Selective role of neuropeptide Y receptor subtype Y2 in the control of gonadotropin secretion in the rat.

Different signals with key roles in energy homeostasis regulate the reproductive axis. These include neuropeptide Y and polypeptide YY(3-36), whose type Y(2) receptor is the most abundant of this family in the brain. We evaluated herein the putative roles of Y(2) receptors in the control of gonadotropin secretion by means of central administration of PYY(13-36) (agonist of Y(2) receptors) and BIIE 0246 (antagonist of Y(2) receptors) to intact and orchidectomized male rats. In addition, the ability of PYY(13-36) to elicit GnRH and gonadotropin secretion in vitro and the impact of fasting on LH responses to PYY(13-36) in vivo were also monitored. Central administration of PYY(13-36) significantly decreased the circulating levels of both gonadotropins, an effect that was observed in prepubertal and adult rats. Yet a dual action of Y(2) receptors in the control of male gonadotropic axis was evidenced as their activation induced 1) stimulation of gonadotropin responses to GnRH at the pituitary but 2) inhibition of GnRH secretion at the hypothalamus. Antagonization of Y(2) receptors failed to modify basal LH secretion in intact males either after being fed ad libitum or after being fasted. In contrast, their central blockade in orchidectomized rats evoked a significant increase in circulating LH and FSH level, suggesting the constitutive activation of Y(2) receptor in such stimulated conditions. In summary, our data evidence a complex mode of action of Y(2) receptors in the control of gonadotropic axis, with stimulatory and inhibitory actions at different levels of the system that are sensitive to the gonadal status.

Neuromedin s as novel putative regulator of luteinizing hormone secretion.

Neuromedin S (NMS), a 36 amino acid peptide structurally related to neuromedin U, was recently identified in rat brain as ligand for the G protein-coupled receptor FM4/TGR-1, also termed neuromedin U receptor type-2 (NMU2R). Central expression of NMS appears restricted to the suprachiasmatic nucleus, and NMS has been involved in the regulation of dark-light rhythms and suppression of food intake. Reproduction is known to be tightly regulated by metabolic and photoperiodic cues. Yet the potential contribution of NMS to the control of reproductive axis remains unexplored. We report herein analyses of hypothalamic expression of NMS and NMU2R genes, as well as LH responses to NMS, in different developmental and functional states of the female rat. Expression of NMS and NMU2R genes was detected at the hypothalamus along postnatal development, with significant fluctuations of their relative levels (maximum at prepubertal stage and adulthood). In adult females, hypothalamic expression of NMS (which was confined to suprachiasmatic nucleus) and NMU2R significantly varied during the estrous cycle (maximum at proestrus) and was lowered after ovariectomy and enhanced after progesterone supplementation. Central administration of NMS evoked modest LH secretory responses in pubertal and cyclic females at diestrus, whereas exaggerated LH secretory bursts were elicited by NMS at estrus and after short-term fasting. Conversely, NMS significantly decreased elevated LH concentrations of ovariectomized rats. In summary, we provide herein novel evidence for the ability of NMS to modulate LH secretion in the female rat. Moreover, hypothalamic expression of NMS and NMU2R genes appeared dependent on the functional state of the female reproductive axis. Our data are the first to disclose the potential implication of NMS in the regulation of gonadotropic axis, a function that may contribute to the integration of circadian rhythms, energy balance, and reproduction.

Telarquia precoz como signo guía de pubertad precoz central / No disponible

La telarquia precoz puede ser una patología benigna sin trascendencia clínica o el inicio de una pubertad precoz verdadera. En este artículo intentamos repasar las diferentes causas de la pubertad precoz, haciendo hincapié en las causas tumorales del sistema nervioso central como etiología de este cuadro, sobre todo, desde la introducción de técnicas de imagen como la resonancia magnética. En el caso clínico que presentamos llama la atención la edad tan temprana a la que se desarrolla la pubertad y cómo en estos casos es obligatorio descartar siempre una etiología tumoral; el hamartoma de hipotálamo es una de las causas más frecuente (AU)

The precocious thelarche can be either a benign condition without clinical significance or the beginning of a real precocious puberty. We try to revise, in this article, the different causes of precocious puberty, emphasizing the tumours of the central nervous system as the aetiology of this condition, especially after the introduction of image techniques as the magnetic resonance. In the clinical case we present, it is remarkable the early age the puberty is developed. In these cases, it is always obligatory to rule out the tumour aetiology being the hypothalamus hamartoma one of the most frequent causes (AU)

Novel role of 26RFa, a hypothalamic RFamide orexigenic peptide, as putative regulator of the gonadotropic axis.

