Background

Precocious puberty refers to the appearance of physical and hormonal signs of pubertal development at
an earlier age than is considered normal. For many years, puberty was considered precocious in girls
younger than 8 years; however, recent studies indicate that signs of early puberty (breasts and pubic
hair) are often present in girls (particularly black girls) aged 6-8 years. For boys, onset of puberty before
age 9 years is considered precocious.

Early onset of puberty can cause several problems. The early growth spurt initially can cause tall stature,
but rapid bone maturation can cause linear growth to cease too early and can result in short adult
stature. The early appearance of breasts or menses in girls and increased libido in boys can cause
emotional distress for some children.

Premature pubarche and premature thelarche are 2 common, benign, normal variant conditions that
can resemble precocious puberty but are nonprogressive or very slowly progressive. Premature
thelarche refers to the isolated appearance of breast development, usually in girls younger than 3 years;
premature pubarche refers to appearance of pubic hair without other signs of puberty in girls or boys
younger than 7-8 years. A thorough history, physical examination, and growth curve review can help
distinguish these normal variants from true sexual precocity.

If the history, physical examination, and laboratory data suggest that a child exhibits early and sustained
evidence of pubertal maturation, the clinician must differentiate central precocious puberty (CPP) from
precocious pseudopuberty. Central precocious puberty, which is gonadotropin-dependent, is the early
maturation of the entire hypothalamic-pituitary-gonadal (HPG) axis, with the full spectrum of physical
and hormonal changes of puberty. Precocious pseudopuberty is much less common and refers to
conditions in which increased production of sex steroids is gonadotropin-independent (see Precocious
Pseudopuberty). Correct diagnosis of the etiology of sexual precocity is critical, because evaluation and
treatment of patients with precocious pseudopuberty is quite different than that for patients with
central precocious puberty.

Pathophysiology

Most patients, particularly girls suspected of having central precocious puberty, are otherwise healthy
children whose pubertal maturation begins at the early end of the normal distribution curve. CNS
imaging studies of these otherwise healthy 6-year-old to 8-year-old girls usually reveal no structural
abnormalities. A study of 200 girls in France identified abnormal brain imaging findings in 2% of girls
whose onset of puberty was between age 6-8 years and in 20% of girls whose onset of puberty was
before age 6 years.[1] A smaller study from the United Kingdom reported abnormal findings in 15% of
67 girls.[2] Abnormal CT scan or MRI findings are more frequent among boys with central precocious
puberty than among girls with central precocious puberty.

The onset of puberty is caused by the secretion of high-amplitude pulses of gonadotropin-releasing

hormone (GnRH) by the hypothalamus. The hypothesized mechanisms that suppress onset of puberty
include (1) the HPG axis, which is highly sensitive to feedback inhibition by small amounts of sex
steroids, and (2) central neural pathways that suppress the release of GnRH pulses.

CNS abnormalities associated with precocious puberty include the following:

Tumors (eg, astrocytomas, gliomas, germ cell tumors secreting human chorionic gonadotropin [HCG])

Hypothalamic hamartomas

Acquired CNS injury caused by inflammation, surgery, trauma, radiation therapy, or abscess

Congenital anomalies (eg, hydrocephalus, arachnoid cysts, suprasellar cysts)

High-amplitude pulses of GnRH cause pulsatile increases in the pituitary gonadotropin-luteinizing

hormone (LH) and follicle-stimulating hormone (FSH). Increased LH levels stimulate production of sex
steroids by testicular Leydig cells or ovarian granulosa cells. Pubertal levels of androgens or estrogens
cause the physical changes of puberty, including penile enlargement and sexual hair in boys and breast
development in girls. These levels also mediate the pubertal growth spurt. Increased FSH levels cause
enlargement of the gonads in both sexes and eventually promote follicular maturation in girls and
spermatogenesis in boys.

Epidemiology

Frequency

United States
The frequency of findings suggestive of precocious puberty in girls and boys largely depends on whether
one is looking at genital hair or breast development as well as the age at which the condition is
considered precocious.

