Molecular basis of normal and pathological puberty: from basic mechanisms to clinical implications

Abstract

Puberty is a major maturational event; its mechanisms and timing are driven by genetic determinants, but also controlled by endogenous and environmental cues. Substantial progress towards elucidation of the neuroendocrine networks governing puberty has taken place. However, key aspects of the mechanisms responsible for the precise timing of puberty and its alterations have only recently begun to be deciphered, propelled by epidemiological data suggesting that pubertal timing is changing in humans, via mechanisms that are not yet understood. By integrating basic and clinical data, we provide a comprehensive overview of current advances on the physiological basis of puberty, with a particular focus on the roles of kisspeptins and other central transmitters, the underlying molecular and endocrine mechanisms, and the pathways involved in pubertal modulation by nutritional and metabolic cues. Additionally, we have summarised molecular features of precocious and delayed puberty in both sexes, as revealed by clinical and genetic studies. This Review is a synoptic up-to-date view of how puberty is controlled and of the pathogenesis of major pubertal alterations, from both a clinical and translational perspective. We also highlight unsolved challenges that will seemingly concentrate future research efforts in this active domain of endocrinology.

Figure 1:. Neuropeptide control of puberty and its metabolic regulation

Schematic presentation of populations of Kiss1 neurons at the two main hypothalamic areas, namely the ARC and AVPV, and related hypothalamic neuronal pathways and cellular energy sensors involved in the physiological control of puberty. Related neuronal pathways seemingly include neurons producing NPY and AgRP, and neurons expressing POMC and CART neurons. These pathways participate in transmitting the modulatory actions of key metabolic hormones, such as leptin. Three possible modes of action of leptin are presented: (1) direct excitatory actions on Kiss1 neurons; (2) indirect excitatory actions via POMC neurons; and (3) indirect inhibitory actions on NPY/AgRP neurons. In addition, these circuits convey the influence of conditions of energy deficit, which result in delayed puberty (denoted by low luteinising hormone levels), and situations of energy excess (obesity), that advance pubertal onset (denoted by high luteinising hormone levels). Cellular energy sensors and metabolic mediators involved in this process include mTOR, AMPK and SIRT1. AgRP=agouti-related protein. AMPK=adenosine monophosphate-activated protein kinase. ARC=arcuate nucleus. AVPV=anteroventral periventricular nucleus. CART=cocaine-regulated and amphetamine-regulated transcript. EED=embryonic ectoderm development (component of polycomb repressive complex 2). GABA=γ-aminobutyric acid. GnRH=gonadotropin-releasing hormone. KNDy=kisspeptin, neurokinin B, and dynorphin. Kp=kisspeptin. MSH=melanocyte-stimulating hormone. mTOR=mammalian target of rapamycin. NPY=neuropeptide Y. POL2=RNA polymerase 2. POMC=proopiomelanocortin. SIRT1=sirtuin 1.

Figure 2:. Monogenic causes of central precocious puberty

Central precocious puberty is a hypothalamic disorder with multiple aetiologies, including congenital and acquired conditions. Schematic representation of the hypothalamic regions and paradigmatic monogenic causes of central precocious puberty in humans are shown. These monogenic forms include gain-of-function mutations in KISS1, gain-of-function mutations of KISS1R, loss-of-function mutations in MKRN3, and loss-of-function mutations in DLK1. Schematic presentation of the main sites of alteration of hypothalamic circuits due to the above mutations is provided. ARC=arcuate nucleus. AVPV=anteroventral periventricular nucleus. GABA=γ-aminobutyric acid. GnRH=gonadotropin-releasing hormone. KNDy=kisspeptin, neurokinin B, and dynorphin. Kp=kisspeptin. ME=median eminence. MnPO=median preoptic nucleus. PMV=ventral pre-mammillary nucleus.

Figure 3:. Flowchart for the evaluation of a patient with delayed puberty

CDGP=constitutional delay of growth and puberty. CHH=congenital hypogonadotropic hypogonadism. FT4=free thyroxine. GHD=growth hormone deficiency. GnRH=gonadotropin-releasing hormone. hCG=human chorionic gonadotropin.