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Definition, etiology, and evaluation of precocious puberty

Authors: Jennifer Harrington, MBBS, PhD, Mark R Palmert, MD, PhD
Section Editors: Peter J Snyder, MD, William F Crowley, Jr, MD, Mitchell E Geffner, MD
Deputy Editors: Alison G Hoppin, MD, Kathryn A Martin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2020. | This topic last updated: Apr 01, 2020.

INTRODUCTION

Precocious puberty is the onset of pubertal development at an age that is 2 to 2.5 standard deviations (SD)
earlier than population norms. The cause of precocious puberty may range from a variant of normal
development (eg, isolated premature adrenarche or isolated premature thelarche) to pathologic conditions
with significant risk of morbidity and even death (eg, malignant germ-cell tumor and astrocytoma).

The clinician faced with a child who presents with early development of secondary sexual characteristics
should consider the following questions:

● Is the child too young to have reached the pubertal milestone in question? – To answer this question, the
clinician needs to know the normal ages for pubertal milestones and how to separate normal from
abnormal development.

● What is causing the early development? – To answer this question, the clinician ascertains whether the
development of secondary sexual characteristics is attributable to androgen and/or estrogen effects and
whether the source of sex hormone is centrally mediated through the hypothalamic-pituitary-gonadal
axis, from an autonomous peripheral origin, or has an exogenous basis.

● Is therapy indicated, and, if so, what therapy?

The definition of precocious puberty and its causes and evaluation will be reviewed here. The treatment of
precocious puberty is discussed separately. (See "Treatment of precocious puberty".)

DEFINITION

Precocious puberty is traditionally defined as the onset of secondary sexual characteristics before the age of
eight years in girls and nine years in boys [1]. These limits are chosen to be 2 to 2.5 standard deviations (SD)
below the mean age of onset of puberty. In most populations, attainment of pubertal milestones
approximates a normal distribution, with a mean age of onset of puberty of approximately 10.5 years in girls
and 11.5 years in boys (figure 1A-B) and an SD of approximately one year [1-9].
NORMAL PUBERTAL DEVELOPMENT

The hypothalamic-pituitary-gonadal axis is biologically active in utero and briefly during the first week of life. It
then becomes more active again during infancy, with peak activity between one and three months of age
[10]. This state yields sex steroid levels comparable with those seen in early-to-mid puberty but without
peripheral effects. In boys, gonadotropin concentrations then decrease to prepubertal levels by six to nine
months of age. In girls, luteinizing hormone (LH) levels decrease at approximately the same time as in boys,
but the follicle-stimulating hormone (FSH) concentrations can remain elevated into the second year of life.
This hypothalamic-pituitary-gonadal activity during infancy is known as the "mini puberty of infancy"; its
biologic relevance is unknown.

The neonatal stage is followed by active suppression of the hypothalamic-pituitary-gonadal axis until puberty
occurs. The physiologic and genetic mechanisms that affect timing of pubertal maturation are discussed
separately. (See "Normal puberty", section on 'Sequence of pubertal maturation'.)

In 1969 and 1970, Marshall and Tanner defined the stages of normal pubertal development in children and
adolescents, known as sexual maturity ratings or "Tanner stages" (picture 1A-C) [2,3]. These studies
reported that the first sign of puberty in English girls was breast development at an average age of 11 years
(thelarche), followed by pubic hair growth (pubarche), and then menarche. In English boys, the first sign was
testicular enlargement at an average age of 11.5 years, followed by penile growth and pubic hair growth.
(See "Normal puberty".)

Since these reports by Marshall and Tanner, several studies in the United States and other countries suggest
that children, especially overweight children, now enter puberty at a younger age than previously [4-9,11]. In
addition, there are racial differences, with puberty occurring earlier in African-American children compared
with non-Hispanic Caucasian and Hispanic children. These data and the proposed explanations for the
trends are discussed separately. (See "Normal puberty", section on 'Trends in pubertal timing'.)

EPIDEMIOLOGY

Using the traditional definition of precocious puberty as the development of secondary sexual characteristics
before age eight in girls and nine in boys (2 to 2.5 standard deviations [SD] below the average age of
pubertal onset in healthy children), one would expect that the prevalence rate should be around 2 percent, ie,
2 in every 100 children. However, population studies looking at the prevalence rates of precocious puberty
yield markedly different rates depending on the population studied:

● In a population-based United States study, breast and/or pubic hair development was present at age
eight in 48 percent of African-American girls and 15 percent of white girls (figure 2) [11]. At seven years
of age, the proportions were 27 percent and 7 percent, respectively.

● In a population-based study of data from Danish national registries from 1993 to 2001, the incidence of
precocious puberty was 20 per 10,000 girls and less than 5 per 10,000 boys [12]. The diagnostic age
limit utilized in this study was eight years for girls and nine for boys. Approximately one-half the patients
had central precocious puberty (CPP), and the remainder were isolated premature thelarche or
adrenarche, or early normal pubertal development. (See "Premature adrenarche".)
These observations suggest that the definition of precocious puberty is problematic, at least in girls, and that
selection of children for evaluation should not only depend on age but also clinical features, race/ethnicity,
and presence/absence of obesity [13]. (See 'Definition' above and 'Threshold for evaluation' below.)

There is a strong female predominance of children evaluated for precocious puberty. In a retrospective
review of 104 consecutive children referred for evaluation of precocious puberty, 87 percent were female
[14]. Whether this represents a true biologic difference or referral bias is not understood.

THRESHOLD FOR EVALUATION

We suggest careful evaluation of children presenting with signs of secondary sexual development younger
than the age of eight years in girls or nine years in boys. The level of concern and extent of evaluation should
increase with younger age at presentation but decrease in the presence of factors associated with earlier
pubertal timing such as increased adiposity, family history of early pubertal development, and/or being a
member of a racial/ethnic group that tends to have earlier pubertal development, such as African Americans
[11,15]. Given the trend towards earlier pubertal development in girls who are between the ages of seven
and eight, a comprehensive history, physical examination, and clinical follow-up may be sufficient if the
clinical evaluation does not raise any additional concerns [16]. Routine use of younger age cutoffs is
controversial, with concern that they would result in failure to identify some children with true disease [17-19].
(See 'Epidemiology' above and 'Evaluation' below and "Normal puberty", section on 'Trends in pubertal
timing'.)

CLASSIFICATION

Precocious puberty can be classified based upon the underlying pathologic process (algorithm 1).

● Central precocious puberty (CPP) – CPP (also known as gonadotropin-dependent precocious puberty
or true precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis.
CPP is characterized by sequential maturation of breasts and pubic hair in girls and of testicular and
penile enlargement and pubic hair in boys. In these patients, the sexual characteristics are appropriate
for the child's gender (isosexual). CPP is pathologic in up to 40 to 75 percent of cases in boys [20,21],
compared with 10 to 20 percent in girls [22-24] (table 1). (See 'Causes of central precocious puberty'
below.)

● Peripheral precocity – Peripheral precocity (also known as peripheral precocious puberty,

gonadotropin-independent precocious puberty) is caused by excess secretion of sex hormones
(estrogens or androgens) from the gonads or adrenal glands, exogenous sources of sex steroids, or
ectopic production of gonadotropin from a germ-cell tumor (eg, human chorionic gonadotropin [hCG])
(table 2). The term precocity is used instead of puberty here because true puberty requires activation of
the hypothalamic-pituitary-gonadal axis, as occurs in CPP. Peripheral precocity may be appropriate for
the child's gender (isosexual) or inappropriate, with virilization of girls and feminization of boys
(contrasexual). (See 'Causes of peripheral precocity' below.)

● Benign or nonprogressive pubertal variants – Benign clinical pubertal variants include isolated breast
development in girls (premature thelarche) or isolated androgen-mediated sexual characteristics (such
 as pubic and/or axillary hair, acne, and apocrine odor) in boys or girls (premature adrenarche, which
results from early activation of the hypothalamic-pituitary-adrenal axis, as confirmed by mildly elevated
levels of dehydroepiandrosterone sulfate [DHEAS] for age) (table 3). Both of these conditions can be a
variant of normal puberty. However, repeat clinical examination, which could be performed by the
primary care provider, is warranted to ensure there is no rapid and/or expanded pubertal progression
and that the diagnosis is correct. (See 'Types of benign or nonprogressive pubertal variants' below.)

CAUSES OF CENTRAL PRECOCIOUS PUBERTY

Central precocious puberty (CPP; also known as gonadotropin-dependent precocious puberty) is caused by
early maturation of the hypothalamic-pituitary-gonadal axis. Although the onset is early, the pattern and
timing of pubertal events is usually normal. These children have accelerated linear growth for age, advanced
bone age, and pubertal levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

CPP can be treated with a gonadotropin-releasing hormone (GnRH) agonist, which leads to downregulation
of the pituitary response to endogenous GnRH, produces a prepubertal hormonal state, and stops the
progression of secondary sexual development, accelerated growth, and undue bone age advancement [25].
(See "Treatment of precocious puberty", section on 'Treatment for central precocious puberty'.)

Idiopathic — CPP is idiopathic in 80 to 90 percent of cases of girls but in only 25 to 60 percent of boys [20-
24]. In some cases, especially those with other affected family members, cases designated as idiopathic
CPP may be due to presence of genetic variants that are associated with early puberty. (See "Normal
puberty", section on 'Physiology of pubertal onset'.)

Central nervous system lesions — Although CPP is idiopathic in up to 90 percent of girls and 60 percent of
boys, some cases are caused by lesions of the central nervous system (CNS), a condition often referred to
as neurogenic CPP (table 1). Contrast-enhanced magnetic resonance imaging (MRI) is therefore
recommended, even in the absence of clinically evident neurologic abnormalities [20,22,24]. However, the
low prevalence of CNS lesions in girls with the onset of puberty that begins after age six years raises the
question if all girls in this age group need imaging [23].

Many different types of intracranial disturbances can cause precocious puberty, including the following:

● Hamartomas – Hamartomas of the tuber cinereum are benign tumors that can be associated with
gelastic (laughing or crying) and other types of seizures [26]. They are the most frequent type of CNS
tumor to cause precocious puberty in very young children, although in most cases, the mechanism by
which these tumors lead to CPP is unknown.

● Other CNS tumors – Other CNS tumors associated with precocious puberty include astrocytomas [27],
ependymomas, pinealomas, and optic and hypothalamic gliomas [22]. Sexual precocity in patients with
neurofibromatosis is usually, but not always, associated with an optic glioma [28]. (See "Clinical
manifestations and diagnosis of central nervous system tumors in children".)

● CNS irradiation – Precocious puberty is a rare complication of CNS irradiation, but, when it occurs, it is
commonly associated with growth hormone (GH) deficiency [29,30]. In this setting, regardless of height
velocity, the GH axis should be evaluated. If testing shows GH deficiency, the patient should be treated
 with GH combined with GnRH agonist therapy. (See "Endocrinopathies in cancer survivors and others
exposed to cytotoxic therapies during childhood", section on 'Growth hormone deficiency'.)

● Other CNS lesions – Precocious puberty has been associated with hydrocephalus, cysts, trauma, CNS
inflammatory disease, and congenital midline defects, such as optic nerve hypoplasia. (See "Congenital
anomalies and acquired abnormalities of the optic nerve", section on 'Hypoplasia'.)

Genetics — Specific genetic mutations have been associated with CPP, although each appears to be
present in only a minority of cases:

● Gain-of-function mutations in the kisspeptin 1 gene (KISS1) [31] and the gene for its G protein-coupled
receptor (KISS1R, formerly known as GPR54) [32] have been implicated in the pathogenesis of some
cases of CPP, while loss-of function mutations in KISS1R can cause hypogonadotropic hypogonadism.
These observations suggest that KISS1/KISS1R is essential for GnRH physiology and for initiation of
puberty [33].

● CPP also can be caused by loss-of-function mutations in MKRN3 (the gene encoding makorin ring finger
protein 3), an imprinted gene in the Prader-Willi syndrome critical region (15q11-q13). The decline of
hypothalamic Mkrn3 expression in mice [34] and serum protein levels in girls prior to the onset of
puberty [35] suggest that MKRN3 is a negative factor involved in repressing pubertal initiation. Thus,
loss-of-function mutations in this gene would lead to diminished inhibition and early onset of puberty.
Paternally inherited loss-of-function mutations in MKRN3 have been reported in up to 46 percent of
familial cases of CPP and nearly 10 percent of idiopathic cases [34,36-38].

● A loss-of-function mutation in another gene, DLK1 (delta-like 1 homolog), leads to undetectable serum
concentrations of the DLK1 protein and has been associated with isolated CPP in five females of one
family [39]. Like MKRN3, this appears to be a paternally imprinted condition, with affected individuals
only developing precocious puberty if the gene mutation is inherited from the father. DLK1 is a paternally
expressed gene, mostly in adrenal, pituitary, and ovarian tissue. No definitive mechanistic link between
DLK1 function and pubertal development has been determined, but polymorphisms in this gene as well
as in MKRN3 are associated with variation in the age of menarche in large genome-wide association
studies providing further evidence of a mechanistic link [40].

Pubertal timing is not only modulated by these single-gene disorders but also by common variants in the
general population, as have been identified through genome-wide association studies. An emerging area of
investigation focuses on the contribution of these variants to pubertal disorders. Genetic factors involved in
pubertal onset are discussed separately. (See "Normal puberty", section on 'Physiology of pubertal onset'.)

Previous excess sex steroid exposure — Children who have been exposed to high serum levels of sex
steroid (eg, those with McCune-Albright syndrome and poorly controlled congenital adrenal hyperplasia) may
sometimes develop superimposed CPP, either from the priming effect of the peripheral precocity-derived sex
steroid on the hypothalamus or in response to the sudden lowering of the sex steroid levels following
improved control of the sexual precocity [41-43]. (See "Treatment of classic congenital adrenal hyperplasia
due to 21-hydroxylase deficiency in infants and children", section on 'Monitoring and dose adjustment' and
'McCune-Albright syndrome' below.)
Pituitary gonadotropin-secreting tumors — These tumors are extremely rare in children and are
associated with elevated levels of LH and/or FSH [44,45].

CAUSES OF PERIPHERAL PRECOCITY

Peripheral precocity (also known as peripheral precocious puberty or gonadotropin-independent precocious

puberty) is caused by excess secretion of sex hormones (estrogens and/or androgens) derived either from
the gonads or adrenal glands or from exogenous sources (table 2). Further characterization is based upon
whether the sexual characteristics are appropriate for the child's gender (isosexual) or inappropriate, with
virilization of girls and feminization of boys (contrasexual). Follicle-stimulating hormone (FSH) and luteinizing
hormone (LH) levels are typically suppressed (into the prepubertal range) and do not increase substantially
with gonadotropin-releasing hormone (GnRH) stimulation.

The approach to treatment for peripheral precocity depends on the cause. GnRH agonist therapy is
ineffective, in contrast to patients with central precocious puberty (CPP). (See "Treatment of precocious
puberty", section on 'Treatment for peripheral precocity'.)

In the following discussion, the causes of peripheral precocity are described based upon sex.

Girls

Ovarian cysts — A functioning follicular cyst of the ovaries is the most common cause of peripheral
precocity in girls [46]. Affected patients often present with breast development, followed by an episode of
vaginal bleeding, which occurs due to estrogen withdrawal once the cyst has regressed. These cysts may
appear and regress spontaneously, so conservative management is usually appropriate [47]. Large cysts
may predispose to ovarian torsion.

