Current Opinion in Endocrinology, Diabetes & Obesity:
GROWTH AND DEVELOPMENT: Edited by Lynne L. Levitsky
Control of puberty: genetics, endocrinology, and environment
Choi, Jin-Hoa,b; Yoo, Han-Wooka
aDepartment of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
bReproductive Endocrine Unit of the Department of Medicine, Harvard Reproductive Endocrine Sciences Center, Massachusetts General Hospital, Boston, Massachusetts, USA
Correspondence to Jin-Ho Choi, MD, PhD, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea. Tel: +82 2 3010 3991; fax: +82 2 473 3725; e-mail: email@example.com
Purpose of review: The aim of this review is to summarize recent advances regarding the genetic components of the complex and coordinated process of puberty, an update of the genes implicated in disorders of puberty, the endocrinologic changes of puberty, and influences of environment in the light of our current understanding of the mechanism of the onset of puberty.
Recent findings: The timing of puberty varies greatly in the general population among ethnic groups throughout the world, suggesting the genetic control of puberty. Several studies on the pathological conditions of pubertal onset provide unique information about the interactions of either the genetic susceptibility of or environmental influences on hypothalamic control of pubertal onset. However, these findings suggested that no isolated pathway or external factor is solely responsible for the neuroendocrine control of puberty.
Summary: Puberty is initiated by gonadotropin-releasing hormone from the hypothalamus followed by a complex sequence of endocrine changes and is regulated by both genetic and environmental factors. New attempts to use genetics and genomics might enhance our understanding of the spectrum of pubertal development.
Puberty is the process of transition from childhood to adulthood and is an important developmental stage during which secondary sex characteristics appear, adolescent growth spurt occurs, reproductive capacity is achieved, and profound psychological changes take place . Puberty results from complex, coordinated neuroendocrine mechanisms involving the maturation and activation of the hypothalamic–pituitary–gonadal (HPG) axis [1,2].
The wide variations among the timing and tempo of normal puberty among normal individuals throughout the world are influenced by both genetic and environmental factors [3–5]. The identification of genes involving pubertal onset has been difficult because the genetic control of the variance in pubertal timing is regulated by complex polygenic traits, and interactions between genetic variants and environmental exposures [4,6].
Under physiological conditions, factors affecting the genetic control of hypothalamic functions are predominant in determining the individual variations in timing of pubertal onset. However, in pathological conditions, these variations can involve different genetic susceptibilities and the interactions of environmental factors . The study of pathological states, such as single gene defects that result in central precocious puberty (CPP) and isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD), have provided valuable insights into the genes that regulate GnRH activity and pathways and modulate pubertal onset and progression, as well as the genetic basis of disorders in pubertal timing. Mutations in specific genes involved in IGD have been identified but how these genes regulate the timing of puberty in the general population or in populations with constitutional delay of growth and puberty (CDGP) remains to be determined . It can be assumed that some of the genes involved in the pathogenesis of delayed or absent puberty may also be candidate genes for mutations that underlie precocious puberty.
GENETIC CONTROL OF PUBERTY IN NORMAL GENERAL POPULATION
Although environmental and metabolic factors are critical regulators of the HPG axis and the timing of puberty, genetic background plays an important role in regulating variations in pubertal timing within the general population at any particular point in time [4,7].
The timing and tempo of puberty is controlled by regulatory gene networks composed of multiple functional modules operating in overlapping of partially redundant pathways instead of strict hierarchies . Many genes are involved in the control of these cellular networks and in the control of the pubertal process as a whole. The KISS1/KISS1R system is a critical component of the HPG axis and is necessary for pubertal onset . KISS1 encodes several kisspeptins, which are the ligands that bind to the G-protein coupled receptor KISS1R. Studies of several mammalian species have shown that kisspeptins stimulate the secretion of gonadotropins from the pituitary by stimulating the release of GnRH from the forebrain after the activation of KISS1R . Kisspeptin is expressed abundantly in the arcuate nucleus (ARC) and the anteroventral periventricular nucleus of the forebrain . Kiss1 neurons in the ARC are plausible generators of GnRH pulses through a system of pulsatile kisspeptin release shaped by the coordinated action of neurokinin B and dynorphin A that are coexpressed in Kiss1 neurons (KNDy neurons) . Hypothalamic levels of Kiss1 and KISS1R mRNA increase dramatically at puberty. Thus, it is clear that activation of KISS1R by kisspeptins plays a pivotal role in the onset of puberty . However, it is not yet known whether the KISS1/KISS1R system is the initial trigger of puberty or whether it acts as a downstream effector of other regulatory factors .
