Precocious Puberty
Sexual precocity is defined as the appearance of secondary sexual
characteristics before the age of 8 years in girls and before the age of 9
years in boys. Recent data suggest that these ages are less than two standard
deviations from the mean. Still, the ramifications of misdiagnosis are great
and, at present, breast or pubic hair development before age 8 or menarche
before age 10 warrants an evaluation in girls. Testicular enlargement or pubic
hair development before age 9 in boys warrants similar investigation. While the
appearance of all secondary sex characteristics results from increased sex
steroid production, the underlying etiology of elevated sex hormone production
and activity may be increased gonadotropin secretion or intrinsic disease of
the adrenal, ovary or testis (Table 28.1). Complete or true sexual precocity
is used to describe precocious puberty resulting from elevated pituitary
gonadotropins. Incomplete or peripheral sexual precocity refers to
precocious puberty resulting from primary diseases of the gonads or adrenals.
Early sexual development that is consistent with the genetic and gonadal sex of
the individual is isosexual precocity. Heterosexual or contrasexual
precocity indicates precocious puberty associated with feminization of a
male or virilization of a female.
Although more than half the cases
of isosexual precocious puberty simply represent the early end of the normal
developmental spectrum, all children with sexual precocity should be evaluated.
There are several reasons for this recommendation. First, some children may
have a serious disorder associated with precocious puberty. Second, regardless
of the etiology, sexual development that occurs before age 6–7 years can be
associated with short stature in adulthood if left untreated. An X-ray of the
left wrist to evaluate bone age can be used to determine when to initiate
and stop chosen treatments for precocious puberty and to follow treatment
efficacy. Finally, sexual precocity is not accompanied by advanced
psychosexual maturation. To this point, young girls with precocious puberty
appear to be at significant risk for sexual abuse. Ovulation and conception are
possible and pregnancies in girls as young as 5 years of age have occurred as
the result of such abuse. Appropriate therapy and support are necessary to
prevent the potential long-term consequences of sexual precocity.
True or complete precocious puberty
True sexual precocity results from early maturation of the hypothalamic–pituitary–gonadal (HPG) axis.
Measurements of serum gonadotropins and sex steroid concentrations will be in
the normal postpubertal range. Gonadotropin pulsatility will have
characteristics and feedback regulation similar to those found in the adult.
The physical characteristics of puberty appear prematurely, but in the proper
chronologic order. One half of cases of true sexual precocity arise from
premature activation of the HPG axis (Table 28.2).
The remaining cases of complete
isosexual precocity are caused by central nervous system (CNS) lesions. These
lesions include neo- plasms, trauma, hydrocephalus, postinfectious
encephalitis, congenital brain defects, tuberous sclerosis and
neurofibromatosis type 1. Most lesions are located in, or near, the posterior
hypothalamus. The most commonly identified neoplasms are astrocytomas,
ependymomas and craniopharyngiomas. Hamartomas of the tuber cinereum account
for one in six cases of isosexual precocious puberty in girls and half of the
cases in boys. Hamartomas are congenital malformations that contain fibre
bundles, glial cells and gonadotropin-releasing hormone (GnRH)-secreting
neurons.
Although a rare cause of
precocious puberty, girls with severe primary hypothyroidism can develop
hyperprolactinemia, associated galactorrhea and true precocious puberty. These
girls have a primary defect in the thyroid gland and very high
thyroid-stimulating hormone (TSH) levels in response to low thyroid hormone
secretion. They also have elevated circulating gonadotropins. The development
of precocious puberty in girls with primary hypothyroidism may be the result of
gonadotropin stimulation of the ovary, or from cross-activation of the
follicle-stimulating hormone (FSH) receptor by the pathologically high TSH. In
the face of low thyroid hormone secretion, hypothalamic thyrotropin-releasing
hormone (TRH) production rises. TRH is a potent stimulator of prolactin
secretion by pituitary lactotrophs (Chapter 32); hyperprolactinemia and
galactorrhea result.
Occasionally, the development of
true sexual precocity will follow the correction of a long-standing virilizing
condition in girls. This may occur with treatment of congenital adrenal
hyperplasia (CAH). Correction of excess androgen production releases the
hypothalamus from androgen-associated negative feedback. This permits GnRH
secretion and gonadotropin stimulation of the ovary. The timing of this stimulation
may be inappropriate and, in a young girl, lead to complete precocious
isosexual development.
Treatment of true precocious
puberty involves recognition and correction of underlying CNS lesions if
etiologic. Additional therapy may be required, including suppression of the HPG
axis with a GnRH agonist or antagonist. GnRH agonists are long-acting analogs
of GnRH that occupy its receptors for long periods of time. Prolonged receptor
occupation removes the GnRH pulsatility required for appropriate gonadotropin
release from the pituitary. GnRH antagonists occupy and block GnRH receptors
and cause immediate cessation of GnRH pulsatility. Both are effective in
protecting adult height and avoiding many psychosexual issues surrounding
untreated precocious puberty.
