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The role of estrogen in cutaneous ageing and repair

      Highlights

      • Pathological wound repair remains a major area of unmet clinical need.
      • 17β-estradiol deficiency contributes to both skin ageing and poor wound healing.
      • 17β-estradiol treatment restores normal healing and protects against infection.
      • Selective estrogen receptor modulators (SERMs) offer a potential future alternative to 17β-estradiol for clinical use.
      • Further molecular and mechanistic studies are needed to develop novel therapeutics.

      Abstract

      Combined advances in modern medical practice and increased human longevity are driving an ever-expanding elderly population. Females are particularly at risk of age-associated pathology, spending more of their lives in a post-menopausal state. Menopause, denoted by a rapid decline in serum sex steroid levels, accelerates biological ageing across the body’s tissues. Post-menopause physiological changes are particularly noticeable in the skin, which loses structural architecture and becomes prone to damage. The sex steroid most widely discussed as an intrinsic contributor to skin ageing and pathological healing is 17β-estradiol (or estrogen), although many others are involved. Estrogen deficiency is detrimental to many wound-healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment widely reverses these effects. Over recent decades, many of the molecular and cellular correlates to estrogen’s beneficial effect on normal skin homeostasis and wound healing have been reported. However, disparities still exist, particularly in the context of mechanistic studies investigating estrogen receptor signalling and its potential cellular effects. New molecular techniques, coupled with increased understanding of estrogen in skin biology, will provide further opportunities to develop estrogen receptor-targeted therapeutics.

