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pediatric endocrinology Board Review Manual
Statement of
Editorial Purpose
The Hospital Physician Pediatric Endocrinology
Board Review Manual is a study guide for fel­
lows and practicing physicians preparing for
board examinations in pediatric endocrinolo­
gy. Each manual reviews a topic essential to the
current practice of pediatric endocrinology.
PUBLISHING STAFF
PRESIDENT, Group PUBLISHER
Bruce M. White
editorial director
Debra Dreger
Associate EDITOR
Tricia Faggioli
EDITORial assistant
Farrawh Charles
executive vice president
Barbara T. White
executive director
of operations
Jean M. Gaul
Partial and GonadotropinDependent Precocious
Puberty
Editor:
Jill D. Jacobson, MD
Professor of Pediatrics, Section of Endocrinology and Diabetes,
Children’s Mercy Hospital and Clinics, University of Missouri–Kansas
City School of Medicine, Kansas City, MO
Contributors:
Maryann N. Mugo, MD
Staff Endocrinologist, Skaggs Diabetes & Endocrinology Care, Skaggs
Community Health Center, Branson, MO
Bert E. Bachrach, MD
Assistant Professor of Pediatrics, Director, Pediatric Endocrinology and
Diabetes, University of Missouri Children’s Hospital, Columbia, MO
Jill D. Jacobson, MD
PRODUCTION Director
Suzanne S. Banish
PRODUCTION associate
Kathryn K. Johnson
ADVERTISING/PROJECT manager
Patricia Payne Castle
sales & marketing manager
Deborah D. Chavis
Table of Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Normal Puberty. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Definition and Classification of Precocious Puberty . . . . . . . 4
Approach to Evaluation of Precocious Puberty. . . . . . . . . . . . 5
NOTE FROM THE PUBLISHER:
This publication has been developed with­
out involvement of or review by the Amer­
ican Board of Pediatrics.
Endorsed by the
Association for Hospital
Medical Education
Partial Precocious Puberty. . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Gonadotropin-Dependent Precocious Puberty. . . . . . . . . . . 10
Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Cover Illustration by May S. Cheney
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Pediatric Endocrinology Volume 1, Part 3 Pediatric Endocrinology Board Review Manual
Partial and Gonadotropin-Dependent
Precocious Puberty
Maryann N. Mugo, MD, Bert E. Bachrach, MD, and Jill D. Jacobson, MD
INTRODUCTION
NORMAL PUBERTY
Puberty is a complex biologic and psychological
pro­cess marked by the appearance of secondary sex
characteristics and the onset of the ability for sexual reproduction in association with skeletal maturation and
a rapid increase in growth velocity. Puberty is a gradual
process initiated by changes in neuronal function in the
hypothalamus that trigger a cascade of neurohormonal
events ultimately leading to the characteristic physical
changes associated with sexual maturation. Although
the neurohormonal process of puberty begins earlier, it
is the appearance of body changes that is typically used
to define the onset of puberty.
Several possibilities exist to describe deranged progression of puberty. Puberty may occur too early (precocious puberty) or too late (delayed puberty), or the
tempo (time from onset to maturation) may be too slow
or too rapid. Additionally, puberty can progress along
the same prepubertal phenotypic gender (isosexual) or
may cross over to the opposite gender (heterosexual, as
in virilization in a female). The most common scenarios
seen in clinical practice involve either early (precocious)
or delayed puberty. Early puberty warrants clinical eval­
uation to rule out the presence of a tumor or other
serious underlying causes and because of the potential
association with premature closure of the growth plates,
which can lead to adult short stature. Not surprisingly,
precocious puberty is alarming to most families, given
the associated implications of premature sexual maturation and the attendant psychosocial issues.1
This manual is the first of a two-part review of precocious puberty. This part begins with an overview of
normal pubertal development and the classification of
precocious puberty. This is followed by a discussion of
the general clinical evaluation of precocious puberty and
the specific approach to the child who presents with partial forms of precocious puberty or with gonadotropindependent precocious puberty (GDPP). The review
continues in the next manual with a discussion of
gonadotropin-independent precocious puberty (GIPP).
TIMING
The timing of normal pubertal development has
come under question in recent years. In 1997, a study
from the Pediatric Research in Office Settings (PROS)
reported that puberty was occurring earlier in girls, with
thelarche (breast development) occurring as early as age
7 years in whites and age 6 years in African-Americans.2
Based on the findings in the PROS study, the Lawson
Wilkins Pediatric Endocrine Society (LWPES) initially
recommended that a pathologic cause for precocious
puberty be pursued only if breast and/or pubic hair development occurred before age 7 in white girls or age 6
in African-American girls.3 The validity of this new standard was called into question, however, partly because
evaluation of girls in the PROS study was performed
via visual inspection only, with no accompanying palpation, and because of concerns about the randomness
of the selected population. Although the PROS study
suggested that pubertal changes were occurring earlier
in girls, the vast majority of patients in the study with
early pubertal changes displayed single signs of puberty
and therefore did not meet the definition of true precocious puberty. The recommendation to lower the ages
of normal puberty was also criticized by several pediatric
endocrinologists, who felt that serious pathology would
be missed if the accepted age of puberty was lowered.4,5
Based largely on these publications, both the LWPES
and The Endocrine Society issued a press release in
2001 reversing their decision and calling for further
evaluation of all girls with early signs of puberty. Despite
the questions about earlier onset of partial forms of precocious puberty, the age of menarche (initiation of the
menstrual cycle) did not appear to have changed.
This review uses the age of puberty originally outlined
by Marshall and Tanner in 1969 and 1970 (ie, 8 years
in girls and 9 years in boys).6,7 These age guidelines are
supported by expert pediatric endocrinologists.8,9 This
conservative approach will aid the caregiver in preventing
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x, Part x Partial and Gonadotropin-Dependent Precocious Puberty
a misdiagnosis of normal puberty in a child who may have
a pathologic cause for early pubertal development.
