Journal of Adolescence 71 (2019) 63–71

Contents lists available at ScienceDirect

Journal of Adolescence
journal homepage: www.elsevier.com/locate/adolescence

Review article

Physiology of puberty in boys and girls and pathological disorders

T
affecting its onset
Mohammed F. Alotaibi
Department of Physiology, College of Medicine, King Saud University and King Khalid University Hospital, P.O Box 2925, Riyadh, 11461, Saudi
Arabia

ARTICLE INFO ABSTRACT

Keywords: Puberty is a physiological event involving the attainment of reproductive capability and complete
Puberty development of sexual and physical organs. Changing from childhood to adulthood is a complex
Physiology process and is tightly controlled by interconnection pathways at the level of the hypothalamus
Girls which can be influenced by environmental, psychosocial, and endocrine factors. Although var-
Boys
ious mechanisms underlying the onset of normal puberty have been investigated in humans and
Disorders
animals, the exact molecular mechanisms thereof remain unclear. The aim of this review is to
summarize the current state of knowledge and provide a synoptic overview about the physiology
of puberty in adolescent boys and girls, and describe pathological disorders affecting its onset.

1. Introduction

Puberty is a physiological process by which reproductive organs and gonads become functionally mature. It is a developmental
stage marked by the gradual transition from childhood to adulthood, and is characterized by the maturation of gonads (testes in boys,
and ovaries in girls), secretion of sex steroid gonadal hormones (testosterone in boys, and estradiol and progesterone in girls), and the
development of secondary sexual characteristics and attainment of reproductive functions. The mechanisms controlling the normal
onset of puberty are complicated and involve hormonal, genetic, environmental and nutritional factors. Puberty is characterized by
changes in physical appearance that are triggered primarily by the rising levels of sex steroid hormones. Gonadal hormones are
secreted in response to the pulsatile secretion of the pituitary gonadotropins follicle stimulating hormone (FSH) and luteinizing
hormone (LH), which occurs under the direct influence of hypothalamic gonadotropin releasing hormone (GnRH). The important
terms used when describing hormonal and physical changes that occur during pubertal development in boys and girls are listed in
Table 1. In pubertal development, interpersonal differences could be described in terms of timing and tempo. Timing of puberty
describes how mature a child is relative to his/her peers at the same age and sex. Pubertal development can be early, on time, or late
(delayed) depending on the physical maturity of the adolescents (Ge, Brody, Conger, Simons, & Murry, 2002). Tempo describes how
quickly or slowly a child progresses throughout the stages of puberty to the complete development. Puberty can be slow, average, or
fast depending on how long it takes the adolescents to progress from Stage 1 to Stage 5 (discussed later). In this review we will focus
on the current available research related to the physiology of puberty in boys and girls (with emphasis on gonadarche) and sum-
marize the important pathological disorders affecting its onset.
The central feature of puberty is the development of the primary reproductive neuroendocrine axis (hypothalamus, pituitary
gland, and gonads) which causes pubertal development and an appearance of secondary sexual characteristics. In the following
sections, we will define the neuroendocrine axis, and identify the differences in its function between boys and girls.

E-mail address: mfalotaibi@ksu.edu.sa.

https://doi.org/10.1016/j.adolescence.2018.12.007
Received 19 September 2018; Received in revised form 26 November 2018; Accepted 28 December 2018
0140-1971/ © 2018 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.
M.F. Alotaibi Journal of Adolescence 71 (2019) 63–71

Table 1
Terms used to describe hormonal and physical changes associated with puberty in boys and girls.
Pubertal Terms Definition

Thelarche The onset of breast budding and development in girls

Pubarche The onset of growth of pubic and axillary hair
Adrenarche The onset of secretion of adrenal androgens
Gonadarche The onset of secretion of sex steroid hormones by the gonads
Menarche The onset of the first menstruation in girls
Spermarche The onset of production of spermatozoa in boys

