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15

Precocious puberty
Paul B. Kaplowitz
Childrens National Medical Center and George Washington University School of Medicine and Health
Sciences, Washington, DC, USA

Early pubertal maturation in girls is a common


concern in pediatric ofces, and while most such
patients are seen by pediatric endocrinologists, it is
important for primary clinicians to be aware of the
major diagnoses encountered, including and perhaps
especially, the benign normal variations which require
no intervention. Central precocious puberty (CPP),
which starts early enough and progresses rapidly
enough to merit treatment, is present in only a minority of cases. It is suggested that most cases can be
diagnosed accurately based on the history and physical exam, and that hormone levels and X-ray and
ultrasound imaging are helpful only in selected cases.
Less common problems include ovarian cysts and
tumors, and a puzzling condition called premature
menarche.
The traditional denition of precocious puberty is
the appearance of breast or pubic hair development
in girls prior to 8 years of age. Recent studies conrm
that the appearance of breasts and pubic hair in girls
prior to age 8 years has become increasingly common.
African-American girls have an earlier onset of pubertal signs than do white girls, with Hispanic girls being
intermediate in their age of pubertal onset.
Approximately 1520% of African-American girls
and 510% of white girls have been found to have
either breast or pubic hair development by age 78

years. It may be concluded from this that many of the


girls labeled as having precocious puberty are in fact
normal girls at the lower end of the new normal
range. It appears that girls may be starting puberty
earlier now but are progressing to menarche more
slowly than in the past, as there has been only a slight
decline in age of menarche over time.

Science revisited
Why are girls starting puberty earlier
than in the past?
Higher BMI is correlated with earlier onset of
breast and pubic hair development, and
menarche. This may be due to higher levels of
leptin, derived from fat cells.
Chemicals in the environment with weak
estrogen-like properties, including pesticides,
phthalates, bisphenol A, and plant-derived
phytoestrogens, or low levels of estrogens in the
food supply have been blamed, although
scientic evidence for this is sparse.

There are two common and benign scenarios: premature adrenarche and premature thelarche.

Practical Pediatric and Adolescent Gynecology, First Edition. Edited by Paula J. Adams Hillard.
2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.

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SECTION 2 CONCERNS IN PREPUBERTAL GIRLS AND IN ADOLESCENTS

Premature adrenarche
The great majority of girls who present with the
early appearance of pubic and/or axillary hair, usually
accompanied by axillary odor, have premature
adrenarche, a benign normal variation, due to an
earlier than normal increase in adrenal androgen
secretion. It can be seen as early as age 34 years and
occasionally earlier, and is more common in black
than white girls. In typical cases, extensive hormonal
testing and adrenal and/or ovarian imaging are not
indicated. The only hormonal abnormality generally
seen is an increase in dehydroepiandrosterone sulfate
(DHEAS). No treatment is needed, but parents may
be advised that these girls, particularly those who are
overweight, have an increased risk of developing
polycystic ovary syndrome in their teenage years.
Early pubic hair is rarely seen in girls with virilizing adrenal or ovarian tumors, but such girls will
generally have clitoral enlargement, a pronounced
growth spurt, and often acne as well. A small proportion of girls have mild nonclassical congenital
adrenal hyperplasia (CAH) with elevated levels of 17hydroxyprogesterone. There is no consensus, however,
that girls with mild nonclassical CAH need to be
treated with glucocorticoids to suppress the adrenal
glands.

Premature thelarche
Breast development starting before age 3 years may
be worrisome to parents and pediatricians, but is
nearly always due to premature thelarche. During
follow-up over a period of 612 months, the size of
the breast tissue increases little if at all, but it may
persist for years or uctuate in size over weeks to
months. Unilateral breast enlargement is not a pathologic process, and there is no need for ultrasound or
biopsy, provided the breast is nontender and feels like
normal glandular tissue.
The etiology is unclear, but some studies have
found that small ovarian cysts are common in this
condition, suggesting estrogen stimulation from a cyst
that then regresses. In typical cases, hormonal testing
is not needed. LH is invariably in the prepubertal
range, and FSH and estradiol do not reliably distinguish prepubertal from early pubertal girls.

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When should true precocious puberty


be suspected?
Progressive enlargement of glandular breast tissue
(which needs to be distinguished from adipose tissue
in chubby girls by careful palpation) starting before
age 8 years and accompanied by accelerated growth
is suggestive of true or central precocious puberty
(CPP). This condition is uncommon before age 6
years but has become increasingly common in
68-year-old girls, probably because the onset of
breast development in the general population has
shifted to younger ages. Many girls with early breast
development have a nonprogressive or slowly progressive form of precocious puberty, so if at the initial
encounter breasts are at Tanner stage 2 (see Appendix
1.9.4 and Figure 14.2), a 46-month period of observation is suggested to make sure that puberty is
advancing; if breasts are at stage 3 at the initial visit,
this period of observation is not needed.

