Abstract
This review recounts the origins and development of the concept of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator. It starts in the late 1960s when striking rhythmic episodes of luteinizing hormone secretion, as reflected by circulating concentrations of this gonadotropin, were first observed in monkeys and ends in the present day. It is currently an exciting time witnessing the application, primarily to the mouse, of contemporary neurobiological approaches to delineate the mechanisms whereby Kiss1/NKB/Dyn (KNDy) neurons in the arcuate nucleus of the hypothalamus generate and time the pulsatile output of kisspeptin from their terminals in the median eminence that in turn dictates intermittent GnRH release and entry of this decapeptide into the primary plexus of the hypophysial portal circulation. The review concludes with an examination of questions that remain to be addressed.
Highlights
This review recounts the origins and development of the concept of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator
Any further responses from the reviewers can be found at the end of the article Introduction The intermittent or pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus into the hypophysial portal circulation is obligatory for driving gonadotropin secretion from the anterior pituitary and for gonadal development and maturation, puberty, and fertility in adulthood[1]
Knobil’s group later reported, again in the ovariectomized rhesus monkey, that discrete bilateral radiofrequency lesions of the arcuate nucleus at the base of the third ventricle abolished luteinizing hormone (LH) secretion but that larger lesions of the mediobasal hypothalamus (MBH) that spared this nucleus were noticeably less disruptive[11]. These findings suggested that the arcuate nucleus, which is located immediately dorsal to the primary plexus of the hypophysial portal circulation, was essential for generating the intermittent GnRH signals driving pulsatile LH release
Summary
F1000 Faculty Reviews are written by members of the prestigious F1000 Faculty. They are commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. Activation was proposed to trigger synaptic release of neurokinin B within the nucleus, which in turn would amplify and synchronize firing by the network, resulting in the output of kisspeptin in the median eminence; this view is consistent with later findings that the action of neurokinin B to elicit GnRH-dependent LH discharges in the monkey lies upstream of KISS1R63 and that intracerebroventricular (ICV) administration of TAC3R agonists in the rat and ewe induced the expression of FOS in KNDy neurons[64,65]. Additional studies that examine the action of continuous kisspeptin administration in models that employ a different approach to abrogating the intermittent kisspeptin output of the pulse generator (for example, KNDy neuron ablation or silencing) are likely to be helpful In this regard, in the anestrous ewe, pulsatile GnRH release is greatly repressed by seasonal cues, but Caraty et al.[37] were unable to induce pulsatile LH secretion in such a model by a 4-hour infusion of kisspeptin. There are differences between the ovine models used by the groups of Clarke[123] and Caraty[37], a potential explanation to reconcile the contradictory results is not forthcoming at present
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