{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:34:39Z","timestamp":1787567679785,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Capital\u2019s Funds for Health Improvement and Research","award":["2026-2-2112"],"award-info":[{"award-number":["2026-2-2112"]}]},{"name":"Capital\u2019s Funds for Health Improvement and Research","award":["2024-1-2112"],"award-info":[{"award-number":["2024-1-2112"]}]},{"name":"Beijing Physician Scientist Training Project","award":["BJPSTP-2025-49"],"award-info":[{"award-number":["BJPSTP-2025-49"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Endometrial cancer is increasingly diagnosed in patients who have not yet completed childbearing. For carefully selected patients with grade 1 endometrioid endometrial carcinoma confined to the endometrium, fertility-sparing treatment (FST) can preserve reproductive potential but requires rigorous histologic surveillance. In eligible patients, oral progestins and\/or the levonorgestrel-releasing intrauterine system (LNG-IUS) remain the mainstay of fertility-sparing treatment, with hysteroscopic lesion resection incorporated in selected cases. Obesity, polycystic ovary syndrome, abnormalities in glucose metabolism, molecular subtype, and primary or acquired progestin resistance collectively contribute to heterogeneity in treatment response and the risk of recurrence. This narrative review critically integrates current guidelines, randomized controlled trials, prospective studies, retrospective cohorts, and early exploratory evidence to evaluate the biological rationale, clinical positioning, efficacy, safety, and maturity of evidence for progestin-based therapy, metabolic interventions, combined endocrine approaches, molecularly guided strategies, and exploratory immunotherapeutic approaches. We further propose an integrated clinical pathway encompassing candidate selection, molecular assessment, response evaluation, transition to pregnancy, retreatment after recurrence, and timely conversion to definitive surgery. Importantly, this review distinguishes guideline-supported approaches from adjunctive, investigational, and exploratory strategies. Major evidence gaps include inconsistent definitions of treatment response, limited prospective molecularly stratified data, uncertain reproductive safety of emerging systemic therapies, and insufficient long-term data on pregnancy outcomes and offspring.<\/jats:p>","DOI":"10.3390\/cancers18172741","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:20:02Z","timestamp":1787563202000},"page":"2741","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanism-Driven Evolution of Fertility-Sparing Treatment and Precision Management of Special Populations in Endometrial Cancer: A Review"],"prefix":"10.3390","volume":"18","author":[{"given":"Kai-Bing","family":"Qu","sequence":"first","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Lin","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo-Ying","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Qian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Li","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4828-8408","authenticated-orcid":false,"given":"Yu-Mei","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China"},{"name":"Clinical Medical Laboratory, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Dong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4041-9271","authenticated-orcid":false,"given":"Yue","family":"He","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China"},{"name":"Clinical Medical Laboratory, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Guo, F., Adekanmbi, V., Hsu, C.D., Hoang, T.N., Soliman, P.T., Baillargeon, J.G., and Berenson, A.B. (2025). Trends in endometrial cancer incidence among premenopausal and postmenopausal women in the United States between 2001 and 2021. Cancers, 17.","DOI":"10.3390\/cancers17061035"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"pkad001","DOI":"10.1093\/jncics\/pkad001","article-title":"Differential trends in rising endometrial cancer incidence by age, race, and ethnicity","volume":"7","author":"Liu","year":"2023","journal-title":"JNCI Cancer Spectr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"hoac057","DOI":"10.1093\/hropen\/hoac057","article-title":"ESGO\/ESHRE\/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma","volume":"2023","author":"Rodolakis","year":"2023","journal-title":"Hum. Reprod. Open"},{"key":"ref_4","unstructured":"National Comprehensive Cancer Network (2026, July 19). NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms, Version 3. Available online: https:\/\/www.nccn.org."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e423","DOI":"10.1016\/S1470-2045(25)00167-6","article-title":"ESGO-ESTRO-ESP guidelines for the management of patients with endometrial carcinoma: Update 2025","volume":"26","author":"Concin","year":"2025","journal-title":"Lancet Oncol."},{"key":"ref_6","unstructured":"Committee of Uterine Corpus Tumors, Chinese Anti-Cancer Association, and Gynecologic Oncology Branch, Chinese Medical Association (2025). Chinese expert consensus on the diagnosis and treatment of endometrial cancer with fertility preservation based on molecular features (2025 edition). Prog. Obstet. Gynecol., 34, 481\u2013488. (In Chinese)."