eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Precocious Puberty

Paul B Kaplowitz, MD, PhD, Professor of Pediatrics, George Washington University School of Medicine and Health Sciences; Chief of Endocrinology, Children's National Medical Center

Updated: Jun 30, 2009

Introduction

Background

Precocious puberty refers to the appearance of physical and hormonal signs of pubertal development at an earlier age than is considered normal. For many years, puberty was considered precocious in girls younger than 8 years; however, recent studies indicate that signs of early puberty (breasts and pubic hair) are often present in girls (particularly black girls) aged 6-8 years. For boys, onset of puberty before age 9 years is considered precocious.

Early onset of puberty can cause several problems. The early growth spurt initially can cause tall stature, but rapid bone maturation can cause linear growth to cease too early and can result in short adult stature. The early appearance of breasts or menses in girls and increased libido in boys can cause emotional distress for some children. 

Premature pubarche and premature thelarche are 2 common, benign, normal variant conditions that can resemble precocious puberty but are nonprogressive or very slowly progressive. Premature thelarche refers to the isolated appearance of breast development, usually in girls younger than 3 years; premature pubarche refers to appearance of pubic hair without other signs of puberty in girls or boys younger than 7-8 years. A thorough history, physical examination, and growth curve review can help distinguish these normal variants from true sexual precocity.

If the history, physical examination, and laboratory data suggest that a child exhibits early and sustained evidence of pubertal maturation, the clinician must differentiate central precocious puberty (CPP) from precocious pseudopuberty. CPP, which is gonadotropin-dependent, is the early maturation of the entire hypothalamic-pituitary-gonadal (HPG) axis, with the full spectrum of physical and hormonal changes of puberty. Precocious pseudopuberty is much less common and refers to conditions in which increased production of sex steroids is gonadotropin-independent (see Precocious Pseudopuberty). Correct diagnosis of the etiology of sexual precocity is critical, because evaluation and treatment of patients with precocious pseudopuberty is quite different than that for patients with CPP.

Pathophysiology

Most patients, particularly girls suspected of having CPP, are otherwise healthy children whose pubertal maturation begins at the early end of the normal distribution curve. CNS imaging studies of these otherwise healthy 6-year-old to 8-year-old girls usually reveal no structural abnormalities. A 2002 study of 200 girls in France found abnormal brain imaging findings in 2% of girls whose onset of puberty was between age 6-8 years and in 20% of girls whose onset of puberty was before age 6 years.¹ A smaller 2003 study from the United Kingdom reported abnormal findings in 15% of 67 girls.² Abnormal CT scan or MRI findings are more frequent among boys with CPP than among girls with CPP.

The onset of puberty is caused by the secretion of high-amplitude pulses of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The hypothesized mechanisms that suppress onset of puberty include (1) the HPG axis, which is highly sensitive to feedback inhibition by small amounts of sex steroids, and (2) central neural pathways that suppress the release of GnRH pulses.

CNS abnormalities associated with precocious puberty include the following:

• Tumors (eg, astrocytomas, gliomas, germ cell tumors secreting human chorionic gonadotropin [HCG])
• Hypothalamic hamartomas
• Acquired CNS injury caused by inflammation, surgery, trauma, radiation therapy, or abscess
• Congenital anomalies (eg, hydrocephalus, arachnoid cysts, suprasellar cysts)

High-amplitude pulses of GnRH cause pulsatile increases in the pituitary gonadotropin-luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Increased LH levels stimulate production of sex steroids by testicular Leydig cells or ovarian granulosa cells. Pubertal levels of androgens or estrogens cause the physical changes of puberty, including penile enlargement and sexual hair in boys and breast development in girls. These levels also mediate the pubertal growth spurt. Increased FSH levels cause enlargement of the gonads in both sexes and eventually promote follicular maturation in girls and spermatogenesis in boys.

Frequency

United States

The frequency of precocious puberty in girls and boys largely depends on the age at which the condition is considered precocious.

In 1969, Marshall and Tanner published the results of their study of 192 white British girls.³ These researchers stated that the average age of thelarche was 11 years and defined precocious puberty in girls as that which started before age 8 years. No studies that looked at the age of appearance of breast and pubic hair in normal children were performed in the United States during that same time. However, many in the United States had the impression that girls had been maturing earlier than in the past.