2. Hypothalamic-pituitary-gonadal (HPG) axis

Normal puberty is initiated primarily by the maturation and reactivation of the HPG axis, which controls adult reproductive
function. The HPG axis is well-developed at birth, suppressed during the early childhood years, and then reactivated at the onset of
puberty. The exact molecular mechanisms underlying the restricted functionality of GnRH during childhood is not fully understood,
but it is known that the central nervous system primarily controls the onset and progression of puberty in boys and girls. When GnRH
neurons are maturated and are activated under physiological conditions, GnRH is released in a pulsatile fashion into the hypophyseal
portal system and transported to the pituitary gonadotropes, resulting in the synthesis and release of gonadotropins into the systemic
circulation (Bliss, Navratil, Xie, & Roberson, 2010). The release of FSH and LH is pulsatile in nature consequent to the pulsatile
release of GnRH (Fig. 1). In fact, the released gonadotropins drive the full development and maturation of gonads, synthesis and

Fig. 1. Neuroendocrine regulation of GnRH secretion and control of the HPG axis. Kiss-1 neurons secrete kisspeptin which stimulates the
GnRH neurons via GPR54. Kiss-1 neurons co-express NKB and Dyn (KNDy neurons), which regulate GnRH release via NK3R and KOR. Hypothalamic
NPY inhibits GnRH neurons, while leptin activates GnRH secretion by inhibiting NPY. These events are affected by distal signals related to en-
vironmental, genetic, nutritional, and psychosocial factors. The pulsatile release of GnRH results in a likewise pulsatile release of gonadotropins (LH
and FSH) from the pituitary gonadotropes, which exert their trophic action on the gonads. The final output of the HPG axis is gamete and sex steroid
production. Sex steroids have wide effects on the body including the development of secondary sexual characteristics at the onset of puberty. KNDy
neuron — kisspeptin, neurokinin B, dynorphin neuron; NKB — neurokinin B, Dyn — dynorphin; NK3ReNKB receptor; KOR — kappa-opioid receptor; NPY
— neuropeptide Y; GPR54 — G-protein coupled receptor 54; GnRH — gonadotropin releasing hormone; LH — luteinizing hormone, FSH — follicle sti-
mulating hormone; + stimulatory, – inhibitory.

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secretion of sex steroid hormones, and development and production of gametes in both sexes. Therefore, the activation of the HPG
axis is vital for the initiation of puberty in both boys and girls and for the maintenance of normal reproductive physiology and
fertility.

3. Physiology of pituitary gonadotropins and sex steroid hormones

Normal puberty in boys and girls is associated with increases in gonadotropins and sex steroid hormones. However, the rising
levels of circulating LH from early pre-puberty to pubertal onset is much greater than the rise of FSH in boys and girls (Mitamura
et al., 1999, 2000), indicating that LH may play a vital role in the onset of puberty than FSH (Apter, Bützow, Laughlin, & Yen, 1993;
Dunkel, Alfthan, Stenman, Tapanainen, & Perheentupa, 1990). On binding to their receptors in the ovaries and testes, gonadotropins
stimulate the synthesis and secretion of sex steroid hormones, which ultimately results in the development of secondary sexual
characteristics and initiation of reproductive functions.
In the following sections, the normal physiology of HPG axis in boys and girls will be briefly described.

3.1. In boys

• Secretion of pituitary LH stimulates the Leydig cells in the testes to produce and secrete testosterone hormone which is responsible
for the development of secondary sexual characteristics and the modulation of LH secretion. .
• FSH binds to its receptors on Sertoli cells in the testes and stimulates continuous production of spermatozoa (spermatogenesis).
• Sertoli cells secrete inhibin B hormone which exerts a negative feedback effects on FSH secretion.
• The levels of sex hormone-binding globulin (SHBG) decline markedly at puberty as higher androgens levels are suggested to
down-regulate SHBG (Elmlinger, Kühnel, Wormstall, & Döller, 2005; Pinkney et al., 2014).

