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Kisspeptins and Puberty JM Castellano, M Tena-Sempere Lnst

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Kisspeptins and Puberty JM Castellano, M Tena-Sempere Lnst Rev Esp Endocrinol Pediatr 2017; Volumen 8. Edición 2 CONFERENCIAS 10.3266/RevEspEndocrinolPediatr.pre2017.Oct.429 Kisspeptins and Puberty JM Castellano, M Tena-Sempere lnst. Maimónides de Investigación Biomédica de Córdoba (IMIBIC); Dep. of Cell Biology, Physiology and Im- munology. Univ. of Córdoba; Hosp. Universitario Reina Sofía; CIBER Fisiopatología de la Obesidad y Nutri- ción, Inst. de Salud Carlos III. Córdoba Abstract endocrine, behavioral and psychological chan- ges, which ultimately lead to the acquisition of a Puberty is a complex developmental phenomenon, complete adult phenotype(1). Accordingly, puberty driven by brain pathways under the modulation of is regarded not only as a specific, relatively narrow external and internal cues, which culminates with stage of development, but rather considered as the acquisition of reproductive competence and se- the final output of a maturational continuum that xual maturity. From a neurobiological perspective, leads to reproductive competence. this process is incumbent to the timed activation of the population of hypothalamic neurons producing The tempo of puberty is dictated by the dynamic gonadotropin-releasing hormone (GnRH); the en- interplay between genetic and environmental fac- hancement of GnRH neurosecretory activity being tors(1), so that perturbation of such dialogue often ultimately responsible for the triggering of puberty. results in the inappropriate development of the re- In the last decade, kisspeptins have emerged as pi- productive axis that commonly leads to alterations votal upstream regulators of GnRH neurons, with of the timing of puberty (precocious, delayed or prominent roles in their activation during the puber- absent). In this sense, beyond its paramount biolo- tal transition and its (direct or indirect) modulation gical relevance, puberty may be considered as by different regulatory signals, including metabolic putative sentinel for perturbations of the gene-en- cues. We will briefly review herein the major features vironment interactions along early stages of deve- of kisspeptins and their producing neurons, the so- lopment, whose alterations may lead to deregula- called Kiss1 neurons, as major gatekeepers and tion of key homeostatic systems. In fact, changes fine regulators of reproductive maturation and pu- in the timing of puberty, especially earlier puberty, berty onset in mammals. might impact important development events, in- cluding somatic and psychological maturation, and appear to be linked to numerous adverse Introduction health outcomes(2), as well as reduced life expec- tancy(3). This is specially worrying given the repor- Puberty is major developmental event in the lifes- ted trends for changes in the age of puberty pan of any individual, which culminates with the (mostly earlier), which seem to be more frequent in attainment of sexual (somatic, psychological) ma- girls but appear to occur also in boys(4-6). These turity and reproductive capacity(1). This intricate observations urge for a better understanding of maturational phenomenon is grounded on early the physiological control of puberty, and of the differentiation events (starting in utero), and invol- pathophysiological basis of its alterations. ves a complex series of morphological, functional, Neuroendocrinology of puberty: the GnRH Secretrory drive Correspondencia: M Tena-Sempere, Inst. Maimónides de Investigación The neuroendocrine system responsible for pu- Biomédica de Córdoba (IMIBIC); Dep. of Cell Biology, Physiology and Immunology, Univ. of Córdoba; Hosp. berty onset is the so-called hypothalamic-pituitary- Universitario Reina Sofía; CIBER Fisiopatología de la gonadal (HPG) axis, whose full activation permits Obesidad y Nutrición, Inst. de Salud Carlos III, Córdoba the acquisition of reproductive competence at pu- E-mail: [email protected] berty(7, 8). This neurohormonal system primarily in- Rev Esp Endocrinol Pediatr 2017 - Volumen 8. Edición 2 8 JM Castellano, M Tena-Sempere tegrates three major groups of factors, which are: cretion and puberty onset. While detailed recapi- (a) the decapeptide, GnRH, which is released in a tulation of the results of these studies clearly exce- pulsatile manner to the portal circuit connecting eds the scope of this review, it is important to the medial-basal hypothalamus and the pituitary; stress that such analyses have unambiguously (b) the gonadotropins, luteinizing hormone (LH) documented a sophisticated developmental pro- and follicle-stimulating hormone (FSH), produced gram of Kiss1 neurons, responsible for their acti- by gonadotropic cells of the anterior pituitary; and vation during the pubertal maturation(11,15). This (c) the