Sexual Hormones in Human Skin

 

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Abstract

The skin locally synthesizes significant amounts of sexual hormones with intracrine or paracrine actions. The local level of each sexual steroid depends upon the expression of each of the androgen- and estrogen-synthesizing enzymes in each cell type, with sebaceous glands and sweat glands being the major contributors. Sebocytes express very little of the key enzyme, cytochrome P450c17, necessary for synthesis of the androgenic prohormones dehydroepiandrosterone and androstenedione, however, these prohormones can be converted by sebocytes and sweat glands, and probably also by dermal papilla cells, into more potent androgens like testosterone and dihydrotestosterone. Five major enzymes are involved in the activation and deactivation of androgens in skin. Androgens affect several functions of human skin, such as sebaceous gland growth and differentiation, hair growth, epidermal barrier homeostasis and wound healing. Their effects are mediated by binding to the nuclear androgen receptor. Changes of isoenzyme and/or androgen receptor levels may have important implications in the development of hyperandrogenism and the associated skin diseases such as acne, seborrhoea, hirsutism and androgenetic alopecia. On the other hand, estrogens have been implicated in skin aging, pigmentation, hair growth, sebum production and skin cancer. Estrogens exert their actions through intracellular receptors or via cell surface receptors, which activate specific second messenger signaling pathways. Recent studies suggest specific site-related distribution of ERα and ERβ in human skin. In contrast, progestins play no role in the pathogenesis of skin disorders. However, they play a major role in the treatment of hirsutism and acne vulgaris, where they are prescribed as components of estrogen-progestin combination pills and as anti-androgens. These combinations enhance gonadotropin suppression of ovarian androgen production. Estrogen-progestin treatment can reduce the need for shaving by half and arrest progression of hirsutism of various etiologies, but do not necessarily reverse it. However, they reliably reduce acne. Cyproterone acetate and spironolactone are similarly effective as anti-androgens in reducing hirsutism, although there is wide variability in individual responses.

