REVIEW

CURRENT
OPINION Control of puberty: genetics, endocrinology,
and environment
Jin-Ho Choi a,b and Han-Wook Yoo a

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
Downloaded from https://journals.lww.com/co-endocrinology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3ZRPSXgVoeNmk/yYblKMeKkDzR4ZD1TBUDWoDLiWFSU8= on 09/17/2018

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.
Keywords
endocrine disrupting chemical, gonadotropin-releasing hormone, isolated gonadotropin-releasing hormone
deficiency, precocious puberty

INTRODUCTION pathological conditions, these variations can

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, reproduc-
tive capacity is achieved, and profound psychologi-
cal changes take place [1]. 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 identi-
fication of genes involving pubertal onset has been
difficult because the genetic control of the variance
in pubertal timing is regulated by complex poly-
genic traits, and interactions between genetic
variants and environmental exposures [4,6].
Under physiological conditions, factors affect-
ing the genetic control of hypothalamic functions
are predominant in determining the individual vari-
ations in timing of pubertal onset. However, in
involve different genetic susceptibilities and the
interactions of environmental factors [2]. 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 pro-
gression, as well as the genetic basis of disorders
in pubertal timing. Mutations in specific genes
a
Department of Pediatrics, Asan Medical Center Children’s Hospital,
University of Ulsan College of Medicine, Seoul, Korea and 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: jhc@amc.seoul.kr
Curr Opin Endocrinol Diabetes Obes 2013, 20:62–68
DOI:10.1097/MED.0b013e32835b7ec7

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KEY POINTS
 The timing and tempo of puberty is controlled by
regulatory gene networks and the interactions of
environmental factors.
 Several genes that play important roles in the
development and regulation of HPG axis have been
identified as causative genes involving precocious
puberty and isolated GnRH deficiency.
 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).
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 [7]. 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 hier-
archies [8]. 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 sys-
tem is a critical component of the HPG axis and is
necessary for pubertal onset [9]. 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 kiss-
peptins stimulate the secretion of gonadotropins
from the pituitary by stimulating the release of
GnRH from the forebrain after the activation of
KISS1R [10]. Kisspeptin is expressed abundantly in
the arcuate nucleus (ARC) and the anteroventral
periventricular nucleus of the forebrain [10]. Kiss1
neurons in the ARC are plausible generators of
GnRH pulses through a system of pulsatile kisspep-
tin release shaped by the coordinated action of
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Control of puberty Choi and Yoo
neurokinin B and dynorphin A that are coexpressed
in Kiss1 neurons (KNDy neurons) [11]. Hypothala-
mic levels of Kiss1 and KISS1R mRNA increase
dramatically at puberty. Thus, it is clear that acti-
vation of KISS1R by kisspeptins plays a pivotal role
in the onset of puberty [10]. 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 [12].
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 [4]. In a study of 184 pairs of
monozygotic and dizygotic twin girls, breast devel-
opment and age at menarche showed a high degree
of genetic correlation, inferring that a common set
of genes control events in puberty [14]. These find-
ings suggest that 50–80% of the variation in puber-
tal timing is regulated by genetic factors [6].
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 polymor-
phism of CYP17 controlling androgen biosynthesis
and thereby possibly accounting for increased
serum estradiol levels [16]. 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 [17]. 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
www.co-endocrinology.com 63
 Growth and development
&&
been identified in patients with CPP [21 ,22]. Fam-
ilial CPP is characterized by an autosomal dominant
mode of transmission with incomplete penetrance
affecting mostly girls [23]. 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 [24]. Heterozygous mutations in
KISS1, the gene encoding the ligand for KISS1R, have
also been described as a cause of CPP [25]. Further
molecular investigation of familial cases with idio-
pathic 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 pub-
erty have been recognized rarely. One condition is
familial male-limited precocious puberty or testo-
toxicosis, 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 [26].
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 develop-
ment 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 hypo-
gonadism (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 [4]. GNRHR was the first gene discovered
64 www.co-endocrinology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
to cause autosomal recessive hypogonadotropic
hypogonadism [28]. However, extensive analyses
suggested that genetic variation in GNRH1 or
GNRHR is not a common cause of delayed puberty
in the general population [29]. The KISS1/KISS1R
signaling complex was demonstrated as an import-
ant regulator of the HPG axis in 2003 by two inde-
pendent groups reporting deletions and inactivating
mutations of KISS1R in patients with hypogonado-
tropic 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 [31].
IGD accompanied by obesity can result from defects
in LEP, LEPR, and PC1, which highlights the import-
ance 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 associ-
ation between common polymorphisms in LEP or
LEPR and CDGP or age at menarche in the general
population [29]. 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) [32].
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 [33]. A
heterozygous deletion in NELF and FGFR1 has been
reported as a component of digenic Kallmann syn-
drome, but is not clear whether mutations in NELF
alone lead to Kallmann syndrome [33]. Cases of
reversible hypogonadotropic hypogonadism have
also been reported [35], further blurring the distinc-
tion between IGD and CDGP. These reports likely
represent only the beginning of our understanding
of the roles that multigenic inheritance and modi-
fier 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,
Volume 20  Number 1  February 2013
 Control of puberty Choi and Yoo

