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Cited by 369Adrenal Hormones and DisordersDermatology and Skin DiseasesEstrogen and related hormone effects

Steroidogenesis in the skin: Implications for local immune functions

Open access
Slominski, Andrzej, Zbytek, Blazej, Nikolakis, Georgios, Manna, Pulak R., Skobowiat, Cezary, Zmijewski, Michal, Li, Wei, Janjetovic, Zorica +3 more·2013·The Journal of Steroid Biochemistry and Molecular Biology
DOI 10.1016/j.jsbmb.2013.02.006PMC PMC3674137
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Abstract

The skin has developed a hierarchy of systems that encompasses the skin immune and local steroidogenic activities in order to protect the body against the external environment and biological factors and to maintain local homeostasis. Most recently it has been established that skin cells contain the entire biochemical apparatus necessary for production of glucocorticoids, androgens and estrogens either from precursors of systemic origin or, alternatively, through the conversion of cholesterol to pregnenolone and its subsequent transformation to biologically active steroids. Examples of these products are corticosterone, cortisol, testosterone, dihydrotesterone and estradiol. Their local production can be regulated by locally produced corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) or cytokines. Furthermore the production of glucocorticoids is affected by ultraviolet B radiation. The level of production and nature of the final steroid products are dependent on the cell type or cutaneous compartment, e.g., epidermis, dermis, adnexal structures or adipose tissue. Locally produced glucocorticoids, androgens and estrogens affect functions of the epidermis and adnexal structures as well as local immune activity. Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases. The cutaneous steroidogenic system can also have systemic effects, which are emphasized by significant skin contribution to circulating androgens and/or estrogens. Furthermore, local activity of CYP11A1 can produce novel 7 -steroids and secosteroids that are biologically active. Therefore, modulation of local steroidogenic activity may serve as a new therapeutic approach for treatment of inflammatory disorders, autoimmune processes or other skin disorders. In conclusion, the skin can be defined as an independent steroidogenic organ, whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases.

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Crossref · 10.1016/j.jsbmb.2013.02.006

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  • Findingcitation

    In HaCaT keratinocytes, progesterone is rapidly metabolized to DOC and then to several products other than corticosterone, aldosterone, and cortisol, including 3β,6α,21-trihydroxy-5α-pregnan-20-one, 3α,6α,21-trihydroxy-α-pregnan-20-one, and 3α,5α- and 3β,5α-tetrahydrodeoxycorticosterone.

    “In our studies on HaCaT keratinocytes, we have detected rapid metabolism of progesterone to DOC with further transformation to several products different from corticosterone, aldosterone and cortisol, some of which were identified by GC/MS as 3β,6α,21-trihydroxy-5α-pregnan-20-one, 3α,6α,21-trihydroxy-α-pregnan-20-one, and 3α,5α-and 3β,5α-tetrahydrodeoxycorticosterone [80].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Slominski A Wortsman J Foecking MF Shackleton C Gomez-Sanchez C Szczesniewski A Gas chromatography/mass spectrometry characterization of corticosteroid metabolism in human immortalized keratinocytes J Invest Dermatol 118 2 2002 310 315 11841549 source

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  • Findingcitation

    Cortisol and corticosterone production was detected in epidermal melanocytes and dermal fibroblasts, with chemical structure confirmed by LC/MS.

    “We have also detected cortisol as well as corticosterone production in epidermal melanocytes and dermal fibroblasts (chemical structure was confirmed by LC/MS) [57, 58, 60].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [57] Slominski A Zbytek B Semak I Sweatman T Wortsman J CRH stimulates POMC activity and corticosterone production in dermal fibroblasts J Neuroimmunol 162 1–2 2005 97 102 15833364 source

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    • cites [58] Slominski A Zbytek B Szczesniewski A Semak I Kaminski J Sweatman T Wortsman J CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH American journal of physiology. Endocrinology and metabolism 288 4 2005 E701 706 15572653 source

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    • cites [60] Slominski A Zbytek B Szczesniewski A Wortsman J Cultured human dermal fibroblasts do produce cortisol J Invest Dermatol 126 5 2006 1177 1178 16484985 PMC1472636 source

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  • Findingown data

    StAR mRNA and steroid synthesis responses to cAMP signaling were substantially lower in HaCaT cells than in adrenal and gonadal cells.

    “However, levels of StAR mRNA and steroid synthesis in response to cAMP signaling were substantially lower in HaCaT cells when compared to responses for adrenal and gonadal cells.”
    Quote in the paperSubstantial claim
  • Findingcitation

    In skin cells, the rate of cholesterol conversion to pregnenolone is about 1% of the rate in placenta.

    “It is noteworthy, that steroidogenesis in non-classical tissues is quite modest regardless of the stimulant, and in skin cells the rate of cholesterol conversion to pregnenolone represents 1% of that seen in the placenta [54].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Slominski A Zjawiony J Wortsman J Semak I Stewart J Pisarchik A Sweatman T Marcos J Dunbar C CTR A novel pathway for sequential transformation of 7-dehydrocholesterol and expression of the P450scc system in mammalian skin European journal of biochemistry/FEBS 271 21 2004 4178 4188 15511223 PMC1201497 source

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    • Rests on an assumption: Steroidogenesis in non-classical tissues is modest regardless of the stimulant, usually less than 1% of that seen with cAMP/PKA-mediated StAR expression and steroid synthesis in adrenal and gonadal cells.
  • Findingown data

    In HaCaT cells, treatment with the cAMP analog (Bu)2cAMP significantly increased StAR mRNA expression and pregnenolone synthesis compared with unstimulated cells.

    “In accordance with the above findings HaCaT cells treated with a cAMP analog, (Bu)2cAMP, significantly elevated StAR mRNA expression and pregnenolone synthesis over unstimulated cells, respectively (Fig. 4).”
    Quote in the paperSubstantial claim
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  • Classified as probably not a substantial claim. 8

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    Findingcitation

    HaCaT keratinocyte studies confirmed expression of 5α-reductase and 3α/βHSD and demonstrated expression of 6α-hydroxylase and reverse Δ4/Δ5 isomerase enzymes.

    “These studies not only confirmed keratinocytic expression of 5α-reductase and 3α/βHSD but also demonstrated expression of 6α-hydroxylase, and reverse Δ4/Δ5 isomerase enzymes [80].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Slominski A Wortsman J Foecking MF Shackleton C Gomez-Sanchez C Szczesniewski A Gas chromatography/mass spectrometry characterization of corticosteroid metabolism in human immortalized keratinocytes J Invest Dermatol 118 2 2002 310 315 11841549

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  • May combine two claims.

    Premisecitation

    Human skin or skin cells can produce deoxycorticosterone, 18(OH)DOC, corticosterone, and cortisol in situ.

    “Since the first demonstration that human skin expresses crucial genes of glucocorticosteroidogenesis including CYP11A1, CYP17, CYP21A2, CYP11B1 and MC2 [55], a series of sequential investigations have shown that the skin or skin cells can produce deoxycorticosterone (DOC), 18(OH)DOC, corticosterone and cortisol in situ [53, 56–61].”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [55] Slominski A Ermak G Mihm M ACTH receptor, CYP11A1, CYP17 and CYP21A2 genes are expressed in skin J Clin Endocrinol Metab 81 7 1996 2746 2749 8675607

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    • cites [53] Slominski A Gomez-Sanchez CE Foecking MF Wortsman J Metabolism of progesterone to DOC, corticosterone and 18OHDOC in cultured human melanoma cells FEBS Lett 455 3 1999 364 366 10437805

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    • cites [56] Slominski A Gomez-Sanchez C Foecking MF Wortsman J Active steroidogenesis in the normal rat skin Biochimica et biophysica acta 1474 2000 1 4 10699483

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    • cites [57] Slominski A Zbytek B Semak I Sweatman T Wortsman J CRH stimulates POMC activity and corticosterone production in dermal fibroblasts J Neuroimmunol 162 1–2 2005 97 102 15833364

      Not checked in the free run.