Ovarian tumors — Ovarian tumors are a rare cause of peripheral precocity in girls. Granulosa cell
tumors, the most common type, typically present as isosexual precocity; Sertoli/Leydig cell tumors
(arrhenoblastoma), pure Leydig cell tumors, and gonadoblastoma may make androgens and cause
contrasexual precocity [48-50]. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features,
and diagnosis in adults".)

Boys

Leydig cell tumors — Leydig cell tumors should be considered in any boy with asymmetric testicular
enlargement. Even if a distinct mass cannot be palpated and none is evident on ultrasonography, the larger
testis should be biopsied if it enlarges during follow-up. These testosterone-secreting tumors are almost
always benign and are readily cured by surgical removal [51]. Radical orchiectomy is the most common
procedure; however, successful treatment by direct enucleation of the tumor with sparing of the remainder of
the testis has been reported [52]. (See "Testicular sex cord stromal tumors", section on 'Leydig cell tumors'.)

Human chorionic gonadotropin-secreting germ-cell tumors — Germ-cell tumors secrete human

chorionic gonadotropin (hCG), which in boys, activates LH receptors on the Leydig cells, resulting in
increased testosterone production [53]. The increase in testicular size (usually only to an early pubertal size)
is less than expected for the serum testosterone concentration and degree of pubertal development. This is
because most of the testis is made up of tubular elements whose maturation depends upon FSH. In girls,
hCG-secreting tumors do not lead to precocious puberty, because activation of both FSH and LH receptors is
needed for estrogen biosynthesis.

These tumors occur in the gonads, brain (usually in the pineal region), liver, retroperitoneum, and anterior
mediastinum, reflecting sites of embryonic germ cells before their coalescence in the gonadal ridge [53]. The
histology of hCG-secreting tumors ranges from dysgerminoma, which respond readily to therapy, to the more
malignant embryonal cell carcinoma and choriocarcinoma. All males with anterior mediastinal germinomas
should have a karyotype because these tumors may be associated with Klinefelter syndrome. (See "Clinical
manifestations, diagnosis, and staging of testicular germ cell tumors" and "Pathology of mediastinal tumors",
section on 'Germ cell tumors'.)

Familial male-limited precocious puberty — This rare disorder (also known as testotoxicosis) is caused
by an activating mutation in the LH receptor gene, which results in premature Leydig cell maturation and
testosterone secretion [54]. Although inherited as an autosomal dominant disorder, girls are not affected
clinically, because (similar to hCG-secreting germ tumors) activation of both the LH and FSH receptors is
required for estrogen biosynthesis [55]. Also similar to hCG-secreting tumors, the increase in testicular size is
usually only to an early pubertal size. Affected boys typically present between one to four years of age.

Treatment of this disorder is discussed separately. (See "Treatment of precocious puberty", section on
'Familial male-limited precocious puberty'.)

Both girls and boys — The following causes of peripheral precocity can occur in either girls or boys.
Physical changes either may be isosexual or contrasexual depending on the sex of the child and the type of
sex hormone produced. Excess estrogen will cause feminization, while excess androgen will result in
virilization.

Primary hypothyroidism — Children with severe, long-standing primary hypothyroidism occasionally

present with precocious puberty. In girls, findings include early breast development, galactorrhea, and
recurrent vaginal bleeding, while affected boys present with premature testicular enlargement [56-58].
Historically this has been referred to as the "overlap" or Van Wyk-Grumbach syndrome [59]. The signs of
pubertal development regress with thyroxine therapy. (See "Acquired hypothyroidism in childhood and
adolescence".)

A proposed mechanism is cross-reactivity and stimulation of the FSH receptor by high serum thyrotropin
(thyroid-stimulating hormone [TSH]) concentrations, given that both TSH and FSH share a common alpha
subunit [60].

Exogenous sex steroids and endocrine-disrupting chemicals — Feminization, including

gynecomastia in boys, has been attributed to excess estrogen exposure from creams, ointments, and sprays.
Caretakers using these topical estrogens to treat menopausal symptoms may inadvertently expose children
to the hormones [61,62]. Other possible sources of estrogen exposure include contamination of food with
hormones, phytoestrogens (eg, in soy), and folk remedies such as lavender oil and tea tree oil [63,64].
Similarly, virilization of young children has been described following inadvertent exposure to androgen-
containing creams [65,66]. A food source was suspected for local "epidemics" of early thelarche in Italy and
Puerto Rico during the 1980s, but no single causative substance was found in food samples [67-69]. There is
ongoing research assessing the influence of endocrine-disrupting chemicals on population trends of earlier
onset of puberty as well as their potential role as causative agents of precocious puberty.
 Adrenal pathology — Adrenal causes of excess androgen production include androgen-secreting tumors
and enzymatic defects in adrenal steroid biosynthesis (congenital adrenal hyperplasia). Boys who have an
adrenal cause for their precocity will not have testicular enlargement (testes will be <4 mL testicular volume
or <2.5 cm in diameter). (See "Genetics and clinical presentation of nonclassic (late-onset) congenital
adrenal hyperplasia due to 21-hydroxylase deficiency".)

Premature pubarche is often caused by premature adrenarche but may also be the presenting feature of an
inherited disorder of adrenal steroid metabolism, including 21-hydroxylase deficiency, 11-beta-hydroxylase
deficiency, 3-beta-hydroxysteroid dehydrogenase type 2 deficiency, hexose-6-phosphate dehydrogenase
deficiency, and phosphoadenosine phosphosulfate synthase type 2 deficiency. (See "Uncommon congenital
adrenal hyperplasias".)

Adrenal estrogen-secreting tumors can lead to feminization. Rarely, adrenal tumors may produce androgen
and estrogen, the latter because of intra-adrenal aromatization of androgen (or production of enough
androgen that is peripherally aromatized to estrogen), causing both male and female pubertal changes [70].
(See "Clinical presentation and evaluation of adrenocortical tumors".)

McCune-Albright syndrome — McCune-Albright syndrome (MAS; MIM #174800) is a rare disorder

defined as the triad of peripheral precocious puberty, irregular café-au-lait ("coast of Maine") skin
pigmentation (picture 2), and fibrous dysplasia of bone (image 1) [71,72]. MAS should be considered in girls
with recurrent formation of follicular cysts and cyclic menses [73]. The skin manifestations and bone lesions
may increase over time. In girls presenting with vaginal bleeding, the ovarian enlargement has often been
mistaken for an ovarian tumor, leading to unnecessary oophorectomy [74]. Girls presenting with premature
vaginal bleeding should therefore be evaluated for features of MAS to avoid this potential mistake.

The clinical phenotype varies markedly, depending on which tissues are affected by the mutation, but
precocious puberty is the most commonly reported manifestation [75]. As in other forms of peripheral
precocity, the sequence of pubertal progression may be abnormal, in that vaginal bleeding often precedes
significant breast development [76]. Prolonged exposure to elevated levels of sex steroids may cause
accelerated growth, advanced skeletal maturation, and compromised adult height. Although the precocious
puberty is typically peripheral precocity, a secondary component of CPP may develop because of sex steroid
withdrawal leading to activation of the hypothalamic-pituitary-gonadal axis [77] (see 'Previous excess sex
steroid exposure' above). In boys with MAS, while sexual precocity is less common, there is a high
prevalence of testicular pathology on ultrasound, including hyper- and hypoechoic lesions (most likely
representing areas of Leydig cell hyperplasia), microlithiasis, and focal calcifications [78].

Patients with MAS have a somatic (postzygotic) mutation of the alpha subunit of the Gs protein that activates
adenylyl cyclase [79-81]. This mutation leads to continued stimulation of endocrine function, including
precocious puberty, thyrotoxicosis, growth hormone excess (gigantism or acromegaly), Cushing syndrome,
and renal phosphate wasting (hypophosphatemic rickets) in various combinations. Mutations can be found in
other nonendocrine organs (liver and heart) resulting in cholestasis and/or hepatitis, intestinal polyps, and
cardiac arrhythmias, respectively [72]. A heightened risk of malignancy has also been reported [82].
Germline occurrences of this mutation would presumably be lethal [79,81,83,84].

Treatment of precocious puberty associated with MAS is described in a separate topic review (see
"Treatment of precocious puberty", section on 'McCune-Albright syndrome'). More detailed information,
including evaluation and management of associated skeletal abnormalities, renal phosphate wasting and
endocrine abnormalities, is described in a guideline from an international consortium [72].

TYPES OF BENIGN OR NONPROGRESSIVE PUBERTAL VARIANTS

Early pubertal development fits into this category when the early development of secondary sexual
characteristics does not herald underlying pathology and is not followed by progressive development (table
3). However, monitoring for evidence of pubertal progression is important as some children presenting with
an apparent benign pubertal variant will instead turn out to have a disorder. As examples, thelarche may be
the initial presenting feature of central precocious puberty (CPP) or progressive pubic hair development may
herald a form of peripheral precocity.

Premature thelarche — Most cases of premature thelarche are idiopathic and present under two years of
age (and may even start at birth). Many cases will remit spontaneously, and most others do not progress.
However, follow-up is warranted because premature thelarche can represent the initial presentation of true
CPP in as many as 10 to 20 percent of children referred to pediatric endocrine units [85-87].

Key features of premature thelarche are:

● Isolated breast development, either unilateral or bilateral – Typically not developing beyond Tanner stage
3
● Absence of other secondary sexual characteristics
● Normal height velocity for age (not accelerated)
● Normal or near-normal bone age

Serum luteinizing hormone (LH) and estradiol concentrations are typically in the prepubertal range, but one
should be cautious in interpreting these levels in children under the age of two years because elevations can
be seen as part of the normal transient "mini-puberty of infancy," and CPP can be diagnosed inappropriately
(See 'Normal pubertal development' above.)

Toddlers and children — Premature thelarche occurs in two peaks: one during the first two years of life
and the other at six to eight years of age [87], with potentially different underlying pathophysiology
accountable for each of these peaks. Postulated mechanisms include transient activation of the
hypothalamic-pituitary-gonadal axis with excess follicle-stimulating hormone (FSH) secretion [88]. In infants,
soy-based formulas have been implicated, although the evidence is weak and may represent only a slower
waning of breast tissue during infancy [89-91]. Use of lavender oil, tea tree oil, or hair care products that
contain placental extract has also been implicated in some cases of premature thelarche [63]. In most
instances, no cause can be found.

In most cases, premature thelarche requires only reassurance. However, the patient should be examined for
other signs of pubertal development and growth data should be plotted; an accelerated height velocity may
be indicative of progressive puberty and requires further evaluation. To identify patients with progressive
puberty, patients should be monitored for several months for evidence of pubertal progression. (See
'Evaluation' below.)

Neonates — Breast hypertrophy can occur in neonates of both sexes and is sometimes quite prominent.
It is caused by stimulation from maternal hormones and usually resolves spontaneously within a few weeks
or months. The breast development may also be associated with galactorrhea ("witch's milk"), which also
resolves spontaneously [92]. While in most cases, neonatal thelarche disappears over the first months of life,
failure to do so almost never has any pathologic significance. (See "Breast masses in children and
adolescents", section on 'Neonates and infants'.)

Premature adrenarche — Premature adrenarche is characterized by the appearance of pubic and/or

axillary hair (pubarche) prior to the age of eight years in girls and nine years in boys, in conjunction with a
mild elevation in serum dehydroepiandrosterone sulfate (DHEAS) for age. It is more common in girls,
African-American and Hispanic females, and individuals with obesity and insulin resistance [16]. Premature
adrenarche is considered a variant of normal development but may be a risk factor for later development of
polycystic ovary syndrome in girls. (See "Premature adrenarche" and "Definition, clinical features, and
differential diagnosis of polycystic ovary syndrome in adolescents".)

In the child presenting with isolated pubarche, monitoring for the development of other secondary sexual
characteristics (breast or testicular enlargement) is important to ensure that the child's presentation is not the
first feature of CPP or a form of peripheral precocity. Premature adrenarche can be associated with mild
growth acceleration and advance in bone age. In children with progressive virilization or with a more
advanced bone age (>2 standard deviations [SD] beyond chronologic age), further investigation for other
causes of early pubertal development should be considered. (See "Premature adrenarche", section on
'Evaluation of premature pubarche'.)

Pubic hair of infancy — Pubic hair of infancy is usually a benign condition where infants present with
isolated genital hair, usually finer in texture than typical pubic hair and located along the labia or over the
scrotum (rather than on the pubic symphysis) [93-95]. The steroid profile of these infants demonstrates
normal or mildly elevated DHEAS concentrations for age. Unlike premature adrenarche, the condition is
transient and the hair typically disappears within 6 to 24 months [96]. In the absence of progressive
development of further genital hair or other secondary sexual characteristics during follow-up, extensive
evaluation is not needed.

Benign prepubertal vaginal bleeding — Benign prepubertal vaginal bleeding is characterized by the
presence of isolated, self-limited vaginal bleeding in the absence of other secondary sexual characteristics
[97]. The underlying etiology is unknown, but potential mechanisms include increased endometrial sensitivity
to circulating estrogens or transient stimulation of the hypothalamic-pituitary-gonadal axis [98]. Pelvic
ultrasonography is normal, and gonadotropins are prepubertal. Genital or vaginal trauma, infection, and
sexual abuse should be excluded. In girls with recurrent episodes of vaginal bleeding, other diagnoses, such
as recurrent functional ovarian cysts or McCune-Albright syndrome, should be considered. These conditions
may not be initially recognized, because vaginal bleeding is associated with regression of the ovarian cyst
and, hence, an ultrasound conducted at or after bleeding has occurred may be normal. (See 'McCune-
Albright syndrome' above.)

Nonprogressive or intermittently progressive precocious puberty — A subgroup of patients presenting

with what clinically appears to be CPP (often with evidence of both gonadarche and pubarche) will either
have stabilization or very slow progression in their pubertal signs [99]. The bone age is typically not as
advanced compared with children with true CPP, and serum LH concentrations are within the pre- or early-
pubertal range, indicating that the hypothalamic-pituitary-gonadal axis is not fully activated and a FSH-
predominant response is typically seen if gonadotropin-releasing hormone (GnRH) agonist stimulation testing
is performed. Monitoring for evidence of pubertal progression is important to distinguish these children from
those with true CPP. In children with nonprogressive precocious puberty, treatment with a GnRH agonist is
not needed, because their adult height is not affected (ie, their adult height untreated is concordant with their
midparental height) [99,100].

EVALUATION

Guiding principles — The evaluation for precocious puberty focuses on answering the following questions:

● Who should be evaluated? – Evaluation is warranted in children presenting with signs of secondary
sexual development younger than the age of eight (girls) or nine (boys) years. The concern and extent of
evaluation should increase with decreasing age at presentation. In girls who are between the ages of
seven and eight, a comprehensive history and physical examination may be sufficient if this examination
does not raise any additional concerns.

● Is the cause of precocity central or peripheral? – The sequence of pubertal development in children
with central precocious puberty (CPP) recapitulates normal pubertal development but at an earlier age
(figure 1A-B). By contrast, individuals with peripheral precocity have a peripheral source of gonadal
hormones and are more likely to display deviations from the normal sequence and/or pace of puberty.
As an example, a girl who progresses to menstrual bleeding within one year of the onset of breast
development is more likely to have ovarian pathology (a cause of peripheral precocity) rather than CPP
[101,102].

● How quickly is the puberty progressing? – The pace of pubertal development reflects the degree and
duration of sex steroid action.

• A rapid rate of linear growth and skeletal maturation (measured as advanced bone age) suggests
either CPP or peripheral precocity with high concentrations of sex steroids (table 4). Pubertal
progression would be considered slow if there is minimal or no change in stage of breast, pubic hair,
or genital development during six or more months of observation. Height velocity is considered
accelerated if it is more than the 95th percentile for age (figure 3A-B).

