The Hair Follicle as an Estrogen Target and Source

Abstract

For many decades, androgens have dominated endocrine research in hair growth control. Androgen metabolism and the androgen receptor currently are the key targets for systemic, pharmacological hair growth control in clinical medicine. However, it has long been known that estrogens also profoundly alter hair follicle growth and cycling by binding to locally expressed high-affinity estrogen receptors (ERs). Besides altering the transcription of genes with estrogen-responsive elements, 17␤-estradiol (E2) also modifies androgen metabolism within distinct subunits of the pilosebaceous unit (i.e., hair follicle and sebaceous gland). The latter displays prominent aromatase activity, the key enzyme for androgen conversion to E2, and is both an estrogen source and target.Here, we chart the recent renaissance of estrogen research in hair research; explain why the hair follicle offers an ideal, clinically relevant test system for studying the role of sex steroids, their receptors, and interactions in neuroectodermal-mesodermal interaction systems in general; and illustrate how it can be exploited to identify novel functions and signaling cross talks of ER-mediated signaling. Emphasizing the long-underestimated complexity and species-, gender-, and site-dependence of E2-induced biological effects on the hair follicle, we explore targets for pharmacological intervention in clinically relevant hair cycle manipulation, ranging from androgenetic alopecia and hirsutism via telogen effluvium to chemotherapy-induced alopecia. While defining major open questions, unsolved clinical challenges, and particularly promising research avenues in this area, we argue that the time has come to pay estrogen-mediated signaling the full attention it deserves in future endocrinological therapy of common hair growth disorders. (Endocrine Reviews 27: 677-706, 2006)

(Neuro-)endocrinology of epithelial hair follicle stem cells

“…by estrogens (Harlow and Hillier, 2002; and that estrogens are recognized key hair growth regulatory steroid hormones (Ohnemus et al 2006), the reported upregulation of Ctgf expression by murine HFeSC ( Table 1) also deserves to be carefully followed up. It is conceivable that increased Ctgf release by these SCs may contribute to condition the bulge SC niche (Cotsarelis, 2006), including its mesenchymal component, i.e.…”

“…for glucocorticoid, retinoid, estrogen, and vitamin D3 receptors (glucocorticoid receptor (GR), retinoic acid receptor (RAR), estrogen receptor (ER), vitamin D receptor (VDR)); and mutations in VDR and retinoid receptors can cause severe alopecia in mice and man (Chebotaev et al, 2007; Billoni et al, 1994;Ohnemus et al, 2006;Reichrath et al, 1994; Page 10 of 38 A c c e p t e d M a n u s c r i p t 10 Zouboulis et al, 2007). Even though a marked, immunohistologically prominent up-or down-regulation of these receptors has not been noted, the hair growth effects of appropriate receptor ligands, especially in mice, is impressive.…”

“…For example, even once weekly topical 17-β-estradiol application suffices to "freeze" murine back skin pelage HFs in the resting stage of the hair cyle (telogen) and induces catagen i.e. apoptosis-driven HF involution (Ohnemus et al, 2006). Topical glucocorticoid administration prevents depilation-induced anagen development and is a very potent catagen-inducer in mice (Paus et al, 1994 a;Stenn et al, 1993).…”

“…HF immune privilege, connective tissue sheath (CTS) mast cell degranulation. (see Arck et al, 2005a; Bodó et al, 2005 and2007; Botchkarev et al, 2004; Colombe et al., 2007; Deplewski and Rosenfield, 2000;Hasse et al, 2007; Kauser et al, 2006;Ohnemus et al, 2006;Paus et al, 2006;Peters et al, 2006b and2007;Philp et al, 2004;Slominski et al, 2007;Telek et al, 2007;Zouboulis et al, 2007) While this remains to be conclusively demonstrated, it is likely that HFeSC are fully integrated into this neuroendocrine tapestry of general HF biology. However, all we have to go by currently are some pointers to potentially important elements in the as yet obscure neuroendocrinology of HFeSC.…”

“…It is, therefore, interesting to note that HFeSCs in mice show an upregulation of transcription for insulin-like growth factor binding proteins 3, 5, 6, which would be Given that the expression of connective tissue growth factor (CTGF) is subject to hormonal regulation e.g. by estrogens (Harlow and Hillier, 2002; and that estrogens are recognized key hair growth regulatory steroid hormones (Ohnemus et al 2006), the reported upregulation of Ctgf expression by murine HFeSC ( Table 1) also deserves to be carefully followed up. It is conceivable that increased Ctgf release by these SCs may contribute to condition the bulge SC niche (Cotsarelis, 2006), including its mesenchymal component, i.e.…”