Regulation of human (adrenal) androgen biosynthesis—New insights from novel throughput technology studies

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• 作者：Sameer S. Udhane ; Christa E. Fl&uuml ; ck ; ^{christa.flueck@dkf.unibe.ch" class="auth_mail" title="E-mail the corresponding author} ; ^{christa.flueck@insel.ch" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AKR1C2/4 ; aldo-keto reductase family 1 ; ASK1 ; apoptosis signal-regulated kinase 1 ; ANGPTL1 ; angiopoietin-like protein 1 ; ATRA ; all-trans-retinoic acid ; BMPs ; bone morphogenetic proteins ; C9orf3 ; chromosome 9 open reading frame 3 ; CRH ; corticotropin-releasing hormone ; CFI ; complement factor I ; CYB5 ; cytochrome b5 ; CYP19A1 ; aromatase ; CYP21A2 ; 21-hydroxylase ; DENND1A ; DENN/MADD domain containing 1A ; DHEA ; dehydroepiandrosterone ; DHEA-S ; dehydroepiandrosterone sulfate ; GCNT1 ; glucosaminyl (N-acetyl
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：102
• 期：Complete
• 页码：20-33
• 全文大小：1956 K

文摘

Androgens are precursors for sex steroids and are predominantly produced in the human gonads and the adrenal cortex. They are important for intrauterine and postnatal sexual development and human reproduction. Although human androgen biosynthesis has been extensively studied in the past, exact mechanisms underlying the regulation of androgen production in health and disease remain vague. Here, the knowledge on human androgen biosynthesis and regulation is reviewed with a special focus on human adrenal androgen production and the hyperandrogenic disorder of polycystic ovary syndrome (PCOS). Since human androgen regulation is highly specific without a good animal model, most studies are performed on patients harboring inborn errors of androgen biosynthesis, on human biomaterials and human (tumor) cell models. In the past, most studies used a candidate gene approach while newer studies use high throughput technologies to identify novel regulators of androgen biosynthesis. Using genome wide association studies on cohorts of patients, novel PCOS candidate genes have been recently described. Variant 2 of the DENND1A gene was found overexpressed in PCOS theca cells and confirmed to enhance androgen production. Transcriptome profiling of dissected adrenal zones established a role for BMP4 in androgen synthesis. Similarly, transcriptome analysis of human adrenal NCI-H295 cells identified novel regulators of androgen production. Kinase p38α (MAPK14) was found to phosphorylate CYP17 for enhanced 17,20 lyase activity and RARB and ANGPTL1 were detected in novel networks regulating androgens. The discovery of novel players for androgen biosynthesis is of clinical significance as it provides targets for diagnostic and therapeutic use.