++
Sexual precocity is the general term for early
puberty. Isosexual precocity refers to a girl who
feminizes or a boy who virilizes early. Central precocious
puberty or true precocious puberty is
a term reserved for children with gonadotropin-releasing hormone
(GnRH)-dependent early puberty that follows the normal pubertal
pattern and the normal control mechanisms through GnRH. The only difference
from normal puberty is the earlier age at onset. Central precocious
puberty can be idiopathic or caused by organic conditions such as
a brain tumor or a hamartoma of the tuber cinereum. GnRH-independent
isosexual precocity is caused by excessive estrogen secretion
in girls or androgen secretion in boys from sources other than the
GnRH-gonadotropin axis (such as the gonads, the adrenal glands,
ectopic human chorionic gonadotropin (hCG) secretion, and exogenous
sources of sex steroids). Gonadotropins are suppressed by negative
feedback in all forms of GnRH-independent isosexual precocity because
sex steroid secretion is autonomous. Contrasexual (or heterosexual)
precocity refers to girls who virilize and boys who feminize.
++
Onset of puberty among Caucasian girls as early as 7 years of
age or among African American girls as early as 6 years of age can
be considered normal if there are no neurologic symptoms or signs
of increased intracranial pressure, if there is not a rapid advancement
in pubertal development or bone age, and if menses is after at least
age 9 years. If there is a family history of a pattern of early
pubertal development, the child is even more likely to have a variant
of normal puberty rather than a pathologic condition causing sexual
precocity. Among boys the earliest limit of normal puberty is 9
years of age. Onset earlier than these limits is considered sexual
precocity.1 The classification schema and causes
of precocious puberty are outlined in Table 541-1.
++
All children with sexual precocity show the effects of increased
sex steroids such as secondary sexual characteristics, excessive growth for
chronologic age, and rapid bone age advancement. Although some children
progress rapidly through precocious puberty, some follow a waxing
and waning course. The more severely affected children have tall
stature and a bone age that advances faster than height velocity.
If untreated, these patients achieve a severely decreased adult
height because of premature epiphyseal closure. Historically, girls
not treated for sexual precocity reached a mean adult height of
151 to 152 cm compared with a mean adult height in the United States
of 164 cm. Boys not treated for sexual precocity reached an adult
height of 161 cm compared with an average adult height in the United
States of 178 cm.
++
Some children start puberty somewhat early compared with current
standards but not strikingly so and may be manifesting a family
tendency toward early puberty. The
milder cases (ie, without marked advancement of bone age, without
marked elevation of the serum level of IGF-I, and among girls, without
marked elevation of the serum level of estrogen) may not need treatment
and still achieve an acceptable adult height as may those with unsustained
precocious puberty that may wax and wane over a period of time.
In both situations, there should be careful follow-up, as slowly
progressive puberty can convert to rapidly progressive true precocious
puberty. The psychological stress of early sexual development and
menarche among girls can influence a parental decision toward therapy.
While boys may exhibit hyperactivity or aggression and masturbation
due to early puberty, girls do not necessarily change their behavior.
+++
True Central Precocious
Puberty (GnRH Dependent)
++
True central precocious puberty results from an increase in GnRH
secretion at a younger age than normal. Most cases are idiopathic,
but because organic causes include brain tumors, further evaluation
is usually indicated. Precocious puberty occurs more frequently
among girls than among boys, but central nervous system tumor as
a cause of precocious puberty is more common among boys than among
girls.
++
Signs of central precocious puberty in boys include the development
of secondary sexual characteristics, and an increase in testicular diameter
to greater than 2.5 cm in longest measurement or a volume greater
than 4 mL. Girls with precocious puberty have an increased growth
rate even before development of the breasts, but the breast development
is more easily detected. Breast development is noticed among girls
with all types of isosexual precocity, but true menarche occurs
only in GnRH-dependent precocious puberty. Fertility can be achieved
early in children with central precocious puberty. There is a report
of a 6-year-old girl delivering a child by Caesarian section due
to the combination of precocious puberty and sexual abuse, emphasizing
the importance of ensuring the safety of girls with early puberty.
