Endocrine Abstracts

Many endocrine disorders exhibit a distinctive biochemical or clinical phenotype and I will illustrate how our research has provided novel genetic and physiological insights into hormone action in the human context. Isolated deficiency of follicle stimulating hormone (FSH), due to loss-of-function mutations in the FSHβ subunit gene, presents with primary amenorrhoea or male infertility. In females, ovarian follicles are preserved and treatment with exogenous FSH induces conception readily, whereas male azoospermia persists following FSH therapy, indicating that deficiency of this hormone is more deleterious for testicular than ovarian development.

We have identified mutations in the DNA binding domain of thyroid transcription factor 2 (TTF-2), resulting in a distinctive, syndromic form of congenital hypothyroidism with thyroid dysgenesis, cleft palate, bifid epiglottis, choanal atresia and spiky hair, suggesting that TTF-2 plays an important role in both thyroid and extrathyroidal development. Resistance to Thyroid Hormone (RTH), due to dominant negative thyroid hormone β receptor mutations, is characterised by elevated thyroid hormones and detectable TSH levels, but pre-receptor defects can also mediate this biochemical phenotype. The features of RTH include both hyperthyroid responses and resistance, delineating the relative roles of α versus β receptors in human target tissues.

Defects in the peroxisome proliferator-activated receptor (PPAR) γ gene, acting via different molecular mechanisms, are associated with severe insulin resistance: dominant negative receptor mutants, either interacting aberrantly with transcriptional corepressors or sequestering coactivators, inhibit normal PPARγ function; receptor haploinsufficency, when combined with either a second gene (PPP1R3A) defect or overnutrition, results in a metabolic phenotype. Delineating how reduced adipose tissue mass (lipodystrophy) and function contribute to the pathogenesis of this disorder may enhance understanding of commoner forms of metabolic syndrome.