In 1969, Marshall and Tanner published the results of their study of 192 white British girls.[3] These
researchers stated that the average age of thelarche was 11 years and they defined precocious puberty
in girls as that which started before age 8 years. No studies that looked at the age of appearance of
breast and pubic hair in normal children were performed in the United States during that same time.
However, many in the United States had the impression that girls had been maturing earlier than in the
past.

No data were available to confirm this impression until 1997, when Herman-Giddens et al reported on
the incidence of breast and pubic hair development by age and race in 17,000 US girls aged 3-12
years.[4] They used the established definition that breast or pubic development in girls was precocious
before age 8 years and estimated that approximately 8% of white and 25% of black girls in the United
States exhibited evidence of sexual precocity. The results of this study are illustrated in the images
below.

Graph represents the prevalence of breast development at Tanner stage 2 or greater by age and race.

Graph represents the prevalence of pubic hair at Tanner stage 2 or greater by age and race.

In 1999, as a result of the Herman-Giddens study, Kaplowitz and Oberfield published new guidelines
recommending that puberty be considered precocious only when breast development or pubic hair
appear before age 7 years in white girls and age 6 years in black girls.[5] However, most clinicians
continue to use the 8 year definition.

In 2010, a new study by Biro et al reported that in a cohort of 1239 girls aged 7-7.99 years from 3 urban
centers, the proportion who had reached Tanner 2 breast development was 10.4% of white girls, 23.4%
of black girls, and 14.9% of Hispanic girls.[6] While this was a cross-sectional study and it was not clear
what proportion of these girls had progressive precocious puberty, the study confirmed that in the
United States, the appearance of breast development prior to age 8 years is quite common.
Reliable estimates of the frequency of precocious puberty in boys have not been published. However,
several centers have reported that they evaluate between one fifth and one tenth as many boys as girls
for sexual precocity. Whether early puberty in boys is becoming more common over time, as is the case
in girls, is unclear. However, a study from Denmark found that the mean age of testicular enlargement in
boys declined from age 11.92 years to 11.66 years between 1991-1993 and 2006-2008, suggesting that
more boys may be starting puberty before age 9 years.[7]

International

A review of trends in timing of puberty around the world showed no clear trend toward earlier puberty
in northern Europe, but earlier mean age of menarche has been reported in some southern European
countries and other warmer parts of the world.[8] A report from Denmark showed that over a 15-year
period (1991-1993 vs 2000-2008), the mean age at which breast tissue appeared in girls decreased from
age 10.88 years to 9.86 years, with a much smaller decline in the mean age at menarche (age 13.42 y vs
age 13.13 y).[9] A study of over 20,000 girls from urban China done from 2003-2005 show that the mean
age of breast development was 9.2 years, with the mean age at menarche falling to 12.27 years; about
20% of 8-year-old girls already had evidence of breast development.[10] Thus, in certain parts of the
world, a decline in the age of puberty in girls has been noted, with parallel changes seen in US girls.

An interesting and still unexplained finding is the high incidence of precocious puberty in girls adopted
into Western Europe from various underdeveloped countries. This has been studied extensively in
Denmark, where the mean age at thelarche and at menarche in international adopted girls was
significantly lower than that observed in a reference group of Danish-born girls.[11] Exposure to
chemicals in the environment has been proposed as the cause, but the fact that LH, FSH, and estradiol
levels rise earlier in adopted girls suggest that their earlier puberty is centrally mediated and not
chemically induced.

Mortality/Morbidity

Isolated sexual precocity of unknown etiology carries no increased risk of mortality; however,
distinguishing between children with idiopathic central precocious puberty and the rare patient with a
CNS, adrenal, or ovarian tumor is important because the latter group may be at risk for tumor-related
complications. Some, but not all, studies have found an association between early puberty in girls and a
higher risk of breast cancer.

Children with precocious puberty may be stressed because of physical and hormonal changes they are
too young to understand. They may be teased by their peers because of their physical difference. Girls
who reach menarche before age 9-10 may become withdrawn and may have difficulty adjusting to
wearing and changing pads. Both sexes, but more so boys than girls, may have increases in libido leading
to increased masturbation or inappropriate sexual behaviors at a young age. Girls with a history of early
puberty have a slightly earlier age of initiation of sexual activity.