+++
Central Nervous
System Causes of Precocious Puberty
++
The most common central nervous system (CNS) abnormality causing
central precocious puberty is hamartoma of the tuber cinereum.2 These
nonmalignant congenital masses of heterotopic tissue, composed of
GnRH-synthesizing neurons, are derived from the embryonic hypothalamus
and escape regulation by the central nervous system, so they cause
pulsatile secretion of gonadotropins with stimulation of the gonads
during childhood. They do not grow so that they are not associated
with a mass effect, but they can be associated with gelastic or laughing
seizures, petit mal seizures, or grand mal seizures. Hamartoma of
the tuber cinereum has a characteristic appearance on magnetic resonance
(MR) images of a sessile or pedunculated mass attached to the posterior
hypothalamus between the tuber cinereum and the mamillary bodies
projecting into the suprasellar cistern.3 Biopsy
is not needed for diagnosis due to the classic radiographic findings.
Surgical management is not usually indicated, as the lesion is responsive
to GnRH agonists as discussed below. However, if seizures are not
responsive to treatment, surgery may be necessary.
++
Craniopharyngioma, astrocytoma, ependymoma, and optic or hypothalamic
glioma and ependymoma all interfere with the normal juvenile pause
and can cause central precocious puberty, as can optic glioma or
neurofibroma in the hypothalamic area associated with neurofibromatosis
type 1 (von Recklinghausen disease). These tumors can cause other
symptoms, such as headache, abnormalities of vision, optic atrophy,
and diabetes insipidus.
++
Central nervous system radiation therapy may also cause central
precocious puberty even if the treated tumor does not cause precocious puberty.
When radiation causes central precocious puberty, the resultant
growth acceleration can mask radiation-induced growth hormone (GH)
deficiency (see Chapter 521). When both occur,
treatment with combined GH and GnRH agonist is necessary to achieve
more normal adult height.
++
High intracranial pressure caused by hydrocephalus or a subarachnoid
cyst can cause precocious puberty, which is reversed solely by means
of release of the elevated intracranial pressure. Fetal or childhood central
nervous system infections of any type, such as tuberculosis and
brain abscess, can cause precocious puberty, as can cerebral vascular
accidents and central nervous system trauma. Developmental delay of
various causes, including static cerebral encephalopathy, can cause
precocious adrenarche (see below) or complete central precocious
puberty. Congenital defects of the central nervous system such as septooptic
dysplasia may cause central precocious puberty.
++
Those who have no hamartoma or other definable cause of central
precocious puberty have idiopathic precocious puberty.
++
Exposure to high serum concentrations of androgens, as seen with
virilizing congenital adrenal hyperplasia, causes early maturation
of the hypothalamus with central precocious puberty even after the
primary cause of increased androgens is treated, and the androgen
levels have reverted to normal levels. Often children diagnosed
with congenital adrenal hyperplasia require treatment with a GnRH
agonist, in addition to the standard treatment of glucocorticoid
and mineralocorticoid, to prevent early puberty. Likewise, children
with androgen-secreting tumors that are removed after years of virilization
can subsequently have central true precocious puberty.
+++
Children Adopted
from Developing Countries
++
Girls adopted into Western families after an infancy in the Third
World may develop central precocious puberty.4 This
is postulated to be linked to early malnutrition followed by normal
or excessive nutrition with both effects tending to advance the
age of puberty.
+++
GnRH-Independent Sexual
Precocity (Incomplete Isosexual Precocity)
++
Sexual precocity occurring in the absence of an increase in GnRH
is caused by either autonomous secretion of sex steroids in both
sexes or, among boys, to production of hCG, which stimulates testicular
testosterone secretion. Follicle-stimulating hormone (FSH) and luteinizing
hormone (LH) are suppressed to nondetectable concentrations in the
face of elevated (often extremely elevated) sex steroid concentrations. Agonists
of GnRH have no effect on these conditions, although as noted above,
exposure to sex steroids may stimulate early hypothalamic maturation
that persists following treatment for the virilizing condition.
