Disentangling puberty: novel neuroendocrine pathways and mechanisms for the control of mammalian puberty.

Puberty is a complex developmental event, controlled by sophisticated regulatory networks that integrate peripheral and internal cues and impinge at the brain centers driving the reproductive axis. The tempo of puberty is genetically determined but is also sensitive to numerous modifiers, from metabolic and sex steroid signals to environmental factors. Recent epidemiological evidence suggests that the onset of puberty is advancing in humans, through as yet unknown mechanisms. In fact, while much knowledge has been gleaned recently on the mechanisms responsible for the control of mammalian puberty, fundamental questions regarding the intimate molecular and neuroendocrine pathways responsible for the precise timing of puberty and its deviations remain unsolved. By combining data from suitable model species and humans, we aim to provide a comprehensive summary of our current understanding of the neuroendocrine mechanisms governing puberty, with particular focus on its central regulatory pathways, underlying molecular basis and mechanisms for metabolic control. A comprehensive MEDLINE search of articles published mostly from 2003 to 2017 has been carried out. Data from cellular and animal models (including our own results) as well as clinical studies focusing on the pathophysiology of puberty in mammals were considered and cross-referenced with terms related with central neuroendocrine mechanisms, metabolic control and epigenetic/miRNA regulation. Studies conducted during the last decade have revealed the essential role of novel central neuroendocrine pathways in the control of puberty, with a prominent role of kisspeptins in the precise regulation of the pubertal activation of GnRH neurosecretory activity. In addition, different transmitters, including neurokinin-B (NKB) and, possibly, melanocortins, have been shown to interplay with kisspeptins in tuning puberty onset. Alike, recent studies have documented the role of epigenetic mechanisms, involving mainly modulation of repressors that target kisspeptins and NKB pathways, as well as microRNAs and the related binding protein, Lin28B, in the central control of puberty. These novel pathways provide the molecular and neuroendocrine basis for the modulation of puberty by different endogenous and environmental cues, including nutritional and metabolic factors, such as leptin, ghrelin and insulin, which are known to play an important role in pubertal timing. Despite recent advancements, our understanding of the basis of mammalian puberty remains incomplete. Complete elucidation of the novel neuropeptidergic and molecular mechanisms summarized in this review will not only expand our knowledge of the intimate mechanisms responsible for puberty onset in humans, but might also provide new tools and targets for better prevention and management of pubertal deviations in the clinical setting