Hormonal Influences on Wound Healing: A Review of Current Experimental Data
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Wounds to the skin heal via a complex series of overlapping stages involving numerous cell and tissue types.1 In young individuals, these events are tightly regulated. However, in elderly subjects, this regulation and synchronization becomes disrupted. Evidence exists that sex hormones have a modulatory function in a range of biological systems. Differences in the timing and quality of cutaneous healing between genders are strongly indicative of hormonal regulation.2,3
Aging, Hormones, and Healing
Aging is accompanied by a reduction in systemic and local hormone levels. In postmenopausal women, this reduction is swift and dramatic. A clear correlation exists between estrogen levels and the rate of healing with retarded cutaneous healing in post-menopausal women reversed by exogenous estrogen.2 The skin has recently been shown to be a steroidogenic tissue containing the full cytochrome P450 system required for the de novo production of sex steroids from cholesterol (Figure 1).4 This raises the possibility that bioactive hormones locally synthesized within the wound microenvironment may also be important in this biological system.
Increased age and the associated reduction in hormone levels are significant risk factors for development of a nonhealing skin wound, such as a venous ulcer.5 Impaired wound healing states—acute wounds that fail to heal and chronic ulcers—are characterized by excessive leukocytosis and subsequently enhanced proteolytic degradation of matrix constituents.6–8 A full discussion of the underlying pathology and treatment modalities for nonhealing wounds is beyond the scope of this article.9
Estrogen Accelerates Healing
Age-related changes in skin structure are most prominent in postmenopausal women, ie, due to low estrogen levels. While estrogens are used extensively in hormone replacement therapy (HRT), their mechanisms of action in the skin are only now beginning to be understood. A wide range of cutaneous cell types (eg, fibroblast, endothelial, epithelial, and inflammatory) express estrogen receptors, indicating potential estrogen responsiveness (G.S. Ashcroft, MA, MRCP, PhD, unpublished data 2003). In normal unwounded skin, topical estrogen treatment to some degree reverses 3 age-related skin conditions: 1) skin atrophy by stimulating keratinocyte proliferation and reducing apoptosis, increasing dermal collagen production, and inhibiting MMP expression; 2) skin dryness by altering keratinocyte function, increasing dermal water holding capacity, and increasing sebum production; and 3) skin wrinkles by increasing dermal water holding capacity and increasing number and improving orientation of elastin fibers.10
Ashcroft et al.11,12 have previously demonstrated a clear inverse correlation between age and efficiency of acute wound healing. Elderly subjects heal more slowly, and wounds are characterized by increased inflammation, delayed re-epithelization, delayed neovascularization, and reduced matrix deposition due to attenuated fibroblast function.11,12 The authors’ recent in-vivo and in-vitro studies have begun to characterize the role of hormones in cutaneous healing. In women, a profound shift in healing ability correlates with a dramatic reduction in sex steroids post-menopause. Numerous local proinflammatory cytokines and growth factors are upregulated, and the rate of wound healing declines. The early inflammatory response (neutrophil response) is increased in aged wounds, and macrophage infiltration is delayed.13,14 Quality of scarring in these estrogen-deprived wounds is substantially improved and associated with reduced local TGF-β1 levels.
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