Sebocytes are the Key Regulators of Androgen Homeostasis in Human Skin

Abstract

The mRNA expression patterns of the androgen receptor and the androgen metabolizing enzymes 3beta-hydroxysteroid dehydrogenase/Delta(5-4)-isomerase, 17beta-hydroxysteroid dehydrogenase, 5alpha-reductase, and 3alpha-hydroxysteroid dehydrogenase were investigated in three different cell populations originating from human skin, SZ95 sebocytes, HaCaT keratinocytes, and MeWo melanoma cells, by means of reverse transcription polymerase chain reaction. Restriction analysis of cDNA fragments was performed to identify isozymes of 3beta-hydroxysteroid dehydrogenase/Delta(5-4)-isomerase and 3alpha-hydroxysteroid dehydrogenase. In addition, 3H-dihydroepiandrosterone and 3H-testosterone were used as substrates to determine the metabolic activity of these enzymes in SZ95 sebocytes, primary sebocyte cultures, and HaCaT keratinocytes. Furthermore, the effects of the selective 5alpha-reductase type 1 and 2 inhibitors, 4,7beta-dimethyl-4-aza-5alpha-cholestan-3-one and dihydrofinasteride, respectively, and of the 3beta-hydroxysteroid dehydrogenase/Delta(5-4)-isomerase inhibitor cyproterone acetate on androgen metabolism were investigated. Androgen receptor mRNA was detected in SZ95 sebocytes and HaCaT keratinocytes but not in MeWo melanoma cells, whereas 3beta-hydroxysteroid dehydrogenase/Delta(5-4)-isomerase isotype 1 mRNA and metabolic activity were only found in SZ95 sebocytes. The enzyme activity could be inhibited by cyproterone acetate. Type 2 17beta-hydroxysteroid dehydrogenase, type 1 5alpha-reductase, and 3alpha-hydroxysteroid dehydrogenase mRNA were expressed in all three cell populations tested, whereas type 3 17beta-hydroxysteroid dehydrogenase mRNA could only be detected in SZ95 sebocytes. The major metabolic steps of testosterone in SZ95 sebocytes, primary sebocyte cultures, and HaCaT keratinocytes were its conversion to androstenedione by 17beta-hydroxysteroid dehydrogenase and further to 5alpha-androstanedione by 5alpha-reductase. The type 1 5alpha-reductase selective inhibitor 4,7beta-dimethyl-4-aza-5alpha-cholestan-3-one, but not the type 2 selective inhibitor dihydrofinasteride, inhibited 5alpha-reductase at low concentrations in SZ95 sebocytes and HaCaT keratinocytes. 5alpha-androstanedione was degraded to androsterone by 3alpha-hydroxysteroid dehydrogenase, which exhibited a stronger activity in HaCaT keratinocytes than in SZ95 sebocytes and in primary sebocyte cultures. Lower levels of 5alpha-dihydrotestosterone and 5alpha-androstanediol were also detected in all cells tested. Our investigations show that specific enzyme expression and activity in cultured sebocytes and keratinocytes seem to allocate different duties to these cells in vitro. Sebocytes are able to synthesize testosterone from adrenal precursors and to inactivate it in order to maintain androgen homeostasis, whereas keratinocytes are responsible for androgen degradation.

Corticotropin-releasing hormone: An autocrine hormone that promotes lipogenesis in human sebocytes

“…Indeed, our experiments revealed that CRH induces an early up-regulation of ⌬ 5 -3␤-HSD mRNA expression. Sebocytes are the only human skin cells that express ⌬ 5 -3␤-HSD and, therefore, are able to convert dehydroepiandrosterone to testosterone (14). Androgens play an important role in sebaceous gland growth and differentiation (26), whereas sebaceous gland function is regulated not only by testosterone and 5␣-dihydrotestosterone, but also by dehydroepiandrosterone sulfate, especially in fetal and neonatal life and with the adrenarche (26,27).…”

“…To detect possible mechanisms of stimulation of sebaceous lipid synthesis by CRH, we investigated the hypothesis that CRH may regulate ⌬ 5 -3␤-HSD, which is the key enzyme for testosterone synthesis in human sebocytes (14). By using real time quantitative RT-PCR of ⌬ 5 -3␤-HSD mRNA levels, CRH was found to exhibit an early up-regulation of ⌬ 5 -3␤-HSD mRNA levels at 6 h (P Ͻ 0.01), which was abolished later (at 12 h) (Fig.…”

“…CRH synthesis in human sebocytes and its control of lipogenesis led us to assess the presence of a feedback mechanism that may involve CRH-R. To investigate this hypothesis, real time quantitative RT-PCR of CRH-R1 and CRH-R2 mRNA levels was performed after treatment of SZ95 sebocytes with CRH, GH, and testosterone, also shown to up-regulate sebaceous lipogenesis (15,16), DHEA and 17␤-estradiol, up-stream and down-stream metabolites of testosterone, respectively (14). CRH was found not to modify mRNA levels of its receptors (Fig.…”

Virilism and Ectopic Expression of HSD17B5 in Mature Cystic Teratoma

“…Several previous pathological studies of sebaceous glands suggest a possible role for alterations of intracrine pathways in various human skin disorders, particularly acne (Thiboutot et al 1998, Fritsch et al 2001). In addition, steroidogenic enzymes including HSD17B5 have been reported in human skin (Azmahani et al 2014).…”

The experience in the use of topical retinoids and azelaic acid in therapy of acne

“…Предпочтение в этом случае отдается топическим ретиноидам, которые воздействуют на процессы дифференцирования фолликулярного эпителия, тормозят пролиферацию себоцитов, угнетают про-дукцию кожного сала и уменьшают воспалительные явления [7,8]. По мнению ведущих экспертов [7,10], топические ретиноиды (преимущественно тре-тьего поколения, такие как адапален), обладающие улучшенной переносимостью, являются препарата-ми выбора или имеют высокую и среднюю степень рекомендаций. Данные литературы [7][8][9] показы-вают высокую эффективность и широкие возмож-ности применения азелаиновой кислоты в лечении акне.…”