+++
Causes of GnRH-Independent Sexual
Precocity among Boys
++
Germ cell tumors secrete hCG, which in high concentrations stimulates
the Leydig cells to produce testosterone. Human chorionic gonadotropin
does not stimulate the seminiferous tubules, so these boys have
only slight enlargement of the testes (to a degree far less than
occurs in central precocious or normal puberty). The penis enlarges;
the serum hCG concentration is elevated, but levels of FSH and LH
are not. (It is essential to use assays that can differentiate hCG
from LH, usually a beta-hCG assay.) The lesion responsible can be
teratoma, chorioepithelioma, dysgerminoma, or a mixed germ cell
tumor, which can be located in the hypothalamus, the mediastinum,
the lungs, the gonads, or the retroperitoneal cavity. Hepatoblastoma
also can be causative. The tumors may secrete -feto protein as well
as hCG. Boys with 47,XXY Klinefelter syndrome have an increased
incidence of hCG-secreting mediastinal germ cell neoplasms.5
++
Virilizing congenital adrenal hyperplasia can
be caused by 21-hydroxylase deficiency, which can be associated
with the salt-loss of mineralocorticoid deficiency, or can be caused
by 11β-hydroxylase deficiency, which can be accompanied
by hypertension because of excess mineralocorticoid secretion. In
boys, these conditions cause virilization without testicular enlargement,
because the androgen originates from the adrenal glands. Because
gonadotropins are suppressed, the testes can be small for age or
small for the degree of virilization. The classical form manifests
during infancy as salt loss and normal genital appearance. Without
salt loss, the condition can manifest as GnRH-independent isosexual
precocity in boys later in infancy (see Chapter 533). Virilizing adenoma and carcinoma of the adrenal
gland secrete large amounts of dehydroepiandrosterone (DHEA)
(and dehydroepiandrosterone sulfate [DHEAS]),
which is peripherally converted to more potent androgens. When the
adrenal gland is the cause of the virilization, the testes remain
prepubertal in size. Leydig cell tumors are rare among boys but
manifest as asymmetrically enlarged testis or testes.
++
Familial gonadotropin-independent sexual precocity with
premature Leydig and germ cell maturation (or “testotoxicosis”)
is a rare, sex-limited dominant condition that manifests clinically
only among boys.1 It is due to an activating mutation
in the luteinizing hormone receptor, rendering it constitutionally
activated, so that it constantly stimulates testosterone production.
Affected boys have enlargement of the penis and virilization but
only minimal enlargement of the testes because there is predominant
stimulation of Leydig cells and relatively less enlargement of the
seminiferous tubules. The boy grows rapidly, but adult height is
markedly decreased; affected girls are normal. Fertility is normal
at adulthood. These patients have elevated testosterone levels with
low gonadotropin concentrations. Spironolactone, an antimineralocorticoid
and antiandrogen agent used to limit androgen effect, has been combined
with testolactone, an inhibitor of aromatase that limits bone age
advancement, as treatment for these boys. An alternative is cyproterone
acetate, a powerful antiandrogen that blocks the androgen receptor,
can be used alone. Ketoconazole, an inhibitor of steroidogenesis,
has also been employed effectively in males with testotoxicosis.
Later in life, central precocious puberty often develops, and these
patients become responsive to GnRH, although they were not responsive
in childhood. This phenomenon appears similar to the hypothalamic-pituitary-gonadal
maturation that occurs among patients with premature puberty after
therapy for other virilizing disorders and is responsive to a GnRH
agonist.
++
Familial cortisol resistance syndrome leads
to a compensatory increase in corticotropin (ACTH) secretion which
increases glucocorticoid secretion; because there is resistance
to glucocorticoids, there is no manifestation of excess glucocorticoid effect
in spite of elevated circulating glucocorticoids.7 However,
because there is an increase in ACTH, adrenal androgen secretion
rises causing premature adrenarche and virilization as well as hypertension
and hypokalemia due to increased mineralocorticoid secretion. Occasionally,
testosterone topically applied by the father may be transferred
to his young son resulting in virilization of the child.
