Pubertal development and regulation (original) (raw)

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Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2017 Mar 1.

Published in final edited form as:

PMCID: PMC5192018

NIHMSID: NIHMS787666

Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

Correspondence to: Prof Ursula B Kaiser, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA, gro.srentrap@resiaku

Abstract

Puberty marks the end of childhood and is a period when individuals undergo physiological and psychological changes to achieve sexual maturation and fertility. The hypothalamic-pituitary-gonadal axis controls puberty and reproduction and is tightly regulated by a complex network of excitatory and inhibitory factors. This axis is active in the embryonic and early postnatal stages of life and is subsequently restrained during childhood, and its reactivation culminates in puberty initiation. The mechanisms underlying this reactivation are not completely known. The age of puberty onset varies between individuals and the timing of puberty initiation is associated with several health outcomes in adult life. In this Series paper, we discuss pubertal markers, epidemiological trends of puberty initiation over time, and the mechanisms whereby genetic, metabolic, and other factors control secretion of gonadotropin-releasing hormone to determine initiation of puberty.

Introduction

Puberty is the period of transition between childhood and adulthood, characterised by the development of secondary sexual characteristics, gonadal maturation, and attainment of reproductive capacity. Puberty and reproduction are controlled by the hypothalamic-pituitary-gonadal axis.1 Gonadotropin-releasing hormone (GnRH) is produced in the preoptic area of the hypothalamus and released from axon terminals in the median eminence in a pulsatile manner to stimulate the secretion of luteinising hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary, which in turn act on the gonads to promote gametogenesis and the production of sex steroids. In human beings, the hypothalamic-pituitary-gonadal axis is active in the mid-gestational fetus, but silenced towards the end of gestation. This restraint is removed at birth, leading to reactivation of the axis and an increase in gonadotropin concentrations.2 These concentrations then gradually decrease towards age 6 months, with the exception of FSH concentration in girls, which remains raised until age 3–4 years. In boys, testosterone concentration rises to a peak at age 1–3 months, but then falls in conjunction with the falling LH concentration.2

Prenatal and postnatal activation of the hypothalamic-pituitary-gonadal axis is associated with penile and testicular growth and testicular descent, and is therefore regarded as important for the development of male genitalia. In girls, raised concentrations of gonadotropins result in the maturation of ovarian follicles and an increase in oestradiol concentrations. This period of activity of the hypothalamic-pituitary-gonadal axis in the early stages of life is called minipuberty and has been proposed to lay the groundwork for pituitary LH and FSH responses to GnRH during the later reproductive phase of life.2

At about age 6 months in boys and 3–4 years in girls, there is an active inhibition of GnRH secretion, which persists throughout childhood. Puberty is initiated with a sustained increase in pulsatile release of GnRH from the hypothalamus after this quiescent period. The precise mechanisms that trigger the initiation of puberty remain elusive. Evidence suggests that the augmentation of activators of GnRH secretion together with the suppression of inhibitors of GnRH secretion culminates in puberty initiation. Whether the stimulatory tonus acting during minipuberty also contributes to puberty initiation is not yet clear. In this Series paper, we will discuss pubertal markers, epidemiological trends of puberty initiation, the currently known modulators of GnRH secretion, the hypothalamic-pituitary-gonadal axis, and the initiation of puberty.

Normal puberty and pubertal markers

The most visible changes during puberty are growth in stature and development of secondary sexual characteristics (figure 1). Equally profound are changes in body composition and the achievement of fertility. The first sign of puberty initiation is typically thelarche (breast development) in girls and testicular enlargement in boys. The landmark studies of Marshall and Tanner (1969), which classified puberty into five stages in girls and boys on the basis of somatic changes in breast, pubic hair, and genital development, have been widely used to assess puberty development.3,4 The ideal assessment of puberty initiation in girls is breast bud palpation. Commonly, self-description, visual assessment of breast development, or age of menarche (ie, the time of first menstrual bleeding) are used as markers of puberty in population studies, although these strategies are less accurate for assessment of the time of puberty initiation. Similarly, although testicular examination is a useful and key sign used in clinical practice when assessing boys for pubertal development, it is impractical to use in population studies of puberty. For these reasons and because of differences in study designs and methods used to assess puberty initiation, it can be difficult to determine the exact age of puberty onset in population studies. Although there is some physiological variation, puberty development usually lasts 3–4 years and consists of a series of events that typically proceed in a predictable sequence. Menarche is regarded as the final marker of puberty in girls.5 In girls with late initiation of puberty, there can be a decrease in the interval between thelarche and menarche.6 In boys, testicular enlargement is followed by an increase in growth velocity and subsequent spermarche.7

Physical changes and secondary sexual characteristics that appear during pubertal development

Changes in body composition are used to detect pubertal development. The figure shows the physical changes that occur as a result of the activation of the hypothalamic-pituitary-gonadal axis.

The development of axillary and pubic hair, a process termed pubarche, is also incorporated in the Tanner stages, but should not be used as a marker of the onset of puberty. In both sexes, pubarche is dependent on an increase in adrenal androgen production, a physiological event termed adrenarche.8 The serum concentration of dehydroepiandrosterone sulphate (DHEAS) is the best marker for the presence of adrenarche. This maturational process generally begins at about age 6 years, several years before activation of the hypothalamic-pituitary-gonadal axis (gonadarche).9 Although development of axillary and pubic hair requires adrenarchal concentrations of androgen, clinically evident pubarche does not usually appear until shortly after physical evidence of gonadarche (ie, breast development in girls and testicular enlargement in boys). Notably, adrenarche seems to be specific to human and some non-human primates, and the absence of adrenarche in human beings does not seem to prevent fertility nor to substantially affect the timing of gonadarche.10 Adrenocorticotropic hormone has been suggested as a regulator of adrenarche because of its absence in children with hypopituitarism.11 However, the precise mechanisms underlying adrenarche are still unknown. Children with precocious puberty do not have a corresponding advance in the timing of adrenarche. Similarly, patients with hypogonadotropic hypogonadism and delayed puberty have no corresponding delay of adrenarche. In both cases, their adrenal androgen concentrations are appropriate for chronological age.

The age at puberty onset varies greatly between individuals, different ethnic populations, and between the sexes; girls on average experience the onset of puberty at younger ages than boys and are more likely to have idiopathic central precocious puberty, whereas boys are more predisposed to idiopathic delayed puberty.12,13 Puberty is deemed physiological when it begins between the ages of 8 and 12 years in girls and between 9 and 14 years in boys.14 These limits are selected to be 2·5–3 SDs below and above the mean age of onset of puberty, as defined by population studies. However, population studies have limitations and thus so do the age limits used to define normal pubertal timing. The initiation of puberty at ages younger than these limits is regarded as precocious puberty and at ages beyond these limits, delayed puberty. The age of puberty onset is associated with subsequent health outcomes. Early age at menarche is a risk factor for breast cancer,15 cardiovascular disease, depression, behavioural disorders, diabetes, and increased all-cause mortality.16,17 Early puberty in boys is a risk factor for testicular cancer and delayed puberty can be a cause of being bullied, poor self-esteem, and psychosocial distress.18 A recent study19 showed that earlier or later timing of puberty in girls or boys was associated with increased risks for 48 adverse outcomes, across a range of cancer, cardiometabolic, gynaecological or obstetric, gastrointestinal, musculoskeletal, and neurocognitive categories. Most of these associations have been based on epidemiological studies and need to be validated and studied further.

