Endocrine Abstracts

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...

In humans, androgen synthesis crucially depends on the enzyme CYP17A1 expressed in adrenals and gonads. The 17,20 lyase activity of CYP17A1 catalyses the key step in human androgen biosynthesis, the conversion of 17-hydroxypregnenolone to the universal sex steroid precursor dehydroepiandrosterone (DHEA). For its catalytic activity, CYP17A1 requires electron transfer from P450 oxidoreductase (POR). Mutations in CYP17A1 and POR are known to disrupt human androgen s...

Background: Adrenal insufficiency is a well-recognised feature of congenital adrenal hyperplasia (CAH).CAH is commonly treated with oral steroid replacement, taken 2–3 times a day, at doses that aim to reproduce normal diurnal variation. Though acceptable for most patients, this does not control others, resulting in high levels of 17-hydroxyprogesterone-acetate (17OHP), ACTH, and the need for increased doses of steroid replacement, with associated c...

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...

Congenital adrenal hyperplasia (CAH) caused by mutations in the electron donor enzyme P450 oxidoreductase (POR) is unique amongst all CAH variants in that it can be associated with ambiguous genitalia (disordered sex differentiation, DSD) both in 46,XX and 46,XY individuals. POR has a pivotal role in facilitating electron transfer from NADPH to microsomal P450 enzymes, including CYP17, which catalyses a key step in human androgen synthesis, the conversion of 17-hydroxypregneno...

P450 oxidoreductase (POR) has a pivotal role as electron donor to all cytochrome P450 enzymes that are microsomally located, i.e. CYP type II enzymes. Importantly, those include key enzymes involved in glucocorticoid and sex steroid biosynthesis such as CYP17 and CYP21. In addition, the activity of hepatic CYP enzymes involved in drug metabolism and detoxification also crucially depend on the transfer of electrons from NADPH via POR. Recently, mutations in P450 oxidoreductase ...

Background: Management of patients with CAH remains challenging. There is increasing evidence to suggest that failure to optimize treatment during childhood not only affects final height but also leads to psychological and psychiatric problems. Previous qualitative structural T2-weighted MRI studies have identified white matter hyper-intensities in up to 46% of CAH patients. The nature and functional relevance of these abnormalities remains unknown.Objec...

Background: Mutations of 21-hydroxylase (CYP21A2) cause congenital adrenal hyperplasia. Its severe (classic) form constitutes a life-threatening disease. Patients suffer a significant disease burden due to co-morbidities that are often treatment-related. The current therapeutic situation is unsatisfying and demands novel treatment approaches. In silico modelling suggests protein misfolding and intracellular retention to play a significant role in the pathogenesis of C...

Background: Treatment of congenital adrenal hyperplasia (CAH) in childhood focuses on growth and development; however the relationship of childhood treatment with adult health outcomes is not established. We explored this by examining relationships between final height (FH) and cardiometabolic risk in CAH adults.Methods: Cross-sectional analysis of 65 men (80% salt wasting (SW) and 20% non-SW) and 134 women (74% SW and 26% non-SW), aged 18–69 years....

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...