References

• 1 Imperato-McGinley J, Gautier T, Cai L-Q, Yee B, Epstein J, Pochi P. The androgen control of sebum production. Studies of subjects with dihydrotestosterone deficiency and complete androgen insensitivity.  J Clin Endocrinol Metab. 1993;  76 524-528
  CrossrefPubMedGoogle Scholar
• 2 Zouboulis CC. Human skin: an independent peripheral endocrine organ.  Horm Res. 2000;  54 230-242
  CrossrefPubMedGoogle Scholar
• 3 Rosenfield RL. Hirsutism and the variable response of the pilosebaceous unit to androgen.  J Investig Dermatol Symp Proc. 2005;  10 205-208
  CrossrefPubMedGoogle Scholar
• 4 Rosenfield RL. Role of androgens in growth and development of the fetus, child, and adolescent.  Adv Pediatr. 1972;  19 171-213
  PubMedGoogle Scholar
• 5 Stewart ME, Downing DT, Cook JS, Hansen JR, Strauss JS. Sebaceous gland activity and serum dehydroepiandrosteron sulfate levels in boys and girls.  Arch Dermatol. 1992;  128 1345-1348
  CrossrefPubMedGoogle Scholar
• 6 Marynick SP, Chakmakjian ZH, McCaffree DL, Herndon JH. Androgen excess in cystic acne.  N Engl J Med. 1983;  308 981-986
  PubMedGoogle Scholar
• 7 Pochi PE, Strauss JS. Sebaceous gland response in man to the administration of testosterone, Δ4-androstenedione, and dehydroisoandrosterone.  J Invest Dermatol. 1969;  52 32-36
  PubMedGoogle Scholar
• 8 Messenger AG. The control of hair growth: an overview.  J Invest Dermatol. 1993;  101 4S-9S
  CrossrefPubMedGoogle Scholar
• 9 Deplewski D, Rosenfield RL. Role of hormones in pilosebaceous unit development.  Endocrine Rev. 2000;  21 363-392
  CrossrefPubMedGoogle Scholar
• 10 Verrijdt G, Haelens A, Claessens F. Selective DNA recognition by the androgen receptor as a mechanism for hormone-specific regulation of gene expression.  Mol Genet Metab. 2003;  78 175-185
  CrossrefPubMedGoogle Scholar
• 11 Zouboulis CC. The human skin as a hormone target and an endocrine gland.  Hormones. 2004;  3 9-26
  PubMedGoogle Scholar
• 12 Zouboulis CC, Degitz K. Androgen action on human skin - From basic research to clinical significance.  Exp Dermatol. 2004;  13 ((Suppl 4)) 5-10
  PubMedGoogle Scholar
• 13 Gad YZ, Berkovitz GD, Migeon CJ, Brown TR. Studies of up-regulation of androgen receptors in genital skin fibroblasts.  Mol Cell Endocrinol. 1988;  57 205-213
  CrossrefPubMedGoogle Scholar
• 14 Fimmel S, Saborowski A, Térouanne B, Sultan C, Zouboulis CC. Inhibition of the androgen receptor by antisense oligonucleotides regulates the biological activity of androgens in SZ95 sebocytes.  Horm Metab Res. , in press
  PubMedGoogle Scholar
• 15 Ibanez L, Ong KK, Mongan N, Jaaskelainen J, Marcos MV, Hughes IA, De Zegher F, Dunger DB. Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism.  J Clin Endocrinol Metab. 2003;  88 3333-3338
  CrossrefPubMedGoogle Scholar
• 16 Hillmer AM, Hanneken S, Ritzmann S, Becker T, Freudenberg J, Brockschmidt FF, Flaquer A, Freudenberg-Hua Y, Jamra RA, Metzen C, Heyn U, Schweiger N, Betz RC, Blaumeiser B, Hampe J, Schreiber S, Schulze TG, Hennies HC, Schumacher J, Propping P, Ruzicka T, Cichon S, Wienker TF, Kruse R, Nothen MM. Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia.  Am J Hum Genet. 2005;  77 140-148
  CrossrefPubMedGoogle Scholar
• 17 Fritsch M, Orfanos CE, Zouboulis CC. Sebocytes are the key regulators of androgen homeostasis in human skin.  J Invest Dermatol. 2001;  116 793-800
  CrossrefPubMedGoogle Scholar
• 18 Thiboutot D, Martin P, Volikos L, Gilliland K. Oxidative activity of the type 2 isozyme of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) predominates in human sebaceous glands.  J Invest Dermatol. 1998;  111 390-395
  CrossrefPubMedGoogle Scholar
• 19 Chen W, Thiboutot D, Zouboulis CC. Cutaneous androgen metabolism - Basic research and clinical perspectives.  J Invest Dermatol. 2002;  119 992-1007
  CrossrefPubMedGoogle Scholar
• 20 Milewich L, Sontheimer RD, Herndon Jr JH. Steroid sulfatase activity in epidermis of acne-prone and non-acne-prone skin of patients with acne vulgaris.  Arch Dermatol. 1990;  126 1312-1314
  CrossrefPubMedGoogle Scholar
• 21 Billich A, Rot A, Lam C, Schmidt JB, Schuster I. Immunohistochemical localization of steroid sulfatase in acne lesions: implications for the contribution of dehydroepiandrosterone sulfate to the pathogenesis of acne (abstract).  Hormone Res. 2000;  53 99
  PubMedGoogle Scholar
• 22 Hoffmann R, Rot A, Niiyama S, Billich A. Steroid sulfatase in the human hair follicle concentrations in the dermal papilla.  J Invest Dermatol. 2001;  117 1342-1348
  CrossrefPubMedGoogle Scholar
• 23 Sakurai N, Miki Y, Suzuki T, Watanabe K, Narita T, Ando K, Yung TM, Aoki D, Sasano H, Handa H. Systemic distribution and tissue localizations of human 17beta-hydroxysteroid dehydrogenase type 12.  J Steroid Biochem Mol Biol. 2006;  99 174-181
  CrossrefPubMedGoogle Scholar
• 24 Hoppe U, Holterhus PM, Wunsch L, Jocham D, Drechsler T, Thiele S, Marschke C, Hiort O. Tissue-specific transcription profiles of sex steroid biosynthesis enzymes and the androgen receptor.  J Mol Med. 2006;  84 651-659
  CrossrefPubMedGoogle Scholar
