Endocrine Abstracts

Hypothesis: Exogenous kisspeptin-10 (Kp10) enhances pulsatile LH. Research strategy: A first-in-man dosing study of kp10 was first performed. Healthy volunteers and hypogonadal patients were subsequently infused with kp10. Dose titration study Rapid increases in LH with clear dose-dependency (P<0.0001) were observed in healthy men (n=6), with the 0.3 and 1 µg/kg doses being maximally stimulatory (P<0.01). Effect of sex-steroid milieu: LH respo...

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor with an extracellular bilobed venus flytrap domain (VFTD) predicted to contain five calcium-binding sites. The major site for calcium-binding is comprised of amino acid residues that line the cleft between the two lobes of the VFTD. We investigated the structure-function relationships of VFTD CaSR mutations identified in patients with familial hypocalciuric hypercalcaemia (FHH), neonatal severe primary hyperpa...

T3-action is regulated by three iodothyronine deiodinases, which contain selenium in the active site. It is proposed that Se availability regulates thyroid function. OPUS is a European population-based prospective cohort study of post-menopausal women in which we showed thyroid function within the upper normal range is associated with reduced bone mineral density (BMD) and increased non-vertebral fracture risk. Using strict exclusion criteria we defined reference ranges for th...

Corepressors and coactivators of thyroid hormone receptor-mediated function facilitate repression and transactivation of positively-regulated target genes respectively, but their role in negative regulation is not understood. A 13 yr old boy, born at 31 weeks gestation, was jittery at birth, with neonatal respiratory distress. Childhood features included poor weight gain, heat intolerance, tachycardia and hyperactivity. Ongoing problems are low frequency hearing loss, poor sig...

Introduction: Thyroid hormones act via receptors encoded by different genes (THRA and THRB) generating receptor subtypes (TRα1, TRβ1, TRβ2) with differing, tissue-specific expression. Resistance to Thyroid Hormone due to THRB defects is well recognised, but no THRA mutations have yet been reported. We describe the first case of human TRα-mediated thyroid hormone resistance due to a dominant negative THRA mutation.Results: A 6-year-old...

Background: Familial Glucocorticoid Deficiency is an autosomal recessive disorder characterised by ACTH resistance of the adrenal cortex, leading to isolated glucocorticoid deficiency. Causative genes include MC2R, its accessory protein MRAP and StAR which account for 50% of cases. Recently nicotinamide nucleotide transhydrogenase (NNT) has been associated with a further 10% of cases. NNT generates the high concentrations of NADPH in mitochondria necessary for detoxification o...

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...

The metastasis related methyltransferase 1 (Merm1), originally designated WBSCR22, is implicated in cancer through H3K9 methylation and silencing of the tumour-suppressor Zac1 gene. Activated GR is a transcription factor with chromatin remodelling activity, and so the functional interaction between GR, and Merm1 was determined. Merm1 consistently potentiated GR transactivation of TAT3-Luc in HeLa cells. This was dependent on the SAM and methyltransferase domains of Merm1. Merm...