Neuroendocrine control of gonadotropin-releasing hormone: Pulsatile and surge modes of secretion

Abstract

The concept that different systems control episodic and surge secretion of gonadotropin-releasing hormone (GnRH) was well established by the time that GnRH was identified and formed the framework for studies of the physiological roles of GnRH, and later kisspeptin. Here, we focus on recent studies identifying the neural mechanisms underlying these two modes of secretion, with an emphasis on their core components. There is now compelling data that kisspeptin neurons in the arcuate nucleus that also contain neurokinin B (NKB) and dynorphin (i.e., KNDy cells) and their projections to GnRH dendrons constitute the GnRH pulse generator in mice and rats. There is also strong evidence for a similar role for KNDy neurons in sheep and goats, and weaker data in monkeys and humans. However, whether KNDy neurons act on GnRH dendrons and/or GnRH soma and dendrites that are found in the mediobasal hypothalamus (MBH) of these species remains unclear. The core components of the GnRH/luteinising hormone surge consist of an endocrine signal that initiates the process and a neural trigger that drives GnRH secretion during the surge. In all spontaneous ovulators, the core endocrine signal is a rise in estradiol secretion from the maturing follicle(s), with the site of estrogen positive feedback being the rostral periventricular kisspeptin neurons in rodents and neurons in the MBH of sheep and primates. There is considerable species variations in the neural trigger, with three major classes. First, in reflex ovulators, this trigger is initiated by coitus and carried to the hypothalamus by neural or vascular pathways. Second, in rodents, there is a time of day signal that originates in the suprachiasmatic nucleus and activates rostral periventricular kisspeptin neurons and GnRH soma and dendrites. Finally, in sheep nitric oxide-producing neurons in the ventromedial nucleus, KNDy neurons and rostral kisspeptin neurons all appear to participate in driving GnRH release during the surge.

Keywords: GnRH pulses; GnRH surge; KNDy neurons; kisspeptin; steroid feedback.

FIGURE 1

Schematic illustrating the role of kisspeptin neurons in the control of pulsatile and surge secretion of gonadotropin-releasing hormone (GnRH) in mice and rats. Arcuate nucleus (ARN) kisspeptin (KNDy) neurons (green) are an interconnected network that fires synchronously to release kisspeptin on to GnRH (blue) dendrons and drive GnRH and luteinising hormone (LH) pulses (green at bottom) at a constant frequency during most of the estrous cycle. Rostral periventricular area of the third ventricle (RP3V) kisspeptin neurons (red) are stimulated by rising titers of estradiol on proestrus and triggered by a signal from the suprachiasmatic nucleus (not shown) to stimulate GnRH cells bodies to release GnRH during the LH surge (red at bottom) on the afternoon of proestrus. Note that, although KNDy neurons are considered to be the GnRH pulse generator in other species, they may act not solely on GnRH dendrons, but rather on cell bodies in the mediobasal hypothalamus (for details, see text)

FIGURE 2

Schematic representation of core components of the gonadotropin-releasing hormone (GnRH) surge generator in reflex ovulators (top), rats and mice (middle), and sheep (bottom). In many reflex ovulators, GnRH release is triggered by a coitus, which acts via noradrenergic (NE) neurons (red) in the brain stem to stimulate rostral kisspeptin (green) neurons (musk shrew) and/or GnRH (blue) neurons in the preoptic area (POA) (rabbits) or mediobasal hypothalamus (MBH) (ferrets). Note that, although Fos expression increases in rostral kisspeptin neurons in the musk shrew, there is no direct evidence that this reflects noradrenergic input as indicated by the question mark on this pathway. Ovarian estradiol facilitates this pathway by acting on NE neurons and likely other neurons in the hypothalamus. In other reflex ovulators, nerve growth factor (NGF) in the semen is carried via the blood stream to stimulate GnRH secretion by mechanisms that remain to be determined. In rodents (middle), estradiol acts on kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V), which transmits a daily signal from the suprachiasmatic nucleus (SCN) to GnRH cells bodies to drive the preovulatory GnRH surge. Vasoactive intestinal peptide (VIP)-containing neurons from the suprachiasmatic nucleus (SCN) to GnRH neurons may also facilitate this process. In sheep (bottom), estradiol acts on ventromedial nucleus (VMN) neurons that produce nitric oxide and somatostatin (orange), immediately activating KNDy cells (i.e., cells containing kisspeptin, neurokinin B and dynorphin) (purple). This sets in motion unknown processes that, approximately 20 h later, activate these two neural populations and rostral kisspeptin neurons to drive the GnRH surge. Note that the somatostatin (SST)/neuronal nitric oxide (nNOS) neurons likely project to POA GnRH neurons, although this connection has been omitted for simplicity and because these studies used SST, not SST/nNOS, to identify these close contacts. AVP, arginine vasopressin; E₂, estradiol; OCh, optic chiasm; Pit, pituitary