3.2. In girls

• Secretion of pituitary LH stimulates the follicular theca cells in the ovaries to produce androgen hormones (mainly testosterone)
during the follicular phase.
• Secretion of pituitary FSH causes: (1) increased proliferation of follicular granulosa cells, (2) enhanced activity of the aromatase
enzyme, and (3) upregulation of LH receptors on granulosa cells. Therefore, androgens diffuse to the granulosa cells and are
converted predominantly to estradiol via aromatase activity. Progesterone is the second gonadal puberty hormone and arises early
in the steroid synthesis pathway.
• Secreted estradiol increases FSH receptors on granulosa cells and further stimulates their proliferation.
• Both estradiol and progesterone cause the development of secondary sexual characteristics and modulate the secretion of pituitary
LH and FSH.
• The levels of SHBG decline slightly at puberty (Elmlinger et al., 2005).

4. GnRH pulse generators

The onset of puberty and the maintenance of normal reproductive functions in male and female adolescents are physiologically
driven and regulated by the pulsatile release of hypothalamic GnRH. An inactivating mutation of the GnRH gene or its receptor can
lead to idiopathic hypogonadotropic hypogonadism in humans (Bouligand et al., 2009; de Roux et al., 1997). The molecular me-
chanism that stimulates GnRH release as puberty approaches is yet not completely elucidated. However, as GnRH-producing neurons
lack the cellular machinery to influence its secretion and also do not express estrogen receptors-alpha (ER-α), intermediate cellular
pathways very likely exist to mediate the gonadal feedback (Herbison & Theodosis, 1992). GnRH pulses are thought to be generated
and regulated by a network of different neurons dispersed in the hypothalamus known as “GnRH pulse generators”. Multiple neu-
ropeptides produced within the hypothalamus have been suggested to modulate the release of GnRH (Lehman, Coolen, & Goodman,
2010); moreover, multiple neurons in the infundibular/arcuate nucleus of the hypothalamus express and secrete critical peptides
including kisspeptins, neurokinin-B (NKB), and dynorphin (Dyn). Cheng and colleagues coined the acronym (KNDy) for these neu-
rons, the coordinated activity of which has been suggested to regulate GnRH release (Cheng, Coolen, Padmanabhan, Goodman, &
Lehman, 2010).

4.1. Kisspeptins, NKB, and Dyn

Kisspeptin is a hypothalamic peptide encoded by the KiSS-1 gene; its stimulatory action is mediated physiologically by the
kisspeptin-1 receptor (KISS1R). This receptor is one of the family of G protein-coupled receptor 54 (GPR54) which has been found to
express in GnRH neurons (Messager et al., 2005). NKB is a tachykinin peptide encoded by the TAC3 gene, and its stimulatory action
on GnRH release is mediated by the NKB receptor (NK3R) that is encoded by the TACR3 gene (Topaloglu et al., 2009). It has been
demonstrated that inactivating mutations in the KiSS-1 or TACR3genes, or in those encoding their receptors, can result in the absence
of puberty or hypogonadotropic hypogonadism in humans and mice (de Roux et al., 2003; de Tassigny et al., 2007; Topaloglu et al.,
2009; Topaloglu et al., 2012). Moreover, kisspeptin antagonists inhibit the pulsatile secretion of GnRH/LH, suggesting that kiss-1
neurons mediate a sex steroid negative feedback effect on GnRH/gonadotropin secretion (Roseweir et al., 2009). Dyn is an

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endogenous opioid peptide that is known to mediate the inhibitory feedback of progesterone on GnRH pulsatile release (Goodman
et al., 2004), and although its exact physiological effect is not fully understood, it is generally recognized as a GnRH inhibitor
(Lehman et al., 2010). The inhibitory action of Dyn on GnRH release is mediated by its kappa-opioid receptor (KOR), which has been
shown to be highly expressed in GnRH neurons (Weems et al., 2016). Furthermore, NK3R and KOR are expressed in KNDy neurons,
suggesting that NKB and Dyn act autosynaptically on KNDy neurons to regulate kisspeptin secretion, which in turn drives the release
of GnRH (Navarro et al., 2009). However, it is not clear if GnRH neurons are targets for NKB, as NK3R is expressed marginally in the
GnRH neurons of rats (Krajewski et al., 2005) but not of sheep (Amstalden et al., 2010). These three neuropeptides, which are present
in the arcuate nucleus, are now considered major pulse generators that influence GnRH release, as they contribute significantly to the
physiology of puberty in boys and girls. The most striking feature of KNDy neurons is that they can be regulated directly by estradiol
and testosterone, indicating that these neurons express sex steroid receptors and that their activity appears to be subject to sex steroid
feedback (Smith et al., 2005; Smith et al., 2005; Weems et al., 2016). It has recently been demonstrated that NK3R agonists and KOR
antagonists can significantly stimulate LH secretion in male rodents (Matsuzaki et al., 2018), and it has therefore been suggested that
kisspeptin and NKB antagonists could be helpful for treating patients with pathological early puberty (Skorupskaite, George, &
Anderson, 2014). Taken together, KNDy neurons appear to act as GnRH/gonadotropin pulse generators within the neural network by
controlling the secretion of kisspeptin via stimulation by NKB/NK3R and inhibition by Dyn/KOR signaling.