No data were available to confirm this impression until 1997, when Herman-Giddens et al reported on the incidence of breast and pubic hair development by age and race in 17,000 US girls aged 3-12 years.⁴ They used the established definition that breast or pubic development in girls was precocious before age 8 years and estimated that approximately 8% of white and 25% of black girls in the United States exhibited evidence of sexual precocity. The results of this study are illustrated in Media files 1-2.

Graph represents the prevalence of breast development at Tanner stage 2 or greater by age and race.

Graph represents the prevalence of pubic hair at Tanner stage 2 or greater by age and race.

Reliable estimates of the frequency of precocious puberty in boys have not been published. However, several centers have reported that they evaluate between one fifth and one tenth as many boys as girls for sexual precocity.

International

A 2003 review of trends in timing of puberty around the world show no clear trend toward earlier puberty in northern Europe, but earlier mean age of menarche has been reported in some southern European countries and other warmer parts of the world.⁶ An interesting and still unexplained finding is the high incidence of precocious puberty in girls adopted into Western Europe from various underdeveloped countries.

Mortality/Morbidity

Isolated sexual precocity of unknown etiology carries no increased risk of mortality; however, distinguishing between children with idiopathic CPP and the rare patient with a CNS, adrenal, or ovarian tumor is important because the latter group may be at risk for tumor-related complications. Some, but not all, studies have found an association between early puberty in girls and a higher risk of breast cancer.

Children with precocious puberty may be stressed because of physical and hormonal changes they are too young to understand. They may be teased by their peers because of their physical difference. Girls who reach menarche before age 9-10 may become withdrawn and may have difficulty adjusting to wearing and changing pads. Both sexes, but more so boys than girls, may have increases in libido leading to increased masturbation or inappropriate sexual behaviors at a young age. Girls with a history of early puberty have a slightly earlier age of initiation of sexual activity.

Some studies have found that children with precocious puberty more frequently exhibit behavioral problems and are less socially competent than age-matched peers. Some, but not all, studies find evidence of emotional problems persisting into adulthood. The distress associated with early menses can be decreased if parents are encouraged to prepare their daughters for this event when they reach stage III-IV of breast development.

Early puberty accelerates growth. These children may initially be considerably taller than their peers. Because bone maturation is also accelerated, growth may be completed at an unusually early age, resulting in short stature. Short stature is more likely if puberty starts very early (ie, before age 6 y) than if it begins moderately early (ie, ages 6-8 y). Several studies show that most untreated girls with idiopathic CPP reach an adult height within the reference range. Determination of bone age can be used to predict adult height and to select patients with high risk for short stature if left untreated.

Race

The 1997 study by Herman-Giddens et al and the data from the National Health and Nutrition Examination Survey (NHANES) III study conducted from 1988-1994 show conclusively showed that black girls in the United States have onset of breast development and pubic hair about one year earlier than white girls; thus using the same age definition of precocious puberty for white and black girls yields a higher incidence in black girls (see Media files 1-2).^4,7 No current evidence shows that black boys mature earlier than white boys; thus, incidence of precocious puberty among boys is similar in both races. The NHANES III study indicated that Mexican-American girls start breast development at a similar age as white girls, and that pubic hair appears slightly later.⁷

Sex

In a series of more than 200 patients evaluated at a single medical center, CPP occurred 5 times more often in girls than boys.⁸ Idiopathic CPP occurred 8 times more often. A possible explanation for this difference is that many girls whose puberty is considered precocious are actually healthy girls at the early end of the normal distribution.

Age

If precocious puberty in females (mostly central) is defined as the early onset of breast development, then the data of Herman-Giddens et al (Media file 1) can be used to estimate frequency of CPP at different ages in both white girls and black girls. Be cautious, however, in equating breast development in 3-year-olds with CPP because most such girls actually have premature thelarche, a benign normal variant (see Differentials). The younger the age of girls with proven CPP, the higher the likelihood of serious underlying disorder.

