The Congenital and Acquired Mechanisms Implicated in the Etiology of Central Precocious Puberty

Abstract

The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP.

Keywords: DLK1; MKRN3; central precocious puberty; endocrine-disrupting chemicals; gonadotropin-releasing hormone; hypothalamic hamartoma; kisspeptins.

Congenital and acquired mechanisms implicated in the etiology of central precocious puberty. ARC, arcuate nucleus; AVPV, anteroventral periventricular nucleus; GABA, gamma-aminobutyric acid; ME, median eminence; MnPO, median preoptic nucleus; PMV, ventral premammillary nucleus; POA, preoptic area; OPG: optic pathways glioma.

Figure 1.

Schematic representation of the putative role of cellular energy sensors and metabolic mediators in the control of puberty. In conditions of energy insufficiency, hypothalamic activation of AMP-activated protein kinase (AMPK), together with persistence of the repressive action of SIRT1 at the Kiss1 promoter, leads to reduced Kiss1 expression and delayed puberty. By contrast, in conditions of energy sufficiency and timely removal of SIRT1 from the Kiss1 promoter, together with the presumable activation of mammalian target of rapamycin (mTOR), allows increased Kiss1 expression and the normal occurrence of puberty. At extreme conditions of energy excess (eg, early-onset obesity), precocious removal of SIRT1 from the Kiss1 promoter causes a change in the chromatin landscape that accelerates the rise in Kiss1 expression, leading to early puberty. In addition, obesity presumably also causes the activation of an alternative pathway, involving kisspeptins innervation of the paraventricular nucleus (PVN) and ceramide (CER) synthesis at this site, which apparently contribute to the precocious activation of the ovary in obesity via direct sympathetic inputs. ARC, arcuate nucleus; Dyn, dynorphin; GnRH, gonadotrophin-releasing hormone; Kp, kisspeptins; mTOR, mammalian target of rapamycin; NKB, neurokinin B; SIRT1, Sirtuin; SNS, sympathetic nervous system.

Figure 2.

Schematic pathophysiology of hypothalamic hamartoma-related CPP. Sagittal MRI view revealing a large parahypothalamic hamartoma (dotted white circle) attached to anterior hypothalamus as cause of CPP. The HH formation may be determined by sporadic/de novo somatic mutations in genes required for hypothalamic morphogenesis. Several genes, most of them encoding proteins of the Sonic hedgehog (SHH) pathway, have been implicated in the development of syndromic and nonsyndromic hypothalamic hamartoma (HH). The underlying mechanisms leading the ability of HHs to activate GnRH secretion and induce CPP are multiple, including autonomous secretion of GnRH by HH, trans synaptic activation, via myelinated fibers, connecting the HH to the hypothalamus, and the secretion of glial products and bioactive substances (TGF-α and downstream factors) capable of stimulating a neuronal network involved in the GnRH secretion. In addition, the effect of the mechanical pressure that HH could apply to the hypothalamus could represent another potential mechanism. There is evidence that the anatomical position (anterior localization) of HH has a pivotal role for the occurrence of CPP.

Figure 3.

Representation of the 2 autosomal alleles of the imprinted MKRN3 gene and distinct genotypes of affected and unaffected CPP individuals. (A) Normal pattern of imprinting of MKRN3 gene, with silencing of the maternal allele (by methylation of its promoter region) and monoallelic expression of the paternal allele. (B) The genotype of an individual who inherited a maternal loss-of-function mutation. The individual will not present with CPP because the paternal allele is normally expressed. (C) The genotype of an individual who inherited a paternal loss-of-function mutation. The individual will present with CPP because both alleles are inactive: the paternal is mutated and the maternal is silenced. Adapted from Canton et al (157).

Figure 4.

Schematic representation of MKRN3 protein structure and location of loss-of-function mutations identified in patients with CPP. Hexagons represent individual amino acids, and corresponding numbers indicate amino acid positions. Top row mutations are frameshift and nonsense, whereas bottom row are missense mutations. Blue and yellow hexagons represent key cysteine and histidine amino acids, respectively, necessary for zinc ion interaction. RING finger C3HC4 is a protein-binding domain responsible for ubiquitin ligase activity. Zinc finger C3H1 are RNA binding domains. Makorin type Zinc finger is a specific Cys–His domain identified in the proteins of the makorin family. Notably, 15 mutations (27%) were detected between the first 2 C3H1 domains, 11 of which are frameshift. Mutations also tend to cluster within the C3HC4 RING finger domain (20%), the vast majority of which are missense.

Figure 5.

Schematic representation of the human DLK1 gene (A) and protein (B), respectively. (A) Human DLK1 gene (transcript ENST00000341267.9): clear blue boxes indicate the coding sequences (5 exons) of the gene. The localization of the allelic variants identified in familial CPP (63, 191) are indicated by arrows.(B) Human DLK1 protein structure (P80370): the orange circle indicates the signaling peptide; dark blue boxes indicate the six EGF-like repeats. Blue star indicates the extracellular TACE (ADAM17) proteolytic cleavage domain. Purple boxes indicate the region of the protein affected by the mutation in DLK1. The numbers represent the amino acid positions of the indicated domain. EGF: epidermal growth fator. Adapted from Montenegro et al. (192).