Article endocrine

Precocious Puberty
Andrew Muir, MD*
Objectives After completing this article, readers should be able to:

1. Know the normal ages of pubertal onset in boys and girls.

Author Disclosure 2. Discuss the clinical signs of puberty, their usual sequence of appearance, and their
Dr Muir did not typical rate of progression.
disclose any financial 3. Use the physiology of puberty to diagnose the cause of abnormal puberty.
relationships relevant 4. Describe the factors involved in the appropriate management of precocious puberty.
to this article. 5. Determine whether to follow or refer children who have signs of early puberty.

Introduction
Although precocious puberty has standard clinical definitions and diagnostic tests are
improving, the management of children who have signs of early puberty has become more
complex in some ways during the last decade than ever before. This review illustrates how
an understanding of the anatomy and physiology of puberty forms the foundation for
managing children who experience puberty early.

Case History
A 4-year-old female has developed pubic hair in the past 3 months and has had an adult body
odor for 6 months. She is otherwise healthy and has no pertinent findings on medical and
surgical history. Her height and weight are just above the 97th percentile for age, and her
physical examination reveals Sexual Maturity Rating (SMR) 2 breast and pubic hair
development.

Definitions
By convention, normal puberty begins between ages 8 and 12 years in girls and between
9 and 14 years in boys. The lower ages of normal pubertal onset recently have been
challenged, but a consensus to accept puberty among younger children as being normal
without diagnostic evaluation has not been reached. Criteria for defining the five stages of
puberty in boys and girls, proposed by Marshall and Tanner in 1969 and 1970, remain the
standard (Fig. 1).
Thelarche (the៮ -lar’ke៮ ), the onset of female breast development, is characterized by
tender nodules of firm tissue centered on the areolae, which usually are appreciable by
palpation before they are by visual inspection. In overweight girls, palpation is essential to
distinguish sex steroid-dependent breast (firm, nodular, and possibly tender) from adipose
tissue (soft, homogeneous, and nontender). Adrenarche (ad‘ren-ar’ke៮ ) is the onset of
androgen-dependent signs of puberty (pubic hair, acne, and adult body odor). In females,
adrenarche is the result of adrenocortical activity. In males, either adrenal or gonadal
maturation can prompt adrenarche. Some sources refer to adrenarche as pubarche
(pu-bar’ke៮ ). Menarche (mĕ-nar’ke៮ ) is the onset of menstruation.

Epidemiology
The estimated incidence of precocious puberty in the United States is 0.01% to 0.05% per
year. It is 4 to10 times more frequent in females than in males and more common among
African-American than among Caucasian children. A century-long secular trend reduced
the age of menarche by about 0.3 years per decade until the 1960s. At that point, the rate
of decline in developed countries slowed or even stopped. In the United States, the mean

*Professor, Department of Pediatrics, Medical College of Georgia, Augusta, Ga.

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endocrine precocious puberty

Figure 1. Stages of normal puberty described by Marshall and Tanner. A. The normal progression of male puberty. Sexual Maturity
Rating (SMR) 1 (not shown) is prepubertal, with testicular volumes less than 4 mL, a thick and rugated scrotum, and an immature
penis. By SMR 2, coarse, sex steroid-dependent hair has appeared on the pubis, but it is sparse and does not typically meet in the
midline. The penis remains immature, but scrotal thinning and testicular enlargement have begun. SMR 3 is characterized by pubic
hair meeting at the midline and the start of penis growth, predominantly in length. At SMR 4, the pubic hair growth is dense and
continuous, but has not reached a full adult pattern. The penis has enlarged in both length and circumference. SMR 5 is that of full
adult development. B. Normal pubic hair development of the female. The descriptions are similar to those for male pubic hair growth.
C. Normal progression of breast development. Stage 1 is the normal prepubertal state. Tender “buds” are felt and seen at stage 2,
and stage 3 is characterized by further development of breast tissue well beyond the areolar diameter and incomplete nipple
development. Stage 4 is easily recognized by secondary elevation of the areola above the contour of the breast, and by stage 5, this
areoloar elevation recedes to the plane of the surrounding breast.

age of menarche in Caucasians is near 12.7 years and in among some 17,000 healthy American children were
African-Americans is about 12.2 years (Table 1). The age 10.0 and 8.9 years for Caucasians and African-
of adrenarche in females is also race-dependent. The Americans, respectively. These ages were about 6 to 12
mean age of adrenarche in African-American girls is months lower than those reported a decade earlier. More
approximately 8.8 years compared with about 10.5 years surprisingly, a significant number of girls had thelarche
in Caucasian girls. In a 1997 report, the ages of thelarche during or before their seventh year. Some of these cases