    • cites [58] Slominski A Zbytek B Szczesniewski A Semak I Kaminski J Sweatman T Wortsman J CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH American journal of physiology. Endocrinology and metabolism 288 4 2005 E701 706 15572653 source

      Not checked in the free run.

    • cites [59] Ito N Ito T Kromminga A Bettermann A Takigawa M Kees F Straub RH Paus R Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol FASEB J 19 10 2005 1332 1334 15946990 source

      Not checked in the free run.

    • cites [60] Slominski A Zbytek B Szczesniewski A Wortsman J Cultured human dermal fibroblasts do produce cortisol J Invest Dermatol 126 5 2006 1177 1178 16484985 PMC1472636

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    • cites [61] Rogoff D Gomez-Sanchez CE Foecking MF Wortsman J Slominski A Steroidogenesis in the human skin: 21-hydroxylation in cultured keratinocytes J Steroid Biochem Mol Biol 78 1 2001 77 81 11530287

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  • May combine two claims.

    Premisecitation

    Skin cells express functionally active CYP11A1, StAR, and MLN64 and can initiate steroidogenesis de novo from cholesterol.

    “Furthermore, skin cells express functionally active CYP11A1 (there are also alternatively spliced isoforms of this enzyme in skin cells [54]), StAR and MLN64, and have the capability of starting the steroidogenic pathway de novo from cholesterol [54, 70].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54] Slominski A Zjawiony J Wortsman J Semak I Stewart J Pisarchik A Sweatman T Marcos J Dunbar C CTR A novel pathway for sequential transformation of 7-dehydrocholesterol and expression of the P450scc system in mammalian skin European journal of biochemistry/FEBS 271 21 2004 4178 4188 15511223 PMC1201497 source

      Not checked in the free run.

    • cites [70] Thiboutot D Jabara S McAllister JM Sivarajah A Gilliland K Cong Z Clawson G Human skin is a steroidogenic tissue: steroidogenic enzymes and cofactors are expressed in epidermis, normal sebocytes, and an immortalized sebocyte cell line (SEB-1) J Invest Dermatol 120 6 2003 905 914 12787114 source

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    Premisereasoning

    Cutaneous DHEA formation proceeds both from endogenous cutaneous cholesterol and from DHEA-S of adrenal origin.

    “Cutaneous formation of DHEA, the main substrate for the more potent androgens T and DHT, proceeds both from endogenous cutaneous cholesterol (see section 2.3) and from DHEA-S of adrenal origin.”
    Quote in the paperSubstantial claim

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    Premisecitation

    5α-reductase type 1 is the predominant isoform in skin and is more abundant in sebaceous and sweat glands, keratinocytes, and dermal fibroblasts.

    “5α-reductase (5αR) type 1 is the predominant isoform detected in the skin [104, 105] and more abundantly expressed in sebaceous and sweat glands [106], keratinocytes [78, 80] and dermal fibroblasts [107].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [104] Grino PB Griffin JE Wilson JD Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone Endocrinology 126 2 1990 1165 1172 2298157

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    • cites [105] 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 type 1 5alpha-reductase expression in cultured human skin cells--evidence of its presence in melanocytes J Invest Dermatol 110 1 1998 84 89 9424094

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    • cites [106] Deplewski D Rosenfield RL Role of hormones in pilosebaceous unit development Endocr Rev 21 4 2000 363 392 10950157

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    • cites [78] Milewich L Kaimal V Shaw CB Sontheimer Epidermal keratinocytes: a source of 5 alpha-dihydrotestosterone production in human skin J Clin Endocrinol Metab 62 4 1986 739 746 3949953

      Not checked in the free run.

    • cites [80] Slominski A Wortsman J Foecking MF Shackleton C Gomez-Sanchez C Szczesniewski A Gas chromatography/mass spectrometry characterization of corticosteroid metabolism in human immortalized keratinocytes J Invest Dermatol 118 2 2002 310 315 11841549

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Positive (SF-1) and negative (DAX-1) regulators of StAR are expressed in the epidermis.

    “Expression of positive [adrenal 4-binding protein/steroidogenic factor 1 (SF-1)] and negative (dosage-sensitive sex reversal, adrenal hypoplasia congenital, critical region on the X chromosome, gene 1) regulators of StAR has also been detected in the epidermis [63, 85–87].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [63] Hannen RF Michael AE Jaulim A Bhogal R Burrin JM Philpott MP Steroid synthesis by primary human keratinocytes; implications for skin disease Biochemical and biophysical research communications 404 1 2011 62 67 21094146

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    • cites [85] Patel MV McKay IA Burrin JM Transcriptional regulators of steroidogenesis, DAX-1 and SF-1, are expressed in human skin J Invest Dermatol 117 6 2001 1559 1565 11886523

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    • cites [86] Manna PR Eubank DW Lalli E Sassone-Corsi P Stocco DM Transcriptional regulation of the mouse steroidogenic acute regulatory protein gene by the cAMP response-element binding protein and steroidogenic factor 1 J Mol Endocrinol 30 3 2003 381 397 12790807 source

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    • cites [87] Manna PR Dyson MT Jo Y Stocco DM Role of dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 in protein kinase A-and protein kinase C-mediated regulation of the steroidogenic acute regulatory protein expression in mouse Leydig tumor cells: mechanism of action Endocrinology 150 1 2009 187 199 18787026 PMC2630909

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    Interpretationreasoning

    These results suggest a slower onset of StAR localization to mitochondria and lower rates of steroid synthesis in epidermal keratinocytes.

    “This suggests a slower onset of StAR localization to mitochondria and lower rates of steroid synthesis in epidermal keratinocytes.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In cultured keratinocytes, silencing 11βHSD1 with siRNA reduced cortisol production from cortisone, while silencing 11βHSD2 increased cortisol levels.

    “Keratinocytes with the type 1 isoenzyme silenced with siRNA produced less cortisol from cortisone than control cells. Conversely, the silencing of 11βHSD2 caused an elevation in cortisol levels [64].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Cirillo N Prime SS Keratinocytes synthesize and activate cortisol Journal of Cellular Biochemistry 112 6 2011 1499 1505 21344493

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  • May combine two claims.

    Premisecitation

    In mouse skin, 11βHSD1 is present in keratinocytes, dermal fibroblasts, and the outer root sheath of hair follicles, with a similar distribution in humans.

    “In the mouse skin, 11βHSD1 was found by immunohistochemical staining in keratinocytes, dermal fibroblasts and the outer root sheath of hair follicles, and appears to have a similar distribution in humans [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Tiganescu A Walker EA Hardy RS Mayes AE Stewart PM Localization, age-and site-dependent expression, and regulation of 11beta-hydroxysteroid dehydrogenase type 1 in skin Journal of Investigative Dermatology 131 1 2011 30 36 20739946

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    Premisecitation

    Skin cells express 3βHSD, which allows the steroidogenic pathway to proceed to glucocorticoids and sex hormones.