Table 1. Stages of Female Sexual Maturation According to
Tanner and Marshall
ENDOCRINE INFLUENCES ON PUBERTY
Puberty involves activation of the hypothalamicpituitary-gonadal (HPG) axis (gonadarche) and maturation of the adrenal axis (adrenarche). The HPG axis is
highly active during the midfetal, neonatal, and early
infancy periods.10 Following this phase, there is a stage of
relative quiescence from approximately age 2 years to age
8 years when the HPG axis is under inhibitory influences
from higher central nervous system (CNS) centers. Only
very low amounts of gonadotropin-releasing hormone
(GnRH) are present in the circulation and even lower
amounts of the gonadotropins, luteinizing hormone
(LH) and follicle-stimulating hormone (FSH).
The process of puberty begins with an increase in
amplitude and frequency of the pulsatile discharge
of GnRH from the hypothalamus. GnRH stimulates
the pituitary gonadotrophs to release LH and FSH.
Nocturnal LH secretion is augmented as is the LH response to exogenous GnRH administration. Release of
LH and FSH promotes maturation of the gonads and
an increase in the synthesis and release of sex steroids
(estrogen and testosterone). Rising levels of estrogen
and testosterone, together with increased adrenal androgens, induce the physical changes of female and
male puberty. Adrenarche has been shown to be a progressive maturational event completely independent
of gonadarche and may actually begin in early childhood.11 Adrenarche occurs in both genders and is a
gradual process occurring after age 8 years in girls and
after age 9 years in boys; however, the effects of adrenal
androgens are not necessarily apparent in boys in the
presence of the overwhelming effect of testosterone.
Recently, leptin has also been implicated as a potential
inducer of puberty, especially in girls, in whom leptin levels rise dramatically during sexual maturation. The opposite is true in boys; testosterone is thought to have a role
in suppressing leptin levels during male sexual maturation.12 In both boys and girls, skeletal maturation is closely
associated with the maturation of the HPG axis.13
Stage
Breast
Pubic Hair
1
Prepubertal
None
2
Breast bud palpable
Barely visible on mons or labia
3
Obvious elevation of
breast tissue
More visible, darker, and same
sites as stage 2
4
Areola and nipple
More extensive and dark, with
separate on enlarging
extension to the suprapubic area
breast
5
Adult size and shape
PHYSICAL CHANGES
Girls
The stages of female sexual maturation according to
Tanner and Marshall are shown in Table 1.6 The initial
clinical sign of puberty in a girl usually is thelarche, occurring between the ages of 8 and 13 years; this correlates with Tanner stage 2 (breast bud palpable). During
this time, the vaginal mucosa begins to change from its
prepubertal reddish color (increased vascularity of the
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5+
Adult triangle
Extension upward in midline and
onto medial aspect of thighs
Adapted from reference 6.
vaginal epithelium) to an estrogenized gray-pink hue
(thickened vaginal epithelium). Pubarche (development of pubic hair), which is primarily controlled by the
adrenal gland and to a lesser extent by ovarian-derived
androgens, usually occurs approximately 1 year after
initiation of breast development. Thelarche and adrenarche are independent of each other. Adrenarche is
the external sign of the effect of androgens on female
sexual maturation. Adrenarche is a maturational change
in the adrenal gland that is responsible for the development of pubic hair, axillary hair, adult body odor, and
acne via the production of androgens. The appearance
of axillary hair is an even later finding, occurring about
2 years after the initiation of pubic hair. Menarche occurs at Tanner stage 4 and occurs on average 2.2 years
after initiation of breast development.
Variations of normal in females can include unilateral breast development, with an up to 2-year difference in
the timing of the development of one breast versus the
other. Breast size is not concordant; size variance from
one breast to the other is a common, normal finding.
Isolated premature menarche (before age 10 years) is
rare and usually associated with true precocious puberty.
Vaginal bleeding in the absence of pubertal development requires evaluation to exclude other pathologic
causes such as sexual abuse, foreign body, infection,
sarcoma botryoides (smooth muscle tumor of the vagina), or granulosa cell tumor of the ovary. Occasionally,
patients with McCune-Albright syndrome can exhibit
vaginal bleeding without other signs of puberty.
Boys
The stages of male sexual maturation according to
Tanner and Marshall are shown in Table 2.7 The first
sign of puberty in boys is testicular enlargement, which
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Partial and Gonadotropin-Dependent Precocious Puberty
Table 2. Stages of Male Sexual Maturation According to
Tanner and Marshall
evaluation of sexual precocity is whether there is a
single sign of puberty or more than one sign.
Stage
Male Genitalia
Pubic Hair
1
Prepubertal penis
None
2
Beginning of enlargement, Barely visible at base of penis
more in length than
or on scrotum
in breadth, and scrotal
skin thickens
3
Further enlargement and More visible, darker and same
early separation of con­
sites as stage 2
tour of glans from shaft
4
Near adult shape, not
fully grown, and scrotal
skin is dark and thick
More extensive and dark,
extending to suprapubic
region
5
Adult penis
Adult triangle with extension
onto medial aspect of thighs
PARTIAL PRECOCIOUS PUBERTY
Isolated Premature Thelarche
Isolated premature thelarche is breast development
in the absence of pubic hair development and a growth
spurt. Isolated premature thelarche is especially common
and unlikely to be associated with pathology between
6 months and 3 years of age. During that age range, isolated premature thelarche is a common normal variant
that may develop as the hypothalamic-pituitary-ovarian
axis winds down to become quiescent. Premature thelarche differs from neonatal breast hyperplasia, which occurs at birth as a result of maternal estrogen exposure, is
transient, and occurs in both boys and girls. The various
etiologies for premature thelarche include heightened
sensitivity to small amounts of estrogen, small functioning ovarian cysts, and enhanced FSH production.