Incomplete isosexual precocity
Incomplete isosexual precocity is
caused by ovarian or adrenal secretion of estrogen in girls and testicular or
adrenal secretion of androgen in boys. In girls, the most common cause of
GnRH-independent precocious puberty is the presence of functionally autonomous
ovarian cysts. Small (<1 cm) follicles occur frequently in the prepubertal
ovary but they rarely secrete significant amounts of estrogen. However,
autonomous secretion of estradiol by the granulosa cells contained in the cyst
wall can occur in larger cysts, and serum estradiol concentrations appear to
correlate directly with cyst size. Progestin therapy can reduce the size of
these cysts and prevent their recurrence.
Solid stromal cell tumors of the
ovary are a rare cause of GnRH-independent precocious puberty in girls. When
compared with functional cysts of the ovary, juvenile granulosa or theca cell
tumors secrete very large amounts of estrogen, often resulting in the rapid
development of sexual characteristics.
Two inherited syndromes,
Peutz–Jeghers and McCune–Albright, are associated with isosexual precocious
puberty. Peutz–Jeghers syndrome is defined by the appearance of mucocutaneous
pigmentation and gastrointestinal polyposis, but may also include gonadal sex
cord tumors. McCune–Albright syndrome is characterized by hyperpigmented
café-au-lait spots on the skin, progressive polyostotic fibrous dysplasia of
the bones and GnRH-independent sexual precocity. Hyperplasia or adenomas of
multiple endocrine glands may also occur.
McCune–Albright syndrome is caused by activating mutations in a signal
transduction protein linked to many of the peptide hormone receptors, the
G-protein subunit, Gsα. These proteins are present in many cells and
therefore many tissues can be affected; distribution may be patchy and
unpredictable because mutations occur in postzygotic somatic cells. In girls
with McCune–Albright syndrome and ovarian involvement, sexual precocity occurs
because of estrogen secretion from luteinized follicular cysts and treatment
involves interruption of estrogen production. CNS involvement is unlikely and
patients with McCune–Albright syndrome can progress normally through
GnRH-dependent puberty.
Incomplete isosexual precocious
puberty is rare in boys. It is always caused by excess androgen exposure.
Adrenal sources of androgen exposure include CAH and adrenal adenomas or cancers.
Most virilizing adrenal tumors in children secrete excess amounts of dehydroepiandrosterone
sulfate (DHEA-S). The DHEA-S, in turn, is converted to more potent androgens
(Chapter 2). Testicular sources of androgen excess include Leydig cell tumors.
These rare tumors of the testis produce testosterone.
Iatrogenic sexual precocity
Breast development has been
reported in girls and boys after exposure to exogenous estrogens found in
tonics, lotions, creams and estrogencontaminated meat. Virilization of boys and
girls has been associated with exposure to androgenic steroid preparations.
Virilizing precocious puberty in girls
Most girls with contrasexual
precocious puberty will develop pubic hair or hirsutism. The most common cause
is CAH. CAH is associated with multiple defects in the steroid synthetic
pathway. Mild alterations in adrenal 21-hydroxylase are present in 0.1–1.0% of
the population. These alterations may not manifest themselves as early as those
of classical CAH; mild deficiencies are associated with late virilization,
premature adrenarche, polycystic ovarian disease and postpubertal
oligoamenorrhea. Diagnosis of this disorder rests on the presence of mild
baseline elevations in 17-hydroxyprogesterone, the steroid precursor
metabolized by 21-hydroxylase. Some patients with CAH will be discovered only
after provocative testing, characterized by the exaggerated release of
17-hydroxyprogesterone to adrenocorticotropic hormone (ACTH) stimulation.
Deficiencies in 11β ciency or cocious puberty in girls, but occur rarely.
Virilizing adrenal tumors that
occur in young girls are very aggressive and usually fatal if malignant.
Ovarian Leydig cell and Sertoli cell tumors are the most common virilizing
neoplasms in women. They are a rare cause of virilizing precocious puberty.
Feminizing precocious puberty in boys Contrasexual precocity is much less common in boys than in girls. Boys
with feminizing precocious puberty will exhibit gynecomastia and accelerated
linear bone growth. The presence of prepubertal-size testes on examination
strongly suggests an adrenal or testicular source for the estrogen. One rare
cause of prepubertal feminization is extraglandular aromatization of androstenedione.
Gynecomastia has occasionally been seen with CAH in boys. Feminizing testicular
tumors have been reported in boys with Peutz–Jeghers
syndrome.