    “They also express 3βHSD [71, 72] allowing the pathway to proceed with final production of glucocorticoids [73] and sex hormones [74].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [71] Labrie F Luu-The V Labrie C Belanger A Simard J Lin SX Pelletier G Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone Endocrine reviews 24 2 2003 152 182 12700178

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    • cites [72] Labrie F Luu-The V Labrie C Pelletier G El-Alfy M Intracrinology and the skin Hormone research 54 5–6 2000 218 229 11595810

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    • cites [73] Slominski A Wortsman J Tuckey RC Paus R Differential expression of HPA axis homolog in the skin Mol Cell Endocrinol 265–266 2007 143 149 PMC1839836 17197073 source

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    • cites [74] Zouboulis CC Chen WC Thornton MJ Qin K Rosenfield R Sexual hormones in human skin Hormone and metabolic research = Hormon-und Stoffwechselforschung = Hormones et metabolisme 39 2 2007 85 95 17326004

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  • May combine two claims.

    Premisecitation

    Skin expresses 11βHSD1, which reduces the 11-keto group to an alcohol, activating cortisone to cortisol.

    “Skin expresses 11βHSD1 which is primarily involved in the reduction of the 11-keto group to the alcohol, such as in the activation of cortisone to cortisol [23, 54, 66, 81].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [23] Miller WL Auchus RJ The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders Endocrine reviews 32 1 2011 81 151 21051590 PMC3365799 source

      Not checked in the free run.

    • cites [54] Slominski A Zjawiony J Wortsman J Semak I Stewart J Pisarchik A Sweatman T Marcos J Dunbar C CTR A novel pathway for sequential transformation of 7-dehydrocholesterol and expression of the P450scc system in mammalian skin European journal of biochemistry/FEBS 271 21 2004 4178 4188 15511223 PMC1201497 source

      Not checked in the free run.

    • cites [66] Tiganescu A Walker EA Hardy RS Mayes AE Stewart PM Localization, age-and site-dependent expression, and regulation of 11beta-hydroxysteroid dehydrogenase type 1 in skin Journal of Investigative Dermatology 131 1 2011 30 36 20739946

      Not checked in the free run.

    • cites [81] Skobowiat C Sayre RM Dowdy JC Slominski AT Ultraviolet radiation regulates cortisol activity in a waveband dependent manner in human skin ex-vivo British Journal of Dermatology in press 2013 PMC3586986 23363016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mouse skin, 11βHSD2 was not detected by immunohistochemistry in keratinocytes, dermal fibroblasts, or outer root sheath, so the predominant activity was activation of cortisone to cortisol.

    “In contrast, 11βHSD2 was not detected in these sites by immunohistochemistry, so that the predominant activity was activation of cortisone to cortisol.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Tiganescu A Walker EA Hardy RS Mayes AE Stewart PM Localization, age-and site-dependent expression, and regulation of 11beta-hydroxysteroid dehydrogenase type 1 in skin Journal of Investigative Dermatology 131 1 2011 30 36 20739946

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    Premisecitation

    DHEA-S is hydrolysed in skin to DHEA by steroid sulfatase, which is detected in sebaceous glands and dermal papilla cells of terminal hair follicles.

    “DHEA-S is hydrolysed in the skin to DHEA by steroid sulfatase, detected in sebaceous glands and dermal papilla cells (DPCs) of terminal HFs [94, 95].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [94] Milewich L Sontheimer RD Herndon JH Jr Steroid sulfatase activity in epidermis of acne-prone and non-acne-prone skin of patients with acne vulgaris Arch Dermatol 126 10 1990 1312 1314 2145810

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    • cites [95] Hoffmann R Rot A Niiyama S Billich A Steroid sulfatase in the human hair follicle concentrates in the dermal papilla J Invest Dermatol 117 6 2001 1342 1348 11886493

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    Interpretationcitation

    Skin is an extra-adrenal organ with endogenous steroidogenic capacity that is integrated into the cutaneous neuro-endocrine-immune regulatory networks.

    “Thus, evidence has accumulated classifying skin as an additional extra-adrenal organ with an endogenous steroidogenic capacity that is integrated into the regulatory networks of the cutaneous neuro-endocrine-immune system(s) [1].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Slominski AT Zmijewski MA Skobowiat C Zbytek B Slominski RM Steketee JD Sensing the environment: regulation of local and global homeostasis by the skin’s neuroendocrine system Adv Anat, Embryol Cell Biol 212 2012 1 115 PMC3422784 22894052 source

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    Premisecitation

    SULT2B1 is detected in skin, and isoform SULTB1b is abundantly expressed in ORSKs, sebocytes, and differentiated epidermal keratinocytes.

    “The SULT2B1 enzyme, member of the SULT2 family, which catalyzes the sulfation of 3β-hydroxysteroids, such as DHEA and pregnenolone, was also detected in the skin [124, 125]. The isoform SULTB1b is abundantly expressed in ORSKs, sebocytes and differentiated epidermal keratinocytes [125].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [124] Higashi Y Fuda H Yanai H Lee Y Fukushige T Kanzaki T Strott CA Expression of cholesterol sulfotransferase (SULT2B1b) in human skin and primary cultures of human epidermal keratinocytes J Invest Dermatol 122 5 2004 1207 1213 15140224

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    • cites [125] Falany CN He D Dumas N Frost AR Falany JL Human cytosolic sulfotransferase 2B1: isoform expression, tissue specificity and subcellular localization J Steroid Biochem Mol Biol 102 1–5 2006 214 221 17055258 PMC1820847

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    Premisecitation

    11βHSD1 and 11βHSD2 regulate local cortisol availability for the glucocorticoid receptor and are expressed in many peripheral organs.

    “Two key enzymes that regulate the local cortisol availability for the GR are 11βHSD1 and 11βHSD2, which are expressed in many peripheral organs [147].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Terao M Murota H Kimura A Kato A Ishikawa A Igawa K Miyoshi E Katayama I 11beta-Hydroxysteroid dehydrogenase-1 is a novel regulator of skin homeostasis and a candidate target for promoting tissue repair PloS one 6 9 2011 e25039 21949844 PMC3176795

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    Premisecitation

    UVC stimulates cortisol production with simultaneous GR downregulation and upregulation of CRH, POMC, ACTH, β-endorphin, CYP11A1, and 11βHSD1.

    “UVC (100–280nm), when applied to the skin, stimulates cortisol production with simultaneous GR down regulation and upregulation of CRH, POMC, ACTH, β-endorphin, CYP11A1 and 11βHSD1 [81, 151].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [81] Skobowiat C Sayre RM Dowdy JC Slominski AT Ultraviolet radiation regulates cortisol activity in a waveband dependent manner in human skin ex-vivo British Journal of Dermatology in press 2013 PMC3586986 23363016

      Not checked in the free run.

    • cites [151] Skobowiat C Dowdy JC Sayre RM Tuckey RC Slominski A Cutaneous hypothalamic-pituitary-adrenal axis homolog: regulation by ultraviolet radiation American journal of physiology. Endocrinology and metabolism 301 3 2011 E484 493 21673307 PMC3174533

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  • May combine two claims.

    Premisecitation

    TNFα has anti-inflammatory properties, including stimulation of the HPA axis resulting in increased steroid production.

    “TNFα, apart from its well-characterized proinflammatory role, has various antiinflammatory properties; an example of the latter is stimulation of the HPA axis resulting in increased steroid production [145].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Noti M Corazza N Mueller C Berger B Brunner T TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis The Journal of experimental medicine 207 5 2010 1057 1066 20439544 PMC2867273

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  • May combine two claims.

    Premisecitation

    The 5αR1 inhibitor MK386 completely blocked conversion of testosterone to DHT in SZ95 sebocytes and HaCaT keratinocytes and reduced testosterone-induced proliferation of sebocytes.

