Topical application of 17β-estradiol increases extracellular matrix protein synthesis by stimulating TGF-β signaling in aged human skin in vivo

To investigate the effects of topically applied 17 beta-estradiol on the expression of extracellular matrix proteins in aged human skin, 17 beta-estradiol (0.01%) and its vehicle (70% propylene glycol, 30% ethanol) were applied to aged (68-82 y, eight females and five males) human buttock skin under occlusion for 2 wk (three times per week). Topical 17 beta-estradiol was found to increase the expression of type 1 procollagen mRNA and protein significantly in human aged skin in vivo. In addition, MMP-1 protein levels were reduced by topical 17 beta-estradiol. The expressions of TGF-beta 1, TGF-beta type II receptor, and Sma and Mad related (Smad)3 were increased by topical 17 beta-estradiol in aged human skin, and TGF-beta 1 neutralizing antibody inhibited 17 beta-estradiol-induced procollagen synthesis in cultured fibroblasts. We also found that the expressions of tropoelastin and fibrillin-1 mRNA and protein, and elastic fibers in aged skin were also increased by topical 17 beta-estradiol. Topical 17 beta-estradiol also increased keratinocyte proliferation and the epidermal thickness in aged human skin. We also observed the same effects of topical 17 beta-estradiol in young skin. In conclusion, our results suggest that topical 17 beta-estradiol treatment may improve the cutaneous function of aged human skin by improving the connective tissue and increasing epidermal thickness.