5. Metabolic regulation of puberty: role of leptin

Leptin is an adipocytokine produced primarily by adipocytes; it is an anorectic factor and plays an essential role in controlling
food intake, body weight, and energy balance by inhibiting the hypothalamic orexigenic neuropeptide Y (NPY), thereby suppressing
appetite (Iwasa et al., 2011). Serum leptin and hypothalamic NPY are inversely correlated. It has been reported that in-
tracerebroventricular administration of leptin can markedly suppress the expression of NPY in the hypothalamic arcuate nucleus and
reduce food intake in rats (Schwartz, Seeley, Campfield, Burn, & Baskin, 1996). NPY also inhibits GnRH release and restrains the
onset of puberty during juvenile development (El Majdoubi, Sahu, Ramaswamy, & Plant, 2000). It has been shown that central
administration of NPY receptor antagonists to juvenile animals can initiate GnRH release and the onset of early puberty (El Majdoubi
et al., 2000), suggesting that NPY may act as a neurobiological brake that holds puberty in check during childhood. The role of leptin
in the physiology of puberty is well-established, and it is now recognized that leptin plays a key permissive role in the onset of
puberty in boys and girls (Farooqi, 2002). It has been shown that leptin injection can significantly accelerate the onset of puberty in
juvenile female mice (Ahima, Dushay, Flier, Prabakaran, & Flier, 1997). Considering the importance of the timing of normal puberty
in boys and girls, normal body weight and composition must be attained during childhood to avoid pubertal dysfunction. In addition
to the leptin-NPY interaction to initiate puberty, there is evidence that leptin can regulate puberty and reproductive function by
directly interacting with the KiSS-1gene. Although GnRH neurons lack leptin receptors (Quennell et al., 2009), KiSS-1 neurons
express these receptors, whereby leptin can directly stimulate kisspeptin release and mediate the pulsatile release of GnRH (Smith,
Acohido, Clifton, & Steiner, 2006). Moreover, low leptin levels in mutant mice are associated with a decrease in KiSS-1gene ex-
pression or inhibition of kisspeptin production (Quennell et al., 2011). Most recently, it has been demonstrated that rats with
abnormal leptin receptors and dysfunctional leptin signaling had significantly lower quantities of KNDy neurons and their peptides,
as well as markedly lower plasma LH levels, than normal rats (Nakao, Iwata, Takeshita, & Ozawa, 2018).

6. Physical changes associated with puberty in boys and girls

Puberty is an important developmental stage of life that involves a broad spectrum of cellular and physical changes. The rising
concentration of gonadotropins increases the level of serum sex steroid hormones and ultimately leads to the development of sec-
ondary sexual characteristics and other physical changes associated with puberty. The usual sequences of physical changes occurring
at puberty in boys and girls were first described by the scientists Marshall and Tanner, who classified these changes into different
physical stages (Marshall & Tanner, 1969, 1970). Tanner's measurement of pubertal maturation is widely accepted and used
nowadays in most clinical settings worldwide to assess pubertal development and progression.
For girls, Tanner defined two main phenotypic pubertal events:

1. Breast development (5 stages B1eB5) which is usually the first sign of puberty experienced by the vast majority of girls
“Thelarche”.
2. Pubic hair (5 stages PH1–PH5).