    “The 5αR1 inhibitor MK386 blocked completely the conversion of T to DHT in SZ95 sebocytes and HaCaT keratinocytes and reduced T-induced proliferation of sebocytes [108].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Seiffert K Seltmann H Fritsch M Zouboulis CC Inhibition of 5alpha-reductase activity in SZ95 sebocytes and HaCaT keratinocytes in vitro Hormone and metabolic research = Hormon-und Stoffwechselforschung = Hormones et metabolisme 39 2 2007 141 148 17326010

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    Premisecitation

    IL-1β can directly stimulate human adrenocortical cells, and similar stimulation has been observed in epidermal keratinocytes.

    “Furthermore, IL-1β can directly stimulate human adrenocortical cells [140], and similar stimulation has been also observed in epidermal keratinocytes [65].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [140] Tkachenko IV Jaaskelainen T Jaaskelainen J Palvimo JJ Voutilainen R Interleukins 1alpha and 1beta as regulators of steroidogenesis in human NCI-H295R adrenocortical cells Steroids 76 10–11 2011 1103 1115 21600230

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    • cites [65] Vukelic S Stojadinovic O Pastar I Rabach M Krzyzanowska A Lebrun E Davis SC Resnik S Brem H Tomic-Canic M Cortisol synthesis in epidermis is induced by IL-1 and tissue injury J Biol Chem 286 12 2011 10265 10275 21239489 PMC3060481

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    Premisecitation

    SOCS suppresses cytokine-induced POMC expression and ACTH release.

    “Suppressor of cytokine signaling (SOCS) acts as a potent negative regulator of cytokine signaling and suppresses cytokine-induced POMC expression and ACTH release [146].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] O’Shea JJ Murray PJ Cytokine signaling modules in inflammatory responses Immunity 28 4 2008 477 487 18400190 PMC2782488

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  • May combine two claims.

    Premisecitation

    Skin shows immunohistochemical reactivity for CYP7B1, which catalyzes 7α-hydroxylation of DHEA and converts DHT metabolites Aene-diol and 3-Adiol into compounds with little or no estrogenic effect.

    “Skin shows immunohistochemical reactivity for the enzyme CYP7B1, which catalyzes the 7α-hydroxylation of DHEA. Moreover, it turns the DHT metabolites 5-androstene-3β,17β-diol (Aene-diol) and 5-androstane-3β,17β-diol (3-Adiol) in compounds with little or no estrogenic effect [128].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Hennebert O Chalbot S Alran S Morfin R Dehydroepiandrosterone 7alpha-hydroxylation in human tissues: possible interference with type 1 11beta-hydroxysteroid dehydrogenase-mediated processes J Steroid Biochem Mol Biol 104 3–5 2007 326 333 17467270 source

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    Premisecitation

    SULT1E1 activity is higher in differentiated normal human epidermal keratinocytes than in proliferating ones, suggesting attenuation of estradiol-induced keratinocyte proliferation.

    “Its activity is higher in differentiated normal human epidermal keratinocytes (NHEKs) in comparison to proliferating ones [117], suggesting a mechanism of attenuation of estradiol-induced keratinocyte proliferation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Kushida A Hattori K Yamaguchi N Kobayashi T Date A Tamura H Sulfation of estradiol in human epidermal keratinocyte Biol Pharm Bull 34 7 2011 1147 1151 21720030

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    Premisecitation

    Aromatase is expressed in anagen and terminal hair follicles, cultured keratinocytes, melanocytes, sebaceous glands, and adipose fibroblasts.

    “mRNA transcripts of the CYP19 gene were reported in dexamethasone-induced human fibroblasts in vitro [113], while aromatase was expressed in anagen and terminal HFs, cultured keratinocytes, melanocytes, sebaceous glands and adipose fibroblasts [114].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Conrad F Paus R Estrogens and the hair follicle J Dtsch Dermatol Ges 2 6 2004 412 423 16281598

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    Premisecitation

    Locally produced CRH may drive inflammatory skin diseases by stimulating pro-inflammatory pathways that glucocorticosteroids do not inhibit.

    “It has recently been proposed that inflammatory skin diseases may be driven by locally produced CRH that stimulates pro-inflammatory pathways that in turn are not inhibited by glucocorticosteroids [130, 169–172].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [130] Slominski A Wortsman J Pisarchik A Zbytek B Linton EA Mazurkiewicz JE Wei ET Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors Faseb J 15 10 2001 1678 1693 11481215

      Not checked in the free run.

    • cites [169] Slominski A On the role of the corticotropin-releasing hormone signalling system in the aetiology of inflammatory skin disorders The British journal of dermatology 160 2 2009 229 232 19187344 PMC2649670

      Not checked in the free run.

    • cites [170] Slominski A Wortsman J Linton E Pisarchik A Zbytek B The skin as a model for the immunomodulatory effects of corticotropin-releasing hormone Schaefer M Stein C Mind over Matter-Regulation of Peripheral Inflammation by the CNS Birkhaeuser Verlag Basel, Boston, Berlin 2003 149 176

      Not checked in the free run.

    • cites [171] Zouboulis CC Acne Vulgaris and Rosacea Granstein R Luger T Neuroimmunology of the Skin Springer Berlin Heidelberg 2009 219 232

      Not checked in the free run.

    • cites [172] Zbytek B Slominski AT CRH mediates inflammation induced by lipopolysaccharide in human adult epidermal keratinocytes J Invest Dermatol 127 3 2007 730 732 17068474 PMC1839835

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CYP11A1 converts 7-dehydrocholesterol by hydroxylation at C22 and then C20, side-chain cleavage, and further metabolism of 7-dehydropregnenolone by existing steroidogenic enzymes.

    “7DHC (7-dehydrocholesterol) can be metabolized by CYP11A1 through hydroxylation at C22 followed by C20, cleavage of the site chain and subsequent metabolism of the 7DHP (7dehydropregnenolone) by existing steroidogenic enzymes [54, 162, 163] (Fig. 5).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [54] Slominski A Zjawiony J Wortsman J Semak I Stewart J Pisarchik A Sweatman T Marcos J Dunbar C CTR A novel pathway for sequential transformation of 7-dehydrocholesterol and expression of the P450scc system in mammalian skin European journal of biochemistry/FEBS 271 21 2004 4178 4188 15511223 PMC1201497 source

      Not checked in the free run.

    • cites [162] Slominski AT Zmijewski MA Semak I Sweatman T Janjetovic Z Li W Zjawiony JK Tuckey RC Sequential metabolism of 7-dehydrocholesterol to steroidal 5,7-dienes in adrenal glands and its biological implication in the skin PloS one 4 2 2009 e4309 19190754 PMC2629546 source

      Not checked in the free run.

    • cites [163] Slominski AT Kim TK Chen J Nguyen MN Li W Yates CR Sweatman T Janjetovic Z Tuckey RC Cytochrome P450scc-dependent metabolism of 7-dehydrocholesterol in placenta and epidermal keratinocytes The international journal of biochemistry & cell biology 44 11 2012 2003 2018 22877869 PMC3520099 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CRH interacts with CRH-R1 to stimulate cAMP production, with a subsequent increase in POMC gene expression and ACTH production.

    “Next, CRH interacts with CRH-R1 stimulating cAMP production with a subsequent increase in POMC gene expression and production of ACTH [57, 60].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [57] Slominski A Zbytek B Semak I Sweatman T Wortsman J CRH stimulates POMC activity and corticosterone production in dermal fibroblasts J Neuroimmunol 162 1–2 2005 97 102 15833364

      Not checked in the free run.