Epidemiological observations suggest that the onset of pubertal timing is highly correlated within racial/ethnic groups, within families with CDGP, and between monozygotic compared with dizygotic twins [3,4,7,13]. It is interesting to note that most boys and girls destined to enter puberty late have a family history of later pubertal development and follow a characteristic program of linear growth throughout childhood, suggesting that variations in the tempo of growth and puberty may well represent the unfolding of a complex mixture of genetic variables . In a study of 184 pairs of monozygotic and dizygotic twin girls, breast development and age at menarche showed a high degree of genetic correlation, inferring that a common set of genes control events in puberty . These findings suggest that 50–80% of the variation in pubertal timing is regulated by genetic factors .
Some candidate genes have been found to exhibit particular single nucleotide polymorphisms (SNPs) associated with alterations in pubertal timing by large-scale genome-wide association studies (GWAS) [15▪]. In Japanese women, early menarche was found to be associated with the A2 polymorphism of CYP17 controlling androgen biosynthesis and thereby possibly accounting for increased serum estradiol levels . However, in American girls, CYP17 alleles were not associated with early breast development. Instead, this event was strongly associated with the A4 allele of CYP3, an enzyme involved in testosterone catabolism . Recently, GWAS have identified the first loci with common variations that were reproducibly associated with population variations at the timing of puberty. These loci were identified at 6q21 in or near LIN28B and at 9q31.2. Variants of at least 10 other genes are also associated with early menarche [6,18–20]. However, the specific genetic factors that regulate the variation in pubertal timing in the general population or in populations with CDGP remain to be discovered.
GENETIC DEFECTS IN PRECOCIOUS PUBERTY
Only a few molecular defects including mutations and SNPs of KISS1, KISS1R, NPY, and LIN28B, have been identified in patients with CPP [21▪▪,22]. Familial CPP is characterized by an autosomal dominant mode of transmission with incomplete penetrance affecting mostly girls . A heterozygous missense mutation in KISS1R, which leads to prolonged activation of kisspeptin-responsive intracellular signaling pathways, has been reported in a girl with idiopathic CPP . Heterozygous mutations in KISS1, the gene encoding the ligand for KISS1R, have also been described as a cause of CPP . Further molecular investigation of familial cases with idiopathic CPP might enable us to verify the hypothesis regarding the genes involved in CPP and might contribute to the understanding of the pathogenesis of CPP.
Single gene defects in peripheral precocious puberty have been recognized rarely. One condition is familial male-limited precocious puberty or testotoxicosis, which is caused by activating mutations in LHR. The McCune–Albright syndrome is also characterized by a peripheral precocious puberty associated with postzygotic activating mutations in GNAS, leading to a group of cells with constitutively active adenylate cyclase .
GENETIC DEFECTS IN ISOLATED GONADOTROPIN-RELEASING HORMONE DEFICIENCY
The study of IGD has led to the identification of several genes that play critical roles in the development and regulation of the HPG axis and olfactory structures, but the specific genetic factors that regulate variation in pubertal timing in the general population are just emerging [4,6]. The genes known to cause IGD are illustrated in Table 1. The genes implicated in the etiology of IGD vary from those that are purely neurodevelopmental genes that impair GnRH development and migration (KAL1 and NELF) to those that are assumed to be purely neuroendocrine genes (GNRH1, GNRHR, KISS1, KISS1R, TAC3, and TACR3). Certain genes have now been implicated in both developmental and neuroendocrine function (FGF8, FGFR1, PROK2, PROKR2, and CHD7) [27▪▪]. Mutations involving neurodevelopmental pathways cause Kallmann syndrome with anosmia/hyposmia, although defects in neuroendocrine pathways lead to normosmic idiopathic hypogonadotropic hypogonadism (nIHH) [27▪▪].