Estrogen is now known to be responsible for advancement of skeletal age and subsequent fusion of
the growth plates.14 As premature thelarche is a sign
of estrogen exposure, girls with isolated premature
thelarche are at a greater risk for advanced bone age
and for adult short stature compared with girls with
isolated premature pubic hair. Further, approximately
14% to 18% of girls with isolated premature thelarche
will develop true precocious puberty.
5+
Extension upward and in mid­
line
Adapted from reference 7.
normally occurs between the ages of 9 and 14.3 years.
Thinning of the scrotal skin can usually be appreciated
around the same time as testicular enlargement. Pubertal testes are greater than 3 mL in volume or 2.5 cm in
length. A color-coded orchiometer is useful in estimating testicular size during puberty. Testosterone released
from the rapidly enlarging testes results in increased
length and breadth of the phallus, with progressive
changes in the scrotal skin and size of the scrotum.
The staging of pubic hair development does not
necessarily correlate with the staging of the phallus
or testes, as pubarche in males can be secondary to
gonad­arche or adrenarche (ie, activation of androgen secretion from the testes or adrenal glands, respectively). However, the most useful clinical staging
involves documenting the size of the testes. Of critical
importance on physical examination is that the testes
are usually 10 mL to 15 mL in size when the pubertal
growth spurt begins.
DEFINITION AND CLASSIFICATION OF
PRECOCIOUS PUBERTY
The appearance of any pubertal changes at an age
more than 2.5 standard deviations below established
normal standards can be considered precocious. Most
children with early pubertal changes, however, will
dis­play partial forms of puberty. These are considered
normal variants. One of the key determinants in the
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Isolated Premature Pubarche
The activation of the adrenal gland (adrenarche)
results in mild signs of hyperandrogenism (eg, acne,
body odor) and precedes the development of pubic
hair. Although premature adrenarche and premature
pubarche are sometimes used interchangeably, adrenarche refers to the signs of adrenal androgens and
pubarche refers specifically to the development of pubic
hair. The occurrence of pubic hair prior to age 8 years
in girls and 9 years in boys warrants further evaluation.
TRUE PRECOCIOUS PUBERTY
True precocious puberty is defined as breast development accompanied by pubic hair development prior to
age 8 years in girls and as testicular enlargement and
pubic hair development prior to age 9 years in boys.
True precocious puberty is associated with a growth
spurt. Precocious puberty can be classified according to
whether or not it is driven by endogenous gonadotropins. Differentiating between these two main forms is
important, as the etiologies and treatments are quite different. In females, 95% of cases of precocious puberty
are idiopathic and GnRH dependent, whereas in males,
Pediatric Endocrinology Volume 1, Part 3 Partial and Gonadotropin-Dependent Precocious Puberty
cases are more likely to involve an underlying pathologic cause. Thus, males warrant an extensive evaluation
when determined to have precocious puberty.
Table 3. Causes of Gonadotropin-Dependent Precocious
Puberty
Gonadotropin-Dependent Precocious Puberty
GDPP, also referred to as true or central precocious
puberty, refers to the premature activation of the HPG
axis and pulsatile release of GnRH by the hypothalamus secondary to a variety of stimuli. In GDPP, there is
physiologically normal activation of the HPG axis, but
it occurs at an earlier age.
There are many causes of GDPP, most of which
are associated with CNS abnormalities (Table 3). CNS
causes appear to interfere with the normal controls on
GnRH release, by directly stimulating GnRH release
or blocking the inhibitory signals for GnRH release.
In addition, correction of a peripheral (gonadotropinindependent) cause of precocious puberty may result
in activation of the HPG axis. For example, if one treats
a patient for congenital adrenal hyperplasia (CAH)
and suppresses adrenal secretion of androgen, the
past hormonal exposure may have already primed the
activation of the hypothalamus, resulting in physiologic,
pulsatile secretion of GnRH. Classically, LH and FSH
are elevated, implicating them in the pathogenesis of
clinical precocious puberty. LH and FSH involvement
can be demonstrated by a robust response to a GnRH
stimulation test. However, as GnRH is no longer commercially available, the diagnosis is often made on clinical grounds. Obesity is prevalent in patients with GDPP.
CNS abnormalities
Gonadotropin-Independent Precocious Puberty
GIPP, also referred to as peripheral precocious puberty
or precocious pseudopuberty, refers to release of estrogen
and testosterone that occurs independently of GnRH
stimulation. Part 2 of this volume will discuss the approach
to diagnosis and treatment of major causes of GIPP.
APPROACH TO EVALUATION OF PRECOCIOUS
PUBERTY
The approach to evaluation of a patient with precocious puberty depends upon gender and clinical signs
at presentation. A practical approach is outlined in
Table 4 and Table 5. Specific questions to guide this approach are: Is the child a boy or a girl? Does the child
have more than one sign of puberty? Is the bone age
abnormal? Is the LH prepubertal or pubertal? Is either
estrogen or testosterone elevated?
A girl who presents with a single sign of puberty
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Idiopathic
Hypothalamic hamartoma
Congenital anomalies (hydrocephalus, suprasellar arachnoid or
ventricular cyst, septo-optic dysplasia, empty sella syndrome,
myelomeningocele)
Postinflammatory (encephalitis, meningitis, abscess, granulomatous
disease)
Radiation therapy
Trauma or other injury (especially if associated with cerebral
atrophy or focal encephalomalacia and hypoxic ischemic
encephalomalacia)
Neoplasms (astrocytoma, ependymoma, glioma, craniopharyn­
gioma, ganglioma, granular cell tumor, pinealomas)
Cysts (arachnoid, pineal, glial)
Various chromosomal abnormalities (trisomy X)
Syndromes
Neurocutaneous syndromes (neurofibromatosis type 1, tuberous
sclerosis)
Russell-Silver syndrome
Williams syndrome
Sequela of treatment of long-standing gonadotropin-independent
precocious puberty
CNS = central nervous system.