Clinical

History

• Precocious puberty in girls
  • The first and most obvious sign of early puberty is usually breast enlargement, which may initially be unilateral.
  • Pubic and axillary hair may appear before, at about the same time, or well after the appearance of breast tissue. Axillary odor usually starts about the same time as the appearance of pubic hair.
  • Menarche is a late event and does not usually occur until 2-3 years after onset of breast enlargement.
  • The pubertal growth spurt occurs early in female puberty and usually appears by the time of initial evaluation.
• Precocious puberty in boys
  • The earliest evidence of puberty is testicular enlargement, a subtle finding that often goes unnoticed by patients and parents.
  • Growth of the penis and scrotum and appearance of pubic hair typically occur at least a year after testicular enlargement.
  • Accelerated linear growth (the pubertal growth spurt) occurs later in the course of male puberty than in female puberty but often occurs by the time other physical changes are noted.

Physical

• Precocious puberty in girls
  • The most reliable sign of increased estrogen production is breast enlargement. Initially, breast budding may be unilateral or asymmetric. Gradually, the breast diameter increases, the areola darkens and thickens, and the nipple becomes more prominent. Distinguishing glandular breast tissue from fat, which can mimic true breast tissue, is essential. Examining the patient while she is in the supine position usually minimizes the chance of misinterpreting fat as true breast enlargement.
  • Genital examination may or may not reveal pubic hair, but enlargement of the clitoris indicates significant androgen excess that must be promptly evaluated. The vaginal mucosa, which is a deep-red color in prepubertal girls, takes on a moist pastel-pink appearance as estrogen exposure increases.
  • Mild acne may be normal in early puberty, but rapid onset of severe acne, like clitoral enlargement, should increase suspicion of an androgen-excess disorder.
• Precocious puberty in boys
  • The earliest sign of central precocious puberty (CPP) is enlargement of the testes, which depends on increased production of follicle-stimulating hormone (FSH); testicular length is more than 2.5 cm or testicular volume (with Prader orchidometer beads) is more than 4 mL. If progressive signs of androgen excess occur in a boy without increased testicular size, consider possible causes of precocious pseudopuberty, including congenital adrenal hyperplasia, familial male precocious puberty, and Leydig-cell tumors (a testicular nodule is usually palpable). Human chorionic gonadotropin (HCG)-secreting tumors somewhat increase testicular size by stimulating testicular Leydig-cell LH receptors.
  • Other signs of puberty (eg, penis growth, reddening and thinning of the scrotum, increased pubic hair) are a consequence of increased testosterone production and occur within 1-2 years after testicular enlargement.
  • Pubic hair growth that occurs without penis and testicular enlargement and other signs of increased androgen production usually reflects increased adrenal androgen production (ie, premature adrenarche) rather than true puberty.
  • Later signs of puberty include the pubertal growth spurt, acne, voice change, and facial hair.

Causes

• Genetics: The timing of puberty has a genetic component. A history of early puberty in a parent or sibling is relevant and decreases the likelihood that early puberty has an organic cause. One study from Israel estimated that precocious puberty was familial in one fourth of cases and that the predominant mode of inheritance was autosomal dominant.⁹
• Body fat
• An increased body mass index (BMI) has been associated with early puberty.¹⁰ In some studies the association is stronger in white girls than in black girls. Obesity is not clearly associated with early puberty in boys.
• In the 1970s, Frisch et al proposed that girls need a certain weight or body fat content to trigger menarche and to maintain cyclical menses.¹¹ The relationship between body fat and puberty is complex and has many exceptions; however, body weight and fat mass are clearly among the factors that may influence puberty onset in girls.
• A recent longitudinal study of 354 girls by Lee et al found that increased BMI at age 3 years and the rate of increase in BMI from age 3-6 years were both positively associated with an earlier onset of puberty.¹²

Differential Diagnoses

Precocious Pseudopuberty

Other Problems to Be Considered

Premature pubarche

Premature pubarche refers to the early appearance of pubic hair, axillary hair, or both in boys and girls without other signs of puberty. An adult-type axillary body odor is the other major clinical finding. Signs of severe androgen excess (eg, clitoral enlargement, growth acceleration, acne) should prompt further investigation to exclude a rare virilizing tumor or a variant form of congenital adrenal hyperplasia. The etiology of premature pubarche is an earlier-than-usual increase in the secretion of weak androgens by the adrenal glands (also termed premature adrenarche). Although regulation of adrenal androgen secretion is poorly understood, it is distinct from that of gonadal steroids. Therefore, early appearance of pubic hair may not temporally correlate with appearance of breast development and is generally not a cause for concern. Exposure to exogenous sex hormones is another potential cause of premature pubarche. Children may be inadvertently exposed to androgens through contact with adult males who use topical androgens such as Androgel.