    • cites [60] Slominski A Zbytek B Szczesniewski A Wortsman J Cultured human dermal fibroblasts do produce cortisol J Invest Dermatol 126 5 2006 1177 1178 16484985 PMC1472636

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UVB has a similar stimulatory effect on CRH and POMC signaling, production of cortisol, and inhibition of the GR.

    “UVB (280–320 nm), a recognized stimulator of melanin pigmentation [152], has similar stimulatory effect on CRH and POMC signaling, production of cortisol and inhibition of the GR [81, 129, 131, 151, 153, 154].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [81] Skobowiat C Sayre RM Dowdy JC Slominski AT Ultraviolet radiation regulates cortisol activity in a waveband dependent manner in human skin ex-vivo British Journal of Dermatology in press 2013 PMC3586986 23363016 source

      Not checked in the free run.

    • cites [129] Slominski A Wortsman J Luger T Paus R Solomon S Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress Physiol Rev 80 3 2000 979 1020 10893429 source

      Not checked in the free run.

    • cites [131] Slominski A Zbytek B Zmijewski M Slominski RM Kauser S Wortsman J Tobin DJ Corticotropin releasing hormone and the skin Front Biosci 11 2006 2230 2248 16720310 PMC1847336 source

      Not checked in the free run.

    • cites [151] Skobowiat C Dowdy JC Sayre RM Tuckey RC Slominski A Cutaneous hypothalamic-pituitary-adrenal axis homolog: regulation by ultraviolet radiation American journal of physiology. Endocrinology and metabolism 301 3 2011 E484 493 21673307 PMC3174533 source

      Not checked in the free run.

    • cites [153] Slominski AT Botchkarev V Choudhry M Fazal N Fechner K Furkert J Krause E Roloff B Sayeed M Wei E Zbytek B Zipper J Wortsman J Paus R Cutaneous expression of CRH and CRH-R. Is there a “skin stress response system?” Annals of the New York Academy of Sciences 885 1999 287 311 10816662 source

      Not checked in the free run.

    • cites [154] Slominski A Baker J Ermak G Chakraborty A Pawelek J Ultraviolet B stimulates production of corticotropin releasing factor (CRF) by human melanocytes FEBS Lett 399 1–2 1996 175 176 8980146 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The CRH signaling system is highly expressed in mammalian skin (epidermis and dermis), and its expression is upregulated by UVR.

    “The CRH signaling system is highly expressed in mammalian skin (epidermis and dermis), and its expression is up-regulated by UVR [1, 131].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Slominski AT Zmijewski MA Skobowiat C Zbytek B Slominski RM Steketee JD Sensing the environment: regulation of local and global homeostasis by the skin’s neuroendocrine system Adv Anat, Embryol Cell Biol 212 2012 1 115 PMC3422784 22894052 source

      Not checked in the free run.

    • cites [131] Slominski A Zbytek B Zmijewski M Slominski RM Kauser S Wortsman J Tobin DJ Corticotropin releasing hormone and the skin Front Biosci 11 2006 2230 2248 16720310 PMC1847336 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Production of glucocorticoids is affected by ultraviolet B radiation.

    “Furthermore the production of glucocorticoids is affected by ultraviolet B radiation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Paracrine communication in skin modulated by internal and external stressors can include nerve fibers, keratinocytes, melanocytes, fibroblasts, and immune cells to maintain cutaneous homeostasis.

    “The paracrine communication in the skin modulated by internal and external stressors can include nerve fibers, keratinocytes, melanocytes, fibroblasts and immune cells to maintain cutaneous homeostasis [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Slominski AT Zmijewski MA Skobowiat C Zbytek B Slominski RM Steketee JD Sensing the environment: regulation of local and global homeostasis by the skin’s neuroendocrine system Adv Anat, Embryol Cell Biol 212 2012 1 115 PMC3422784 22894052 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Smith-Lemli-Opitz syndrome, deficiency of 7-dehydrocholesterol reductase leads to UVA photosensitivity of the skin and to formation of atypical steroids.

    “Firstly, the 7-Δ reductase deficiency observed in Smith–Lemli–Opitz syndrome (SLOS), in an addition to severe malformations, results in development of skin photosensitivity to UVA [158, 159] and production a series of unusual steroids [79, 160, 161].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [158] Chignell CF Kukielczak BM Sik RH Bilski PJ He YY Ultraviolet A sensitivity in Smith-Lemli-Opitz syndrome: Possible involvement of cholesta-5,7,9(11)-trien-3 beta-ol Free Radic Biol Med 41 2 2006 339 346 16814115 source

      Not checked in the free run.

    • cites [159] Gambichler T Bader A Vojvodic M Bechara FG Sauermann K Altmeyer P Hoffmann K Impact of UVA exposure on psychological parameters and circulating serotonin and melatonin BMC Drmatology 2 2002 6 PMC113771 11952999 source

      Not checked in the free run.

    • cites [79] Slominski A Worstman J Foecking MF Shackleton CH Gomez-Sanchez CE Szczesniewski A Gas chromatography/mass spectrometry characterization of corticosteroid metabolism in human immortalized keratinocytes J Invest Dermatol 118 2002 310 315 11841549 source

      Not checked in the free run.

    • cites [160] Shackleton C Roitman E Guo LW Wilson WK Porter FD Identification of 7 (8) and 8(9) unsaturated adrenal steroid metabolites produced by patients with 7-dehydrosterol-delta7-reductase deficiency (Smith-Lemli-Opitz syndrome) Journal of Steroid Biochemistry and Molecular Biology 82 2–3 2002 225 232 12477489 source

      Not checked in the free run.

    • cites [161] Shackleton CH Roitman E Kelley R Neonatal urinary steroids in Smith-Lemli-Opitz syndrome associated with 7-dehydrocholesterol reductase deficiency Steroids 64 7 1999 481 490 10443904 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-1 affects expression of steroidogenic enzymes and cortisol production in skin.

    “Note, that IL-1 affects expression of steroidoigenic enzymes and production of cortisol in the skin [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Vukelic S Stojadinovic O Pastar I Rabach M Krzyzanowska A Lebrun E Davis SC Resnik S Brem H Tomic-Canic M Cortisol synthesis in epidermis is induced by IL-1 and tissue injury J Biol Chem 286 12 2011 10265 10275 21239489 PMC3060481

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UVA had no effect on cortisol, CRH, and ACTH production but stimulated β-endorphin and 11βHSD2 expression.

    “UVA (320–400 nm) had no effect on cortisol, CRH and ACTH production but stimulated β-endorphin and 11βHSD2 expression [81, 151, 155].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [81] Skobowiat C Sayre RM Dowdy JC Slominski AT Ultraviolet radiation regulates cortisol activity in a waveband dependent manner in human skin ex-vivo British Journal of Dermatology in press 2013 PMC3586986 23363016 source

      Not checked in the free run.

    • cites [151] Skobowiat C Dowdy JC Sayre RM Tuckey RC Slominski A Cutaneous hypothalamic-pituitary-adrenal axis homolog: regulation by ultraviolet radiation American journal of physiology. Endocrinology and metabolism 301 3 2011 E484 493 21673307 PMC3174533 source

      Not checked in the free run.

    • cites [155] Yamate Y Hiramoto K Kasahara E Jikumaru M Sato EF Inoue J Inoue M Ultraviolet-A irradiation to the eye modulates intestinal mucosal functions and properties of mast cells in the mouse Photochemistry and photobiology 87 1 2011 191 198 21073474 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases.

    “Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Locally produced POMC-derived peptides and locally produced glucocorticoids can counteract pro-inflammatory activities.

