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INTRODUCTION

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Normal pubertal development is dependent on a change in the activity of the hypothalamic-pituitary-gonadal (HPG) axis from a period of relative quiescence during childhood to its reactivation during puberty. Any disruption to the normal inhibition of this axis during childhood results in central precocious puberty. Alternatively, secretion of or exposure to sex steroids independent of this axis can result in a peripheral form of precocious puberty. The challenge to the practitioner is to identify children with pathologic forms of precocious puberty and determine whether the etiology is central (gonadotropin-releasing hormone [GnRH]-dependent) or peripheral (GnRH-independent) in order to initiate appropriate therapy.

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NORMAL PUBERTAL DEVELOPMENT

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The HPG Axis

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For several decades, it has been proposed that the end phenomenon that triggers puberty is an increase in the secretion of GnRH by hypothalamic neurons producing GnRH. In turn, this phenomenon is regulated by a complex mechanism of interrelated genes that act at different levels: 1) synaptic changes: an increase of excitatory stimuli (glutamate, kisspeptin, neurokinin) of neurons secreting GnRH, decreased of the inhibitory stimuli (GABA neurons, GnRH inhibitory neurons and opioids), and 2) glial changes: through the release of growth factors that act on receptors of GnRH neurons and by changes in the adhesiveness of glial cells on GnRH neurons.1,2 Identification of the physiological roles of kisspeptins and their receptor (GPR54) resulted in a major advance in our understanding of neuronal mechanisms controlling GnRH secretion and gonadal function. Studies have revealed that kisspeptins, a family of neuropeptides secreted by hypothalamic neurons, are pivotal upstream regulators of GnRH neurons, which express kisspeptin receptors. Kisspeptin-producing hypothalamic neurons in the arcuate nucleus and anteroventral periventricular area coexpress neurokinin B and dynorphin and are known as KNDy neurons. These neurons may be a site of action for the negative feedback of estradiol. Thus, kisspeptins have emerged as an important factor in diverse aspects of reproductive maturation and function, including sexual differentiation of the brain and puberty onset, adult regulation of gonadotropin secretion, and metabolic control of reproduction. It is accepted that reproductive function is sensitive to energy reserves and the modulatory actions of diverse metabolic factors, especially leptin. This hormone is an essential integrator linking body adipose stores and reproduction. However, leptin’s effects on GnRH neurons are most likely indirect, as these neurons do not physiologically express leptin receptors. It has recently been reported that kisspeptin neurons express leptin receptors, suggesting that the relation between metabolism and reproduction is mediated by the interaction among leptin and kisspeptin neurons and subsequently GnRH neurons. Indeed, the hypothalamic kiss1 system is altered in conditions of metabolic distress, showing decreased expression in models of negative balance.3,4 Finally, recent studies have demonstrated that mutations affecting kisspeptin or kisspeptin receptor (GPR54) are related to human pubertal disorders (precocious and delayed puberty).5

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Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) enter the systemic circulation and stimulate ...

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