Endocrine Abstracts

The past decade has seen significant advances in our understanding of the molecular mechanisms of pituitary development and function. However, relatively few gonadotrope specific factors have been identified to date. Through characterization of patients with endocrine disorders as well as transgenic mice, it has emerged that the nuclear receptor transcription factors SF-1 and DAX-1 play an important role in the regulation of gonadotrope activity. SF-1 (NR5A1) activates multiple genes involved in adrenal, gonadal and reproductive function and may represent a major “switch” in gonadotrope development during pituitary cellular differentiation. Targeted deletion of the gene encoding Sf-1 in mice results in variable forms of gonadotropin insufficiency. However, elucidating the exact contribution of SF-1 to gonadotrope function is complicated by the effects of SF-1 at other levels of the hypothalmo-pituitary(gonadotrope)-gonadal (HPG) axis. Nevertheless, certain patients with SF-1 mutations likely have abnormal gonadotrope function, and new insights into possible cell-specific signalling- and ligand-dependent interactions of SF-1 raises the possibility that more diverse phenotypes associated with SF-1 changes could exist. In contrast, the association of hypogonadotropic hypogonadism with X-linked adrenal hypoplasia (AHC) due to mutations in the related nuclear receptor DAX-1 (NR0B1) is well established. More than 150 patients or families with this condition have been identified, including a patient presenting with a predominantly reproductive phenotype. Whilst impaired pubertal development is a central feature of X-linked AHC, the HPG axis is often intact in early childhood and some individuals with DAX-1 mutations may even show signs of sexual precocity. Such HPG “activation” could be consistent with the model of DAX-1 as a functional repressor of SF-1, but the exact effects of DAX-1 in gonadotrope function remain unclear, and potential insight from Dax1 transgenic mice is influenced by the oestrogenic effects of aromatase excess. Thus, although SF-1 and DAX-1 clearly influence gonadotrope function, much remains to be learned about the exact role of these factors in pituitary pathophysiology.