GnRH is the proximate regulator of reproduction. GnRH, a C-terminal amidated decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), is found in a small number of neurons that are located diffusely throughout the anterior hypothalamus in primates (1). GnRH neurons send axons through subventricular and periventricular pathways to terminate in the capillary space within the median eminence. GnRH from these axons enters the capillaries and is transported in the hypothalamic portal blood to the cells of the anterior pituitary.
Many factors influence the amount of GnRH that is secreted. GnRH mRNA levels are determined by the transcription rate of the pro-GnRH gene, which is controlled by the POU-homeodomain protein, Oct-1, adhesion-related kinase (Ark), and retinoid-X receptors, among other factors (2). Studies in GT1-7 cells, a GnRH-producing murine neuronal cell line, suggest that mRNA stability also plays an important role in maintaining GnRH gene expression. GnRH mRNA levels increase in the hypothalamus of adult male monkeys after bilateral orchidectomy (3), indicating that the testis secretes endocrine hormones, presumably testosterone, that suppress GnRH gene expression. GnRH mRNA transcription produces a pro-GnRH precursor, and yet another control level in GnRH neurons involves the posttranslational processing of the inactive precursor to the active decapeptide. Subsequent to its secretion, peptidases in the median eminence inactivate and thereby further regulate the GnRH concentration.
GnRH, like most hypophysiotropic peptides, is released into the portal blood in bursts. The average GnRH concentration in hypothalamic portal blood (in rams) is approx 20 pg/mL (0.02 nM), and levels in conscious sheep ranged from nadir values of less than 5 pg/mL to pulse peak values of approx 30 pg/ml (4). In those studies, the amplitudes of GnRH pulses in intact, castrated, and testosterone-replaced rams were roughly equivalent; by contrast, GnRH pulse frequency was higher in castrates than in intact animals, and was reduced by testosterone replacement. The implication of those observations is that GnRH secretion rises with testosterone deficiency, primarily because GnRH pulse frequency is accelerated.
GnRH pulse frequency is controlled by the "GnRH pulse generator," the term used to describe the highly synchronized firing of GnRH neurons in the mediobasal hypothalamus (MBH). The belief that changes in cell membrane potentials predispose to bursts of GnRH release is based on the finding that bursts of electrical activity in the MBH in the nonhuman primate coincide with LH secretion pulses (5). The coincident firing of multiple GnRH-expressing neurons may reflect communication by gap junctions, through interneurons, or second messengers. The identification of GnRH-recep-tors on GnRH neurons and the observation that adding GnRH to GnRH neuronal cultures depresses GnRH pulsatile release provide a possible framework for intraneuronal communication by GnRH (6). Experiments using various 5' deletion constructs of the GnRH promoter-luciferase vector suggest that episodic GnRH gene expression is a promoter-dependent event that is mediated by Oct-1 (7).
As shown in Fig. 1, GnRH release is influenced by multiple neurotransmitters, including glutamate, y-aminobutyric acid (GABA), neuropeptide Y, opiates, dopamine, norepinephrine, cyclic adenosine monophosphate (cAMP), and nitric oxide (8). The presence of receptors on GnRH neurons for most of these substances implies that they directly influence GnRH neurons. N-methyl-D-aspartate (NMDA) receptors that medi-
ate glutamate GnRH activation may involve the nitric oxide signaling pathway. Neurotransmitters with receptors that are not expressed on GnRH neurons may regulate GnRH via synaptic connections between GnRH neurons and other interneurons. GnRH secretion regulation may also occur directly on neuronal axon terminals that abut on capillaries in the median eminence.
A second form of GnRH, GnRH-2 (9,10) that was initially identified in nonverte-brates, is also found in the primate brain (11). GnRH-2 activates a unique GnRH-II receptor (12) but this receptor is not expressed in humans (13). Thus, the significance of GnRH-2 in humans is not yet known.
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