      Keywords

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      References

        • Croft D.P.
        • Johnstone R.A.
        • Ellis S.
        • Nattrass S.
        • Franks D.W.
        • Brent L.J.
        • Mazzi S.
        • Balcomb K.C.
        • Ford J.K.
        • Cant M.A.
        Reproductive conflict and the evolution of menopause in killer whales.
        Curr. Biol. 2017; 27: 298-304
        • Labrie F.
        All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause.
        J. Steroid. Biochem. Mol. Biol. 2015; 145: 133-138
        • Raine-Fenning N.J.
        • Brincat M.P.
        • Muscat-Baron Y.
        Skin aging and menopause.
        Am. J. Clin. Dermatol. 2003; 6: 371-378
        • Labrie F.
        • Bélanger A.
        • Cusan L.
        • Candas B.
        Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology.
        J. Clin. Endocrinol. Metab. 1997; 82: 2403-2409
        • Debacq-Chainiaux F.
        • Ameur R.B.
        • Bauwens E.
        • Dumortier E.
        • Toutfaire M.
        • Toussaint O.
        Stress-Induced (Premature) Senescence, in Cellular Ageing and Replicative Senescence.
        Springer, 2016: 243-262
        • Tchkonia T.
        • Zhu Y.
        • Van Deursen J.
        • Campisi J.
        • Kirkland J.L.
        Cellular senescence and the senescent secretory phenotype: therapeutic opportunities.
        J. Clin. Invest. 2013; 123: 966-972
        • Baker D.J.
        • Wijshake T.
        • Tchkonia T.
        • LeBrasseur N.K.
        • Childs B.G.
        • Van De Sluis B.
        • Kirkland J.L.
        • van Deursen J.M.
        Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.
        Nature. 2011; 479: 232-236
        • Imanishi T.
        • Hano T.
        • Nishio I.
        Estrogen reduces angiotensin II-induced acceleration of senescence in endothelial progenitor cells.
        Hypertens. Res. 2005; 28: 263-271
        • Bayne S.
        • Jones M.E.
        • Li H.
        • Pinto A.R.
        • Simpson E.R.
        • Liu J.P.
        Estrogen deficiency leads to telomerase inhibition, telomere shortening and reduced cell proliferation in the adrenal gland of mice.
        Cell. Res. 2008; 18: 1141-1150
        • Bottai G.
        • Mancina R.
        • Muratori M.
        • Di Gennaro P.
        • Lotti T.
        17β-estradiol protects human skin fibroblasts and keratinocytes against oxidative damage.
        Eur. Acad. Dermatol. Venereol. 2013; 27: 1236-1243
        • Baeza I.
        • De Castro N.M.
        • Gimenez-Llort L.
        • De la Fuente M.
        Ovariectomy, a model of menopause in rodents, causes a premature aging of the nervous and immune systems.
        J. Neuroimmunol. 2010; 219: 90-99
        • Kasımay Ö.
        • Şener G.
        • Çakır B.
        • Yüksel M.
        • Çetinel Ş.
        • Contuk G.
        • Yeğen B.Ç.
        Estrogen protects against oxidative multiorgan damage in rats with chronic renal failure.
        Ren. Fail. 2009; 31: 711-725
        • Tresguerres J.A.
        • Kireev R.
        • Tresguerres A.F.
        • Borras C.
        • Vara E.
        • Ariznavarreta C.
        Molecular mechanisms involved in the hormonal prevention of aging in the rat.
        J. Steroid. Biochem. Mol. Biol. 2008; 108: 318-326
        • Gosain A.
        • DiPietro L.A.
        Aging and wound healing.
        World J. Surg. 2004; 28: 21-326
        • Blume-Peytavi U.
        • Kottner J.
        • Sterry W.
        • Hodin M.W.
        • Griffiths T.W.
        • Watson R.E.
        • Hay R.J.
        • Griffiths C.E.
        Age-associated skin conditions and diseases: current perspectives and future options.
        Gerontologist. 2016; 56: S230-S242
        • Emmerson E.
        • Hardman M.J.
        The role of estrogen deficiency in skin ageing and wound healing.
        Biogerontology. 2012; 13: 3-20
        • Quan T.
        • Qin Z.
        • Xu Y.
        • He T.
        • Kang S.
        • Voorhees J.J.
        • Fisher G.J.
        Ultraviolet irradiation induces CYR61/CCN1 a mediator of collagen homeostasis, through activation of transcription factor AP-1 in human skin fibroblasts.
        J. Invest. Dermatol. 2010; 130: 1697-1706
        • Ressler S.
        • Bartkova J.