Some studies have found that children with precocious puberty more frequently exhibit behavioral
problems and are less socially competent than age-matched peers. Some, but not all, studies find
evidence of emotional problems persisting into adulthood. The distress associated with early menses
can be decreased if parents are encouraged to prepare their daughters for this event when they reach
stage III-IV of breast development.

Early puberty accelerates growth. These children may initially be considerably taller than their peers.
Because bone maturation is also accelerated, growth may be completed at an unusually early age,
resulting in short stature. Short stature is more likely if puberty starts very early (ie, before age 6 y) than
if it begins moderately early (ie, ages 6-8 y). Several studies show that most untreated girls with
idiopathic central precocious puberty reach an adult height within the reference range. Determination
of bone age can be used to predict adult height and to select patients with high risk for short stature if
left untreated.

Race

The study by Herman-Giddens et al and the data from the National Health and Nutrition Examination
Survey (NHANES) III study conclusively showed that black girls in the United States have onset of breast
development and pubic hair about one year earlier than white girls; thus, using the same age definition
of precocious puberty for white and black girls yields a higher incidence in black girls.[4, 12] No current
evidence shows that black boys mature earlier than white boys; thus, incidence of precocious puberty
among boys is similar in both races. The NHANES III study indicated that Mexican-American girls start
breast development at a similar age as white girls, and that pubic hair appears slightly later.[12]

Sex

In a series of more than 200 patients evaluated at a single medical center, central precocious puberty
occurred 5 times more often in girls than boys.[13] Idiopathic central precocious puberty occurred 8
times more often. A possible explanation for this difference is that many girls whose puberty is
considered precocious are actually healthy girls at the early end of the normal distribution.

Age
If precocious puberty in females (mostly central) is defined as the early onset of breast development,
then the data of Herman-Giddens et al can be used to estimate frequency of central precocious puberty
at different ages in both white girls and black girls. Be cautious, however, in equating breast
development in 3-year-olds with central precocious puberty because most such girls actually have
premature thelarche, a benign normal variant (see Differentials). The younger the age of girls with
proven central precocious puberty, the higher the likelihood of serious underlying disorder.

History

Precocious puberty in girls

The first and most obvious sign of early puberty is usually breast enlargement, which may initially be
unilateral.

Pubic and axillary hair may appear before, at about the same time, or well after the appearance of
breast tissue. Axillary odor usually starts about the same time as the appearance of pubic hair.

Menarche is a late event and does not usually occur until 2-3 years after onset of breast enlargement.

The pubertal growth spurt occurs early in female puberty and usually is evident by the time of initial
evaluation.

Precocious puberty in boys

The earliest evidence of puberty is testicular enlargement, a subtle finding that often goes unnoticed by
patients and parents.

Growth of the penis and scrotum and typically occur at least a year after testicular enlargement.
Accelerated linear growth (the pubertal growth spurt) occurs later in the course of male puberty than in
female puberty but often occurs by the time other physical changes are noted.

Physical

Precocious puberty in girls

The most reliable sign of increased estrogen production is breast enlargement. Initially, breast budding
may be unilateral or asymmetric. Gradually, the breast diameter increases, the areola darkens and
thickens, and the nipple becomes more prominent. Distinguishing glandular breast tissue from fat,
which can mimic true breast tissue, is essential. Examining the patient while she is in the supine position
usually minimizes the chance of misinterpreting fat as true breast enlargement.

Genital examination may or may not reveal pubic hair, but enlargement of the clitoris indicates
significant androgen excess that must be promptly evaluated. The vaginal mucosa, which is a deep-red
color in prepubertal girls, takes on a moist pastel-pink appearance as estrogen exposure increases.

Mild acne may be normal in early puberty, but rapid onset of severe acne, like clitoral enlargement,
should increase suspicion of an androgen-excess disorder.

Precocious puberty in boys

The earliest sign of central precocious puberty (CPP) is enlargement of the testes, which depends on
increased production of follicle-stimulating hormone (FSH); testicular length is more than 2.5 cm or
testicular volume (with Prader orchidometer beads) is 4 mL or more. If progressive signs of androgen
excess occur in a boy without increased testicular size, consider possible causes of precocious
pseudopuberty, including congenital adrenal hyperplasia, familial male precocious puberty, and Leydig-
cell tumors (a testicular nodule is usually palpable). Human chorionic gonadotropin (HCG)-secreting
tumors somewhat increase testicular size by stimulating testicular Leydig-cell LH receptors.

