Puberty in humans is comprised of two developmental processes; namely, gonadarche and adrenarche. Of the two, gonadarche is fundamentally the most important, and this review examines the neurobiological mechanisms that first prevent, and later trigger, progression into this critically important phase of human development when the ability to first reproduce is established. The review draws extensively upon results obtained by studies of the rhesus monkey (Macaca mulatta), a representative higher primate which, like man, exhibits a postnatal pattern in activity of the hypothalamic-pituitary-gonadal axis that is characterized by a prolonged period of relative quiescence from late infancy until the initiation of the pubertal process. The proximate cause of the prepubertal quiescence in this neuroendocrine axis is the arrest or restraint of the pulsatile mode of hypothalamic GnRH release by a neurobiological brake that holds in check release of this decapeptide, without seeming to down-regulate the transcriptional activity of the gene encoding GnRH (GnRH-I). Thus, if neurogenomes control the onset of gonadarche, they must reside upstream from that of the GnRH neuron. The genetic and physiological factors (with a particular emphasis on leptin) that time the application and duration of the prepubertal brake on GnRH release are also considered.
Neuropeptide Y1-36 (NPY1-36) acts through Y1 and Y2 receptors while the C-terminal NPY fragments NPY18-36 and N-acetyl[Leu28,31]pNPY24-36 act only through the Y2 receptor. We have investigated the effects of intracerebroventricular (i.c.v.) administration of NPY1-36, NPY18-36 and N-acetyl[Leu28,31]pNPY24-36 on LH secretion in the ovariectomised (OVX) ewe. These peptides were administered into a lateral ventricle (LV) or the third ventricle (3V) of OVX ewes during the non-breeding and breeding seasons. Microinjections of NPY were also made into the preoptic area (POA) during both seasons to investigate the effects of NPY at the level of the GnRH cell bodies. Tamed sheep were fitted with 19 gauge guide tubes into the LV, 3V or the septo-preoptic area (POA). Jugular venous blood samples were taken every 10 min for 3 h. Sheep were then given NPY1-36 (10 micrograms), NPY18-36 (100 micrograms) or saline vehicle into the LV; N-acetyl[Leu28,31]pNPY24-36 (100 micrograms), NPY1-36 (10 micrograms or 100 micrograms), NPY18-36 (10 micrograms or 100 micrograms) or saline vehicle into the 3V, or NPY1-36 (1 microgram, 5 micrograms, 10 micrograms) into the POA. Blood sampling continued for a further 3 h. LH was measured in plasma by radioimmunoassay. LV or 3V injection of 10 micrograms NPY1-36 caused a small but significant (P < 0.025) increase in the interval from the last pre-injection pulse of LH to the first post-injection LH pulse during the breeding season. Other LH pulse parameters were not significantly affected. NPY18-36 did not produce any significant change in LH pulsatility when injected into the LV, and neither peptide had any effect on plasma prolactin or GH levels. There was a significant (P < 0.01) reduction in LH pulse frequency after 3V injection of 10 micrograms and 100 micrograms NPY and 100 micrograms NPY18-36. Pulse amplitude was reduced by 3V administration of the Y2 agonist, N-acetyl[Leu28-31]pNPY24-36 and 100 micrograms NPY18-36. When the amplitude of the first post-injection LH pulse was analysed, 10 micrograms NPY also had a significant (P < 0.05) suppressive effect. During the non-breeding season, 100 micrograms NPY1-36 (but not 10 micrograms) decreased (P < 0.01) LH pulse frequency. LH pulse amplitude was significantly (P < 0.01) decreased by 100 micrograms NPY18-36. Doses of 10 micrograms NPY1-36 and 100 micrograms NPY18-36 had greater inhibitory effects on pulse frequency during the breeding season but the suppressive effect of 100 micrograms NPY was similar between seasons. Microinjections of NPY into the POA decreased (P < 0.01) average plasma LH levels during the non-breeding season at a dose of 10 micrograms but did not significantly affect pulse frequency or amplitude. We conclude that a substantial component of the inhibitory action of NPY on LH secretion in the absence of steroids is mediated by the Y2 receptor. This inhibition is probably exerted by way of a presynaptic action on GnRH terminals in the median eminence as NPY does not modulate the frequency or amplitude of LH pulses at the lev...