• 25 Courchay G, Boyera N, Bernard BA, Mahe Y. Messenger RNA expression of steroidogenesis enzyme subtypes in the human pilosebaceous unit.  Skin Pharmacol. 1996;  9 169-176
  PubMedGoogle Scholar
• 26 Grino PB, Griffin JE, Wilson JD. Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone.  Endocrinology. 1990;  126 1165-1172
  PubMedGoogle Scholar
• 27 Chen W, Zouboulis CC, Fritsch M, Blume-Peytavi U, Kodelja V, Goerdt S, Luu-The V, Orfanos CE. Evidence of heterogeneity and quantitative differences of the type1 5α-reductase expression in cultured human skin cells - First evidence of its presence in melanocytes.  J Invest Dermatol. 1998;  110 84-89
  CrossrefPubMedGoogle Scholar
• 28 Qin K, New MI, Cheng KC. Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase.  J Steroid Biochem Mol Biol. 1993;  46 673-679
  CrossrefPubMedGoogle Scholar
• 29 Thornton MJ, Nelson LD, Taylor AH, Birch MP, Laing I, Messenger AG. The modulation of aromatase and estrogen receptor alpha in cultured human dermal papilla cells by dexamethasone: a novel mechanism for selective action of estrogen via estrogen receptor beta?.  J Invest Dermatol. 2006;  126 2010-2018
  CrossrefPubMedGoogle Scholar
• 30 Chen W, Yang CC, Liao CY, Hung CL, Tsai SJ, Chen KF, Sheu HM, Zouboulis CC. Expression of sex-determining genes in human sebaceous glands and their possible roles in pathogenesis of acne.  J Eur Acad Dermatol Venereol. 2006;  20 846-852
  PubMedGoogle Scholar
• 31 Patel MV, McKay IA, Burrin JM. Transcriptional regulators of steroidogenesis, DAX-1 and SF-1, are expressed in human skin.  J Invest Dermatol. 2001;  117 1559-1565
  CrossrefPubMedGoogle Scholar
• 32 Thiboutot D, Chen W. Update and future of hormonal therapy in acne.  Dermatology. 2003;  206 57-67
  CrossrefPubMedGoogle Scholar
• 33 Lookingbill DP, Horton R, Demers LM, Egan N, Marks Jr JG, Santen RJ. Tissue production of androgens in women with acne.  J Am Acad Dermatol. 1985;  12 481-487
  PubMedGoogle Scholar
• 34 Akamatsu H, Zouboulis CC, Orfanos CE. Control of human sebocyte proliferation in vitro by testosterone and 5-alpha-dihydrotestosterone is dependent on the localization of the sebaceous glands.  J Invest Dermatol. 1992;  99 509-511
  CrossrefPubMedGoogle Scholar
• 35 Chen W, Yang C-C, Sheu H-M, Seltmann H, Zouboulis CC. Expression of peroxisome proliferator-activated receptor and CCAAT/enhancer binding protein transcription factors in cultured human sebocytes.  J Invest Dermatol. 2003;  121 441-447
  CrossrefPubMedGoogle Scholar
• 36 Makrantonaki E, Zouboulis CC. Testosterone metabolism to 5α-dihydrotestosterone and synthesis of sebaceous lipids is regulated by the peroxisome proliferators-activated receptor ligand linoleic acid in human sebocytes.  Brit J Dermatol. , in press
  PubMedGoogle Scholar
• 37 Asada Y, Sonoda T, Ojiro M, Kurata S, Sato T, Ezaki T, Takayasu S. 5alpha-reductase type 2 is constitutively expressed in the dermal papilla and connective tissue sheath of the hair follicle in vivo but not during culture in vitro.  J Clin Endocrinol Metab. 2001;  86 2875-2880
  CrossrefPubMedGoogle Scholar
• 38 Sawaya ME, Shalita AR. Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne.  J Cutan Med Surg. 1998;  3 9-15
  PubMedGoogle Scholar
• 39 Paus R. The biology of hair follicles.  N Engl J Med. 1999;  341 491-497
  CrossrefPubMedGoogle Scholar
• 40 Ando Y, Yamaguchi Y, Hamada K, Yoshikawa K, Itami S. Expression of mRNA for androgen receptor, 5alpha-reductase and 17beta-hydroxysteroid dehydrogenase in human dermal papilla cells.  Brit J Dermatol. 1999;  141 840-845
  PubMedGoogle Scholar
• 41 Winiarska A, Mandt N, Kamp H, Hossini A, Seltmann H, Zouboulis CC, Blume-Peytavi U. Effect of 5alpha-dihydrotestosterone and testosterone on apoptosis in human dermal papilla cells.  Skin Pharmacol Physiol. 2006;  19 311-321
  CrossrefPubMedGoogle Scholar
• 42 Serafini P, Ablan F, Lobo RA. 5alpha-Reductase activity in the genital skin of hirsute women.  J Clin Endocrinol Metab. 1985;  60 349-355
  PubMedGoogle Scholar
• 43 Randall VA, Thornton MJ, Hamada K, Messenger AG. Mechanism of androgen action in cultured dermal papilla cells derived from human hair follicles with varying responses to androgens in vivo.  J Invest Dermatol. 1992;  98 86S-91S
  CrossrefPubMedGoogle Scholar
• 44 Kaufman KD, Dawber RP. Finasteride, a type 2 5alpha-reductase inhibitor, in the treatment of men with androgenetic alopecia.  Expert Opin Investig Drugs. 1999;  8 403-415
  CrossrefPubMedGoogle Scholar
• 45 Chen W, Tsai S-J, Liao C-Y, Tsai R-Y, Chen Y-R, Pan B-J, Hung C-L, Zouboulis CC. Higher levels of steroidogenic acute regulatory protein and type I 3β-hydroxysteroid dehydrogenase in the scalp of men with androgenetic alopecia.  J Invest Dermatol. 2006;  126 2332-2335
  CrossrefPubMedGoogle Scholar
• 46 Kim SS, Rosenfield RL. Hyperhydrosis as the only manifestation of hyperandrogenism in an adolescent girl.  Arch Dermatol. 2000;  136 430-431
  CrossrefPubMedGoogle Scholar
• 47 Kurata S, Itami S, Komada S, Takayasu S. Intranuclear androgen and cytosolic receptor concentrations in the axillary skin of osmidrosis.  Arch Dermatol Res. 1990;  282 33-37
  CrossrefPubMedGoogle Scholar