• By contrast, a child with normal linear growth and skeletal maturation (bone age normal or minimally
advanced) suggests a benign pubertal variant with low concentrations of sex steroids, rather than
true CPP or peripheral precocity.

● Is the precocity because of excess androgen or estrogen? – Are the secondary sexual
characteristics virilizing or feminizing? Isolated contrasexual development (isolated virilization in girls or
isolated feminization in boys) excludes central etiologies. While in girls the most common cause of
virilization is due to excess adrenal androgens, a rare ovarian cause of virilization is ovarian
arrhenoblastoma (Sertoli-Leydig cell tumor) [103]. Conversely, a rare testicular cause of feminization is a
feminizing Sertoli cell tumor, which may be associated with Peutz-Jeghers syndrome [104]. (See "Sex
cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults" and "Testicular
sex cord stromal tumors", section on 'Sertoli cell tumors'.)

Initial evaluation — The evaluation of a patient suspected to have precocious puberty begins with a history
and physical examination. In most cases, radiographic measurement of bone age is performed to determine
whether there is a corresponding increase in epiphyseal maturation.

● Medical history – The history focuses on when the initial pubertal changes were first noted, as well as
the timing of pubertal onset in the parents and siblings. In addition, other questions are directed toward
evidence of linear growth acceleration, headaches, changes in behavior or vision, seizures, or
abdominal pain (indicative of either a central nervous system [CNS] or ovarian process) and previous
history of CNS disease or trauma. The possibility of exposure to exogenous sex steroids (medicinal or
cosmetic sources) or compounds with sex steroid-like properties (endocrine-disrupting chemicals, for
example) should always be explored [61].

● Physical examination – This includes height, weight, and height velocity (cm/year). Children with
benign forms of precocious puberty do not usually display the early growth acceleration pattern that is
seen among those with progressive forms of precocious puberty [105]. The physical examination should
include assessment of visual fields (a defect suggests the possibility of a CNS mass) and examination
for café-au-lait spots (which would suggest neurofibromatosis or McCune-Albright syndrome) (picture 2).
(See 'McCune-Albright syndrome' above.)

● Pubertal staging – Secondary sexual development should be assessed to determine the sexual
maturity rating (Tanner stage) of pubertal development. This means staging breast development in girls
(picture 1A), genital development in boys, and pubic hair development in both sexes (picture 1B-C). In
girls, the diameter of glandular breast tissue (by direct palpation including compression to differentiate
from adipose tissue when warranted) and the nipple-areolar complex should be assessed. In boys,
measurements are made of the testicular volume (figure 4) [106]. Penile size (stretched length of the
non-erect penis, measuring from the pubic bone to tip of glans, excluding the foreskin) 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 the "pubertal threshold" for
penile-stretched length is not as clear as it is for testicular volume. Accurate measurements of testicular
volume are critical to determine whether further radiologic or laboratory testing is necessary. (See
"Normal puberty", section on 'Sexual maturity rating (Tanner stages)' and "Normal puberty", section on
'Sequence of pubertal maturation'.)

● Bone age – In patients with early development of secondary sexual characteristics confirmed by
physical examination, evaluation of skeletal maturation by radiographic assessment of bone age can
help with both the differential diagnosis and assessment of whether there may be an impact on final
height. However, in patients presenting with typical features indicative of either isolated premature
thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for
pubertal progression is likely sufficient.

A significant advance in the bone age (greater than approximately 2 standard deviations [SD] beyond
chronologic age) is more likely to be indicative of either CPP or peripheral precocity rather than a benign
pubertal variant. A significantly advanced bone age does not, however, exclude a diagnosis of a benign
pubertal variant. As an example, up to 30 percent of children with benign premature adrenarche have
bone ages more than two years in advance of their chronologic age [107]. (See 'Types of benign or
nonprogressive pubertal variants' above.)
Initial laboratory evaluation — If there is evidence of progressive development of secondary sexual
characteristics, further evaluation is needed to determine its cause, whether therapy is needed, and, if so,
which treatment is appropriate.

The first step is to measure basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), and either
estradiol and/or testosterone concentrations. The results are used to differentiate between CPP and
peripheral precocity, which then guides additional testing (algorithm 1 and table 4).

Basal serum luteinizing hormone — A good initial screening test to identify activation of the
hypothalamic-pituitary-gonadal axis is measurement of basal LH concentration (ideally in the morning), using
sensitive immunochemiluminescence assays with a lower limit of detection of ≤0.1 mIU/mL (where mIU =
milli-international units) [108]. Results are interpreted as follows:

● LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral
precocity or a benign pubertal variant such as premature thelarche.

● LH concentrations greater than 0.2 to 0.3 mIU/mL (the threshold depends on the assay used) can
identify children with progressive CPP with high sensitivity and specificity [25,109-111].

● LH concentrations are less informative in the evaluation of children with nonprogressive or intermittently
progressive precocious puberty. While such children typically have basal LH concentrations <0.2 to 0.3
mIU/mL, levels can be in the early pubertal range in some children. Additional clinical characteristics
such as lack of progression in secondary sexual characteristics or low LH:FSH ratio post-gonadotropin
stimulation test can help to differentiate these children from those with progressive CPP. (See 'Serum LH
concentrations after GnRH agonist stimulation' below.)

Care should be used in the interpretation of LH levels in girls under the age of two years as gonadotropin
concentrations may be elevated at this age in association with the "mini-puberty of infancy" and CPP can be
misdiagnosed during this phase of development [10,112].

An emerging approach is to identify cases of progressive CPP using first-morning urinary gonadotropin
levels. These early results need further validation, but this could be an important alternative diagnostic
strategy in the future [113-115].

Basal serum follicle-stimulating hormone — Basal FSH concentrations have limited diagnostic utility in
distinguishing children with CPP from those with benign pubertal variants. FSH concentrations are often
higher in children with CPP compared with benign pubertal variants, but there is substantial overlap between
these groups of children [108,109]. Like LH, FSH concentrations are typically suppressed in children with
peripheral precocity.

Serum estradiol — Very high concentrations of estradiol, with associated suppression of gonadotropins,
are generally indicative of peripheral precocity, such as from an ovarian tumor or cyst. Most estradiol
immunoassays, however, have poor ability to discriminate at the lower limits of the assay between
prepubertal and early pubertal concentrations [116]. More sensitive methods of estimating estradiol
concentrations, such as tandem mass spectrometry, distinguish better between prepubertal and pubertal
estradiol concentrations [117] and should be ordered exclusively. However, further studies are still needed to
clarify threshold concentrations.
 Serum testosterone — Elevated testosterone concentrations are indicative of testicular testosterone
production in boys, or of adrenal testosterone production or exogenous exposure in both sexes. Very high
concentrations, with associated suppression of gonadotropins, are generally indicative of peripheral
precocity. Measurement of other adrenal steroids (eg, dehydroepiandrosterone sulfate [DHEAS]) may be
necessary to help discriminate between adrenal and testicular sources of the androgens. In children with
CPP, testosterone immunoassays cannot always distinguish between prepubertal and early pubertal
testosterone concentrations, but tandem mass spectroscopy methods are more discriminative [118] (similar
to the estradiol assays discussed above), so these should be ordered whenever available.

Subsequent laboratory testing — Subsequent laboratory testing depends on the results of the tests
outlined above (basal LH, FSH, and estrogen or testosterone) and on the patient's clinical characteristics:

Serum LH concentrations after GnRH agonist stimulation — In children in whom the clinical picture is
discordant with the initial baseline investigations (ie, ongoing pubertal progression with basal LH level <0.3
mIU/mL), a gonadotropin-releasing hormone (GnRH) stimulation test may help differentiate those with CPP
from those with a benign pubertal variant. This test consists of measurement of serum LH concentrations
before and after administration of GnRH. GnRH is not available in the United States; a GnRH agonist may be
used instead because of the initial stimulatory effect on the hypothalamic-pituitary-gonadal axis following a
single dose of a GnRH agonist.

A common protocol is as follows:

● Blood is sampled at baseline for LH, FSH, and either estradiol in girls or testosterone in boys.

● The child is then given a single dose of GnRH at a dose of 100 mcg or the GnRH agonist leuprolide
acetate at a dose of 20 mcg/kg.

● LH is measured at 30 to 40 minutes post-GnRH or 60 minutes post-GnRH agonist [119-121]. Other

protocols employ sampling every 30 minutes for up to two hours [119,122] or testing of estradiol or
testosterone 24 hours later [123,124].

The results are interpreted as follows:

● Peak stimulated LH – The optimal cutoff value of peak stimulated LH for identifying children with CPP
has not been established and varies somewhat among assays. For most LH assays, a value of 3.3 to 5
mIU/mL defines the upper limit of normal for stimulated LH values in prepubertal children [119,125].
Stimulated LH concentrations above this normal range suggest CPP.

● Peak stimulated LH:FSH ratio – Children with progressive CPP tend to have a more prominent LH
increase post-stimulation and higher peak LH:FSH ratios compared with those with non- or intermittently
progressive precocious puberty [123,126]. While a definite diagnostic threshold has not been well
defined, a peak LH:FSH ratio >0.66 is typically seen with CPP, whereas a ratio <0.66 suggests
nonprogressive precocious puberty [126].

● Stimulated estradiol/testosterone – Children with progressive CPP tend to have higher stimulated serum
estradiol and testosterone concentrations when measured 24 hours after administration of GnRH or
GnRH agonist [123,124]. However, the disadvantage of requiring venipunctures on two consecutive
 days as well as the lack of consistent published diagnostic thresholds limits the clinical utility of these
measurements.

As with basal LH levels, care must be taken in interpreting the results of GnRH stimulation test in girls under
the age of two years, as both basal and stimulated LH levels can be elevated as part of the normal hormonal
changes associated with the mini-puberty of infancy [112].

Serum adrenal steroids — In children with precocious pubarche, measurement of adrenal steroids may
be necessary to help distinguish between peripheral precocity and benign premature adrenarche. Children
with premature adrenarche can have mild elevation in adrenal hormones, with DHEAS concentrations of 40
to 135 mcg/dL (1.1 to 3.7 micromol/L), and testosterone levels ≤35 ng/dL (1.2 nmol/L) [127]. (See
"Premature adrenarche", section on 'Hormonal measurements at baseline'.)

Concentrations above these thresholds warrant further investigation for causes of peripheral precocity, such
as nonclassic congenital adrenal hyperplasia and virilizing adrenal tumors. An early-morning 17-
hydroxyprogesterone (17-OHP) value >200 ng/dL (6 nmol/L) has a high sensitivity and specificity for
nonclassic congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency [128,129], although an
adrenocorticotropic hormone (ACTH) stimulation test is still needed to confirm the diagnosis. A 17-OHP
>1500 ng/dL (45 nmol/L) is essentially diagnostic for nonclassic congenital adrenal hyperplasia. In contrast, a
mildly elevated 17-OHP between 115 and 200 ng/dL (4.1 to 6.0 nmol) is more consistent with a diagnosis of
benign premature adrenarche. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal
hyperplasia due to 21-hydroxylase deficiency" and "Premature adrenarche".)

Other biochemical tests — In boys, human chorionic gonadotropin (hCG) should be measured to
evaluate for the possibility of an hCG-secreting tumor leading to peripheral precocity. If a tumor is found in
the anterior mediastinum, a karyotype should be performed to evaluate for Klinefelter syndrome because of
its association with mediastinal germinoma [53]. A thyroid-stimulating hormone (TSH) concentration should
be measured if chronic primary hypothyroidism is suspected as the underlying cause for the sexual precocity.

Imaging

● Central precocious puberty (CPP)

• Brain magnetic resonance imaging (MRI) – We recommend performing a contrast-enhanced

brain MRI for all boys with CPP and for girls with onset of secondary sexual characteristics before
six years of age because of higher rates of CNS abnormalities in these groups of patients (see
'Central nervous system lesions' above). In our practice, we usually do not perform MRI for girls with
CPP onset between seven and eight years of age if there is no clinical evidence of CNS pathology
and if there is a family history of earlier pubertal onset, or if the child has an increased body mass
index.

However, we note that in girls with CPP onset after their sixth birthday, there is ongoing debate
about the utility of brain imaging in this age group because of conflicting data about the risk for CNS
pathology: In a 2018 meta-analysis, the prevalence of intracranial lesions was 3 percent among girls
presenting with CPP after six years of age, compared with 25 percent among those presenting
before six years [130]. In contrast, in a study that was not included in the above meta-analysis, 13 of
208 girls (6.3 percent) had related MRI brain abnormalities, all of whom had onset of CPP after the
 age of six years [22]. A younger age of onset of pubertal signs and higher basal LH and estradiol
concentrations have been proposed as predictive features for intracranial pathology [22,23,131].
Still, because these features and clinical suspicion have been shown to have variable sensitivity to
detect girls with abnormal brain MRIs, some have recommended imaging for all girls with CPP
[22,24].

• Pelvic ultrasound – Pelvic ultrasonography may be a useful adjunct investigation to help

differentiate between CPP and benign pubertal variants, especially when the evaluation remains
equivocal. Girls with CPP have greater uterine and ovarian volumes compared with girls who are
prepubertal or those with premature thelarche [132-135]. Diagnostic thresholds for uterine and
ovarian volumes have been proposed; however, these are variable and some studies have
suggested that there is considerable overlap between patients with and without CPP [132,133].

● Peripheral precocity

• In girls with progressive peripheral precocity, a pelvic ultrasound can be performed to help identify
the presence of an ovarian cyst or tumor. As noted above, the presence of a normal ovarian
ultrasound does not exclude a diagnosis of a functional ovarian cyst, because the cyst may have
regressed by the time of the study (see 'Benign prepubertal vaginal bleeding' above). For suspected
adrenal pathology (for example, when there is rapid virilization), an adrenal ultrasound should be
strongly considered.

• Ultrasound examination of the testes can be performed in boys with peripheral precocity to evaluate
for the possibility of a Leydig cell tumor.

• In children where an adrenal tumor is suspected (due to evidence of progressive virilization and
elevated serum adrenal androgens, eg, DHEAS), an abdominal ultrasound and/or computed
tomography (CT) of the abdomen should be performed.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world
are provided separately. (See "Society guideline links: Normal puberty and related disorders".)

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 5th to 6th 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, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the
10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable
with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
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.)

● Basics topic (see "Patient education: Early puberty (The Basics)")

SUMMARY

● Precocious puberty is defined as the onset of pubertal development more than 2 to 2.5 standard
deviations (SD) earlier than the average age (figure 1A-B). (See 'Definition' above.)

● Because of the trend of earlier pubertal development, there is controversy about the lower age limit for
normal pubertal development. Nonetheless, we recommend evaluation in children presenting with
secondary sexual development younger than eight years in girls or nine years in boys (figure 2). (See
'Definition' above and 'Evaluation' above.)

● The etiology of precocious puberty is classified by the underlying pathogenesis into three categories
(see 'Classification' above):

• Central precocious puberty (CPP) is caused by an early activation of the hypothalamic-pituitary-

gonadal axis. CPP is pathologic in up to 40 to 75 percent of boys and 10 to 20 percent of girls (table
1). (See 'Causes of central precocious puberty' above.)

• Peripheral precocity is caused by secretion of sex hormones either from the gonads or adrenal
glands, ectopic human chorionic gonadotropin (hCG) production by a germ-cell tumor, or by
exogenous sources of sex steroids and is independent from the hypothalamic-pituitary-gonadal axis
(table 2). (See 'Causes of peripheral precocity' above.)