Epidemiology and trends

Studies have shown a decrease in the average age of menarche between the mid-19th and the mid-20th centuries in the USA and in some countries in Europe.20 This change has been attributed to improvements in general health, nutrition, and other living conditions during this period. Although still controversial because of the limited comparability of the data from studies in different populations and the use of different methods, it has also been proposed that there was a trend towards an earlier onset of breast development and menarche in girls from 1940 to 1994.21 The amount of body fat and exposure to endocrine disruptors, particularly oestrogenic compounds and antiandrogens, have been suggested as important factors associated with this trend in pubertal timing.21 The effects of endocrine disruptors on GnRH secretion and therefore on the initiation of puberty and reproduction are still controversial and difficult to assess in human beings.22 Environmental factors might have effects on the neuroendocrine system, particularly during fetal and early postnatal life;22 however, we will not discuss the effects of specific compounds in this Series paper because of the controversies around this topic and the paucity of definitive data.

The characterisation of thelarche has varied from study to study. In some studies, breast development was characterised by visualisation only, making appropriate assessment difficult, especially in overweight or obese girls. A large cross-sectional study of about 17 000 girls done in an office setting in the USA (the Pediatric Research in Office Settings [PROS] study) used information obtained from mothers and photography, and the results suggested an advancement of pubertal development in the second half of the 20th century.23 By contrast, two European studies in which careful physical examination was used to ascertain breast development showed no substantial advance in age of puberty onset.24,25 However, in a more recent Danish study, 954 girls assessed in 2006–08 were compared with those studied in 1991–93, and substantially earlier breast development was noted in the girls born more recently.26

The assessment of secular trends in male pubertal development is even more challenging because there are so few studies analysing puberty development in boys, and pubertal markers are even less reliable in boys than in girls. Similar to what has been reported in girls, results from some studies have suggested that age of puberty onset in boys might be occurring earlier than in the past, but additional studies are required to confirm this tendency.27

There are substantial racial differences in sexual maturation; it is thought that non-Hispanic black and Mexican-American ethnic origins are independently associated with earlier pubertal development in girls.13 The age at menarche of non-Hispanic black girls is substantially earlier than that of non-Hispanic white and Mexican-American girls, and the mean age for onset of breast development in African-American girls is also earlier than that in white girls.28

Disorders of puberty

Classification of pubertal disorders

Puberty onset varies between normal individuals and there is a 4–5-year window judged to be the normal age of pubertal development. Changes in the limits of what is regarded as normal puberty initiation have occurred over the past few decades. The onset of puberty before or after these limits is deemed pathological. Precocious puberty generally has been defined as pubertal onset before age 8 years in girls and before age 9 years in boys. Because of the apparent advances in the age of onset of puberty in population studies, researchers have suggested that age 7 years in white girls, and age 6 years in African-American girls, should be used as the thresholds for classification of precocious puberty.29 However, other investigators have subsequently concluded that signs of puberty in girls aged 6–8 years should not be regarded as normal or benign as this might lead to underdiagnosis of endocrine disorders, so the appropriate thresholds for assessment have returned to the previously recommended parameters.30

Precocious puberty

Precocious puberty can be a variant of normal development—eg, premature adrenarche or isolated premature thelarche—or can be attributable to pathological conditions (panel). GnRH-dependent or central precocious puberty is caused by early maturation of the hypothalamic-pituitary-gonadal axis, resulting in pulsatile secretion of GnRH and subsequent activation of the gonads. In these cases, the sexual characteristics are appropriate for the patient’s sex (isosexual). Several neurological disorders can cause central precocious puberty, such as tumours, trauma, or malformations (panel). Chronic exposure to sex steroids from external sources or as a result of some disorders with peripheral production of sex steroids have been proposed to result in early activation of the hypothalamic-pituitary-gonadal axis.31 Most cases of central precocious puberty in girls and up to 60% of cases in boys do not have a detectable CNS lesion and are described as idiopathic central precocious puberty. Some or most of these cases might have a genetic, metabolic, or environmental component, or a combination of these factors.

Panel

Variants of normal pubertal development and classification of pubertal disorders

Variants of normal pubertal development

Isolated precocious thelarche

• Isolated breast development with no other signs of oestrogen action

Isolated precocious pubarche

• Axillary hair, increased growth velocity, and slight advancement of bone age
• Increase in adrenal hormones

Isolated precocious menarche

• Isolated vaginal bleeding without other pubertal signs or advancement of bone age

Constitutional delay of growth and puberty

• Puberty initiation between ages 14 and 18 years
• More frequent in boys with family history

Precocious puberty

Gonadotropin-dependent precocious puberty or central precocious puberty

• Without CNS abnormalities
  • Genetic causes
  • Secondary to previous chronic exposure to sex steroids (rare)
  • After exposure to endocrine disruptors (proposed mechanism)
  • Idiopathic
• CNS abnormalities
  • Tumours
  • Congenital malformations: hypothalamic hamartoma, arachnoid cyst, and others
  • Acquired diseases: infections and inflammatory processes of the CNS

Gonadotropin-independent precocious puberty or peripheral precocious puberty

• Tumour
  • Adrenal, ovarian, or testicular tumours
• Autonomous ovarian cysts
• Severe long-term untreated primary hypothyroidism
• Genetic causes
  • Testotoxicosis
  • McCune-Albright syndrome
  • Prader-Willi syndrome, Williams syndrome, Temple syndrome
  • Others

Hypogonadism

Hypogonadotropic hypogonadism

• Isolated congenital
  • With olfactory defects: Kallmann’s syndrome
  • Normal olfaction: isolated hypogonadotropic hypogonadism
• Functional hypogonadotropic hypogonadism
  • Hypothalamic amenorrhoea
  • Male functional hypogonadism
• Tumours
• Malformations
• Combined with other pituitary dysfunction
  • Congenital hypopituitarism or due to systemic disorders, drugs, or radiation exposure
• Syndromes with hypogonadotropic hypogonadism
  • Prader-Willi syndrome, Laurence-Moon-Biedl syndrome, CHARGE syndrome, Gordon’s syndrome, and others

Hypergonadotropic hypogonadism

• Turner’s syndrome
• Klinefelter’s syndrome
• Bilateral gonadal failure
• Anorchia
• Primary ovarian or testicular failure
• Radiation
• Drugs or chemotherapy
• Trauma
• Infection
• Isolated forms of gonadal failure: LH receptor and FSH receptor gene mutations

LH=luteinising hormone. FSH=follicle-stimulating hormone.

