Endocrine Abstracts

Sex development in zebrafish is highly plastic, making this species an ideal model for investigation of endocrine disruption and gonadal development and function. However, the hormonal regulation of these processes in zebrafish is poorly understood. We have used a model of androgen and glucocorticoid deficiency to explore these processes. In humans, ferredoxin (FDX1) is an electron-providing cofactor required for steroid biosynthesis. The zebrafish homologue of FDX1, ...

Background: Congenital adrenal hyperplasia (CAH) is the underlying diagnosis in most newborns presenting with 46,XX disorders of sex development (DSD). Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of CAH caused by inactivating mutations in the POR gene. The hallmark feature of PORD is combined sex-steroid and glucocorticoid deficiency due to impairment of CYP17A1 and CYP21A2. Skeletal malformations resembling the Antley-Bixler Syndrome phenotype are common i...

Congenital adrenal hyperplasia (CAH) is one of the most common inherited disorders. The majority of CAH cases are due to 21-hydroxylase deficiency (21-OHD) caused by mutations in CYP21A2. Because of the profound impact of steroids on physiology and gene expression, the imbalances in steroid hormones resulting from 21-OHD are supposedly leading to a whole-organism response on transcriptome and metabolome level. The systemic consequences of severe 21-OHD during early development...

Steroid hormones are important regulators of many physiological processes. The steroid precursor pregnenolone is converted through several enzymatic steps into all types of steroids, including the stress hormone cortisol. Mitochondrial steroidogenic cytochrome P450 (CYP) enzymes crucially relying on electron transfer from the redox partner ferredoxin (FDX1) are involved in key steps of the cortisol biosynthesis pathway.Cortisol is well-known regulator of...

Introduction: There is evidence that an early morning plasma cortisol (EMC) below <160 nmol/l is predictive of failing the SST and the corollary is seen with an EMC above >340 nmol/l. Using an EMC to screen patients for AI has been advocated, although there is a paucity of paediatric studies. Modern sensitive and specific cortisol assays make deriving local diagnostic thresholds important. We analysed our SST data since the introduction of a new cortisol assay to deriv...

Introduction: Diagnostic cut-offs for plasma cortisol on Short Synacthen Test (SST) are controversial, made more complicated by modern assays and paediatric normative values extrapolated from adult data. Some advocate a division between biochemical and clinical AI, with different cut-offs and management strategies. For asymptomatic children, with a low-index of suspicion, and borderline SST results our department has evolved a tendency to advise hydrocortisone replacement in t...

Background: HbA1c is a marker for the risk of long-term complications of Diabetes. Our unit cares for 349 children and young people (CYP) from a population with a higher than average prevalence of low-income families, ethnic minority families, and high unemployment. Over the last 10 years there have been service improvements, increased resources and changes in practice.Aims: To review HbA1c outcomes achieved annually from 2003, compared with published na...

Disorders of sex development (DSDs) refer to a range of congenital disorders where the chromosomal, gonadal or anatomical sex is atypical. Patients typically present in the newborn period where ambiguous genitalia often prevents immediate gender assignment or during the adolescent period where atypical sexual development becomes apparent. Genetic testing is key in establishing the diagnosis allowing for personalised management of these patients, and can significantly reduce th...

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...

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...