Endocrine Abstracts

The gonadotropin-releasing hormone (GnRH) neurons are key cells regulating fertility in all mammals including humans. They release GnRH in an episodic manner to drive the pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone critical for gonadal function. Remarkably, the GnRH neurons are not born in the brain but arise from the nose and migrate into the brain during early embryogenesis. This unique origin engenders a variety of unusual and unique properties in the GnRH neuron. Foremost is their scattered location throughout the basal forebrain from where they send projections to the median eminence at the base of the brain to release GnRH into the pituitary portal system. Again, remarkably, this projection is not an axon but a blended process called a ‘dendron’ with unique properties of both dendrites and axons. Decades of study have focused upon defining the special characteristics of the GnRH neuron that may underlie their ability to generate pulsatile GnRH secretion. By and large, this has been unsuccessful. The discovery in 2003 of key role for kisspeptin in human fertility and pulsatile gonadotrophin secretion provided an important clue suggesting that an external neuronal input to the GnRH neuron may be critical for pulsatility. Since that time, studies in genetically-manipulated mouse models have addressed the role of kisspeptin neurons in pulse generation using a range of cellular approaches combined with the latest optogenetic techniques enabling high precision investigations in vivo. Together, these studies have identified the GnRH pulse generator as being a population of kisspeptin neurons located in the hypothalamic arcuate nucleus that exhibit synchronized episodes of activity which activate the GnRH neuron dendron to evoke pulsatile LH secretion. This represents an unusual and unexpected mechanism of generating pulsatile hormone secretion and opens up new possibilities for the manipulation of fertility in the clinic.