(ie, breast development or pubic hair) has isolated
premature thelarche or isolated premature pubarche,
respectively. Although both are considered benign
conditions, they must be regarded as diagnoses of exclusion. More serious pathology may need to be ruled
out, as true precious puberty usually starts with just one
sign of puberty. A child who presents with two signs of
puberty (breast development and pubic hair in a girl;
testicular enlargement and pubic hair in a boy) accompanied by a growth spurt meets the definition of true
precocious puberty and will require an extensive workup. The potential pathology and clinical approach
differ depending on the number of signs of puberty.
In clinical situations in which growth records are not
available, reassurance may not be possible and more
extensive laboratory evaluation may be necessary. One
commonality in the approach, regardless of the presenting sign(s), is continued observation over time.
HISTORY AND PHYSICAL EXAMINATION
A detailed history and thorough physical examination
are essential for developing the differential diagnosis of
precocious puberty.
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Partial and Gonadotropin-Dependent Precocious Puberty
Table 4. Approach to Evaluation of Precocious Puberty in
Girls
Step
Initial
screening*
Subsequent
testing
Clinical Finding(s)
Breast development
alone before age
8 yr
Pubic hair alone
before age 8 yr
Breast development
AND pubic hair
before age 8 yr
Elevated estradiol or
testosterone with
prepubertal LH
LH elevated to
pubertal range
Elevated 17-OHP
Elevated DHEA-S
Monitoring
Evaluation
Bone age, estradiol, PAH
Step
Clinical
Finding(s)
Evaluation
Bone age, 17-OHP, DHEA-S,
testosterone, PAH
Bone age, estradiol, PAH, 17OHP, DHEA-S, testosterone,
baseline and stimulated LH,
unless bone age already
≥ 12 yr†
Initial
Testicular enlarge­ Bone age, hCG, testosterone,
screening*
ment alone
PAH
before age 9 yr
Pubic hair alone
Bone age, 17-OHP, DHEA-S,
before age 9 yr
testosterone, PAH
Testicular enlarge­ Bone age, hCG, PAH, testosterone,
ment AND
17-OHP, DHEA-S, baseline and
pubic hair
stimulated LH, unless bone age
already ≥ 13 yr†
Evaluation for GIPP, including
ovarian ultrasonography
Subsequent
testing
Evaluation for GDPP, including
cranial MRI
High-dose ACTH-stimulation
test
Abdominal CT to rule out
adrenal tumor
Repeat height, weight, and
pubertal status every 4–6 mo
If bone age advanced or PAH
compromised, repeat bone
age every 6 mo
ACTH = adrenocorticotropic hormone; CT = computed tomography;
DHEA-S = dehydroepiandrosterone sulfate; GDPP = gonadotropindependent precocious puberty; GIPP = gonodotropin-independent
precocious puberty; 17-OHP = 17-hydroxyprogesterone; LH = lutein­
izing hormone; MRI = magnetic resonance imaging; PAH = predicted
adult height.
*Can be initiated by primary care provider.
†In girls, if bone age is ≥ 12 yr, baseline and stimulated LH levels may
be pubertal even if the original etiology of puberty was GnRH inde­
pendent. Although GnRH stimulation may not be necessary, it will be
necessary to consider both GIPP and GDPP causes of puberty.
History
The history should include the current age of the
child and the age at onset of the physical change
(ie, breast, pubic hair, and/or external genitalia development). Additional specific information that should
be gathered from the parent/guardian includes exactly
when the change(s) began and, if ascertainable, at what
rate of progression (eg, over 3–6 months versus 3 years).
The presence or absence of other signs or symptoms
(eg, headaches, visual disturbance, rapid growth, rapid
weight gain) should be determined. Possible exposure
of the child to any hormone-containing medications or
products (eg, estrogen, testosterone creams, placental
extract–containing hair products) and exposure to
chem­icals (eg, organochlorine pesticides) also should
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Table 5. Approach to Evaluation of Precocious Puberty in
Boys
Monitoring
Elevated testos­
terone with
prepubertal LH
LH elevated to
pubertal range
Elevated 17-OHP
Elevated DHEA-S
Evaluation for GIPP, including tes­
ticular ultrasonography
Evaluation for GDPP, including
cranial MRI
High-dose ACTH-stimulation test
Abdominal CT to rule out adrenal
tumor
Repeat height, weight, and pubertal
status every 4–6 mo
If bone age advanced or PAH
compromised, repeat bone age
every 6 mo
ACTH = adrenocorticotropic hormone; CT = computed tomography;
DHEA-S = dehydroepiandrosterone sulfate; GDPP = gonadotropindependent precocious puberty; GIPP = gonodotropin-independent
precocious puberty; hCG = human chorionic gonadotropin; 17-OHP =
17-hydroxyprogesterone; LH = luteinizing hormone; MRI = magnetic
resonance imaging; PAH = predicted adult height.
*Can be initiated by primary care provider.
†In boys, if bone age is ≥ 13 yr, baseline and stimulated LH levels may
be pubertal even if the original etiology was GnRH independent. Al­
though GnRH stimulation may not be necessary, it will be necessary
to consider both GIPP and GDPP causes of puberty.
be determined. A history of bone fractures should be
obtained, as patients with McCune-Albright syndrome
or neurofibromatosis may exhibit lytic bony lesions that
predispose to fractures.
