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The biological significance of 11β-hydroxyandrostenedione (11OHA4) has eluded researchers for the past six decades. It is now known that 11OHA4 is biosynthesized in the androgen arm of the adrenal steroidogenesis pathway and subsequently metabolized by steroidogenic enzymes in vitro, serving as precursor to recognized and novel androgenic steroids. These in vitro findings extend beyond the adrenal, suggesting that 11OHA4 could be metabolized in steroid-responsive peripheral tissues, as is the case for androgen precursor metabolites of adrenal origin. The significance thereof becomes apparent when considering that the metabolism of 11OHA4 in LNCaP androgen dependent prostate cancer cells yields androgenic steroid metabolites. It is thus possible that 11OHA4 may be metabolized to yield ligands for steroid receptors in not only the prostate but also in other steroid-responsive tissues. Future investigations of 11OHA4 may therefore characterize it as a vital steroid with far-reaching physiological consequences. An overview of the research on 11OHA4 since its identification in 1953 will be presented, with specific focus on the most recent works that have advanced our understanding of its biological role, thereby underscoring its relevance in health and disease.

Abstract: We have previously revealed that treating pregnant rats with 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) reduces the expression of gonadotropins and growth hormone (GH) in the fetal and neonatal pituitary. A change in gonadotropin expression impairs the testicular expression of steroidogenic proteins in perinatal pups, and imprint defects in sexual behavior after reaching maturity. In this study, we examined whether TCDD also affects the expression of gonadotropin and GH in mice using C57BL/6J and DBA/2J strains which express the aryl hydrocarbon receptor (Ahr) exhibiting a different affinity for TCDD. When pregnant C57BL/6J mice at gestational day (GD) 12 were given oral TCDD (0.2–20μg/kg), all doses significantly attenuated the pituitary expression of gonadotropin mRNAs in fetuses at GD18. On the other hand, in DBA/2J mice, a much higher dose of TCDD (20μg/kg) was needed to produce a significant attenuation. Such reduction in the C57BL/6J strain continued until at least postnatal day (PND) 4. In agreement with this, TCDD reduced the testicular expression of steroidogenic proteins in C57BL/6J neonates at PND2 and 4, although the same did not occur in the fetal testis and ovary. Furthermore, TCDD reduced the perinatal expression of GH, litter size and the body weight of newborn pups only in the C57BL/6J strain. These results suggest that 1) also in mice, maternal exposure to TCDD attenuates gonadotropin-regulated steroidogenesis and GH expression leading to the impairment of pup development and sexual immaturity; and 2) Ahr activation during the late fetal and early postnatal stages is required for these defects. [Copyright &y& Elsevier]

Abstract: SMP-028 is a drug candidate developed for the treatment of asthma. In a 13-week repeated dose toxicity study of SMP-028 in rats and monkeys, differences of endocrine toxicological events between rats and monkeys were observed. In rats, these toxicological events mainly consisted of pathological changes in the adrenal, testis, ovary, and the other endocrine-related organs. On the other hand, in monkeys, no toxicological events were observed. The goal of this study is to try to understand the reason why only rats, but not monkeys, showed toxicological events following treatment with SMP-028 and to eventually predict the possible toxicological effect of this compound on human endocrine organs. Our results show that SMP-028 inhibits neutral cholesterol esterase more strongly than other steroidogenic enzymes in rats. Although SMP-028 also inhibits monkeys and human neutral cholesterol esterase, this inhibition is much weaker than that of rat neutral cholesterol esterase. These results indicate (1) that the difference in endocrine toxicological events between rats and monkeys is mainly due to inhibition of steroidogenesis by SMP-028 in rats, not in monkeys, and (2) that SMP-028 may not affect steroidogenesis in humans and therefore might cause no endocrine toxicological events in clinical studies. [Copyright &y& Elsevier]

Highlights: [•] The HPA axis is a complex neuroendocrine loop that integrates stressor-related information. [•] Sex differences in the HPA axis arise through effects of gonadal steroid hormones. [•] Estrogen can alter HPA function though divergent actions mediated by ERalpha and ERbeta. [•] Androgens inhibit HPA function through actions at the androgen receptor or ERbeta. [ABSTRACT FROM AUTHOR]

