Puberty: Physiology and Abnormalities, 1st ed. 2016

2. Genetics of Puberty

Shehla Tabassum  and Salman Kirmani 


Department of Diabetes, Endocrinology and Metabolism, Aga Khan University, Faculty Office Building, Stadium Road, Karachi, 74800, Pakistan


Departments of Paediatrics and Child Health, Aga Khan University Hospital, 3500, Stadium Road, Karachi, 74800, Sindh, Pakistan

Shehla Tabassum


Salman Kirmani (Corresponding author)



PubertyGeneticsPhysiologyMechanismSexual maturation

Puberty is defined as the physical transition from sexual immaturity to being sexually mature. Adolescence is sometimes considered a synonymous term, but implies more of a psychosocial maturation that comes with puberty. The mean age for the onset of first signs of puberty among girls is around 10.5 years of age (range, 8–13 years), while among boys, it is around 11.5 years (range, 9–14 years) [14]. Some variability occurs between individuals with regard to the timing and sequence of pubertal maturation. However, most of boys and girls follow a predictable course through pubertal maturation.

Pubertal onset in both girls and boys appears to be occurring earlier all over the world as compared to that reported in the literature previously [57]. Several factors like increased BMI and fat mass have been implicated in causing this earlier pubertal onset, but substantial evidence is still lacking in this regard. Also, pubertal timing varies significantly between different ethnic groups. Genetics seem to play an important role in causing these racial/ethnic differences [8].

Gonadotropin-releasing hormone (GnRH) is the master hormone of the reproductive endocrine system, largely controlling the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from pituitary gonadotrope cells. An increase in the pulsatile secretion of GnRH from the hypothalamus is considered to be a critical hormonal event in puberty. FSH and LH then evoke steroidogenesis and gametogenesis from the gonads, culminating in secondary sexual features’ development and fertility. There are multiple other factors involved in the initiation of puberty as well, and the complex interactions between genetic and environmental factors controlling this process are just beginning to be understood (Fig. 2.1).


Fig. 2.1

Multiple factors implicated in pubertal onset . CNS central nervous system, GnRH gonadotropin-releasing hormone, LH luteinizing hormone, FSH follicle-stimulating hormone (Reprinted from Martos-Moreno GA, Chowen JA, Argente J. Metabolic signals in human puberty: Effects of over and Undernutrition. Molecular and Cellular Endocrinology 2010; 324(1–2): 70–81. With permission from Elsevier.)

Regulation of Puberty

Puberty is a mysterious phenomenon, and not all is known to answer the various complicated steps occurring in this process. Several mechanisms have been implicated in the onset of puberty. The process seems to undergo neuropeptide, genetic, metabolic, and environmental regulation.

Neuropeptide Regulation of Puberty

A sustained increase in pulsatile release of gonadotrophin-releasing hormone (GnRH) from the hypothalamus is an essential, final event that defines the initiation of puberty. This depends on coordinated changes in transsynaptic and glial–neuronal communication, consisting of activating neuronal and glial excitatory inputs to the GnRH neuronal network and the loss of transsynaptic inhibitory tone.

The prevalent excitatory systems stimulating GnRH secretion involve a neuronal component and a glial component. The neuronal component consists of excitatory amino acids such as glutamate and peptides such as kisspeptin and neurokinin B. The glial component uses growth factors such as TGF-β, EGF, IGF-1,and bFGF and small molecules for cell–cell signaling such as SynCAM1 and RPTPβ.

KiSS1, located on chromosome 1q32.1, encodes the peptide kisspeptin, which acts via its receptor, encoded by the gene KISS1R (also known as GPR54) located on 19p13.3. It is thought that KISS1 signaling through KISS1R in the hypothalamus at the end of the juvenile phase of development may contribute to the pubertal resurgence of pulsatile GnRH release. The three key features of the kisspeptin–Gpr54–GnRH neuron axis leading up to puberty are (i) the expression of adult-like levels of Gpr54 mRNA in GnRH neurons well in advance of puberty, (ii) a modest increase in the electrical response of GnRH neurons to Gpr54 activation across postnatal development, and (iii) the “sudden” appearance of kisspeptin fibers surrounding GnRH neuron cell bodies/proximal dendrites just prior to puberty onset. Another important pathway in the initiation of puberty may be TAC3 signaling. TAC3 is located on chromosome 12q13.3, and the gene that encodes its receptor TACR3 on chromosome 4q24 and loss-of-function mutation in these genes have been associated with hypogonadotropic hypogonadism [9].