Family history should address the timing of puberty
and growth spurt in the parents; any history of ambiguous genitalia, familial diseases (eg, neurofibromatosis),
neonatal deaths, skin spots, or other relevant anomalies as well as illness in general; and any familial use
of gonadal steroids (eg, oral contraceptives, hormone
creams). When evaluating timing of puberty in parents, women often will remember time of menarche
or initiation of breast development. Many men do not
recall the earliest event in puberty (ie, when their testes
started increasing in size). However, most men recall
whether they grew after high school.
Pediatric Endocrinology Volume 1, Part 3 Partial and Gonadotropin-Dependent Precocious Puberty
Physical Examination
The physical examination similarly should encompass a specific set of assessments. Growth pattern should
be assessed (eg, does it follow a steady channel or does
it cross percentiles?). Calculation of the midparental
height (MPH) using the following formula is extremely
useful and usually is accurate within 3 in:
MPH in girls =
MPH in boys =
mother’s height + (father’s height − 5 in)
2
(mother’s height + 5 in) + father’s height
2
If the MPH for a girl using the above formula is 5 ft
4.5 in, this is at the 50th percentile for an adult woman.
If the girl is currently growing at the 90th percentile,
this should suggest the possibility of a growth spurt and
should be a red flag.
The precise stage of puberty also should be assessed.
In boys, it should be noted whether there is pubic hair
without testicular enlargement. In girls, it should be
noted whether the vaginal mucosa is prepubertal (reddish) or estrogenized (pink) and whether there is breast
development without any signs of pubic hair or acne.
The child should also be examined for any neurologic,
visual, or other endocrine findings (eg, hypothyroidism
or signs of androgen excess [acne, hirsutism]) as well
as for pigmented birth marks (eg, café au lait spots in
neurofibromatosis and McCune-Albright syndrome)
or hypopigmented skin lesions (eg, tuberous sclerosis).
Any abdominal (hepatic) or pelvic masses should be
noted. Finally, blood pressure should be evaluated, as it
can be abnormal in certain forms of CAH.
SPECIFIC TESTING
Bone Age
Bone age assessment via radiography of the left
hand and wrist and comparison to the standards of
Greulich and Pyle15 is essential. Bone age within 2
standard de­viations of chronologic age is considered
normal; a difference greater than this is considered
abnormal and warrants further evaluation, especially
if associated with signs of precocious puberty. Bayley
Pinneau tables can be used to determine the standard
percentage of growth completed and remaining at
each bone age as well as the predicted adult height
(PAH) for the child.16 Endocrinologists can compare
the PAH based on the Bayley Pinneau method with the
MPH that is based on the parents’ heights. If the PAH
is more than 3 in below the MPH, excessive hormone
exposure must be suspected. On the other hand, perfect concordance between the PAH and MPH can be
reassuring. The reading of bone age is highly operator
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dependent and must be carried out by someone experienced in the field. This issue is even more critical
when serial bone age testing is used to monitor patients with suspected precocious puberty.
Growth Curve
Evaluation of the gender-appropriate growth curve
to identify any increase in growth velocity is essential in
management of the patient. A growth chart containing
multiple historical points is invaluable in evaluating
precocious puberty.
Biochemical Testing
Several biochemical tests are available to evaluate
precocious puberty. It is not necessary to perform biochemical tests in all suspected cases; however, testing
is appropriate when the suspicion is strong and the
growth curves and bone age support this suspicion.
The tests used depend on gender as well as presentation. This testing can be initiated by the primary care
provider.
Girls with premature thelarche should have estradiol
levels measured (in addition to bone age assessment).
Boys and girls with premature adrenarche should have
17-hydroxyprogesterone (17-OHP) and dehydroepian­
drosterone sulfate (DHEA-S) levels measured. Boys and
girls with true precocious puberty (2 signs of puberty in
girls; testicular enlargement and growth spurt in boys)
should have free thyroxine and thyroid-stimulating
hormone levels measured. Patients with hypothyroidism can occasionally exhibit early puberty, but thyroid
hormone levels are an excellent way to screen for a
hypothalamic-pituitary defect. Boys with testicular enlargement before age 9 should have human chorionic
gonadotropin (hCG) levels measured. hCG binds to
the LH receptor, and hCG-secreting tumors can cause
precocious puberty in boys. Measurement of hCG is
unnecessary in girls, as girls need both LH and FSH
stimulation to enter puberty.
Patients with true precocious puberty, premature
menarche, or advanced bone age may require GnRH
stimulation to assess the status of the HPG axis (pubertal versus prepubertal). GnRH-stimulated LH and
FSH testing is still the gold standard. Although the
standard GnRH preparation previously used in stimulation testing is no longer available, several centers now
use a GnRH superagonist (leuprolide) in stimulation
testing. Two forms exist, a short-acting aqueous leuprolide (given subcutaneously) and a long-acting depot
leuprolide (given intramuscularly). Both have proven
useful in diagnostic testing. Generally, a single injection
is followed 30 to 40 minutes later by LH measurements
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Partial and Gonadotropin-Dependent Precocious Puberty
by immunochemiluminescent assay. The advantage of
the depot form is that a single injection can be used for
therapeutic effect and for determination of therapeutic
efficacy. The thresholds to distinguish prepubertal from
pubertal LH levels are not as well established using
these preparations as with older GnRH. One published
study used a peak LH of up to 2.3 IU/L after aqueous
leuprolide to define prepubertal levels, whereas another used a peak of 1.4 IU/L.17,18 With either the aqueous
or depot form, a level greater than 8 IU/L is diagnostic
of GDPP. With stimulation, prepubertal children will
have a predominantly FSH response, while pubertal
children will have a LH-predominant response, with
the LH-to-FSH ratio often greater than 1. A sensitive
LH assay should actually be able to distinguish between
prepubertal and early pubertal gonadotropin levels
even without GnRH stimulation. Although the older
radioimmunoassays were not sensitive enough to ensure this discrimination, the newer immunochemiluminescent assays are very sensitive, and an unstimulated
LH greater than 0.3 IU/L generally indicates a central
process.19
Estrogen results should be interpreted relative to the
clinical situation. Estradiol levels in GDPP are appropriate for the Tanner stage of development, whereas in
estrogen-producing tumors the estradiol concentrations are markedly elevated. Levels of inhibin A and
inhibin B appear to be elevated in GDPP.