• Benign pubertal variants include isolated breast development (premature thelarche), isolated pubic
hair development (premature pubarche/adrenarche), benign prepubertal vaginal bleeding, and
nonprogressive precocious puberty (table 3). These patterns are usually a variant of normal puberty
and require no intervention. If the finding is isolated breast development or isolated pubarche and
there is no evidence of pubertal progression or accelerated growth, laboratory evaluation may not
be necessary. However, close follow-up is recommended because some of these patients will turn
out to have progressive precocity. (See 'Types of benign or nonprogressive pubertal variants'
above.)

● The first step in the laboratory evaluation of progressive development of precocious secondary sexual
characteristics is to measure basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), and
either estradiol or testosterone concentrations. The results are used to differentiate between CPP and
peripheral precocity, which then guides additional testing (algorithm 1 and table 4). A good initial
screening test to distinguish CPP from benign pubertal variants is measurement of a basal LH
concentration (see 'Basal serum luteinizing hormone' above):

• In CPP, basal LH levels are often elevated into the pubertal range (greater than 0.2 to 0.3 mIU/mL,
depending on the assay)
• LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral
precocity or a benign pubertal variant such as premature thelarche
 ● If the clinical picture is discordant with the initial baseline investigations (ie, ongoing pubertal progression
with basal LH level <0.3 mIU/mL), a gonadotropin-releasing hormone (GnRH) stimulation test can be
performed to help distinguish CPP from a benign pubertal variant. Children with CPP have a pubertal
(heightened) LH response to GnRH stimulation (table 4). (See 'Serum LH concentrations after GnRH
agonist stimulation' above.)

● Recommendations for imaging depend on the type of precocious puberty (see 'Imaging' above):

• All boys with CPP should have brain imaging because of the high prevalence of central nervous
system (CNS) lesions in this group. While all girls with onset of CPP below the age of six years
should also have a contrast-enhanced brain magnetic resonance imaging (MRI), there is ongoing
controversy about the need for more routine imaging of girls between the ages of six and eight
years.

• Boys with peripheral precocity may warrant an ultrasound examination of the testes to evaluate for
the possibility of a Leydig cell tumor. Girls with peripheral precocity may warrant a pelvic ultrasound
performed to help identify the presence of an ovarian cyst or tumor. In both sexes, ultrasound of the
adrenal glands may be indicated if adrenal pathology is suspected and should be performed if there
is suspicion for an adrenal tumor.

• Other than a bone age, no further imaging is usually required for children with benign or
nonprogressive pubertal variants.

ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge Paul Saenger, MD, MACE, who contributed to an
earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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32:819.

Topic 5812 Version 36.0

GRAPHICS

Sequence of puberty in girls

Sequence of events in girls with average timing of pubertal development in the United States. The median age for
achieving each milestone is younger for African American girls (dashed vertical line) compared with Caucasian girls (dotted
vertical line). The median length of time between the onset of puberty (breast Tanner stage 2) and menarche is 2.6 years,
and the 95 th percentile is 4.5 years.

SMR: sexual maturity rating (also known as Tanner stage).

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.

Graphic 52047 Version 9.0

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 1988-1994
Third National Health and Nutrition Examination Survey. J Adolesc Health 2002; 30:205-12.
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.

Graphic 72046 Version 3.0

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 contour of the areola and breast.

Figure from: Roede MJ, van Wieringen JC. Growth diagrams 1980: Netherlands third nation-wide
survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with permission from the author.

Graphic 72038 Version 8.0

Sexual maturity rating (Tanner staging) of pubic hair and external
genitalia 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 mid-pubis.
Stage 4: Hair is adult-like in appearance, but does not extend to thighs.
Stage 5: Hair is adult in appearance, extending from thigh to thigh.
Stages of external genitalia development in boys:
Stage 1: Prepubertal.
Stage 2: Enlargement of testes and scrotum; 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.

Figure from: Roede MJ, van Wieringen JC. Growth diagrams 1980: Netherlands third nation-wide
survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with permission from the author.

Graphic 80005 Version 6.0

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 adult-like in appearance, but does not extend to the thighs.
Stage 5: Hair is adult in appearance, extending from thigh to thigh.

Figure from: Roede MJ, van Wieringen JC. Growth diagrams 1980: Netherlands third nation-wide
survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with permission from the author.

Graphic 79782 Version 5.0

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 Herman-Giddens, ME, Slora, EJ, Wasserman, RC, et al, Pediatrics 1997; 99:505.

Graphic 72226 Version 2.0

Etiology and mechanisms of precocious puberty

CNS: central nervous system; GnRH: gonadotropin-releasing hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone.

From: Harrington J, Palmert MR, Hamilton J. Use of local data to enhance uptake of published recommendations: an example from the diagnostic evaluation of pr
puberty. Arch Dis Child 2014; 99:15. Reproduced with permission from BMJ Publishing Group Ltd. Copyright © 2014.

Graphic 104041 Version 3.0

Central (gonadotropin-dependent) precocious puberty

Etiology Clinical features Bone age Additional evaluation

Idiopathic
(80 to 90% of girls with CPP and
25 to 60% of boys with CPP)
Secondary to CNS lesions
(eg, hypothalamic hamartomas,
other CNS tumors and lesions,
cranial radiation)
Early progressive pubertal development, ↑↑ Increased ovarian and uterine volumes on
but proceeds in normal sequence. ultrasound may help differentiate girls with
CPP from those with premature thelarche.
Contrast-enhanced MRI to rule out CNS
Early progressive pubertal development ↑↑
abnormality.
that usually proceeds in normal sequence,
but abnormal tempo or sequence can be
seen with CNS lesions.
CPP secondary to a CNS lesion occurs
more commonly in boys and younger
children.

Post-early exposure to sex History of treatment of peripheral ↑↑ Basal and stimulated LH concentrations
steroids precocity. are pubertal.
(after treatment for peripheral Progressive pubertal development with
precocity) breast development in girls and testicular
enlargement in boys.

CPP is characterized by basal LH concentrations >0.2 to 0.3 mIU/L and/or stimulated LH concentration post-GnRH or GnRH agonist of >3.3 to
5.0 mIU/L.

↑↑: significantly advanced for chronologic age (eg, ≥2 standard deviations); CPP: central precocious puberty; MRI: magnetic resonance imaging; CNS:
central nervous system; LH: luteinizing hormone; GnRH: gonadotropin-releasing hormone.

Courtesy of Drs. Jennifer Harrington and Mark Palmert.

Graphic 52565 Version 14.0

Peripheral precocity (gonadotropin-independent precocious puberty)
Etiology Clinical features
Girls only
Ovarian cysts Breast development and/or vaginal bleeding.
Occasionally presents with ovarian torsion and
abdominal pain.
Ovarian tumor Development of either isosexual or contrasexual
sexual precocity, depending of tumor type.
Boys only
Leydig cell tumor Asymmetrical enlargement of the testes.
hCG-secreting germ- Symmetric testicular enlargement to an early
cell tumors pubertal size, but testes remain smaller than
expected for degree of pubertal development.
Peripheral precocity is seen only in boys because
hCG only activates LH receptors (estrogen
biosynthesis in the ovaries requires both FSH and
LH receptor activation).
Familial male-limited Symmetric testicular enlargement to an early
precocious puberty pubertal size, but testes remain smaller than
expected for degree of pubertal development;
spermatogenesis may occur.
Familial – Male-limited autosomal dominant trait.
Peripheral precocity is seen only in boys
because there is only activation of the LH
receptors (ovarian estrogen biosynthesis requires
both FSH and LH receptor activation).
Girls and boys
Exogenous sex steroids Estrogen preparations cause feminization, while
(estradiol and topical androgens cause virilization in both sexes.
testosterone creams)
and endocrine
disrupting chemicals
McCune-Albright In girls, may present with recurrent episodes of
syndrome breast development, regression, and vaginal
(girls>boys) bleeding. In boys, sexual precocity is less
common.
Skin – Multiple irregular-edged café-au-lait spots.
Bone – Polyostotic fibrous dysplasia.
Primary hypothyroidism Girls – Vaginal bleeding, breast development, and
galactorrhea.
Boys – Testicular enlargement.
Other clinical features of hypothyroidism such as
short stature.
Congenital adrenal Boys have prepubertal testes with enlarged
hyperplasia phallus and pubic hair development. Girls with
(untreated) nonclassic congenital adrenal hyperplasia may
present with early pubic and/or axillary hair and
other signs of androgen excess.
Bone
Additional evaluation
age
↑ to ↑↑ Pelvic ultrasound may visualize the cyst, although
in some cases, the cyst may have involuted by
the time of the study. Vaginal bleeding is
indicative of estrogen withdrawal. Recurrent
ovarian cysts suggest McCune-Albright
syndrome.
↑↑ Pelvic ultrasound
↑↑ Pubertal testosterone concentrations. Testicular
ultrasound aids in diagnosis.
↑↑ These tumors may occur in gonads, brain, liver,
retroperitoneum, or mediastinum.
When a tumor is identified in the anterior
mediastinum, a karyotype must be performed
because of an association of this finding with
Klinefelter syndrome.
↑↑ Genetic testing for mutations of the LH receptor
gene.
↑ to ↑↑ Clinical history explores use of exogenous sex
steroids and folk remedies by caregivers and
exposure to endocrine disrupting chemicals.
↑ to ↑↑ Ultrasound – Ovaries enlarged, with follicular
cysts. In boys, testicular ultrasound can
demonstrate hyper- and hypoechoic lesions (most
likely representing areas of Leydig cell
hyperplasia), microlithiasis, and focal
calcifications.
May have other hyperactive endocrine disorders,
ie, thyrotoxicosis, glucocorticoid excess, and/or
gigantism.
↓ Elevated TSH.
↑↑ Sex hormone levels vary depending on the
adrenal enzyme block. An early-morning 17-OHP
>200 ng/dL (>6 nmol/L) has a high sensitivity and
specificity for congenital adrenal hyperplasia
secondary to 21-hydroxylase deficiency, but an
ACTH stimulation test is still recommended to
confirm the diagnosis for 17-OHP concentrations
between 200 and 1500 ng/dL (6 to 45 nmol/L).
After therapy with glucocorticoids, CPP may
develop.
 Virilizing adrenal tumor Boys – Pubic and/or axillary hair and penile ↑↑ High DHEA or DHEAS, androstenedione and
growth with prepubertal testes. testosterone.
Girls – Pubic and/or axillary hair, other significant CT and/or ultrasound of adrenal glands to locate
signs of androgen excess (acne and tumor.
clitoromegaly).
May present with signs of glucocorticoid excess.
May be associated with hereditary cancer
syndromes.

Peripheral precocity is characterized by low or suppressed gonadotropin concentrations with elevated sex hormone levels. Pubertal status should
be monitored for 6 months after treatment because treatment of peripheral precocity can trigger CPP.

↑: advanced for chronologic age; ↓: delayed for chronologic age; hCG: human chorionic gonadotropin; LH: luteinizing hormone; FSH: follicle-stimulating
hormone; TSH: thyroid-stimulating hormone; 17-OHP: 17-hydroxyprogesterone; ACTH: adrenocorticotropic hormone; CPP: central precocious puberty;
DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulfate; CT: computed tomography.

Courtesy of Drs. Jennifer Harrington and Mark Palmert.

Graphic 59268 Version 17.0

Types of benign pubertal variants

Etiology Clinical features Bone age Additional evaluation

Premature adrenarche
(boys or girls)
Isolated pubarche. Gonads are prepubertal in
size and there is no breast development in girls.
Typical age of onset 4 to 8 years.
Seen more commonly in African-American and
Hispanic girls and in children with obesity and
insulin resistance.
↑ to ↑↑* Further investigations needed only if there is
significant progressive virilization, to help exclude
peripheral precocity.
Mild elevation in DHEAS for chronologic age (but
appropriate for bone age).
Prepubertal concentrations of 17-OHP and
testosterone.

Premature thelarche Isolated breast development with normal growth Normal No further evaluation needed in most cases,
(girls) velocity. (prepubertal) unless evidence of pubertal progression.
Most commonly seen in girls less than 3 years of Basal LH concentrations typically <0.2 to 0.3
age. mIU/L ¶.

Nonprogressive or
intermittently
progressive precocious
puberty
(boys or girls)
Development of gonadarche (breast or testicular
enlargement) with pubarche (pubic and/or axillary
hair), with either no progression or intermittent
slow progression in clinical pubertal signs.
Normal to ↑ Basal LH concentrations typically <0.2 to 0.3
mIU/L, although can be in early pubertal range in
some children.
Lower stimulated LH:FSH ratio compared with
children with progressive central precocious
puberty Δ.
Patients with nonprogressive precocious puberty
do not need treatment with GnRH
agonist, because final height untreated is
concordant with mid-parental height.

If further evaluation is needed and performed, patients with benign pubertal variants typically have prepubertal basal LH concentrations (<0.2 to
0.3 mIU/L) and/or stimulated LH concentration post-GnRH agonist of <3.3 to 5.0 mIU/L.

↑: elevated for chronologic age; DHEAS: dehydroepiandrosterone sulfate; 17-OHP: 17-hydroxyprogesterone; LH: luteinizing hormone; FSH: follicle-
stimulating hormone; GnRH: gonadotropin-releasing hormone.
* Up to 30% of children with premature adrenarche can have a bone age more than 2 years advanced than their chronologic age [1].
¶ Interpretation of basal LH and stimulated LH concentrations can be difficult in girls younger than 2 years of age because normal gonadotropin
concentrations can be elevated as part of the mini-puberty of infancy [2].
Δ A peak LH:FSH ratio <0.66 suggests nonprogressive precocious puberty, whereas a ratio >0.66 is typically seen with central precocious puberty [3].

1. DeSalvo, DJ, Mehra R, Vaidyanathan P, Kaplowitz PB. In children with premature adrenarche, bone age advancement by 2 or more years is
common and generally benign. J Pediatr Endocrinolo Metab 2013; 26: 215.
2. Bizzarri C, Spadoni G, Bottaro G et al. The response to gonadotropin releasing hormone (GnRH) stimulation test does not predict the progression to
true precocious puberty in girls with onset of premature thelarche in the first three years of life. JCEM 2014; 99:433.
3. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab 1990;
71:1251.

Graphic 72054 Version 15.0

Café-au-lait spots in McCune-Albright syndrome

(A) A typical lesion on the face, chest, and arm of a five-year-old girl with McCune-Albright
syndrome, which demonstrates jagged "coast of Maine" borders and the tendency for the
lesions to both respect the midline and follow the developmental lines of Blaschko (a
configuration of skin lesions characterized by arcs on the upper chest, S shapes on the
abdomen, and V shapes over the posterior midline, caused by patterns of X-chromosome
inactivation).
(B) Typical lesions that are often found on the nape of the neck and crease of the buttocks
are shown (arrows).

Reproduced from: Dumitrescu CE, Collins MT. McCune-Albright syndrome. Orphanet J Rare Dis
2008; 3:12. Copyright ©2008 BioMed Central Ltd.

