The role of estrogen deficiency in skin ageing and wound healing

Abstract

The links between hormonal signalling and lifespan have been well documented in a range of model organisms. For example, in C. elegans or D. melanogaster, lifespan can be modulated by ablating germline cells, or manipulating reproductive history or pregnenolone signalling. In mammalian systems, however, hormonal contribution to longevity is less well understood. With increasing age human steroid hormone profiles change substantially, particularly following menopause in women. This article reviews recent links between steroid sex hormones and ageing, with special emphasis on the skin and wound repair. Estrogen, which substantially decreases with advancing age in both males and females, protects against multiple aspects of cellular ageing in rodent models, including oxidative damage, telomere shortening and cellular senescence. Estrogen's effects are particularly pronounced in the skin where cutaneous changes post-menopause are well documented, and can be partially reversed by classical Hormone Replacement Therapy (HRT). Our research shows that while chronological ageing has clear effects on skin wound healing, falling estrogen levels are the principle mediator of these effects. Thus, both HRT and topical estrogen replacement substantially accelerate healing in elderly humans, but are associated with unwanted deleterious effects, particularly cancer promotion. In fact, much current research effort is being invested in exploring the therapeutic potential of estrogen signalling manipulation to reverse age-associated pathology in peripheral tissues. In the case of the skin the differential targeting of estrogen receptors to promote healing in aged subjects is a real therapeutic possibility.

Reduced DNA methylation patterning and transcriptional connectivity define human skin aging

“…Considering that our samples were exclusively derived from female volunteers, it seems reasonable to link the latter window to menopause, which is also known to distinctly accelerate skin aging (Thornton, 2013). The high temporal and spatial specificity of these methylation changes suggests that defined signaling pathways, such as estrogen signaling (Emmerson & Hardman, 2012), may be involved in their establishment.…”

Intracrine sex steroid synthesis and signaling in human epidermal keratinocytes and dermal fibroblasts

“…Inhibitors of aromatase (Arimidex, 100 nM) and STS (STX64, 100 nM) were included alone or in combination with relevant steroids. Migration was measured at 4,8,12,24, and 48 h in triplicate dishes for each donor. Conditioned medium, collected from dermal fibroblast cultures 24 h after scratching as previously described (37), was also assessed for its effect on the migration of epidermal keratinocytes.…”

“…DHEA-S, DHEA, and 17b-estradiol but not testosterone stimulates the migration of wounded human epidermal keratinocytes and dermal fibroblasts in vitro A scratch assay as previously described (28, 30) measured epidermal keratinocyte (n = 3) and dermal fibroblast (n = 5) migration in response to 10 mM DHEA-S, 10 mM DHEA, 1 nM 17b-estradiol or 50 nM testosterone at 5 fixed time points (4,8,12,24, and 48 h). Previous dose-response assays using this technique have shown that a range of concentrations of 17b-estradiol (10 27 -10 29 M) and DHEA (10 25 -10 28 M) all stimulated cell migration to a similar level (37,39).…”

“…Estrogens significantly modulate human skin and insufficiency in postmenopausal women leads to a diminished defense against oxidative stress, resulting in atrophic skin changes, acceleration of skin aging, and higher incidence of nonhealing chronic wounds (1)(2)(3)(4)(5). Although estrogen replacement significantly reverses or delays these changes, it carries the risk of breast and uterine cancer (6).…”

“…The half-life of DHEA-S in plasma is significantly longer than that of unconjugated DHEA. However, DHEA-S requires transportation inside the cell by an organic anion transporting polypeptide such as OATP2B1.The enzyme STS removes the sulfate group, and the resulting DHEA can undergo oxidation to androstenedione (4-DIONE) by 3b-hydroxysteroid dehydrogenase type-1/D 5 -D 4 -isomerase (3b-HSD-1) (17) or reduction to 5-androstenediol (5-Diol) by 17b-HSD-1 (18). Both steroids can be converted to testosterone, which is metabolized to 17b-estradiol by aromatase, or to 5a-dihydrotestosterone (5a-DHT) by 5a-reductase (19).…”