        • Niederegger H.
        • Bartek J.
        • Scharffetter‐Kochanek K.
        • Jansen‐Dürr P.
        • Wlaschek M.
        p16INK4A is a robust in vivo biomarker of cellular aging in human skin.
        Aging Cell. 2006; 5: 379-389
        • Brincat M.
        • Versi E.
        • Moniz C.F.
        • Magos A.
        • De Trafford J.
        • Studd J.W.W.
        Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy.
        Obstet. Gynecol. 1987; 70: 123-127
        • Affinito P.
        • Palomba S.
        • Sorrentino C.
        • Di Carlo C.
        • Bifulco G.
        • Arienzo M.P.
        • Nappi C.
        Effects of postmenopausal hypoestrogenism on skin collagen.
        Maturitas. 1999; 33: 239-247
        • Tsukahara K.
        • Nakagawa H.
        • Moriwaki S.
        • Kakuo S.
        • Ohuchi A.
        • Takema Y.
        • Imokawa G.
        Ovariectomy is sufficient to accelerate spontaneous skin ageing and to stimulate ultraviolet irradiation-induced photoageing of murine skin.
        Br. J. Dermatol. 2004; 151: 984-994
        • Thornton M.J.
        Estrogens and aging skin.
        Dermatoendocrinology. 2013; 5: 264-270
        • Inoue T.
        • Miki Y.
        • Abe K.
        • Hatori M.
        • Hosaka M.
        • Kariya Y.
        • Kakuo S.
        • Fujimura T.
        • Hachiya A.
        • Aiba S.
        • Sasano H.
        The role of estrogen-metabolizing enzymes and estrogen receptors in human epidermis.
        Mol. Cell. Endocrinol. 2011; 344: 35-40
        • Chang K.C.
        • Wang Y.
        • Oh I.G.
        • Jenkins S.
        • Freedman L.P.
        • Thompson C.C.
        • Chung J.H.
        • Nagpal S.
        Estrogen receptor (is a novel therapeutic target for photoaging.
        Mol. Pharmacol. 2010; 77: 744-750
        • Beral V.
        • Collaborators M.W.S.
        Breast cancer and hormone-replacement therapy in the Million Women Study.
        Lancet. 2003; 362: 419
        • Kumar M.M.
        • Davuluri S.
        • Poojar S.
        • Mukherjee G.
        • Bajpai A.K.
        • Bafna U.D.
        • Devi U.K.
        • Kallur P.P.
        Role of estrogen receptor alpha in human cervical cancer-associated fibroblasts: a transcriptomic study.
        Tumor Biol. 2016; 37: 4409-4420
        • Arai N.
        • Ström A.
        • Rafter J.J.
        • Gustafsson J.Å.
        Estrogen receptor β mRNA in colon cancer cells: growth effects of estrogen and genistein.
        Biochem. Biophys. Res. Commun. 2000; 270: 425-431
        • Edvardsson K.
        • Nguyen-Vu T.
        • Kalasekar S.M.
        • Pontén F.
        • Gustafsson J.Å.
        • Williams C.
        Estrogen receptor β expression induces changes in the microRNA pool in human colon cancer cells.
        Carcinogenesis. 2013; 34: 1431-1441
        • Hardman M.J.
        • Emmerson E.
        • Campbell L.
        • Ashcroft G.S.
        Selective estrogen receptor modulators accelerate cutaneous wound healing in ovariectomized female mice.
        Endocrinology. 2008; 149: 551-557
        • Hardman M.J.
        • et al.
        Patterned acquisition of skin barrier function during development.
        Development. 1998; 125: 1541-1552
        • Velnar T.
        • Bailey T.
        • Smrkolj V.
        The wound healing process: an overview of the cellular and molecular mechanisms.
        J. Int. Med. Res. 2009; 37: 1528-1542
        • Ashcroft G.S.
        • Dodsworth J.
        • Van Boxtel E.
        • Tarnuzzer R.W.
        • Horan M.A.
        • Schultz G.S.
        • Ferguson M.W.
        Estrogen accelerates cutaneous wound healing associated with an increase in TGF-b1 levels.
        Nat. Med. 1997; 3: 1209-1215
        • Yang J.
        • Zhou X.
        • Fan X.
        • Xiao M.
        • Yang D.
        • Liang B.
        • Dai M.
        • Shan L.
        • Lu J.
        • Lin Z.
        • Liu R.
        mTORC1 promotes aging-related venous thrombosis in mice via elevation of platelet volume and activation.
        Blood. 2016; 128: 615-624
        • Komosinska-Vassev K.
        • Olczyk P.
        • Winsz-Szczotka K.
        • Kuznik-Trocha K.
        • Klimek K.
        • Olczyk K.
        Age-and gender-dependent changes in connective tissue remodeling: physiological differences in circulating MMP-3 MMP-10, TIMP-1 and TIMP-2 level.