GABAergic and opiatergic neurons provide transsynaptic inhibitory control to the system, but GABA neurons also exert direct excitatory effects on GnRH neurons. New evidence suggests that additional peptides inhibit GnRH neuronal activity. The discovery of such gonadotropin-inhibitory factors, examples of which include the RF amide peptides, RFRP1 and RFRP3 (encoded by the QFRP gene on chromosome 9q34.12), has further clarified the role of genes that inhibit the GnRH axis until the appropriate signals to initiate puberty come into play [10].

Other pathways, especially in the appetite control center of the hypothalamus , have also been shown to influence pubertal onset. Neuropeptide Y (NPY) and agouti-related peptide (AgRP) are orexigenic peptides that have been found to influence the production of pro-opiomelanocortin (POMC), another neuropeptide which affects normal pubertal onset [11].

Genetic Factors Regulating Puberty

Genetic factors have been established to account for 50–75 % of the variability in timing of normal pubertal onset. Several genetic loci have been identified which are associated with age of pubertal onset. The genetic mechanisms that provide encompassing coordination to this cellular network are not clearly known. The timing of puberty varies greatly among healthy individuals in the general population and is influenced by both genetic and environmental factors [8]. The high correlation of the onset of puberty seen within racial/ethnic groups, within families, and between monozygotic compared to dizygotic twins all provides evidence for genetic regulation of pubertal timing. These data suggest that 50–80 % of the variation in pubertal timing is determined by genetic factors. Environmental and physiologic effects also influence the timing of puberty, and there is evidence supporting secular trends in the timing of puberty. It is possible that gene by environment interactions plays an important role in regulating the timing of puberty.

It is tempting to consider that a single gene may be responsible for the initiation of puberty, since mutations in genes such as GNRHR, GPR54, TAC3, TACR3, and KiSS1 result in pubertal failure [12] (Table 2.1). Functional studies have failed to demonstrate that any one of these single genes plays a commanding role in synchronizing the neuronal and glial networks involved in the initiation of puberty. This has led to the current concept of genetic networks regulating the neuroendocrine control of puberty initiation [13]. This network is envisioned to be a host of functionally related genes hierarchically arranged. The highest level of control in this network is likely provided by transcriptional regulators that, by directing expression of key subordinate genes, impose an integrative level of coordination to the neuronal and glial subsets involved in initiating the pubertal process.

Table 2.1

Genes implicated in the disorders of delayed puberty







GnRH secretion


GPR54 (KiSS1R)

Kisspeptin receptor

GnRH secretion stimulation



Gonadotropin-releasing hormone

GnRH synthesis



GnRH receptor

GnRH signaling



Neurokinin B




Neurokinin B receptor




Fibroblast growth factor 8

Migration of GnRH neurons



Receptor for FGF8 protein

Migration of GnRH neurons




Migration of GnRH neurons



Prokineticin receptor

Migration of GnRH neurons



Chromodomain helicase DNA-binding protein 7

Development of GnRH neurons

CHARGE syndrome, KS/NHH


Nasal embryonic LHRH factor

Migration of GnRH neurons




Migration of GnRH neurons




GnRH secretion

Obesity and HH


Leptin receptor

GnRH secretion

Obesity and HH


Prohormone convertase

Cleavage of POMC

Obesity and HH


Pituitary transcription factor

Pituitary development



Pituitary transcription factor

Pituitary development



Pituitary transcription factor

Pituitary development


GnRH gonadotropin-releasing hormone, NHH normosmic hypogonadotropic hypogonadism, HH hypogonadotropic hypogonadism, KS Kallmann syndrome, POMC pro-opiomelanocortin

The use of new techniques of genetic analysis coupled to systems biology strategies should provide not only the experimental bases supporting this concept but also unveil the existence of crucial components of network control not yet identified. The question of whether the first step in the initiation of puberty is a loss of central restraint, or the activation of stimulatory inputs to GNRH neurons still remains unanswered. It may very well be that transcriptional repression and activation of key genes occur simultaneously to orchestrate this complex process. One recent advance in this direction is the identification of the polymorphisms with age at menarche in the leptin and leptin receptor genes in humans [1415]. In addition, we are learning more about various transcription factors such as thyroid transcription factor 1 (TTF1) and a transcription factor encoded by the gene C14ORF4 located on chromosome 14q24.3 which modulate gonadotropin-releasing hormone (GnRH) expression [16] (Figs. 2.2 and 2.3).