Premature thelarche

Premature thelarche is the appearance of breast development in young girls in the absence of other signs of precocious puberty (eg, growth acceleration, changes in uterine size and vaginal mucosa). Premature thelarche is typically seen in girls aged 3 years or younger. Breast tissue normally seen in the newborn period due to maternal estrogens can persist for a year or more in some infants. The keys to making this diagnosis include the following:

• Observing that the child is growing in length along her established percentile channel
• Noting that the amount of breast tissue increases only minimally over time (or may even decrease)
• Observing a lack of thickening and pigmentation of the nipples and the areola as seen in girls with precocious puberty

The etiology of this condition is unknown. In some cases, small ovarian cysts that transiently produce estrogens may be responsible. In Puerto Rico, an epidemic of premature thelarche in the 1970s was suspected to have been caused by exposure to estrogens in poultry. Despite a lack of firm evidence, phytoestrogens in soy products and other environmental estrogenlike agents (eg, pesticides) have the potential to cause breast development in young children.

Workup

Laboratory Studies

• Sex steroid levels
• Measurement of serum testosterone is useful in boys with suspected precocious puberty.
• Early morning testosterone levels in boys in early puberty are higher than afternoon levels because luteinizing hormone (LH) and testosterone levels rise with sleep onset in early puberty.
• The stages of puberty as indicated by serum testosterone levels are as follows:
• Testosterone level less than 30 ng/dL – Generally prepubertal (Depending on the laboratory, testosterone levels of 11-30 ng/dL may represent early puberty)
• Testosterone level of 30-100 ng/dL – Early pubertal
• Testosterone level of 100-300 ng/dL – Mid-to-late pubertal
• Testosterone level of more than 300 ng/dL – Adult
• For girls, estradiol measurements are less reliable indicators of the stage of puberty. Many commercial assays are not sufficiently specific or sensitive enough to demonstrate an increase during early puberty. levels that exceed 20 pg/mL usually indicate puberty, but some girls who are clearly pubertal may have levels of less than 20 pg/mL. In addition, estradiol levels may fluctuate from week to week. Girls who have ovarian tumors or cysts often have estradiol levels that exceed 100 pg/mL.
• Levels of adrenal androgens (eg, dehydroepiandrosterone [DHEA], dehydroepiandrosterone sulfate [DHEAS]) are usually elevated in boys and girls with premature pubarche. DHEA-S, the storage form of DHEA, is the preferred steroid to measure because its levels are much higher and vary much less during the day. In most children with premature pubarche, DHEA-S levels are 20-100 mcg/dL, whereas in rare patients with virilizing adrenal tumors, levels may exceed 500 mcg/dL.
• Consider obtaining a 17-OH serum progesterone study if congenital adrenal hyperplasia is suspected. If a random level is within the reference range, the diagnosis can be excluded; however, if the random 17-OH progesterone level is elevated, an adrenocorticotropic hormone (ACTH) (ie, Cortrosyn) stimulation test provides the greatest diagnostic accuracy.
• Gonadotropins
• Because of the development of more sensitive third-generation assays for LH, which can detect levels as low as 0.1 IU/L or lower, the random LH is now the best screening test for central precocious puberty (CPP). The immunochemiluminometric (ICMA) method for LH seems more specific than the immunofluorometric (IFMA) method. An LH level of less than 0.1 IU/L is generally prepubertal, and a recent study suggested an upper reference range limit for LH measured by ICMA of 0.2 IU/L in both boys and girls, with no overlap between prepubertal and pubertal levels in boys and a 10% overlap in girls.¹³  Random follicle-stimulating hormone (FSH) levels do not discriminate between prepubertal and pubertal children. Suppressed levels of LH and FSH accompanied by highly elevated testosterone or estradiol levels point to precocious pseudopuberty rather than CPP.
• A definitive diagnosis of CPP may be confirmed by measuring LH and FSH levels 30-60 minutes after stimulation with gonadotropin-releasing hormone (GnRH) at 100 mcg or with a GnRH analog. Because native GnRH is no longer available, most centers are using the analog leuprolide (aqueous form) at a dose of 20 mcg/kg, up to a maximum of 500 mcg. An increase in FSH levels much greater than the increase in LH levels suggests that the child is prepubertal. Some studies suggest that an increase in LH levels to more than 8 IU/L is diagnostic of CPP, but this depends on the specific LH assay used. A study by Carel et al stated that the peak LH level measured by ICMA that defined CPP was 4.1 IU/L in boys and 3.3 IU/L in girls.¹⁴ No increase in LH and FSH levels after the infusion of GnRH suggests precocious pseudopuberty.
• Thyroid: Thyroid tests are not a routine requirement in the evaluation of precocious puberty. Severe hypothyroidism rarely leads to precocious puberty. Major clues of severe hypothyroidism include growth arrest instead of growth acceleration, galactorrhea, and signs of thyroid hormone deficiency.

