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      Contemporary issues in precocious puberty

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          Abstract

          Precocious puberty poses significant diagnostic and therapeutic challenge to the physician. Recent advances in the understanding of pathophysiology of precocious puberty have resulted in improved management. Timely intervention is mandatory to achieve successful outcome. The identification of critical role of KISS-1-kisspeptin-GPR54 system has gone a long way to provide an insight into pubertal physiology. It is likely that the system would become an important diagnostic and therapeutic target in children with precocious puberty. Epidemiological studies point toward earlier thelarche. This is, however, associated with slower progression as the age of menarche is static. These changes have led to suggestions of lowering the age cutoffs for precocious puberty in girls. New developments in assessment of precocious puberty including gonadotropin releasing hormone (GnRH) agonist test have made characterization of precocious puberty easier. Longstanding GnRH analogs have become the mainstay of treatment of gonadotropin-dependent precocious puberty, while aromatase inhibitors and inhibitors of sex hormone action are increasingly being used in gonadotropin-independent precocious puberty.

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          Most cited references 49

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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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            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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              Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network.

              To determine the current prevalence and mean ages of onset of pubertal characteristics in young girls seen in pediatric practices in the United States. A cross-sectional study was conducted by 225 clinicians in pediatric practices belonging to Pediatric Research in Office Settings, a practice-based research network. After standardized training in the assessment of pubertal maturation, practitioners rated the level of sexual maturation on girls 3 through 12 years who were undergoing complete physical examinations. Data were analyzed for 17,077 girls, of whom 9.6% were African-American and 90.4% white. At age 3, 3% of African-American girls and 1% of white girls showed breast and/or pubic hair development, with proportions increasing to 27.2% and 6.7%, respectively, at 7 years of age. At age 8, 48.3% of African-American girls and 14.7% of white girls had begun development. At every age for each characteristic, African-American girls were more advanced than white girls. The mean ages of onset of breast development for African-American and white girls were 8.87 years (SD, 1.93) and 9.96 years (SD, 1.82), respectively; and for pubic hair development, 8.78 years (SD, 2.00) and 10.51 years (SD, 1.67), respectively. Menses occurred at 12.16 years (SD, 1.21) in African-American girls and 12.88 years (SD, 1.20) of age in white girls. These data suggest that girls seen in a sample of pediatric practices from across the United States are developing pubertal characteristics at younger ages than currently used norms. Practitioners may need to revise their criteria for referral of girls with precocious puberty, with attention to racial differences.
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                Author and article information

                Journal
                Indian J Endocrinol Metab
                IJEM
                Indian Journal of Endocrinology and Metabolism
                Medknow Publications (India )
                2230-8210
                2230-9500
                September 2011
                : 15
                : Suppl3
                : S172-S179
                Affiliations
                Department of Pediatric Endocrinology, Regency Hospital Limited, Kanpur, Uttar Pradesh, India
                [1 ] Department of Pediatrics, Jaber Al-Ahmed Armed Forces Hospital, Kuwait
                Author notes
                Corresponding Author: Dr. Anurag Bajpai, Department of Pediatric Endocrinology, Regency Hospital Limited, A2 Sarvodaya Nagar, Kanpur, Uttar Pradesh, India. E-mail: dr_anuragbajpai@ 123456yahoo.com
                Article
                IJEM-15-172
                10.4103/2230-8210.84855
                3183522
                22029021
                Copyright: © Indian Journal of Endocrinology and Metabolism

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Review Article

                Endocrinology & Diabetes

                gnrh analog, recent advances, precocious puberty

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