The close link between reproductive function and body energy stores relies on a complex neuroendocrine network of common regulatory signals, the nature of which is yet to be fully elucidated. Recently, 26RFa was identified in amphibians and mammals as a conserved hypothalamic neuropeptide of the RFamide family, with a potent orexigenic activity. Yet, despite its proposed role as hypophysiotropic factor, the function of 26RFa in the control of pituitary gonadotropins and, hence, of the reproductive axis remains unexplored. In the present study, the effects of 26RFa on gonadotropin secretion were evaluated in the rat by a combination of in vitro and in vivo approaches. At the pituitary, 26RFa dose-dependently enhanced basal and gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone (LH) secretion from male and cyclic female rats. This effect was mimicked by the active fragment 26RFa(20-26), as well as by the related 43RFa peptide. Moreover, expression of the genes encoding 26RFa and its putative receptor, GPR103, was demonstrated in rat pituitary throughout postnatal development. In vivo, intracerebral injection of 26RFa evoked a significant increase in serum LH levels in cyclic and ovariectomized females; this response which was also observed after central injection of 26RFa(20-26) and 43RFa peptides, as well as after systemic administration of 26RFa. Conversely, central and systemic injection of 26RFa failed to significantly modify gonadotropin secretion in adult male rats, even after repeated administration of the peptide. In summary, we present herein novel evidence for the potential role of the orexigenic peptide 26RFa in the control of the gonadotropic axis, thus suggesting its potential involvement in the joint control of energy balance and reproduction, especially in the female.

Hypothalamic expression of KiSS-1 system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female Rat.

Kisspeptins, products of the KiSS-1 gene with ability to bind G protein-coupled receptor 54 (GPR54), have been recently identified as major gatekeepers of reproductive function with ability to potently activate the GnRH/LH axis. Yet, despite the diversity of functional states of the female gonadotropic axis, pharmacological characterization of this effect has been mostly conducted in pubertal animals or adult male rodents, whereas similar studies have not been thoroughly conducted in the adult female. In this work, we evaluated maximal LH and FSH secretory responses to kisspeptin-10, as well as changes in sensitivity and hypothalamic expression of KiSS-1 and GPR54 genes, in different physiological and experimental models in the adult female rat. Kisspeptin-10 (1 nmol, intracerebroventricular) was able to elicit robust LH bursts at all phases of the estrous cycle, with maximal responses at estrus; yet, in diestrus LH, responses to kisspeptin were detected at doses as low as 0.1 pmol. In contrast, high doses of kisspeptin only stimulated FSH secretion at diestrus. Removal of ovarian sex steroids did not blunt the ability of kisspeptin to further elicit stimulated LH and FSH secretion, but restoration of maximal responses required replacement with estradiol and progesterone. Finally, despite suppressed basal levels, LH and FSH secretory responses to kisspeptin were preserved in pregnant and lactating females, although the magnitude of LH bursts and the sensitivity to kisspeptin were much higher in pregnant dams. Interestingly, hypothalamic KiSS-1 gene expression significantly increased during pregnancy, whereas GPR54 mRNA levels remained unaltered. In summary, our current data document for the first time the changes in hypothalamic expression of KiSS-1 system and the gonadotropic effects (maximal responses and sensitivity) of kisspeptin in different functional states of the female reproductive axis. The present data may pose interesting implications in light of the potential therapeutic use of kisspeptin analogs in the pharmacological manipulation of the gonadotropic axis in the female.

Comparative analysis of the effects of ghrelin and unacylated ghrelin on luteinizing hormone secretion in male rats.

Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as pleiotropic modulator of diverse biological functions, including energy homeostasis and, recently, reproduction. Although inhibitory actions of ghrelin on LH secretion and puberty onset have been reported previously, the receptor mechanisms mediating these actions, and the potential gonadotropic effects of the unacylated isoform of ghrelin (UAG), remain unclear. In this work, the effects of single and repeated administration of ghrelin or UAG on LH secretion were compared in pubertal and adult male rats. In addition, the effects of ghrelin were assessed in models of transient or persistent hypergonadotropism. Daily injection of ghrelin or UAG throughout puberty similarly decreased LH levels and partially delayed balanopreputial separation. Likewise, chronic infusion of ghrelin or UAG to adult males resulted in significant decreases in circulating LH and FSH concentrations. Moreover, acute injection of ghrelin induced a transient reduction in LH levels in freely moving males, an effect that was fully mimicked by administration of UAG. Yet in contrast to ghrelin, UAG failed to modify GH secretion. Finally, injection of ghrelin moderately, but significantly, reduced the duration of LH secretory responses to the potent gonadotropin secretagogue kisspeptin-10, whereas ghrelin infusion in a model of chronic elevation of serum gonadotropin levels (the transgenic growth retarded male rat) evoked a significant reduction of LH concentrations. Altogether our present results further substantiate the inhibitory effect of ghrelin on basal and stimulated LH secretion in a wide array of experimental conditions. Moreover, our data are the first to demonstrate the ability of UAG, originally considered an inert form of the molecule, to mimic the actions of acylated ghrelin on LH release. These observations reinforce the contention that ghrelin, as putative signal for energy insufficiency, may operate as negative modifier of male puberty and LH secretion, an effect that might be, at least partially, conducted through a GH secretagogue receptor type 1a-independent mechanism.

Stimulatory effect of PYY-(3-36) on gonadotropin secretion is potentiated in fasted rats.

Development and normal function of the reproductive axis requires a precise degree of body energy stores. Polypeptide YY-(3-36) [PYY-(3-36)] is a gastrointestinal secreted molecule recently shown to be involved in the control of food intake with agonistic activity on neuropeptide Y (NPY) receptor subtypes Y2 and Y5. Notably, PYY-(3-36) has been recently demonstrated as putative regulator of gonadotropin secretion in the rat. However, the "reproductive" facet of this factor remains to be fully elucidated. In this context, we report herein our analyses of the influence of the nutritional status on the effects of PYY-(3-36) upon GnRH and gonadotropin secretion. The major findings of our study are 1) the stimulatory effect of central administration of PYY-(3-36) on LH secretion was significantly enhanced after fasting and blocked by a GnRH antagonist; 2) besides central effects, PYY-(3-36) elicited LH and FSH secretion directly at the pituitary level, a response that is also augmented by fasting; 3) PYY-(3-36) inhibited GnRH secretion by hypothalamic fragments from male rats fed ad libitum, whereas a significant stimulatory effect was observed after fasting; and 4) the increase in the gonadotropin responsiveness to PYY-(3-36) in fasting was not associated with changes in the expression of Y2 and Y5 receptor genes at hypothalamus and/or pituitary. In conclusion, our study extends our previous observations suggesting a relevant, mostly stimulatory, role of PYY-(3-36) in the control of gonadotropin secretion. Strikingly, such an effect was significantly enhanced by fasting. Considering the proposed decrease in PYY-(3-36) levels after fasting, the possibility that reduced PYY-(3-36) secretion might contribute to defective function of the gonadotropic axis after food deprivation merits further investigation.

Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition.

Activation of the gonadotropic axis critically depends on sufficient body energy stores, and conditions of negative energy balance result in lack of puberty onset and reproductive failure. Recently, KiSS-1 gene-derived kisspeptin, signaling through the G protein-coupled receptor 54 (GPR54), has been proven as a pivotal regulator in the control of gonadotropin secretion and puberty. However, the impact of body energy status upon hypothalamic expression and function of this system remains unexplored. In this work, we evaluated the expression of KiSS-1 and GPR54 genes at the hypothalamus as well as the ability of kisspeptin-10 to elicit GnRH and LH secretion in prepubertal rats under short-term fasting. In addition, we monitored the actions of kisspeptin on food intake and the effects of its chronic administration upon puberty onset in undernutrition. Food deprivation induced a concomitant decrease in hypothalamic KiSS-1 and increase in GPR54 mRNA levels in prepubertal rats. In addition, LH responses to kisspeptin in vivo were enhanced, and its GnRH secretagogue action in vitro was sensitized, under fasting conditions. Central kisspeptin administration failed to change food intake patterns in animals fed ad libitum or after a 12-h fast. However, chronic treatment with kisspeptin was able to restore vaginal opening (in approximately 60%) and to elicit gonadotropin and estrogen responses in a model of undernutrition. In summary, our data are the first to show an interaction between energy status and the hypothalamic KiSS-1 system, which may constitute a target for disruption (and eventual therapeutic intervention) of pubertal development in conditions of negative energy balance.