Highlights: [•] A schema of all possible porcine steroid biosynthesis pathways is proposed. [•] Transcripts and genomic sequences for 32 genes in the pig are provided. [•] The transcript and genomic sequence of the unique pig CYP11B gene is provided. [•] Pig genes included in AKR1 cluster are characterized. [•] Steroid biosynthesis pathways in boars and in humans are compared. [ABSTRACT FROM AUTHOR]

Highlights: [•] DEHP and MEHP cause reproductive dysfunction in marine medaka. [•] DEHP and MEHP disturb the sex hormone balance. [•] DEHP and MEHP induce liver vitellogenin in male and change gonad histology. [•] DEHP and MEHP change the gene expressions of genes along the HPG axis. [•] The toxicity effects of DEHP are induced by DEHP itself and DEHP metabolites. [Copyright &y& Elsevier]

Abstract: Breast and prostate constitute organs of intense steroidogenic activity. Clinical and epidemiologic data provide strong evidence on the influence of androgens and estrogens on the risk of typical hormone-dependent malignancies, like breast and prostate cancer. Recent studies have focused on the role of androgen metabolites in regulating androgen concentrations in hormone-sensitive tissues. Steroid glucuronidation has been suggested to have a prominent role in controlling the levels and the biological activity of unconjugated androgens. It is well-established that serum levels of androgen glucuronides reflect androgen metabolism in androgen-sensitive tissues. Quantitative analysis of androgen metabolites in blood specimens is the only minimally invasive approach permitting an accurate estimate of the total pool of androgens. During the past years, androgen glucuronides analysis most often involved radioimmunoassays (RIA) or direct immunoassays, both methods bearing serious limitations. However, recent impressive technical advances in mass spectrometry, and particularly in high performance liquid chromatography coupled with mass spectrometry (LC–MS/MS), have overcome these drawbacks enabling the simultaneous, quantitative analysis of multiple steroids even at low concentrations. Blood androgen profiling by LC–MS/MS, a robust and reliable technique of high selectivity, sensitivity, specificity, precision and accuracy emerges as a promising new approach in the study of human pathology. The present review offers a contemporary insight in androgen glucuronides profiling through the application of LC–MS/MS, highlighting new perspectives in the study of steroids and their implication in hormone-dependent malignancies. [Copyright &y& Elsevier]

Highlights: [•] Extraadrenal de novo glucocorticoid synthesis has been identified in various organs. [•] The locally produced glucocorticoids usually act in a paracrine or autocrine manner. [•] Locally produced glucocorticoids influence cell differentiation and inflammation. [•] In the thymus both thymic epithelial cells and thymocytes produce glucocorticoids. [•] Local glucocorticoid production is suggested to affect thymic homeostasis. [ABSTRACT FROM AUTHOR]

The biological significance of 11β-hydroxyandrostenedione (11OHA4) has eluded researchers for the past six decades. It is now known that 11OHA4 is biosynthesized in the androgen arm of the adrenal steroidogenesis pathway and subsequently metabolized by steroidogenic enzymes in vitro, serving as precursor to recognized and novel androgenic steroids. These in vitro findings extend beyond the adrenal, suggesting that 11OHA4 could be metabolized in steroid-responsive peripheral tissues, as is the case for androgen precursor metabolites of adrenal origin. The significance thereof becomes apparent when considering that the metabolism of 11OHA4 in LNCaP androgen dependent prostate cancer cells yields androgenic steroid metabolites. It is thus possible that 11OHA4 may be metabolized to yield ligands for steroid receptors in not only the prostate but also in other steroid-responsive tissues. Future investigations of 11OHA4 may therefore characterize it as a vital steroid with far-reaching physiological consequences. An overview of the research on 11OHA4 since its identification in 1953 will be presented, with specific focus on the most recent works that have advanced our understanding of its biological role, thereby underscoring its relevance in health and disease. [ABSTRACT FROM AUTHOR]