Graphic 80844 Version 6.0

Radiographic appearance of fibrous dysplasia in McCune-Albright
syndrome

(A) A proximal femur with typical ground-glass appearance and shepherd's crook deformity
characteristic of FD in a 10-year-old child.
(B) The appearance of FD in the femur of an untreated 40-year-old man demonstrates the tendency
for FD to appear more sclerotic with time.
(C) The typical ground-glass appearance of FD in the craniofacial region on a CT image of a 10-year-
old child is shown. The white arrows indicate the optic nerves, which are typically encased with FD.
(D) A CT image in a 40-year-old woman demonstrates the typical appearance of craniofacial FD in an
older person, with mixed solid and "cystic" lesions. The Hounsfield Unit measurements of "cystic"
lesions are quite useful in distinguishing soft tissue "cystic" lesions from true fluid-filled cysts, which are
much more uncommon and tend to behave aggressively with rapid expansion and compression of vital
structures.
(E to G) Bone scintigraphy in FD. Representative 99Tc-MDP bone scans, which show tracer uptake at
affected skeletal sites, and the associated skeletal disease burden score are shown.
(E) A 50-year-old woman with monostotic FD confined to a single focus involving contiguous bones
in the craniofacial region.
(F) A 42-year-old man with polyostotic FD shows the tendency for FD to be predominantly (but not
exclusively) unilateral and to involve the skull base and proximal femur.
(G) A 16-year-old boy with McCune-Albright syndrome and involvement of virtually all skeletal sites
(panostotic) is shown.

FD: fibrous dysplasia; CT: computed tomography.

Reproduced from: Dumitrescu, CE, Collins, MT. McCune-Albright syndrome. Orphanet J Rare Dis 2008; 3:12.
Copyright ©2008 BioMed Central Ltd.

Graphic 81627 Version 3.0

Clinical characteristics of forms of early pubertal development

Nonprogressive Central precocious

Peripheral precocity
precocious puberty puberty

Physical examination: No progression in Tanner staging Progression to next pubertal stage Progression
Advancement through pubertal during 3 to 6 months of in 3 to 6 months
stages (Tanner stage) observation

Growth velocity Normal for bone age Accelerated (>6 cm per year)* Accelerated*

Bone age Normal to mildly advanced Advanced for height age Advanced for height age

Serum estradiol concentration Prepubertal Δ Prepubertal to pubertal Increased in ovarian causes of

(girls) ¶ peripheral precocity or with
exogenous estrogen exposure

Serum testosterone Prepubertal Δ Prepubertal to pubertal Pubertal and increasing

concentration (boys, or girls
with virilization) ¶

Basal (unstimulated) serum LH Prepubertal Δ◊ Pubertal ◊ Suppressed or prepubertal ◊

concentration ¶

GnRH (or GnRH agonist) LH peak in the prepubertal LH peak elevated (in the pubertal No change from baseline or LH
stimulation test ¶ range Δ § range) § peak in the prepubertal range
Lower stimulated LH:FSH ratio ¥ Higher stimulated LH:FSH ratio ¥

CPP: central precocious puberty; LH: luteinizing hormone; GnRH: gonadotropin-releasing hormone; FSH: follicle-stimulating hormone.
* Unless the patient has concomitant growth hormone deficiency (as in the case of a neurogenic form of CPP) or has already passed his or her peak height
velocity at the time of evaluation, in which case, growth velocity may be normal or decreased for chronologic age.
¶ Using most commercially available immunoassays, serum concentrations of gonadal steroids have poor sensitivity to differentiate between prepubertal
and early pubertal concentrations.
Δ In most cases, these levels will be prepubertal; however, in children with intermittently progressive CPP, these levels may reach pubertal concentrations
during times of active development.
◊ Using ultrasensitive assays with detection limit of LH <0.1 mIU/L, prepubertal basal LH concentrations are <0.2 to 0.3 mIU/L.
§ In most laboratories, the upper limit of normal for LH after GnRH stimulation is 3.3 to 5.0 mIU/mL. Stimulated LH concentrations above this normal range
suggests CPP.
¥ A peak stimulated LH:FSH ratio <0.66 usually suggests nonprogressive precocious puberty, whereas a ratio >0.66 is typically seen with CPP [1].

Reference:
1. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab 1990;
71:1251.
Courtesy of Drs. Mark Palmert and Jennifer Harrington.

Graphic 72017 Version 10.0

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 2 other curves outline a
trajectory (50 th percentile) for a child with "early" (solid blue) or "late" (solid orange) timing of peak growth
velocity.
Other height velocity curves have been developed that reflect population averages (eg, Kelly A, JCEM
2014, not shown here). Those curves are substantially flatter than the trajectory followed by any individual
patient. they 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 for evaluation
of the growth of an individual patient.

SD: standard deviations.

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.

Graphic 96367 Version 7.0

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 2 other curves outline a trajectory
(50 th percentile) for a child with "early" (solid blue) or "late" (solid orange) timing of peak growth velocity.
Other height velocity curves have been developed that reflect population averages (eg, Kelly A, JCEM
2014, not shown here). Those curves are substantially flatter than the trajectory followed by any individual
patient. they 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 for evaluation
of the growth of an individual patient.

SD: standard deviations.

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.

Graphic 96366 Version 6.0

Reference chart for testicular volume

Reference chart of testicular volume measured with an orchidometer, based upon data from 769 healthy Dutch
boys aged 6 months to 19 years. [1]

Reference:
1. Joustra S, van der Plas E, Goede J, et al. New reference charts for testicular volume in Dutch children and
adolescents allow calculation of standard deviation scores. Acta Paediatrica 2015; 104:e271.
Reproduced with permission. Copyright ©2015 TNO.

Graphic 104080 Version 1.0

Contributor Disclosures
Jennifer Harrington, MBBS, PhD Nothing to disclose Mark R Palmert, MD, PhD Nothing to disclose Peter J Snyder,
MD Grant/Research/Clinical Trial Support: AbbVie [Hypogonadism]; Novartis [Cushing's]. Consultant/Advisory Boards:
AbbVie [Hypogonadism]; Novartis [Cushing's]; Pfizer [Acromegaly]. William F Crowley, Jr, MD Equity Ownership/Stock
Options: Dare Bioscience [Endocrinology]. Consultant/Advisory Boards: Dare Bioscience [Endocrinology]. Mitchell E
Geffner, MD Grant/Research/Clinical Trial Support: Novo Nordisk [Growth]. Consultant/Advisory Boards: Adrenas and
Neurocrine Biosciences [CAH]; Daiichi-Sankyo [Type 2 diabetes]; Ferring, Novo Nordisk, Nutritional Growth Solutions,
Nutritional Growth Solutions, Pfizer, and QED [Growth]; Gilead [Growth/HIV]. Other Financial Interest: McGraw-Hill
[Pediatric endocrinology textbook royalties]; Ascendis data safety monitoring board [Growth]; Tolmar data safety
monitoring board [Precocious puberty]; Millendo data safety monitoring board [Prader-Willi syndrome]. Alison G Hoppin,
MD Nothing to disclose Kathryn A Martin, 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 multi-level 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

 Official reprint from UpToDate®
www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Treatment of precocious puberty

Authors: Jennifer Harrington, MBBS, PhD, Mark R Palmert, MD, PhD
Section Editors: Peter J Snyder, MD, William F Crowley, Jr, MD, Mitchell E Geffner, MD
Deputy Editors: Alison G Hoppin, MD, Kathryn A Martin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2020. | This topic last updated: May 18, 2020.

INTRODUCTION

Precocious puberty is traditionally defined as the onset of secondary sexual development

before the age of eight years in girls and nine years in boys. Because of trends towards
earlier pubertal development, some healthy girls will have breast or pubic hair
development before this age, and extensive evaluation and treatment may not be required.
If the evaluation leads to a diagnosis of progressive precocious puberty, treatment may be
considered.

The treatment of precocious puberty, which depends upon the underlying cause, will be
discussed in this topic. The definition, etiology, and evaluation of precocious puberty are
reviewed separately. (See "Definition, etiology, and evaluation of precocious puberty".)

CLASSIFICATION

Precocious puberty can be classified based upon the underlying pathologic process.

● Central precocious puberty – Central precocious puberty (CPP, also known as

gonadotropin-dependent precocious puberty or true precocious puberty) is caused by
early maturation of the hypothalamic-pituitary-gonadal axis. It is characterized by
sequential maturation of breasts and pubic hair in girls, and of maturation of the
testes, penis, and pubic hair in boys. The sexual characteristics are appropriate for the
child's gender (isosexual). CPP is idiopathic in 80 to 90 percent of cases in girls,
whereas intracranial lesions are detected in 40 to 75 percent of boys with CPP (table
 1A). (See "Definition, etiology, and evaluation of precocious puberty", section on
'Causes of central precocious puberty'.)

● Peripheral precocity – Peripheral precocity (also known as gonadotropin-

independent precocious puberty or peripheral precocious puberty) is caused by
excess secretion of sex hormones (estrogens or androgens) derived either from the
gonads or adrenal glands, exogenous sources of sex steroids, or ectopic production
of gonadotropins from a germ cell tumor (eg, human chorionic gonadotropin [hCG])
(table 1B). We use the term precocity instead of puberty because puberty implies
activation of the hypothalamic-pituitary-gonadal axis, as occurs in CPP, whereas
precocity refers only to the secondary sexual characteristics. Peripheral precocity is
most commonly either isosexual (concordant with the child's gender), or contrasexual
(with virilization of girls and feminization of boys), but can also present with both
virilizing and feminizing features in rare cases. (See "Definition, etiology, and
evaluation of precocious puberty", section on 'Causes of peripheral precocity'.)

● Benign or nonprogressive pubertal variants – Benign pubertal variants include

isolated breast development in girls (premature thelarche) or isolated androgen-
mediated sexual characteristics (such as pubic and/or axillary hair, acne, and apocrine
odor) in boys or girls that result from early activation of the hypothalamic-pituitary-
adrenal axis (premature adrenarche) (table 1C). Both of these conditions can be a
variant of normal puberty. However, repeat evaluations may be warranted in these
children to be certain that the diagnosis is correct. (See "Definition, etiology, and
evaluation of precocious puberty", section on 'Types of benign or nonprogressive
pubertal variants'.)

TREATMENT FOR CENTRAL PRECOCIOUS PUBERTY

When warranted, pubertal progression in central precocious puberty (CPP) can be treated
by administration of a gonadotropin-releasing hormone (GnRH) agonist. GnRH agonists
work by providing continuous stimulation to the pituitary gonadotrophs, instead of
physiologic pulsatile stimulation from hypothalamic GnRH. Continuous stimulation leads to
desensitization of the gonadotroph cells and suppression of gonadotropins, resulting in
decreased sex steroid production [1], a phenomenon referred to as pituitary-gonadal axis
suppression. This treatment can be used for patients with idiopathic or neurogenic CPP
[2,3], or for secondary activation of CPP, which may occur in patients who initially present
with peripheral precocity. However, not all patients require treatment, as outlined in the
following section.

When CPP is caused by an identifiable central nervous system (CNS) lesion, therapy is
also directed toward the underlying pathology when possible. Benign hypothalamic
hamartomas are often left in situ and monitored neuroradiologically over time [4], unless
associated with significant generalized epileptic activity [5].

Decision to treat — The decision of whether to treat CPP with a GnRH agonist depends
upon the child's age, the rate of pubertal progression (sexual maturation), height velocity,
and the estimated adult height as determined from the rate of bone age advancement.
Pubertal progression would be considered slow if there is no change in stage of breast,
pubic hair, or genital development during six or more months of observation (table 2) [6].
Height velocity is considered accelerated if it is more than 6 cm per year. The relationship
between pubertal stages and height velocity in normally developing children is outlined in
the figure (figure 1A-B) and discussed in detail elsewhere. (See "Normal puberty", section
on 'Pubertal changes'.)

Clinical decision-making related to height preservation is guided by the following

considerations (decision-making related to psychosocial concerns is described below (see
'Goals of treatment' below)):

● Age – Children with CPP who present at a younger age and have a rapid progression
of maturation benefit the most from therapy because they have early epiphyseal
fusion and reduced adult height if they are not treated [7,8]. In contrast, children who
present close to the age of normal puberty or who have a very slowly progressive
variant of precocious puberty usually do not require any therapy, because their adult
height without treatment is concordant with their midparental height range [9-12].

• For girls with onset of CPP before the age of six years, GnRH agonist treatment
results in an average gain in adult height of 9 to 10 cm, whereas for those with
onset of CPP between six and eight years, treatment results in an average gain in
adult height of 4 to 7 cm [8,13]. The degree of bone age advancement prior to
treatment initiation can, however, attenuate this height gain [13].

• For boys, fewer data are available. One study estimated that GnRH treatment
beginning at an average age of 7.6 years resulted in a mean height gain of
6.2±8.7 cm [14]. Two expert panels concluded that it is reasonable to consider
GnRH agonist treatment for boys with progressive CPP if they present before
 nine years of age [7,8]. As in girls, GnRH agonist therapy may result in less
height gain for boys with a more advanced bone age at the initiation of therapy.

● Rate of maturation (pubertal progression) – If precocious puberty is slowly

progressive, it is unlikely to compromise adult height and in that instance we do not
suggest therapy [15]. In a study of 16 such girls who were followed for 12 years
without treatment, all reached normal adult height [9]. Despite the early onset of
breast development in this group, menarche occurred at a normal age (average age
11 years). Similarly, in a group of 35 boys with slowly progressive puberty (defined as
progression from sexual maturity rating [Tanner] stage 2 to 3 over more than 18
months) who were not treated, adult height was within the range of their target height
[11]. Clinical experience has shown that many cases of precocious puberty,
particularly in girls with onset after six years of age, will be slowly progressive.

● Estimated adult height – If the estimated adult height is above 150 cm in girls and
above 160 cm in boys, therapy is probably not needed to achieve normal adult height,
and a conservative approach is therefore warranted [16]. A variety of methods can be
used to predict adult height. A common method developed by Bayley and Pinneau
employs a table to predict adult height based upon the child's bone age and
chronologic age. Height prediction methods have, however, often been found to
overpredict the adult height in children with precocious puberty.

Based upon the data described above, we suggest initiation of GnRH agonist therapy for a
girl presenting with progressive CPP before the age of six with breast and pubic hair
development, advanced bone age, and accelerated height velocity. Conversely, in a girl
with somewhat later onset of CPP and/or historically slow progression of pubertal
development without a substantial increase in height velocity, we suggest monitoring
without treatment for three to six months to establish the pace of the pubertal progression
before making treatment decisions [7,8]. For boys, we treat all those presenting with CPP
before the age of nine years, unless there is evidence of slow pubertal progression, in
which case, we monitor clinically to assess the pace of pubertal progression before making
treatment decisions [11].

Goals of treatment

● A primary goal of treatment for CPP is to allow a child to grow to a normal adult
height. Therefore, as noted above, the decision to treat should include analysis of the
predicted height benefit from treatment. (See 'Decision to treat' above.)
 ● Another goal of therapy is to relieve psychosocial stress. Parents are often concerned
about the prospect of early menses, which might be distressing to a young girl.
However, the data regarding the psychosocial impact of CPP are limited. A study of 19
girls with CPP prior to treatment initiation found no difference in psychological distress
as compared with girls with normal puberty [17]. A study of 10 girls with CPP
demonstrated reduced stress levels following one year of GnRHa therapy [18].
However, another study of 36 girls with CPP demonstrated improvement in
psychological scores irrespective of GnRHa treatment [19]. Because of scant data in
this area, treatment primarily to address perceived psychosocial consequences of
precocious puberty should be approached with caution [7]. This caution is especially
true for girls with pubertal onset at the edge of the normal range, whereas treatment of
a very young girl may be warranted even in the absence of strong data. In girls with
developmental disabilities where the goal of treatment may be suppression of menses
rather than height preservation, alternate treatment approaches such as intramuscular
(depot) medroxyprogesterone, continuous oral contraceptive pills, or intrauterine
devices can be considered [15,20] (see "Hormonal contraception for suppression of
menstruation"). It is important to take a family-centered approach to the decision to
initiate therapy for CPP by ensuring that the caregivers are fully informed about the
pros and cons of the therapy.