Fig. 2.2

Different genes involved in disorders of delayed puberty . HH hypogonadotropic hypogonadism, CDGP constitutional delay of growth and development (Reprinted from Gajdos ZKZ, Henderson KD, Hirschhorn JN, Palmert MR. Genetic determinants of pubertal timing in the general population. Molecular and Cellular Endocrinology 2010; 324(1–2):21–29. With permission from Elsevier.)


Fig. 2.3

Transcriptional regulation of the initiation of puberty (Reprinted from Ojeda SR, Dubay C, Lomniczi A, Kaidar G, Matagne V, Sandau US, Dissen GA. Gene networks and the neuroendocrine regulation of puberty. Molecular and Cellular Endocrinology 2010; 324(1–2):3–11. With permission from Elsevier.)

Metabolic Control of Puberty

Both growth and reproduction consume high levels of energy, requiring suitable energy stores to face these physiological functions. The state of body energy reserves is a key determinant for the onset of puberty. During the last two decades, our knowledge concerning how peptides produced in the digestive tract (in charge of energy intake) and in adipose tissue (in charge of energy storage) provide information regarding metabolic status to the CNS has increased dramatically. Moreover, these peptides have been shown to play an important role in modulating the gonadotropic axis with their absence or an imbalance in their secretion being able to disturb pubertal onset or progression [11].

Leptin is an adipocyte-derived hormone and its synthesis is directly related to the amount of body fat. Thus, it is involved in the control of energy homeostasis and modulates several neuroendocrine systems, including the HPG axis. Animal knockout models have shown that infertility is characteristic of leptin-deficient mice (ob/ob) and that this can be overcome by leptin treatment. Humans that are leptin deficient due to homozygous gene mutations present with hypogonadotropic hypogonadism, with long-term recombinant leptin treatment being able to achieve pulsatile nocturnal gonadotropin secretion in these patients. Humans with leptin receptor deficiency present with different degrees of hypogonadotropic hypogonadism.

Leptin is considered to be the main peripheral signal providing information about the body’s energy stores to the hypothalamic circuits in charge of controlling energy homeostasis, thus communicating this information to the HPG axis by means of mechanisms that are far from being fully understood. Leptin appears to play a permissive role in the initiation of puberty and in the maintenance of the reproductive function . The earlier initiation of puberty seen in obese children may also be partly explained by higher leptin levels. The role of other adipokines such as adiponectin and resistin on the HPG axis is currently poorly understood.

Growing evidence suggests that insulin and leptin interact to downregulate arcuate nucleus (ARC) production of orexigenic peptides such as NPY and AgRP and, in collaboration with serotonin, enhance POMC production and release. Thus, insulin could be another peripheral metabolic signal involved in HPG axis functioning.

Ghrelin is a gut-derived hormone, whose function as a growth hormone secretagogue is well described. More recently, it has been shown that ghrelin modulates energy homeostasis by stimulating the expression of the genes encoding NPY and AgRP in the arcuate nucleus of the hypothalamus and by binding to presynaptic terminals of arcuate NPY and POMC neurons, respectively, stimulating and inhibiting their activity and peptide release. This results in a net orexigenic effect, functionally opposite to that produced by leptin. Thus, it is currently thought that ghrelin plays a role in reporting information regarding the fuel availability in the body to the CNS and that there is an inverse relationship between activation of the HPG axis and ghrelin levels. The role of other gut-derived factors such as peptide YY (PYY) is currently being explored.

Environmental Influences on Puberty

Since genetic background explains 50–80 % of variability in the timing of puberty, it is not surprising that the observed environmental effects are rather modest when individual exposures are assessed. The fact that the age of onset of puberty has been declining in the USA since the mid-1990s, with similar trends are being seen more recently in Europe, points toward such rapid changes having environmental rather than genetic causes [17].

Endocrine-disrupting chemicals have thus been implicated as being such environmental factors affecting pubertal onset. Endocrine disrupters can cause pubertal disorders by several mechanisms. They can act as hormone agonists or antagonists or both depending on the dose and background hormone levels, i.e., the same compound can be an agonist when the level of endogenous hormone is very low (childhood), whereas it can be an antagonist when the real hormone is available (adulthood). Multiple chemical exposures have been considered, but definitive studies are lacking. Examples of such chemicals include polychlorinated and polybrominated biphenyls (PCBs and PBBs), phthalates, dioxins, DDT, and lead. Apart from the association of lead and delayed puberty, the evidence is unclear.


It is now clear that initiation of puberty involves complex neurohormonal stimuli that are regulated by various genetic and environmental factors. Advances in genetic technologies and a systems biology approach will help with diagnosis and treatment of disorders of pubertal development and help us understand environmental influences that perturb the balance of pubertal development.



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