Review 85 Sexual Hormones in Human Skin Authors C. C. Zouboulis 1 , 2 , W . - C . C h e n 3 , M . J . T h o r n t o n4 , K. Qin 5 , R . R o s e n fi eld 5 , 6 Affi liations Affi liation addresses are listed at the end of the article Key words Abstract the development of hyperandrogenism and the ᭹ ᭤ androgens & associated skin diseases such as acne, sebor- ᭹᭤ estrogens The skin locally synthesizes signifi cant amounts rhoea, hirsutism and androgenetic alopecia. On ᭹᭤ progestins of sexual hormones with intracrine or paracrine the other hand, estrogens have been implicated ᭹ ᭤ human skin actions. The local level of each sexual steroid in skin aging, pigmentation, hair growth, sebum ᭹ ᭤ acne depends upon the expression of each of the production and skin cancer. Estrogens exert androgen- and estrogen-synthesizing enzymes their actions through intracellular receptors or in each cell type, with sebaceous glands and via cell surface receptors, which activate specifi c sweat glands being the major contributors. second messenger signaling pathways. Recent Sebocytes express very little of the key enzyme, studies suggest specifi c site-related distribution cytochrome P450c17, necessary for synthesis of ER and ER in human skin. In contrast, pro- of the androgenic prohormones dehydroepi- gestins play no role in the pathogenesis of skin androsterone and androstenedione, however, disorders. However, they play a major role in the these prohormones can be converted by sebo- treatment of hirsutism and acne vulgaris, where cytes and sweat glands, and probably also by they are prescribed as components of estrogen- dermal papilla cells, into more potent androgens progestin combination pills and as anti-andro- like testosterone and dihydrotestosterone. Five gens. These combinations enhance gonadotropin major enzymes are involved in the activation suppression of ovarian androgen production. and deactivation of androgens in skin. Andro- Estrogen-progestin treatment can reduce the gens affect several functions of human skin, need for shaving by half and arrest progression such as sebaceous gland growth and differentia- of hirsutism of various etiologies, but do not nec- tion, hair growth, epidermal barrier homeostasis essarily reverse it. However, they reliably reduce and wound healing. Their effects are mediated acne. Cyproterone acetate and spironolactone are by binding to the nuclear androgen receptor. similarly effective as anti-androgens in reducing received 23. 11. 2006 Changes of isoenzyme and / or androgen recep- hirsutism, although there is wide variability in accepted 28. 11. 2006 tor levels may have important implications in individual responses. Bibiliography DOI 10.1055/s-2007-961807 Introduction unit to androgens that is not yet completely Horm Metab Res 2007; & understood [3] . 39: 85 – 95 Several functions of the human skin appear © Georg Thieme Verlag KG Stuttgart · New York · strongly dependent on biologically active sexual ISSN 0018-5043 hormones, namely androgens, estrogens, and Androgens and skin progestins. Their effect is mediated by binding to & Correspondence nuclear receptors, and lack of functional recep- Androgens relevant to the skin C. C. Zouboulis tors prevents the action of sexual hormones on Among the circulating androgens, dehydroepian- Departments of Dermato- the skin [1] . The effects of sexual hormones can drosterone (DHEA) and DHEA sulfate (DHEA-S) logy and Immunology · Dessau differ from cell type to cell type and among cells are predominantly produced in the adrenal cor- Medical Center · Auenweg of different locations [2] . Androgen effects on the 38 · 06847 Dessau · Germany tex. Androstenedione is produced approximately Tel.: + 49 / 340 / 501 40 00 pilosebaceous unit are best known and best char- equally by the adrenal cortex and the ovaries, Fax: + 49 / 340 / 501 40 25 acterized. Nevertheless there is considerable and somewhat less by the testes [4] . These are christos.zouboulis@klinikum- variability in the response of the pilosebaceous weak prohormones that act only after conversion dessau.de Zouboulis CC et al. Sexual Hormones in Skin … Horm Metab Res 2007; 39: 85– 95 86 Review to the more potent androgens, testosterone and 5 -dihydrotes- with sebaceous glands and sweat glands being the major con- tosterone (DHT). Testosterone is mainly secreted by the testes in tributors [9, 17] . males beginning at puberty; in reproductive-age females it The skin, especially sebocytes, is capable of synthesizing choles- arises almost equally from the ovary and adrenal cortex by a terol, which is utilized in cell membranes, formation of the epi- combination of secretion and conversion of androstenedione in dermal barrier and sebum; however, sebocytes express very peripheral organs. DHT is mainly synthesized