Production of sex steroids independent of the activation of the hypothalamic-pituitary-gonadal axis results in gonadotropin-independent or peripheral precocious puberty. In this form of puberty, sex hormones are usually derived from the gonads or adrenal glands, or from exogenous sources (panel). In patients with peripheral precocious puberty, the sexual characteristics can be appropriate for the child’s sex (isosexual) or inappropriate, with virilisation of girls or feminisation of boys (contrasexual).

Delayed puberty

Delayed puberty is defined clinically by the absence or incomplete development of secondary sexual characteristics by age 13 years in girls or age 14 years in boys. Delayed puberty can be a variant of normal development, known as constitutional delay of growth and puberty, when healthy teenagers spontaneously develop puberty after the upper age limit (panel). The absence or incomplete development of secondary sexual characteristics by age 18 years in both sexes is classified as hypogonadism. The absence of activation of the hypothalamic-pituitary-gonadal axis because of a defect in the CNS defines hypogonadotropic hypogonadism. This disorder can be caused by a deficiency in GnRH secretion, action, or both, also known as isolated hypogonadotropic hypogonadism. A genetic defect has been identified in approximately 40% of known cases. Alternatively, hypogonadotropic hypogonadism can have an organic cause such as a tumour, use of drugs, or inflammatory or systemic disorders (panel). Isolated hypo gonadotropic hypogonadism can be classified as Kallmann’s syndrome when associated with absence of smell (anosmia), or isolated hypogonadotropic hypogonadism when there is no effect on olfaction. Kallmann’s syndrome typically results from abnormal fetal development of GnRH neurons; both GnRH and olfactory neurons originate from the olfactory placode and migrate together into the CNS during embryogenesis.32 Impairment of the migration of these neurons is often associated with genetic defects.33–35 By contrast, isolated hypogonadotropic hypogonadism is more typically associated with normal olfactory and GnRH neuronal development, but impaired regulation of GnRH secretion.33,35 The absence of pubertal development caused by an intrinsic defect in the gonads results in hypergonadotropic hypogonadism, which can also be caused by genetic or organic disorders.

Normal physiological controls of the timing of onset and progression of puberty

Role of GnRH

In the 1970s, Belchetz and colleagues36 showed in animal models that intermittent release of GnRH is required for the activation of the pituitary-gonadal axis. Although the mechanism that causes the pulsatility of the GnRH neuronal network can be intrinsic to the GnRH neurons themselves,37 lesions of the arcuate nucleus have been shown to abolish LH pulsatility, consistent with the idea that there is a higher order input into the network of GnRH neurons regulating GnRH secretion.38 Puberty is initiated with a sustained increase in pulsatile release of GnRH from the hypothalamus after a quiescent period during childhood. Studies of agonadal human beings have shown that the prepubertal suppression of hypothalamic-pituitary-gonadal function occurs even in the absence of feedback by sex steroids, suggesting that the juvenile pause represents a state of neurally determined functional stasis rather than immaturity of the GnRH neurons.39 The exact mechanism that leads to the reinstatement of pulsatile GnRH secretion is not known, but evidence suggests that a complex interaction between nutritional, environmental, and genetic factors is involved in the regulation of puberty initiation.40

Many neurotransmitters can modify the GnRH secretory pattern, with an excitatory or inhibitory effect on GnRH secretion. During childhood the predominant pathway is believed to be the inhibitory network, which decreases around the time of puberty initiation, along with augmentation of the excitatory tonus. Studies in animal models have identified several of the regulatory components of the GnRH system. Results for these studies suggest that catecholamines and glutamate are components of the excitatory input, whereas -aminobutyric acid (GABA) might be a component of the inhibitory network.1 Studies in patients with pubertal disorders have not identified genetic defects in the genes encoding these factors, which undermines the evidence for their potential roles, but does not rule them out entirely as important for puberty initiation.

Genes involved in GnRH regulation

Overview

Data showing an association between the ages at which a mother and her children attain pubertal milestones and between the timing of puberty within ethnic groups are suggestive of genetic modulation of the reproductive endocrine axis.23,41 These and other data suggest that around 50–80% of the variation in pubertal onset might be genetically determined.40

Many studies have been done to investigate candidate mechanisms governing GnRH release; however, the most compelling evidence for specific GnRH neural inputs comes from genetic studies in patients with pubertal disorders. Two of the most important excitatory components of the GnRH network were identified with the demonstration that the genetic loss of such inputs results in failure to initiate the GnRH pulse generator at the expected time of puberty, resulting in isolated hypogonadotropic hypogonadism.42–45

Kisspeptin system

The discovery of the kisspeptin system as a crucial component for pubertal activation of the hypothalamic-pituitary-gonadal axis occurred in 2003, when loss-of-function mutations of the KISS1R (previously known as GPR54) gene were identified in individuals with isolated hypogonadotropic hypogonadism, establishing KISS1R inactivation as a cause of this disorder (table, figure 2).42,43 Physiological and pharmacological studies have shown that kisspeptin is an essential part of the complex excitatory network that regulates GnRH secretion. Administration of kisspeptin results in increases in plasma LH concentrations in healthy men,54,55 and in women kisspeptin also induces LH release, although the response varies across the menstrual cycle.56 Kisspeptin stimulates gonadotropin release less potently but in a more physiologically effective way than do current treatments with GnRH analogues.57 A non-constitutively activating mutation in KISS1R was the first identified genetic cause of central precocious puberty, reported in an adopted girl with breast development with slow progression that had first been noted at birth and that progressed at age 7 years.49 Mutations in KISS1 were also identified in patients with isolated hypogonadotropic hypogonadism and central precocious puberty, strengthening the evidence base for the association of this system with pubertal onset.47,48

Mechanisms of action of the genetic factors involved in the control of puberty onset

Important regulators of GnRH have been identified in patients with pubertal disorders. The figure depicts essential regulators of GnRH secretion in which mutations have been identified in human beings. Dashed line represents proposed pathway. FSH=follicle-stimulating hormone. GnRH=gonadotropin-releasing hormone. GnRHR=gonadotropin-releasing hormone receptor. KISS1=kisspeptin. KISS1R=kisspeptin receptor. LH=luteinising hormone. MKRN3=makorin ring finger protein 3. NKB=neurokinin B. NK3R=neurokinin B receptor. +=stimulatory effect. –=inhibitory effect. ?=proposed mechanism.