Diagnosis
Laboratory evaluation of precocious puberty should
be kept simple:
Random LH is the most useful test to discriminate
prepubertal from pubertal girls: a random LH greater
than 0.3 U/L is diagnostic of CPP; most prepubertal
girls have a LH of less than 0.1 U/L.
An estradiol level of greater than 20 pg/mL supports a diagnosis of CPP.
Measuring adrenal steroids in girls with both early
breast and pubic hair development is not helpful.
Thyroid testing is rarely necessary as long-standing
primary hypothyroidism is associated with large multicystic ovaries; there are obvious signs and symptoms
of hypothyroidism, and growth is slowed instead of
accelerated.
If results are unclear, the girl should be referred
to a pediatric endocrinologist for additional dynamic
testing [measurement of LH after administration
of a gonadotropin-releasing hormone (GnRH)
analog].
There is controversy as to whether all girls with
CPP need to have a brain MRI to rule out tumors or
the non-neoplastic hypothalamic hamartoma. One

CHAPTER 15 PRECOCIOUS PUBERTY

large study of over 200 girls found that the incidence


of central nervous system (CNS) ndings in girls with
onset before age 6 years is about 20%, but only 2%
for girls with onset between the ages of 6 and 8 years.
Unless there is unusually rapid progression or worrisome CNS symptoms, such as headache or alterations
in vision, many endocrinologists elect not to order a
brain MRI in girls with onset of puberty between the
ages 6 and 8 years.
The value of pelvic ultrasound in the evaluation
of early breast development is also debatable. Several
studies have shown that while the ovaries and
uterus are enlarged relative to age-matched controls,
there is overlap between measurements in prepubertal and early pubertal girls. For early-maturing
girls who are midlate pubertal, ultrasound is likely
to show bilateral ovarian enlargement, but in such
cases, physical exam and hormone testing are generally diagnostic. One situation where ultrasound
is essential is in the girl with rapidly progressing
breast enlargement whose screening lab results show
a very elevated estradiol (>50100 pg/mL) combined
with a suppressed LH of less than 0.1 U/L, ndings
suggestive of an ovarian tumor or large ovarian
cyst. Ovarian tumors in young girls are quite rare,
but the most common, the granulosa cell tumor
(see Chapter 48.2), has low malignant potential,
typically following a benign course, with only a
small percentage showing aggressive behavior.
Primary treatment is surgical, with a unilateral
salpingo-oophorectomy.
A more challenging scenario is the girl with similar
clinical and lab ndings as above but the pelvic ultrasound shows a large ovarian cyst (see Chapter 48.1).
Most clinicians cite cases where large solitary cysts
have regressed without intervention and argue for
conservative management. One diagnosis which
needs to be considered is McCuneAlbright syndrome. Findings in classic cases include rapid breast
development with typically a single large ovarian cyst,
irregular large caf-au-lait pigmentation which does
not cross the midline, and cystic bone lesions called
polyostotic brous dysplasia. However, only two of
the three ndings are present in a high proportion of
cases. It is important to make this diagnosis, as GnRH
analogs, which are effective in treating CPP, are of no
benet in this and other forms of gonadotropinindependent precocious puberty.

Management
GnRH analog therapy works in CPP to desensitize
the pituitary gonadotropes by exposing them to continuous rather than pulsatile GnRH. The question of
when and whether to use GnRH analog therapy is
best left to pediatric endocrinologists with experience
and expertise in this area. Treatment is expensive,
with costs typically in the range of $10 00015 000
per year.
The most compelling reason for treating CPP is to
prevent compromise of adult stature due to early
closure of the epiphyses. However, the majority of
girls with CPP, particularly those with the slowly
progressive form, achieve a normal adult height
without treatment.
The greatest concern of most parents of girls with
CPP is the negative psychological impact of early
menses. Using a GnRH analog solely to delay menses
or to alleviate the consequences of a girl being more
physically developed than her peers has not been convincingly shown to improve psychological outcomes,
though controlled studies addressing this issue are
lacking. Girls who start puberty at age 8 years or later
rarely attain menarche prior to age 10, and the
authors experience is that few experience severe
stress, particularly if a parent has prepared them
ahead of time. However, girls who have progressive
CPP starting at age 7 years often have menarche by
age 9, which tends to worry parents greatly, and these
girls may benet psychologically from GnRH analog
therapy to delay menarche until after age 1011
years.

Premature menarche
A puzzling situation which can be easily confused
with precocious puberty is the onset of vaginal bleeding in a girl who has not yet started to develop breast
tissue. The differential diagnosis includes vaginal
foreign body, vaginal tumors, and sexual abuse. If,
after consideration of these conditions, no specic
cause is found, the diagnosis of premature menarche
can be made. While these episodes are quite worrisome for the family, they almost always resolve over
a period of 14 months. Ultrasound or vaginoscopy
may be considered in cases where the bleeding is

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SECTION 2 CONCERNS IN PREPUBERTAL GIRLS AND IN ADOLESCENTS

heavy, the problem does not resolve quickly or there


is considerable parental anxiety. There is still no satisfactory hormonal explanation for this paradoxical
situation.

Caution
Situations indicating need for rapid evaluation
by a specialist (pediatric endocrinology or
pediatric gynecology for vaginal bleeding) are:
Early appearance of pubic hair:
If accompanied by growth acceleration (not
just tall stature)
If accompanied by clitoral enlargement or
severe acne.
Early appearance of breast development:
If Tanner 3 or greater at the rst visit
If the amount of breast tissue has increased
signicantly over a period of 46 months in a
girl younger than 8 years old.
Early onset of vaginal bleeding:
If there is no or very little breast
development, the genital exam is normal, and
bleeding persists or recurs for more than a
month
If there is late pubertal breast development
and the child is younger than 9 years old
If there are caf-au-lait spots suggestive of
McCuneAlbright syndrome.

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Further reading
Carel J-C, Eugster E, Rogol A, et al. Consensus statement
on the use of gonadotropin-releasing hormone analogs in
children. Pediatrics 2009;123(4):e752762.
Kaplowitz PB. Link between body fat and the timing of
puberty. Pediatrics 2008;121(2;Suppl 3):S208217.
Kaplowitz PB, Obereld SE. Reexamination of the age limit
for dening when puberty is precocious in girls in the
United States: implications for evaluation and treatment.
Pediatrics 1999;104(4):936941.