in peripheral little of the key enzyme, cytochrome P450c17, necessary for syn- organs, including skin, in both genders. thesis of the androgenic prohormones DHEA and androstenedi- Testosterone, particularly free testosterone, is the major circu- one [18] . However, DHEA and androstenedione, and possibly lating androgen because of its concentration and potency [3] . DHEA-S, can be converted by sebocytes and sweat glands, and The less potent DHEA-S is the androgen with by far the highest probably also by dermal papilla cells, into more potent andro- serum concentration in both sexes and is related to sebum pro- gens like testosterone and DHT [2] . Five major enzymes are duction prepubertally [5] and to cystic acne in adults [6] . Andros- involved in the activation and deactivation of androgens in skin tenedione and DHEA have also been shown to stimulate sebum [19] . In a fi rst step, steroid sulfatase hydrolyzes DHEA-S to DHEA secretion in humans [7] . Male levels of testosterone stimulate in skin [20] . The sebaceous gland has been suggested to carry full axillary and pubic hair growth, but in the absence of DHT out this reaction since strong steroid sulfatase immunoreactivity formation do not suffi ce to stimulate male beard growth and was found in acne skin, primarily associated with the monocytes scalp hair recession [8] . infi ltrating the lesions [21] , but further evidence is required to corroborate this preliminary report. This enzyme activity has The androgen receptor and skin also been detected in the dermal papillae of human terminal Testosterone and DHT act through a single nuclear receptor, the hair follicles [22] . Subsequently, 3 -hydroxysteroid dehydroge- androgen receptor (AR), with DHT being the more active ligand nase / 5 – 4 -isomerase (3 -HSD) converts DHEA to androstenedi- [9] . AR is an X-chromosome-encoded, ligand-activated, intracel- one. Two isoforms of this enzyme have been described. Human lular transcription factor that belongs to the steroid/ nuclear skin seems to express exclusively the type 1 isoform. Several receptor superfamily [2, 10] . Like all nuclear receptors, AR is a studies led to the conclusion that type 1 3 -HSD is mainly soluble molecule with a proclivity for employing transcriptional located in the sebaceous glands [17] . regulation as a means of promoting its biological effects. In com- In a further step, androstenedione is activated by conversion to mon with other steroid receptors, AR is compartmentalized in testosterone through androgenic 17 -hydroxysteroid dehydro- the cytoplasm, where it exists in polymeric complexes that genase (17 -HSD). The cutaneous expression of 17 -HSD was include the heat shock proteins hsp 90, hsp 70, and hsp 56. Asso- mainly demonstrated in the pilosebaceous unit and epidermal ciation of androgens with AR results in dissociation of the heat keratinocytes. To date, twelve isoforms of this enzyme have been shock proteins. This in turn exposes a nuclear translocation sig- identifi ed [19, 23] . 17 -HSD types 3 and 5 form the active andro- nal previously buried in the receptor structure and initiates gen testosterone from androstenedione, whereas the oxidative transport of the ligand-receptor complex to the nucleus. There, reaction of 17 -HSD types 2 and 4 is in the reverse direction, AR occupies androgen response elements in the promoter regions inactivating the potent sexual steroids. The human sebaceous of androgen-regulated genes to initiate the signaling cascade. gland possesses the cellular machinery needed to transcribe the AR is present in epidermal and follicular keratinocytes, sebo- genes for 17 -HSD types 1– 5; among them a strong 17 -HSD2 cytes, sweat gland cells, dermal papilla cells, dermal fi broblasts, and 17 -HSD5 expression have been reported [17, 18, 24] . The endothelial cells, and genital melanocytes [11, 12] . It is stabilized predominance of the strongly pro-oxidative 17 -HSD2 suggests by ligand binding and is up-regulated in genital skin fi broblasts its protective role against the effects of locally excessive amounts and sebocytes [13, 14] . of potent androgens [18] . Greater reductive activity of andro- Polymorphisms that confer enhanced receptor activity have genic17 -HSD types 3 and 5 was noted in sebaceous glands from been variably associated with the androgen-dependent skin dis- the facial than from non-acne prone areas, suggesting an orders. Studies of CAG trinucleotide repeats have shown them to increased net production of potent androgens in facial areas. In have been inconsistently related to hirsutism [9, 15] . Failure to addition, 17 -HSD3 expression was detected in human sebo- account for possible skewed X-inactivation of the affected alle- cytes, but not in keratinocytes, further indicating the importance