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Current therapies, such as progestins and GnRH agonists, have significant side effects (weight gain, mood changes, decreased bone mineral density, and menopausal symptoms) and fail to prevent disease recurrence or address fertility concerns. The current study is the first to demonstrate the therapeutic potential of combined treatment with dydrogesterone (a progestin) and letrozole (an aromatase inhibitor) in a preclinical mouse model of endometriosis. Our results revealed that the dydrogesterone\u2013letrozole combination reduced the volume of endometriotic lesions, suppressed cell proliferation, and decreased inflammation relative to the disease control, with trends suggesting greater effects than those observed with individual agents or standard treatments such as dienogest and leuprolide. The dydrogesterone\u2013letrozole combination also exhibited a reduction in fibrosis, indicating a potential role in managing chronic endometriosis and associated symptoms such as pelvic pain and adhesions. These findings suggest that the dydrogesterone\u2013letrozole combination may offer a broader therapeutic approach for endometriosis. Based on existing literature, dydrogesterone is thought to counteract estrogen\u2010driven endometrial proliferation through progesterone receptor activation, while letrozole is believed to reduce estrogen biosynthesis by inhibiting aromatase, which may collectively influence lesion growth and inflammatory processes. Additional long\u2010term studies are warranted to thoroughly assess the safety profile, clinical effectiveness, and overall therapeutic relevance of the dydrogesterone\u2013letrozole combination for the treatment of endometriosis.<\/jats:p>","DOI":"10.1155\/ogi\/5464578","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T09:00:22Z","timestamp":1770973222000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dydrogesterone and Letrozole Combination for the Treatment of Endometriosis: A Mechanism\u2010Based Therapeutic Approach"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3319-4691","authenticated-orcid":false,"given":"Santosh Kumar","family":"Rai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rakesh","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohd Imran","family":"Khan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anil","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0804690"},{"key":"e_1_2_10_2_2","doi-asserted-by":"publisher","DOI":"10.1177\/228402651000200102"},{"key":"e_1_2_10_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-012419-032654"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1677\/erc.0.0060293"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12300"},{"key":"e_1_2_10_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/s43043-025-00221-0"},{"key":"e_1_2_10_7_2","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.75590"},{"key":"e_1_2_10_8_2","doi-asserted-by":"publisher","DOI":"10.1177\/0091270011423664"},{"key":"e_1_2_10_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0015-0282(16)60364-3"},{"key":"e_1_2_10_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00404-020-05900-z"},{"key":"e_1_2_10_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2018.11.017"},{"key":"e_1_2_10_12_2","doi-asserted-by":"publisher","DOI":"10.12998\/wjcc.v8.i15.3259"},{"key":"e_1_2_10_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2005.09.064"},{"key":"e_1_2_10_14_2","doi-asserted-by":"publisher","DOI":"10.5114\/pm.2016.58773"},{"key":"e_1_2_10_15_2","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S315726"},{"key":"e_1_2_10_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7827-9-88"},{"key":"e_1_2_10_17_2","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/9946060"},{"key":"e_1_2_10_18_2","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines8110528"},{"key":"e_1_2_10_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2020.153214"},{"key":"e_1_2_10_20_2","first-page":"917","article-title":"Effect and Mechanism of Formation of Intrauterine Adhesion at Different Doses of Estrogen","volume":"45","author":"Chen F.","year":"2010","journal-title":"Zhonghua Fu Chan Ke Za Zhi"},{"key":"e_1_2_10_21_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.87.7.8683"},{"key":"e_1_2_10_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12958-018-0347-9"},{"key":"e_1_2_10_23_2","volume-title":"Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers","author":"Rockville","year":"2005"},{"key":"e_1_2_10_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2009.08.058"},{"key":"e_1_2_10_25_2","doi-asserted-by":"publisher","DOI":"10.3109\/00498254.2015.1134852"},{"key":"e_1_2_10_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-007-9696-3"},{"key":"e_1_2_10_27_2","first-page":"87","article-title":"Antiproliferative Effect of Leuprorelin Acetate, Alone or Combined With Tamoxifen or Medroxyprogesterone Acetate, on Human Breast Cancer Cell Lines","volume":"14","author":"Sica G.","year":"1992","journal-title":"Clinical Therapeutics"},{"key":"e_1_2_10_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-021-09666-w"},{"key":"e_1_2_10_29_2","doi-asserted-by":"publisher","DOI":"10.1056\/nejmcp1000274"},{"key":"e_1_2_10_30_2","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.38136"},{"key":"e_1_2_10_31_2","doi-asserted-by":"publisher","DOI":"10.1080\/09513590.2021.2016692"},{"key":"e_1_2_10_32_2","doi-asserted-by":"publisher","DOI":"10.18203\/2320-1770.ijrcog20241298"},{"key":"e_1_2_10_33_2","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/j.breast.2004.09.003","article-title":"Are All Aromatase Inhibitors the Same? 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