• 48 Sato T, Sonoda T, Itami S, Takayasu S. Predominance of type I 5alpha-reductase in apocrine sweat glands of patients with excessive or abnormal odour derived from apocrine sweat (osmidrosis).  Br J Dermatol. 1998;  139 806-810
  CrossrefPubMedGoogle Scholar
• 49 Kao JS, Garg A, Mao-Qiang M. Testosterone perturbs epidermal permeability barrier homeostasis.  J Invest Dermatol. 2001;  116 443-451
  CrossrefPubMedGoogle Scholar
• 50 Ashcroft G, Mills S. Androgen receptor-mediated inhibition of cutaneous wound healing.  J Clin Invest. 2002;  110 615-624
  CrossrefPubMedGoogle Scholar
• 51 Gilliver SC, Ashworth JJ, Mills SJ, Hardman MJ, Ashcroft GS. Androgens modulate the inflammatory response during acute wound healing.  J Cell Sci. 2006;  119 722-732
  CrossrefPubMedGoogle Scholar
• 52 Fimmel S, Zouboulis CC. Influence of physiological androgen levels on wound healing and immune status in men.  Aging Male. 2005;  8 166-174
  PubMedGoogle Scholar
• 53 Lucky AW. A review of infantile and pediatric acne.  Dermatology. 1998;  196 95-97
  CrossrefPubMedGoogle Scholar
• 54 New MI. An update of congenital adrenal hyperplasia.  Ann N Y Acad Sci. 2004;  1038 14-43
  CrossrefPubMedGoogle Scholar
• 55 Imperato-McGinley J. 5alpha-reductase-2 deficiency and complete androgen insensitivity: lessons from nature.  Adv Exp Med Biol. 2002;  511 121-131
  PubMedGoogle Scholar
• 56 Eklof AC, Thurelius AM, Garle M, Rane A, Sjoqvist F. The anti-doping hot-line, a means to capture the abuse of doping agents in the Swedish society and a new service function in clinical pharmacology.  Eur J Clin Pharmacol. 2003;  59 571-577
  CrossrefPubMedGoogle Scholar
• 57 Cappel M, Mauger D, Thiboutot D. Correlation between serum levels of insulin-like growth factor 1, dehydroepiandrosterone sulfate, and dihydrotestosterone and acne lesion counts in adult women.  Arch Dermatol. 2005;  141 333-338
  CrossrefPubMedGoogle Scholar
• 58 Guy R, Ridden C, Kealey T. The improved organ maintenance of the human sebaceous gland: modeling in vitro the effects of epidermal growth factor, androgens, estrogens, 13-cis retinoic acid, and phenol red.  J Invest Dermatol. 1996;  106 454-460
  CrossrefPubMedGoogle Scholar
• 59 Deplewski D, Liao S, Rosenfield RL. Preputial sebocyte 5alpha-reductase isoform specificity.  Endocrinology. 1997;  138 4416-4420
  CrossrefPubMedGoogle Scholar
• 60 Rosenfield RL, Deplewski D, Kentsis A, Ciletti N. Mechanisms of androgen induction of sebocyte differentiation.  Dermatology. 1998;  196 43-46
  CrossrefPubMedGoogle Scholar
• 61 Zouboulis CC, Seltmann H, Neitzel H, Orfanos CE. Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95).  J Invest Dermatol. 1999;  113 1011-1020
  CrossrefPubMedGoogle Scholar
• 62 Zouboulis CC, Piquero-Martin J. Update and future of systemic acne treatment.  Dermatology. 2003;  206 37-53
  CrossrefPubMedGoogle Scholar
• 63 van Vloten WA, Sigurdsson V. Selecting an oral contraceptive agent for the treatment of acne in women.  Am J Clin Dermatol. 2004;  5 435-441
  CrossrefPubMedGoogle Scholar
• 64 Thiboutot DM, Knaggs H, Gilliland K, Hagari S. Activity of type 1 5 alpha-reductase is greater in the follicular infrainfundibulum compared with the epidermis.  Brit J Dermatol. 1997;  136 166-171
  CrossrefPubMedGoogle Scholar
• 65 Carmina E, Godwin AJ, Stanczyk FZ, Lippman JS, Lobo RA. The association of serum androsterone glucuronide with inflammatory lesions in women with adult acne.  J Endocrinol Invest. 2002;  25 765-768
  PubMedGoogle Scholar
• 66 Zouboulis CC, Seltmann H, Hiroi N, Chen W, Young M, Oeff M, Scherbaum WA, Orfanos CE, McCann SM, Bornstein SR. Corticotropin-releasing hormone: an autocrine hormone that promotes lipogenesis in human sebocytes.  Proc Nat Acad Sci USA. 2002;  99 7148-7153
  CrossrefPubMedGoogle Scholar
• 67 Baillie AH, Thomson J, Milne JA. The distribution of hydroxysteroid dehydrogenase in human sebaceous glands.  Br J Dermatol. 1966;  78 451-457
  CrossrefPubMedGoogle Scholar
• 68 Billich A, Meingassner JG, Nussbaumer P, Desrayaud S, Lam C, Winiski A, Schreiner E. 6-[2-(adamantylidene)-hydroxybenzoxazole]-O-sulfamate, a steroid sulfatase inhibitor for the treatment of androgen- and estrogen-dependent diseases.  J Steroid Biochem Mol Biol. 2004;  92 29-37
  CrossrefPubMedGoogle Scholar
• 69 Thiboutot D, Harris G, Iles V, Cimis G, Gilliland K, Hagari S. Activity of the type 1 5 alpha-reductase exhibits regional differences in isolated sebaceous glands and whole skin.  J Invest Dermatol. 1995;  105 209-214
  CrossrefPubMedGoogle Scholar
• 70 Thiboutot D, Gilliland K, Light J, Lookingbill D. Androgen metabolism in sebaceous glands from subjects with and without acne.  Arch Dermatol. 1999;  135 1041-1045
  CrossrefPubMedGoogle Scholar
• 71 Leyden J, Bergfeld W, Drake L, Dunlap F, Goldman MP, Gottlieb AB, Heffernan MP, Hickman JG, Hordinsky M, Jarrett M, Kang S, Lucky A, Peck G, Phillips T, Rapaport M, Roberts J, Savin R, Sawaya ME, Shalita A, Shavin J, Shaw JC, Stein L, Stewart D, Strauss J, Swinehart J, Swinyer L, Thiboutot D, Washenik K, Weinstein G, Whiting D, Pappas F, Sanchez M, Terranella L, Waldstreicher J. A systemic type I 5 alpha-reductase inhibitor is ineffective in the treatment of acne vulgaris.  J Am Acad Dermatol. 2004;  50 443-447