+++
Causes of GnRH-Independent Sexual
Precocity among Girls
++
Gonadotropin-independent isosexual precocity among girls can
be caused by ovarian cysts or neoplasms, exposure
to exogenous estrogens, or abnormalities of the adrenal glands.
Prepubertal girls normally have small ovarian cysts, but some cysts
enlarge and secrete sufficient estrogen to cause breast development and
even withdrawal bleeding.8 The estrogen levels
are usually only at pubertal values, but occasionally very high
levels, characteristic of tumors, are encountered. Most cysts do
not recur, but repetitive cyst formation can occur. Affected girls
secreted more FSH than normal prepubertal girls which may explain
the pathogenesis of this condition.
++
Several neoplasms can cause gonadotropin-independent isosexual
precocity among girls. Granulosa cell tumors of
the ovary are rare, being discovered by bimanual examination in
80% of cases.9 Antimüllerian
hormone and inhibin are useful tumor markers for postoperative follow-up
evaluation of these tumors. Gonadoblastomas can arise in streak
gonads and secrete estrogen or even testosterone. These tumors are
benign but can harbor malignant ovarian tumors. Estrogen-secreting
adrenal neoplasms are infrequent compared with those that secrete
androgens. Tumors that secrete human chorionic gonadotropin (hCG)
cause no physical pubertal changes in girls due to endocrine effects
alone. Girls and boys can be exposed to estrogens through ingestion
of their mothers’ oral contraceptives or contact with estrogen-containing
ointment; lavender oil and tea tree oil contain estrogen and exert
these effects. Feminization also has been attributed to estrogen
contamination of milk, meat, or even vitamins prepared on machinery previously
used to package estrogen.
+++
Causes of GnRH-Independent Sexual
Precocity among Boys and Girls
++
McCune-Albright syndrome is a disorder including
irregular café-au-lait spots (“Coast of California
pattern”), polyostotic fibrous dysplasia (cysts in the
long bones and thickening of the skull), and autonomous endocrine
function, usually manifesting as GnRH-independent sexual precocity.
Patients may have autonomous hyperactivity of the somatotropes (acromegaly
or gigantism), thyroid cells (thyrotoxicosis), parathyroid glands,
or adrenal glands (Cushing syndrome). The widespread endocrine activity
is caused by activating mutations of the stimulatory G-protein subunit
of the adenyl cyclase system attached to the membrane receptor of
the affected cells. Because these are somatic cell mutations that
are not in the germline, the disease affects some organs while skipping
others, leading to the variable manifestations.
++
This syndrome is most common among girls but can affect boys.
The skin and skeletal manifestations develop after birth. The sexual
precocity of the McCune-Albright syndrome is initially autonomous,
but exposure to the endogenous estrogens or androgens eventually can
mature the hypothalamic-pituitary-gonadal axis and cause GnRH-dependent
precocious puberty. Therapy in girls typically includes the use
of an antiestrogen, and treatment options in boys include an antiandrogen
in combination with an aromatase inhibitor.10,11 Agonists
of GnRH have been effective later in childhood in managing secondary
central precocious puberty, which occurs after maturation of the
hypothalamic-pituitary-gonadal axis.
++
Severe, uncontrolled hypothyroidism can be associated
with incomplete sexual precocity of both boys and girls. The extremely
high levels of TSH caused by hypothyroidism can stimulate gonadotropin
receptors (hormonal overlap syndrome). Plasma level of prolactin
is elevated, and galactorrhea can occur, especially among girls.
Growth is impaired as for any child with hypothyroidism, so there
is no pubertal growth spurt. Girls may have breast development,
menstrual flow, and estrogen effects on the vaginal mucosa. In boys,
the size of the testes may increase because of enlargement of the
seminiferous tubules. The pituitary gland may enlarge and erode
the sella turcica in a manner incorrectly suggesting a tumor because
of increased TSH secretion and thyrotroph hyperplasia. Once hypothyroidism
is controlled, sexual precocity reverts and the sella turcica becomes
smaller.