Abstract: DAX1 is an orphan nuclear receptor with actions in mammalian sex determination, regulation of steroidogenesis, embryonic development and neural differentiation. Conserved patterns of DAX1 gene expression from mammals to fish have been taken to suggest conserved function. In the present study, the European sea bass, Dicentrarchus labrax, DAX1 promoter was isolated and its conserved features compared to other fish and mammalian DAX1 promoters in order to derive common regulators and functional gene networks. Fish and mammalian DAX1 promoters share common sets of transcription factor frameworks which were also present in the promoter region of another 127 genes. Pathway analysis clustered these into candidate gene networks associated with the fish and mammalian DAX1. The networks identified are concordant with described functions for DAX1 in embryogenesis, regulation of transcription, endocrine development and steroid production. Novel candidate gene network partners were also identified, which implicate DAX1 in ion homeostasis and transport, lipid transport and skeletal development. Experimental evidence is provided supporting roles for DAX1 in steroid signalling and osmoregulation in fish. These results highlight the usefulness of the in silico comparative approach to analyse gene regulation for hypothesis generation. Conserved promoter architecture can be used also to predict potentially new gene functions. The approach reported can be applied to genes from model and non-model species. [Copyright &y& Elsevier]

Abstract: Steroidogenic acute regulatory protein (StAR) mRNA levels in the eel ovary were assayed by quantitative PCR and related to plasma steroid levels throughout oogenesis in order to shed light on the previously considered ‘aberrant’ prematurational increase in plasma levels of estradiol-17β (E2). Total ovarian StAR transcript abundance mirrored circulating levels of E2, but not of 11-ketotestosterone (11KT). The study was complemented by evaluation of in vitro effects of follicle-stimulating hormone (FSH) on ovarian StAR transcript abundance and on short-term (‘acute’) radiolabelled pregnenolone-supported steroid metabolism by ovarian fragments to understand how the production of steroids during previtellogenic oocyte growth is regulated. We observed a significant effect of FSH on StAR mRNA levels within 24h of incubation, but these were no longer evident by 4 days of culture. Unexpectedly, FSH had no effect on substrate-supported steroidogenesis, as comparable yields of steroid products were detected using semi-quantitative HPLC and scintillation counting. We conclude that the eel ovarian follicle can respond to FSH from a very early stage of development (early oil droplet stage) by increasing StAR mRNA levels, but that there is no evidence for acute effects of FSH on bioactive steroid production downstream of cytochrome P450 side-chain cleavage. Furthermore, the prematurational increase in StAR mRNA in vivo is in keeping with general teleost models and is likely to be a ‘normal’ response to reaching advanced stages of development. [Copyright &y& Elsevier]

Highlights: [•] TGFβ1 increased human prostate stromal cell metabolism of DHEA to androgens. [•] Androstenedione and testosterone accumulated over time with increasing doses of TGFβ1. [•] TGFβ1 altered stromal cell expression of 3βHSD, and 17βHSD2 and 17βHSD5. [•] TGFβ1 did not increase androgen metabolism in prostate cancer cells (LAPC4). [•] Inflammation in prostate microenvironment may also increase androgenic metabolites. [ABSTRACT FROM AUTHOR]

Highlights: [•] Androgen deprivation therapy (ADT) is an effective treatment for prostate cancer. [•] We present a method for quantification of free and conjugated keto-androgens using SID-LC/ESI/SRM/MS. [•] This method was validated using standards set by the United States Food and Drug Administration (US FDA). [•] This was applied to patients enrolled in the Targeted Androgen Pathway Suppression (TAPS) clinical trial. [•] The method can be used to interrogate personalized response and resistance to ADT. [ABSTRACT FROM AUTHOR]

Abstract: 3-Hydroxyhexobarbital dehydrogenase (3HBD) catalyzes NAD(P)+-linked oxidation of 3-hydroxyhexobarbital into 3-oxohexobarbital. The enzyme has been thought to act as a dehydrogenase for xenobiotic alcohols and some hydroxysteroids, but its physiological function remains unknown. We have purified rabbit 3HBD, isolated its cDNA, and examined its specificity for coenzymes and substrates, reaction directionality and tissue distribution. 3HBD is a member (AKR1C29) of the aldo-keto reductase (AKR) superfamily, and exhibited high preference for NADP(H) over NAD(H) at a physiological pH of 7.4. In the NADPH-linked reduction, 3HBD showed broad substrate specificity for a variety of quinones, ketones and aldehydes, including 3-, 17- and 20-ketosteroids and prostaglandin D2, which were converted to 3α-, 17β- and 20α-hydroxysteroids and 9α,11β-prostaglandin F2, respectively. Especially, α-diketones (such as isatin and diacetyl) and lipid peroxidation-derived aldehydes (such as 4-oxo- and 4-hydroxy-2-nonenals) were excellent substrates showing low K m values (0.1–5.9μM). In 3HBD-overexpressed cells, 3-oxohexobarbital and 5β-androstan-3α-ol-17-one were metabolized into 3-hydroxyhexobarbital and 5β-androstane-3α,17β-diol, respectively, but the reverse reactions did not proceed. The overexpression of the enzyme in the cells decreased the cytotoxicity of 4-oxo-2-nonenal. The mRNA for 3HBD was ubiquitously expressed in rabbit tissues. The results suggest that 3HBD is an NADPH-preferring reductase, and plays roles in the metabolisms of steroids, prostaglandin D2, carbohydrates and xenobiotics, as well as a defense system, protecting against reactive carbonyl compounds. [Copyright &y& Elsevier]