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 endocrine precocious puberty

Table 1. Pubertal Milestones twins. As expected, the correla-

tion in dizygotic twins was equal
Mean Age of Pubertal Milestone (y) to that seen in singleton siblings.
Start of Testicular Currently, candidate puberty con-
Adrenarche Menarche Growth Spurt Volume >3 mL trol genes include steroid hor-
mone receptors, biosynthetic and
Female
African-American 8.8 12.2 — — catabolic enzymes, and transcrip-
Caucasian 10.5 12.7 9.8 — tion factors.
Male 12.0 — 11.5 11.5
Pathogenesis
Much as neurologists are chal-
of early thelarche may reflect inaccurate reporting be- lenged to locate the anatomic site of a lesion, clinicians
cause assessments were made by observation rather than assessing children who have precocious puberty must
by palpation. Nonetheless, the age of thelarche in Amer- identify the source of pubertal signals (Fig. 2 and Table
ican children appears to be declining, whereas the age of 2). Lesions may involve neural signals, hormones, recep-
menarche is remaining stable. Typically, menarche oc- tors, and postreceptor signals. Abnormal levels of sex
curs about 2 years after thelarche, with longer intervals in steroids can be derived from endogenous (adrenal or
girls who have early breast development and shorter gonadal) or exogenous sources. If the source is gonadal,
intervals in girls whose breast development is later. the dependence of sex steroid production on gonado-
Male puberty is more difficult to assess in research tropin activity must be determined. Gonadotropin-
settings than is female puberty. Using increased testicular dependent puberty arises from either central dysregu-
size to mark pubertal onset, most studies report a mean lation, causing overproduction of luteinizing hormone
age of pubertal onset near 11.5 years in males (Table 1). (LH) and follicle-stimulating hormone (FSH), or ec-
Adrenarche typically is seen around the 12th birthday in topic hormone production, usually a neoplasm pro-
boys, with African-Americans having a slightly lower ducing human chorionic gonadotropin (hCG).
mean age of onset compared with Caucasians. Males take
an average of 4 years to progress through puberty. Control of Normal Pubertal Onset
Genetic and environmental factors influence the onset Because central dysregulation is the most frequent cause
of puberty. Improved nutrition is considered the primary of precocious puberty, it is useful to review the physiol-
reason for the secular decline in pubertal age. Further- ogy of puberty. Hypothalamic neurons produce
more, childhood obesity has been associated in longitu- gonadotropin-releasing hormone (GnRH), a decapep-
dinal studies with early puberty in girls. However, there tide that travels through a portal venous system to the
are other important determinants of puberty. Precocious anterior pituitary gland, where it induces pulsatile release
puberty was noted among children who had been
adopted recently from a developing to a developed
county. This was seen more frequently among girls than
boys and could not be explained entirely by changes in
nutrition, body weight, or body fat. Birth date uncer-
tainty accounts for a portion of the children believed to
have early pubertal development. Other environmental
determinants, however, may include stress, climate and
light cycles, and chemical exposures.
Environmental determinants of puberty are important
because such exposures can be changed when necessary.
It appears likely, however, that among healthy children in
developed countries, genetic influences on puberty
outweigh the environmental influences by a factor of Figure 2. Causes of precocious puberty. This approach to
about three. Genetic determinants of pubertal onset identifying a cause of precocious puberty works by determin-
were demonstrated in traditional twin studies in which ing the source of the sex steroids that are inducing pubertal
the correlation coefficient between age of pubertal features. CAHⴝcongenital adrenal hyperplasia, LHⴝluteinizing
onset in monozygotic twins exceeded that in dizygotic hormone

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endocrine precocious puberty