++
Peutz-Jeghers syndrome is an autosomal dominant condition characterized
by nasal polyps, hyperpigmentation of the lips, and macules of the buccal
mucosa; affected boys can have gynecomastia and precocious puberty
with Sertoli cell tumors, and girls can develop ovarian cysts.
+++
Diagnosis of
Sexual Precocity
++
The approach to diagnosis of the cause of sexual precocity is
shown in Figures 541-1, 541-2, and 541-3. The goal in diagnosis of sexual
precocity is first to eliminate the possibility of life-threatening
tumors or other central nervous system conditions and second to
determine optimal therapy to suppress pubertal development and bone
age advancement.1 In girls with breast development
before age 7 in Caucasians, and age 6 in African Americans, evaluation
begins with measurement of basal or gonadotropin-releasing hormone
(GNRH) stimulated levels of luteinizing hormone (LH) (Fig.
541-1). If they are pubertal, central causes of precocious
puberty are considered, and cranial MR imaging is usually indicated.
If not, serum estradiol levels are measured. If these are not elevated,
a diagnosis of premature thelarche is made. If elevated, an ultrasound
of the uterus and ovary should be performed. In cases presenting
with pubic hair before age 7 years in white girls and age 6 years
in African American girls, the evaluation begins with determination
of DHEAS levels. If elevated, virilizing adrenal tumors need to
be considered. If normal, other diagnosis need to be considered
as outlined in Figure 541-2. The diagnostic approach
to boys with puberty before age 9 years is outlined in Figure
541-3. The possibility of exogenous androgen or hCG needs to
be considered. Then testicular size is determined. Based upon the
size, and adrenal etiology, or androgen or hCG-secreting tumor,
or testotoxicosis are considered prior to making a diagnosis of
idiopathic precocious puberty. Idiopathic central precocious puberty
is a diagnosis of exclusion in both sexes. All aspects of the pubertal
process mirror the normal condition, albeit at an early age. Children
can enter puberty even before their first birthday without a sign
of an organic condition as the cause.
++
++
++
++
Patients with true precocious puberty have many laboratory findings
similar to the results obtained in normal puberty. Alkaline phosphatase
is elevated for chronologic age but not for bone age. Resting concentrations
of gonadotropins are elevated to the pubertal range when measured
with sensitive third-generation assays. Nocturnal episodic gonadotropin
secretion increases, as does the gonadotropin secretory response
to administration of GnRH. Laboratories have their own standards,
and if LH level increases more than the standard prepubertal value
after GnRH or GnRH agonist is administered, the response is considered
pubertal. Baseline LH values in new third-generation assays can
also help establish the diagnosis.12
+++
Management of
Precocious Puberty
++
Central precocious puberty is best managed with administration
of GnRH agonists that have a strong binding affinity for the GnRH
receptor and resist enzymatic degradation.13 After
a brief period of stimulation of LH and FSH secretion, binding of
the GnRH agonist to the receptor downregulates the GnRH receptor,
which decreases or eliminates further LH and FSH secretion. Levels
of sex steroids decrease, bone age advancement decreases, and growth
rate decreases. If therapy is started early enough, adult height
equals or approximates the genetic potential. Menses ceases in girls, although
an initial episode may occur after initiation of therapy. The most
widely used preparation, leuprolide acetate, is available as a daily,
a once-per-month, or a once per 3 months injection. A new subcutaneous
implant of long-acting GnRH agonist provides 1 year of therapy.
Agonists of GnRH are used to manage most types of central precocious
puberty, including hamartoma of the tuber cinereum (as noted above,
these congenital lesions do not necessitate surgery). Agonists of
GnRH are not indicated for children with borderline early onset
of puberty who are progressing slowly, have not had menarche, and
have no central nervous system signs or symptoms.
++
Gonadotropin-independent sexual precocity is managed in an individual
manner depending upon the etiology as described above.