Manipulation of diet is known to affect the secretion of the gonadotropins and growth hormone (GH). The former are under the direct regulation of hypothalamic gonadotropin-releasing hormone (GnRH) and the latter is under the dual control of GH-releasing hormone (GHRH) and somatostatin (SRIH). At the level of the hypothalamus, both galanin (GAL) and neuropeptide Y (NPY) are thought to regulate the secretion of the above releasing and inhibiting factors. Both peptides are also potent orexigenic agents. We have studied ovariectomised ewes that were either well-fed (HIGHs) or underfed (LOWs) and used immunocytochemistry and image analysis to measure the levels of GAL and NPY in hypothalamic nuclei in which GnRH, GHRH and SRIH are found and which are also involved in the regulation of appetite and feeding. The sheep were given a normal diet or a restricted diet for 15 months. Four pairs of ewes were then blood-sampled to measure GH, luteinising hormone (LH), and follicle-stimulating hormone (FSH) and then killed for recovery of the brains. After perfusion, cryostat sections were cut through the entire hypothalamus, mounted, and stained fro NPY or GAL. All treatments and analyses were performed in pairs. The number of immunoreactive cells, density of terminals and total immunoreactivity (IR) were quantified by image analysis by sampling 6-16 subareas (depending on region) on sections through the pre-optic area (POA), paraventricular nucleus (PVN), arcuate nucleus (ARC) and median eminence (ME). Mean ( ± SEM) live weight of the LOWs was significantly (p < 0.0001) lower than that of the HIGHs (37.6 ± 0.6 kg vs. 60.6 ± 0.5 kg). There was no difference in the plasma levels of LH and FSH but the area under the GH curve (ng/ml/h) was significantly (p < 0.0001) greater in the LOWs (320 ± 40.9 vs. 67.3 ± 16.1). There was an increased number of cells staining for NPY but not GAL in the ARC/ME of the LOWs. Nevertheless, the oveall level of immunostaining for both peptides was increased in the LOWs. GAL IR was restricted to the mediobasal hypothalamus. In the LOWs, the density of NPY terminal fields in each area of the ARC was significantly (p < 0.05) increased. Food restriction also increased the density of NPY terminals in the POA and PVN (p < 0.025) but not in the ME. These data indicate that a dietary manipulation which affects GH secretion but not the gonadotropins may be mediated by NPY and GAL neuronal systems in specific brain regions within the hypothalamus.
The purpose of this study was to examine the hypothesis that the pubertal reaugmentation of pulsatile GnRH release in male primates is triggered by a rise in circulating leptin concentrations. Agonadal juvenile male rhesus monkeys (n = 7) were implanted with indwelling venous catheters and housed in specialized cages that allow continuous access to the venous circulation. GnRH release was monitored indirectly using LH secretion from the in situ pituitary sensitized to the LH releasing action of GnRH as a bioassay for the hypothalamic peptide. Infusion of recombinant human leptin (5 micro g/kg body weight.h for 16 d resulted in a marked square wave increment in circulating leptin concentration from approximately 2-20 ng/ml but did not elicit precocious GnRH release. GH secretion, however, was stimulated confirming that the heterologous leptin preparation was bioactive in the monkey. Parenthetically, recombinant human leptin was found to be immunogenic in the monkey and circulating antileptin IgG was demonstrable 22-35 d after the initial exposure to the human protein. These findings further support the view that circulating leptin is unlikely to provide the signal that triggers the onset of puberty in male primates.
Sheep experience well-documented seasonal changes in reproductive activity and voluntary food intake (VFI). Within the hypothalamus, neurones that express neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) have been implicated in the regulation of reproduction and appetite. In this study, we aimed to determine the extent to which the expression of these two neuronal systems is linked to the seasonal reproductive cycle and/or the seasonal appetite cycle. VFI in our sheep reaches a nadir in August with no difference occurring between December and February. We examined the brains of ovariectomized (OVX) female sheep (n=5-7) that were killed during the breeding season (February) or during the early or late nonbreeding season (August and December, respectively). The brains of these animals were perfused with paraformaldehyde and processed for in situ hybridization histochemistry, using ribonucleotide probes labelled with 35S. The number of NPY and POMC cells and the number of silver grains per cell were counted using an image analysis system. For NPY, the number of cells counted in the arcuate nucleus/median eminence region and the number of silver grains per cell was significantly lower in animals killed during August than in animals killed in February or December. The number of grains per cell over NPY cells was also significantly lower in animals killed during August. For POMC, the number of cells was lower in February than in August and December. Similarly, the number of grains per cell for POMC were lower in February than in August and December. VFI was significantly lower in animals during August than at other times of the year. We conclude that in OVX ewes: (i) NPY gene expression is lower at the time of the year when VFI is reduced and (ii) POMC gene expression is greater at the time of the nonbreeding season than during the breeding season. Because these results were obtained in OVX animals, the changes appear to be independent of alterations in the secretion and/or action of ovarian steroids. Thus, the activity of NPY neurones appears to relate to changes in appetite whereas changes in POMC expression may be relevant to the seasonal breeding cycle.
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