Breast ultrasonography is useful in both boys and
girls when unilateral breast growth is difficult to distinguish from a tumor.20 Ultrasonographic assessment
of the size of the uterus and ovaries can be used as an
adjunct to diagnosing precocious puberty.21,22 Measurement of uterine and ovarian volumes by pelvic ultrasonography has been found to be sensitive and specific for
differentiating between early premature thelarche and
early GDPP, which can present similarly.23 The presence
of masses or cysts suggests a cause for GIPP, whereas
pubertal/maturational changes in the ovaries (increased size with mature follicles) suggests GDPP.
Magnetic resonance imaging (MRI) of the brain
should be used to rule out a CNS lesion as an etiology
for GDPP. In boys, a search for a CNS cause of GDPP is
imperative, while in girls there is still debate on whether
imaging is always required.24 Abdominal computed tomography is the best way to search for an adrenal mass as
an etiology for premature adrenarche. Pelvic or testicular ultrasonography is use­ful in seeking gonadal sources
of excess hormone production. An evidence-based diagnosis rule for use of imaging studies in girls was recently
developed and is widely used in Europe.25,26
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PARTIAL PRECOCIOUS PUBERTY
CASE 1 PRESENTATION
An African-American girl, aged 7 years, 7 months, is
brought by her mother for evaluation of early breast development. This was first noted approximately 6 months
ago by the mother. The patient’s twin sister is currently
being followed in the clinic for early breast development, which began about 3 months earlier in that child.
The mother believes that the child being seen today has
recently begun developing pubic hair as well. She also
believes that both girls are growing too fast.
Past medical history is significant for a twin pregnancy. There is no history of birth marks or bone fractures.
There is no family history of diabetes, thyroid disease,
or neurologic conditions. The mother is roughly 5 ft
7 in and had menarche at age 10 years. The father is 6 ft
and reportedly had normal pubertal development.
Review of the growth curve shows that the patient
has been tracking between the 90th and 95th percentiles for height and between the 50th and 75th
percentiles for weight. Vital signs are normal. Breast
examination reveals moderate glandular tissue (firm
and resistant to compression). The vaginal mucosa is
reddish pink. There is no clitoral enlargement. Pubic
hair is Tanner stage 1, with vellus hair present but no
terminally differentiated hair. Neurologic examination
is normal. There are no café au lait spots.
• What is the most likely diagnosis?
Breast tissue growth is driven primarily by estrogen,
and this may be gonadotropin dependent or independent. The differential diagnosis for this child’s early
breast development includes GDPP (as the initial presentation before pubic hair), an estrogen-producing tumor
(eg, granulosa cell tumor, functioning ovarian cysts or
tumor, teratoma), and isolated premature thelarche.
Obese children often have fatty tissue in the breast area
that may mimic the appearance of breast tissue on visual
inspection. Palpation is critical in differentiating firmer
true breast tissue from the softer fatty tissue.
A key feature of this child’s history is that her breast
development is of recent onset and is occurring close
to the normal time of puberty. The child’s growth pattern has not shown any recent acceleration that would
suggest long-standing effect of estrogen, and there are
no other signs of excess estrogen, such as changes to
the vaginal mucosa or vaginal bleeding. The absence
of both a growth spurt and pubic hair rules out true
Pediatric Endocrinology Volume 1, Part 3 Partial and Gonadotropin-Dependent Precocious Puberty
precocious puberty. Like her twin sister, this patient
most likely has isolated premature thelarche.
• What management approach would be appropriate
for this child? Is further evaluation indicated?
The initial evaluation of the patient with suspected
premature thelarche should include obtaining a bone
age (radiograph of the left hand and wrist) and
con­sulting the Bayley Pinneau tables to determine
whether the patient is on track to reach her MPH. Depending upon the timing of the premature thelarche
and physical examination findings, baseline estradiol,
LH, and FSH measurements also may be indicated.
Unfortunately, estrogen levels in girls with premature
thelarche are not easily quantified because of poor
sensitivity of the current estradiol assays. Several different methods to improve upon this have been tried
including an ultrasensitive recombinant cell bioassay.27
However, premature thelarche has been shown to be
associated with enhanced follicular development similar to that in early puberty, and this is thought to be
under the influence of FSH.28
Rarely, premature thelarche may be associated with
growth hormone (GH) therapy.29 Some rare conditions
have also been associated with premature thelarche,
including the Coffin-Siris syndrome30 and RubinsteinTaybi syndrome.31 In some girls, premature thelarche or
fluctuating thelarche may be the earliest sign of McCuneAlbright syndrome, which is caused by an activating mutation of the GNAS1 gene.32 Aromatase excess syndrome is
a familial condition associated with feminization of both
sexes, leading to premature thelarche and macromastia
in girls and peripubertal gynecomastia in boys.33
If isolated premature thelarche is diagnosed based
on the initial clinical assessment, the patient should be
monitored closely and return at 4- to 6-month intervals
for evaluation to rule out other pathology that may become apparent later. Follow-up visits will be necessary to
document a normal growth velocity, lack of continued
progression into puberty, and normal bone age. Lack
of progression will continue to support the diagnosis
of isolated premature thelarche. Imaging other than
bone age is not indicated in this case.
