Endocrine Abstracts

In women, gonadotropin releasing hormone (GnRH) is secreted from the hypothalamus and conveyed via the portal vasculature to the anterior pituitary gland every 60-90 minutes. This binds GnRH receptor and triggers pulsatile release of gonadotrophin hormones, Follicle stimulating and Luteinising hormone (FSH and LH), which stimulate and regulate folliculogenesis. The interdependence of these events accounts for the high number of cycling disorders in women, and the origin of the primary defect, whether hypothalamic, pituitary or ovarian can be difficult to determine.

We focus on the molecular regulation of gonadotrophin gene expression, and previously characterised GnRH-regulation of Fanconi anaemia A (FAA) mRNA and protein expression in gonadotrophs. FAA mRNA is up-regulated 2 fold 1-2h after addition of GnRH. Furthermore, FAA protein was found to redistribute after hormonal stimulation. Western blotting analysis of nuclear and cytosolic LbetaT2 gonadotroph cellular extracts localised FAA primarily to the nucleus in the absence of GnRH. After addition of GnRH FAA protein was detected in both nuclear and cytoplasmic cellular compartments. Therefore, the presence or absence of FAA in the nucleus may impact on GnRH regulation of gonadotrophin gene expression and suggests a pivotal role for FAA in regulating the GnRH response in gonadotrophs. Indeed, co-transfection of a FAA expression construct with gonadotrophin subunit gene promoters into LbetaT2 cells had profound effects on the GnRH-regulated expression of alpha-subunit, some effect on LH beta and no effect on FSH beta.

In conclusion, FAA is highly regulated by GnRH, and in turn regulates gonadotrophin gene promoter GnRH responsiveness. FAA may have a role in regulating fertility, since gene targeting in mice progressively reduced fecundity.