attenuates OxLDL toxicity in EA. hy926 cells. PLoS ONE. 2018;13. https://doi.org/10.1371/journal.pone.0191477. Zeng J, Liu J, Yang GY, Kelly MJS, James TL, Litt L. Exogenous ethyl pyruvate versus pyruvate during metabolic recovery after oxidative stress in neonatal rat cerebrocortical slices. Anesthesiology. 2007;107. https://doi.org/10.1097/01.anes.0000281898.01966.1e. Yako H, Niimi N, Kato A, Takaku S, Tatsumi Y, Nishito Y, et al. Role of pyruvate in maintaining cell viability and energy production under high-glucose conditions. Sci Rep. 2021;11. https://doi.org/10.1038/s41598-021-98082-w. Kobayashi H, Shigetomi H, Imanaka S. Nonhormonal therapy for endometriosis based on energy metabolism regulation. Reprod Fertility. 2021. https://doi.org/10.1530/RAF-21-0053. Chakhtoura M, Chain RW, Sato PY, Qiu CC, Lee MH, Meissler JJ, et al. Ethyl pyruvate modulates murine dendritic cell activation and survival through their immunometabolism. Front Immunol. 2019;10. https://doi.org/10.3389/fimmu.2019.00030. Konrad L, Dietze R, Riaz MA, Scheiner-Bobis G, Behnke J, Horné F, et al. Epithelial–mesenchymal transition in endometriosis—when does it happen? J Clin Med. 2020. https://doi.org/10.3390/jcm9061915. Huang Q, Fu Y, Zhang S, Zhang Y, Chen S, Zhang Z. Ethyl pyruvate inhibits glioblastoma cells migration and invasion through modulation of NF-κB and ERK-mediated EMT. PeerJ. 2020;8. https://doi.org/10.7717/peerj.9559. Chaudhury K, Babu KN, Singh AK, Das S, Kumar A, Seal S. Mitigation of endometriosis using regenerative cerium oxide nanoparticles. Nanomedicine. 2013;9. https://doi.org/10.1016/j.nano.2012.08.001. Singh AK, Chakravarty B, Chaudhury K. Nanoparticle-assisted combinatorial therapy for effective treatment of endometriosis. J Biomed Nanotechnol. 2015;11. https://doi.org/10.1166/jbn.2015.2020. de Almeida Borges VR, Tavares MR, da Silva JH, Tajber L, Boylan F, Ribeiro AF, et al. Development and characterization of poly(lactic-co-glycolic) acid nanoparticles loaded with copaiba oleoresin. Pharm Dev Technol. 2018;23. https://doi.org/10.1080/10837450.2017.1290107. Abbas MA, Taha MO, Zihlif MA, Disi AM. β-Caryophyllene causes regression of endometrial implants in a rat model of endometriosis without affecting fertility. Eur J Pharmacol. 2013;702. https://doi.org/10.1016/j.ejphar.2013.01.011. Henriques Da Silva J, Borges VRDA, Pereira LDCB, Ferrari R, De Mattos RM, Barros EGDO, et al. The oil-resin of the tropical rainforest tree Copaifera langsdorffii reduces cell viability, changes cell morphology and induces cell death in human endometriotic stromal cultures. J Pharm Pharmacol. 2015;67. https://doi.org/10.1111/jphp.12479. Lei L, Lv Q, Jin Y, An H, Shi Z, Hu G, et al. Angiogenic microspheres for the treatment of a thin endometrium. ACS Biomater Sci Eng. 2021;7. https://doi.org/10.1021/acsbiomaterials.1c00615. Brading AF. Calcium-induced increase in membrane permeability in the guinea‐pig taenia coli: evidence for involvement of a sodium‐calcium exchange mechanism. J Physiol. 1978;275. https://doi.org/10.1113/jphysiol.1978.sp012178. National Library of Medicine, National Center for Biotechnology Information. CTI-01 (Ethyl Pyruvate) safety and complication prevention in cardiac surgery patients on cardiopulmonary bypass (CPB). https://clinicaltrials.gov/show/NCT00107666. 2005. Bennett-Guerrero E, Swaminathan M, Grigore AM, Roach GW, Aberle LG, Johnston JM, et al. A phase II multicenter double-blind placebo-controlled study of ethyl pyruvate in high-risk patients undergoing cardiac surgery with cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2009;23. https://doi.org/10.1053/j.jvca.2008.08.005.

The authors acknowledge Guru Nanak Dev University, Amritsar, Punjab, India, Gujarat Biotechnology University, Gandhinagar, Gujarat, India, SERB (ANRF), New Delhi, India, and RLS-DBT, New Delhi, India, for facilitating this work. Funding The researchers did not receive any specific grants from funding agencies in the public or not-for-profit sectors. Author information Authors and Affiliations Contributions Rohini Ravindran Nair: Conceptualization, formal analysis, investigation, writing-original draft, visualization and supervision. Suresh Singh Yadav: Conceptualization, formal analysis, investigation, visualization, writing-review & editing. Corresponding author Ethics declarations Competing Interests The authors disclose no conflict of interest. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Yadav, S.S., Nair, R.R. Ethyl Pyruvate as a Potential Therapeutic Agent for Endometriosis: A Perspective. Reprod. Sci. 32, 1979–1986 (2025). https://doi.org/10.1007/s43032-025-01875-x Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s43032-025-01875-x