Differential Diagnosis of Precocious

Table 2. by 20 weeks’ gestation and remains
active throughout much of the re-
Puberty maining gestation. A brief spurt of
central pubertal axis activity on the
Category Diagnosis
first day after birth is followed by a
Central Idiopathic—most frequent cause period of quiescence. During the
(Gonadotropin-dependent) Adoption from underdeveloped to developed first postnatal month, GnRH pulses
region
Tumor—eg, astrocytoma, glioma, germinoma recur spontaneously. In males, this
Congenital anomaly—eg, hydrocephalus, infantile central activity reduces to
hamartoma near prepubertal levels by about
Infection/postinfection—encephalitis, 3 to 6 months of age. Gonadotro-
meningitis pin secretion, particularly of FSH,
Radiation—usually >18 cGy
Trauma—neurosurgical, nonsurgical may persist in females until 18
Ischemia months of age. During the subse-
Gonadal Steroid-dependent McCune-Albright syndrome—females quent prepubertal period, gonado-
(Gonadotropin-independent) predominate tropin secretion is minimal and
Familial male-limited precocious puberty cannot be stimulated by a single
Gonadal neoplasia (benign, malignant)
Ovarian follicular cyst intravenous GnRH infusion. As pu-
Leydig cell nodular hyperplasia berty begins, gonadotropins are re-
Aromatase excess leased from the pituitary gland in a
Human chorionic gonadotropin-secreting pulsatile fashion, particularly at night.
tumor With increased gonadotropin release
Primary hypothyroidism
Exogenous steroids (oral contraceptive pills, comes the ability of exogenous
skin creams, testosterone) GnRH to stimulate release of FSH
Adrenal Steroid-dependent Congenital adrenal hyperplasia and later both LH and FSH.
(Gonadotropin-independent) —21 hydroxylase deficiency Normal onset of puberty is de-
—11 hydroxylase deficiency termined by multiple incompletely
11 hydroxysteroid dehydrogenase
deficiency understood intracerebral processes.
Glucocorticoid resistance In a simplified model, gamma-
Adrenal tumor (benign, malignant) aminobutyric acid (GABA) is the
Adrenal rest tumors major inhibitory neurotransmitter
Exogenous steroids (eg, dehydroepian- that inhibits GnRH secretion. In
drosterone)
Incomplete Precocious Puberty Premature thelarche contrast, glutamatergic neurotrans-
(Gonadotropin-independent) Premature adrenarche mission stimulates GnRH produc-
Premature menarche—look for gynecologic tion. Changes in the balance of
cause these signals trigger puberty. It is
not yet known whether GABA-
mediated neurotransmission is re-
duced at pubertal onset, allowing
of two gonadotropins: LH and FSH. These related het- increased glutamatergic signals, or vice versa. The results
erodimeric glycoproteins share a common alpha chain, of recent investigations of the ligand-receptor pair of
but have unique beta chains. After transport to the Kisspeptin-1 and GPR54 need to be incorporated into
gonads, gonadotropins bind membrane receptors that the neurochemical model of puberty. Kisspeptin-1, re-
are coupled to G-protein complexes within target cells. leased by forebrain neurons, becomes an efficient activa-
In females, LH enhances thecal cell production of andro- tor of GPR54 on GnRH-secreting neurons at the time of
gens and granulosa cell production of progesterone. puberty, and this activation is associated with GnRH
FSH stimulates granulosa cell production of estrogen. In release. Much, however, remains to be learned. For
males, LH stimulation of Leydig cells causes testosterone example, GnRH production is influenced by neuropep-
production, and FSH stimulation of Sertoli cells is vital tides, such as neuropeptide Y and norepinephrine. Fur-
for germ cell development. thermore, neurocommunications exist between astro-
The hypothalamic-pituitary-gonadal axis is functional glial cells and GnRH-producing neurons.

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 endocrine precocious puberty