  CrossrefPubMedGoogle Scholar
• 72 Thiboutot D, Bayne E, Thorne J, Gilliland K, Flanagan J, Shao Q, Light J, Helm K. Immunolocalization of 5alpha-reductase isozymes in acne lesions and normal skin.  Arch Dermaol. 2000;  136 1125-1129
  PubMedGoogle Scholar
• 73 Mindnich R, Moller G, Adamski J. The role of 17 beta-hydroxysteroid dehydrogenases.  Mol Cell Endocrinol. 2004;  218 7-20
  CrossrefPubMedGoogle Scholar
• 74 Orfanos CE, Adler YD, Zouboulis CC. The SAHA syndrome.  Horm Res. 2000;  54 251-258
  CrossrefPubMedGoogle Scholar
• 75 Adler YD, Orfanos CE, Zouboulis CC. HAIRAN syndrome: a fifth variant of SAHA syndrome (abstract).  Horm Res. 2000;  53 94
  CrossrefPubMedGoogle Scholar
• 76 Speiser PW, White PC. Congenital adrenal hyperplasia.  New Engl J Med. 2003;  349 776-788
  CrossrefPubMedGoogle Scholar
• 77 Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, Jabs EW, Van Vliet G, Sack J, Fluck CE, Miller WL. Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.  Am J Hum Genet. 2005;  76 729-749
  CrossrefPubMedGoogle Scholar
• 78 Ramsay B, Alaghband Zadeh J, Carter G, Wheeler MJ, Cream JJ. Raised serum 11-deoxycortisol in men with persistent acne vulgaris.  Clin Endocrinol Oxf. 1995;  43 305-310
  PubMedGoogle Scholar
• 79 Jabbour SA. .  Am J Clin Dermatol. 2003;  4 315-331
  CrossrefPubMedGoogle Scholar
• 80 Zouboulis CC. Therapie der Akne mit Antiandrogenen - Eine evidenzbasierte Übersicht.  J Dtsch Dermatol Ges. 2003;  1 535-546
  PubMedGoogle Scholar
• 81 Sitruk-Ware R. Pharmacology of different progestogens: the special case of drospirenone.  Climacteric. 2005;  8 ((Suppl 3)) 4-12
  CrossrefPubMedGoogle Scholar
• 82 Degitz K, Placzek M, Arnold B, Schmidt H, Plewig G. Congenital adrenal hyperplasia and acne in male patients.  Brit J Dermatol. 2003;  148 1263-1266
  PubMedGoogle Scholar
• 83 Zouboulis CC. Moderne Aknetherapie.  Akt Dermatol. 2003;  29 49-57
  Article in Thieme ConnectPubMedGoogle Scholar
• 84 Thornton MJ. The biological actions of estrogens on skin.  Exp Dermatol. 2002;  11 487-502
  CrossrefPubMedGoogle Scholar
• 85 Thornton MJ. Oestrogen functions in skin and skin appendages.  Expert Opin Ther Targets. 2005;  9 617-629
  CrossrefPubMedGoogle Scholar
• 86 Brincat MP. Hormone replacement therapy and the skin.  Maturitas. 2000;  29 107-117
  PubMedGoogle Scholar
• 87 Sator PG, Schmidt JB, Rabe T, Zouboulis CC. Skin aging and sex hormones in women - clinical perspectives for intervention by hormone replacement therapy.  Exp Dermatol. 2004;  13 ((Suppl 4)) 36-40
  CrossrefPubMedGoogle Scholar
• 88 Shah MG, Maibach HI. Estrogen and skin.  An overview Am J Clin Dermatol. 2001;  2 143-150
  PubMedGoogle Scholar
• 89 Brincat M, Versi E, Moniz CF, Magos A, De Trafford J, Studd JW. Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy.  Obstet Gynecol. 1987;  70 123-127
  PubMedGoogle Scholar
• 90 Varila E, Rantala I, Oikarinen A, Risteli J, Reunala T, Oksanen H, Punnonen R. The effect of topical estradiol on skin collagen of postmenopausal women.  Br J Obstet Gynaecol. 1995;  102 985-989
  PubMedGoogle Scholar
• 91 Sumino H, Ichikawa S, Abe M, Endo Y, Ishikawa O, Kurabayashi M. Effects of aging, menopause, and hormone replacement therapy on forearm skin elasticity in women.  J Am Geriatr Soc. 2004;  52 945-949
  CrossrefPubMedGoogle Scholar
• 92 Ashcroft Gs, Ashworth JJ. Potential role of estrogens in wound healing.  Am J Clin Dermatol. 2003;  4 737-743
  CrossrefPubMedGoogle Scholar
• 93 Boyd AS, Morris LF, Phillips CM, Menter MA. Psoriasis and pregnancy: hormone and immune system interaction.  Int J Dermatol. 1996;  35 169-172
  PubMedGoogle Scholar
• 94 Raychaudhuri SP, Navare T, Gross J, Raychaudhuri SK. Clinical course of psoriasis during pregnancy.  Int J Dermatol. 2003;  42 518-520
  CrossrefPubMedGoogle Scholar
• 95 Dunna SF, Finlay AY. Psoriasis: improvement during and worsening after pregnancy.  Br J Dermatol. 1989;  120 584
  CrossrefPubMedGoogle Scholar
• 96 Weinstock MA. Epidemiologic investigation of non melanoma skin cancer mortality: the Rhode Island Follow-Back Study.  J Invest Dermatol. 1994;  102 6S-9S
  CrossrefPubMedGoogle Scholar
• 97 Miller JG, Mac Neil S. Gender and cutaneous melanoma.  Br J Dermatol. 1997;  136 657-665
  CrossrefPubMedGoogle Scholar
• 98 Hasselquist MB, Goldberg N, Schroeter A, Spelsberg TC. Isolation and characterisation of the estrogen receptor in human skin.  J Clin Endocrinol Metab. 1980;  50 76-82
  PubMedGoogle Scholar
• 99 Punnonen R, Lovgrent T, Kouvonen I. Demonstration of estrogen receptors in the skin.  J Endocrinol Invest. 1980;  3 217-221
  PubMedGoogle Scholar
• 100 Gustafsson JA. An update on estrogen receptors.  Semin Perinatol. 2000;  24 66-69
  PubMedGoogle Scholar
• 101 Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β.  Endocrinol. 1997;  138 863-870
  CrossrefPubMedGoogle Scholar
• 102 Levin ER. Cellular functions of plasma membrane estrogen receptors.  Steroids. 2002;  67 471-475
  CrossrefPubMedGoogle Scholar
• 103 Nadal A, Ropero AB, Fuentes E, Soria B. The plasma membrane estrogen receptor: nuclear or unclear?.  Trends Pharm Sci. 2001;  22 597-599
  CrossrefPubMedGoogle Scholar
