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      New Causes of Central Precocious Puberty: The Role of Genetic Factors

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          Abstract

          A pivotal event in the onset of puberty in humans is the reemergence of the pulsatile release of the gonadotropin-releasing hormone (GnRH) from hypothalamic neurons. Pathways governing GnRH ontogeny and physiology have been discovered by studying animal models and humans with reproductive disorders. Recent human studies implicated the activation of kisspeptin and its cognate receptor (KISS1/KISS1R) and the inactivation of MKRN3 in the premature reactivation of GnRH secretion, causing central precocious puberty (CPP). MKRN3, an imprinted gene located on the long arm of chromosome 15, encodes makorin ring finger protein 3, which is involved in ubiquitination and cell signaling. The MKRN3 protein is derived only from RNA transcribed from the paternally inherited copy of the gene due to maternal imprinting. Currently, MKRN3 defects represent the most frequent known genetic cause of familial CPP. In this review, we explored the clinical, hormonal and genetic aspects of children with sporadic or familial CPP caused by mutations in the kisspeptin and MKRN3 systems, essential genetic factors for pubertal timing.

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          Most cited references 35

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          Early age at menarche associated with cardiovascular disease and mortality.

          The relationship between age at menarche and cardiovascular disease remains unclear. Two recent studies found an inverse association between age at menarche and all-cause mortality. The aim of this study was to examine the relationship between age at menarche and cardiovascular disease risk factors, events, and mortality. A population-based prospective study involving 15,807 women, aged 40-79 yr in 1993-1997 and followed up to March 2007 for cardiovascular disease events (median follow-up 10.6 yr) and February 2008 for mortality (median follow-up 12.0 yr) was used. Odds ratios for cardiovascular disease risk factors and hazard ratios for incident cardiovascular disease and mortality were calculated. There were 3888 incident cardiovascular disease events (1323 coronary heart disease, 602 stroke, and 1963 other) and 1903 deaths (640 cardiovascular disease, 782 cancer, and 481 other) during follow-up. Compared with other women, those who had early menarche (<12 yr) had higher risks of hypertension [1.13 (1.02-1.24)], incident cardiovascular disease [1.17 (1.07-1.27)], incident coronary heart disease [1.23 (1.06-1.43)], all-cause mortality [1.22 (1.07-1.39)], cardiovascular disease mortality [1.28 (1.02-1.62)], and cancer mortality [1.25 (1.03-1.51)], adjusted for age, physical activity, smoking, alcohol, educational level, occupational social class, oral contraceptive use, hormone replacement therapy, parity, body mass index, and waist circumference. Early age at menarche (before age 12 yr) was associated with increased risk of cardiovascular disease events, cardiovascular disease mortality, and overall mortality in women, and this association appeared to be only partly mediated by increased adiposity.
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            Epigenetic Control of Female Puberty

            The timing of puberty is controlled by many genes. The elements coordinating this process have not, however, been identified. Here we show that an epigenetic mechanism of transcriptional repression times the initiation of female puberty in rats. We identify silencers of the Polycomb group (PcG) as major contributors to this mechanism, and show that PcG proteins repress Kiss1, a puberty-activating gene. Hypothalamic expression of two key PcG genes, Eed and Cbx7, decreases and methylation of their promoters increases preceding puberty. Inhibiting DNA methylation blocks both events and results in pubertal failure. The pubertal increase in Kiss1 is accompanied by EED loss from the Kiss1 promoter and enrichment of histone H3 modifications associated with gene activation. Preventing the eviction of EED from the Kiss1 promoter disrupts pulsatile GnRH release, delays puberty, and compromises fecundity. Our results identify epigenetic silencing as a novel mechanism underlying the neuroendocrine control of female puberty.
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              Age at menarche and risk of type 2 diabetes: results from 2 large prospective cohort studies.

              The authors investigated the association between age at menarche and risk of type 2 diabetes mellitus (T2DM) among 101,415 women from the Nurses' Health Study (NHS) aged 34-59 years (1980-2006) and 100,547 women from Nurses' Health Study II (NHS II) aged 26-46 years (1991-2005). During 2,430,274 and 1,373,875 person-years of follow-up, respectively, 7,963 and 2,739 incident cases of T2DM were documented. Young age at menarche was associated with increased risk of T2DM after adjustment for potential confounders, including body figure at age 10 years and body mass index (BMI; weight (kg)/height (m)(2)) at age 18 years. Relative risks of T2DM across age-at-menarche categories ( or =15 years) were 1.18 (95% confidence interval (CI): 1.10, 1.27), 1.09 (95% CI: 1.02, 1.17), 1.00 (referent), 0.92 (95% CI: 0.83, 1.01), and 0.95 (95% CI: 0.84, 1.06), respectively, in the NHS (P for trend < 0.0001) and 1.40 (95% CI: 1.24, 1.57), 1.13 (95% CI: 1.00, 1.27), 1.00 (referent), 0.98 (95% CI: 0.82, 1.18), and 0.96 (95% CI: 0.78, 1.19), respectively, in NHS II (P for trend < 0.0001). Associations were substantially attenuated after additional control for updated time-varying BMI. These data suggest that early menarche is associated with increased risk of T2DM in adulthood. The association may be largely mediated through excessive adult adiposity. The association was stronger among younger women, supporting a role for sex hormones in younger onset of T2DM, in addition to BMI.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2014
                November 2014
                09 August 2014
                : 100
                : 1
                : 1-8
                Affiliations
                Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Disciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil
                Author notes
                *Ana Claudia Latronico, Disciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, 7° andar, sala 7037, São Paulo 05403-900 (Brazil), E-Mail anacl@usp.br
                Article
                366282 Neuroendocrinology 2014;100:1-8
                10.1159/000366282
                25116033
                © 2014 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 1, Pages: 8
                Categories
                At the Cutting Edge

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