Abstract: Bile acids, bile alcohols, and hormonal steroids represent the ultimate biologically active products of cholesterol metabolism in vertebrates. However, intermediates in their formation, including oxysterols and cholestenoic acids, also possess known, e.g., as ligands to nuclear and G-protein-coupled receptors, and unknown regulatory activities. The potential diversity of molecules originating from the cholesterol structure is very broad and their abundance in biological materials ranges over several orders of magnitude. Here we describe the application of enzyme-assisted derivatization for sterol analysis (EADSA) in combination with liquid chromatography–electrospray ionization–mass spectrometry to define the oxysterol and cholestenoic acid metabolomes of human plasma. Quantitative profiling of adult plasma using EADSA leads to the detection of over 30 metabolites derived from cholesterol, some of which are ligands to the nuclear receptors LXR, FXR, and pregnane X receptor or the G-protein-coupled receptor Epstein–Barr virus-induced gene 2. The potential of the EADSA technique in screening for inborn errors of cholesterol metabolism and biosynthesis is demonstrated by the unique plasma profile of patients suffering from cerebrotendinous xanthomatosis. The analytical methods described are easily adapted to the analysis of other biological fluids, including cerebrospinal fluid, and also tissues, e.g., brain, in which nuclear and G-protein-coupled receptors may have important regulatory roles. [Copyright &y& Elsevier]

Abstract: Hypoxia modulates the production of proteins involved in e.g. inflammation, angiogenesis and glucose utilization and hypoxia may therefore be an important factor underlying adipose tissue dysfunction in obesity. Resveratrol (RSV) is a natural polyphenolic compound and has been shown to have powerful anti-inflammatory effects and beneficial effects on several obesity-related complications. Thus, in the present study we investigated whether RSV has effects on hypoxic markers (GLUT-1, VEGF), hypoxia-induced key markers of inflammation (IL8, IL6), and leptin in human adipose tissue in vitro. Hypoxia was induced by incubating human adipose tissue fragments with 1% O2 for 24h as compared to 21% O2 The gene expressions were investigated by RT-PCR and protein release by Elisa. Hypoxia increases the expression of glucose transporter-1 (GLUT-1) (19-fold, p <0.001), vascular endothelial growth factor (VEGF) (10-fold, p <0.05), interleukin-8 (IL8) (8-fold, p <0.05), interleukin-6 (IL6) (5-fold, p <0.05) and leptin (9-fold). The protein levels of VEGF released to the medium was increased (8-fold, p <0.01) by hypoxia. RSV dose-dependently inhibited several of these hypoxia-induced expressions and at a concentration of 50μM RSV almost completely inhibited the hypoxic responses at the above mentioned gene expression levels (p <0.05–p <0.001) and significantly attenuated the hypoxia-induced protein releases by 50–60%. These results demonstrate that hypoxia induces extensive changes in human adipose tissue in the expression and release of inflammation and angiogenesis-related adipokines. In addition the inhibition of hypoxia-mediated inflammation and angiogenesis might represent a novel mechanism of RSV in preventing obesity-related pathologies. [Copyright &y& Elsevier]

Abstract: The effect of glycyrrhetinic acid (GA) and GA-derivatives towards 11β-hydroxysteroid dehydrogenase (11β-HSD) was investigated. Novel compounds with modifications at positions C-3, C-11 and C-29 of the GA skeleton were prepared. Single crystal X-ray diffraction data of selected substances are reported and discussed. [Copyright &y& Elsevier]

