5alpha-dihydrotestosterone (DHT) retards wound closure by inhibiting re-epithelialization.
The ongoing search for explanations as to why elderly males heal acute skin wounds more slowly than do their female counterparts (and are more strongly disposed to conditions of chronic ulceration) has identified endogenous oestrogens and androgens as being respectively enhancers and inhibitors of repair. We previously demonstrated that blocking the conversion of testosterone to 5alpha-dihydrotestosterone (DHT) limits its ability to impair healing, suggesting that DHT is a more potent inhibitor of repair than is testosterone. The present study aimed to delineate the central mechanisms by which androgens delay repair. Whilst the contractile properties of neither rat wounds in vivo nor fibroblast-impregnated collagenous discs in vitro appeared to be influenced by androgen manipulations, the global blockade of DHT biosynthesis markedly accelerated re-epithelialization of incisional and excisional wounds and reduced local expression of beta-catenin, a key inhibitor of repair. Moreover, DHT retarded the in vitro migration of epidermal keratinocytes following scratch wounding. By contrast, it failed to influence the migratory and proliferative properties of dermal fibroblasts, suggesting that its primary inhibitory effect is upon re-epithelialization. These novel findings may be of particular significance in the context of chronic ulceration, for which being male is a key risk factor.
Gilliver
S C
SC
Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
Ruckshanthi
J P D
JP
Hardman
M J
MJ
Zeef
L A H
LA
Ashcroft
G S
GS
D058891:5-alpha Reductase Inhibitors; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004817:Epidermis / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D018120:Finasteride / Q000031:analogs & derivatives / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
C088478:17 beta-benzoyl-4-aza-5 alpha-androst-1-ene-3-one; D058891:5-alpha Reductase Inhibitors; D000728:Androgens; C495268:Ctnnb1 protein, rat; D004791:Enzyme Inhibitors; D051176:beta Catenin; D013196:Dihydrotestosterone; D018120:Finasteride