hrp0082p3-d2-967 | Sex Development (1) | ESPE2014

Phenotypic and Genotypic Variability of Patients with 5-α Reductase Type 2 Deficiency

Hu Kun , Krone Nils , Kirk Jeremy

Background: Steroid 5-α reductase type 2 (SRD5A2) deficiency is an rare inherited disorder resulting from mutations in the SRD5A2 gene, causing 46,XY DSD (Disorder of Sex Development). The mutated SRD5A2 enzyme can no longer convert testosterone to dihydrotestosterone, which is needed for virilisation of external genitalia.Objective and hypotheses: To describe the phenotype, investigations and management of SRD5A2 deficiency.<p class="a...

hrp0082fc1.3 | Adrenal | ESPE2014

Genetic Engineering Using TALENs to Study the Redox Regulation of Steroidogenesis in vivo

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

Background: Transcription activator-like effects nucleases (TALENs) have recently been developed as an efficient method for in vivo genome engineering. Zebrafish are becoming an increasingly popular model to study translational aspects in endocrinology. The redox cofactor ferredoxin (FDX1) is essential for mitochondrial cytochrome P450 (CYP) enzymes including those required for steroidogenesis. In vitro, FDX1 modifications influence the catalytic rate of ster...

hrp0092fc10.1 | Sex Differentiation, Gonads and Gynaecology or Sex Endocrinology | ESPE2019

Investigating the Roles of Androgens in Male Reproductive Development, Maintenance and Function by Characterisation of Androgen and Cortisol Deficient 11ß-Hydroxylase Mutant Zebrafish Lines

Oakes James A , Storbeck Karl-Heinz , Cunliffe Vincent T , Krone Nils P

The zebrafish is established as an important model system for studying development and disease, and characterisation of the developmental and functional roles of steroids is crucial for its effective employment in this remit. Whilst oestrogens are known to be essential for female development in zebrafish, the roles of androgens in the development, maintenance and function of the male reproductive system remain unclear.In order to investigate these proces...

hrp0092fc15.3 | Late Breaking Abstracts | ESPE2019

The P450 Side-Chain Cleavage Isozyme Cyp11A2 Facilitates Interrenal and Gonadal Steroid Hormone Biosynthesis in Developing and Adult Zebrafish

Li Nan , Oakes James A , Storbeck Karl-Heinz , Cunliffe Vincent T , Krone Nils P

Cytochrome P450 side-chain cleavage enzyme, encoded by the CYP11A1 gene, catalyzes the first and rate-limiting step of steroid hormone biosynthesis. Previous morpholino knockdown studies described the divergent functions of the two cyp11a paralogs in zebrafish. Cyp11a1 has been suggested to be required for early development, whereas cyp11a2 is a functional equivalent of human CYP11A1 and is essential for the initiation and maintenan...

hrp0089fc8.6 | Sex differentiation, Gonads and Gynaecology or Sex Endocrinology | ESPE2018

The Roles of Steroids in Gonadal Development and Maintenance – Insights from a Zebrafish Model of Androgen and Cortisol Deficiency

Oakes James A. , Li Nan , Wistow Belinda , Storbeck Karl-Heinz , Cunliffe Vincent T. , Krone Nils

Increasing evidence suggests that the aetiology of disorders of sex development cannot be solely explained by genetic alterations. It is highly likely that environmental factors hitting susceptible genetic backgrounds are partly causative. Zebrafish sex is highly plastic during development, 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...

hrp0089fc14.4 | Multisystem Endocrine Disorders | ESPE2018

Glucocorticoid Deficiency Causes Differentially Dysregulated Oxidative Stress Depending on the Steroidogenic Defects

Li Nan , Weger Meltem , Griffin Aliesha , Eachus Helen , Cunliffe Vincent T , Krone Nils

Glucocorticoids regulate a wide range of biological processes including metabolism. Patients with adrenal insufficiency show impaired glucocorticoid biosynthesis either caused by adrenal defects (primary adrenal insufficiency) or by defects in the pituitary gland or hypothalamus (secondary or tertiary adrenal insufficiency). The systemic consequences of differentially disrupted steroid hormone biosynthesis remain unclear. Increasing evidence suggested steroid hormone precursor...

hrp0089p1-p009 | Adrenals and HPA Axis P1 | ESPE2018

The Relationship of Baseline, Incremental and Peak Cortisol Following a Short Synacthen Test – Single-centre Analysis of Three Years’ Data

Aji Apoorva , Colyer Sharon , Burn Sarah , Dimitri Paul , Wright Neil , Krone Nils , Elder Charlotte

Introduction: The Short Synacthen Test (SST) is the most popular diagnostic investigation of adrenal insufficiency (AI) amongst adult and paediatric endocrinologists. AI can present insidiously and symptoms may be non-specific. The number of medical indications for glucocorticoids is growing and SST usage is correspondingly increasing. There is evidence that an early morning plasma cortisol (EMC) of below ~100–150 nmol/l is highly predictive of failing the SST and the cor...

hrp0089p2-p021 | Adrenals and HPA Axis P2 | ESPE2018

Borderline Peak Plasma Cortisol Following Synacthen Stimulation – Single-centre Analysis of Three Years Data

Burn Sarah , Colyer Sharon , Dimitri Paul , Wright Neil , Krone Nils , Elder Charlotte

Introduction: The Short Synacthen Test (SST) is the most popular diagnostic investigation of adrenal insufficiency (AI) worldwide. Symptoms of AI are frequently non-specific, often delaying diagnosis, however fortunately cases of adrenal crisis remain relatively rare. Diagnostic cut-offs for plasma cortisol on SST are controversial, made more complicated by modern assays and paediatric normative values extrapolated from adult data. Some advocate a division between biochemical ...

hrp0089p1-p220 | Sex Differentiation, Gonads and Gynaecology or Sex Endocrinology P1 | ESPE2018

Pitfalls in the Diagnosis of An Infant with 46,XX DSD with Congenital Adrenal Hyperplasia due to Cytochrome P450 Oxidoreductase Deficiency – the Value of Simultaneous Genetic Analysis to the Diagnosis in DSD

Idkowiak Jan , Mohamed Zainaba , Allen Stephanie , Chandran Harish , McCarthy Liam , Kirk Jeremy , Cole Trevor , Krone Nils

Introduction: 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. POR is a crucial electron donor to all microsomal type 2 P450 cytochromes (CYPs), including 21-hydroxylase (CYP21A2) and 17alpha-hydroxylase (CYP17A1). The hallmark feature of PORD is combined sex-steroid a...

hrp0086rfc1.2 | Adrenals | ESPE2016

Glucocorticoid Deficiency Due to Disruption of Mitochondrial Steroidogenesis Leads to Dysregulation of Antioxidant Pathways and Nucleotide Biosynthesis

Weger Meltem , Gorling Benjamin , Poschet Gernot , Griffin Aliesha , Hell Rudiger , Luy Burkhard , Muller Ferenc , Krone Nils

Glucocorticoids are important regulators of systemic homeostasis. However, the role of these steroid hormones has been mainly studied by using synthetic glucocorticoids or in states of glucocorticoid excess. Thus, the pathophysiologic consequences of cortisol deficiency on metabolic and biosynthesis pathways remain largely elusive. Zebrafish is a well-established vertebrate model for studying whole organism biology. Similar to humans, zebrafish are day active and the key gluco...