The mystery of puberty initiation: genetics and epigenetics of idiopathic central precocious puberty (ICPP)

• Published in: Journal of endocrinological investigation 2017-08, Vol.40 (8), p.789-802
• Main Authors: Leka-Emiri, Sofia, Chrousos, George P., Kanaka-Gantenbein, Christina
• Format: Article
• Language: English
• Subjects: Cell migration; Dynorphin; Embryogenesis; Endocrinology; Epigenesis, Genetic; Epigenetics; Fibroblast growth factor 8; Fibroblast growth factor receptor 1; Gonadotropin-releasing hormone; Humans; Hypogonadism; Hypothalamus; Kallmann's syndrome; Kiss1 protein; Medicine; Medicine & Public Health; Metabolic Diseases; Molecular modelling; Neurokinin; Neurokinin B; Neuropeptide Y; Oscillations; Pituitary; Prophet of pit-1 protein; Puberty; Puberty, Precocious - genetics; Puberty, Precocious - pathology; Review; Secretion; γ-Aminobutyric acid
• ISSN: 1720-8386; 0391-4097; 1720-8386
• DOI: 10.1007/s40618-017-0627-9

Puberty is a major developmental stage. Damaging mutations, considered as “mistakes of nature”, have contributed to the unraveling of the networks implicated in the normal initiation of puberty. Genes involved in the abnormal hypothalamic–pituitary–gonadal (HPG) axis development, in the normosmic idiopathic hypogonadotropic hypogonadism (nIHH), in the X-linked or autosomal forms of Kallmann syndrome and in precocious puberty have been identified (GNRH1, GNRHR, KISS1, GPR54, FGFR1, FGF8, PROK2, PROKR2, TAC3, TACR3, KAL1, PROK2, PROKR2, CHD7, LEP, LEPR, PC1, DAX1, SF-1, HESX-1, LHX3, PROP-1). Most of them were found to play critical roles in HPG axis development and regulation, the embryonic GnRH neuronal migration and secretion, the regulation and action of the hypothalamic GnRH. However, the specific neural and molecular mechanisms triggering GnRH secretion remain one of the scientific enigmas. Although GnRH neurons are probably capable of autonomously generating oscillations, many gonadal steroid-dependent and -independent mechanisms have also been proposed. It is now well proven that the secretion of GnRH is regulated by kisspeptin as well as by permissive or opposing signals mediated by neurokinin B and dynorphin. These three supra-GnRH regulators compose the kisspeptin-neurokinin B-dynorphin neuronal (KNDy) system, a key player in pubertal onset and progression. Moreover, an ongoing increasing number of inhibitory, stimulatory and permissive networks acting upstream on GnRH neurons, such as GABA, NPY, LIN28B, MKRN3 and others integrate diverse hormonal and peripheral signals and have been proposed as the “gate-keepers” of puberty, while epigenetic modifications play also an important role in puberty initiation.