GnRH agonist therapy — For children with CPP, GnRH agonist administration results in
an initial transient stimulation of gonadotropin secretion from the pituitary, followed by a
complete, but reversible, suppression of the pituitary-gonadal axis. The initial stimulation of
gonadotropins is the basis for using these drugs in a stimulation test to distinguish CPP
from peripheral precocity or benign pubertal variants. (See "Definition, etiology, and
evaluation of precocious puberty", section on 'Serum LH concentrations after GnRH
agonist stimulation'.)

Formulations and dosing — Sustained-release formulations of several GnRH

agonists have been developed: depot preparations for monthly, three-, or six-monthly
dosing and a subcutaneous implant that is surgically inserted every 12 months (table 3)
[6]. The choice of GnRH agonist formulation depends on patient and clinician preference
and local regulatory approvals [8]. These preparations have not been directly compared in
randomized trials but appear to be similarly effective in suppressing the pituitary-gonadal
axis [21-31].

Short-acting GnRH agonist formulations are also available, including daily subcutaneous
injections and multiple daily dosing intranasal sprays (nafarelin acetate). Depot
preparations are preferable because of improved compliance and thus better pituitary-
gonadal axis suppression [32]. However, in certain clinical situations, such as the
development of sterile abscesses with depot GnRH agonist therapy, these daily
preparations can be used as an alternative.

The different GnRH agonist preparations and typical starting doses used in various
countries are outlined in the table (table 3). Our typical approach to GnRH agonist depot
dosing using formulations available in North America is described below. (See 'Our
approach' below.)

Monitoring — After GnRH agonist therapy has begun, follow-up monitoring should be
performed to ensure that the goals of GnRH agonist therapy are being achieved (eg,
suppression of the pituitary-gonadal axis, slowing of development of secondary sexual
characteristics and of bone age advancement, and, ultimately, increases in predicted adult
height). If treatment is effective, further breast and testicular development and menses
should cease and height velocity and rate of bone age advancement should decline.
Therefore, routine monitoring should include:

● Evaluation of pubertal development and growth every three to six months. Effective
GnRH agonist therapy should result in a decrease in height velocity, cessation of
menses, and arrest pubertal progression.

● Periodic bone age measurements (eg, every 6 to 12 months), looking for a reduction
in the bone age advancement [2,7]. Once this has been documented, bone age
measurements can be performed less frequently (eg, every one to two years).

In our practice, we do not routinely monitor serum LH and sex steroid concentrations
during GnRH agonist therapy, because we believe there are insufficient data to
demonstrate that using such measurements to adjust therapy improves adult height
outcomes. However, we recognize that this is a controversial topic and that other clinicians
prefer to monitor biochemically for evidence of pituitary-gonadal axis suppression and
adjust treatment accordingly. Such measurements include basal LH and sex steroid
concentrations (estradiol in girls and testosterone in boys) or stimulated LH and sex steroid
levels (after GnRH or a GnRH agonist). Native GnRH is not available in the United States;
therefore, some clinicians use the next scheduled GnRH agonist injection for the
stimulated LH sample.

Regardless of whether biochemical monitoring is performed, ongoing careful clinical

assessment is paramount. If there is evidence of ongoing pubertal progression once
therapy has begun, then the above biochemical measurements may be used to assess
whether there is complete suppression of the pituitary-gonadal axis [33,34]. If this testing
shows incomplete suppression of the pituitary-gonadal axis, the GnRH agonist dose
should be increased or the interval between doses decreased. (See "Definition, etiology,
and evaluation of precocious puberty", section on 'Basal serum luteinizing hormone' and
"Definition, etiology, and evaluation of precocious puberty", section on 'Serum LH
concentrations after GnRH agonist stimulation'.)

Within the first weeks after the initial dose of the GnRH agonist, vaginal bleeding may
occur due to estradiol withdrawal because the treatment initially stimulates estradiol
production before suppressing the pituitary-gonadal axis. If vaginal bleeding occurs later in
the course of treatment, this either indicates lack of suppression of the pituitary-gonadal
axis or an alternative diagnosis to CPP (eg, a cause of peripheral precocity). Pubic hair
stage may advance due to adrenarche despite effective treatment with GnRH agonists
because these agents have no effect on adrenal androgen production [35].

Treatment duration — The duration of GnRH agonist therapy should be long enough
to optimize final adult height, yet still allow progression of pubertal characteristics at an age
that is concurrent with the individual's peers. When GnRH agonist therapy with monthly
depot preparations is stopped, normal puberty returns, on average, within 12 to 18
months.

In one study, menarche occurred 17.5±11.2 months after the last injection of GnRH. It was
somewhat earlier in girls who had menstruated prior to GnRH treatment (mean age of
resuming menses 12.7±1.3 years, approximately nine months after the last GnRH
injection), compared with those who had not previously menstruated (mean age of
menarche 13.1±1.5 years, approximately 19 months after the last GnRH injection) [36]. In
boys, the interval between the last injection of GnRH and achievement of adult
testosterone levels was 11±10.9 months. If histrelin implants are used, preliminary reports
suggest that the average length of time between removal of the implant and resumption of
menses is approximately 12 months, with wide variability [29,30].

Safety — Adverse effects of the one-, three-, and six-monthly depot injections include
pain and local reactions at the injection sites, and, although uncommon, sterile abscess
formation [37]. For histrelin implants, the extraction procedure can be complicated by
breakage of the implant in 15 to 39 percent of cases, with a higher likelihood of breakage if
the implant is left in for two years rather than shorter periods of time [38,39]. Because
GnRH agonist therapy of men with prostate cancer has been associated with a prolonged
QT interval [40], the Pediatric Endocrine Society has recommended monitoring by
electrocardiogram (ECG) of susceptible patients prior to commencement of GnRH agonist
therapy and again when the GnRH agonist dose has reached steady state. Susceptible
patients include children who are receiving concomitant medications known to prolong the
QT interval or who have a family history of congenital heart disease, arrhythmia, sudden
death, or long QT syndrome [41].

Regarding long-term outcome of GnRH agonist therapy for CPP:

● Treatment with GnRH agonists appears to have no significant long-term effects on the
pituitary-gonadal axis [42]. In long-term follow-up of girls who were treated with GnRH
agonists, the rate of regular menstrual cycles and fertility was not different from the
general population [43-45]. For boys, small studies show normal gonadal function
after completing treatment with GnRH agonists [46].

● Although earlier pubertal development is associated with obesity, long-term treatment

with GnRH agonists does not appear to cause or exacerbate obesity in adolescence
or adulthood [8,47,48].

● While bone mineral density may slightly decrease during GnRH agonist
administration, these changes are not sustained, with preservation of peak bone mass
accrual after discontinuation of therapy [49,50].

● Overall, there is no clear evidence that GnRH agonist treatment increases the risk for
polycystic ovary syndrome [7,8,42]. The reported incidence of polycystic ovary
syndrome in girls with CPP is variable, with some series reporting up to a 32 percent
incidence [51], while others report rates of 0 to 12 percent, an incidence not different
from the general population [7].

Our approach — After a progressive form of CPP has been identified and discussion
with the family has resulted in a decision to treat, the choice of GnRH agonist formulation
depends upon patient and clinician preference, insurance company coverage, and local
regulatory approvals. Families should be counseled that some vaginal bleeding may occur
after the initiation of GnRH agonist therapy due to transient stimulation of the pituitary-
gonadal axis with the first dose. Similarly, boys can experience a transient increase in
erections.

A variety of dosing schemes are effective. Starting doses used in Europe tend to be
somewhat lower than those in the United States (as outlined in the table (table 3));
additionally, other products are available worldwide but not in the United States. Our
approach includes the following:

● We typically use the three-month preparation of leuprolide depot (Lupron Depot PED
[three month]) at a starting dose of 11.25 mg. If puberty is not adequately suppressed,
we decrease the interval between doses or titrate up the dose. Because histrelin and
triptorelin are not yet approved in Canada, they do not form part of our clinical
practice.

● For young children (under two years of age) or children with hypothalamic
hamartomas (groups in which control of puberty may be more difficult), we often
instead consider using leuprolide depot (Lupron Depot PED [one month]), given
intramuscularly every 28 days, with a starting dose of 7.5 mg. After suppression is
achieved, and if the family wants, we often switch to three-monthly preparations. (See
'Formulations and dosing' above.)

● We monitor the response to the GnRH agonist by assessing pubertal development

and height velocity every three to six months and bone age initially every 6 to 12
months. If pubertal progression is not suppressed, the dose of GnRH agonist is
adjusted upward or the interval between doses is shortened. (See 'Monitoring' above.)

● We generally continue treatment until approximately age 11 years in girls and age 12
years in boys. The decision of when to discontinue GnRH agonist therapy is
individualized; contributing factors include the age of the child, bone age and height
age, predicted height, and desire to have pubertal progression concurrent with their
peers. (See 'Treatment duration' above.)

TREATMENT FOR PERIPHERAL PRECOCITY

Peripheral sexual precocity (also referred to as gonadotropin-independent precocious

puberty or peripheral precocious puberty) is caused by excess secretion of sex hormones
(estrogens or androgens) derived from the gonads, adrenal glands, exogenous sources, or
ectopic production of gonadotropin from a germ cell tumor (eg, human chorionic
gonadotropin [hCG]) (table 1B). The causes and evaluation of peripheral precocity are
discussed in a separate topic review. (See "Definition, etiology, and evaluation of
precocious puberty", section on 'Causes of peripheral precocity'.)
General approach — Peripheral precocity does not respond to gonadotropin-releasing
hormone (GnRH) agonist therapy. Instead, treatment is directed at blocking the production
of and/or response to the excess sex steroids, depending on the cause:

● Tumors of the testis, adrenal gland, or ovary – These are treated by surgery. hCG-
secreting tumors may also require radiation therapy and chemotherapy, depending
upon the site and histologic type.

● Functioning follicular cysts of the ovary – These develop and regress spontaneously,
so conservative management without surgery is generally appropriate [52-54].
Patients should be followed clinically to document regression in the clinical signs of
precocity. If there is no clinical evidence of pubertal regression, ultrasonography of the
ovaries should be performed. (See "Definition, etiology, and evaluation of precocious
puberty", section on 'Ovarian cysts'.)

● Exposure to exogenous sex steroids – The source should be identified and removed.
After removal, the pubertal changes are likely to regress. (See "Definition, etiology,
and evaluation of precocious puberty", section on 'Exogenous sex steroids and
endocrine-disrupting chemicals'.)

● Defects in adrenal steroidogenesis, such as classic congenital adrenal hyperplasia –

These should be treated with glucocorticoids. (See "Genetics and clinical presentation
of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and
"Definition, etiology, and evaluation of precocious puberty", section on 'Adrenal
pathology'.)

● McCune-Albright syndrome and familial male-limited precocious puberty – These

disorders require a different approach because they are caused by mutations resulting
in overstimulation of the tissues that produce sex steroids. (See 'McCune-Albright
syndrome' below.)

Children with peripheral precocity with associated exposure to high serum sex steroid
levels are at risk for developing secondary central precocious puberty (CPP) once the
cause of peripheral precocity has been treated. Clinical monitoring for signs of progressive
breast or testicular development is therefore important after treating a child with peripheral
precocity. Addition of a GnRH agonist may be warranted if CPP has developed. (See
'GnRH agonist therapy' above.)

McCune-Albright syndrome — McCune-Albright syndrome (MAS; MIM #174800) is a

rare genetic disorder defined as the triad of peripheral sexual precocity, café-au-lait skin
pigmentation, and fibrous dysplasia of bone. It is caused by a somatic (postzygotic)
mutation of the gene encoding the alpha subunit of the Gs protein that results in
constitutive activation of adenylyl cyclase in affected tissues [55].

Affected girls tend to form recurrent ovarian cysts, resulting in estradiol secretion and
intermittent vaginal bleeding. The ovarian enlargement is sometimes mistaken for an
ovarian tumor, leading to unnecessary oophorectomy [56]. Affected boys produce excess
testosterone, but they are less likely to develop sexual precocity. Testicular abnormalities
on ultrasound that most likely represent Leydig cell hyperplasia are common [57]. To
preserve fertility, children with these disorders should be treated with drugs that inhibit
gonadal steroidogenesis or gonadal steroid action, rather than surgery.

The clinical presentation and diagnosis of MAS is discussed separately (see "Definition,
etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome').
More detailed information, including evaluation and management of associated skeletal
abnormalities, renal phosphate wasting, and other endocrine abnormalities, is described in
a guideline from an international consortium [58].

Girls — Approximately 85 percent of girls with MAS develop precocious puberty [55].
One goal of treatment is to reduce the potential for compromised adult height due to early
epiphyseal fusion from sustained estrogen exposure in young girls. A second goal is to
reduce the psychological impact of recurrent vaginal bleeding [59]. Treatment for girls with
MAS has included strategies to block estrogen biosynthesis with aromatase inhibitors or
block estrogen action (figure 2). While there is no consensus on the optimum treatment,
we use an aromatase inhibitor (letrozole); this practice is based upon the limited clinical
experience outlined below:

● Aromatase inhibitors – Treatment with letrozole has become one of the commonly
used therapeutic approaches for girls with MAS [58]. In a pilot study of nine girls
treated with letrozole, the episodes of vaginal bleeding either ceased or decreased
and there was a decrease in bone age advancement [60]. One patient, however,
developed a large ovarian cyst with clinical symptoms suggestive of torsion. A follow-
up study of 28 girls treated with letrozole for a mean of 4.1 years demonstrated further
improvement in predicted adult height, without any further cases of ovarian torsion
[61]. More data on the long-term safety and impact of letrozole on adult height from
larger cohorts of patients are still needed.

Clinical experience suggests that other aromatase inhibitors are less effective.
Testolactone, a first-generation aromatase inhibitor, is partially effective for reducing
 the recurrence of ovarian cysts and slowing pubertal progression [62], but there is a
loss of efficacy over time [63]. For reasons that are not clear, the newer-generation
aromatase inhibitors, fadrozole and anastrozole, are largely ineffective for long-term
treatment [64-66].

● Blockers of estrogen action – Drugs that block estrogen action appear to have some
efficacy, but their clinical role remains unclear because evidence is limited to small
case series. Treatment with tamoxifen, a selective estrogen receptor modulator
(SERM), has been shown to decrease the vaginal bleeding episodes and slow the
rate of bone age advancement in a study of 28 girls [67]. However, uterine and
ovarian volumes increased by the end of the study, raising concerns about long-term
safety. In a retrospective study of eight girls treated with tamoxifen, the predicted adult
height improved during treatment [68]. However, in the four girls who had completed
their growth during the follow-up period, the gain in adult height was modest (average
of 4.3 cm).

In a one-year open-label trial of fulvestrant, a pure estrogen receptor antagonist, most

subjects who had vaginal bleeding at baseline experienced either a substantial
reduction or cessation of bleeding, and rates of bone age advancement decreased
significantly [69]. These results are promising but long-term safety or efficacy
outcomes for fulvestrant treatment of MAS are not yet available.

A few patients with MAS will develop a component of central precocious puberty (CPP).
This is probably caused by prolonged fluctuating exposure to elevated levels of sex
steroids and is most often found in patients with advanced bone age. Such patients may
respond to adjuvant treatment with a GnRH agonist, as do other children with CPP [70].
(See 'GnRH agonist therapy' above.)