duction of adrenocortical androgens (Fig. 4) and cause

premature adrenarche and rapid skeletal growth in males
and females. Clitoromegaly can occur in girls, but normal
phallus size is seen in males. Central precocious puberty
also can arise in children who have CAH if their bone age
advances to the age of normal pubertal onset.
Prolonged hypothyroidism is a curious cause of pre-
cocious puberty that may result from gonadotropin-like
action of thyroid-stimulating hormone (TSH) or activa-
tion of gonadotropin receptors by TSH. TSH is another
heterodimeric glycoprotein that shares the alpha chain of
gonadotropins. Hyperprolactinemia, induced in hypothy-
roidism by high concentrations of thyrotropin-releasing
hormone, may sensitize the ovary to gonadotropins.
A number of genetic lesions in hormone synthetic
enzymes, receptors, and postreceptor signals cause ab-
normal sex steroid production. Excess aromatase activity,
converting androgens to estrogens, has been reported to
Figure 3. Hamartoma of the tuber cinereum. Median section cause premature thelarche in girls and gynecomastia in
shows the large mass (A) lying posterior to the pituitary gland boys. Mutations of the LH receptor can result in unbri-
(B). dled Leydig cell activity and the syndrome of familial
male-limited precocious puberty (testotoxicosis). Con-
Applying Physiology to Precocious Puberty stitutive postreceptor signals from mutated stimulatory
Currently, no cause for central precocious puberty can be G-protein complexes cause the McCune-Albright syn-
found in two thirds or more of affected girls. An identi- drome (precocious puberty, café au lait macules, polyos-
fiable cause is much more likely to be found in males. As totic fibrous dysplasia).
detailed in Table 2, disturbances of the hypothalamus or
higher neurologic centers can result in abnormal
GnRH release. Hypothalamic hamartomas are non-
neoplastic, congenital malformations that contain
GnRH-secreting cells. The masses have a typical radio-
graphic appearance and are nonprogressive (Fig. 3). Au-
tonomous production of gonadotropins by a pituitary
adenoma is a very rare cause of premature puberty.
Gonad stimulation by hCG produced in tumors (usually
in brain, liver, mediastinum) can appear clinically similar
to true central disease, but is not associated with eleva-
tions of LH and FSH. Cross-reactive binding of hCG,
however, occurs in some commercial LH assays.
Gonadotropin-independent sexual precocity can arise Figure 4. Simplified scheme of adrenal and gonadal steroid
from a variety of anatomic or functional lesions that are production. Specific enzyme actions are highlighted. In the
discussed only briefly here. Benign or malignant tumors rate-limiting step of steroid biosynthesis, ACTH drives the
of the adrenal cortex or gonad can produce sex steroids production of pregnenolone in response to lowering con-
autonomously. Follicular ovarian cysts may cause tran- centrations of cortisol. Deficiency of 21-hydroxylase (21-
OHase) causes congenital adrenal hyperplasia and is diag-
sient or persistent signs of puberty. Usually, estrogen-
nosed by the presence of high serum concentrations of
dependent effects, such as breast development, matura-
17-hydroxyprogesterone. Gonadal sex steroid production
tion of the vaginal mucosal, or vaginal bleeding, (boxed) is distinguished from adrenal sex steroid production
predominate. by the activity of 17 beta-hydroxysteroid dehydrogenase (17
Biosynthetic defects of glucocorticoids causing con- beta-HSD). Aromatase (arom) is more active in ovaries than in
genital adrenal hyperplasia (CAH) and glucocorticoid testes. It also is active in adipose tissue, often contributing to
resistance are conditions that raise ACTH-induced pro- gynecomastia in adolescent males.

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 endocrine precocious puberty

Sources of exogenous sex steroids can include oral Physical Examination

contraceptives, skin creams, meat from hormone-treated The linear growth spurt is a feature of early puberty in
animals, plant phytoestrogens, and anabolic steroids. females. Maturation of the vaginal mucosa is a sensitive
Unless a hormone preparation contains both androgens indicator of estrogen activity that may appear before
and estrogens, exogenous steroid exposure usually causes breast tissue can be appreciated. Clitoromegaly, a sign of
a picture of incomplete puberty. abnormally high androgen levels, is never part of normal
Other syndromes of incomplete puberty include be- female puberty. The first signs of male puberty are thin-
nign premature thelarche and adrenarche. In the former ning of the scrotum and enlargement of the testes be-
condition, unilateral or bilateral breast development is yond 3 mL. The Prader orchidometer is used to deter-
observed with minimal or no other clinically apparent mine testicular volume, although testicle length
estrogen effects. About 60% of cases are identified be- standards also are available. Growth of the phallus and
tween 6 to 24 months of age, and diagnosis after 4 years pubic hair follow. The skeletal growth spurt usually peaks
is unusual. Normal, rather than accelerated, growth ve- at SMR 4 in males. Dental development provides the
locity and minimal progression of breast development examiner a simple method of approximating bone age in
distinguish this condition from those that require treat- both females and males.
ment. Importantly, about 10% of girls who have typical Much can be learned from the testicular examinaton
benign idiopathic thelarche eventually develop true cen- of boys who have early puberty. Testicle volumes greater
tral precocious puberty and require treatment. Children than 3 mL bilaterally usually indicate gonadotropin ac-
who have premature adrenarche have isolated signs of tion. Lesions causing premature testicular enlargement,
adrenal sex steroid production (pubic hair, acne, body however, are not always neurologic. Owing to the selec-
tive stimulation of Leydig cells by hCG,
testes that have been exposed to tumor-

