Immunolocalization of 5α-Reductase Isozymes in Acne Lesions and Normal Skin

Thiboutot, Diane; Bayne, Ellen K.; Thorne, Jen; Gilliland, Kathyrn; Flanagan, J.; Shao, Qing; Light, Jan; Helm, Klaus F.

doi:10.1001/archderm.136.9.1125

Cited by 45 publications

(37 citation statements)

References 17 publications

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“…Skin cells are able to synthesise locally acting estrogens from the precursors cholesterol and DHEA (Fig. 2) (Simpson et al 1997;Bulun et al 1999;Chen et al 2002;Chen et al 1998;Thiboutot et al 1998;Hughes et al 1997;Sawaya and Penneys 1992;Dumont et al 1992;Eicheler et al 1995;Thiboutot et al 2000). Additionally, local production of 11b-HSD by epidermal keratinocytes, dermal fibroblasts and hair follicles (Tiganescu et al 2011) increases cortisol conversion and has been speculated to control the inflammatory response (Vukelic et al 2011).…”

Section: Skin Ageing and Estrogensmentioning

confidence: 99%

The role of estrogen deficiency in skin ageing and wound healing

2011

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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.

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Section: Skin Ageing and Estrogensmentioning

confidence: 99%

The role of estrogen deficiency in skin ageing and wound healing

2011

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“…The primary 'male' sex steroid testosterone is converted to its more active metabolite 5␣-dihydrotestosterone (DHT) by the enzyme 5␣-reductase (5␣-R), of which two isoforms exist (5␣-R1 and 5␣-R2); both are expressed by hair follicles and the epidermis in uninjured skin (Eicheler et al, 1995;Thiboutot et al, 2000). Several studies have demonstrated cell-specific and differential regulation by testosterone and DHT of proteins with key roles in cutaneous repair.…”

Section: Introductionmentioning

confidence: 99%

Androgens modulate the inflammatory response during acute wound healing

Gilliver¹,

Ashworth²,

Mills³

et al. 2006

Journal of Cell Science

128

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Impaired wound healing states in the elderly lead to substantial morbidity and mortality, and a cost to the health services of over $9 billion per annum. In addition to intrinsic ageing processes that per se cause delayed healing, studies have suggested marked differences in wound repair between the sexes. We have previously reported that, castration of male mice results in a striking acceleration of local cutaneous wound healing and dampens the associated inflammatory response. In this study, we report that systemic 5α-reductase inhibition, which blocks the conversion of testosterone to its more active metabolite 5α-dihydrotestosterone, mimics the effects of castration in a rat model of cutaneous wound healing. The mechanisms underlying the observed effects involve a direct, cell-specific upregulation of pro-inflammatory cytokine expression by macrophages, but not fibroblasts, in response to androgens. Androgens require the transforming growth factor β signalling intermediate Smad3 to be present in order to influence repair and local pro-inflammatory cytokine levels. That reducing 5α-dihydrotestosterone levels through 5α-reductase antagonism markedly accelerates healing suggests a specific target for future therapeutic intervention in impaired wound healing states in elderly males.

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“…M NIXON and others 115 Zyirek et al (1987) M NIXON and others . Actions of 5a-reduced glucocorticoids Price 1997, Thiboutot et al 2000, Thiele et al 2005, lungs (Normington & Russell 1992, Provost et al 2002, Kimura et al 2003, and in the gastrointestinal tract (Nienstedt et al 1980a,b, Normington & Russell 1992, all sites of importance in inflammatory diseases and GC therapies. In metabolic tissues, 5aR1 is highly expressed in the liver (Normington & Russell 1992, Livingstone et al 2005 but is also present in lower abundance in adipose (Livingstone et al 2005, Wake et al 2007), but not in human skeletal muscle (Thigpen et al 1993b).…”

Section: Therapeutic Actions Of Gcs To Relieve Inflammationmentioning

confidence: 99%

5α-Reduced glucocorticoids: a story of natural selection

Nixon¹,

Upreti²,

Andrew³

2011

Journal of Endocrinology

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5a-Reduced glucocorticoids (GCs) are formed when one of the two isozymes of 5a-reductase reduces the D 4-5 double bond in the A-ring of GCs. These steroids are largely viewed inert, despite the acceptance that other 5a-dihydro steroids, e.g. 5a-dihydrotestosterone, retain or have increased activity at their cognate receptors. However, recent findings suggest that 5a-reduced metabolites of corticosterone have dissociated actions on GC receptors (GRs) in vivo and in vitro and are thus potential candidates for safer anti-inflammatory steroids. 5a-Dihydro-and 5a-tetrahydro-corticosterone can bind with GRs, but interest in these compounds had been limited, since they only weakly activated metabolic gene transcription. However, a greater understanding of the signalling mechanisms has revealed that transactivation represents only one mode of signalling via the GR and recently the abilities of 5a-reduced GCs to suppress inflammation have been demonstrated in vitro and in vivo. Thus, the balance of parent GC and its 5a-reduced metabolite may critically affect the profile of GR signalling. 5a-Reduction of GCs is up-regulated in liver in metabolic disease and may represent a pathway that protects from both GC-induced fuel dyshomeostasis and concomitant inflammatory insult. Therefore, 5a-reduced steroids provide hope for drug development, but may also act as biomarkers of the inflammatory status of the liver in metabolic disease. With these proposals in mind, careful attention must be paid to the possible adverse metabolic effects of 5a-reductase inhibitors, drugs that are commonly administered long term for the treatment of benign prostatic hyperplasia.

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Immunolocalization of 5α-Reductase Isozymes in Acne Lesions and Normal Skin

Cited by 45 publications

References 17 publications

The role of estrogen deficiency in skin ageing and wound healing

The role of estrogen deficiency in skin ageing and wound healing

Androgens modulate the inflammatory response during acute wound healing

5α-Reduced glucocorticoids: a story of natural selection

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