Table 1. Genes involved in hypogonadotropic hypogonadism

Genes Location Structure Inheritance Phenotypes

KAL1 Xp22.3 14 exons XR KS, unilateral renal agenesis, bimanual synkinesia,

high arched palate
FGFR1 (KAL2) 8p11.2-p11.1 18 exons AD KS, cleft lip/palate, skeletal anomalies (hand and foot),
external ear hypoplasia, dental agenesis
PROKR2 (KAL3) 20p13 2 exons AR, AD KS, nIHH, AHH
PROK2 (KAL4) 3p21.1 4 exons AR, (AD?) KS
CHD7 (KAL5) 8q12.1 38 exons AD<Sporadic CHARGE syndrome, KS, nIHH
FGF8 (KAL6) 10q24 6 exons AD nIHH, AHH, cleft lip/palate, skeletal anomalies (hand and foot),
external ear hypoplasia, dental agenesis
GNRH1 8p21-p11.2 3 exons AR nIHH
GNRHR 4q21.2 3 exons AR nIHH
KISS1 1q32 3 exons AR nIHH
KISS1R 19p13.3 5 exons AR, AD nIHH (AR), Precocious puberty (AD)
TAC3 12q13-q21 7 exons AR nIHH, microphallus, cryptorchidism, reversal of GnRH deficiency
TACR3 4q25 5 exons AR nIHH, microphallus, cryptorchidism, reversal of GnRH deficiency
NELF 9q34.3 15 exons Digenic KS
NR0B1/DAX1 Xp21.3-p21.2 2 exons XR X-linked adrenal hypoplasia congenita, hypogonadotropic
hypogonadism
LEP 7q31.3 3 exons AR nIHH, severe obesity
LEPR 1p31 20 exons AR nIHH, severe obesity
LHb 19q13.32 3 exons AR, (AD) Isolated LH deficiency
FSHb 11p13 3 exons AR Isolated FSH deficiency
PHF6 Xq26.3 11 exons XL Borjeson–Forssman–Lehmann syndrome

AR, autosomal recessive; AD, autosomal dominant; CHARGE, Coloboma, Heart defects, choanal Atresia, Retardation of growth and development, Gonadal
defects, and Ear/hearing abnormalities, MIM 214800; FSH, follicle-stimulating hormone; KS, Kallmann syndrome; LH, luteinizing hormone; nIHH, normosmic
idiopathic hypogonadotropic hypogonadism; XL, X-linked; XR, X-linked recessive.