About 60% of cases of premature

thelarche are identified between 6 and 24
derived hCG exceed the size of prepu-
bertal gonads, but are smaller than those
seen in children who have true central
precocity. Familial male-limited preco-
months of age. . . . cious puberty causes bilateral testicular
enlargement and usually is suspected
because of the young age of onset and a
family history of sexual precocity in
odor) that progress slowly and are associated with normal males. Testicular tumors typically are unilateral, although
growth velocity and a height commensurate with their bilateral adrenal rest in boys who have poorly controlled
skeletal maturation (bone age). Children who experience CAH is a cause of bilateral testicular enlargement. Testes
intrauterine growth restriction are at risk for this condi- of prepubertal size in a boy who has isosexual precocious
tion. Although treatment of idiopathic premature adre- puberty usually indicates that androgen is arising from
narche is not recommended in children, some 20% of either the adrenal gland or an exogenous source.
affected girls develop clinically significant ovarian hy-
perandrogenism as adults. Laboratory Evaluation
The diagnostic laboratory evaluation of children who
Clinical Evaluation experience early puberty should confirm the source of
History hormone. The normal ranges of pubertal hormones vary
The medical history should define which features of with the stage of pubertal development. When interpret-
puberty are present, their duration, and the rate of pro- ing hormone results, it is important, therefore, to deter-
gression. Questioning should seek abnormalities of other mine whether a result is consistent with the stage of
anterior and posterior pituitary gland function, neurologic pubertal development, rather than with the child’s chro-
(especially visual) dysfunction, or intracranial mass effects. nologic age. For a child whose hepatic function is normal,
Pelvic pain may indicate ovarian pathology, and symptoms the serum dehydroepiandrosterone sulfate (DHEA-S) con-
of systemic illness may indicate the presence of a tumor. centration provides an estimate of adrenocortical sex steroid
Virilizing adrenocortical tumors may be accompanied by production. Values elevated beyond that expected for pu-
Cushing syndrome. A family history of premature puberty bertal stage suggest adrenal pathology (eg, CAH, adrenal
may suggest the presence of a genetic condition. tumor). Biosynthetic defects of adrenocortical steroids are

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 endocrine precocious puberty

identified best by high concentrations of the substrate for gressive central lesion, such as a hamartoma, usually is
the enzyme that is deficient. For example, 21-hydroxylase treated medically. Many children who have central pre-
deficiency is diagnosed by determining the serum 17- cocious puberty require treatment solely to delay addi-
hydroxyprogesterone concentration (Fig. 4). Random tional maturation. Clinical features suggesting that med-
measures of testosterone or estradiol are helpful for de- ical intervention to arrest central precocious puberty will
tecting gonadal steroid production. Advanced bone age, benefit the patient are male sex, age younger than 6 years,
especially if it has progressed beyond the height age, skeletal age advancing more rapidly than height age, and
serves as a nonspecific biomarker of abnormal sex steroid psychosocial disturbances (eg, menses will be arrested).
production. Among children who have idiopathic central GnRH agonist (eg, leuprolide) therapy is the most effec-
precocious puberty, bone age helps determine whether tive medical therapy available for central precocious pu-
treatment to stop additional development will be of berty. Tonic stimulation of the pituitary gland results in a
value. short period of pubertal stimulation, followed by down-
Because normal pituitary gland secretion of gonado- regulation of GnRH receptors and reduced gonadotro-
tropins is pulsatile, randomly obtained serum samples do pin synthesis. Although antagonists to GnRH (eg, cetro-
not reliably contain enough LH and FSH to permit relix, ganirelix) are not yet approved for use in precocious
traditional assays to diagnose the onset of puberty. Al- puberty, they promise to suppress puberty without the
though today’s most sensitive gonadotropin assays may initial gonadotropin stimulation seen with current
be able to distinguish between basal gonadotropin levels agents.
of prepubertal and pubertal children, most commercial The management of autonomous gonadal steroid se-
gonadotropin assays do not. Therefore, definitive dem- cretion in McCune-Albright syndrome and familial male-
onstration of an activated central
axis driving early puberty usually

