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      Serum Kisspeptin Levels in Korean Girls with Central Precocious Puberty

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          Abstract

          Central precocious puberty (CPP) is caused by premature activation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin and G-protein coupled receptor-54 system is the essential gatekeeper of the reproductive system, playing a key role in the activation of the gonadotropic axis at puberty. We aimed to determine whether serum kisspeptin may function as a marker for CPP by investigating serum kisspeptin levels in Korean girls with CPP and their prepubertal controls. Serum kisspeptin levels of Korean girls with CPP (n = 30) and age-matched healthy prepubertal controls (n = 30) were measured with a competitive enzyme immunoassay. Serum kisspeptin levels were significantly higher in CPP group than in control group (4.61 ± 1.78 vs 2.15 ± 1.52 pM/L, P < 0.001). Serum kisspeptin was positively correlated with peak luteinizing hormone (LH), peak/basal LH ratio and peak LH/follicular-stimulating hormone (FSH) ratio during GnRH stimulation test. CPP is supposed to be triggered by premature increase of kisspeptin. Serum kisspeptin may be used as a marker of CPP. Further studies on KISS1 gene polymorphisms leading to higher risk of premature increase of kisspeptin and upstream regulator of kisspeptin are also needed.

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          Most cited references 23

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          Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54.

          We have recently described a molecular gatekeeper of the hypothalamic-pituitary-gonadal axis with the observation that G protein-coupled receptor 54 (GPR54) is required in mice and men for the pubertal onset of pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion to occur. In the present study, we investigate the possible central mode of action of GPR54 and kisspeptin ligand. First, we show that GPR54 transcripts are colocalized with gonadotropin-releasing hormone (GnRH) neurons in the mouse hypothalamus, suggesting that kisspeptin, the GPR54 ligand, may act directly on these neurons. Next, we show that GnRH neurons seem anatomically normal in gpr54-/- mice, and that they show projections to the median eminence, which demonstrates that the hypogonadism in gpr54-/- mice is not due to an abnormal migration of GnRH neurons (as occurs with KAL1 mutations), but that it is more likely due to a lack of GnRH release or absence of GnRH neuron stimulation. We also show that levels of kisspeptin injected i.p., which stimulate robust LH and FSH release in wild-type mice, have no effect in gpr54-/- mice, and therefore that kisspeptin acts directly and uniquely by means of GPR54 signaling for this function. Finally, we demonstrate by direct measurement, that the central administration of kisspeptin intracerebroventricularly in sheep produces a dramatic release of GnRH into the cerebrospinal fluid, with a parallel rise in serum LH, demonstrating that a key action of kisspeptin on the hypothalamo-pituitary-gonadal axis occurs directly at the level of GnRH release. The localization and GnRH release effects of kisspeptin thus define GPR54 as a major control point in the reproductive axis and suggest kisspeptin to be a neurohormonal effector.
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            A role for kisspeptins in the regulation of gonadotropin secretion in the mouse.

            Kisspeptins are products of the KiSS-1 gene, which bind to a G protein-coupled receptor known as GPR54. Mutations or targeted disruptions in the GPR54 gene cause hypogonadotropic hypogonadism in humans and mice, suggesting that kisspeptin signaling may be important for the regulation of gonadotropin secretion. To examine the effects of kisspeptin-54 (metastin) and kisspeptin-10 (the biologically active C-terminal decapeptide) on gonadotropin secretion in the mouse, we administered the kisspeptins directly into the lateral cerebral ventricle of the brain and demonstrated that both peptides stimulate LH secretion. Further characterization of kisspeptin-54 demonstrated that it stimulated both LH and FSH secretion, at doses as low as 1 fmol; moreover, this effect was shown to be blocked by pretreatment with acyline, a potent GnRH antagonist. To learn more about the functional anatomy of kisspeptins, we mapped the distribution of KiSS-1 mRNA in the hypothalamus. We observed that KiSS-1 mRNA is expressed in areas of the hypothalamus implicated in the neuroendocrine regulation of gonadotropin secretion, including the anteroventral periventricular nucleus, the periventricular nucleus, and the arcuate nucleus. We conclude that kisspeptin-GPR54 signaling may be part of the hypothalamic circuitry that governs the hypothalamic secretion of GnRH.
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              Kisspeptin Activation of Gonadotropin Releasing Hormone Neurons and Regulation of KiSS-1 mRNA in the Male Rat

              The KiSS-1 gene codes for a family of neuropeptides called kisspeptins which bind to the G-protein-coupled receptor GPR54. To assess the possible effects of kisspeptins on gonadotropin secretion, we injected kisspeptin-52 into the lateral cerebral ventricles of adult male rats and found that kisspeptin-52 increased the serum levels of luteinizing hormone (p < 0.05). To determine whether the kisspeptin-52-induced stimulation of luteinizing hormone secretion was mediated by gonadotropin-releasing hormone (GnRH), we pretreated adult male rats with a GnRH antagonist (acyline), then challenged the animals with intracerebroventricularly administered kisspeptin-52. The GnRH antagonist blocked the kisspeptin-52-induced increase in luteinizing hormone. To examine whether kisspeptins stimulate transcriptional activity in GnRH neurons, we administered kisspeptin-52 intracerebroventricularly and found by immunocytochemistry that 86% of the GnRH neurons coexpressed Fos 2 h after the kisspeptin-52 challenge, whereas fewer than 1% of the GnRH neurons expressed Fos following injection of the vehicle alone (p < 0.001). To assess whether kisspeptins can directly act on GnRH neurons, we used double-label in situ hybridization and found that 77% of the GnRH neurons coexpress GPR54 mRNA. Finally, to determine whether KiSS-1 gene expression is regulated by gonadal hormones, we measured KiSS-1 mRNA levels by single-label in situ hybridization in intact and castrated males and found significantly higher levels in the arcuate nucleus of castrates. These results demonstrate that GnRH neurons are direct targets for regulation by kisspeptins and that KiSS-1 mRNA is regulated by gonadal hormones, suggesting that KiSS-1 neurons play an important role in the feedback regulation of gonadotropin secretion.
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                Author and article information

                Journal
                J Korean Med Sci
                JKMS
                Journal of Korean Medical Science
                The Korean Academy of Medical Sciences
                1011-8934
                1598-6357
                July 2011
                20 June 2011
                : 26
                : 7
                : 927-931
                Affiliations
                [1 ]Department of Pediatrics, Korea University College of Medicine, Seoul, Korea.
                [2 ]Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
                [3 ]Institute of Endocrinology, Yonsei University College of Medicine, Seoul, Korea.
                Author notes
                Address for Correspondence: Ho-Seong Kim, MD. Department of Pediatrics, Yonsei University College of Medicine, 262 Seongsan-no, Seodaemun-gu, Seoul 120-752, Korea. Tel: +82.2-2228-2055, Fax: +82.2-393-9118, kimho@ 123456yuhs.ac
                Article
                10.3346/jkms.2011.26.7.927
                3124724
                21738347
                © 2011 The Korean Academy of Medical Sciences.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Original Article
                Pediatrics

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