For boys, Tanner defined two main phenotypic pubertal events:

1. Testicular and penile development (5 stages G1–G5).

Although Tanner staging did not include testicular volume, which correlates with the physical changes occurring with the pro-
gression of puberty, it is worth noting since it represents a key physical finding associated with pubertal development in boys
(Ankarberg-Lindgren & Norjavaara, 2004). Testicular volume is assessed clinically using a Prader orchidometer, which comprises dif-
ferent sizes of ellipsoid beads equivalent to testicular volumes of 1–25 mL (Prader, 1966). A testicular volume greater than 3 mL is
considered the first sign of puberty in boys (Biro, Lucky, Huster, & Morrison, 1995; Zachmann, Prader, Kind, Häfliger, & Budliger, 1974).

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Table 2
Staging of pubertal development in girls and boys. “B” refers to breast development. “G” refers to genitals development. “PH” refers to pubic hair
development.
Physical development (Girls) Stage Physical development (Boys)

B1 (Prepubertal). No glandular breast tissue palpable. Just an G1 (Prepubertal).Testicular volume < 3 mL. No pubic hair.
PH1 elevation of breast papilla. No pubic hair. PH1
B2 Breast budding with elevation of breast and papilla as a small G2 Enlargement of testicular volume (3–6 mL) [1st pubertal sign in boys].
PH2 mound [1st pubertal sign in girls]. Downy soft pubic hair. PH2 Little or no change in penile size. Downy soft pubic hair.
Growth spurt (between stage 2–3)
B3 Further enlargement of breast and areola. Darker, coarser and G3 Testicular volume 8–12 mL. Penile lengthening. Darker, coarser, and
PH3 curled hair. PH3 curled hair.
Growth spurt (between stage 3–4)
B4 Projection of areola and papilla to form a “double mound” G4 Testicular volume 12–15 mL. Penile lengthening and broadening.
PH4 above the level of the breast. More dense hair that fills the PH4 Terminal hair that fills the entire triangle overlying the pubic region and
entire triangle overlying the pubic region and external genitalia external genitalia and no spread to the inner thigh.
and no spread to the inner thigh.
Menarche (between stage 4–5)
B5 Mature breast. Loss of double mound due to the projection of G5 Testicular volume > 15 mL. Adult genitalia. Terminal hair that extends
PH5 papilla only and recession of the areola to the level of the PH5 beyond the inguinal area onto the inner thigh.
breast. Dense hair that extends beyond the inguinal area onto
the inner thigh.

2. Pubic hair (5 stages PH1–PH5).

The adolescent growth spurt (peak height velocity) is defined as a period of maximum rate of growth achieved during puberty. In
girls, the adolescent growth spurt usually occurs before the onset of menarche and happens 2 years earlier than in boys (Marshall &
Tanner, 1970).
Table 2 describes the physical changes that occur during pubertal stages in boys and girls. Tanner stage 1 is prepubertal (child-
hood), while Tanner stage 5 is complete development (adulthood).