CASE 2 PRESENTATION
A 5-year-old Caucasian girl is brought by her parents, who report noting pubic hair growth over the last
6 months. The parents have not noted any breast or axillary hair development or any excess hair on the child’s
face or on any other part of her body. They report that
the child has been growing well up to this point. Since
starting kindergarten, she has gained some weight as a
result of decreased activity compared with what she had
had in preschool. The family has not noted salt cravings,
and there is no history of polyuria or polydipsia.
On physical examination, the child is at the 95th
percentile for weight and at the 80th percentile for
height. Blood pressure is normal for age, and other
vital signs are normal. She has no breast buds. The
vaginal mucosa is red, there is no clitorimegaly, and the
external genitalia are otherwise normal. Skin examination reveals no acne and no acanthosis nigricans. Evaluation of the growth curve reveals a normal pattern.
• What is the differential diagnosis for this child’s presentation?
• What tests would be indicated at this time?
CASE 1 CONCLUSION
Bone age is assessed at 7 years, 10 months (at a
chronologic age of 7 years, 7 months), which is within
2 standard deviations of normal. The patient’s PAH
based on this bone age is 5 ft 8.5 in, which is within
3 in and actually higher than her calculated MPH of 5 ft
7 in. At this point, reassurance is indicated, with plans
for close follow-up of both sisters.
Although most likely a benign condition, isolated
premature pubarche must be differentiated from pathologic and potentially treatable causes such as CAH, adrenal tumor, exposure to exogenous testosterone creams,
hyperinsulinism, ovarian tumors, and (in boys) familial
male-limited precocious puberty (testotoxicosis). Girls
with obesity and early adrenarche are at increased risk
for development of polycystic ovary syndrome (functional ovarian hyperandrogenism) in adolescence and
adulthood, along with its attendant cardiovascular disease risk.
The initial evaluation for patients with suspected
isolated premature pubarche includes bone age assessment to screen for excessive hormone exposure,
a random 17-OHP level (for the most common form
of CAH, 21-hydroxylase deficiency), and a DHEA-S
level (for adrenal tumor). An elevated DHEA-S level
that is appropriate for the Tanner staging will support
a diagnosis of benign premature adrenarche. A complete biochemical evaluation is not necessary unless
physical examination findings, bone age, and linear
growth suggest a pathologic process. If all findings are
normal, having the patient return at 4- to 6-month
intervals for reevaluation of the physical examination,
linear growth, and bone age will suffice. If weight gain
accelerates or acanthosis nigricans appears, it may be
necessary to perform an oral glucose tolerance test.
Supportive evidence for a benign process include a normal linear growth, lack of acceleration of the bone age,
10 Hospital Physician Board Review Manual
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Partial and Gonadotropin-Dependent Precocious Puberty
and absence of other signs of puberty, such as breast
development or increasing testicular size.
CASE 2 CONCLUSION
The child is found to have a mildly elevated DHEA-S
level appropriate for degree of pubic hair, with no elevation in 17-OHP. The diagnosis of isolated premature
pubarche is made. The physician recommends monitoring the child every 6 months with a clinical examination and bone age assessment. Nutrition education,
increased activity, and weight loss management are also
recommended.
GONADOTROPIN-DEPENDENT PRECOCIOUS
PUBERTY
CASE 3 PRESENTATION
A Caucasian girl, aged 8 years, 4 months, is referred
by her pediatrician and presents with her mother for
evaluation. The pediatrician reported that she recently
evaluated the child (at age 7 years, 11 months) and
noted her to be in the earliest stages of breast and
pubic hair development. She then received a call from
the mother 5 months later, reporting that her child just
experienced menstrual bleeding. The pediatrician initiated a work-up and referred the child for evaluation.
History reveals that the patient has been healthy.
She was hospitalized once at age 20 months for a
head injury from a fall. She experienced dehydration related to recurrent vomiting after that injury.
There were no other known sequelae to this incident.
There is no history of bone fractures. Family history
reveals that the mother is 5 ft 6 in and the father is 5 ft
11 in, giving the patient a calculated MPH of 5 ft 6 in.
The mother had menarche at age 12 years.
Review of growth records reveals that the patient was
tracking between the 75th and 90th percentiles until
24 months of age and then, between the ages of 4 and
6 years, crossed down to between the 25th and 50th
percentiles. She subsequently had a growth spurt. On
current evaluation, the child’s height is above the 75th
percentile. Her weight also has recently increased.
Physical examination reveals normal vital signs. The
main findings are Tanner stage 3 pubic hair and Tanner stage 3 breast development. There is no acne, and
there are no changes in skin pigmentation.
Bone age is assessed as 12 years (at a chronologic
age of 8 years, 4 months), giving the patient a PAH
of 4 ft 11 in. Initial laboratory studies reveal normal
thyroid function, a 17-OHP level of 181 ng/dL, and an
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adrenocorticotropic hormone (ACTH)–stimulated 17OHP level of 206 ng/dL. The remainder of the CAH
work-up is negative.
• What is the differential diagnosis for this child’s presentation?
With both breast and pubic hair development and a
growth spurt occurring before age 8 years, this patient
meets the definition of true precocious puberty. The
documented decrease in height percentiles between the
ages of 24 months and 4 years is highly unusual. Most
children do not cross percentiles beyond 19 months of
age. This might raise the suspicion of GH deficiency.
Pathologic central processes can often result in GH
deficiency in combination with precocious puberty.
These two conditions can mask each other, resulting in
a normal growth velocity.
• What can be surmised from the initial test results?
