Evaluation of Effects of Topical Estradiol Benzoate Application on Cutaneous Wound Healing in Ovariectomized Female Mice.

Kanae Mukai,Yukari Nakajima,Tamae Urai,Kimi Asano,Toshio Nakatani,Andrzej T Slominski

doi:10.1371/journal.pone.0163560

Abstract

Estrogen promotes cutaneous wound healing in ovariectomized (OVX) female mice. However, the effects of topical estrogen application on wounds remain unclear. Therefore, the aim of this study was to compare the effects of topical estrogen application on wounds with standard treatment methods. Eight-week-old C57BL/6J female mice underwent OVX and received two full-thickness wounds four weeks later. Mice were divided into three groups: topical estradiol benzoate (EB) (0.75 μg/g/day) wound treatment, subcutaneous estradiol (E2) pellets (0.05 mg, 21 days), and topical E2 (0.01 g/day) skin application. Wound healing was observed until day 14. Wound area ratios were significantly smaller in the topical EB wound treatment group than in the subcutaneous E2 pellet group on days 1–14 (p < 0.05) and topical E2 skin application group on days 1–9 (p < 0.05). Neutrophil and macrophage numbers were significantly smaller in the topical EB wound treatment group than in the subcutaneous E2 pellet and topical E2 skin application groups on day 7 (p < 0.05). Moreover, the number of new blood vessels and ratio of myofibroblasts were significantly larger in the topical EB wound treatment group than in the subcutaneous E2 pellet and topical E2 application skin groups on day 7 (p < 0.05). These results demonstrate that the application of estrogen to wounds reduced inflammatory responses and promoted angiogenesis and wound contraction more than the two other standard treatment methods.

Highlights

Cutaneous wound healing is a complex and tightly orchestrated response to injury, is carefully regulated at temporal and spatial levels [1], and involves three major stages: inflammation, proliferation, and remodeling
We compared the effects of the topical application of estrogen on wounds with two other standard treatment methods
Wound area ratios were significantly smaller in the topical estradiol benzoate (EB) wound treatment group than in the subcutaneous E2 pellet group on days 1–14 and topical E2 skin application group on days 1–9

Summary

Introduction

Cutaneous wound healing is a complex and tightly orchestrated response to injury, is carefully regulated at temporal and spatial levels [1], and involves three major stages: inflammation, proliferation, and remodeling. Recent studies reported that female sex hormones, in particular estrogen, affect cutaneous wound healing. Estrogen is the predominant steroid responsible for secondary sexual characteristics in girls and women and influences the function of all major organ systems within the body [3], and the ovary is the major source of estrogen production in the premenopausal. As the estrogen product decreases after the menopause, the skin is an important site of estrogen production [4]. In menopausal women, cutaneous wound healing was shown to be delayed and inflammatory responses prolonged following marked reductions in estrogen [5, 6]. These studies indicated that estrogen production in the skin is not sufficient to maintain cutaneous wound healing. Since delayed cutaneous wound healing increases health service costs [7], available treatments need to be performed in order to promote cutaneous wound healing

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