• 104 Aronica SM, Kraus WL, Katzenellenbogen BS. Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription.  Proc Natl Acad Sci USA. 1994;  91 8517-8521
  CrossrefPubMedGoogle Scholar
• 105 Shaul PW. Rapid activation of endothelial nitric oxide synthase by estrogen.  Steroids. 1999;  64 28-34
  CrossrefPubMedGoogle Scholar
• 106 Pappas TC, Gametchu B, Watson CS. Membrane estrogen receptors identified by multiple antibody labelling and impeded-ligand binding.  FASEB J. 1995;  9 404-410
  PubMedGoogle Scholar
• 107 Razandi M, Pedram A, Greene GL, Levin ER. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells.  Mol Endocrinol. 1999;  13 307-319
  CrossrefPubMedGoogle Scholar
• 108 Benten WPM, Stephan C, Lieberherr M, Wunderlich F. Estradiol signalling via sequestrable surface receptors.  Endocrinol. 2001;  142 1669-1677
  CrossrefPubMedGoogle Scholar
• 109 Saji S, Hirose M, Toi M. Clinical significance of estrogen receptor beta in breast cancer.  Cancer Chemother Pharmacol. 2005;  56 ((Suppl 1)) 21-26
  CrossrefPubMedGoogle Scholar
• 110 Mosselman S, Polman J, Dijkema R. ERβ. Identification and characterisation of a novel human estrogen receptor.  FEBS Lett. 1996;  392 49-53
  CrossrefPubMedGoogle Scholar
• 111 Thornton MJ, Taylor AH, Mulligan K, Al-Azzawi F, Lyon CC, O’Driscoll JB, Messenger AG. Estrogen receptor beta (ERβ) is the predominant estrogen receptor in human scalp.  Exp Dermatol. 2003;  12 181-190
  CrossrefPubMedGoogle Scholar
• 112 Thornton MJ, Taylor AH, Mulligan K, Al-Azzawi F, Lyon CC, O’Driscoll JB, Messenger AG. The distribution of estrogen receptor beta (ERβ) is distinct to that of ER alpha and the androgen receptor in human skin and the pilosebaceous unit.  J Investig Dermatol Symp Proc. 2003;  8 100-103
  CrossrefPubMedGoogle Scholar
• 113 Brandenberger AW, Tee MK, Lee JY, Chao V, Jaffe RB. Tissue distribution of estrogen receptors alpha (ER-alpha) and beta (ER-beta) mRNA in the midgestational human fetus.  J Clin Endocrinol Metab. 1997;  82 3509-3512
  CrossrefPubMedGoogle Scholar
• 114 Kanda N, Watanabe S. 17beta-estradiol inhibits the production of interferon-induced protein of 10 kDa by human keratinocytes.  J Invest Dermatol. 2003;  120 411-419
  CrossrefPubMedGoogle Scholar
• 115 Kanda N, Watanabe S. 17beta-estradiol inhibits the production of RANTES in human keratinocytes.  J Invest Dermatol. 2003;  120 420-427
  CrossrefPubMedGoogle Scholar
• 116 Verdier-Sevrain S, Yaar M, Cantatore J, Traish A, Gilchrest BA. Estradiol induces proliferation of keratinocytes via a receptor mediated mechanism.  FASEB J. 2004;  18 1252-1254
  PubMedGoogle Scholar
• 117 Berthois Y, Katzenellenbogen JA, Katzenellenbogen BS. Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture.  Proc Natl Acad Sci USA. 1986;  83 2496-2500
  CrossrefPubMedGoogle Scholar
• 118 Kanda N, Watanabe S. 17beta-estradiol stimulates the growth of human keratinocytes by inducing cyclin D2 expression.  J Invest Dermatol. 2004;  123 319-328
  CrossrefPubMedGoogle Scholar
• 119 Haczynski J, Tarkowski R, Jarzabek K, Slomczynska M, Wolczynski S, Magoffin DA, Jakowicki J, Jakimiuk AJ. Human cultured skin fibroblasts express estrogen receptor alpha and beta.  Int J Mol Med. 2002;  10 149-153
  PubMedGoogle Scholar
• 120 Haczynski J, Tarkowski R, Jarzabek K, Wolczynski S, Magoffin DA, Czarnocki KJ, Ziegert M, Jakowicki J, Jakimiuk AJ. Differential effects of estradiol, raloxifene and tamoxifen on estrogen receptor expression in cultured human skin fibroblasts.  Int J Mol Med. 2004;  13 903-908
  PubMedGoogle Scholar
• 121 Conrad F, Paus R. strogene und der Haarfollikel.  J Dtsch Dermatol Ges. 2004;  2 412-423
  PubMedGoogle Scholar
• 122 Chanda S, Robinette CL, Couse JF, Smart RC. 17beta-estradiol and ICI-182780 regulate the hair follicle cycle in mice through an estrogen receptor-alpha pathway.  Am J Physiol Endocrinol Metab. 2000;  278 E202-E210
  PubMedGoogle Scholar
• 123 Ohnemus U, Uenalan M, Conrad F, Handjiski B, Mecklenburg L, Nakamura M, Inzunza J, Gustafsson JA, Paus R. Hair cycle control by estrogens: Catagen induction via ER(alpha) is checked by ER(beta) signalling.  Endocrinology. 2005;  145 1214-1225
  PubMedGoogle Scholar
• 124 Conrad F, Ohnemus U, Bodo E, Biro T, Tychsen B, Gerstmayer B, Bosio A, Schmidt-Rose T, Altgilbers S, Bettermann A, Saathoff M, Meyer W, Paus R. Substantial sex-dependent differences in the response of human scalp hair follicles to estrogen stimulation in vitro advocate gender-tailored management of female versus male pattern ba ding.  J Invest Dermatol Symp Proc. 2005;  10 243-246
  CrossrefPubMedGoogle Scholar
• 125 Sansone-Bazzano G, Reisner RM, Bazzano G. A possible mechanism of action of estrogen at the cellular level in a model sebaceous gland.  J Invest Dermatol. 1972;  59 299-304
  CrossrefPubMedGoogle Scholar
• 126 Mesquita-Guimaraes J, Coimbra A. The effect of sexual hormones on the lipid and proteinaceous secretion of the rat preputial sebaceous gland.  Arch Dermatol Res. 1981;  270 325-331
  CrossrefPubMedGoogle Scholar
• 127 Plewig G, Kligman AM. Acne and Rosacea 3rd ed. Berlin: Springer 2003