Abstract: Zearalenone (ZEA) is a mycoestrogen found in diverse food and feed materials, particularly in corn and small grains. Following ingestion, the parent zearalenone is converted predominantly into α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL) by hepatic hydroxy steroid dehydrogenases (HSD). The present study demonstrated by standard RT-PCR the expression of 3α- and 3β-HSD also in porcine cumulus oocyte complexes (COCs) and granulosa cells isolated form cumulus oocyte complexes. Analysis of the rate of bioconversion of zearalenone (ZEA) by the cultured granulose cells showed the extra-hepatic production of both hydroxy metabolites of ZEA with α-ZOL being the dominating metabolites as previously observed in incubations with liver microsomes. The endogenous steroids 5α-dihydrotestosterone (5α-DHT), and progesterone (PGTN), both known substrates for 3α-HSD inhibited the conversion of ZEA into α-ZOL. In the presence of pregnelonone (PGN), a major substrate for 3β-HSD only a slight inhibitory effect on the apparent β-ZOL formation could be observed. In conclusion, these data indicate that both 3α- and 3β-HSDs are expressed in porcine COCs and GCs, whereas the biotransformation experiments confirm the involvement of these enzymes in the extra-hepatic biotransformation of ZEA. [Copyright &y& Elsevier]

Abstract: The steroids allopregnanolone and allotetrahydrodeoxycorticosterone (3α,5α-THDOC) are positive allosteric modulators of GABAA receptors, generated by the reduction of 5α-dihydroprogesterone (5α-DHP) and 5α-DHDOC, respectively, under the catalysis of human type 3 3α-hydroxysteroid dehydrogenase (HSD). However, brain enzymes catalyzing the conversion of such tetrahydrosteroids back to the corresponding 5α-dihydrosteroids remain to be identified. Characterization of human type 10 17β-HSD provides a new insight into its importance for the oxidation of steroid modulators of GABAA receptors. The apparent catalytic efficiency (kcat/Km) of this enzyme for the oxidation of allopregnanolone and 3α,5α-THDOC are 432 and 1381min-1mM-1, respectively. This enzyme has negligible 3-ketosteroid reductase activity for 5α-DHP and 5α-DHDOC even in an acidic environment. Immunoreactivity against 17β-HSD10 was found in a number of neuronal populations. Taken together, evidence suggests that 17β-HSD10 is the brain enzyme capable of catalyzing the oxidation of steroid modulators of GABAA receptors. [Copyright &y& Elsevier]

Separate genes encode the human type 1 (placenta, breast tumors, other peripheral tissues) and type 2 (gonad, adrenal) isoforms of 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD1, 3β-HSD2). Mutagenesis of 3β-HSD1 produced the Y154F, H156Y and K158Q mutant enzymes in the probable Y154-P-H156-S-K158 catalytic motif. The H156Y mutant of the 3β-HSD1 created a chimera of the 3β-HSD2 motif (Y154-P-Y156-S-K158) in 3β-HSD1. The D241N, D257L, D258L and D265N mutants are in the potential isomerase site of the 3β-HSD1 enzyme. Homology modeling with UDP-galactose-4-epimerase predicted that Asp36 in the Rossmann-fold domain is responsible for the NAD(H) specificity of human 3β-HSD1, and our D36A/K37R mutant tested that assignment. The H156Y mutant of the 3β-HSD1 enzyme shifted the substrate (DHEA) kinetics to the 14-fold higher Km value measured for the 3β-HSD2 activity. From Dixon analysis, epostane inhibited the 3β-HSD1 activity with 17-fold greater affinity compared to 3β-HSD2 and H156Y. The mutants of Tyr154 and Lys158 exhibited no dehydrogenase activity and appear to be catalytic 3β-HSD residues. The D257L and D258L mutations eliminated isomerase activity, suggesting that Asp257 or Asp258 may be catalytic residues for isomerase activity. The D36A/K37R mutant shifted the cofactor preference of both 3β-HSD and isomerase from NAD(H) to NADP(H). In addition to characterizing catalytic residues, these studies have identified the structural basis (His156) for an exploitable difference in the substrate and inhibition kinetics of 3β-HSD1 and 3β-HSD2. Hence, it may be possible to selectively inhibit human 3β-HSD1 to slow the growth of hormone-sensitive breast tumor cells and control placental steroidogenesis near term to prevent premature labor. [Copyright &y& Elsevier]