Boys — MAS is less common in males than females [71], and approximately 15
percent of affected boys develop precocious puberty, which is due to overproduction of
testosterone [55,57].

Due to the rarity of this disorder in boys, information about treatment outcomes is very
limited. A few case reports describe successful treatment of these boys with an
antiandrogen in combination with an aromatase inhibitor to prevent conversion to estradiol
and subsequent bone age advancement, similar to the regimen used for familial male-
limited precocious puberty described below [57,58,70,72]. (See 'Familial male-limited
precocious puberty' below.)
The pathogenesis and presentation of MAS are outlined in a separate topic review. (See
"Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright
syndrome'.)

Familial male-limited precocious puberty — Familial male-limited precocious puberty,

also called familial gonadotropin-independent precocious puberty or familial testotoxicosis,
is a rare genetic condition in boys that is caused by an activating mutation in the gene
encoding the luteinizing hormone (LH) receptor, which results in premature Leydig cell
maturation and testosterone secretion.

The disorder is treated with a combination of an antiandrogen (an androgen receptor

antagonist; eg, spironolactone, bicalutamide) and an aromatase inhibitor, eg anastrozole,
which inhibits the conversion of testosterone to estradiol, thereby retarding further
epiphyseal fusion (figure 2) [73-75]. The resulting decrease in sex steroid levels may lead
to CPP. If so, it is treated with a GnRH agonist [56,70].

The optimal treatment regimen has not been established, because data are limited to small
case series and direct comparisons are lacking. Based upon available published data, we
use the combination of spironolactone and anastrozole (testolactone is no longer
available). Preliminary results of such combination therapy are promising. Results of
published case series are:

● In the largest case series to date, 25 subjects with familial male-limited precocious
puberty were treated with a combination of spironolactone and either testolactone or
anastrozole (once testolactone was no longer available) and followed to adult height.
GnRH agonist therapy was introduced if there was evidence of secondary activation of
CPP. This treatment regimen resulted in an increased adult height compared with the
predicted adult height at the time of initial assessment of 12.4 cm (1.3 standard
deviations) [76] and is consistent with initial findings from a smaller case series
published by the same investigators [75].

● In a case report of two boys with familial male-limited precocious puberty, a regimen of
bicalutamide and anastrozole was effective in reducing height velocity and decreasing
secondary sexual characteristics without serious adverse effects [77]. In an open-label
study in 14 boys, the same combination effectively reduced height velocity and bone
age maturation; gynecomastia and breast tenderness were the most common side
effects [78]. Further data on final adult height and safety are needed for this
combination of medications.
 ● Other regimens have included ketoconazole, an inhibitor of steroid synthesis, which
was effective in two small series [79,80] but may cause hepatotoxicity and adrenal
insufficiency [81].

BENIGN OR NONPROGRESSIVE PUBERTAL VARIANTS

For patients presenting with idiopathic isolated premature thelarche or premature

adrenarche, clinical reexamination and follow-up are important to confirm the diagnosis
because some patients with an initial presentation that is consistent with a benign pubertal
variant will turn out to have a progressive disorder such as central precocious puberty
(CPP) or peripheral precocity. If reexamination confirms lack of rapid progression in
secondary sexual characteristics, these children need no therapy and can be discharged
from clinical care. Similarly, intermittent or slowly progressive precocious puberty does not
warrant therapy. (See "Definition, etiology, and evaluation of precocious puberty", section
on 'Types of benign or nonprogressive pubertal variants'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links: Normal
puberty and related disorders".)

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 5th to 6th
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, easy-to-read materials. Beyond the Basics patient education pieces
are longer, more sophisticated, and more detailed. These articles are written at the 10th to
12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail 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.)
 ● Basics topic (see "Patient education: Early puberty (The Basics)")

SUMMARY AND RECOMMENDATIONS

● The etiology of precocious puberty is classified by the underlying pathogenesis into

three categories: central precocious puberty (CPP; also known as gonadotropin-
dependent precocious puberty or true precocious puberty), peripheral precocity (also
known as gonadotropin-independent precocious puberty or peripheral precocious
puberty), and benign or nonprogressive pubertal variants (table 1A-C). (See
'Classification' above.)

● The primary goal of treatment for CPP is to allow a child to grow to a normal adult
height; relieving psychosocial distress, if present, is an additional goal. For patients
with CPP, the decision about whether to treat largely depends on the age of onset of
CPP, the rate of sexual maturation, and the estimated adult height as determined by
the rate of bone age advancement (table 2). In general, treatment is most likely to be
beneficial for children who are younger, have rapid pubertal progression, and shorter
predicted adult height. Children with slowly progressive forms of CPP do not require
treatment, because they reach their height potential without treatment. (See 'Decision
to treat' above.)

● If treatment for CPP is indicated, gonadotropin-releasing hormone (GnRH) agonists

are used. For children with progressive CPP, younger age at initiation of therapy is
associated with greater height benefits. (See 'Decision to treat' above.)

• Clinically significant increments in height potential are achieved with a variety of

GnRH agonists, and outcome data are insufficient to recommend one form over
another; several preparations are listed in the table (table 3). The choice of GnRH
agonist formulation depends on patient and clinician preference and local
insurance and regulatory approvals; in our practice, we use leuprolide depot
given intramuscularly, with either the one-month or three-month preparation.
Because histrelin and triptorelin are not yet approved in Canada, they are not part
of our clinical practice. (See 'Formulations and dosing' above and 'Our approach'
above.)

• During treatment with a GnRH agonist, patients should be monitored periodically

for pubertal development, height velocity, and bone age to determine whether the
dose is adequate. (See 'Monitoring' above.)
 ● Peripheral precocity is caused by excess secretion of sex hormones either from the
gonads or adrenal glands, ectopic human chorionic gonadotropin (hCG) production by
a germ cell tumor, or by exogenous sources of sex steroids and is GnRH-
independent. Causes of peripheral precocity are listed in the table (table 1B). (See
"Definition, etiology, and evaluation of precocious puberty", section on 'Causes of
peripheral precocity'.)

● Treatment for peripheral precocity is directed at blocking the production of and/or

response to the excess sex steroids; these patients do not respond to GnRH agonist
therapy, unless they have developed secondary CPP (figure 2). (See 'Treatment for
peripheral precocity' above.)

● Benign or nonprogressive pubertal variants include isolated breast development

(premature thelarche) or isolated characteristics such as pubic hair development
mediated by androgens produced by early maturation of the adrenal glands
(premature adrenarche). Either of these patterns usually is a variant of normal puberty
and requires no intervention. However, clinical reexamination and follow-up are
important to confirm the diagnosis because some patients with an initial presentation
that is consistent with a benign pubertal variant will turn out to have a progressive
disorder. (See 'Benign or nonprogressive pubertal variants' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Paul

Saenger, MD, MACE, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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testicular pathology in McCune-Albright syndrome. J Clin Endocrinol Metab 2012;
97:E1782.

58. Javaid MK, Boyce A, Appelman-Dijkstra N, et al. Best practice management

guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus statement
from the FD/MAS international consortium. Orphanet J Rare Dis 2019; 14:139.

59. Eugster EA. Peripheral precocious puberty: causes and current management. Horm
Res 2009; 71 Suppl 1:64.

60. Feuillan P, Calis K, Hill S, et al. Letrozole treatment of precocious puberty in girls with
the McCune-Albright syndrome: a pilot study. J Clin Endocrinol Metab 2007; 92:2100.

61. Estrada A, Boyce AM, Brillante BA, et al. Long-term outcomes of letrozole treatment
for precocious puberty in girls with McCune-Albright syndrome. Eur J Endocrinol
2016; 175:477.

62. Feuillan PP, Foster CM, Pescovitz OH, et al. Treatment of precocious puberty in the
McCune-Albright syndrome with the aromatase inhibitor testolactone. N Engl J Med
1986; 315:1115.

63. Feuillan PP, Jones J, Cutler GB Jr. Long-term testolactone therapy for precocious
puberty in girls with the McCune-Albright syndrome. J Clin Endocrinol Metab 1993;
77:647.
64. Nunez SB, Calis K, Cutler GB Jr, et al. Lack of efficacy of fadrozole in treating
precocious puberty in girls with the McCune-Albright syndrome. J Clin Endocrinol
Metab 2003; 88:5730.

65. Shulman DI, Francis GL, Palmert MR, et al. Use of aromatase inhibitors in children
and adolescents with disorders of growth and adolescent development. Pediatrics
2008; 121:e975.

66. Mieszczak J, Lowe ES, Plourde P, Eugster EA. The aromatase inhibitor anastrozole
is ineffective in the treatment of precocious puberty in girls with McCune-Albright
syndrome. J Clin Endocrinol Metab 2008; 93:2751.

67. Eugster EA, Rubin SD, Reiter EO, et al. Tamoxifen treatment for precocious puberty
in McCune-Albright syndrome: a multicenter trial. J Pediatr 2003; 143:60.

68. de G Buff Passone C, Kuperman H, Cabral de Menezes-Filho H, et al. Tamoxifen

Improves Final Height Prediction in Girls with McCune-Albright Syndrome: A Long
Follow-Up. Horm Res Paediatr 2015; 84:184.

69. Sims EK, Garnett S, Guzman F, et al. Fulvestrant treatment of precocious puberty in
girls with McCune-Albright syndrome. Int J Pediatr Endocrinol 2012; 2012:26.

70. Haddad N, Eugster E. An update on the treatment of precocious puberty in McCune-

Albright syndrome and testotoxicosis. J Pediatr Endocrinol Metab 2007; 20:653.

71. Lumbroso S, Paris F, Sultan C, European Collaborative Study. Activating Gsalpha

mutations: analysis of 113 patients with signs of McCune-Albright syndrome--a
European Collaborative Study. J Clin Endocrinol Metab 2004; 89:2107.

72. Lenz AM, Shulman D, Eugster EA, et al. Bicalutamide and third-generation
aromatase inhibitors in testotoxicosis. Pediatrics 2010; 126:e728.

73. Holland FJ, Fishman L, Bailey JD, Fazekas AT. Ketoconazole in the management of
precocious puberty not responsive to LHRH-analogue therapy. N Engl J Med 1985;
312:1023.

74. Laue L, Kenigsberg D, Pescovitz OH, et al. Treatment of familial male precocious
puberty with spironolactone and testolactone. N Engl J Med 1989; 320:496.

75. Leschek EW, Jones J, Barnes KM, et al. Six-year results of spironolactone and
testolactone treatment of familial male-limited precocious puberty with addition of
 deslorelin after central puberty onset. J Clin Endocrinol Metab 1999; 84:175.

76. Leschek EW, Flor AC, Bryant JC, et al. Effect of Antiandrogen, Aromatase Inhibitor,
and Gonadotropin-releasing Hormone Analog on Adult Height in Familial Male
Precocious Puberty. J Pediatr 2017; 190:229.

77. Kreher NC, Pescovitz OH, Delameter P, et al. Treatment of familial male-limited
precocious puberty with bicalutamide and anastrozole. J Pediatr 2006; 149:416.

78. Reiter EO, Mauras N, McCormick K, et al. Bicalutamide plus anastrozole for the
treatment of gonadotropin-independent precocious puberty in boys with
testotoxicosis: a phase II, open-label pilot study (BATT). J Pediatr Endocrinol Metab
2010; 23:999.

79. Soriano-Guillén L, Lahlou N, Chauvet G, et al. Adult height after ketoconazole

treatment in patients with familial male-limited precocious puberty. J Clin Endocrinol
Metab 2005; 90:147.

80. Almeida MQ, Brito VN, Lins TS, et al. Long-term treatment of familial male-limited
precocious puberty (testotoxicosis) with cyproterone acetate or ketoconazole. Clin
Endocrinol (Oxf) 2008; 69:93.

81. US Food and Drug Administration Drug Safety Communication 7/26/13. Nizoral (keto
conazole): Potentially Fatal Liver Injury, Risk of Drug Interactions and Adrenal Gland
Problems. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safet
yAlertsforHumanMedicalProducts/ucm362672.htm?source=govdelivery (Accessed o
n July 30, 2013).

Topic 16318 Version 31.0

GRAPHICS

Central (gonadotropin-dependent) precocious puberty

Etiology Clinical features Bone age Additional evaluation

Idiopathic Early progressive pubertal ↑↑ Increased ovarian and uterine

(80 to 90% of girls with CPP
and 25 to 60% of boys with
CPP)
Secondary to CNS lesions
(eg, hypothalamic
hamartomas, other CNS
tumors and lesions, cranial
radiation)
development, but proceeds in volumes on ultrasound may help
normal sequence. differentiate girls with CPP
from those with premature
thelarche.
Early progressive pubertal ↑↑
Contrast-enhanced MRI to rule
development that
out CNS abnormality.
usually proceeds in normal
sequence, but abnormal tempo or
sequence can be seen with CNS
lesions.
CPP secondary to a CNS lesion
occurs more commonly in boys
and younger children.

Post-early exposure to History of treatment of peripheral ↑↑ Basal and stimulated LH

sex steroids
(after treatment for
peripheral precocity)
precocity. concentrations are pubertal.
Progressive pubertal development
with breast development in girls
and testicular enlargement in
boys.

CPP is characterized by basal LH concentrations >0.2 to 0.3 mIU/L and/or stimulated LH concentration post-GnRH or
GnRH agonist of >3.3 to 5.0 mIU/L.

↑↑: significantly advanced for chronologic age (eg, ≥2 standard deviations); CPP: central precocious puberty; MRI: magnetic
resonance imaging; CNS: central nervous system; LH: luteinizing hormone; GnRH: gonadotropin-releasing hormone.

Courtesy of Drs. Jennifer Harrington and Mark Palmert.

Graphic 52565 Version 14.0

Peripheral precocity (gonadotropin-independent precocious puberty)

Bone
Etiology Clinical features Additional evaluation
age

Girls only

Ovarian cysts Breast development and/or vaginal
bleeding. Occasionally presents with
ovarian torsion and abdominal pain.
↑ to ↑↑ Pelvic ultrasound may visualize the cyst,
although in some cases, the cyst may
have involuted by the time of the study.
Vaginal bleeding is indicative of
estrogen withdrawal. Recurrent ovarian
cysts suggest McCune-Albright
syndrome.

Ovarian tumor Development of either isosexual or ↑↑ Pelvic ultrasound

contrasexual sexual precocity,
depending of tumor type.

Boys only

Leydig cell tumor Asymmetrical enlargement of the testes. ↑↑ Pubertal testosterone concentrations.
Testicular ultrasound aids in diagnosis.

hCG-secreting Symmetric testicular enlargement to an ↑↑ These tumors may occur in gonads,

germ-cell tumors early pubertal size, but testes remain
smaller than expected for degree of
pubertal development.
Peripheral precocity is seen only in boys
because hCG only activates LH
receptors (estrogen biosynthesis in the
ovaries requires both FSH and LH
receptor activation).
brain, liver, retroperitoneum, or
mediastinum.
When a tumor is identified in the anterior
mediastinum, a karyotype must be
performed because of an association of
this finding with Klinefelter syndrome.

Familial male- Symmetric testicular enlargement to an ↑↑ Genetic testing for mutations of the LH
limited precocious early pubertal size, but testes remain receptor gene.
puberty smaller than expected for degree of
pubertal development; spermatogenesis
may occur.
Familial – Male-limited autosomal
dominant trait.
Peripheral precocity is seen only in boys
because there is only activation of the
LH receptors (ovarian estrogen
biosynthesis requires both FSH and LH
receptor activation).

