Endocrine Abstracts

The androgen receptor (AR) is the conduit for androgen-induced fetal male sex differentiation, the acquisition of secondary sexual characteristics at male puberty and subsequently, the onset of spermatogenesis. The AR is expressed ubiquitously in early fetal development to permit male sex differentiation to occur: stabilisation of the Wolffian ducts to form the vas deferens, epididymis and seminal vesicles and morphogenesis of the genital tubercle and folds to form the penis, ...

Gender or sex assignment is instantaneous at birth in the vast majority of infants. Rarely, the external genitalia are sufficiently ambiguous to render an assignment impossible and genetic, hormonal and radiological investigations are necessary before a decision can be reached about the sex of rearing. The commonest cause of such ambiguous genitalia is adrenal 21-hydroxylase deficiency (congenital adrenal hyperplasia) leading to virilisation of an affected female newborn. The ...

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder affecting adrenal steroid biosynthesis.For the paediatric endocrinologist,the presentation is at birth manifest as ambiguous genitalia in girls and as salt loss in both sexes.The affected male has normal external genitalia and the salt loss is delayed until the second week of life.Hence,a life threatening salt-losing crisis may occur accounting for the sex imbalance of this disorder in the past.Several cou...

Wolffian duct (WD) development is believed to be testosterone dependent. However, patients with complete androgen insensitivity syndrome (CAIS) and a causative mutation in the androgen receptor (AR) still develop WDs. Exceptions to this observation are those patients with severe N-terminal mutations. We investigated the role of the AR in WD development in these patients.AR expression in genital skin fibroblasts (GSF) from eleven patients with CAIS was studied by Western hy...

Sex differentiation is the development of the internal and external genitalia following gonad determination. Genital ridge formation is regulated by WT1, SF1 and LHX9 whereas SRY is a major player in testis determination. Quite how SRY functions as a transcription factor is still unknown twelve years after the (i)SRY(/i) gene was cloned. How testis determination is regulated is incomplete, as the cause of sex reversal is unknown in the majority of patients with XY gonadal dysg...

The Androgen Receptor (AR) is a ligand dependent transcription factor that regulates the development and maintenance of the male reproductive system. Previous studies in AIS have demonstrated ligand binding domain mutations resulting in decreased trans-activation activity through reduced N-terminal/C-terminal interaction of the AR, despite unaltered ligand binding ability.We have introduced mutations in the hinge region of the Androgen Receptor (AR) and assessed the effect...

Hormonal activation of the androgen receptor plays a critical role in male fetal sex differentiation.Current hypotheses concerning estrogen/androgen balance and the role of estrogenic environmental contaminants have led us to investigate the capacity for androgenic/antiandrogenic activity in such chemicals. We have previously developed a sensitive in vitro assay using a telomerase-immortalised human cell line capable of detecting putative endocrine disrupting activi...

Complete androgen insensitivity syndrome (CAIS), is generally caused by a mutation in the androgen receptor (AR) gene. In sequencing genomic DNA from patients with CAIS, we identified 7 novel mutations in the AR. Their effects on AR function are speculated in relation to AR functional domains and crystal structure. Local Ethical Committee approval was obtained for the use of patient samples.Exon 1 mutations, Q86X and Y480X, are located in the transactiv...

Biochemical assessment of control of CAH includes measurement of adrenal-derived androgens in blood. Some androgens like 17-hydroxyprogesterone (17OHP) have a diurnal rhythm and show a widespread of values in well controlled children. Testosterone in children (except pubertal boys) may be useful in monitoring control as it may reflect the potential for androgen action better than weaker androgens. Our salivary testosterone (SalT) assay measures free testosterone and is sensiti...

Neonates harbouring germline gain-of-function TSHR mutations (M453T, L629F) have been reported with transient proptosis. This resolves once euthyroidism is achieved. In contrast children expressing TSHR mutations (V597L, I486T) fail to thrive, with weight gain and height between the 0.4th and 2nd centiles. We have previously demonstrated TSHR expression in preadipocytes undergoing adipogenesis. We now investigate the consequences of constitutively active TSHR mutation expressi...