gonadal hormones, mainly sex steroids and complex and multifaceted phenomenon includes, several peptides, which operate via feedback at least, the following major components: (a) an in- loops at upper levels of the HPG axis to conduct crease in the hypothalamic Kiss1 mRNA/kisspep- its homeostatic regulation. In addition, the HPG tin content during the juvenile-pubertal transition axis is also modulated by other endogenous fac- that drives the full activation of the GnRH/gonado- tors, e.g., metabolic hormones, and exogenous tropin system(16-19); (b) a rise in the sensitivity to the signals, e.g., nutrition and light conditions(8), which excitatory actions of kisspeptins on GnRH secre- contribute also to the dynamic control of puberty. tion(20,21); (c) an enhancement of Gpr54 signaling efficiency in GnRH neurons; (d) a state of partial From its reproductive perspective, the initiation of resistance to desensitization to kisspeptin stimula- puberty is founded on the heightening of the pul- tion(21, 22); and (e) a rise of kisspeptin-positive neu- satile release of hypothalamic GnRH(9). Yet, the in- rons and their projections to GnRH neurons(23,24). In timate mechanisms whereby this increase occurs good agreement, pharmacological blockade of remain ill defined. The current view, articulated in kisspeptin signaling has been reported to delay the so-called “central drive” hypothesis, concurs the onset of puberty in female rats(25), whereas that the increase in the pulsatile GnRH secretion ablation of Kiss1 neurons in the juvenile period leading to the onset of puberty is the result of prevented pubertal maturation in female mice(26). changes in the activity of the central pathways controlling GnRH neurons, with a switch in the ba- Despite the solid clinical and experimental eviden- lance between excitatory inputs (which increase) ce suggesting a role of kisspeptins in the timing of and inhibitory signals (which decrease at the time puberty, one study using functional genomics to of puberty), thus causing the drive for the pubertal congenitally ablate Kiss1 neurons suggested that activation of the HPG axis(9). Notably, the activator kisspeptin signaling seems to be dispensable for afferents of GnRH neurons include not only trans- the attainment of female fertility(26). In the same synaptic inputs but also glial-born factors(10). vein, another study in a mouse model causing a congenital 95% reduction in hypothalamic Kiss1 expression was compatible with roughly preser- Kisspeptins and the central control of puberty ved reproductive function in male mice(27); yet, a similar reduction in hypothalamic Kiss1 levels se- While the control of GnRH neurons is multifactorial, verely altered fertility in female mice. A tenable ex- and numerous neuropeptides and transmitters planation is that these phenotypes might be due to have been shown in the last decades to regulate incomplete neuronal/Kiss1 expression elimination, GnRH secretion, kisspeptins have emerged in re- coupled to potential developmental compensa- cent years as fundamental regulatory signals, with tion(26), which can be activated by such congenital an essential role in the control of puberty(11). manipulations. Thus, these findings would not re- Kisspeptins are a family of structurally related pep- fute the essential role of hypothalamic kisspeptins tides, encoded by the Kiss1 gene, which act via in the physiological timing of puberty, but rather the G protein-coupled receptor, Gpr54, also ter- suggest that redundancy in Kiss1 signaling may med Kiss1R or kisspeptin receptor(11,12). The repro- help to safeguard reproduction in relatively adver- ductive facet of kisspeptins, and their role in the se conditions, at least in rodents. precise control of puberty, was surfaced by semi- nal observations, back in 2003, that inactivating mutations of GPR54 were linked to absence of pu- Putative regulators of kisspeptins: neurokinin berty and hypogonadism of central origin (aka, hy- B and leptin pogonadotropic hypogonadism) in humans(13, 14). Such reproductive role was further demonstrated Two major populations of Kiss1 neurons have been by the observation of similar phenotypes in pa- identified in the hypothalamus, as characterized in tients with inactivating mutations of KISS1 and in detail in rodents(28). One is located in the rostral hy- null mice for Gpr54 or Kiss1(11). pothalamus, mainly at the antero-ventral periven- tricular nucleus (AVPV), while the other is placed in These findings boosted enormous interest and the arcuate nucleus (ARC) or its equivalent infun- prompted the analysis of the physiological roles of dibular region in humans(28,29). The latter, which is Kiss1 neurons in the regulation of GnRH neurose- primarily involved in the tonic control of pulsatile Rev Esp Endocrinol Pediatr 2017 - Volumen 8. Edición 2 9 Kisspeptins and Puberty gonadotropin
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