    “These proinflammatory activities can be counteracted by locally produced POMC derived peptides [73, 129, 173] and by locally produced glucocorticoids [1, 73].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [73] Slominski A Wortsman J Tuckey RC Paus R Differential expression of HPA axis homolog in the skin Mol Cell Endocrinol 265–266 2007 143 149 PMC1839836 17197073 source

      Not checked in the free run.

    • cites [129] Slominski A Wortsman J Luger T Paus R Solomon S Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress Physiol Rev 80 3 2000 979 1020 10893429 source

      Not checked in the free run.

    • cites [173] Zbytek B Pfeffer LM Slominski AT CRH inhibits NF-kappaB signaling in human melanocytes Peptides 27 12 2006 3276 3283 16959375 PMC1839005 source

      Not checked in the free run.

    • cites [1] Slominski AT Zmijewski MA Skobowiat C Zbytek B Slominski RM Steketee JD Sensing the environment: regulation of local and global homeostasis by the skin’s neuroendocrine system Adv Anat, Embryol Cell Biol 212 2012 1 115 PMC3422784 22894052 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The skin can be defined as an independent steroidogenic organ whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases.

    “In conclusion, the skin can be defined as an independent steroidogenic organ, whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The cutaneous steroidogenic system contributes significantly to circulating androgens and/or estrogens.

  • May combine two claims.

    Premisecitation

    UVB stimulated CREB phosphorylation and binding of phosphorylated CREB to CRE sites in the CRH promoter.

    “UVB stimulated CREB phosphorylation and the binding of phosphorylated CREB to CRE sites in the CRH promoter [156].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Zbytek B Wortsman J Slominski A Characterization of a ultraviolet B-induced corticotropin-releasing hormone-proopiomelanocortin system in human melanocytes Mol Endocrinol 20 10 2006 2539 2547 16740657 PMC1847418

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Higher elements of the HPA axis are functional within the pilosebaceous unit and help maintain its immune privilege.

    “The higher elements of the HPA axis are functional within the pilosebaceous unit and provide another important element maintaining the immune privilege of this site [131, 133, 171, 183].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [131] Slominski A Zbytek B Zmijewski M Slominski RM Kauser S Wortsman J Tobin DJ Corticotropin releasing hormone and the skin Front Biosci 11 2006 2230 2248 16720310 PMC1847336 source

      Not checked in the free run.

    • cites [133] Slominski A Wortsman J Paus R Elias PM Tobin DJ Feingold KR Skin as an endocrine organ: implications for its function Drug discovery today 5 2 2008 137 144 19492070 PMC2658605 source

      Not checked in the free run.

    • cites [171] Zouboulis CC Acne Vulgaris and Rosacea Granstein R Luger T Neuroimmunology of the Skin Springer Berlin Heidelberg 2009 219 232

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [183] Paus R Arck P Tiede S (Neuro-)endocrinology of epithelial hair follicle stem cells Mol Cell Endocrinol 288 1–2 2008 38 51 18423849 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-23, IL-17 and Th17 lymphocytes increase IL-22, which stimulates keratinocyte proliferation.

    “IL-23, IL-17 and Th17 lymphocytes lead to increased levels of IL-22 that stimulates keratinocyte proliferation [16, 178].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Maddur MS Miossec P Kaveri SV Bayry J Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies AmJ Pathol 181 1 2012 8 18 22640807

      Not checked in the free run.

    • cites [178] Tokura Y Mori T Hino R Psoriasis and other Th17-mediated skin diseases J Uoeh 32 4 2010 317 328 21226422

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Down-regulation of immune privilege and local immune activation are considered operative in alopecia areata.

    “Down-regulation of immune privilege and local activation of the immune system is considered to be operative in alopecia areata [180].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [180] Gilhar A Etzioni A Paus R Alopecia areata N Engl J Med 366 16 2012 1515 1525 22512484

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cortisol levels change within hair follicles, possibly reflecting systemic concentration or local production.

    “Levels of cortisol change within the HFs, which might reflect its systemic concentration or change in local production [184].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [184] Meyer JS Novak MA Minireview: hair cortisol: a novel biomarker of hypothalamic-pituitary-adrenocortical activity Endocrinology 153 9 2012 4120 4127 22778226 PMC3423616

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a mouse model of alopecia areata, basal plasma ACTH and cortisol are higher than normal, but stress-induced levels are lower.

    “However, in a mouse model of alopecia areata, the basal plasma levels of ACTH and cortisol are higher than in normal mice, although in response to stress the levels are lower [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Rainey WE Carr BR Sasano H Suzuki T Mason JI Dissecting humanadrenal androgen production Trends in endocrinology and metabolism: TEM 13 6 2002 234 239 12128283

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The androgen/AR complex augments inflammatory responses of neutrophils and macrophages in addition to affecting sebaceous gland activity.

    “The androgen/AR complex does not only affect sebaceous gland activity, but also its inflammation, by augmenting the inflammatory responses of neutrophils and macrophages [230, 231].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [230] Lai JJ Lai KP Chuang KH Chang P Yu IC Lin WJ Chang C Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-alpha expression The Journal of clinical investigation 119 12 2009 3739 3751 19907077 PMC2786793

      Not checked in the free run.

    • cites [231] Lee WJ Jung HD Chi SG Kim BS Lee SJ Kim do W Kim MK Kim JC Effect of dihydrotestosterone on the upregulation of inflammatory cytokines in cultured sebocytes Arch Dermatol Res 302 6 2010 429 433 20043171

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Estrogens increase acid mucopolysaccharides, hyaluronic acid, and collagen I and III synthesis.

    “increase acid mucopolysaccharides, hyaluronic acid, collagen I and III synthesis [210, 211]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [210] Raine-Fenning NJ Brincat MP Muscat-Baron Y Skin aging and menopause: implications for treatment Am J Clin Dermatol 4 6 2003 371 378 12762829

      Not checked in the free run.

    • cites [211] Bentley JP Brenner RM Linstedt AD West NB Carlisle KS Rokosova BC MacDonald N Increased hyaluronate and collagen biosynthesis and fibroblast estrogen receptors in macaque sex skin J Invest Dermatol 87 5 1986 668 673 3772161

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro E2 inhibits hair shaft elongation in female occipital scalp but promotes it in fronto-temporal male hair follicles.

    “In vitro E2 has an inhibitory effect in hair shaft elongation in female occipital scalp, while it promotes it in fronto-temporal male HFs [213, 215].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [213] Thornton MJ Oestrogen functions in skin and skin appendages Expert Opin Ther Targets 9 3 2005 617 629 15948678

      Not checked in the free run.

    • cites [215] Conrad F Ohnemus U Bodo E Bettermann R Paus A Estrogens and human scalp hair growth-still more questions than answers J Invest Dermatol 122 3 2004 840 842 15086574

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Estrogens are believed to stimulate hair growth in men by prolonging anagen and postponing the transition to telogen.

    “Estrogens are believed to stimulate hair growth in men, by prolonging the anagen phase of the HF and postponing their transition to telogen phase [114].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Conrad F Paus R Estrogens and the hair follicle J Dtsch Dermatol Ges 2 6 2004 412 423 16281598

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Estrogens prevent wrinkle formation and skin dryness in post-menopausal women.

    “and prevent wrinkle formation and skin dryness of post-menopausal women [214].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [214] Kanda N Watanabe S Regulatory roles of sex hormones in cutaneous biology and immunology J Dermatol Sci 38 1 2005 1 7 15795118

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human sebocytes express TLR-2, which is activated by P. acnes and triggers innate immunity.