Table

Genes involved in the control of GnRH

In animal models, the KISS1 neurons appear to mediate sex steroid feedback effects in the hypothalamus.58,59 These neurons express oestrogen receptor a and receive sex steroid signals from the gonads, which regulate KISS1 expression and control the release of GnRH.60 In many mammalian species, KISS1 expression is negatively regulated in the arcuate nucleus and positively regulated in the anteroventral periventricular nucleus and preoptic area by sex steroids. The KISS1 positive regulation is believed to be important for the LH surge in females of many mammalian species.61

Tachykinins

Neurokinin B (NKB) belongs to a family of closely related peptides called tachykinins. The role of NKB in the control of reproductive function was the subject of investigation for several years because of neuroanatomical evidence for potential NKB inputs to GnRH neurons.62 It was not until 2009 that Topaloglu and colleagues44 identified NKB as an important factor for human puberty initiation, studying ten consanguineous families with multiple affected members who had isolated hypogonadotropic hypogonadism. Homozygous loss-of-function mutations in the genes encoding the NKB receptor (TACR3) and neurokinin B (TAC3) were identified, providing compelling evidence that the NKB system is necessary for the activation of the hypothalamic-pituitary-gonadal axis in puberty (table, figure 2). The report by Gianetti and colleagues63 of reversibility of isolated hypogonadotropic hypogonadism in a high proportion of patients with TACR3 mutations suggested that the NKB system is not absolutely required for GnRH regulation after the maturation of the hypothalamic-pituitary-gonadal axis. However, other studies did not show a similar frequency of reversibility,45 and it is still not definitively known whether the NKB system is essential for the excitatory GnRH regulatory network after pubertal development.

Although the effect of NKB on GnRH secretion depends on the hormonal context, administration of NKB has been shown to elicit strong stimulation of LH production mediated by GnRH in animal models.64 Neurons co-expressing kisspeptin and NKB in the human mediobasal hypothalamus often co-express substance P.65 Substance P belongs to the tachykinin family along with neurokinin B and neurokinin A. Substance P and neurokinin A have been reported to stimulate the gonadotropic axis in men.66 The regulation of gonadotropin release by the tachykinins and their receptors occurs at least partly through actions on KISS1 neurons in mice.67

Makorin ring finger protein 3

The first gene with an inhibitory effect on GnRH secretion with mutations identified in human beings was MKRN3 (table, figure 2). The identification of this novel factor in the GnRH network arose from whole-exome sequencing analysis of families with central precocious puberty.52 MKRN3 is located in the Prader-Willi syndrome critical region on chromosome 15 and before the identification of its role in puberty, the few reports about this gene came from research into Prader-Willi syndrome.68,69 The maternal MKRN3 allele is imprinted and only the paternal allele is expressed.68–70 Following this inheritance pattern, all MKRN3 mutations identified in patients with central precocious puberty were inherited from their fathers.52

MKRN3 is the most common genetic defect associated with central precocious puberty so far; families with central precocious puberty from several different ethnic groups harbour mutations in this gene.52,71–76 There was no previous association of MKRN3 with the hypothalamic-pituitary-gonadal axis and the mechanism by which MKRN3 regulates puberty initiation is not yet completely understood. The mutations identified in patients with central precocious puberty are expected to disrupt protein function. MKRN3 expression in the arcuate nucleus of mice is high prepubertally and decreases before puberty initiation, reaching very low levels in adult life.52 Taken together, these findings suggest that the loss of function of MKRN3 results in early puberty, implying an inhibitory role of MKRN3 on GnRH secretion.77 The very low expression of MKRN3 in the adult mouse, the similarity of the phenotype of patients with central precocious puberty with and without MKRN3 mutations, and the absence of an identified phenotype beyond central precocious puberty in patients with MKRN3 loss-of-function mutations imply that MKRN3 is important for puberty initiation, but not for the maintenance of pulsatile GnRH secretion later in life. However, further studies and larger samples of children with central precocious puberty and MKRN3 mutations are necessary to more fully clarify whether the clinical course of puberty might differ as compared with idiopathic central precocious puberty and whether there might be any other associated reproductive or non-reproductive phenotypes.

MKRN3 belongs to the Makorin family, a family of E3 ubiquitin ligases.78 Its protein structure has a ubiquitin ligase domain and it has been postulated that MKRN3 might inhibit stimulators of GnRH secretion (figure 2).79 Further research into the mechanism of action of MKRN3 will expand our knowledge of the GnRH inhibitory network.

In a recent meta-analysis of genome-wide association and custom-genotyping array studies of age at menarche in up to 182 416 women of European descent, a variant downstream of MKRN3 had the largest effect size for association with menarche when the variant was paternally inherited.80 This finding implicates common variation near MKRN3 as an important source of variation in pubertal timing in the general population.

LIN33B

In 2009, genome-wide association studies identified an association between the locus 6q21 (in or near the LIN28B gene) with age at menarche and height.81–84 LIN28B encodes a regulator of the let-7 class of microRNAs. Although several other human studies replicated the findings from the genome-wide association studies, the mechanism by which this gene is associated with the control of GnRH secretion is unknown.85 Mutations in LIN28B have not been identified in patients with central precocious puberty or constitutional delay of growth and puberty.86,87

Many other genes have been identified in association with developmental defects in GnRH neurons. These genes affect GnRH neuronal migration and are associated with hypogonadotropic hypogonadism with anosmia, or Kallmann’s syndrome (table).35,46,47,53,88–90 Other genes have been identified in association with hypogonadotropic hypogonadism in conjunction with syndromic disorders, but are beyond the scope of this Series paper.

Metabolic factors that affect GnRH secretion

Animal and human studies in the 1960s and 1970s showed that the proper function of the hypothalamic-pituitary-gonadal axis is gated by metabolic and nutritional factors.91,92 A threshold bodyweight is necessary for pubertal development and reproduction.91 The identification of peripheral hormones (such as leptin, insulin, and ghrelin) that signal the metabolic status to the reproductive axis has expanded our knowledge about the neuroendocrine mechanisms linking metabolism and reproduction (figure 3). Nonetheless, our understanding of how such dynamic interplay occurs remains incomplete.

Tentative model for the metabolic control of GnRH secretion by peripheral metabolic hormones

The peripheral hormones that transmit metabolic signals to GnRH neurons are shown: leptin, a signal for energy abundance, is a permissivefactor for GnRH secretion. Ghrelin, a putative signal of energy insufficiency, is an inhibitory factor for GnRH secretion. Insulin and IGF-1 have stimulatory effects on the reproductive axis. Dashed line represents proposed pathway. FSH=follicle-stimulating hormone. GnRH=gonadotropin-releasing hormone. GnRHR=gonadotropin-releasing hormone receptor. IGF-1=insulin-like growth factor 1. KISS1=kisspeptin. KISS1R=kisspeptin receptor. LH=luteinising hormone. +=stimulatory effect. –=inhibitory effect.

Leptin, an adipocyte-derived hormone, is a satiety factor secreted in proportion to the amount of body energy stores, and was one of the first factors linking metabolism with the reproductive axis.93 Serum leptin concentrations and leptin mRNA concentrations in adipose tissue are associated positively and very closely with fat mass.94 Leptin is a permissive metabolic signal to the reproductive system; its circulating concentrations inform of the actual size of energy reserves not only to the reproductive axis, but to several body systems.95 As has been shown for bodyweight, the attainment of appropriate leptin concentrations is indispensable for the maturation of the hypothalamic-pituitary-gonadal axis, normal pubertal progression, and maintenance of fertility.96

Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine receptor family.97 The finding that homozygous mutations in genes encoding leptin (LEP) or leptin receptor (LEPR) cause hypogonadotropic hypogonadism in human beings emphasises the role of leptin in reproduction.98–100 In addition to the reproductive phenotype, individuals with homozygous mutations in LEPR presented with early-onset morbid obesity and reduced growth hormone and thyrotropin secretion.100 Leptin treatment of patients with hypogonadotropic hypogonadism and a homozygous mutation in LEP resulted in the induction of menstrual cycles, development of secondary sexual characteristics, and pulsatile gonadotropin secretion.101,102 Moreover, leptin administration in women with hypothalamic amenorrhoea (a state of relative leptin deficiency) restored reproductive function, induced ovulation, and increased circulating concentrations of thyroxine, insulin-like growth factor 1 (IGF-1), and bone markers, reinforcing the central role of leptin for normal reproductive and neuroendocrine function.103

Another systemic hormone with a major role in the regulation of reproduction is the pancreatic hormone insulin (figure 3).104 Studies have suggested that insulin acts on the hypothalamic-pituitary-gonadal axis at the level of the hypothalamus to directly or indirectly modulate GnRH secretion (possibly via kisspeptin), as well as at the level of the pituitary gonadotrope.105 Insulin is a major regulator of leptin production; therefore, some of the positive effects of insulin on the reproductive system might derive from its ability to stimulate leptin secretion.106 However, the precise site of action of insulin at the hypothalamic level in vivo remains in question.107 IGF-1 is structurally homologous to insulin and findings suggest that it is also involved in GnRH regulation.108 Moreover, studies show an increase in IGF-1 expression during puberty in human beings.109

Ghrelin, a peptide predominantly secreted by the stomach, has been postulated to be a peripheral signal for energy insufficiency, acting as a potent orexigen (figure 3).110 Ghrelin has direct actions on the brain and the pituitary, where it has an inhibitory effect on gonadotropin pulsatility and decreases LH responsiveness to GnRH, as well as a stimulatory effect on prolactin secretion, probably involving direct action on somatomammotroph cells.111

Conclusions

The triggers of puberty initiation have puzzled scientists for many years. Pubertal development culminates with reproductive competence. Because of its paramount evolutionary importance, the reproductive system is controlled by a complex regulatory network. In this system, a major hierarchical role is held by GnRH neurons. GnRH is secreted in a unique pulsatile manner by neurons located in the hypothalamus to stimulate the pituitary gonadotropins and gonadal sex steroids. The regulation of GnRH secretion is still not completely understood, but we have witnessed a substantial expansion of our understanding of the signals involved in this regulation in the past two decades. The decrease in the average age of puberty initiation between the mid-19th and mid-20th centuries suggested an association of nutrition and environmental factors with reproduction,20,41 which was substantiated by the identification of leptin as an important link between both systems, together with the characterisation of the effects of the metabolic hormones, insulin and ghrelin, on the reproductive axis. Although studies in animals have led to identification of regulators of GnRH such as catecholamines, GABA, and glutamate, genetic studies of patients with pubertal disorders have resulted in the identification of a major regulatory hub for the GnRH neurons—ie, the hypothalamic neurons expressing kisspeptin and neurokinin B.42–44 These findings have important clinical implications, not only to aid in diagnosis and improve genetic counselling, but also to contribute to the development of new therapies for reproductive disorders. For example, kisspeptin has been used in clinical studies to induce ovulation in infertile women.112

Search strategy and selection criteria

We searched MEDLINE and PubMed for articles published in English up to June 1, 2015, using the search terms “puberty”, “puberty onset”, or “GnRH regulation”, combined with “regulation”, “puberty onset”, “hypothalamic-pituitary-gonadal axis”, “markers”, “Tanner stages”, “trends”, “metabolism”, “kisspeptin”, “tachykinin”, “MKRN3”, “leptin”, “insulin”, and “GWAS”. We read relevant papers in full, searched their reference lists, and selected the most relevant on the basis of design, findings, and time of publication.

More recently, genetic studies have led to the identification of the most common known genetic cause of central precocious puberty, MKRN3.52 Although the mechanism by which MKRN3 regulates the hypothalamic-pituitary-gonadal axis is still to be elucidated, the identification of mutations in this gene in patients with different ethnic origins and its expression pattern in the hypothalamus of mice support the association of MKRN3 with GnRH regulation. Different from the other genetic factors regulating the hypothalamic-pituitary-gonadal axis, MKRN3 operates in an inhibitory mode. It is the first imprinted gene to be implicated in GnRH regulation. Genomic imprinting hypothetically evolved to control the dosage of developmentally important genes and occurs in about 100 mammalian genes.113 Increasing evidence implicates epigenetic mechanisms in timing of puberty.114 After identification of the association of MKRN3 with puberty regulation, single nucleotide polymorphisms in imprinted gene regions were linked to the age of menarche, supporting puberty timing as a selective trait.80 The availability of powerful new technologies has contributed to expanding our knowledge of the regulation of puberty and recognising the role of genetic imprinting in the control of the activation of GnRH secretion at the time of puberty initiation.114 An increased understanding of puberty regulation will help to improve the treatment of reproductive disorders.

Acknowledgments

We thank Anna Zhang for her contributions to the preparation of the figures. This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICDH; part of the US National Institutes of Health [NIH]) through cooperative agreement U54 HD028138 (as part of the Specialised Cooperative Centers Program in Reproduction and Infertility Research), grant NIH/NICHD R01 HD019938 (to UBK), and grant NIH/NICHD R01 HD082314 (to UBK); and grant 1F05HD072773 (to APA).

Footnotes

Contributors

APA and UBK searched the scientific literature and wrote the report.

Declaration of interests

UBK has received personal fees from Takeda, unrelated to this work. APA declares no competing interests.

