Sexual Precocity

Basics
DESCRIPTION

Sexual precocity has traditionally been defined as physical signs of sexual development before age 8 years in girls
and age 9 in boys.

Recently, new guidelines were proposed for lowering the age considered to be normal for sexual development in
girls:
1. Signs of puberty as young as age 7 in white girls and age 6 in black girls may be normal.
2. These new guidelines have not been universally adopted.

The entire clinical picture, including rate of progression and the presence of neurologic symptoms, must be taken
into account.
EPIDEMIOLOGY

Precocious puberty is 56 times more common in girls.

8090% of affected girls have central precocious puberty.

Precocious puberty in boys is more likely to be associated with underlying pathology.

~50% of affected boys have central precocious puberty.

Increased incidence seen in internationally adopted children and in children born premature or small for gestational
age
Incidence

Precocious puberty occurs in 1 in 5,000 children

RISK FACTORS
Genetics

Familial male precocious puberty (testitoxicosis): Sex-limited, autosomal dominant inheritance of activating
mutation in the luteinizing hormone (LH) receptor

McCuneAlbright syndrome: Sporadic, postzygotic, somatic mutation in the stimulatory subunit of G-protein
receptor; more common in girls
PATHOPHYSIOLOGY

Central precocious puberty can be associated with CNS disorders

Peripheral precocious puberty is associated with gonadal and adrenal disorders.

Peripheral precocious puberty can progress to central precocious puberty due to maturation of the hypothalamic
pituitary axis by sex steroids.
ETIOLOGY

Central precocious puberty (gonadotropin-releasing hormone [GnRH]dependent):

Associated with gonadotropin (LH and/or follicle-stimulating hormone [FSH]) levels that are elevated beyond the

normal prepubertal range. Results from activation of hypothalamicpituitarygonadal axis.

Peripheral precocious puberty (GnRH-independent): Gonadotropin-independent elevation of sex steroids arising (i)
directly from gonads and/or adrenals, (ii) through stimulation of gonads by GnRH-independent mechanism, or (iii)
from an exogenous source

Diagnosis
SIGNS AND SYMPTOMS

Careful chronology of physical changes, growth spurt, onset of menses

Presence of neurologic, visual, or behavioral changes to suggest a CNS lesion

History

Family history of early puberty

Presence of exogenous sex steroids in the home

Physical Exam

Plot accurate height (using wall-mounted stadiometer), weight, and growth velocity.

Carefully stage breasts, color of vaginal mucosa, and pubic hair in girls.

Carefully stage testicular volume (with Prader gonadometer), penile size, and pubic hair in boys.

Carefully evaluate for abdominal masses.

Examine skin for acne and caf au lait spots.

Perform comprehensive neurologic evaluation to assess for possible CNS pathology.

TESTS

LABORATORY

Sex steroids: Estradiol, testosterone

Adrenal steroids: 17-OH progesterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione

Gonadotropins: FSH, LH (ultrasensitive or immunochemiluminometric [ICMA]-LH most accurate)

Prolactin: May be elevated with CNS tumors

Thyroid-stimulating hormone (TSH) and free thyroxine (T4)

Human chorionic gonadotropin levels

Provocative tests should be done when the aforementioned tests are abnormal or equivocal:
1. GnRH test for central precocious puberty; prepubertal GnRH response is predominately FSH, whereas
pubertal response is predominately LH
2. Adrenocorticotropic hormone (ACTH) stimulation test for adrenal abnormalities. Exogenous
corticosteroid therapy will interfere with ACTH test, but does not interfere with GnRH test of pituitary
gonadal axis.

IMAGING

Bone age: If advanced, further studies are warranted, guided by history and physical examination. If not advanced,
or if the patient has only mild breast or pubic hair development (but not both), premature thelarche or premature
adrenarche, respectively, is the most likely diagnosis.

MRI of head: As indicated by history, physical examination, and laboratory tests; almost always done in boys
because they are much less likely than are girls to have idiopathic sexual precocity

Ultrasound of gonads/adrenals: As indicated by examination and studies. Look for tumors in both sexes; in girls,
ultrasound can also evaluate development of ovaries and uterus.
CLINICAL:

Obese children often have advanced bone age.