Four soluble human 3α-hydroxysteroid dehydrogenase (HSD) isoforms exist which are aldo–keto reductase (AKR) superfamily members. They share 86% sequence identity and correspond to: AKR1C1 (20α(3α)-HSD); AKR1C2 (type 3 3α-HSD and bile-acid binding protein); AKR1C3 (type 2 3α-HSD and type 5 17β-HSD); and AKR1C4 (type 1 3α-HSD). Each of the homogeneous recombinant enzymes are plastic and display 3-, 17- and 20-ketosteroid reductase and 3α- 17β- and 20α-hydroxysteroid oxidase activities with different kcat/Km ratios in vitro. The crystal structure of the AKR1C2·NADP+·ursodeoxycholate complex provides an explanation for this functional plasticity. Ursodeoxycholate is bound backwards (D-ring in the A-ring position) and upside down (β-face of steroid inverted) relative to the position of 3-ketosteroids in the related rat liver 3α-HSD (AKR1C9) structure. Transient transfection indicates that in COS-1 cells, AKR1C enzymes function as ketosteroid reductases due to potent inhibition of their oxidase activity by NADPH. By acting as ketosteroid reductases they may regulate the occupancy of the androgen, estrogen and progesterone receptors. RT-PCR showed that AKRs are discretely localized. AKR1C4 is virtually liver specific, while AKR1C2 and AKR1C3 are dominantly expressed in prostate and mammary gland. AKR1C genes are highly conserved in structure and may be transcriptionally regulated by steroid hormones and stress. [Copyright &y& Elsevier]

Recent studies have revealed the presence of intracellular lipid droplets in wide variety of species. In mammalian cells, there exist proteins specifically localize in lipid droplets. However, the protein profile in the droplet remains yet to be clarified. In this study, a fraction enriched with lipid droplets was isolated from a human hepatocyte cell line HuH7 using sucrose density gradient centrifugation, and 17 major proteins in the fraction were identified using nano LC-MS/MS techniques. Adipose differentiation-related protein (ADRP) was the most abundant protein in the fraction. The secondary abundant proteins were identified to be acyl-CoA synthetase 3 (ACS3) and 17β-hydroxysteroid dehydrogenase 11 (17βHSD11). Included in the identified proteins were five lipid-metabolizing enzymes as well as two lipid droplet-specific proteins. When HuH7 cell lysate was fractionated by a density gradient, most of 17βHSD11 was found in the droplet-enriched fraction. In immunocytochemical analysis, 17βHSD11 showed ring-shaped images which overlapped with those for ADRP. These results suggest that a specific set of proteins is enriched in the lipid droplet-enriched fraction and that 17βHSD11 localizes specifically in the fraction. [Copyright &y& Elsevier]

In vitro enzyme assays have demonstrated that human type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10) catalyzes the oxidation of 5α-androstane-3α,17β-diol (adiol), an almost inactive androgen, to dihydrotestosterone (DHT) rather than androsterone or androstanedione. To further investigate the role of this steroid-metabolizing enzyme in intact cells, we produced stable transfectants expressing 17β-HSD10 or its catalytically inactive Y168F mutant in human embryonic kidney (HEK) 293 cells. It was found that DHT levels in HEK 293 cells expressing 17β-HSD10, but not its catalytically inactive mutant, will dramatically increase if adiol is added to culture media. Moreover, certain malignant prostatic epithelial cells have more 17β-HSD10 than normal controls, and can generate DHT, the most potent androgen, from adiol. This event might promote prostate cancer growth. Analysis of the 17β-HSD10 sequence shows that this enzyme does not have any ER retention signal or transmembrane segments and has not originated by divergence from a retinol dehydrogenase. The data suggest that the unique mitochondrial location of this HSD [Eur. J. Biochem. 268 (2001) 4899] does not prevent it from oxidizing the 3α-hydroxyl group of a C19 sterol in living cells. The experimental results lead to the conclusion that mitochondrial 17β-HSD10 plays a significant part in a non-classical androgen synthesis pathway along with microsomal retinol dehydrogenases. [Copyright &y& Elsevier]