References

1. Terasawa E, Fernandez DL. Neurobiological mechanisms of the onset of puberty in primates. Endocr Rev. 2001;22:111–51. [PubMed] [Google Scholar]

2. Kuiri-Hänninen T, Sankilampi U, Dunkel L. Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty. Horm Res Paediatr. 2014;82:73–80. [PubMed] [Google Scholar]

3. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 1970;45:13–23. [PMC free article] [PubMed] [Google Scholar]

4. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44:291–303. [PMC free article] [PubMed] [Google Scholar]

5. Kaprio J, Rimpelä A, Winter T, et al. Common genetic influences on BMI and age at menarche. Hum Biol. 1995;67:739–53. [PubMed] [Google Scholar]

6. Parent AS, Teilmann G, Juul A, et al. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev. 2003;24:668–93. [PubMed] [Google Scholar]

7. Biro FM, Lucky AW, Huster GA, et al. Pubertal staging in boys. J Pediatr. 1995;127:100–02. [PubMed] [Google Scholar]

8. Kempná P, Marti N, Udhane S, et al. Regulation of androgen biosynthesis—a short review and preliminary results from the hyperandrogenic starvation NCI-H295R cell model. Mol Cell Endocrinol. 2015;408:124–32. [PubMed] [Google Scholar]

9. Xing Y, Lerario AM, Rainey W, et al. Development of adrenal cortex zonation. Endocrinol Metab Clin North Am. 2015;44:243–74. [PMC free article] [PubMed] [Google Scholar]

10. Grumbach MM. The neuroendocrinology of human puberty revisited. Horm Res. 2002;57(suppl 2):2–14. [PubMed] [Google Scholar]

11. Boettcher C, Hartmann MF, de Laffolie J, et al. Absent adrenarche in children with hypopituitarism: a study based on urinary steroid metabolomics. Horm Res Paediatr. 2013;79:356–60. [PubMed] [Google Scholar]

12. Biro FM, Huang B, Crawford PB, et al. Pubertal correlates in black and white girls. J Pediatr. 2006;148:234–40. [PubMed] [Google Scholar]

13. Wu T, Mendola P, Buck GM. Ethnic differences in the presence of secondary sex characteristics and menarche among US girls: the Third National Health and Nutrition Examination Survey, 1988–1994. Pediatrics. 2002;110:752–57. [PubMed] [Google Scholar]

14. Rosenfield RL, Lipton RB, Drum ML. Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index. Pediatrics. 2009;123:84–88. [PubMed] [Google Scholar]

15. Velie EM, Nechuta S, Osuch JR. Lifetime reproductive and anthropometric risk factors for breast cancer in postmenopausal women. Breast Dis. 2005–2006;24:17–35. [PubMed] [Google Scholar]

16. Elks CE, Ong KK, Scott RA, et al. the InterAct Consortium. Age at menarche and type 2 diabetes risk: the EPIC-InterAct study. Diabetes Care. 2013;36:3526–34. [PMC free article] [PubMed] [Google Scholar]

17. Lakshman R, Forouhi NG, Sharp SJ, et al. Early age at menarche associated with cardiovascular disease and mortality. J Clin Endocrinol Metab. 2009;94:4953–60. [PubMed] [Google Scholar]

18. Golub MS, Collman GW, Foster PM, et al. Public health implications of altered puberty timing. Pediatrics. 2008;121(suppl 3):S218–30. [PubMed] [Google Scholar]

19. Day FR, Elks CE, Murray A, et al. Puberty timing associated with diabetes, cardiovascular disease and also diverse health outcomes in men and women: the UK Biobank study. Sci Rep. 2015;5:11208. [PMC free article] [PubMed] [Google Scholar]

20. Wyshak G, Frisch RE. Evidence for a secular trend in age of menarche. N Engl J Med. 1982;306:1033–35. [PubMed] [Google Scholar]

21. Euling SY, Herman-Giddens ME, Lee PA, et al. Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings. Pediatrics. 2008;121(suppl 3):S172–91. [PubMed] [Google Scholar]

22. Parent AS, Franssen D, Fudvoye J, et al. Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: revision of human observations and mechanistic insight from rodents. Front Neuroendocrinol. 2015;38:12–36. [PubMed] [Google Scholar]

23. Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics. 1997;99:505–12. [PubMed] [Google Scholar]

24. Mul D, Fredriks AM, van Buuren S, et al. Pubertal development in The Netherlands 1965–1997. Pediatr Res. 2001;50:479–86. [PubMed] [Google Scholar]

25. Juul A, Teilmann G, Scheike T, et al. Pubertal development in Danish children: comparison of recent European and US data. Int J Androl. 2006;29:247–55. [PubMed] [Google Scholar]

26. Aksglaede L, Sørensen K, Petersen JH, et al. Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics. 2009;123:e932–39. [PubMed] [Google Scholar]

27. Herman-Giddens ME, Wang L, Koch G. Secondary sexual characteristics in boys: estimates from the national health and nutrition examination survey III, 1988–1994. Arch Pediatr Adolesc Med. 2001;155:1022–28. [PubMed] [Google Scholar]

28. Chumlea WC, Schubert CM, Roche AF, et al. Age at menarche and racial comparisons in US girls. Pediatrics. 2003;111:110–13. [PubMed] [Google Scholar]

29. Kaplowitz PB, Oberfield SE the Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Pediatrics. 1999;104:936–41. [PubMed] [Google Scholar]

30. Midyett LK, Moore WV, Jacobson JD. Are pubertal changes in girls before age 8 benign? Pediatrics. 2003;111:47–51. [PubMed] [Google Scholar]

31. Pescovitz OH, Comite F, Cassorla F, et al. True precocious puberty complicating congenital adrenal hyperplasia: treatment with a luteinizing hormone-releasing hormone analog. J Clin Endocrinol Metab. 1984;58:857–61. [PubMed] [Google Scholar]

32. Schwanzel-Fukuda M. Origin and migration of luteinizing hormone-releasing hormone neurons in mammals. Microsc Res Tech. 1999;44:2–10. [PubMed] [Google Scholar]

33. Bianco SD, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol. 2009;5:569–76. [PMC free article] [PubMed] [Google Scholar]

34. Cadman SM, Kim SH, Hu Y, et al. Molecular pathogenesis of Kallmann’s syndrome. Horm Res. 2007;67:231–42. [PubMed] [Google Scholar]

35. Semple RK, Topaloglu AK. The recent genetics of hypogonadotrophic hypogonadism—novel insights and new questions. Clin Endocrinol (Oxf) 2010;72:427–35. [PubMed] [Google Scholar]

36. Belchetz PE, Plant TM, Nakai Y, et al. Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science. 1978;202:631–33. [PubMed] [Google Scholar]

37. Terasawa E, Keen KL, Mogi K, et al. Pulsatile release of luteinizing hormone-releasing hormone (LHRH) in cultured LHRH neurons derived from the embryonic olfactory placode of the rhesus monkey. Endocrinology. 1999;140:1432–41. [PubMed] [Google Scholar]

38. Plant TM, Krey LC, Moossy J, et al. The arcuate nucleus and the control of gonadotropin and prolactin secretion in the female rhesus monkey (Macaca mulatta) Endocrinology. 1978;102:52–62. [PubMed] [Google Scholar]

39. Conte FA, Grumbach MM, Kaplan SL, et al. Correlation of luteinizing hormone-releasing factor-induced luteinizing hormone and follicle-stimulating hormone release from infancy to 19 years with the changing pattern of gonadotropin secretion in agonadal patients: relation to the restraint of puberty. J Clin Endocrinol Metab. 1980;50:163–68. [PubMed] [Google Scholar]

40. Palmert MR, Hirschhorn JN. Genetic approaches to stature, pubertal timing, and other complex traits. Mol Genet Metab. 2003;80:1–10. [PubMed] [Google Scholar]