• 128 Kariya Y, Moriya T, Suzuki T, Chiba M, Ishida K, Takeyama J, Endoh M, Watanabe M, Sasano H. Sex steroid hormone receptors in human skin appendage and its neoplasms.  Endocr J. 2005;  52 317-325
  CrossrefPubMedGoogle Scholar
• 129 Beier K, Ginez I, Schaller H. Localization of steroid hormone receptors in the apocrine sweat glands of the human axilla.  Histochem Cell Biol. 2005;  123 61-65
  CrossrefPubMedGoogle Scholar
• 130 Simpson ER, Zhao Y, Agarwal VR. , et al Aromatase expression in health and disease.  Recent Prog Horm Res. 1997;  52 185-213
  PubMedGoogle Scholar
• 131 Simpson ER. Role of aromatase in sex steroid action.  J Mol Endocrinol. 2000;  25 149-156
  CrossrefPubMedGoogle Scholar
• 132 Harada N. A new aspect of the pharmacological and physiological significance of the aromatase/estrogen system.  (in Japanese) Nippon Yakurigaku Zasshi - Folia Pharmacologica Japonica. 1998;  112 51-58
  PubMedGoogle Scholar
• 133 Harada N. Aromatase and intracrinology of estrogen in hormone-dependent tumors.  Oncology. 1999;  57 ((Suppl 2)) 7-16
  PubMedGoogle Scholar
• 134 Sawaya ME, Price VH. Different levels of 5alpha-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia.  J Invest Dermatol. 1997;  109 296-300
  CrossrefPubMedGoogle Scholar
• 135 Hoffmann R, Niiyama S, Huth A, Kissling S, Happle R. 17alpha-estradiol induces aromatase activity in intact human anagen hair follicles ex vivo.  Exp Dermatol. 2002;  11 376-380
  CrossrefPubMedGoogle Scholar
• 136 Hughes SV, Robinson E, Bland R, Lewis HM, Stewart PM, Hewison M. 1,25-dihydroxyvitamin D3 regulates estrogen metabolism in cultured keratinocytes.  Endocrinology. 1997;  138 3711-3718
  CrossrefPubMedGoogle Scholar
• 137 Svenstrup B, Brunner N, Dombernowsky P, Nohr I, Micic S, Bennett P, Spang-Thomsen M. Comparison of the effect of cortisol on aromatase activity and androgen metabolism in two human fibroblast cell lines derived from the same individual.  J Steroid Biochem. 1990;  35 679-687
  CrossrefPubMedGoogle Scholar
• 138 Rink JD, Simpson ER, Barnard JJ, Bulun SE. Cellular characterization of adipose tissue from various body sites of women.  J Clin Endocrinol Metab. 1996;  81 2443-2447
  CrossrefPubMedGoogle Scholar
• 139 Kroumpouzos G, Cohen LM. Dermatoses of pregnancy.  J Am Acad Dermatol. 2001;  45 1-19
  CrossrefPubMedGoogle Scholar
• 140 Wade TR, Wade SL, Jones HE. Skin changes and diseases associated with pregnancy.  Obstet Gynecol. 1978;  52 233-242
  PubMedGoogle Scholar
• 141 Beas F, Vargas L, Spada RP, Merchak N. Pseudoprecocious puberty in infants caused by a dermal ointment containing estrogens.  J Pediatr. 1969;  75 127-130
  PubMedGoogle Scholar
• 142 Taylor AH, Thornton MJ, Messenger AG, Tobin DJ. Human epidermal melanocytes express the androgen receptor and both estrogen receptors (ERα) and (ERβ) in situ.  J Invest Dermatol. 2002;  119 801
  PubMedGoogle Scholar
• 143 Jee SH, Lee SY, Chiu HC, Chang CC, Chen TY. Effects of estrogen and estrogen receptor in normal human melanocytes.  Biochem Biophys Res Commun. 1994;  199 1407-1412
  CrossrefPubMedGoogle Scholar
• 144 Im S, Lee ES, Kim W, On W, Kim J, Lee M, Kang WH. Donor specific response of estrogen and progesterone on cultured human melanocytes.  J Korean Med Sci. 2002;  17 58-64
  PubMedGoogle Scholar
• 145 Meskiri AN, Thornton MJ, Tobin DJ. Expression of estrogen receptors in cutaneous melanocytes and their potential role in the regulation of pigment cell phenotype. In: Trüeb RM (ed) Understanding Hair Biology. European Hair Research Society, 11th Meeting, Zurich, Dermatology 2005; 211(special issue 1)
  Google Scholar
• 146 Meskiri AN, Thornton MJ, Tobin DJ. , Induction of pigmentation up regulates ERalpha and aromatase in epidermal melanocytes and melanoma cells http://http:/www.endocrine-abstracts.org , 196th Meeting of the Society for Endocrinology, London, UK 7-9 November 2005, Endocrine Abstracts 2005;  10 78
  PubMed
• 147 Schleicher RL, Hitselberger MH, Beattie CW. Inhibition of hamster melanoma growth by estrogen.  Cancer Res. 1987;  47 453-459
  PubMedGoogle Scholar
• 148 Hitselberger MH, Schleicher RL, Beattie CW. Effects of estradiol on estrogen receptor, progesterone receptor, and tyrosinase in hamster melanoma transplanted into athymic mice.  Cancer Res. 1988;  48 3720-3727
  PubMedGoogle Scholar
• 149 Feucht KA, Walker MJ, Das Gupta TK, Beattie CW. Effect of 17 beta-estradiol on the growth of estrogen receptor-positive human melanoma in vitro and in athymic mice.  Cancer Res. 1988;  48 7093-7101
  PubMedGoogle Scholar
• 150 Armstrong LE, Maresh CM, Keith NR, Elliott TA, Vanheest JL, Scheett TP, Stoppani J, Judelson DA, De Souza MJ. Heat acclimation and physical training adaptations of young women using different contraceptive hormones.  Am J Physiol Endocrinol Metab. 2005;  288 E868-E875
  PubMedGoogle Scholar
• 151 Houghton BL, Holowatz LA, Minson CT. Influence of progestin bioactivity on cutaneous vascular responses to passive heating.  Med Sci Sports Exerc. 2005;  37 45-51 , discussion 2
  CrossrefPubMedGoogle Scholar
• 152 Landau RL, Bergenstal DM, Lugibihl K, Kascht ME. The metabolic effects of progesterone in man.  J Clin Endocrinol Metab. 1955;  15 1194-1215
  PubMedGoogle Scholar