The
requires stimulation testing with
exogenous GnRH. A single injec-
tion of GnRH will not increase
the serum gonadotropin concen-
demonstration of central precocious
trations in children who have a puberty should prompt a magnetic resonance
quiescent central pubertal axis (ie,
prepubertal or precocious puberty
study of the brain. . . .
from noncentral dysfunction).
Once the hypothalamic-pituitary
axis has become active, however, the injection causes a limited precocious puberty can be difficult. Medications
rise of FSH in early puberty, and increased LH release is to block: a) steroid production (eg, ketoconazole), b)
the most specific indicator of central puberty. The dem- 5-alpha reductase activity (eg, finasteride), c) steroid
onstration of central precocious puberty by GnRH test- receptors (eg, flutamide, spironolactone), and d) aro-
ing should prompt a magnetic resonance study of the matase activity (eg, testolactone, anastrozole) have been
brain with high-resolution imaging of the hypothalamus suggested, but formal trials are limited.
and pituitary gland. Children who have severe brain dysfunction and cen-
tral precocious puberty present special ethical concerns.
Management GnRH therapy may reduce behavioral problems and
Although general pediatricians may follow children who provide effective contraception. Therefore, it may be
have premature adrenarche or thelarche, initial evalua- tempting to offer this treatment to children who have
tion and management of precocious puberty often re- limited cognitive abilities and multiple special care needs.
quires subspecialty consultation. When a primary cause Reduced bone mineral density, eunuchoid growth, and
of precocious puberty can be identified, treatment of that ethical considerations arising from “chemical castra-
condition is paramount. Judgment is required to deter- tion,” however, are important disadvantages that must
mine whether central precocious puberty requires inter- be considered.
vention. Whereas some intracerebral tumors that cause Adrenocortical steroid production of androgens can
early puberty may require surgery for complete resection be controlled with glucocorticoid replacement in pa-
or preservation of normal cerebral function, other tu- tients who have CAH. This treatment, however, may be
mors (eg, germinoma) may be radiosensitive. A nonpro- ill advised for children who have late-onset forms of

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endocrine precocious puberty

21-hydroxylase deficiency and who are able to mount a observation or should be referred to a subspecialist for
normal glucocorticoid response to stress and predicted evaluation and treatment.
to have a normal final height. The risk of iatrogenic
adrenocortical suppression may outweigh any benefits
that treated children may accrue from chronic glucocor-
Suggested Reading
ticoid therapy.
Chalumeau M, Charalambos G, Hadjiathanasiou MD, et al. Select-
ing girls with precocious puberty for brain imaging: validation of
Prognosis European evidence-based diagnosis rule. J Pediatr. 2003;143:
The cause of precocious puberty determines the progno- 445– 450
sis. In most cases, central precocious puberty is arrested Denburg MR, Silfen ME, Manibo AM, et al. Insulin sensitivity and the
by adequate treatment with GnRH agonists. Menses insulin-like growth factor system in prepubertal boys with prema-
ture adrenarche. J Clin Endocrionol Metab. 2002;87:5704 –5709
stop, although a single period may occur 2 weeks after
Dungan HM, Clifton DK, Steiner RA. Kisspeptin neurons as cen-
therapy has been started. Breast, pubic hair, testicular, tral processors in the regulation of gonadotropin-releasing hor-
and phallus growth stop and often regress. Skeletal mone secretion. Endocrinology. 2006;147:1154 –1158
growth and maturation slow to age-appropriate rates. Kaplowitz PB, Oberfield SE. Reexamination of the age limit for
Serum testosterone or estradiol concentrations fall to defining when puberty is precocious in girls in the United States:
prepubertal levels, and GnRH infusions induce insignif- implications for evaluation and treatment. Drug and Therapeu-
tics and Executive Committees of the Lawson Wilkins Pediatric
icant changes in serum LH or FSH concentrations. Apart Endocrine Society. Pediatrics. 1999;104:936 –941
from the immediate benefits of GnRH agonist therapy, Klein KO, Barnes KM, Jones JV, et al. Increased final height in
final height in children who have central precocious precocious puberty after long-term treatment with LHRH ago-
puberty may increase by 8 to 12 cm compared with the nists: the National Institutes of Health experience. J Clin Endo-
crinol Metab. 2001;86:4711– 4716
heights of children diagnosed as having the same condi-
Marshall WA, Tanner JM. Variations in pattern of pubertal changes
tion before therapy was available. Earlier treatment is in girls. Arch Dis Child. 1969;44:291–303
associated with improved final height. The combined use Marshall WA, Tanner JM. Variations in pattern of pubertal changes
of growth hormone and GnRH agonists is controversial, in boys. Arch Dis Child. 1970;45:13–23
but may allow more growth in children who are particu- Midyett LK, Moore WV, Jacobson JD. Are pubertal changes in girls
before age 8 benign? Pediatrics. 2003;111:47–51
larly short. Once treatment has been stopped, puberty
Parent A-S, Teilmann G, Juul A, et al. The timing of normal puberty
usually resumes and progresses at a normal rate. and the age limits of sexual precocity: variations around the
world, secular trends, and changes after migration. Endocrine
Summary Rev. 2003;24:668 – 693
General pediatricians must be able to distinguish chil- Pucarelli I, Segni M, Ortore M, et al. Effects of combined
dren who are growing normally from those who are not. gonadotropin-releasing hormone agonist and growth hormone
therapy on adult height in precocious puberty: a further contri-
An understanding of the regulation and effects of sex bution. J Pediatr Endocrinol Metab. 2003;16:1005–1010
steroid production allows clinicians to determine Terasawa EI, Fernandez DL. Neurobiological mechanisms of the
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 endocrine precocious puberty