    “Human sebocytes express TLR-2 [225], which is activated by P. acnes, thus triggering innate immunity mechanisms.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [225] Oeff MK Seltmann H Hiroi N Nastos A Makrantonaki E Bornstein SR Zouboulis CC Differential regulation of Toll-like receptor and CD14 pathways by retinoids and corticosteroids in human sebocytes Dermatology 213 3 2006 266 17033190

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ERα expression has been reported in foreskin normal human epidermal keratinocytes in vitro.

    “ERα expression of foreskin NHEKs was also reported in vitro [204, 205].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [204] Verdier-Sevrain S Yaar M Cantatore J Traish A Gilchrest BA Estradiol induces proliferation of keratinocytes via a receptor mediated mechanism FASEB J 18 11 2004 1252 1254 15208259

      Not checked in the free run.

    • cites [205] 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 ProcNatl Acad Sci U S A 83 8 1986 2496 2500 PMC323325 3458212

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ERβ is the predominant estrogen receptor in human scalp skin and is expressed in normal human epidermal keratinocytes.

    “Of the two intracellular estrogen receptors, ERα and ERβ, ERβ is the predominant ER of human scalp skin [203] and is expressed in NHEKs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] Thornton MJ Taylor AH Mulligan K Al-Azzawi F Lyon CC O’Driscoll J Messenger AG Oestrogen receptor beta is the predominant oestrogen receptor in human scalp skin Experimental dermatology 12 2 2003 181 190 12702147

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ERRβ and ERRγ are expressed in human skin and may have a role in cutaneous estrogen signaling.

    “ERRβ and ERRγ, two orphan members of the nuclear receptor superfamily, are expressed in human skin and may also have a role in cutaneous estrogen signaling [217, 218].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [217] Archer DF Postmenopausal skin and estrogen Gynecol Endocrinol 2012 1 5 22849791

      Not checked in the free run.

    • cites [218] Krahn-Bertil E Bolzinger MA Andre V Orly I Kanitakis J Rousselle P Damour O Expression of estrogen-related receptor gamma (ERRgamma) in human skin Eur J Dermatol 18 4 2008 427 432 18573717

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acne pathogenesis is multifactorial, including local sex-hormone hyperproduction or hyperresponsiveness, inflammation, and adaptive immunity defects.

    “Its multifactorial pathogenesis includes local cutaneous sex-hormone hyperproduction or hyperresponsiveness of the epithelial cells involved, inflammatory processes and defects of adaptive immunity [219–224].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [219] Zouboulis CC Eady A Philpott M Goldsmith LA Orfanos C Cunliffe WC Rosenfield R What is the pathogenesis of acne? Experimental dermatology 14 2 2005 143 152 15679586

      Not checked in the free run.

    • cites [220] Zampeli VA Makrantonaki E Tzellos T Zouboulis CC New Pharmaceutical Concepts for Sebaceous Gland Diseases: Implementing Today’s Pre-Clinical Data into Tomorrow’s Daily Clinical Practice Curr Pharm Biotechnol 13 10 2012 1898 1913 22250709

      Not checked in the free run.

    • cites [221] Jeremy AH Holland DB Roberts SG Thomson KF Cunliffe WJ Inflammatory events are involved in acne lesion initiation J Invest Dermatol 121 1 2003 20 27 12839559

      Not checked in the free run.

    • cites [222] Anttila HS Reitamo S Saurat JH Interleukin 1 immunoreactivity in sebaceous glands The British journal of dermatology 127 6 1992 585 588 1476918

      Not checked in the free run.

    • cites [223] Boone DL Lee EG Libby S Gibson PJ Chien M Chan F Madonia M Burkett PR Ma A Recent advances in understandingNF-kappaB regulation Inflamm Bowel Dis 8 3 2002 201 212 11979142

      Not checked in the free run.

    • cites [224] Kang S Cho S Chung JH Hammerberg C Fisher GJ Voorhees JJ Inflammation and extracellular matrix degradation mediated by activated transcription factors nuclear factor-kappaB and activator protein-1 in inflammatory acne lesions in vivo Am J Pathol 166 6 2005 1691 1699 15920154 PMC1602424

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Apocrine and eccrine glands express ERβ but not ERα.

    “Apocrine and eccrine glands also express ERβ, but not ERα [74, 207, 208].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [74] Zouboulis CC Chen WC Thornton MJ Qin K Rosenfield R Sexual hormones in human skin Hormone and metabolic research = Hormon-und Stoffwechselforschung = Hormones et metabolisme 39 2 2007 85 95 17326004

      Not checked in the free run.

    • cites [207] Beier K Ginez I Schaller H Localization of steroid hormone receptors in the apocrine sweat glands of the human axilla Histochem Cell Biol 123 1 2005 61 65 15609040

      Not checked in the free run.

    • cites [208] Thornton MJ Taylor AH Mulligan K Al-Azzawi F Lyon CC O’Driscoll J Messenger AG The distribution of estrogen receptor beta is distinct to that of estrogen receptor alpha and the androgen receptor in human skin and the pilosebaceous unit J Investig Dermatol Symp Proc 8 1 2003 100 103 12895004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both ERα and ERβ are immunohistochemically detected in human sebocytes in situ, with ERα restricted to basal sebocytes.

    “Both receptors have been immunohistochemically detected in human sebocytes in situ, but ERα was restricted in basal sebocytes [206].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] 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 52 3 2005 317 325 16006726

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Corticosteroids are one of the main medications used for lupus erythematosus.

    “Corticosteroids are one of the main medications used for treatment [4, 247].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Bolognia J Jorizzo JL Rapini RP Dermatology Elsevier 2008

      Not checked in the free run.

    • cites [247] Liu Z Davidson A Taming lupus-a new understanding of pathogenesis is leading to clinical advances Nat Med 18 6 2012 871 882 22674006 PMC3607103

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Defective angiogenesis, neointimal proliferation, and vascular spasm contribute to tissue hypoxia, which further stimulates extracellular matrix deposition in systemic sclerosis.

    “Defective angiogenesis, neointimal proliferation and vascular spasm contribute to tissue hypoxia further stimulating ECM deposition [252].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [252] Pattanaik D Brown M Postlethwaite AE Vascular involvement in systemic sclerosis (scleroderma) Journal of inflammation research 4 2011 105 125 22096374 PMC3218751

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CYP19A1 gene expression is higher in subcutaneous than omental adipose tissue.

    “Interestingly, CYP19A1 gene expression is higher in subcutaneous than omental adipose tissue [258–260].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [258] Bulun SE Simpson ER Competitive reverse transcription-polymerase chain reaction analysis indicates that levels of aromatase cytochrome P450 transcripts in adipose tissue of buttocks, thighs, and abdomen of women increase with advancing age J Clin Endocrinol Metab 78 2 1994 428 432 8106632

      Not checked in the free run.

    • cites [259] Bujalska IJ Kumar S Stewart PM Does central obesity reflect “Cushing’s disease of the omentum”? Lancet 349 9060 1997 1210 1213 9130942

      Not checked in the free run.

    • cites [260] Kamat A Hinshelwood MM Murry BA Mendelson CR Mechanisms in tissue-specific regulation of estrogen biosynthesis in humans Trends in endocrinology and metabolism: TEM 13 3 2002 122 128 11893526

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In untreated lupus erythematosus patients, 17-hydroxypregnenolone and cortisol levels are similar to controls, while progesterone, 17-hydroxypogesterone, androstenedione, DHEA, and DHEA-S levels are lower.