Girls and boys

Exogenous sex Estrogen preparations cause ↑ to ↑↑ Clinical history explores use of

steroids (estradiol feminization, while topical androgens exogenous sex steroids and folk
and testosterone cause virilization in both sexes. remedies by caregivers and exposure to
creams) and endocrine disrupting chemicals.
endocrine
disrupting
chemicals

McCune-Albright In girls, may present with recurrent
syndrome episodes of breast development,
(girls>boys) regression, and vaginal bleeding. In
boys, sexual precocity is less common.
↑ to ↑↑ Ultrasound – Ovaries enlarged, with
follicular cysts. In boys, testicular
ultrasound can demonstrate hyper- and
hypoechoic lesions (most likely
representing areas of Leydig cell
 Skin – Multiple irregular-edged café-au-
lait spots.
Bone – Polyostotic fibrous dysplasia.
hyperplasia), microlithiasis, and focal
calcifications.
May have other hyperactive endocrine
disorders, ie, thyrotoxicosis,
glucocorticoid excess, and/or gigantism.

Primary Girls – Vaginal bleeding, breast ↓ Elevated TSH.

hypothyroidism development, and galactorrhea.
Boys – Testicular enlargement.
Other clinical features of hypothyroidism
such as short stature.

Congenital adrenal Boys have prepubertal testes with
hyperplasia enlarged phallus and pubic hair
(untreated) development. Girls with
nonclassic congenital adrenal
hyperplasia may present with early
pubic and/or axillary hair and other signs
of androgen excess.
↑↑ Sex hormone levels vary depending on
the adrenal enzyme block. An early-
morning 17-OHP >200 ng/dL (>6
nmol/L) has a high sensitivity and
specificity for congenital adrenal
hyperplasia secondary to 21-
hydroxylase deficiency, but an ACTH
stimulation test is still recommended to
confirm the diagnosis for 17-OHP
concentrations between 200 and 1500
ng/dL (6 to 45 nmol/L). After therapy
with glucocorticoids, CPP may develop.

Virilizing adrenal Boys – Pubic and/or axillary hair and ↑↑ High DHEA or DHEAS,
tumor penile growth with prepubertal testes. androstenedione and testosterone.
Girls – Pubic and/or axillary hair, other CT and/or ultrasound of adrenal glands
significant signs of androgen excess to locate tumor.
(acne and clitoromegaly).
May present with signs of glucocorticoid
excess.
May be associated with hereditary
cancer syndromes.

Peripheral precocity is characterized by low or suppressed gonadotropin concentrations with elevated sex hormone
levels. Pubertal status should be monitored for 6 months after treatment because treatment of peripheral precocity can
trigger CPP.

↑: advanced for chronologic age; ↓: delayed for chronologic age; hCG: human chorionic gonadotropin; LH: luteinizing hormone;
FSH: follicle-stimulating hormone; TSH: thyroid-stimulating hormone; 17-OHP: 17-hydroxyprogesterone; ACTH:
adrenocorticotropic hormone; CPP: central precocious puberty; DHEA: dehydroepiandrosterone; DHEAS:
dehydroepiandrosterone sulfate; CT: computed tomography.

Courtesy of Drs. Jennifer Harrington and Mark Palmert.

Graphic 59268 Version 17.0

Types of benign pubertal variants

Etiology Clinical features Bone age Additional evaluation

Premature Isolated pubarche. Gonads are
adrenarche prepubertal in size and there is no
(boys or girls) breast development in girls. Typical
age of onset 4 to 8 years.
Seen more commonly in African-
American and Hispanic girls and in
children with obesity and insulin
resistance.
↑ to ↑↑* Further investigations needed only if
there is significant progressive
virilization, to help exclude peripheral
precocity.
Mild elevation in DHEAS for
chronologic age (but appropriate for
bone age).
Prepubertal concentrations of 17-OHP
and testosterone.

Premature Isolated breast development with Normal No further evaluation needed in most
thelarche normal growth velocity. (prepubertal) cases, unless evidence of pubertal
(girls) Most commonly seen in girls less than progression.
3 years of age. Basal LH concentrations typically <0.2
to 0.3 mIU/L ¶.

Nonprogressive or Development of gonadarche (breast or Normal to ↑ Basal LH concentrations typically <0.2

intermittently testicular enlargement) with pubarche to 0.3 mIU/L, although can be in early
progressive (pubic and/or axillary hair), with either pubertal range in some children.
precocious puberty no progression or intermittent slow Lower stimulated LH:FSH ratio
(boys or girls) progression in clinical pubertal signs. compared with children with
progressive central precocious
puberty Δ.
Patients with nonprogressive
precocious puberty do not need
treatment with GnRH agonist, because
final height untreated is concordant
with mid-parental height.

If further evaluation is needed and performed, patients with benign pubertal variants typically have prepubertal basal LH
concentrations (<0.2 to 0.3 mIU/L) and/or stimulated LH concentration post-GnRH agonist of <3.3 to 5.0 mIU/L.

↑: elevated for chronologic age; DHEAS: dehydroepiandrosterone sulfate; 17-OHP: 17-hydroxyprogesterone; LH: luteinizing
hormone; FSH: follicle-stimulating hormone; GnRH: gonadotropin-releasing hormone.
* Up to 30% of children with premature adrenarche can have a bone age more than 2 years advanced than their chronologic
age [1].
¶ Interpretation of basal LH and stimulated LH concentrations can be difficult in girls younger than 2 years of age because
normal gonadotropin concentrations can be elevated as part of the mini-puberty of infancy [2].
Δ A peak LH:FSH ratio <0.66 suggests nonprogressive precocious puberty, whereas a ratio >0.66 is typically seen with central
precocious puberty [3].

1. DeSalvo, DJ, Mehra R, Vaidyanathan P, Kaplowitz PB. In children with premature adrenarche, bone age advancement
by 2 or more years is common and generally benign. J Pediatr Endocrinolo Metab 2013; 26: 215.
2. Bizzarri C, Spadoni G, Bottaro G et al. The response to gonadotropin releasing hormone (GnRH) stimulation test does
not predict the progression to true precocious puberty in girls with onset of premature thelarche in the first three years of
life. JCEM 2014; 99:433.
3. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin
Endocrinol Metab 1990; 71:1251.

Graphic 72054 Version 15.0

Clinical characteristics of forms of early pubertal development

Nonprogressive Central precocious

Peripheral precocity
precocious puberty puberty

Physical examination: No progression in Tanner Progression to next pubertal Progression

Advancement through staging during 3 to 6 stage in 3 to 6 months
pubertal stages (Tanner months of observation
stage)

Growth velocity Normal for bone age Accelerated (>6 cm per Accelerated*
year)*

Bone age Normal to mildly advanced Advanced for height age Advanced for height age

Serum estradiol Prepubertal Δ Prepubertal to pubertal Increased in ovarian

concentration (girls) ¶ causes of peripheral
precocity or with exogenous
estrogen exposure

Serum testosterone Prepubertal Δ Prepubertal to pubertal Pubertal and increasing

concentration (boys, or
girls with virilization) ¶

Basal (unstimulated) Prepubertal Δ◊ Pubertal ◊ Suppressed or prepubertal ◊

serum LH concentration ¶

GnRH (or GnRH agonist) LH peak in the prepubertal LH peak elevated (in the No change from baseline or
stimulation test ¶ range Δ § pubertal range) § LH peak in the prepubertal
Lower stimulated LH:FSH Higher stimulated LH:FSH range
ratio ¥ ratio ¥

CPP: central precocious puberty; LH: luteinizing hormone; GnRH: gonadotropin-releasing hormone; FSH: follicle-stimulating
hormone.
* Unless the patient has concomitant growth hormone deficiency (as in the case of a neurogenic form of CPP) or has already
passed his or her peak height velocity at the time of evaluation, in which case, growth velocity may be normal or decreased for
chronologic age.
¶ Using most commercially available immunoassays, serum concentrations of gonadal steroids have poor sensitivity to
differentiate between prepubertal and early pubertal concentrations.
Δ In most cases, these levels will be prepubertal; however, in children with intermittently progressive CPP, these levels may
reach pubertal concentrations during times of active development.
◊ Using ultrasensitive assays with detection limit of LH <0.1 mIU/L, prepubertal basal LH concentrations are <0.2 to 0.3 mIU/L.
§ In most laboratories, the upper limit of normal for LH after GnRH stimulation is 3.3 to 5.0 mIU/mL. Stimulated LH
concentrations above this normal range suggests CPP.
¥ A peak stimulated LH:FSH ratio <0.66 usually suggests nonprogressive precocious puberty, whereas a ratio >0.66 is typically
seen with CPP [1].

Reference:
1. Oerter KE, Uriarte MM, Rose SR, et al. Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin
Endocrinol Metab 1990; 71:1251.
Courtesy of Drs. Mark Palmert and Jennifer Harrington.

Graphic 72017 Version 10.0

Sequence of puberty in girls

Sequence of events in girls with average timing of pubertal development in the United States. The median age for
achieving each milestone is younger for African American girls (dashed vertical line) compared with Caucasian girls (dotted
vertical line). The median length of time between the onset of puberty (breast Tanner stage 2) and menarche is 2.6 years,
and the 95 th percentile is 4.5 years.

SMR: sexual maturity rating (also known as Tanner stage).

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.

Graphic 52047 Version 9.0

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 1988-1994
Third National Health and Nutrition Examination Survey. J Adolesc Health 2002; 30:205-12.
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.

Graphic 72046 Version 3.0

Long-acting gonadotropin-releasing hormone agonists for treatment of central
(gonadotropin-dependent) precocious puberty

Trade names
GnRH agonist Dose, frequency, and method of administration
and availability

Histrelin acetate Supprelin LA (US) Subcutaneous implant. Children ≥2 years – 50 mg implant surgically
subcutaneous implant inserted every 12 months. Releases approximately 65 mcg per day
over 12 months.

Leuprolide acetate Lupron Depot-Ped (1 Intramuscular depot injection, given every 28 days.
(leuprorelin) month) (US) Available strengths:
Lupron Depot CPP 3.75, 7.5, 11.25, or 15 mg
(CAN) Starting doses vary among countries:
Lucrin (EU, AU, SA, US – 7.5 to 15 mg
elsewhere) Europe and Asia – 3.75 mg
Weight-based dosing is no longer recommended.

Lupron Depot-Ped (3 Intramuscular depot injection, given every 3 months.

month) Available strengths:
Lucrin Depot 11.25 or 30 mg
Paediatric (3 month) Criteria for selection of the 11.25 mg versus 30 mg dose have not been
(AU) established.

Fensolvi (6 month) Subcutaneous injection, to be administered by a health professional,

(US) given every 6 months. Approved by the US FDA for children ≥2 years
with central precocious puberty.
Available strength:
45 mg

Triptorelin pamoate Gonapeptyl (UK, EU, Intramuscular depot injections.

SA, elsewhere) Available strengths:
Decapeptyl (UK, 3.75 mg every 28 days
elsewhere) 11.25 mg every 3 months
Triptodur (US) 22.5 mg every 6 months

Approval of these GnRH agonists for use in central precocious puberty, dosing, and schedules of administration vary
between products in different countries. Consult local product information. Short-acting GnRH preparations requiring
daily subcutaneous injections or multiple daily dosing nasal spray (such as nafarelin) are not recommended, due to
compliance difficulty; use of these products usually is limited to patients with sterile abscesses from depot injections.
Note that the doses used to treat central precocious puberty in children are substantially higher than those used in adults
for other indications, such as prostate cancer and endometriosis.

GnRH: gonadotropin-releasing hormone; US: United States; CAN: Canada; EU: European Union; AU: Australia; SA: South
America; UK: United Kingdom; FDA: Food and Drug Administration.

Graphic 72979 Version 16.0

Treatment of children with precocious puberty

Schematic depiction of the pathways leading to precious puberty and the mechanisms of action for several drugs used for
treatment. Central precocious puberty is also known as gonadotropin-dependent precocious puberty. For peripheral precocity
(also known as gonadotropin-independent precocious puberty), the pathway for boys is shown on the left, and girls on the
right.

GnRH: gonadotropin-releasing hormone; GnRHa: gonadotropin-releasing hormone analogue (eg, leuprolide, histrelin); LH: luteinizing
hormone; FSH: follicle-stimulating hormone; AR: androgen receptor; ER: estrogen receptor.
* Preliminary data have been reported; treatment is still experimental.

References:
1. Reiter EO, Mauras N, McCormick K, et al. Bicalutamide plus anastrozole for the treatment of gonadotropin-independent
precocious puberty in boys with testotoxicosis: a phase II, open-label pilot study (BATT). J Pediatr Endocrinol Metab 2010;
23:999.
2. Lenz AM, Shulman D, Eugster EA, et al. Bicalutamide and third-generation aromatase inhibitors in testotoxicosis. Pediatrics
2012; 126:e728.
3. Leschek EW, Jones J, Barnes KM, et al. Six-year results of spironolactone and testolactone treatment of familial male-limited
precocious puberty with addition of deslorelin after central puberty onset. J Clin Endocrinol Metab 1999; 84:175.
4. Leschek EW, Flor AC, Bryant JC, et al. Effect of antiandrogen, aromatase inhibitor, and gonadotropin-releasing hormone
analog on adult height in familial male precocious puberty. J Pediatr 2017; 190:229.
5. Feuillan PP, Jones J, Cutler GB, et al. Letrozole treatment of precocious puberty in girls with the McCune Albright syndrome:
A pilot study. J Clin Endocrinol Metab 2007; 92:2100.
6. Feuillan PP, Jones J, Cutler GB Jr. Long-term testolactone therapy for precocious puberty in girls with the McCune-Albright
syndrome. J Clin Endocrinol Metab 1993; 77:647.
7. Eugster EA, Rubin SD, Reiter EO, et al. Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a
multicenter trial. J Pediatr 2003; 143:60.
8. Sims EK, Garnett S, Guzman F, et al. Fulvestrant treatment of precocious puberty in girls with McCune-Albright syndrome. Int
J Pediatr Endocrinol 2012; 2012:26.
Fuqua JS. Treatment and outcomes of precocious puberty: An update. J Clin Endocrinol Metab 2013; 98:2198.
Graphic 62460 Version 7.0
Contributor Disclosures
Jennifer Harrington, MBBS, PhD Nothing to disclose Mark R Palmert, MD, PhD Nothing to
disclose Peter J Snyder, MD Grant/Research/Clinical Trial Support: AbbVie [Hypogonadism];
Novartis [Cushing's]. Consultant/Advisory Boards: AbbVie [Hypogonadism]; Novartis [Cushing's];
Pfizer [Acromegaly]. William F Crowley, Jr, MD Equity Ownership/Stock Options: Dare Bioscience
[Endocrinology]. Consultant/Advisory Boards: Dare Bioscience [Endocrinology]. Mitchell E Geffner,
MD Grant/Research/Clinical Trial Support: Novo Nordisk [Growth]. Consultant/Advisory Boards:
Adrenas and Neurocrine Biosciences [CAH]; Daiichi-Sankyo [Type 2 diabetes]; Ferring, Novo
Nordisk, Nutritional Growth Solutions, Nutritional Growth Solutions, Pfizer, and QED [Growth]; Gilead
[Growth/HIV]. Other Financial Interest: McGraw-Hill [Pediatric endocrinology textbook royalties];
Ascendis data safety monitoring board [Growth]; Tolmar data safety monitoring board [Precocious
puberty]; Millendo data safety monitoring board [Prader-Willi syndrome]. Alison G Hoppin,
MD Nothing to disclose Kathryn A Martin, 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 multi-level 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.

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