(WHS-P57) ESTETROL DAMPENS INFLAMMATION AND ACCELERATES WOUND REPAIR IN VITRO AND IN VIVO
Friday, May 17, 2024
7:30 AM – 5:00 PM East Coast USA Time
Chronic non-healing wounds, which primarily affect the elderly and diabetic, remain a significant area of clinical unmet need. In ageing women, the rapid loss of circulating 17β-estradiol (E2) post-menopause contributes to skin structural decline and delayed wound repair. Studies over 20 years ago first demonstrated the importance of E2 in reversing age-related delayed wound healing. Since then, E2 has been linked to a diverse range of wound cell processes, yet the risk of off-target effects has hampered development of E2-mediated therapies for clinical use. More recently, estetrol (E4), a natural estrogenic steroid produced exclusively by the human fetal liver during pregnancy, has been suggested as a promising alternative to E2 due to its more favorable safety profile. E4 is the estrogenic component of a recently approved combined oral contraceptive and is currently in late-stage clinical development as a hormone replacement therapy. However, no studies to date have investigated the effects of E4 on wound repair. The primary aim of this study was to determine the effect of E4 on multiple aspects of wound healing. Here, E4 significantly increased scratch wound closure in fibroblasts and keratinocytes at comparable levels to E2, while the pro-migratory effects of E4 were also conserved in senescent fibroblasts. Similar to E2, E4 demonstrated substantial anti-inflammatory properties, significantly reducing MMP2 activity in fibroblasts and dampening the expression of pro-inflammatory markers in M1-polarized macrophages. Moreover, E4 effects appeared to be regulated by both ERα and ERβ in a cell type specific manner. Finally, topical administration of E4 in an LPS model of delayed wound healing reduced inflammation and significantly accelerated wound closure. Collectively, these pre-clinical data show that E4 mediates multiple stages of healing, supporting future clinical investigation of the impact of E4 on delayed wound healing in the elderly.