The first identified gene involved in Kallmann syndrome is KAL1, which encodes anosmin, a cellular matrix protein required for the normal migration of olfactory processes and GnRH neurons from their common site of origin, the olfactory placode . GNRHR was the first gene discovered to cause autosomal recessive hypogonadotropic hypogonadism . However, extensive analyses suggested that genetic variation in GNRH1 or GNRHR is not a common cause of delayed puberty in the general population . The KISS1/KISS1R signaling complex was demonstrated as an important regulator of the HPG axis in 2003 by two independent groups reporting deletions and inactivating mutations of KISS1R in patients with hypogonadotropic hypogonadism [9,30]. Recently, mutations in CHD7, a gene responsible for CHARGE (Coloboma, Heart defects, choanal Atresia, Retardation of growth and development, Gonadal defects, and Ear/hearing abnormalities, MIM 214800) syndrome, which shares some developmental features with Kallmann syndrome, were identified in patients with both nIHH and Kallmann syndrome . IGD accompanied by obesity can result from defects in LEP, LEPR, and PC1, which highlights the importance of nutrition in modulating the HPG axis. People with a homozygous mutation in LEP or LEPR not only have morbid obesity but also a striking delay in puberty owing to IGD. However, recent association studies have found no substantial association between common polymorphisms in LEP or LEPR and CDGP or age at menarche in the general population . Other causes of hypogonadotropic hypogonadism include mutations in genes that are critical to HPG development, including DAX1, SF1, and several pituitary transcription factors (HESX1, LHX3, and PROP1) .
IGD can result from the combination of mutations in different genes [33,34]. One of the patients in this series was heterozygous for both a PROKR2 mutation and a KAL1 mutation, suggesting a possible digenic mode of inheritance . A heterozygous deletion in NELF and FGFR1 has been reported as a component of digenic Kallmann syndrome, but is not clear whether mutations in NELF alone lead to Kallmann syndrome . Cases of reversible hypogonadotropic hypogonadism have also been reported , further blurring the distinction between IGD and CDGP. These reports likely represent only the beginning of our understanding of the roles that multigenic inheritance and modifier genes play in the phenotypic variability within IGD.
ENDOCRINOLOGIC CHANGES DURING PUBERTY
Gonadotropin levels are low at birth. A transient increase during the first months of life has been termed ‘minipuberty’. Thereafter, levels return to a very low, often undetectable range during the prepubertal phase as a result of intrinsic restraint, ‘the juvenile pause’ . The onset of puberty is characterized by the increase in amplitude of GnRH pulses and, consequently, of luteinizing hormone and follicle-stimulating hormone (FSH) pulses, initially at night, and then as puberty advances, throughout a 24-h period [4,36].
The timing of puberty can be influenced by signals involving neurotransmitters and neuropeptides that originate in the hypothalamus, in addition to peripheral or gonadal signals . The pubertal activation of GnRH-release requires coordinated changes in excitatory and inhibitory inputs to GnRH-secreting neurons. These inputs are provided by both transsynaptic and glia-to-neuron communication pathways . The transsynaptic changes consist of a coordinated increase in excitatory inputs and a reduction in inhibitory influences. The EAP1 protein localizes to neuronal nuclei and is able to transregulate the promoter activity of genes involved in the transsynaptic control of GnRH secretion . GABAergic and opiatergic neurons provide transsynaptic inhibitory control to the system, but GABA neurons also exert direct excitatory effects on GnRH neurons . The glial component of the system is mostly facilitatory, and it is provided by growth factors and small diffusible molecules that directly or indirectly stimulate GnRH secretion . Kisspeptin neurons of the ARC produce two additional peptides: neurokinin B (TAC3), which is encoded by a gene recently shown to be required for puberty to occur , and dynorphin, an opioid peptide that inhibits GnRH secretion . These observations indicate that the excitatory transsynaptic regulation of GnRH secretion is provided by neurons that use glutamate, kisspeptin, and perhaps neurokinin B for transsynaptic communication  (Fig. 1).