7. Factors influencing puberty and physical growth

Physical growth and timing of puberty can be affected by a number of factors that act independently or in concert, and may affect
normal development and puberty. Such factors can be hormonal, genetic, environmental or nutritional. Several hormones are im-
portant for normal pubertal development and for the appearance of secondary sexual characteristics. In addition to the secretion of
sex steroid hormones (gonadarche), an increase in the secretion of adrenal androgens (adrenarche) continues throughout the pubertal
stages. The adrenal cortex continually secretes weak androgens such as dehydroepiandrosterone (DHEA), dehydroepiandrosterone
sulfate (DHEAS), and androstenedione at increasing levels beginning at 8 years of age in both boys and girls (Hopper & Yen, 1975).
However, the onset of adrenarche usually occurs before gonadarche; both lead to the onset of pubic and axillary hair development
(pubarche). Moreover, growth hormone (GH), insulin like growth factor-1 (IGF-1), thyroid hormones, and cortisol are also essential
for the normal developmental of organs and somatic growth (Robson, Siebler, Shalet, & Williams, 2002). Onset of first pubertal sign,
adult stature, acceleration of sexual maturation, and somatic development/growth can be affected by genetic and environmental
factors (Eaves et al., 2004; Towne et al., 2005). Some of the variations in the timing of puberty are determined by genetic factors, and
a number of genes responsible for disorders associated with puberty in boys and girls have already been identified (Gajdos,
Henderson, Hirschhorn, & Palmert, 2010). Geographical differences, psychosocial stresses, endocrine disruptors from pollutants, and
exposure to chemical and industrial compounds at the time of puberty can all influence the timing of normal puberty in both boys and
girls (Ellis & Garber, 2000; Toppari & Juul, 2010; Özen & Darcan, 2011). Obesity can play a significant role in the timing of puberty,
and it has been reported that obese children had higher serum leptin levels than similarly aged normal-weight children (Falorni et al.,
1997; Hassink et al., 1996), and it is known that leptin can accelerate the onset of puberty (Ahima et al., 1997). In girls, the
association between fat mass and timing of puberty is well established, with the majority of previous research reporting early
pubertal development among obese and overweight girls (Addo, Miller, Lee, Hediger, & Himes, 2014; Davison, Susman, & Birch,
2003; Kaplowitz, Slora, Wasserman, Pedlow, & Herman-Giddens, 2001; Lee et al., 2007). In boys, there have been fewer studies
conducted and their findings are conflicting. Some studies have found that obese and overweight boys attain early puberty than
normal weight boys (De Leonibus et al., 2014; Sandhu, Ben-Shlomo, Cole, Holly, & Smith, 2006), while other studies have reported
delayed puberty in overweight boys (Lee et al., 2010; Wang, 2002). Furthermore, one study has reported earlier onset of puberty in
overweight boys and delayed onset in obese boys compared with normal weight boys (Lee et al., 2016), and they suggested that
increased estrogen production (via aromatase activity from adipose tissues) in obese boys may suppress the pubertal process in obese
but not in overweight boys.
Therefore, controlling overweight and obesity in children can avert the early activation of the HPG axis and the onset of early
puberty (Addo et al., 2014). On the other hand, severe malnutrition and strenuous physical activities can delay sexual maturation and
the onset of normal puberty.

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8. Disorders of puberty in boys and girls

The timing of puberty is slightly variable among children and is dependent on the aforementioned factors. In general, the lower
age limit for the commencement of normal puberty is 8 years in girls and 9 years in boys; puberty is usually complete within 3–5
years of its onset (Argente, 1999; Wolfenden & Ryan, 2014). Puberty-associated disorders are classified into two major types: pre-
cocious and delayed which are described in the following sections.

8.1. Precocious puberty

Precocious puberty (PP) is defined as the onset of the first sign of puberty (primary sexual maturation) and/or early appearance of
secondary sexual characteristics before the age of 8 years in girls and 9 years in boys, or as menarche before the age of 10 years in
girls (Lebrethon & Bourguignon, 2000). Precocious puberty is caused by either the premature activation of the HPG axis, and results
in the secretion of sex steroids and the early appearance of secondary sexual characteristics (central precocious puberty (CPP). It can
also be caused by autonomous premature sex steroid secretion owing to a primary disorder of the gonads or adrenal gland in-
dependent of hypothalamo-pituitary control (i.e., pseudoprecocious or peripheral precocious puberty). It has been estimated that pre-
cocious puberty affects 1 in 5000 children and is 10 times more common in girls than in boys (Cesario & Hughes, 2007). Furthermore,
the majority of CPP in girls are idiopathic (Prété, Couto-Silva, Trivin, & Brauner, 2008), whereas higher prevalence of CPP in boys is
frequently caused by a pathological brain lesions (Choi et al., 2013).
Youngsters with precocious puberty experience accelerated sexual/physical growth in conjunction with a growth spurt. If un-
treated, the accelerated and rapid epiphysial growth could initially lead to tall stature in childhood and to a short stature in adulthood
owing to premature epiphysial closure. This could lead to adverse health and psychosocial consequences with respect to the children's
peers, as well as a shorter final height which requires timely medical and psychosocial support. The causes of precocious puberty are
multifactorial and are listed in Table 3.

Table 3
Types and causes of puberty-associated disorders.
Types Of Puberty Disorders Causes

Precocious puberty (1) Central Precocious Puberty

- Idiopathic central precocious puberty
- CNS tumours
- CNS congenital abnormalities
- Infectious or post-infectious conditions of hypothalamus
(2) Pseudoprecocious (Peripheral) Puberty
- Congenital adrenal hyperplasia (CAH)
- Gonads or adrenal gland tumours
- Human chorionic gonadotropin (hCG) secreting tumour (in boys)
- McCune-Albright Syndrome (MAS)
- Familial male-limited precocious puberty (FMPP) (in boys)
- Severe hypothyroidism (rare)
Delayed puberty (1) Pubertal Delay
- Constitutional delay of growth and puberty (CDGP)
- Psychosocial stresses
- Malnutrition, anorexia nervosa and strenuous physical activity
- Endocrine and gastrointestinal disorders
- Renal failure
(2) Pubertal Failure
➢ Hypogonadotropic hypogonadism:
- Idiopathic
- Kallmann and Prader-Willi syndromes
- KiSS-1 or GPR54 gene mutations
- CNS congenital anomalies and panhypopituitarism
- Leptin gene and leptin receptor gene mutations
- FSH and LH gene mutations from pituitary gonadotropes
- Low FSH and LH levels
➢ Hypergonadotropic hypogonadism:
- Klinefelter and Turner syndromes
- Chemo/radio therapies
- Congenital gonadal dysgenesis or Cryptorchidism
- High FSH and LH levels
- FSH, LH and androgen receptor gene mutations
- Aromatase gene mutations from follicular granulosa cells (in girls)
- Gonadal damage secondary to trauma, tumours, surgical removal, and infectious or autoimmune diseases.

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8.2. Delayed puberty

Delayed puberty is arbitrarily defined as the lack of signs of secondary sexual characteristics by the age of ∼13 years in girls (lack
of thelarche) and ∼14 years in boys (testicular volume < 3 mL) (Argente, 1999; Sedlmeyer & Palmert, 2002; Traggiai & Stanhope,
2002). Practically, it is defined as a delay in the onset, progression, or completion of pubertal development. Puberty is considered
delayed if the elapsed time between the onset of the first pubertal sign to the final stage of puberty (pubertal arrest) exceeds 4–5 years
(Argente, 1999). Moreover, a boy is said to have delayed puberty if a testicular volume of > 3 mL was not attained by the age of 14
years (Marshall & Tanner, 1970). The absence of menarche in a girl by the age of 15 years (primary amenorrhoea) or a failure of
pubertal progression warrants urgent investigation (Wolfenden & Ryan, 2014). Delayed puberty is classified into pubertal delay and
pubertal failure; their potential causes are listed in Table 3.
Deviations of pubertal development from the average timing (precocious or delayed) or tempo can be associated with an adverse
psychological disorders. Previous studies have shown that early or late puberty can be associated with negative outcomes (mainly
internalizing and externalizing problems), eating disorders, anxiety, and sexual behavior in both sexes (Graber, Seeley, Brooks-Gunn,
& Lewinsohn, 2004; Miller, Norton, Fan, & Christopherson, 1998; Zehr, Culbert, Sisk, & Klump, 2007).

9. Conclusion

Puberty is the process of HPG axis maturation and the attainment of reproductive function. The exact underlying mechanisms that
awaken the HPG axis from its prepubertal quiescence remain obscure, but newly discovered neuroendocrine pathways have been
suggested. The hallmark of puberty is the increased secretion of GnRH in a pulsatile fashion followed by the pulsatile secretion of
gonadotropins, which act in concert to activate gonadal function, secretion of sex steroid hormones, and gametogenesis. Rising levels
of serum sex steroids affect a wide array of sexual and physical developments attributes, including growth spurt activation and the
development of secondary sexual characteristics in both sexes. Although major advances in understanding the timing of puberty have
been made in the past decade, the exact molecular mechanisms that herald the onset of puberty remain obscure. Several factors can
influence the secretion of GnRH and the onset of puberty, including hormonal, genetic, environmental, and nutritional which can
modify the timing or the tempo of puberty in some populations. Any aberration in pubertal growth and development should be taken
seriously and investigated carefully.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgments

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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