        Gerontology. 2011; 57: 44-52
        • Keyes B.E.
        • Liu S.
        • Asare A.
        • Naik S.
        • Levorse J.
        • Polak L.
        • Lu C.P.
        • Nikolova M.
        • Pasolli H.A.
        • Fuchs E.
        Impaired epidermal to dendritic T cell signaling slows wound repair in aged skin.
        Cell. 2016; 167: 1323-1338
        • Hardman M.J.
        • Ashcroft G.S.
        Estrogen, not intrinsic aging, is the major regulator of delayed human wound healing in the elderly.
        Genome Biol. 2008; 9: R80
        • Campbell L.
        • Emmerson E.
        • Davies F.
        • Gilliver S.C.
        • Krust A.
        • Chambon P.
        • Ashcroft G.S.
        • Hardman M.J.
        Estrogen promotes cutaneous wound healing via estrogen receptor β independent of its antiinflammatory activities.
        J. Exp. Med. 2010; 207: 1825-1833
        • Emmerson E.
        • Campbell L.
        • Ashcroft G.S.
        • Hardman M.J.
        The phytoestrogen genistein promotes wound healing by multiple independent mechanisms.
        Mol. Cell. Endocrinol. 2010; 321: 184-193
        • Ashcroft G.S.
        • Greenwell-Wild T.
        • Horan M.A.
        • Wahl S.M.
        • Ferguson M.W.
        Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response.
        Am. J. Pathol. 1999; 155: 1137-1146
        • Margolis D.J.
        • Knauss J.
        • Bilker W.
        Hormone replacement therapy and prevention of pressure ulcers and venous leg ulcers.
        Lancet. 2002; 359: 675-677
        • Gilliver S.C.
        • Emmerson E.
        • Bernhagen J.
        • Hardman M.J.
        MIF: a key player in cutaneous biology and wound healing.
        Exp. Dermatol. 2011; 20: 1-6
        • Ashcroft G.S.
        • Mills S.J.
        • Lei K.
        • Gibbons L.
        • Jeong M.J.
        • Taniguchi M.
        • Burow M.
        • Horan M.A.
        • Wahl S.M.
        • Nakayama T.
        Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor.
        J. Clin. Invest. 2003; 111: 1309-1318
        • Hardman M.J.
        • Waite A.
        • Zeef L.
        • Burow M.
        • Nakayama T.
        • Ashcroft G.S.
        Macrophage migration inhibitory factor: a central regulator of wound healing.
        Am. J. Pathol. 2005; 167: 1561-1574
        • Routley C.E.
        • Ashcroft G.S.
        Effect of estrogen and progesterone on macrophage activation during wound healing.
        Wound Rep. Regen. 2009; 17: 42-50
        • Crompton R.
        • Williams H.
        • Ansell D.
        • Campbell L.
        • Holden K.
        • Cruickshank S.
        • Hardman M.J.
        Oestrogen promotes healing in a bacterial LPS model of delayed cutaneous wound repair.
        Lab. Invest. 2016; 96: 439-449
        • Zhuge Y.
        • Liu Z.
        • Pincus D.J.
        • Thaller S.R.
        • Elliot S.
        • Velazquez O.C.
        A novel role of estrogen in diabetic wound healing: improved function of bone marrow-derived endothelial progenitor cells.
        J. Surg. Res. 2010; 158: 360
        • Gilliver S.C.
        • Emmerson E.
        • Campbell L.
        • Chambon P.
        • Hardman M.J.
        • Ashcroft G.S.
        17β-Estradiol inhibits wound healing in male mice via estrogen receptor-α.
        Am. J. Pathol. 2010; 176: 2707-2721
        • Maninger N.
        • Wolkowitz O.M.
        • Reus V.I.
        • Epel E.S.
        • Mellon S.H.
        Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS).
        Front. Neuroendocrinol. 2009; 30: 65-91
        • Droog M.
        • Mensink M.
        • Zwart W.
        The estrogen receptor α-cistrome beyond breast cancer.
        Mol. Endocrinol. 2016; 30: 1046-1058
        • Ashworth J.J.
        • Smyth J.V.
        • Pendleton N.
        • Horan M.
        • Payton A.
        • Worthington J.
        • Ollier W.E.
        • Ashcroft G.S.
        Polymorphisms spanning the 0N exon and promoter of the estrogen receptor-beta (ER() gene ESR2 are associated with venous ulceration.
        Clin. Genet. 2008; 73: 55-61
        • Prough R.A.
        • Clark B.J.
        • Klinge C.M.
        Novel mechanisms for DHEA action.
        J. Mol. Endocrinol. 2016; 56: R139-R155