Palpation of breast tissue (buds) can be difficult due to adiposity.

DIFFERENTIAL DIAGNOSIS

Causes of central precocious puberty:

1. Often idiopathic (girls more often than boys)
2. Any cause of peripheral precocious puberty
3. Tumors:
1. CNS tumors
2. Hypothalamic hamartoma: Most common CNS mass to cause precocious puberty; benign
(nonprogressive), congenital malformation of neurons that secrete GnRH
3. Hypothalamic-chiasmatic glioma: Often associated with neurofibromatosis
4. Astrocytoma
5. Ependymoma
4. Post-CNS trauma or damage:
1. Surgery
2. Radiation: May occur after 18-Gy exposure
3. Hydrocephalus and other CNS malformations
4. Infection: Brain abscess, meningitis, encephalitis, granuloma. Lesions may result in stimulation
or lack of inhibition of the GnRH-secreting area of the hypothalamus, resulting in early activation
of the pituitary

Causes of peripheral precocious puberty:

1. Tumors:
1. Human chorionic gonadotropin-secreting tumors: May arise from pineal gland or liver
2. Gonadal tumors
3. Adrenal tumors
2. Environmental: Exogenous estrogens (creams and oral forms) and/or exogenous androgens (anabolic

steroids or testosterone formulations)

3. Congenital adrenal hyperplasia: Poorly controlled CAH can activate the hypothalamicpituitarygonadal
axis in either gender
4. Severe acquired hypothyroidism: High levels of TSH may cross-stimulate gonadal FSH and/or LH
receptors.
5. McCuneAlbright syndrome: Triad of precocious puberty, caf au lait spots, and polyostotic fibrous
dysplasia
6. Familial male precocious puberty (familial testitoxicosis)
7. Refeeding after severe malnutrition during early development (such as adopted children who had
kwashiorkor)

Other disorders:
1. Premature thelarche
2. Premature adrenarche
3. Obesity

Treatment
GENERAL MEASURES
As indicated by cause of the precocious puberty, removal of CNS lesions or cessation of exogenous sex steroids
MEDICATIONS

Central precocious puberty: GnRH agonists such as leuprolide (Lupron) are the treatment of choice. Adjunctive
therapy with growth hormone may improve final adult height.

Calcium supplementation may preserve bone mass accretion during GnRH agonist therapy.

Peripheral precocious puberty: Aromatase inhibitors and antiandrogens (spironolactone or ketoconazole).

Glucocorticoids for congenital adrenal hyperplasia
SURGERY

Removal of CNS lesions if present

Follow-up Recommendations

When to expect improvement:

1. Depends on cause. For example, sexual changes of McCuneAlbright syndrome are due to autonomously
functioning ovarian cysts, which regress variably over time.
2. Treatment of central precocious puberty with a GnRH agonist usually results in cessation of menses within
2 months, slowing or nonprogression of pubertal changes over 46 months, and decreased acceleration of
bone age within 12 months.

Typically, GnRH agonists are given in a depot form every 28 days. Some children require shortening of this
interval, often prompted by reports of moodiness, development of acne, or breakthrough menses.

EXPECTED COURSE/PROGNOSIS

With treatment, improvement in predicted height is achieved, but most children do not reach target height predicted
by midparental height measurements. Earlier treatment results in improved final height.

Effect of GnRH agonists on fertility has not been fully elucidated.

POSSIBLE COMPLICATIONS

Short stature

Psychosocial stresses of early puberty

Frequently Asked Questions

Q: If my child is treated with GnRH agonists, will he/she go through puberty when we stop the medication?

A: Yes, children on GnRH agonist treatment do proceed through normal puberty when the medication is stopped.
Effects on fertility have not been fully studied long-term.

Q: If my child already has some pubertal changes, can they be reversed?

A: If GnRH agonists are used, menses will cease, and breast tissue and pubic hair will often regress.