},{"key":"ref_7","first-page":"CD013111","article-title":"Fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer","volume":"7","author":"Sabadell","year":"2025","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"American College of Obstetricians and Gynecologists (2023). Management of Endometrial Intraepithelial Neoplasia or Atypical Endometrial Hyperplasia: ACOG Clinical Consensus No. 5. Obstet. Gynecol., 142, 735\u2013744.","DOI":"10.1097\/AOG.0000000000005297"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.tem.2011.01.005","article-title":"Progesterone: The ultimate endometrial tumor suppressor","volume":"22","author":"Yang","year":"2011","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1309\/AJCPM2TSDDF1MHBZ","article-title":"Assessing endometrial hyperplasia and carcinoma treated with progestin therapy","volume":"138","author":"Mentrikoski","year":"2012","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2798","DOI":"10.1200\/JCO.2006.08.8344","article-title":"Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women","volume":"25","author":"Ushijima","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"266.e1","DOI":"10.1016\/j.ajog.2012.08.011","article-title":"Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: A systematic review and meta-analysis","volume":"207","author":"Gallos","year":"2012","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.ajog.2024.07.018","article-title":"Fertility-preserving treatment for stage IA endometrial cancer: A systematic review and meta-analysis","volume":"231","author":"Suzuki","year":"2024","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"191.e1","DOI":"10.1016\/j.ajog.2020.08.032","article-title":"Prospective phase II trial of levonorgestrel intrauterine device: Nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer","volume":"224","author":"Westin","year":"2021","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"57642","DOI":"10.18632\/oncotarget.17588","article-title":"Comparison among fertility-sparing therapies for well differentiated early-stage endometrial carcinoma and complex atypical hyperplasia","volume":"8","author":"Zhang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1111\/aogs.14815","article-title":"Oncological and reproductive outcomes of endometrial atypical hyperplasia and endometrial cancer patients undergoing conservative therapy with hysteroscopic resection: A systematic review and meta-analysis","volume":"103","author":"Zhao","year":"2024","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"114573","DOI":"10.1016\/j.ejogrb.2025.114573","article-title":"Whether hysteroscopy contributes to intraperitoneal cell dissemination, progression and recurrence in endometrial cancer: Systematic review and meta-analysis","volume":"313","author":"Pivazyan","year":"2025","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1136\/ijgc-2022-003882","article-title":"Oncological and reproductive outcomes for gonadotropin-releasing hormone agonist combined with aromatase inhibitors or levonorgestrel-releasing intra-uterine system in women with endometrial cancer or atypical endometrial hyperplasia","volume":"32","author":"Chen","year":"2022","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s12958-022-01006-0","article-title":"Metabolic syndrome is an independent risk factor for time to complete remission of fertility-sparing treatment in atypical endometrial hyperplasia and early endometrial carcinoma patients","volume":"20","author":"Ding","year":"2022","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1093\/annonc\/mdv539","article-title":"Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer","volume":"27","author":"Mitsuhashi","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e90","DOI":"10.3802\/jgo.2019.30.e90","article-title":"Long-term outcomes of progestin plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer patients","volume":"30","author":"Mitsuhashi","year":"2019","journal-title":"J. Gynecol. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1111\/1471-0528.16108","article-title":"Metformin plus megestrol acetate compared with megestrol acetate alone as fertility-sparing treatment in patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer: A randomised controlled trial","volume":"127","author":"Yang","year":"2020","journal-title":"BJOG"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Shao, F., Li, Y., and Zhao, Y. (2023). Progestin plus metformin improves outcomes in patients with endometrial hyperplasia and early endometrial cancer more than progestin alone: A meta-analysis. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1139858"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s00432-025-06369-6","article-title":"Fertility-sparing treatment for overweight patients with early-stage endometrial cancer or atypical endometrial hyperplasia under weight loss intervention","volume":"151","author":"Fu","year":"2025","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2421305","DOI":"10.1001\/jamanetworkopen.2024.21305","article-title":"Glucagon-like peptide 1 receptor agonists and 13 obesity-associated cancers in patients with type 2 diabetes","volume":"7","author":"Wang","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1001\/jamaoncol.2025.2681","article-title":"GLP-1 receptor agonists and cancer risk in adults with obesity","volume":"11","author":"Dai","year":"2025","journal-title":"JAMA Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1002\/cncr.32058","article-title":"Microsatellite instability in endometrial cancer: New purpose for an old test","volume":"125","author":"Kurnit","year":"2019","journal-title":"Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.ejogrb.2024.09.006","article-title":"Fertility-sparing treatment in MSI-H\/MMRd endometrial carcinoma or atypical endometrial hyperplasia: A systematic review and meta-analysis","volume":"302","author":"Zhang","year":"2024","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e59","DOI":"10.3802\/jgo.2025.36.e59","article-title":"Fertility-sparing treatment outcomes using immune checkpoint inhibitors in endometrial cancer patients with Lynch syndrome","volume":"36","author":"Yang","year":"2025","journal-title":"J. Gynecol. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"104697","DOI":"10.1016\/j.ijgc.2026.104697","article-title":"The effects of immune checkpoint inhibitors and targeted therapies on female fertility and ovarian function: A systematic review","volume":"36","author":"Ates","year":"2026","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4225","DOI":"10.1200\/JCO.2016.69.4638","article-title":"Addressing the role of obesity in endometrial cancer risk, prevention, and treatment","volume":"34","author":"Onstad","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"41404","DOI":"10.1038\/srep41404","article-title":"Cholesterol synthetase DHCR24 induced by insulin aggravates cancer invasion and progesterone resistance in endometrial carcinoma","volume":"7","author":"Dai","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e80","DOI":"10.3802\/jgo.2021.32.e80","article-title":"Does polycystic ovary syndrome independently affect oncologic and reproductive outcomes in patients with endometrial cancer receiving fertility-sparing treatment?","volume":"32","author":"Harada","year":"2021","journal-title":"J. Gynecol. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e70","DOI":"10.3802\/jgo.2021.32.e70","article-title":"Fertility-preserving treatment outcome in endometrial cancer or atypical hyperplasia patients with polycystic ovary syndrome","volume":"32","author":"Wang","year":"2021","journal-title":"J. Gynecol. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"100016","DOI":"10.1016\/j.ijgc.2024.100016","article-title":"Performance of molecular classification in predicting oncologic outcomes of fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer","volume":"35","author":"Ferrari","year":"2025","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1001\/jamaoncol.2015.2151","article-title":"Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1","volume":"1","author":"Howitt","year":"2015","journal-title":"JAMA Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zhang, C., Wang, M., and Wu, Y. (2023). Features of the immunosuppressive tumor microenvironment in endometrial cancer based on molecular subtype. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1278863"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Lv, M., Chen, P., Bai, M., Huang, Y., Li, L., Feng, Y., Liao, H., Zheng, W., Chen, X., and Zhang, Z. (2022). Progestin resistance and corresponding management of abnormal endometrial hyperplasia and endometrial carcinoma. Cancers, 14.","DOI":"10.3390\/cancers14246210"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.2147\/OTT.S95267","article-title":"PI3K\/AKT\/mTOR pathway promotes progestin resistance in endometrial cancer cells by inhibition of autophagy","volume":"10","author":"Liu","year":"2017","journal-title":"OncoTargets Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1186\/s12957-024-03439-w","article-title":"Fertility-sparing re-treatment for endometrial cancer and atypical endometrial hyperplasia patients with progestin-resistance: A retrospective analysis of 61 cases","volume":"22","author":"Chen","year":"2024","journal-title":"World J. Surg. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1136\/ijgc-2022-003546","article-title":"Retreatment with progestin for recurrence after complete response with fertility-sparing treatment in patients with endometrial cancer","volume":"32","author":"Lee","year":"2022","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e71355","DOI":"10.1002\/cam4.71355","article-title":"Using machine learning to predict the prognosis in endometrial cancer patients undergoing fertility-sparing treatment","volume":"14","author":"Yuan","year":"2025","journal-title":"Cancer Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s43556-025-00341-z","article-title":"Clinical-grade AI model for molecular subtyping of endometrial cancer: A multi-center cohort study in China","volume":"6","author":"Qi","year":"2025","journal-title":"Mol. Biomed."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/17\/2741\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:33:11Z","timestamp":1787563991000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/17\/2741"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,24]]},"references-count":43,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cancers18172741"],"URL":"https:\/\/doi.org\/10.3390\/cancers18172741","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,24]]}}}