Searchable abstracts of presentations at key conferences in endocrinology

ea0044p29 | Adrenal and Steroids | SFEBES2016

Oestrogen excess induces instability and loss of arterial identity in the forming vascular system

Parajes Silvia , Stainier Didier

Disturbed oestrogen homeostasis is associated with an increased risk of cardiovascular disease. However, the impact of dysregulated oestrogen signalling on vascular development, maintenance and disease is not fully understood. Zebrafish is a well-established model in translational vascular research. In addition, oestrogen receptor expression and oestrogen-responsiveness in endothelial cells (EC) is conserved in zebrafish. Therefore, the aim of this study was to characterise th...

ea0034oc3.2 | Steroids | SFEBES2014

5α-reductase is a regulator of glucocorticoid action and metabolic phenotype in human liver

Nasiri Maryam , Nikolaou Nikolaos , Parajes Silvia , Bujalska Iwona , Gathercole Laura , Tomlinson Jeremy

Patients with GC excess (Cushing’s syndrome) develop central obesity, insulin resistance and hepatic steatosis. The A-ring reductases (5α-reductase type 1 (5αR1) and 2 (5αR2)) generate dihydrotestosterone from testosterone, but importantly also inactivate cortisol and are highly expressed in human liver. We propose that 5αR may regulate GC exposure and therefore may modulate metabolic phenotype in human liver.Primary human hepato...

ea0033p53 | (1) | BSPED2013

Rapid molecular genetic diagnosis aiding personalised treatment of 5-α reductase type 2 deficiency

Kumaran Anitha , Parajes Silvia , Cole Trevor R , Hogler Wolfgang , Kirk Jeremy , Krone Nils

Introduction: Steroid 5-α reductase type 2 deficiency causes 46,XY disorder of sex development (DSD) and is an autosomal recessive disorder resulting from mutations in the SRD5A2 gene. SRD5A2 facilitates the conversion of testosterone to dihydrotestosterone (DHT), crucially required for masculinisation of external genitalia. Thus 46,XY individuals with SRD5A2 mutations present with varying severity of undermasculinisation.We descri...

ea0031p321 | Steroids | SFEBES2013

The zebrafish ferredoxin orthologue Fdx1b is essential for the redox regulation of interrenal steroidogenesis in larvae and adult fish

Griffin Aliesha , Parajes Silvia , Taylor Angela , Shackleton Cedric , Mueller Ferenc , Krone Nils

Mitochondrial steroidogenic cytochrome P450 (CYP) enzymes, such as P450 side-chain cleavage, rely on electron transfer from the redox partner ferredoxin (FDX1) for catalytic activity. Previous in vitro data suggest these cofactors are key regulators of CYP enzyme activity. This study aims to establish the role of redox regulation on steroidogenesis using zebrafish as a vertebrate in vivo model.In contrast to humans, zebrafish have two F...

ea0028p309 | Steroids | SFEBES2012

Modifying impact of 17-hydroxyprogesterone and sex steroids on mineralocorticoid receptor transactivation by aldosterone

Mooij Christiaan , Parajes Silvia , Arlt Wiebke , Claahsen-van der Grinten Hedi , Krone Nils

Context: Congenital adrenal hyperplasia (CAH) is caused by 21-hydroxylase deficiency in 95% of the cases. This leads to accumulation of steroid precursors prior to the enzymatic block and increased adrenal androgen production; accordingly serum concentrations of 17-hydroxyprogesterone (17OHP), androstenedione and testosterone are elevated in affected patients.Objective: To analyse the effect of 17OHP, androstenedione and testosterone on aldosterone-media...

ea0021p364 | Steroids | SFEBES2009

Functional characterisation of 21-hydroxylase gene mutations is a valuable tool for genetic counselling: in vitro and in silico analysis of six novel CYP21A2 sequence variants

Parajes Silvia , Loidi Lourdes , Dhir Vivek , Morey Marcos , Dominguez Fernando , Arlt Wiebke , Krone Nils

Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency (21OHD) is the commonest inborn error in steroid biosynthesis. It is caused by mutations in the 21-hydroxylase gene (CYP21A2). A good genotype–phenotype correlation exists allowing for prediction of the expressed adrenal phenotype. We performed functional and structural analysis of six novel CYP21A2 variants (p.Trp22Cys; p.Asp184Asn; p.Leu198Phe; p.Val305Gly; p.His310Asn; p.Thr443Asn), i...

ea0034p363 | Steroids | SFEBES2014

Androgen receptor over expression drives lipid accumulation in human hepatocytes

Nikolaou Nikolaos , Nasiri Maryam , Gathercole Laura , Castro Silvia Parajes , Krone Nils , Valsamakis George , Mastorakos George , Tomlinson Jeremy

Non-alcoholic fatty liver disease NAFLD has been associated with androgen deficiency, yet in the majority of patients with non-alcoholic steatohepatitis NASH, androgens levels are normal. In contrast, women with polycystic ovarian syndrome PCOS, which is characterised by androgen excess, have evidence of increased liver fat. Our hypothesis is that androgen exposure to the liver may be crucial in the amount of lipid that can accumulate in hepatocytes. C3A human hepatoma cells w...

ea0031p319 | Steroids | SFEBES2013

Identification of a duplicated P450 side-chain cleavage enzyme (zCyp11a2) defines initiation and maintenance of steroidogenesis in zebrafish

Parajes Silvia , Griffin Aliesha , Taylor Angela , Shackleton Cedric , Miguel-Escalada Irene , Arlt Wiebke , Mueller Ferenc , Krone Nils

Zebrafish has emerged as an important vertebrate in vivo model to study human disease. Steroidogenesis in zebrafish is not well characterised. Human CYP11A1 (hCYP11A1) catalyses the first step of steroidogenesis, the conversion of cholesterol to pregnenolone. Zebrafish Cyp11a1 (zCyp11a1) is essential during embryogenesis. Published data suggest that zCyp11a1 facilitates steroidogenesis in the interrenal (equivalent to mammalian adrenal), gonad and brain. We identified...

ea0028oc1.7 | Young Endocrinologists prize session | SFEBES2012

Progressive adrenal insufficiency and 46,XY DSD caused by two novel mutations in the cytochrome P450 side-chain cleavage (CYP11A1) gene

Parajes Silvia , Chan Angel , But Betty , Rose Ian , Taylor Angela , Griffin Aliesha , Dhir Vivek , Arlt Wiebke , Krone Nils

Cytochrome P450 side-chain cleavage enzyme (CYP11A1) catalyses the first and rate-limiting step of steroidogenesis. CYP11A1 firstly converts cholesterol into 22R-hydroxycholesterol, which relies on mitochondrial steroidogenic acute regulatory protein (StAR)-mediated cholesterol import. Two further StAR-independent CYP11A1 reactions facilitate pregnenolone biosynthesis. CYP11A1 deficiency is rare and manifests with adrenal insufficiency (AI), and, in 46,XY individuals, with nor...

ea0025oc2.5 | Steroids | SFEBES2011

A novel entity of isolated adrenal insufficiency caused by partial inactivation of P450 side-chain cleavage (CYP11A1) enzyme

Parajes Silvia , Kamrath Clemens , Rose Ian , Taylor Angela , Mooij Christiaan , Dhir Vivek , Grotzinger Joachim , Arlt Wiebke , Krone Nils

Cytochrome P450 side-chain cleavage enzyme (CYP11A1) catalyses the first and rate-limiting step of steroidogenesis, facilitating conversion of cholesterol to pregnenolone. Cholesterol, transported by steroidogenic acute regulatory protein (StAR) into the inner mitochondrial membrane, is converted by CYP11A1 into 22R-hydroxycholesterol. Subsequently, CYP11A1 converts 22R-hydroxycholesterol by 20alpha-hydroxylation and cleavage of the C20–C22 bond into pregnenolone. All pat...