Dydrogesterone and Letrozole Combination for the Treatment of Endometriosis: A Mechanism‐Based Therapeutic Approach

Endometriosis is a complex, estrogen-dependent disease with limited effective treatments that often focus on symptom management rather than addressing the underlying pathology. 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-letrozole 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-letrozole 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-letrozole combination may offer a broader therapeutic approach for endometriosis. Based on existing literature, dydrogesterone is thought to counteract estrogen-driven 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-term studies are warranted to thoroughly assess the safety profile, clinical effectiveness, and overall therapeutic relevance of the dydrogesterone-letrozole combination for the treatment of endometriosis.