Leptin, and insulin-like growth factor-1 (IGF-1) have been shown to be involved in the control of GnRH secretion, but their role in the timing of puberty remains controversial . The pubertal growth spurt results mainly from the synergistic effect of the gonadal sex steroids, growth hormone, and IGF-1, all of which show a significant increase in serum levels during this period . Both androgens and estrogens also appear to have a direct growth-modulating effect on the growth plate by stimulating the local production of IGF-1 and other growth factors .
ENVIRONMENTAL INFLUENCES ON PUBERTY
It has been well established that pubertal onset may be related to environmental conditions, such as light, geographic location , nutrition, chronic diseases, frequent infectious diseases, pollution , stressful events, interfamilial relationships , and exposure to endocrine-disrupting chemicals (EDCs) . Environmental factors may also play a prominent role in situations. There are secular trends in the advancement in the onset of breast development seen in some industrialized countries and an increased incidence of precocious puberty in children migrating to such countries .
Environmental effects on the mechanism of pubertal onset may start during intrauterine life. Earlier onset of menarche, more rapid progression of puberty, and increased prevalence of polycystic ovary disease and premature adrenarche have been described in girls with low birth weight or intrauterine growth retardation .
Nutrition is likely to play a key role in the timing of puberty and can explain, at least partially, the downward secular trend in the timing of puberty . In a longitudinal assessment of a birth cohort of 156 girls, it was noted that girls who were light and long at birth and had greater circulating fat mass in mid-childhood had earlier ages of menarche . Rapid weight gain early in infancy has been linked to relatively early puberty . A high calorie diet and accelerated body weight gain during juvenile period significantly advance the onset of puberty and serum leptin levels were elevated before early menarche [47▪]. Leptin is considered the link between adipose tissue and growth. Leptin, which is produced and secreted by white adipose tissue, has a crucial role in pubertal onset, the pubertal process, and pubertal growth . The increased levels of leptin just before the onset of puberty might induce both augmented proliferation and differentiation of chondrocytes in the epiphyseal growth plate . However, leptin itself is not considered a strong metabolic trigger for the onset of puberty, although it acts as a permissive signal for the onset of puberty .
Migration may interrupt exposure to endocrine disrupters, and precocious puberty might then result from withdrawal of their negative feedback effect and/or from accelerated hypothalamic maturation. The high incidence of precocious puberty in foreign children migrating to Belgium and the detection in their plasma of long-lasting 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (DDT) residue suggests the potential role of environmental EDCs in the early onset of puberty . DDT is able to promote hypothalamic maturation, exerting an inhibitory effect at the pituitary level that is most effective in prepubertal individuals . In addition, early pubertal development and an increased incidence of precocious puberty have been noticed in children migrating to a number of Western European countries . These differences in the timing of puberty seem to result from interactions of environmental factors irrespective of genetic susceptibility, as children migrating from several continents and belonging to several ethnic groups are involved .
There is a great variation in the timing and course of puberty in the general population, which is influenced by familial, ethnic, and sex patterns of signals or signal receptors in the hypothalamus. Puberty is likely regulated by an intricate and coordinated gene network controlling several physiological pathways in humans. However, the exact primary mechanisms that underlie activation of HPG axis maturation and regulate the onset of puberty remain to be discovered. Further investigation of the maturation of GnRH secretion and pituitary responsiveness is vital to understanding the mechanisms of the wide spectrum of pubertal development.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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endocrine disrupting chemical; gonadotropin-releasing hormone; isolated gonadotropin-releasing hormone deficiency; precocious puberty
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