Semaglutide, Weight Loss, and LNG-IUD for Conservative Treatment of Endometrial Atypical Hyperplasia and Grade 1 Endometrial Cancer

Summary

The goal of this clinical trial is to learn if a combination treatment of a hormonal intrauterine device (LNG-IUD), semaglutide, and a structured weight loss program can treat endometrial atypical hyperplasia or grade 1 endometrioid endometrial cancer while preserving fertility in women of reproductive age with endometrial atypical hyperplasia (EAH) or FIGO grade 1 endometrioid endometrial cancer who wish to preserve their fertility. The main questions it aims to answer are: * What proportion of participants achieve a complete pathological response after treatment? * How durable is the response at 12 months? * What effect does the treatment have on metabolic outcomes (weight, BMI, HbA1c) and quality of life? Participants will: * Receive an LNG-IUD * Receive semaglutide 2.4mg * Participate in a structured weight loss program * Undergo hysteroscopy with endometrial sampling to assess treatment response * Complete quality-of-life assessments at baseline, 6 months, and 12 months

Timeline

Start

2027-01-01

Primary completion

2028-12-31

Completion

2031-12-31

Publications

• Background Podder V, Coleman RL, Hagemann AR, Singhania P, Powell MA, Herzog TJ, Slomovitz BM. Repositioning GLP-1 Receptor Agonists in Endometrial Cancer: Molecular Rationale, Preclinical Insights, and Translational Opportunities. Clin Cancer Res. 2026 Feb 4;32(3):447-454. doi: 10.1158/1078-0432.CCR-25-2819.
• Background Peevey JF, Seagle BL, Maniar KP, Kim JJ. Association of body mass index with ER, PR and 14-3-3sigma expression in tumor and stroma of type I and type II endometrial carcinoma. Oncotarget. 2017 Jun 27;8(26):42548-42559. doi: 10.18632/oncotarget.17209.
• Background Zhang Z, Dong L, Sui L, Yang Y, Liu X, Yu Y, Zhu Y, Feng Y. Metformin reverses progestin resistance in endometrial cancer cells by downregulating GloI expression. Int J Gynecol Cancer. 2011 Feb;21(2):213-21. doi: 10.1097/IGC.0b013e318207dac7.
• Background Burzawa JK, Schmeler KM, Soliman PT, Meyer LA, Bevers MW, Pustilnik TL, Anderson ML, Ramondetta LM, Tortolero-Luna G, Urbauer DL, Chang S, Gershenson DM, Brown J, Lu KH. Prospective evaluation of insulin resistance among endometrial cancer patients. Am J Obstet Gynecol. 2011 Apr;204(4):355.e1-7. doi: 10.1016/j.ajog.2010.11.033. Epub 2011 Feb 16.
• Background Zhu XX, Feng ZH, Liu LZ, Zhang Y. Liraglutide suppresses the proliferation of endometrial cancer cells through the adenosine 5'-monophosphate (AMP)-activated protein kinase signaling pathway. Chin Med J (Engl). 2021 Jan 19;134(5):576-578. doi: 10.1097/CM9.0000000000001363. No abstract available.
• Background Dai H, Li Y, Lee YA, Lu Y, George TJ, Donahoo WT, Lee KP, Nakshatri H, Allen J, Guo Y, Sun RC, Guo J, Bian J. GLP-1 Receptor Agonists and Cancer Risk in Adults With Obesity. JAMA Oncol. 2025 Oct 1;11(10):1186-1193. doi: 10.1001/jamaoncol.2025.2681.
• Background Wang L, Xu R, Kaelber DC, Berger NA. Glucagon-Like Peptide 1 Receptor Agonists and 13 Obesity-Associated Cancers in Patients With Type 2 Diabetes. JAMA Netw Open. 2024 Jul 1;7(7):e2421305. doi: 10.1001/jamanetworkopen.2024.21305.
• Background Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002. doi: 10.1056/NEJMoa2032183. Epub 2021 Feb 10.
• Background Wichmann IA, Cuello MA. Obesity and gynecological cancers: A toxic relationship. Int J Gynaecol Obstet. 2021 Oct;155 Suppl 1(Suppl 1):123-134. doi: 10.1002/ijgo.13870.
• Background Kailasam A, Cucinella G, Fought AJ, Cliby W, Mariani A, Glaser G, Langstraat C. Nonsurgical management of early-stage endometrial cancer due to obesity: a survey of the practice patterns of current Society of Gynecologic Oncology members. Gynecol Oncol Rep. 2023 Oct 4;50:101280. doi: 10.1016/j.gore.2023.101280. eCollection 2023 Dec.
• Background Kong W, Deng B, Shen X, John C, Haag J, Sinha N, Lee D, Sun W, Chen S, Zhang H, Clontz A, Hursting SD, Zhou C, Bae-Jump V. Tirzepatide as an innovative treatment strategy in a pre-clinical model of obesity-driven endometrial cancer. Gynecol Oncol. 2024 Dec;191:116-123. doi: 10.1016/j.ygyno.2024.10.004. Epub 2024 Oct 10.
• Background Westin SN, Fellman B, Sun CC, Broaddus RR, Woodall ML, Pal N, Urbauer DL, Ramondetta LM, Schmeler KM, Soliman PT, Fleming ND, Burzawa JK, Nick AM, Milbourne AM, Yuan Y, Lu KH, Bodurka DC, Coleman RL, Yates MS. Prospective phase II trial of levonorgestrel intrauterine device: nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer. Am J Obstet Gynecol. 2021 Feb;224(2):191.e1-191.e15. doi: 10.1016/j.ajog.2020.08.032. Epub 2020 Aug 15.
• Background Janda M, Robledo KP, Gebski V, Armes JE, Alizart M, Cummings M, Chen C, Leung Y, Sykes P, McNally O, Oehler MK, Walker G, Garrett A, Tang A, Land R, Nicklin JL, Chetty N, Perrin LC, Hoet G, Sowden K, Eva L, Tristram A, Obermair A. Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial. Gynecol Oncol. 2021 Apr;161(1):143-151. doi: 10.1016/j.ygyno.2021.01.029.

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