• What further tests would be indicated at this time?
The normal thyroid function in this patient argues against a major hypothalamic-pituitary defect. Although the baseline 17-OHP was elevated, the ACTHstimulated 17-OHP value of just 206 ng/dL rules out
21-hydroxylase deficiency as well as the carrier state.
The discrepancy between the patient’s PAH (4 ft 11 in)
and her calculated MPH (5 ft 6 in) indicates hormone
excess leading to advanced bone age, and a work-up for
the source of hormone excess is indicated. Because of
the close relationship between skeletal maturation and
central puberty, it would be expected that gonadotropin
levels would be pubertal in a girl with a bone age of
12 years, regardless of whether the original etiology of
sexual precocity was GnRH dependent or GnRH independent. In other words, once the bone age is advanced
to 12 years by any mechanism, the GnRH pulse generator will be activated. Thus, when the bone age is greater
than 12 years, peripheral etiologies of sexual precocity
should remain in the differential diagnosis. On the other
hand, GnRH-stimulation tests may not be helpful or even
necessary in these cases, as they do not aid in the differential diagnosis. Pelvic ultrasonography and brain MRI
should be performed. For GDPP, if a CNS mass or tumor
is causing the condition, surgery or other appropriate
therapy (eg, radiation) may be needed.
CASE 3 CONTINUED
Results on further biochemical studies are: LH,
0.3 IU/L (low pubertal range); FSH, 2.9 IU/L; testosterone, 26 ng/dL (normal, 14–76 ng/dL); DHEA-S,
101 mg/dL (normal, 35–43 mg/dL); estradiol,
11 pg/mL; peak GH, 20.2 ng/mL (normal). Pelvic
Pediatric Endocrinology Volume 1, Part 3 11
Partial and Gonadotropin-Dependent Precocious Puberty
ultrasonography shows a pubertal uterus and multiple
follicles in the ovaries. Brain MRI is normal, suggesting
an idiopathic etiology.
• How should this patient be treated, and what is her
prognosis?
Failure to treat this patient would result in reduced
final height and the risk for psychosocial problems.
Most girls younger than 10 years are not emotionally
equipped to deal with menstrual bleeding.
Treatment of idiopathic GDPP is nonsurgical. The
mainstay of therapy is the use of leuprolide, a GnRH
agonist that can slow the sexual maturation as well as
improve final height potential.34 Several GnRH analogs are currently available for intramuscular injection
(every 4 to 12 weeks) or daily sub­cutaneous injection.
GnRH analogs work by initially stimulating the LH receptor, which then becomes down-regulated until it is
no longer functional.
Leuprolide is usually administered as depot (intramuscular) injections (at a dose of 0.3 mg/kg every
28 days). The dose will require titration based on the
child’s growth pattern and the effect on puberty. Once
the child has reached an acceptable final height prediction and her peers are undergoing puberty, treatment
can be discontinued to allow her to proceed through
puberty (around age 11 for girls and age 12 for boys).
The child’s prognosis is good if she is monitored closely
during treatment, with adjustments made according
to her progress. This raises the question of how to
adjust dosing. Brito et al35 used a peak LH response of
6.6 IU/L 2 hours after depot leuprolide dosing to define acceptable suppression. In another recent study,
the investigators measured LH 40 minutes after a therapeutic dose of depot leuprolide; they considered a peak
LH response of 6.6 IU/L too high and empirically used
a threshold of 5 IU/L to define adequate therapy.36
In some patients started on GnRH analogs, the
growth velocity is so markedly reduced that it impairs
final height potential. In these patients, GH has been
shown to significantly improve final height when added
for 2 to 4 years while a child is on treatment with GnRH
analogs.37 Controversy still exists and more data are
needed on the issue of combination GH and GnRH
agonist therapy, as a large number of patients on GnRH
alone never attain adult height.38 In some of the slowly
progressive cases, GnRH analogs may not be indicated
as final height is not compromised.39
In patients with GDPP in whom GnRH agonists are
used, calcium supplementation may potentially attenuate bone demineralization if instituted at the onset of
therapy.40 A more recent study by van der Sluis et al41
12 Hospital Physician Board Review Manual
showed that there was no decrease in peak bone mass
or change in body composition after GnRH therapy
in patients with GDPP. In GH-deficient children, delay
of normal puberty to maximize adult height has been
contemplated. Because of a lack of knowledge about
long-term effects on bone mineralization, this therapy
cannot be recommended widely.42 A significant determinant of growth during therapy with a GnRH agonist
is senescence of the growth plate, secondary to the exposure to estrogen, prior to the initiation of therapy.43
CASE 3 CONCLUSION
The patient is started on intramuscular leuprolide
injections (11.25 mg every 28 days). After 1 year of treat­
ment, her breast tissue has regressed but she maintains
Tanner stage 3 pubic hair, and her PAH has increased
slightly to 5 ft 0 in.
CONCLUSION
The evaluation and management of precocious puberty need not be complicated, and with a pragmatic
approach, the appropriate diagnosis and management
can be implemented. The gender of the patient, age
of onset and progression of symptoms, and associated
signs assist in determining whether the condition is a
variant of normal not requiring treatment or a more
serious entity, such as a brain tumor requiring surgical intervention. An important factor often missed is
the family history, as this is a powerful modifier of the
differential diagnosis. Obesity appears to play a role
especially in adrenarche and to some degree in GDPP,
and a preventive approach in toddlers may need to be
implemented to avoid later problems. A shift in apparent age of onset in the partial forms of puberty especially in Western communities may lead to a paradigm
shift in the management of these patients in the future.
Nonetheless, an aggressive and vigilant approach to
patients with true precocious puberty should remain
the standard of care.
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Pediatric Endocrinology Volume 1, Part 3 13