Other signs of puberty (eg, penis growth, reddening and thinning of the scrotum, increased pubic hair)
are a consequence of increased testosterone production and occur within 1-2 years after testicular
enlargement.
Pubic hair growth that occurs without penis and testicular enlargement and other signs of increased
androgen production (eg, premature adrenarche or a mild, nonclassic form of congenital adrenal
hyperplasia) rather than true puberty.

Later signs of puberty include the pubertal growth spurt, acne, voice change, and facial hair.

Causes

The timing of puberty has a genetic component. A history of early puberty in a parent or sibling is
relevant and decreases the likelihood that early puberty has an organic cause. One study from Israel
estimated that precocious puberty was familial in one fourth of cases and that the predominant mode of
inheritance was autosomal dominant.[14]

An increased body mass index (BMI) has been associated with early puberty.[15] In some studies the
association is stronger in white girls than in black girls. Obesity is not clearly associated with early
puberty in boys.

In the 1970s, Frisch et al proposed that girls need a certain weight or body fat content to trigger
menarche and to maintain cyclical menses.[16] The relationship between body fat and puberty is
complex and has many exceptions; however, body weight and fat mass are clearly among the factors
that may influence puberty onset in girls.

A longitudinal study of 354 girls by Lee et al found that increased BMI at age 3 years and the rate of
increase in BMI from age 3-6 years were both positively associated with an earlier onset of puberty.[17]
In addition, a meta-analysis of 2 datasets from adolescent girls in 34 countries in Europe and North
America revealed an inverse association between age at menarche and individual BMI.[18]

Laboratory Studies

Sex steroid levels

Measurement of serum testosterone is useful in boys with suspected precocious puberty.

Early morning testosterone levels in boys in early puberty are higher than afternoon levels because
luteinizing hormone (LH) and testosterone levels rise with sleep onset in early puberty.
The stages of puberty as indicated by serum testosterone levels are as follows:

Testosterone level less than 30 ng/dL – Generally prepubertal (Depending on the laboratory,
testosterone levels of 11-30 ng/dL may represent early puberty)

Testosterone level of 30-100 ng/dL – Early pubertal

Testosterone level of 100-300 ng/dL – Mid-to-late pubertal

Testosterone level of more than 300 ng/dL – Adult

For girls, estradiol measurements are less reliable indicators of the stage of puberty. Many commercial
assays are not sufficiently specific or sensitive enough to demonstrate an increase during early puberty.
levels that exceed 20 pg/mL usually indicate puberty, but some girls who are clearly pubertal may have
levels of less than 20 pg/mL. In addition, estradiol levels may fluctuate from week to week. Girls who
have ovarian tumors or cysts often have estradiol levels that exceed 100 pg/mL.

levels of adrenal androgens (eg, dehydroepiandrosterone [DHEA], dehydroepiandrosterone sulfate

[DHEAS]) are usually elevated in boys and girls with premature pubarche. DHEA-S, the storage form of
DHEA, is the preferred steroid to measure because its levels are much higher and vary much less during
the day. In most children with premature pubarche, DHEA-S levels are 20-100 mcg/dL, whereas in rare
patients with virilizing adrenal tumors, levels may exceed 500 mcg/dL.

Consider obtaining a 17-OH serum progesterone study if mild or nonclassic congenital adrenal
hyperplasia is suspected. One recent study from Paris found that if a basal level is below 200 ng/dL, the
diagnosis of nonclassic congenital adrenal hyperplasia can be excluded; however, if the random 17-OH
progesterone level is elevated, a corticotropin (ie, Cortrosyn)–stimulation test provides the greatest
diagnostic accuracy, with a post corticotropin 17-hydroxyprogesterone of greater than 1000 ng/dL being
diagnostic.[21]

Gonadotropins

Because of the development of more sensitive third-generation assays for LH, which can detect levels as
low as 0.1 IU/L or lower, the random LH is now the best screening test for central precocious puberty
(CPP).