‘the juvenile pause’ [4]. 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 neuro-
peptides that originate in the hypothalamus, in
addition to peripheral or gonadal signals [3]. The
pubertal activation of GnRH-release requires coor-
dinated changes in excitatory and inhibitory inputs
to GnRH-secreting neurons. These inputs are pro-
vided by both transsynaptic and glia-to-neuron
communication pathways [37]. The transsynaptic
changes consist of a coordinated increase in excit-
atory inputs and a reduction in inhibitory influ-
ences. The EAP1 protein localizes to neuronal
nuclei and is able to transregulate the promoter
activity of genes involved in the transsynaptic con-
trol of GnRH secretion [38]. GABAergic and opiater-
gic neurons provide transsynaptic inhibitory
control to the system, but GABA neurons also exert
direct excitatory effects on GnRH neurons [8]. 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 [39]. Kisspeptin neurons
of the ARC produce two additional peptides: neuro-
kinin B (TAC3), which is encoded by a gene recently
shown to be required for puberty to occur [40], and
dynorphin, an opioid peptide that inhibits GnRH
secretion [41]. These observations indicate that the
excitatory transsynaptic regulation of GnRH
secretion is provided by neurons that use glutamate,
kisspeptin, and perhaps neurokinin B for transsy-
naptic communication [39] (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 pub-
erty remains controversial [3]. 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 [5]. Both androgens and estrogens
also appear to have a direct growth-modulating effect
on the growth plate by stimulating the local pro-
duction of IGF-1 and other growth factors [5].

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 Growth and development

KISS1 neuron AVPN ARC

Mediobasal hypothalamus
GNRH1/KISS1R
GABA
FGF8/FGFR1 (KAL2) Kisspeptin
TAC3/TACR3 Glutamate
PROK2/PROKR2
KAL1/NELF
LEP/LEPR
PCSK1/WDR11
SF1DAX1
Other factors GnRH
IGF-1
Leptin
FGF
Pituitary gland TGFβ
GNRHR
PROP1/HESX1
LHX3/LHX4 Inhibin B
SOX2/SOX3 LH/FSH
SF1/DAX1

Gonads
LHβ/FSHββ
LHR/FSHR Excitatory
Sex steroids
SF1/DAX1 Inhibitory

FIGURE 1. Overview of the hypothalamic–pituitary–gonadal (HPG) axis. Kisspeptin released by neurons in the anteroventral
periventricular nucleus (AVPN) and arcuate nucleus (ARC) stimulates GnRH release, which induces the release of LH and FSH.
The gonads respond to gonadotropins by secreting sex steroids, and sex steroids differentially regulate the expression of Kiss1
mRNA in different nuclei within the forebrain by inhibiting Kiss1 expression in the ARC and inducing its expression in the
AVPN. Mutations in several genes involved in each site have been shown to cause isolated GnRH deficiency in humans.

ENVIRONMENTAL INFLUENCES ON relatively early puberty [46]. A high calorie diet

PUBERTY
It has been well established that pubertal onset
may be related to environmental conditions, such
as light, geographic location [3], nutrition, chronic
diseases, frequent infectious diseases, pollution [5],
stressful events, interfamilial relationships [42], and
exposure to endocrine-disrupting chemicals (EDCs)
[43]. Environmental factors may also play a prom-
inent role in situations. There are secular trends in
the advancement in the onset of breast develop-
ment seen in some industrialized countries and an
increased incidence of precocious puberty in chil-
dren migrating to such countries [3].
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 intra-
uterine growth retardation [44].
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 [3].
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 [45]. Rapid
weight gain early in infancy has been linked to
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 [7]. 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 [48].
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
[49].
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 matu-
ration. The high incidence of precocious puberty in
foreign children migrating to Belgium and the
detection in their plasma of long-lasting 1,1,1-tri-
chloro-2,2-bis(4-chlorophenyl) ethane (DDT) resi-
due suggests the potential role of environmental
EDCs in the early onset of puberty [2]. DDT is able
to promote hypothalamic maturation, exerting an
inhibitory effect at the pituitary level that is most
effective in prepubertal individuals [50]. In addition,

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early pubertal development and an increased inci-
dence of precocious puberty have been noticed in
children migrating to a number of Western Euro-
pean countries [3]. These differences in the timing of
puberty seem to result from interactions of environ-
mental factors irrespective of genetic susceptibility,
as children migrating from several continents and
belonging to several ethnic groups are involved [3].
CONCLUSION
There is a great variation in the timing and course of
puberty in the general population, which is influ-
enced 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 mech-
anisms of the wide spectrum of pubertal develop-
ment.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.
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