The Sex Steroid Precursor DHEA Accelerates Cutaneous Wound Healing Via the Estrogen Receptors

Abstract

Age-related impaired wound healing states lead to substantial morbidity and cost, with treatment in the USA resulting in an expenditure of over $9 billion per annum. Dehydroepiandrosterone (DHEA) is a ubiquitous adrenal hormone with immunomodulatory properties whose levels decline significantly with advanced age in humans. Conversion of DHEA locally to downstream steroid hormones leads to estrogenic and/or androgenic effects which may be important in age-related skin homeostasis, and which would avoid systemic adverse effects related to estrogen. We report that systemic DHEA levels are strongly associated with protection against chronic venous ulceration in humans. DHEA accelerated impaired healing in an impaired healing model (mice rendered hypogonadal) associated with increased matrix deposition and dampens the exaggerated inflammatory response. Such effects were mediated by local conversion of DHEA to estrogen, acting through the estrogen receptor, and vitro studies suggest a direct effect on specific pro-inflammatory cytokine production by macrophages via mitogen activated kinase (MAP) and phosphatidylinositol 3 (PI3) kinase pathways. In addition, we show that local injection of DHEA accelerates impaired healing in an ageing mouse colony. We suggest that exogenous application of DHEA accelerates impaired wound repair, results which may be applicable to the prophylaxis and treatment of human impaired wound healing states.

The role of estrogen deficiency in skin ageing and wound healing

“…Of note, the beneficial effects of 17b-estradiol on outcome in a skin flap necrosis model is reportedly mediated via ERa (Toutain et al 2009) while Ovx rats treated with PPT exhibit reduced wound tensile strength (Gal et al 2010). A crucial link between our mouse data and aged human healing is provided by the observation that polymorphisms in the human ERb gene are significantly associated with venous ulceration in the Caucasian population (Ashworth et al 2005(Ashworth et al , 2008.…”

“…2008) and male rats(Rajabi and Rajabi 2007). Systemic treatment with the sex steroid precursor DHEA accelerates wound healing in young Ovx female mice and old male mice, a result attributed to the local conversion of DHEA to estrogen(Mills et al 2005). Of interest, androgens are detrimental to healing.…”

“…Estrogen dampens expression of numerous pro-inflammatory cytokines, including MIF, TNFa, MCP-1, IL-1b and IL-6 (Kovacs et al 1996; Hu et al 1988). The reduction in Macrophage Migration Inhibitory Factor (MIF), in particular, plays a major role in the beneficial effects of estrogen on wound repair(Ashcroft et al 2003;Hardman et al 2005; Emmerson et al 2009). Of interest, plasma MIF levels, which inversely correlate with systemic estrogen(Aloisi et al 2005), are increased postmenopause and fall followingHRT (Hardman et al 2005).…”

Delayed wound healing in elderly people

“…In humans, reduced systemic DHEA levels positively correlate with an increased risk of developing a chronic (non-healing) venous leg ulcer. 66 In a murine incisional wound model, systemic DHEA treatment completely reverses the delayed wound healing phenotype exhibited by mice lacking systemic oestrogen. 66 Moreover, local DHEA treatment reverses impaired wound healing in aged mice.…”

“…66 In a murine incisional wound model, systemic DHEA treatment completely reverses the delayed wound healing phenotype exhibited by mice lacking systemic oestrogen. 66 Moreover, local DHEA treatment reverses impaired wound healing in aged mice. 66 DHEA administration may therefore act as an effective therapy for treatment of delayed healing wounds in older people.…”