    “In other studies, untreated LE patients had levels of 17-hydroxypregnenolone and cortisol similar to controls, and levels of progesterone, 17-hydroxypogesterone, androstenedione, DHEA and DHEA-S lower than controls [250].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [250] Vogl D Falk W Dorner M Scholmerich J Straub RH Serum levels of pregnenolone and 17-hydroxypregnenolone in patients with rheumatoid arthritis and systemic lupus erythematosus: relation to other adrenal hormones J Rheumatol 30 2 2003 269 275 12563679

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Systemic sclerosis patients have lower DHEA and higher ACTH levels.

    “Levels of DHEA are lower and of ACTH are higher in SSc patients [254].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [254] Imrich R Lukac J Rovensky J Radikova Z Penesova A Kvetnansky R Huckova M Vigas M Macho L Koska J Lower adrenocortical and adrenomedullary responsesto hypoglycemia in premenopausal women with systemic sclerosis J Rheumatol 33 11 2006 2235 2241 17086608

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stromal cells of adipose tissue express CYP19A1 (aromatase) and provide a source of androgens for both sexes.

    “The stromal cells of adipose tissue express CYP19A1 (aromatase) [256, 257] and provide a source of androgens for both sexes.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [256] Simpson ER Zhao Y Agarwal VR Michael MD Bulun SE Hinshelwood MM Graham-Lorence S Sun T Fisher CR Qin K Mendelson CR Aromatase expression in health and disease Recent Prog Horm Res 52 1997 185 213 discussion 213–184 9238853

      Not checked in the free run.

    • cites [257] Simpson ER Mahendroo MS Means GD Kilgore MW Hinshelwood MM Graham-Lorence S Amarneh B Ito Y Fisher CR Michael MD Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis Endocr Rev 15 3 1994 342 355 8076586

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Glucocorticoid treatment is probably not responsible for the altered steroid levels in lupus erythematosus; abnormal cytokines or a Th17/Th1 imbalance may be responsible.

    “Glucocorticoid treatment seems not to be responsible for these changes but they are possibly due to abnormal cytokine levels or a Th17/Th1 imbalance [248, 249].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [248] Zietz B Reber T Oertel M Gluck T Scholmerich J Straub RH Altered function of the hypothalamic stress axes in patients with moderately active systemic lupus erythematosus. II. Dissociation between androstenedione, cortisol, or dehydroepiandrosterone and interleukin 6 or tumor necrosis factor J Rheumatol 27 4 2000 911 918 10782815

      Not checked in the free run.

    • cites [249] Prado C de Paz B Gomez J Lopez P Rodriguez-Carrio J Suarez A Glucocorticoids enhance Th17/Th1 imbalance and signal transducer and activator of transcription 3 expression in systemic lupus erythematosus patients Rheumatology (Oxford) 50 10 2011 1794 1801 21750002

      Not checked in the free run.

62 of 62

  • The paper relies on this without support.

    Steroidogenesis in non-classical tissues is modest regardless of the stimulant, usually less than 1% of that seen with cAMP/PKA-mediated StAR expression and steroid synthesis in adrenal and gonadal cells.

    “It is noteworthy that steroidogenesis in non-classical tissues is quite modest regardless of the stimulant, usually being less than 1% of that seen with cAMP/PKA mediated StAR expression and steroid synthesis in adrenal and gonadal cells.”

  • The paper relies on this without support.

    Sebocytes normally metabolize testosterone mainly to androstenedione rather than DHT, because low DHT levels are required for skin homeostasis.

    “Sebocytes normally metabolize T mainly to androstenedione, rather than DHT, since low DHT levels are required for skin homeostasis.”

  • The paper relies on this without support.

    ACTH stimulates the cutaneously distributed MC2R to start steroidogenesis leading to cortisol/corticosterone production.

    “ACTH stimulates the cutaneously distributed MC2R to start steroidogenesis leading to cortisol/corticosterone production.”

  • The paper relies on this without support.

    The cutaneous steroidogenic system contributes significantly to circulating androgens and/or estrogens.

    “The cutaneous steroidogenic system can also have systemic effects, which are emphasized by significant skin contribution to circulating androgens and/or estrogens.”

  • The paper relies on this without support.

    Progesterone causes autoimmune progesterone dermatitis only in some women.

    “Progesterone clearly causes this condition only in some women.”

  • The paper relies on this without support.

    UVR reactions of 5–7-dienes produce tachysterol- and lumisterol-like derivatives in addition to vitamin D analogues.

    “It has to be stressed that such reactions lead not only to formation of vitamin D analogues, but also to other tachysterol- and lumisterol-like derivatives.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Aromatase is linked to androgen production despite the paper describing the reverse conversion

    Minor

    The conclusion links CYP19A1 (aromatase) expression in adipose stromal cells to a source of androgens. Earlier, the paper describes aromatase as converting the androgen androstenedione into estrogens, so the stated link points in the opposite direction.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Slominski, 2000, Neuroendocrinology of the skin, Endocrine Reviews, 21, 457
  2. Slominski, 2002, Gas chromatography/mass spectrometry characterization of corticosteroid metabolism in human immortalized keratinocytes, Journal of Investigative Dermatology, 118, 310, 10.1046/j.0022-202x.2001.01648.x · DOI · Paper page
  3. Billich, 2000, Immunohistochemical localization of steroid sulfatase in acne lesions: implications for the contribution of dehydroepiandrosterone sulfate to the pathogenesis of acne, Hormone and metabolic research=Hormon- und Stoffwechselforschung=Hormones et metabolisme, 53, 99
  4. Skobowiat, 2011, Cutaneous hypothalamic–pituitary–adrenal axis homolog: regulation by ultraviolet radiation, American Journal of Physiology – Endocrinology and Metabolism, 301, E484, 10.1152/ajpendo.00217.2011 · DOI · Paper page

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Authors
Slominski, A., Zbytek, B., Nikolakis, G., Manna, P. R., Skobowiat, C., Zmijewski, M., Li, W., Janjetovic, Z., Postlethwaite, A., Zouboulis, C. C., & Tuckey, R. C.
Affiliations
  • University of Tennessee Health Science Center (US)
  • Städtisches Klinikum Dessau (DE)
  • Texas Tech University (US)
  • Gdańsk Medical University (PL)
  • The University of Western Australia (AU)
Corresponding author
Slominski, Andrzej
ORCID
Venue
The Journal of Steroid Biochemistry and Molecular Biology
Publisher
Elsevier BV
Published
2013-09
Volume
137
Pages
107-123
ISSN
0960-0760 (ISSN-L)
DOI
10.1016/j.jsbmb.2013.02.006
PMC
PMC3674137
OpenAlex
W1982421644
Semantic Scholar
4b98bdebedbe73448d089b03924849add29bf4fd
Cited by
369
References
260
Citations by year
2026: 13 · 2025: 17 · 2024: 23 · 2023: 36 · 2022: 28 · 2021: 32 · 2020: 25 · 2019: 21 · 2018: 23 · 2017: 24 · 2016: 38 · 2015: 39 · 2014: 30 · 2013: 18 · 2012: 2
FWCI
6.17
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion)
Funders
  • NIH/NAIMS (R01AR052190, 1R01AR056666-01A2)
  • NSF to ATS (IOS-0918934)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
androgens, estrogen, corticosterone, cortisol, testosterone, dihydrotestosterone, estradiol, corticotropin-releasing factor, ACTH, cytokines, UV-B radiation, CYP11A1, secosteroids, skin immune function, epidermis, adnexal structures, inflammatory skin diseases, autoimmune disease
MeSH terms
Humans, Inflammation, Skin, Steroids

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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