The immunochemiluminometric (ICMA) method for LH seems more specific than the
immunofluorometric (IFMA) method. An LH level of less than 0.1 IU/L is generally prepubertal, and one
study suggested an upper reference range limit for LH measured by an ICMA of 0.2 IU/L in both boys and
girls, with no overlap between prepubertal and pubertal levels in boys and a 10% overlap in girls.[22]
Another study found that a basal LH level measured by 2 different ICMA assays was sufficient to
document central precocious puberty in 90% of girls, with levels of more than 0.83 IU/L in all but one
patient; 29 of 34 prepubertal girls had undetectable values (< 0.15 IU/L to < 0.2 IU/L).[23]
Random follicle-stimulating hormone (FSH) levels do not discriminate between prepubertal and pubertal
children. Suppressed levels of LH and FSH accompanied by highly elevated testosterone or estradiol
levels point suggest precocious pseudopuberty rather than central precocious puberty.

A definitive diagnosis of central precocious puberty may be confirmed by measuring LH and FSH levels
30-60 minutes after stimulation with gonadotropin-releasing hormone (GnRH) at 100 mcg or with a
GnRH analog.

Because native GnRH is no longer available, most centers are using the analog leuprolide (aqueous form)
at a dose of 20 mcg/kg, up to a maximum of 500 mcg. An increase in FSH levels much greater than the
increase in LH levels suggests that the child is prepubertal.

Some studies suggest that an increase in LH levels to more than 8 IU/L is diagnostic of central precocious
puberty, but this depends on the specific LH assay used.

A study by Carel et al stated that the peak LH level measured by ICMA that defined CPP was 4.1 IU/L in
boys and 3.3 IU/L in girls.[24]

Another study suggests that when the baseline LH level is prepubertal, an increase in LH level to 5 IU/L
or more after leuprolide correlates well with progression of pubertal signs during a 6-month period of
observation.[25] No increase in LH and FSH levels after the infusion of GnRH suggests precocious
pseudopuberty.

Thyroid: Thyroid tests are not a routine requirement in the evaluation of precocious puberty. Severe
hypothyroidism rarely leads to precocious puberty. Major clues of severe hypothyroidism include
growth arrest instead of growth acceleration, goiter, and symptoms of thyroid hormone deficiency
(fatigue, cold intolerance).

Imaging Studies

Radiography: Radiography of the hand and wrist used to determine bone age is a quick and helpful
means to estimate the likelihood of precocious puberty and its speed of progression. If bone age is
within one year of chronological age, puberty has not started (eg, a 2-year-old girl with premature
thelarche) or the duration of the pubertal process has been relatively brief. If bone age is advanced by 2
years or more, puberty likely has been present for a year or more or is progressing more rapidly.

Head MRI

MRI may be indicated to look for a tumor or a hamartoma after hormonal studies indicate a diagnosis of
central precocious puberty. Ask the radiologist to obtain a high-resolution study that focuses on the
hypothalamic-pituitary area.
For healthy girls aged 6-8 years with no signs or symptoms of CNS disease, the likelihood of finding a
tumor or hamartoma is only about 2%; therefore, this test may be unnecessary depending on the clinical
situation.

The younger the child with central precocious puberty, the greater the chance of finding CNS pathology
(among children younger than 6 y).

For boys younger than 9 years, the incidence of CNS findings is much higher than in girls, and MRI should
be part of the evaluation.

Pelvic ultrasonography

Ultrasonography is unnecessary for girls with a definite diagnosis of central precocious puberty. If
performed, however, ultrasonography usually reveals bilaterally enlarged ovaries, often with multiple
small follicular cysts, and an enlarged uterus with an endometrial stripe.

Pelvic ultrasonography is essential when precocious pseudopuberty is suspected in girls (based on

examination or hormone levels) because an ovarian tumor or cyst may be detected.

Histologic Findings

If central precocious puberty is caused by a tumor in the hypothalamic-pituitary area, the histology of
the tumor can be important to the patient's prognosis.

Gliomas tend to grow more rapidly than astrocytomas, whereas hamartomas are benign.

Treatment of precocious puberty associated with a hamartoma suppresses gonadotropin production by

the pituitary without effect on the hamartoma itself.

For information on different non-CNS tumors associated with precocious puberty see Precocious
Pseudopuberty.