41. Zacharias L, Wurtman RJ. Age at menarche. Genetic and environmental influences. N Engl J Med. 1969;280:868–75. [PubMed] [Google Scholar]

42. de Roux N, Genin E, Carel JC, et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA. 2003;100:10972–76. [PMC free article] [PubMed] [Google Scholar]

43. Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614–27. [PubMed] [Google Scholar]

44. Topaloglu AK, Reimann F, Guclu M, et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet. 2009;41:354–58. [PMC free article] [PubMed] [Google Scholar]

45. Topaloglu AK, Semple RK. Neurokinin B signalling in the human reproductive axis. Mol Cell Endocrinol. 2011;346:57–64. [PubMed] [Google Scholar]

46. Silveira LF, Latronico AC. Approach to the patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013;98:1781–88. [PubMed] [Google Scholar]

47. Topaloglu AK, Tello JA, Kotan LD, et al. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med. 2012;366:629–35. [PubMed] [Google Scholar]

48. Silveira LG, Noel SD, Silveira-Neto AP, et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab. 2010;95:2276–80. [PMC free article] [PubMed] [Google Scholar]

49. Teles MG, Bianco SD, Brito VN, et al. A _GPR54_-activating mutation in a patient with central precocious puberty. N Engl J Med. 2008;358:709–15. [PMC free article] [PubMed] [Google Scholar]

50. Bouligand J, Ghervan C, Tello JA, et al. Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med. 2009;360:2742–48. [PubMed] [Google Scholar]

51. Chan YM, de Guillebon A, Lang-Muritano M, et al. GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci USA. 2009;106:11703–08. [PMC free article] [PubMed] [Google Scholar]

52. Abreu AP, Dauber A, Macedo DB, et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med. 2013;368:2467–75. [PMC free article] [PubMed] [Google Scholar]

53. Miraoui H, Dwyer AA, Sykiotis GP, et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013;92:725–43. [PMC free article] [PubMed] [Google Scholar]

54. Dhillo WS, Chaudhri OB, Patterson M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab. 2005;90:6609–15. [PubMed] [Google Scholar]

55. George JT, Veldhuis JD, Roseweir AK, et al. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J Clin Endocrinol Metab. 2011;96:E1228–36. [PMC free article] [PubMed] [Google Scholar]

56. Chan YM, Butler JP, Sidhoum VF, et al. Kisspeptin administration to women: a window into endogenous kisspeptin secretion and GnRH responsiveness across the menstrual cycle. J Clin Endocrinol Metab. 2012;97:E1458–67. [PMC free article] [PubMed] [Google Scholar]

57. Jayasena CN, Abbara A, Narayanaswamy S, et al. Direct comparison of the effects of intravenous kisspeptin-10, kisspeptin-54 and GnRH on gonadotrophin secretion in healthy men. Hum Reprod. 2015;30:1934–41. [PMC free article] [PubMed] [Google Scholar]

58. Li D, Mitchell D, Luo J, et al. Estrogen regulates KiSS1 gene expression through estrogen receptor alpha and SP protein complexes. Endocrinology. 2007;148:4821–28. [PubMed] [Google Scholar]

59. Smith JT, Clay CM, Caraty A, et al. KiSS-1 messenger ribonucleic acid expression in the hypothalamus of the ewe is regulated by sex steroids and season. Endocrinology. 2007;148:1150–57. [PubMed] [Google Scholar]

60. Smith JT, Cunningham MJ, Rissman EF, et al. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology. 2005;146:3686–92. [PubMed] [Google Scholar]

61. Adachi S, Yamada S, Takatsu Y, et al. Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats. J Reprod Dev. 2007;53:367–78. [PubMed] [Google Scholar]

62. Goubillon ML, Forsdike RA, Robinson JE, et al. Identification of neurokinin B-expressing neurons as an highly estrogen-receptive, sexually dimorphic cell group in the ovine arcuate nucleus. Endocrinology. 2000;141:4218–25. [PubMed] [Google Scholar]

63. Gianetti E, Tusset C, Noel SD, et al. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J Clin Endocrinol Metab. 2010;95:2857–67. [PMC free article] [PubMed] [Google Scholar]

64. Ramaswamy S, Seminara SB, Ali B, et al. Neurokinin B stimulates GnRH release in the male monkey (Macaca mulatta) and is colocalized with kisspeptin in the arcuate nucleus. Endocrinology. 2010;151:4494–503. [PMC free article] [PubMed] [Google Scholar]

65. Hrabovszky E, Borsay BA, Rácz K, et al. Substance P immunoreactivity exhibits frequent colocalization with kisspeptin and neurokinin B in the human infundibular region. PLoS One. 2013;8:e72369. [PMC free article] [PubMed] [Google Scholar]

66. Coiro V, Volpi R, Capretti L, et al. Luteinizing hormone response to an intravenous infusion of substance P in normal men. Metabolism. 1992;41:689–91. [PubMed] [Google Scholar]

67. Navarro VM, Bosch MA, León S, et al. The integrated hypothalamic tachykinin-kisspeptin system as a central coordinator for reproduction. Endocrinology. 2015;156:627–37. [PMC free article] [PubMed] [Google Scholar]

68. Jong MT, Carey AH, Caldwell KA, et al. Imprinting of a RING zinc-finger encoding gene in the mouse chromosome region homologous to the Prader–Willi syndrome genetic region. Hum Mol Genet. 1999;8:795–803. [PubMed] [Google Scholar]

69. Jong MT, Gray TA, Ji Y, et al. A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader–Willi syndrome critical region. Hum Mol Genet. 1999;8:783–93. [PubMed] [Google Scholar]

70. Hershko A, Razin A, Shemer R. Imprinted methylation and its effect on expression of the mouse Zfp127 gene. Gene. 1999;234:323–27. [PubMed] [Google Scholar]

71. de Vries L, Kauschansky A, Shohat M, et al. Familial central precocious puberty suggests autosomal dominant inheritance. J Clin Endocrinol Metab. 2004;89:1794–800. [PubMed] [Google Scholar]

72. Hagen CP, Sørensen K, Mieritz MG, et al. Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls. J Clin Endocrinol Metab. 2015;100:1920–26. [PubMed] [Google Scholar]

73. Lee HS, Jin HS, Shim YS, et al. Low frequency of MKRN3 mutations in central precocious puberty among Korean girls. Horm Metab Res. 2015 doi: 10.1055/s-0035-1548938. published online May 4. [PubMed] [CrossRef] [Google Scholar]

74. Macedo DB, Abreu AP, Reis AC, et al. Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J Clin Endocrinol Metab. 2014;99:E1097–103. [PMC free article] [PubMed] [Google Scholar]

75. Schreiner F, Gohlke B, Hamm M, et al. MKRN3 mutations in familial central precocious puberty. Horm Res Paediatr. 2014;82:122–26. [PubMed] [Google Scholar]

