Objective: To evaluate the effectiveness of topical estradiol in stimulating collagen I and III production in naturally aged and photoaged human skin of postmeno-pausal women and age-matched men. Design: Vehicle-controlled treatment followed by biochemical and immunohistochemical analyses of skin biopsy specimens. Setting: Academic referral center. Participants: Seventy healthy volunteers (40 postmeno-pausal women with a mean age of 75 years, and 30 men with a mean age of 75 years) with photodamaged skin. Interventions: Topical application of estradiol, 0.01%, 0.1%, 1%, or 2.5% or vehicle on aged or photoaged skin, with biopsy specimens taken after last treatment. Main Outcome Measures: De novo synthesis of collagen by quantitative polymerase chain reaction, immu-nohistochemistry, and enzyme-linked immunosorbent assay. Results: Topical estradiol increased procollagen I and III messenger RNA and collagen I protein levels in sun-protected aged hip skin in postmenopausal women and, to a lesser extent, in age-matched men. Surprisingly, no significant changes in production were observed in women or men after 2-week estradiol treatment of photoaged forearm or face skin, despite similar expression of estrogen receptors (ER-α, ER-β, and GPR30) in aged and photoaged skin. Estradiol treatment induced the estrogen-responsive gene GREBI, indicating that penetration of topical estradiol and genomic response to estrogen were similar in the 3 anatomic sites. Conclusions: Two-week topical estradiol treatment stimulates collagen production in sun-protected hip skin, but not in photoaged forearm or face skin, in postmenopausal women and aged-matched men. These findings suggest that menopause-associated estrogen decline is involved in reduced collagen production in sun-protected skin. Interestingly, alterations induced by long-term sun exposure hinder the ability of topical 2-week estradiol to stimulate collagen production in aged skin.
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