Effects of polypeptide YY(3-36) upon luteinizing hormone-releasing hormone and gonadotropin secretion in prepubertal rats: in vivo and in vitro studies.

Polypeptide YY(3-36) (PYY(3-36)) is a gastrointestinal secreted molecule, agonist of neuropeptide Y (NPY) receptor subtypes Y2 and Y5, recently involved in the control of food intake. Notably, several factors with key roles in energy homeostasis conduct pleiotropic effects upon the reproductive axis. However, whether PYY(3-36) is provided with similar biological actions remains so far largely unexplored. To address this issue, expression analyses of neuropeptide Y receptor Y2 and Y5 genes were conducted at the pituitary and the hypothalamus, and functional studies testing the effects of PYY(3-36) in vivo and in vitro were implemented, using the prepubertal rat as a model. Expression of the genes encoding Y2 and Y5 receptors was demonstrated, albeit at low levels, in whole hypothalamic and pituitary samples, and challenge of pituitary tissue with increasing doses of PYY(3-36) elicited LH and FSH secretion in male and female rats, a response that was persistently observed in the absence of extracellular calcium. Moreover, 10(-6) m PYY(3-36) enhanced LH and FSH responsiveness to LHRH in vitro. In contrast, systemic ip administration of PYY(3-36) over a range of doses (3, 10, and 30 microg/kg) failed to significantly modify serum LH levels in males and females, whereas central (intracerebroventricular) injection of 3 nmol PYY(3-36) inhibited LH secretion in vivo, and 10(-6) m PYY(3-36) decreased LHRH release by hypothalamic fragments in vitro in male but not in female rats. Overall, our data document the complex mode of action of the gut-derived anorexigenic signal PYY(3-36) at the hypothalamic-pituitary unit in the control of gonadotropin secretion and evidence that, as is the case for other peripheral factors with key roles in energy balance (as leptin and ghrelin), PYY(3-36) might play a role in the neuroendocrine modulation of the reproductive axis.

Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide.

The gonadotropic axis is centrally controlled by a complex regulatory network of excitatory and inhibitory signals that is activated at puberty. Recently, loss of function mutations of the gene encoding G protein-coupled receptor 54 (GPR54), the putative receptor for the KiSS-1-derived peptide metastin, have been associated with lack of puberty onset and hypogonadotropic hypogonadism. Yet the pattern of expression and functional role of the KiSS-1/GPR54 system in the rat hypothalamus remain unexplored to date. In the present work, expression analyses of KiSS-1 and GPR54 genes were conducted in different physiological and experimental settings, and the effects of central administration of KiSS-1 peptide on LH release were assessed in vivo. Persistent expression of KiSS-1 and GPR54 mRNAs was detected in rat hypothalamus throughout postnatal development, with maximum expression levels at puberty in both male and female rats. Hypothalamic expression of KiSS-1 and GPR54 genes changed throughout the estrous cycle and was significantly increased after gonadectomy, a rise that was prevented by sex steroid replacement both in males and females. Moreover, hypothalamic expression of the KiSS-1 gene was sensitive to neonatal imprinting by estrogen. From a functional standpoint, intracerebroventricular administration of KiSS-1 peptide induced a dramatic increase in serum LH levels in prepubertal male and female rats as well as in adult animals. In conclusion, we provide novel evidence of the developmental and hormonally regulated expression of KiSS-1 and GPR54 mRNAs in rat hypothalamus and the ability of KiSS-1 peptide to potently stimulate LH secretion in vivo. Our current data support the contention that the hypothalamic KiSS-1/GPR54 system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood.