Normal puberty

10/2/2016 Normal puberty
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Authors
Frank M Biro, MD
YeeMing Chan, MD, PhD
Section Editors
Teresa K Duryea, MD
Peter J Snyder, MD
Mitchell Geffner, MD
Diane Blake, MD
Deputy Editor
Alison G Hoppin, MD
Normal puberty
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2016. | This topic last updated: Jul 09, 2015.
INTRODUCTION — Adolescents experience several types of maturation, including cognitive (the development
of formal operational thought), psychosocial (the stages of adolescence), and physical. This complex series of
physical transitions is known as puberty, and these changes may impact psychosocial factors.
The most visible changes during puberty are growth in stature and development of secondary sexual
characteristics. Equally profound are changes in body composition; the achievement of fertility; and changes in
most body systems, such as the neuroendocrine axis, and bone size and mineralization; and the
cardiovascular system. As an example, puberty is associated with cardiovascular changes, including greater
aerobic power reserve, electrocardiographic changes, and blood pressure changes.
The normal sequence of pubertal events and perils of puberty are reviewed here. Precocious and delayed
puberty are discussed separately. (See "Definition, etiology, and evaluation of precocious puberty" and
"Diagnosis and treatment of delayed puberty".)
DEFINITIONS — Puberty is the general term for the transition from sexual immaturity to sexual maturity.
There are two main physiological events in puberty:
While puberty encompasses changes due to both gonadarche and adrenarche, the term "puberty" is often used
to refer specifically to gonadarche and associated changes, particularly in the phrases "precocious puberty"
and "delayed puberty." Adrenarche is discussed in detail separately. (See "Normal adrenarche" and "Premature
adrenarche".)
A number of other terms describe specific components of puberty:
Precocious puberty (more accurately, precocious gonadarche) is defined as pubertal onset at an age 2 to 3
standard deviations (SD) below the mean age of onset of puberty. In the United States, this has led to a
traditional definition of precocious puberty as the appearance of breast development before the age of eight
years in girls, and testicular enlargement before the age of nine years in boys. However, the age threshold for
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Gonadarche is the activation of the gonads by the pituitary hormones folliclestimulating hormone (FSH)
and luteinizing hormone (LH).
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Adrenarche is the activation of production of androgens by the adrenal cortex.
●
Thelarche is the appearance of breast tissue, which is primarily due to the action of estradiol from the
ovaries.
●
Menarche is the time of first menstrual bleed. The first menstrual bleed is often not associated with
ovulation; it typically is caused solely by the effects of estradiol on the endometrial lining. Menstrual
bleeding in regular menstrual cycles after maturity is caused by the interplay of estradiol and progesterone
produced by the ovaries. (See "Physiology of the normal menstrual cycle".)
●
Spermarche is the time of the first sperm production (heralded by nocturnal sperm emissions and
appearance of sperm in the urine), which is due to the effects of FSH and LH, via testosterone [1].
●
Pubarche is the appearance of pubic hair, which is primarily due to the effects of androgens from the
adrenal gland. The term is also applied to first appearance of axillary hair, apocrine body odor, and acne.
●

undertaking a clinical evaluation for early puberty remains a subject of ongoing discussion. For girls who
develop signs of puberty between six and eight years of age, the need for clinical evaluation depends on the
degree and rate of maturation as well as the family history of pubertal timing. (See "Definition, etiology, and
evaluation of precocious puberty".)
Delayed puberty is defined as the absence of signs of puberty by an age 2 to 3 SD above the mean age of
onset of puberty, ie, by an age at which 95 to 98 percent of children of that sex and culture have initiated
sexual maturation. In the United States, this corresponds to an upper limit of 12 to 13 years for girls (for breast
development) [25], and of 13 to 14 years for boys (for testicular enlargement) [2,68]. (See "Diagnosis and
treatment of delayed puberty".)
PHYSIOLOGY AND ENDOCRINOLOGY OF PUBERTY — Gonadarche is driven by an increase in the
pulsatile secretion of gonadotropinreleasing hormone (GnRH) from the hypothalamus, resulting in increases in
both frequency and amplitude of pulses of luteinizing hormone (LH) secretion, a surrogate measure of GnRH
secretory pulses [9] (see "Physiology of gonadotropinreleasing hormone"). GnRH stimulates the gonadotroph
cells of the anterior pituitary gland to secrete folliclestimulating hormone (FSH) and LH, which in turn stimulate
sexsteroidogenesis and eventually gametogenesis in the gonads.
In girls, FSH stimulates the growth of ovarian follicles and, in conjunction with LH, stimulates production of
estradiol by the ovaries (figure 1A). Early in puberty, estradiol stimulates breast development and growth of the
skeleton, leading to pubertal growth acceleration. Later in puberty, the interplay between pituitary secretion of
FSH and LH, and secretion of estradiol by ovarian follicles leads to ovulation and menstrual cycles (see
"Physiology of the normal menstrual cycle"). Estradiol also induces maturation of the skeleton, eventually
resulting in fusion of the growth plates and cessation of linear growth.
In boys, LH stimulates the Leydig cells of the testes to produce testosterone, the high local concentration of
which stimulates the growth of the seminiferous tubules, leading to an increase in testicular volume (figure 1B).
FSH stimulates further growth of seminiferous tubules and testicular volume. Testosterone also induces growth
of the penis, deepening of the voice, growth of hair, and increases in muscularity. Some testosterone is
converted to estradiol, which has the same effects on growth and skeletal maturation as in girls (and can also
lead to some breast development in males, as it does in females). (See 'Gynecomastia' below.)
Though temporally correlated, gonadarche and adrenarche are physiologically distinct events. Individuals with
defects in the hypothalamicpituitarygonadal axis can still undergo adrenarche. Similarly, individuals with no
adrenal function can achieve gonadarche [10].
Adrenarche begins when the zona reticularis of the adrenal gland begins to synthesize the adrenal androgens
dehydroepiandrosterone (DHEA) and androstenedione. Though less potent than testosterone, these induce
androgenic changes including growth of pubic and axillary hair, maturation of the apocrine sweat glands
(leading to adulttype body odor), and development of acne. (See "Normal adrenarche".)
PUBERTAL CHANGES
Sexual maturity rating (Tanner stages) — Puberty consists of a series of predictable events that usually
proceed in a predictable pattern, with some variation in timing of onset, sequence, and tempo (figure 2AB).
The staging system utilized most frequently is that of sexual maturity ratings (SMR). These are also known as
"Tanner stages" because they were initially published by Marshall and Tanner [11,12]. These consist of
systematized descriptions of the development of secondary sexual characteristics, consisting of breast
changes in females, genital changes in males, and pubic hair changes in both males and females. SMR for
pubic hair, breast, and genitalia consists of five stages, with stage 1 representing prepuberty and stage 5
representing adult development (table 1). The stages are illustrated by the figure in girls (picture 1AB) and boys
(picture 2).
As is discussed below, the timing of pubertal maturation has an important influence on selfesteem, behavior,
growth, and weight. As an example, early maturation is associated with slightly shorter adult stature [13,14]
and with greater adult ponderosity and adiposity [14,15]. Details of the physiologic changes expected during
puberty are discussed below. (See 'Sequence of pubertal maturation' below.)
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Growth spurt — Approximately 17 to 18 percent of adult height accrues during puberty [16]. The timing of the
growth spurt (peak height velocity) varies by gender, occurring approximately two years earlier in girls than in
boys. The increase in height affects both axial (trunk) and appendicular (limb) components [17]. The limbs
accelerate before the trunk, with the distal portions of the limbs accelerating before the proximal portions; thus,
the adolescent in early puberty is "all hands and feet." In later puberty, however, the growth spurt is primarily
truncal [17].
Height velocity can be plotted and compared with norms using height velocity growth charts. The most
commonly used charts are those published by Tanner and Davies (figure 3AB) [2]. Although these are used for
longitudinal tracking and acknowledge the variation between early, average, and late maturers, their accuracy
is limited because they were prepared from crosssectional rather than longitudinal data. Other growth charts
were generated from longitudinal data, such as the series of charts published by the Harvard SixCities study,
but are less widely available [18].
The disparity in mean adult height of men and women results from the timing and magnitude of the growth
spurt in boys and girls. In girls, peak height velocity occurs, on average, 0.5 years prior to menarche [19].
Because the pubertal growth spurt starts approximately two years later in boys than in girls, boys have an
additional two years of prepubertal growth (at a rate of 3 to 8 cm per year) compared with girls at the time the
growth spurt starts. Furthermore, boys experience a greater peak height velocity than do girls (10.3 versus 9.0
cm/year) (figure 3AB). The growth spurt typically lasts for about two years in both sexes. When evaluating
growth, the clinician should look at wholeyear changes because of seasonal variability; greater growth
typically occurs in spring, although the time of year may vary when a given individual has a seasonal peak.
Extremely early onset of puberty (precocious puberty) results in earlier peak height velocity, which often leads
to a transient period of tall stature, but is associated with reduced adult height due to early epiphyseal closure
(see "Treatment of precocious puberty", section on 'Decision to treat'). Whether pubertal onset that is early but
within the normal range is also associated with reduced adult stature is less clear. In girls, early menarche was
associated with greater peak height velocity but shorter adult stature, while early thelarche had no effect on
adult stature [20]. In boys, those who mature relatively early but within the normal range have a modest
reduction in adult height [21]. The diminished adult height is attributable to shorter leg length; sitting height is
not reduced. Body weight appears to influence these results: in the same study, boys who were underweight
during childhood tended to have longer leg length and no change in adult height. It is probably not appropriate to
extrapolate these results to girls because obesity is sometimes associated with earlier onset of puberty in girls,
and obesity may have the opposite effect in boys. (See "Comorbidities and complications of obesity in children
and adolescents", section on 'Growth and puberty'.)
Bone growth — Bone growth accelerates during puberty, in concert with height velocity, but bone
mineralization lags behind. Bone growth occurs first in length, followed by width, then mineral content, and then
bone density [22]. The rate of bone mineral accrual peaks around the age of menarche in girls, which occurs
approximately 9 to 12 months later than peak height velocity [23,24]. The disparity in the timing of bone growth
and mineralization may place the growing adolescent at increased risk for fracture. (See 'Musculoskeletal
injuries' below.)
Approximately onehalf of total body calcium is laid down during puberty in females, and onehalf to twothirds
in males [22,25]. By the end of puberty, males have nearly 50 percent more total body calcium than do
females. The increase in bone density during puberty is greater in African American females than in Caucasian
females [26].
The risk for osteoporosis during adulthood may be related to both specific "insults" and the timing of factors
impacting bone deposition during puberty [17]. These data suggest that the window of opportunity to maximize
peak bone mass may be limited [22]. Possible effects of certain hormonal contraceptives on peak bone mass
are discussed separately. (See "Prevention of osteoporosis", section on 'Maximizing peak bone mass' and
"Contraception: Overview of issues specific to adolescents", section on 'Bone density'.)
Weight and body composition — Puberty is associated with significant changes in body weight and
alterations in body composition, especially in lean body mass and the proportion of body fat (adiposity), with
different patterns in girls as compared with boys. Growth curves for body mass index (BMI) describe the

typical increase in body mass that occurs during puberty (figure 4AB), but do not reflect the differences
between earlymaturing and latematuring children, nor do they distinguish between changes in lean body mass
versus adipose tissue.
In early puberty, the annual increase in BMI is driven primarily by changes in lean body mass. Later, the
increase in BMI tends to be driven by increases in fat mass [27]. This general pattern diverges between the
genders: boys tend to have a decrease in body fat in early puberty and then proceed to a substantial increase
in lean body mass. Girls tend to have a higher proportion of fat mass than boys at each phase, and after 16
years of age, the annual increase in BMI is largely because of increases in fat mass [27,28]. These general
patterns are altered by the individual's nutritional status; either boys or girls who gain excessive weight during
puberty may experience an ongoing increase in body fat, regardless of gender or pubertal stage. Obesity tracks
from adolescence to adulthood, and earlier onset of obesity is associated with increased cardiovascular
morbidity and mortality [2931]. (See "Clinical evaluation of the obese child and adolescent".)
SEQUENCE OF PUBERTAL MATURATION — Some variability occurs between individuals with regard to
the timing, sequence, and tempo of pubertal maturation. However, most adolescents follow a predictable path
through pubertal maturation.
Girls — The earliest detectable secondary sexual characteristic on physical examination in most girls is
breast/areolar development (thelarche) (picture 1A), although about 15 percent have pubic hair as the initial
manifestation (pubarche) (picture 1B) [32]. Ovarian enlargement and growth acceleration typically precede
breast development but are not apparent on a single physical examination. Estrogen stimulation of the vaginal
mucosa causes a physiologic leukorrhea, which is a thin, white, nonfoulsmelling vaginal discharge that
typically begins 6 to 12 months before menarche. Menarche occurs, on average, 2 to 2.5 years after the onset
of puberty (figure 2A) [11,19,24]. (See "The pediatric physical examination: The perineum", section on
'Preadolescent and adolescent females'.)
The likelihood of pubarche as the initial manifestation of puberty increases threefold with maternal
preeclampsia; the likelihood is directly related to the severity of preeclampsia [33,34]. The initial manifestation
predicts body morphology and composition throughout pubertal maturation into early adulthood. As an example,
girls with breast development as the initial manifestation of puberty have both an earlier age of menarche and
greater body mass index (BMI) throughout puberty and as adults, as compared with girls who exhibit pubarche
first [35]. Earlier menarche (before 12 years of age) is associated with higher BMI during adulthood as
compared with later menarche [15,3638]. Most of this effect may be attributable to the influence of childhood
obesity on both menarcheal age and adult obesity [39].
Boys — The earliest stage of male maturation that is detectable on physical examination is an increase in
testicular volume (figure 5). Almost all boys have an increase in testicular size (volume ≥4 mL and length ≥2.5
cm) approximately six months prior to the appearance of penile growth and pubic hair (picture 2) [32,40]. The
appearance of sperm in the urine and the onset of nocturnal sperm emissions occur shortly after the attainment
of peak height velocity; many consider these events the male equivalent of menarche (figure 2B).
Testicular volume is typically measured using the Prader orchidometer, a series of threedimensional ellipsoids
with a volume from 1 to 25 mL or more.
Penile length is measured using a straight edge on the dorsal surface in the nonerect state from the pubic
ramus to the tip of the glans while compressing the suprapubic fat pad and applying gentle traction. Mean
stretched penile length is approximately 3.75 cm (± 0.54 cm) at one year of age and gradually increases to 4.84
cm by late childhood, then increases sharply to about 9.5 cm (± 1.12 cm) by late puberty (according to
measurements from a predominantly white population) [41]. This measurement is rarely used for monitoring of
pubertal progress because penile growth is not an early event in puberty, accurate measurement is difficult and
may be awkward for the adolescent boy, and there is not as clear of a "pubertal threshold" for penile stretched
length as there is for testicular volume.
Although there is some temporal variation in the appearance and progression of testicular volume, penile
growth, and pubic hair development, a clear discrepancy between these physical findings may indicate a
pathological condition. For example, a finding of small testicular volumes in a fully virilized adolescent boy may
be a sign of Klinefelter syndrome or inappropriate use of exogenous testosterone. The following figure provides

a guide for the clinician to evaluate the relationship between testicular volume and pubic hair (figure 5) [40].
TIMING OF PUBERTAL EVENTS — As noted above, the timing of pubertal onset varies widely among
individuals of a given sex and ethnic background (see 'Definitions' above). Demographic studies over the past
15 to 20 years have indicated a trend towards earlier pubertal timing in girls and possibly boys as well, a trend
that has captured the attention of the lay press (which often exaggerates the findings). While several factors
are known to influence pubertal timing, the precise physiologic determinants of pubertal timing remain obscure.
Trends in pubertal timing — Pubertal onset in girls has been trending earlier in the United States and in most
other developed countries. In a 1997 study of over 18,000 females from the United States and Puerto Rico,
Pediatric Research in Office Settings (PROS), the earliest signs of puberty were at ages considerably younger
than had been reported previously, and striking racial differences in timing were found [3]. The mean ages for
the onset of breast development were 8.87 years in AfricanAmerican girls and 9.96 years in white girls, and
the mean age for pubic hair growth was 8.78 years in African American girls and 10.51 years in white girls
(figure 6). In a subsequent longitudinal study of over 1200 girls conducted a decade later, white participants
began to mature earlier than white participants in the PROS study (9.62 years contrasted with 9.96 years) [4].
Furthermore, participants with body mass index (BMI) >85 percentile matured before those <85 percentile
(p<0.001). In contrast, studies comparing the timing of menarche between African American and white girls
have reported smaller differences.
Pubertal onset in boys also appears to be occurring earlier in the United States. In a study including more than
4000 healthy boys, the mean age for entering puberty (sexual maturity rating [SMR] for genital development
stage 2) was 10.14 years for white boys, 10.04 years for Hispanic boys, and 9.14 years for African American
boys [6]. These thresholds are 1.5 to 2 years earlier than historical norms. Similar trends have been reported
from several European and Scandinavian countries and China [4246]. The relationship between pubertal onset
and obesity in boys is not clear. Some studies suggest that being overweight or obese is associated with later
onset of puberty in boys, in contrast with findings in girls [40,4749]. Conversely, other studies report that
increased BMI and fat mass is associated with earlier puberty in boys, similar to findings in girls [6,42,50,51].
However, several studies are inconclusive or demonstrate no relationship [7,36].
The earlier onset of puberty has had important implications for the diagnosis of precocious puberty. Precocious
puberty usually has been defined as breast development prior to eight years of age in girls and testicular
enlargement before the age of nine years in boys. Because of the earlier onset of puberty in the United States,
it has been suggested that a threshold of seven years in white girls and six years in African American girls be
used for evaluation for precocious puberty [13]. Following these suggestions may lead to underdiagnosis of
endocrine disorders, and the appropriate threshold for evaluation remains controversial and probably varies
among populations; the need for evaluation depends not only on age but also on the degree and rate of
maturation [52]. (See "Definition, etiology, and evaluation of precocious puberty".)
Determinants of pubertal timing — Genetics accounts for the majority of the variability in the timing of
pubertal onset in developed countries. The timing of puberty and menarche in a girl is best predicted by the
timing of menarche in her mother (see 'Physiology of pubertal onset' below). Other factors that influence
pubertal onset include overall health (with poor health associated with delayed pubertal onset), and social
environment (such as family stress or the presence of an adult nonbiologicallyrelated male in the household,
which are associated with earlier pubertal onset) [5356]. Studies have suggested an interaction between
genetics and the environment. As an example, age of menarche is generally earlier in African American as
compared with white girls, but the difference between the groups decreased between the 1970s and the 1990s
[56]. The influence of environmental factors, including endocrine disruptors, on timing of pubertal maturation is
a subject of active research [57]. (See 'Trends in pubertal timing' above.)
Pubertal timing varies substantially between race/ethnic groups. In a 2001 study in the United States, the rates
of early maturation (menarche ≤11 years) were 7.8 percent for white, 12.3 percent for black, 13.6 percent for
Hispanic, and 5.2 percent for Asian girls [58]. The frequency of late maturation (menarche ≥14 years) ranged
from 15.2 percent among white girls to 27 percent among Asian girls. This relationship appears to be primarily
mediated by differences in rates of overweight; within each race/ethnic group, early maturing girls were
approximately twice as likely to be overweight as compared with those maturing at an average age. The data in
this study did not establish whether the relationship between age of menarche and obesity varies among racial
th th

and ethnic groups.
Body fat and leptin — It has been proposed that a critical body weight [59] or body composition [60] is the
most salient issue in the development and maintenance of pubertal events [36,5961]. However, body weight
alone probably is not a sufficient explanation. The overall earlier onset of puberty among the general population
has been attributed to the increasing prevalence of obesity. (See 'Trends in pubertal timing' above.)
Leptin has been proposed as the hormone responsible for the initiation and progression of puberty. Leptin is
produced largely in adipocytes; large fat cells produce more leptin than do small ones, and serum leptin
concentrations are highly correlated with body fat content. The potential importance of leptin is illustrated by
the observations that mice or humans deficient in leptin fail to undergo pubertal development and that the
administration of leptin to these animals or individuals results in pubertal onset, but only at a normal age;
administration of leptin does not induce precocious puberty [62,63]. Furthermore, higher serum leptin
concentrations in girls are associated with increased body fat and an earlier onset of puberty [64]. In one study,
a 1 ng/mL increase in serum leptin was associated with earlier menarche by one month, and a 1 kg increase in
body fat was associated with earlier menarche by 13 days. (See "Physiology of leptin".)
Leptin appears to be one of several factors that influence the activity of the gonadotropinreleasing hormone
(GnRH) pulse generator, probably as a signal of the availability of metabolic fuel [65]. One study of eight boys
showed that serum leptin concentrations increased immediately before puberty [66], but this was not observed
in other studies, which have suggested that changes in serum leptin are a result of changes in body
composition with puberty rather than a trigger of pubertal onset [6769].
Overall, leptin appears to be a permissive signal that is required for normal reproductive endocrine function and
puberty, but not the instructive signal that initiates the onset of puberty.
Physiology of pubertal onset — A critical hormonal event in puberty is an increase in the pulsatile
secretion of GnRH from the hypothalamus. The question, "What triggers puberty?" can therefore be reframed
as, "What triggers the increase in GnRH secretion at puberty?". These questions remain fundamentally
unanswered, but research over the decades has started to shed light on this mysterious phenomenon.
Theoretically, puberty can start as the result of the emergence of activators of GnRH secretion or the
suppression of inhibitors of GnRH secretion. Evidence suggests that both mechanisms are involved in the
onset of puberty.
Activators of GnRH secretion – Glutamate has long been known to stimulate GnRH neuronal activity in
animal models, but whether glutamate is directly involved in determining pubertal timing remains unclear
[70]. Similarly, while the hormone leptin is required for normal pubertal onset in humans, it seems unlikely
to play a role in determining puberty timing, as discussed in detail above. (See 'Body fat and leptin'
above.)
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Another stimulatory factor, kisspeptin, appears to have an important role in the initiation of puberty in
humans [71,72]. Kisspeptin is secreted by neurons in the hypothalamus and potently stimulates
hypothalamic GnRH secretion. In humans, lossoffunction mutations in KISS1, which encodes the
kisspeptin preprohormone, or in KISS1R (formerly GPR54), which encodes the kisspeptin receptor, cause
lack of pubertal development due to idiopathic hypogonadotropic hypogonadism [73,74]. Expressions of
hypothalamic KISS1 mRNA and kisspeptin peptide appear to increase across the pubertal transition in
animal models, suggesting that kisspeptin may be a key instructive signal in the initiation of puberty [75].
Signaling by neurokinin B also appears to be an important stimulus for pubertal onset [72]. In humans,
mutations in TAC3, which encodes the neurokinin B preprohormone, and TACR3, which encodes the
primary neurokinin B receptor, also cause idiopathic hypogonadotropic hypogonadism [74]. A unique
feature of patients with mutations in TAC3 or TACR3 is that they have a propensity for "reversal" of their
hypogonadotropic hypogonadism, that is, recovery of reproductive endocrine function in adulthood [76].
This suggests that signaling by neurokinin B is less important for reproductive endocrine function in
adulthood and thus may have a more specific role in activation of the reproductive endocrine system at
the time of puberty.

Overall, genetic factors have been estimated to account for 50 to 75 percent of the variation in normal pubertal
timing [8083]. Several genetic loci have now been identified that are associated with age of pubertal onset [80
84]. A large genomewide study including more than 180,000 women identified common variants or single
nucleotide polymorphisms (SNPs) at 106 genetic loci that were associated with age at menarche [84]. Several
of these loci have also been shown to be associated with the timing of pubertal events in boys [83,84].
Some of the genes near these loci have known roles in reproduction, such as ESR1, which encodes the
estrogen receptor alpha, TACR3, which encodes the neurokinin B receptor, and MKRN3, which encodes
makorin ring finger protein 3. Furthermore, some of the genetic variants associated with age at menarche have
also been associated with variation in adult height [8082]. These observations suggest a genetic basis for
previously observed associations between age at menarche and height; in some cases, this association might
be mediated by earlier epiphyseal closure caused by earlier exposure to estrogens. Similarly, several genes
that are associated with childhood obesity were also associated with earlier age at menarche [80,81] (see
"Pathogenesis of obesity", section on 'Common obesity'). However, it is unclear how most of the loci may
regulate menarchal timing. As an example, one of the strongest associations is with LIN28B
(Caenorhabditis elegans, homolog of B), which is a regulator of microRNA processing involved in
developmental timing in C. elegans but whose role in human reproduction is unclear [8184].
Despite these significant advances in understanding the genetics of pubertal timing, most of the genetic basis
remains unexplained, as the variants described in these studies account for only 2.7 percent of the variation in
pubertal timing. Collectively, these findings provide glimpses into the physiological mechanisms that determine
pubertal timing, but an integrated model for the onset of puberty remains elusive.
ISSUES ARISING WITH PUBERTY — Puberty is associated with a number of complications that present
challenges to the patient and family. These "perils of puberty" include anemia, gynecomastia, acne,
psychological correlates of puberty, certain types of sportsrelated injuries, myopia, scoliosis, and
dysfunctional uterine bleeding.
Anemia — Anemia and iron deficiency are more common among adolescent girls as compared with
adolescent boys or schoolaged children. The Third National Health and Nutrition Examination Survey
(NHANES III) found a 9 percent incidence of iron deficiency and a 2 percent incidence of anemia among
American girls between the ages of 12 and 15 years; the respective values were less than 2 percent for boys in
this age group (table 2) [85]. Hemoglobin and serum ferritin concentrations increase with advancing pubertal
stage in males, but not in females [86,87]. Males are less prone to anemia because testosterone increases
erythropoiesis, while females are more prone to anemia because of menstrual bleeding and insufficient iron
intake [87]. (See "Iron requirements and iron deficiency in adolescents".)
Gynecomastia — Pubertal gynecomastia (in contrast with neonatal or senescent gynecomastia) occurs in
GnRH inhibitors – Patients with precocious puberty provide insight into potential inhibitors of GnRH
secretion. It has long been recognized that lesions of the central nervous system (CNS) can cause
precocious puberty (see "Definition, etiology, and evaluation of precocious puberty"). This implies that
pathways within the CNS suppress GnRH neuronal activity during childhood, such that disruption of
these pathways results in precocious puberty, though the precise identity of these pathways remains
obscure.
●
The neurotransmitter gammaaminobutyric acid (GABA) appears to play an important role in these
inhibitory pathways. In rhesus monkeys, secretion of GABA in the hypothalamus decreases across the
pubertal transition [77], and pharmacological disruption of signaling through the GABA receptor induces
early puberty [78].
A
Lossoffunction mutations in the gene MKRN3 have been found to be a genetic cause of precocious
puberty [79]. MKRN3 is maternally imprinted, ie, only the paternal allele is expressed; mutations in
MKRN3 therefore cause precocious puberty only if inherited from the father. MKRN3 encodes makorin
ring finger protein 3, a protein that may have a role in ubiquitination (addition of the protein ubiquitin, the
precise function of which is unclear). In mice, Mkrn3 expression decreases around the time of sexual
maturation, suggesting that Mkrn3 has a role in suppressing reproductive endocrine function prior to
puberty.

approximately onehalf of teenage boys at an average age of 13 years, and it persists for 6 to 18 months [88].
Boys with persistent gynecomastia (ie, lasting two years or more) have a diameter of palpable tissue ≥2 cm
during the first year (odds ratio 8.7) [89]. Although the underlying diagnosis usually is "idiopathic pubertal
gynecomastia," a variety of other etiologies including drugs, medications, hypogonadism (most notably due to
Klinefelter syndrome), testicular tumors, and hyperthyroidism, must be considered. The underlying mechanisms
presumably reflect an imbalance in the effective estrogenictoandrogenic stimulation because of an increase in
the production or action of estrogens or estrogenlike compounds, a decrease in the production or action of
androgens, or enhanced breast tissue sensitivity to estrogens or estrogenlike compounds [89]. (See
"Epidemiology, pathophysiology, and causes of gynecomastia" and "Clinical features, diagnosis, and
evaluation of gynecomastia".)
Acne — Acne, a disorder of the pilosebaceous unit, is characterized by follicular occlusion and inflammation
caused by androgenic stimulation. If the opening of the comedone is widely dilated, oxidation of keratinous
material leads to the development of a blackhead without inflammatory acne. With a small opening, a closed
comedo (whitehead) forms and may lead to inflammatory acne if the comedo ruptures into the dermis. With
pubertal maturation in both boys and girls, the number of acne lesions increases, with a greater number of
comedones than inflammatory lesions at all stages [90]. In girls, the severity of acne in later puberty is
associated with higher serum levels of dehydroepiandrosterone sulfate (DHEAS) and a greater number of acne
lesions in early puberty [91]. Although acne is common during puberty, moderate or severe acne in early
puberty, usually with other signs of androgen excess, should alert the clinician to the possibility of an
endocrinologic disorder, such as nonclassical congenital adrenal hyperplasia or polycystic ovary syndrome.
(See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris" and "Definition, clinical features
and differential diagnosis of polycystic ovary syndrome in adolescents".)
Psychological changes — Pubertal maturation has an impact on psychological and social issues [92].
Puberty does not affect cognitive development [93], although the timing of pubertal maturation may affect
psychosocial functioning.
Prior to adolescence, no gender differences in depression occur; during adolescence, however, the prevalence
of depression is twice as great in girls compared with boys [94]. As puberty progresses, boys develop a more
positive selfimage and mood. By contrast, girls tend to become less satisfied with their physical appearance,
and this tendency is more pronounced in white as compared with black girls. White girls also exhibit diminished
selfworth as they pass from early to midadolescence [95]. The epidemiology and clinical assessment of
depression in adolescents is discussed in a separate topic review. (See "Pediatric unipolar depression:
Epidemiology, clinical features, assessment, and diagnosis".)
Pubertal development may have an especially negative impact when a lack of synchrony between the timing of
pubertal development and chronologic age exists. For example, the earlymaturing girl may experience a
greater decrease in selfesteem and body satisfaction when compared with ontime or latematuring girls [96].
In a large crosssectional study, girls who were earlymaturing and boys who were latematuring were more
likely to have psychopathology. Girls who matured early were more likely to have a lifetime history of disruptive
behavior (attentiondeficit, hyperactivity, oppositional, or conduct disorders) and suicide attempts, whereas
boys who were latematuring were more likely to have internalizing behaviors and emotional reliance on others
[97]. Girls with early maturation are more likely to have older friends [98] and to be more vulnerable to peer
pressures [99].
Certain cognitive characteristics have long been observed in adolescents, in which they make very different
decisions when under the influence of strong emotions ("hot" cognition) as compared with decisions made
under conditions of low emotional arousal ("cool" cognition) [100]. Adolescents may display these cognitive
characteristics because the dorsolateral prefrontal cortex, an area of the brain involved in impulse control,
matures later than the remainder of the brain [101]. Thus, in times of stress, the brain of the adolescent may be
less able to modulate the affective component as compared with adults.
Musculoskeletal injuries — Pubertal status may help predict the specific type of musculoskeletal injuries that
adolescents may encounter during participation in sports [102]. The greatest risk of damage to epiphyseal
growth plates occurs during periods of peak height velocity, which also is the time of greatest change in bone
mineral content [23]. Similarly, the age of peak incidence of distal radius fractures matches the age of peak

height velocity in both boys and girls [103] (see 'Bone growth' above). The asynchronous growth of body parts
may result in a limited range of motion of some joints; when combined with the increase in muscle mass that
occurs shortly after peak height velocity, the limited range of motion may lead to sprains or strains. (See
'Growth spurt' above.)
A common overuse injury in teens is OsgoodSchlatter disease, which is an inflammation of the tibial tubercle
apophysis. (See "OsgoodSchlatter disease (tibial tuberosity avulsion)".)
Gynecologic consequences — Once a girl reaches menarche, rapid maturation of the reproductive axis
ensues. By one year after menarche, 65 percent of girls have regular menstrual cycles, with 10 or more periods
per year [104]. Girls with later onset of menarche progress more slowly to regular ovulatory cycles; when
menarche occurs after the age of 13, only onehalf will ovulate regularly within 4.5 years [105].
Abnormal uterine bleeding (AUB) refers to excessive, prolonged, and/or irregular endometrial bleeding. In
adolescents, anovulation accounts for approximately 80 percent of cases of AUB. With anovulatory cycles,
unopposed estrogen stimulates the endometrium, leading to a sustained proliferative phase rather than
maturing to a secretory endometrium. Estrogen levels ultimately cannot sustain the hyperplastic endometrial
lining, leading to irregular, sometimes heavy, menstrual bleeding. (See "Abnormal uterine bleeding in
adolescents: Definition and evaluation", section on 'Abnormal uterine bleeding (AUB) in adolescents' and
"Abnormal uterine bleeding in adolescents: Management".)
Myopia — The greatest incidence of myopia occurs during puberty and is caused by growth in the axial
diameter of the eye [106]. (See "Refractive errors in children", section on 'Refractive errors'.)
Scoliosis — Accelerated progression of the degree of scoliosis occurs during puberty because of growth in the
axial skeleton. (See "Adolescent idiopathic scoliosis: Management and prognosis", section on 'Risk for
progression'.)
Sexually transmitted infections — Sexually active adolescents represent the highestrisk age group for nearly
all sexually transmitted infections [107]. Both behavioral and biological factors are important. (See "Adolescent
sexuality", section on 'Adolescent development' and "Sexually transmitted diseases: Overview of issues
specific to adolescents", section on 'Epidemiology'.)
Behavioral issues that increase risk for sexually transmitted infections include younger age at onset of
intercourse, the number of lifetime partners, and the perceived prevalence of sexually transmitted infections
[108].
Biological factors include age of menarche (which influences behavioral factors) and gynecologic maturation. In
the first year or two after menarche, there is persistence of columnar epithelial cells on the exocervix (cervical
ectopy) as well as the transformation zone of columnar to squamous epithelial cells on the exocervix. These
factors may enhance infection with Chlamydia [109] and genital human papillomavirus (HPV) [110,111].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics"
and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 to 6
grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easytoread
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed.
These articles are written at the 10 to 12 grade reading level and are best for patients who want indepth
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Here are the patient education articles that are relevant to this topic. We encourage you to print or email these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)
SUMMARY — Puberty consists of a series of predictable events that usually proceed in a predictable pattern,
with some variation in timing of onset, sequence, and tempo.
th th
th th
Basics topics (see "Patient information: Normal sexual development (puberty) (The Basics)" and "Patient
information: Early puberty (The Basics)" and "Patient information: Late puberty (The Basics)")
●

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●
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●

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108. Rosenthal SL, Biro FM, Succop PA, et al. Impact of demographics, sexual history, and psychological
functioning on the acquisition of STDS in adolescents. Adolescence 1997; 32:757.
109. Harrison HR, Costin M, Meder JB, et al. Cervical Chlamydia trachomatis infection in university women:
relationship to history, contraception, ectopy, and cervicitis. Am J Obstet Gynecol 1985; 153:244.
110. Moscicki AB, Winkler B, Irwin CE Jr, Schachter J. Differences in biologic maturation, sexual behavior,
and sexually transmitted disease between adolescents with and without cervical intraepithelial neoplasia.
J Pediatr 1989; 115:487.
111. Shew ML, Fortenberry JD, Miles P, Amortegui AJ. Interval between menarche and first sexual
intercourse, related to risk of human papillomavirus infection. J Pediatr 1994; 125:661.
Topic 5849 Version 21.0

GRAPHICS
Hypothalamicpituitaryovarian axis and puberty
Puberty is marked by an increase in the pulsatile secretion of GnRH from the
hypothalamus. GnRH stimulates the secretion of FSH and LH from the gonadotroph
cells in the anterior pituitary gland. In girls, FSH stimulates the growth of ovarian
follicles and, in conjunction with LH, stimulates production of estradiol by the
ovaries. Early in puberty, estradiol stimulates breast development and growth of
the skeleton, leading to pubertal growth acceleration. Later in puberty, the interplay
between pituitary secretion of FSH and LH and secretion of estradiol by ovarian
follicles leads to ovulation and menstrual cycles. The skeletal maturation induced
by estradiol eventually results in fusion of the growth plates and cessation of
growth.

GnRH: gonadotropin releasing hormone; FSH: follicle stimulating hormone; LH: luteinizing
hormone.
Graphic 98701 Version 2.0

Hypothalamicpituitarytesticular axis and puberty
Puberty is marked by an increase in the pulsatile secretion of GnRH from the
hypothalamus. GnRH stimulates the secretion of FSH and LH from the gonadotroph cells
of the anterior pituitary gland. In boys, FSH stimulates growth of seminiferous tubules,
leading to an increase in testicular volume. FSH also stimulates the Sertoli cells of the
testes to produce inhibin B, which inhibits secretion of FSH. LH stimulates the Leydig
cells of the testes to produce testosterone, which induces growth of the penis,
deepening of the voice, growth of facial and body hair, and increases in muscularity.
The high local concentration of testosterone in the testes further stimulates growth of
the seminiferous tubules. Some testosterone is converted to estradiol, which stimulates
growth and skeletal maturation and frequently leads to some breast development
(gynecomastia).

GnRH: gonadotropin releasing hormone; FSH: folliclestimulating hormone; LH: luteinizing
hormone.

Sequence of puberty in girls
Sequence of events in girls with average timing of pubertal
development in the United States. African American girls tend to reach
a milestone at a younger age (lefthand side of the bracket)
than Caucasian girls (righthand side of the bracket). The median
length of time between the onset of puberty (breast Tanner stage 2)
and menarche is 2.6 years, and the 95th percentile is 4.5 years.
Data from: Biro FM, Huang B, Lucky AW, et al. Pubertal correlates in black and
white US girls. J Pediatr 2006; 148:234, and from: Tanner JM, Davies PS. J
Pediatr 1985; 107:317.

Sequence of puberty in boys
Sequence of pubertal events in boys with average timing of pubertal
development in the United States.
Data from:
1. Biro FM et al, Pubertal staging in boys. J Pediatr 1995; 127:100.
2. Karpati AM et al, Stature and pubertal stage assessment in American
boys: the 19881994 Third National Health and Nutrition Examination
Survey. J Adolesc Health 2002; 30:20512.
3. Dore E et al. Gender differences in peak muscle performance during
growth. Int J Sports Med 2005; 26:274.
4. Neu CM et al. Influence of puberty on muscle development at the
forearm. Amer J Physiol Endocrin Metab 2002; 283:E103.
5. Tanner et al. Clinical longitudinal standards for height and height velocity
for North American children. J Pediatr 1985; 107:317.

Sexual maturity rating (Tanner stages) of secondary sexual
characteristics
Boys Development of external genitalia
Stage 1: Prepubertal
Stage 2: Enlargement of scrotum and testes; scrotal skin reddens and changes in texture
Stage 3: Enlargement of penis (length at first); further growth of testes
Stage 4: Increased size of penis with growth in breadth and development of glans; testes
and scrotum larger, scrotal skin darker
Stage 5: Adult genitalia
Girls Breast development
Stage 1: Prepubertal
Stage 2: Breast bud stage with elevation of breast and papilla; enlargement of areola
Stage 3: Further enlargement of breast and areola; no separation of their contour
Stage 4: Areola and papilla form a secondary mound above level of breast
Stage 5: Mature stage: projection of papilla only, related to recession of areola
Boys and girls Pubic hair
Stage 1: Prepubertal (the pubic area may have vellus hair, similar to that of forearms)
Stage 2: Sparse growth of long, slightly pigmented hair, straight or curled, at base of penis or
along labia
Stage 3: Darker, coarser and more curled hair, spreading sparsely over junction of pubes
Stage 4: Hair adult in type, but covering smaller area than in adult; no spread to medial
surface of thighs
Stage 5: Adult in type and quantity, with horizontal upper border

Sexual maturity rating (Tanner staging) of breast
development in girls
Stages in breast development in girls.
Stage 1: Prepubertal, with no palpable breast tissue.
Stage 2: Development of a breast bud, with elevation of the papilla
and enlargement of the areolar diameter.
Stage 3: Enlargement of the breast, without separation of areolar
contour from the breast.
Stage 4: The areola and papilla project above the breast, forming a
secondary mound.
Stage 5: Recession of the areola to match the contour of the breast;
the papilla projects beyond the countour of the areola and breast.
Figure from: Roede MJ, van Wieringen JC. Growth diagrams 1980:
Netherlands third nationwide survey. Tijdschr Soc Gezondheids 1985; 63:1.
Reproduced with permission from the author.

Sexual maturity rating (Tanner staging) of pubic
hair development in girls
Stages of development in pubic hair in girls.
Stage 1: Prepubertal with no pubic hair.
Stage 2: Sparse, straight hair along the lateral vulva.
Stage 3: Hair is darker, coarser, and curlier, extending over the mid
pubis.
Stage 4: Hair is adultlike in appearance, but does not extend to the
thighs.
Stage 5: Hair is adult in appearance, extending from thigh to thigh.

Sexual maturity rating (Tanner staging) of pubic
hair development in boys
Stages of pubic hair development in boys. Stage 1: Prepubertal, with
no pubic hair. Stage 2: Sparse, straight pubic hair along the base of
the penis. Stage 3: Hair is darker, coarser, and curlier, extending over
the midpubis. Stage 4: Hair is adultlike in appearance, but does not
extend to thighs. Stage 5: Hair is adult in appearance, extending from
thigh to thigh.

Height velocity in American boys
Height velocity by age for American boys. The main set of curves (black lines) is
centered on the population with average timing of peak growth velocity (around
13.5 years for boys), and show an approximate trajectory for individual children
with this average pubertal timing. The two other curves outline a trajectory (50th
percentile) for a child with 'early' (solid blue) or 'late' (solid orange) timing of
peak growth velocity.
Other height velocity curves (not shown here) have been developed that reflect
population averages; those curves are substantially flatter than the trajectory
followed by any individual patient. Those curves are based on data from a
more recent and ethnically diverse population of children, and are valuable for
understanding overall growth patterns in the population, but are less appropriate
[1]

for evaluation of the growth of an individual patient.
SD: standard deviations.
Reference:
1. Kelly A, Winer KK, Kalkwarf H, et al. Agebased reference ranges for annual height
velocity in US children. J Clin Endocrinol Metab 2014; 99:2104.

Reproduced with permission from: Tanner JM, Davies S. Clinical longitudinal standards for
height and height velocity for North American children. J Pediatr 1985; 107:317. Copyright ©
1985 Elsevier.

Height velocity in American girls
Height velocity by age for American girls. The main set of curves (black lines) is
centered on the population with average timing of peak growth velocity (around
11.5 years for girls), and show an approximate trajectory for individual children
with this average pubertal timing. The two other curves outline a trajectory (50th
percentile) for a child with 'early' (solid blue) or 'late' (solid orange) timing of
peak growth velocity.
Other height velocity curves (not shown here) have been developed that reflect
population averages; those curves are substantially flatter than the trajectory
followed by any individual patient. Those curves are based on data from a
more recent and ethnically diverse population of children, and are valuable for
understanding overall growth patterns in the population, but are less appropriate
[1]

for evaluation of the growth of an individual patient.
SD: standard deviations.
Reference:
1. Kelly A, Winer KK, Kalkwarf H, et al. Agebased reference ranges for annual height
velocity in US children. J Clin Endocrinol Metab 2014; 99:2104.

Reproduced with permission from: Tanner JM, Davies S. Clinical longitudinal standards for
height and height velocity for North American children. J Pediatr 1985; 107:317. Copyright ©
1985 Elsevier.

Body mass indexforage percentiles, boys, 2 to 20 years, CDC
growth charts: United States
Developed by the National Center for Health Statistics in collaboration with the National Center
for Chronic Disease Prevention and Health Promotion (2000).

Body mass indexforage percentiles, girls, 2 to 20 years, CDC
growth charts: United States
Developed by the National Center for Health Statistics in collaboration with the National Center
for Chronic Disease Prevention and Health Promotion (2000).

Testicular volume in each pubertal stage
Testicular volume in adolescents as a function of pubertal
stage. These data are from serial evaluations of 539 boys, ages 10 to
15 years; the subjects were evaluated every 6 months over 3 years.
Pubertal stage represents the sexual maturity rating (Tanner stage of
pubertal development).
Reproduced with permission from: Biro FM. Physical growth and development.
In: Principles of Adolescent Medicine, Friedman SB, Fisher M, Schonberg SK.
MosbyYear Book, Inc, 1997. Figure 63, p.31. Copyright ©1997 Elsevier.

Timing of puberty in Caucasian and African
American girls in the United States
In this study, the first signs of puberty occurred at a younger age than
had been previously reported; the mean age of onset was earlier for
African American versus Caucasian girls.
Data from HermanGiddens, ME, Slora, EJ, Wasserman, RC, et al, Pediatrics
1997; 99:505.

Prevalence of iron deficiency and iron deficiency anemia in the
National Health and Nutrition Examination Survey (NHANES III),
19881994
Sex and age,
years
Iron deficiency,
percent
Iron deficiency anemia,
percent
Both sexes
12 9 3*
35 3 <1
611 2 <1
Females
1215 9 2*
1619 11* 3*
2049 11 5*
5069 5 2
≥70 7* 2*
Males
1215 1 <1
1619 <1 <1
2049 <1 <1
5069 2 1
≥70 4 2
* Prevalence in nonblacks is 1 percent lower than in all races.
Adapted from Looker, AC, Dallman, PR, Carroll, MD, et al, JAMA 1997; 277:973.

Disclosures: Frank M Biro, MD Nothing to disclose. YeeMing Chan, MD, PhD Nothing to disclose. Teresa K Duryea, MD Nothing
to disclose. Peter J Snyder, MD Grant/Research/Clinical Trial Support: AbbVie [Hypogonadism (Testosterone gel)]; Novo Nordisk
[GH deficiency (Somatropin)]; Ipsen [Acromegaly (Lanreotide)]. Consultant/Advisory Boards: Novartis [Cushing's syndrome
(Pasireotide)]; Pfizer [Acromegaly (Pegvisomant)]. Mitchell Geffner, MD Grant/Research/Clinical Trial Support: Eli Lilly Inc [growth
(Somatotropin/rhGH)]; Novo Nordisk [growth (Somatotropin/rhGH)]; Verartis [growth (Somatotropin/rhGH)]. Consultant/Advisory
Boards: Ipsen [growth (Mecasermin/rhIGFI)]; Pfizer [growth (Somatotropin/rhGH)]; Sandoz [growth (Somatotropin/rhGH)]; Tolmar
Data Safety Monitoring Board [puberty (Somatotropin/rhGH)]. Other Financial Interest: Sandoz [growth (lecture to company MSL's)];
McGrawHill [pediatric endocrinology (textbook royalties)]. Diane Blake, MD Nothing to disclose. Alison G Hoppin, MD Nothing to
disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting
through a multilevel review process, and through requirements for references to be provided to support the content. Appropriately
referenced content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
Disclosures

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