P03 Anti-ageing effects of oestetrol on the skin: protection from cellular senescence and restoration of dermal architecture

Abstract

Abstract Introduction and aims Skin is a major endocrine organ, undergoing profound structural and functional alterations in response to hormonal changes. Postmenopause, the rapid decline in circulating 17β-oestradiol (E2) leads to skin ageing, while exogenous E2 administration restores skin function, promoting the regenerative capacity of aged skin. Nevertheless, the risk of off-target effects limits the clinical use of E2 for skin indications. Oestetrol (E4), a natural oestrogenic steroid currently undergoing clinical trials as a hormone replacement therapy, presents a favourable safety profile and could be a suitable alternative to E2. However, as no studies have investigated the effects E4 on skin ageing, the aim of this study was to evaluate the potential of E4 to overcome effects of skin ageing. Methods Micro-osmotic pumps were subcutaneously implanted into 14-month-old female mice, allowing sustained systemic delivery of E2 or E4 over 3 weeks. Reversal of skin ageing was assessed via noninvasive skin parameter testing, histological analysis and biomechanics. Aged human dermal fibroblasts were treated with E4 to measure effects on the extracellular matrix deposition (ECM) in vitro. Finally, human keratinocytes were treated with E4 prior to inducing senescence to assess potential protective effects against skin ageing. Readouts included senescence-associated beta galactosidase staining, immunofluorescence and quantitative polymerase chain reaction. Results Systemic administration of E4 reversed multiple characteristics of skin ageing. E4 treatment significantly increased skin hydration, stimulated collagen deposition and elevated elastic fibre synthesis. These structural changes improved the biomechanical function of skin, increasing breaking strength and elasticity. In vitro studies confirmed direct anti-ageing activity on multiple cell types. E4 substantially increased ECM deposition in aged human dermal fibroblasts and protected against senescence induction in human keratinocytes. Conclusions Collectively, these preclinical data demonstrate significant beneficial effects of E4 on aged skin, strongly supporting future clinical evaluation of E4 to alleviate the effects of skin ageing following menopause.