• 153 Kagawa CM, Cella JA, Van Arman CG. Action of new steroids in blocking effects of aldosterone and desoxycorticosterone on salt.  Science. 1957;  126 1015-1016
  CrossrefPubMedGoogle Scholar
• 154 Edgren RA, Elton RL. Estrogen antagonisms: effects of several steroidal spironolactones on estrogen-induced uterine growth in mice.  Proc Soc Exp Biol Med. 1960;  104 664-665
  PubMedGoogle Scholar
• 155 Neumann F. Intersexuality of male foetuses and inhibition of androgenic function in adult animals with a testosterone blocker.  Ger Med Month. 1967;  12 182-188
  PubMedGoogle Scholar
• 156 Cumming DC, Yang JC, Rebar RW, Yen SS. Treatment of hirsutism with spironolactone.  JAMA. 1982;  247 1295-1298
  CrossrefPubMedGoogle Scholar
• 157 Drill VA. Endocrine properties and long-term safety of oral contraceptives.  Metabolism. 1965;  14 ((Suppl)) 295-310
  CrossrefPubMedGoogle Scholar
• 158 Forman B, Samuels H. Interactions among a subfamily of nuclear hormone receptors: the regulatory zipper model.  Mol Endocrinol. 1990;  4 1293-1301
  PubMedGoogle Scholar
• 159 Chang CS, Kokontis J, Liao ST. Structural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors.  Proc Natl Acad Sci USA. 1988;  85 7211-7215
  CrossrefPubMedGoogle Scholar
• 160 de Gooyer ME, Deckers GH, Schoonen WG, Verheul HA, Kloosterboer HJ. Receptor profiling and endocrine interactions of tibolone.  Steroids. 2003;  68 21-30
  CrossrefPubMedGoogle Scholar
• 161 Liu JH. Therapeutic effects of progestins, androgens, and tibolone for menopausal symptoms.  Am J Med. 2005;  118 88-92
  CrossrefPubMedGoogle Scholar
• 162 Mauvais-Jarvis P, Kuttenn F, Baudot N. Inhibition of testosterone conversion to dihydrotestosterone in men treated percutaneously by progesterone.  J Clin Endocrinol Metab. 1974;  38 142-147
  PubMedGoogle Scholar
• 163 Juchem M, Pollow K, Elger W, Hoffmann G, Mobus V. Receptor binding of norgestimate - a new orally active synthetic progestational compound.  Contraception. 1993;  47 283-294
  CrossrefPubMedGoogle Scholar
• 164 Wiegratz I, Kuhl H. Progestogen therapies: differences in clinical effects?.  Trends Endocrinol Metab. 2004;  15 277-285
  CrossrefPubMedGoogle Scholar
• 165 Sitruk-Ware R. Pharmacological profile of progestins.  Maturitas. 2004;  47 277-283
  CrossrefPubMedGoogle Scholar
• 166 Thomas CP, Liu KZ, Vats HS. Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate (alpha)-ENaC and sgk1 expression in renal collecting duct epithelia.  Am J Physiol Renal Physiol. 2006;  290 F306-F312
  CrossrefPubMedGoogle Scholar
• 167 Stachenfeld NS, Silva C, Keefe DL, Kokoszka CA, Nadel ER. Effects of oral contraceptives on body fluid regulation.  J Appl Physiol. 1999;  87 1016-1025
  PubMedGoogle Scholar
• 168 Suzuki T, Nakamura Y, Moriya T, Sasano H. Effects of steroid hormones on vascular functions.  Microsc Res Tech. 2003;  60 76-84
  CrossrefPubMedGoogle Scholar
• 169 Perusquia M, Villalon CM, Navarrete E, Garcia GA, Perez-Palacios G, Lemus AE. Vasodilating effect of norethisterone and its 5 alpha metabolites: a novel nongenomic action.  Eur J Pharmacol. 2003;  475 161-169
  CrossrefPubMedGoogle Scholar
• 170 Dumont M, Luu-The V, Dupont E, Pelletier G, Labrie F. Characterization, expression, and immunohistochemical localization of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase in human skin.  J Invest Dermatol. 1992;  99 415-421
  CrossrefPubMedGoogle Scholar
• 171 Pelletier G, Ren L. Localization of sex steroid receptors in human skin.  Histol Histopathol. 2004;  19 629-636
  PubMedGoogle Scholar
• 172 Thody AJ, Shuster S. Effect of progesterone on the sebaceous glands.  Postgrad Med J. 1978;  54 ((Suppl 2)) 88-90
  PubMedGoogle Scholar
• 173 Girard J, Barbier A, Lafille C. Inhibition of testosterone metabolism and lipogenesis in animal sebaceous glands by progesterone.  Arch Dermatol Res. 1980;  269 281-290
  CrossrefPubMedGoogle Scholar
• 174 Kanda N, Watanabe S. Regulatory roles of sex hormones in cutaneous biology and immunology.  J Dermatol Sci. 2005;  38 1-7
  CrossrefPubMedGoogle Scholar
• 175 Rosenfield RL. Clinical practice.  Hirsutism. N Engl J Med. 2005;  353 2578-2588
  CrossrefPubMedGoogle Scholar
• 176 Arowojolu AO, Gallo MF, Grimes DA, Garner SE. Combined oral contraceptive pills for treatment of acne.  Cochrane Database Syst Rev. 2004;  CD004425
  PubMedGoogle Scholar
• 177 Thorneycroft H, Gollnick H, Schellschmidt I. Superiority of a combined contraceptive containing drospirenone to a triphasic preparation containing norgestimate in acne treatment.  Cutis. 2004;  74 123-130
  PubMedGoogle Scholar
• 178 Cormia FE. Alopecia from oral contraceptives.  JAMA. 1967;  201 635-637
  CrossrefPubMedGoogle Scholar
• 179 Ross EK, Shapiro J. Management of hair loss.  Dermatol Clin. 2005;  23 227-243
  CrossrefPubMedGoogle Scholar
• 180 Freedman RR. Hot flashes: behavioral treatments, mechanisms, and relation to sleep.  Am J Med. 2005;  118 124-130
  CrossrefPubMedGoogle Scholar

Correspondence

C. C. Zouboulis

Departments of Dermatology and Immunology

Dessau Medical Center

Auenweg 38

06847 Dessau

Germany

Phone: +49/340/501 40 00

Fax: +49/340/501 40 25

Email: christos.zouboulis@klinikum-dessau.de