P8.112 Corticotropin-releasing hormone is involved in androgen-dependent skin disorders

Ch.C. Zouboulis, K. Orlowski, A. Schnitger, E. Glass, S. Fimmel, N. Hiroi*, H. Seltmann, W. Chen^§, S.R. Bornstein*

Department of Dermatology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany; *Department of Endocrinology, University Medical Center, Heinrich Heine University of Duesseldorf, Duesseldorf, Germany; §Department of Dermatology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Corticotropin-releasing hormone (CRH) is the most proximal element of the hypothalamic-pituitary-adrenal (HPA) axis and it acts as central coordinator for neuroendocrine and behavioral responses to stress. CRH is also present in the human skin and CRH, CRH-binding protein (CRH-BP), and CRH receptor 1 (CRH-R1) and 2 (CRH-R2) were detectable in SZ95 sebocytes at the mRNA and protein levels: CRH-R1 was the predominant type. In different culture models, CRH was biologically active on human sebocytes. It induced biphasic increase in synthesis of sebaceous lipids with a maximum stimulation at 10^-7 M and up-regulated mRNA levels of 3β-hydroxysteroid dehydrogenase/∆^5-4 isomerase, while it did not affect cell viability or IL1β-induced IL-8 release. In another system, CRH and urocortin, a CRH-like peptide sharing a 45% homology to CRH, inhibited SZ95 sebocyte growth. In contrast, other CRH-like peptides, such as urotensin, a CRH-R2 ligand, and sauvagine were inactive. CRH and urocortin stimulated IL-6 and IL-8 release from SZ95 sebocytes but they exhibited no effect on IL-1α and -β release. α-helical CRH, a CRH antagonist, annulled the CRH effect – but not that of urocortin – on SZ95 sebocyte proliferation and interleukin synthesis. CRH, dehydroepiandrosterone and 17β-estradiol did not modulate CRH-R expression, whereas testosterone at 10^-7 M down-regulated CRH-R1 and CRH-R2 mRNA expression at 6 to 24 h and growth hormone switched CRH-R1 mRNA expression to CRH-R2 at 24 h. Based on these findings, CRH may be an autocrine hormone for human sebocytes that exerts a receptor-mediated activity. Androgens may induce a CRH-R negative feedback. These findings implicate CRH in the clinical development of several inflammatory and sexual hormone-dependent skin diseases, such as acne and androgenetic alopecia.