76. Settas N, Dacou-Voutetakis C, Karantza M, et al. Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene. J Clin Endocrinol Metab. 2014;99:E647–51. [PubMed] [Google Scholar]

77. Hughes IA. Releasing the brake on puberty. N Engl J Med. 2013;368:2513–15. [PubMed] [Google Scholar]

78. Gray TA, Hernandez L, Carey AH, et al. The ancient source of a distinct gene family encoding proteins featuring RING and C(3)H zinc-finger motifs with abundant expression in developing brain and nervous system. Genomics. 2000;66:76–86. [PubMed] [Google Scholar]

79. Abreu AP, Macedo DB, Brito VN, et al. A new pathway in the control of the initiation of puberty: the MKRN3 gene. J Mol Endocrinol. 2015;54:R131–39. [PMC free article] [PubMed] [Google Scholar]

80. Perry JR, Day F, Elks CE, et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014;514:92–97. [PMC free article] [PubMed] [Google Scholar]

81. Perry JR, Stolk L, Franceschini N, et al. Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat Genet. 2009;41:648–50. [PMC free article] [PubMed] [Google Scholar]

82. Sulem P, Gudbjartsson DF, Rafnar T, et al. Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche. Nat Genet. 2009;41:734–38. [PubMed] [Google Scholar]

83. He C, Kraft P, Chen C, et al. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet. 2009;41:724–28. [PMC free article] [PubMed] [Google Scholar]

84. Ong KK, Elks CE, Li S, et al. Genetic variation in LIN28B is associated with the timing of puberty. Nat Genet. 2009;41:729–33. [PMC free article] [PubMed] [Google Scholar]

85. Gajdos ZK, Henderson KD, Hirschhorn JN, et al. Genetic determinants of pubertal timing in the general population. Mol Cell Endocrinol. 2010;324:21–29. [PMC free article] [PubMed] [Google Scholar]

86. Tommiska J, Wehkalampi K, Vaaralahti K, et al. LIN28B in constitutional delay of growth and puberty. J Clin Endocrinol Metab. 2010;95:3063–66. [PubMed] [Google Scholar]

87. Silveira-Neto AP, Leal LF, Emerman AB, et al. Absence of functional LIN28B mutations in a large cohort of patients with idiopathic central precocious puberty. Horm Res Paediatr. 2012;78:144–50. [PMC free article] [PubMed] [Google Scholar]

88. Tornberg J, Sykiotis GP, Keefe K, et al. Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci USA. 2011;108:11524–29. [PMC free article] [PubMed] [Google Scholar]

89. Kim HG, Ahn JW, Kurth I, et al. WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet. 2010;87:465–79. [PMC free article] [PubMed] [Google Scholar]

90. Hanchate NK, Giacobini P, Lhuillier P, et al. SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PLoS Genet. 2012;8:e1002896. [PMC free article] [PubMed] [Google Scholar]

91. Frisch RE, Revelle R. Height and weight at menarche and a hypothesis of critical body weights and adolescent events. Science. 1970;169:397–99. [PubMed] [Google Scholar]

92. Frisch RE, McArthur JW. Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science. 1974;185:949–51. [PubMed] [Google Scholar]

93. Ahima RS, Saper CB, Flier JS, et al. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol. 2000;21:263–307. [PubMed] [Google Scholar]

94. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334:292–95. [PubMed] [Google Scholar]

95. Tena-Sempere M. Roles of ghrelin and leptin in the control of reproductive function. Neuroendocrinology. 2007;86:229–41. [PubMed] [Google Scholar]

96. Farooqi IS, O’Rahilly S. 20 years of leptin: human disorders of leptin action. J Endocrinol. 2014;223:T63–70. [PubMed] [Google Scholar]

97. Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263–71. [PubMed] [Google Scholar]

98. Farooqi IS, Wangensteen T, Collins S, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356:237–47. [PMC free article] [PubMed] [Google Scholar]

99. Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387:903–08. [PubMed] [Google Scholar]

100. Clément K, Vaisse C, Lahlou N, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392:398–401. [PubMed] [Google Scholar]

101. Licinio J, Caglayan S, Ozata M, et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA. 2004;101:4531–36. [PMC free article] [PubMed] [Google Scholar]

102. von Schnurbein J, Moss A, Nagel SA, et al. Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism. Horm Res Paediatr. 2012;77:127–33. [PubMed] [Google Scholar]

103. Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351:987–97. [PubMed] [Google Scholar]

104. Pralong FP. Insulin and NPY pathways and the control of GnRH function and puberty onset. Mol Cell Endocrinol. 2010;324:82–86. [PubMed] [Google Scholar]

105. Moret M, Stettler R, Rodieux F, et al. Insulin modulation of luteinizing hormone secretion in normal female volunteers and lean polycystic ovary syndrome patients. Neuroendocrinology. 2009;89:131–39. [PubMed] [Google Scholar]

106. Barr VA, Malide D, Zarnowski MJ, et al. Insulin stimulates both leptin secretion and production by rat white adipose tissue. Endocrinology. 1997;138:4463–72. [PubMed] [Google Scholar]

107. Roa J, Tena-Sempere M. Connecting metabolism and reproduction: roles of central energy sensors and key molecular mediators. Mol Cell Endocrinol. 2014;397:4–14. [PubMed] [Google Scholar]

108. Wolfe A, Divall S, Wu S. The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1) Front Neuroendocrinol. 2014;35:558–72. [PMC free article] [PubMed] [Google Scholar]

109. Luna AM, Wilson DM, Wibbelsman CJ, et al. Somatomedins in adolescence: a cross-sectional study of the effect of puberty on plasma insulin-like growth factor I and II levels. J Clin Endocrinol Metab. 1983;57:268–71. [PubMed] [Google Scholar]

110. Zigman JM, Elmquist JK. Minireview: From anorexia to obesity—the yin and yang of body weight control. Endocrinology. 2003;144:3749–56. [PubMed] [Google Scholar]

111. Lanfranco F, Bonelli L, Baldi M, et al. Acylated ghrelin inhibits spontaneous luteinizing hormone pulsatility and responsiveness to naloxone but not that to gonadotropin-releasing hormone in young men: evidence for a central inhibitory action of ghrelin on the gonadal axis. J Clin Endocrinol Metab. 2008;93:3633–39. [PubMed] [Google Scholar]

112. Prague JK, Dhillo WS. Potential clinical use of kisspeptin. Neuroendocrinology. 2015;102:238–45. [PubMed] [Google Scholar]

113. Bartolomei MS, Ferguson-Smith AC. Mammalian genomic imprinting. Cold Spring Harb Perspect Biol. 2011;3:3. [PMC free article] [PubMed] [Google Scholar]

114. Lomniczi A, Wright H, Ojeda SR. Epigenetic regulation of female puberty. Front Neuroendocrinol. 2015;36:90–107. [PMC free article] [PubMed] [Google Scholar]