PIR Quiz
Quiz also available online at www.pedsinreview.org.

6. An 8-year-old African-American girl has recently developed pubic hair and adult body odor. She also has
scattered comedones and papules on her cheeks and forehead. On examination, her sexual maturity rating
(SMR) for pubic hair is 3. SMR for breast tissue is 1. Her linear growth velocity continues along the
percentile established by age 2 years. The most appropriate conclusion is that she:
A. Has been exposed to a large dose of exogenous estrogen.
B. Is experiencing normal adrenarche.
C. Requires immediate evaluation for a masculinizing tumor.
D. Will have elevated concentrations of thyroid-stimulating hormone (TSH).
E. Will have pubertal concentrations of follicle-stimulating hormone (FSH).

7. A 2-year-old Caucasian girl has had stable SMR stage 3 breast development for the past 9 months. Her
linear growth velocity has remained at the 75th percentile since age 1 year. The remainder of her
examination findings are normal. The most appropriate conclusion is that she:
A. Has a reduced risk for developing central precocious puberty compared with other girls of the same
age who have no breast development.
B. Has been exposed to a large dose of exogenous estrogen.
C. Is experiencing benign premature thelarche.
D. Must be evaluated for precocious puberty now.
E. Needs suppressive doses of gonadotropin-releasing hormone (GnRH) to prevent short stature.

8. An 8-year-old boy has recently experienced accelerated statural growth, impressive muscular development,
and enlargement of his phallus. His testicles are symmetric, each having a volume of 3 mL. The most
appropriate conclusion is that he:
A. Is undergoing normal puberty.
B. Likely has a human chorionic gonadotropin-producing tumor.
C. Likely has a very elevated concentration of dehydroepiandrosterone sulfate (DHEA-S).
D. Will have pubertal concentrations of serum leutinizing hormone (LH).
E. Will show an impressive increase in FSH in response to an injection of GnRH.

9. An 8-year-old boy has recently experienced accelerated statural growth, impressive muscular development,
and enlargement of his phallus. His testicles are symmetric, and each has a volume of 8 mL. An injection
of GnRH results in increased LH release. The most appropriate next step is:
A. Bone age studies of the wrist.
B. Magnetic resonance imaging of the brain and pituitary gland.
C. Serum DHEA-S measurement.
D. Serum 17-hydroxyprogesterone measurement.
E. Serum testosterone measurement.

10. An 8-year-old boy of normal intelligence has been diagnosed with idiopathic central precocious puberty.
Time-limited treatment with the GnRH agonist leuprolide most likely will:
A. Increase adult stature compared with no treatment.
B. Increase the risk of osteoporosis.
C. Produce irreversible gynecomastia.
D. Produce permanent chemical castration.
E. Selectively diminish expected adult phallus size.

Pediatrics in Review Vol.27 No.10 October 2006 381

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 Precocious Puberty
Andrew Muir
Pediatrics in Review 2006;27;373
DOI: 10.1542/pir.27-10-373

Updated Information & including high resolution figures, can be found at:
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Adolescent Health/Medicine
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 Precocious Puberty
Andrew Muir
Pediatrics in Review 2006;27;373
DOI: 10.1542/pir.27-10-373

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/27/10/373

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