Imaging Studies

• Radiography: Radiography of the hand and wrist used to determine bone age is a quick and helpful means to estimate the likelihood of precocious puberty and its speed of progression. If bone age is within one year of chronological age, puberty has not started (eg, a 2-year-old girl with premature thelarche) or the duration of the pubertal process has been relatively brief. If bone age is advanced by 2 years or more, puberty likely has been present for a year or more or is progressing more rapidly.
• Head MRI
  • MRI may be indicated to look for a tumor or a hamartoma after hormonal studies indicate a diagnosis of CPP. Ask the radiologist to obtain a high-resolution study that focuses on the hypothalamic-pituitary area.
  • For healthy girls aged 6-8 years with no signs or symptoms of CNS disease, the likelihood of finding a tumor or hamartoma is only about 2%; therefore, this test may be unnecessary depending on the clinical situation.
  • The younger the child with CPP, the greater the chance of finding CNS pathology (among children younger than 6 y).
  • For boys younger than 9 years, the incidence of CNS findings is much higher than in girls, and MRI should be part of the evaluation.
• Pelvic ultrasonography
  • Ultrasonography is unnecessary for girls with a definite diagnosis of CPP. If performed, however, ultrasonography usually reveals bilaterally enlarged ovaries, often with multiple small follicular cysts, and an enlarged uterus with an endometrial stripe.
  • Pelvic ultrasonography is essential when precocious pseudopuberty is suspected in girls (based on examination or hormone levels) because an ovarian tumor or cyst may be detected.

Histologic Findings

• If CPP is caused by a tumor in the hypothalamic-pituitary area, the histology of the tumor can be important to the patient's prognosis.
• Gliomas tend to grow more rapidly than astrocytomas, whereas hamartomas are benign.
• Treatment of precocious puberty associated with a hamartoma suppresses gonadotropin production by the pituitary without effect on the hamartoma itself.
• For information on different non-CNS tumors associated with precocious puberty see Precocious Pseudopuberty.

Treatment

Surgical Care

When central precocious puberty (CPP) is caused by a CNS tumor other than a hamartoma, a resection should be attempted to the extent possible without impinging on vital structures such as the optic nerves. Radiation therapy is often indicated if surgical resection is incomplete. Unfortunately, removal of the tumor rarely causes regression of precocious puberty.

Medication

Gonadotropin-releasing hormone analog

Continuous administration of LHRH and GnRH agonists provides negative feedback and results in decreased levels of LH and FSH 2-4 wk after initiating treatment. An excellent review and consensus statement on the use of GnRH analogues in children by Resende et al has been published.¹⁴

Leuprolide acetate (Lupron, Lupron Depot-Ped, Lupron Depot 3 month)

Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels. Available in a monthly depot formulation. Annual cost is approximately $10,000-15,000. Individualize duration of therapy according to age and maturity of child and predicted adult height; in most cases, continuing treatment after age 10-11 y is unnecessary. Recently, a study that examined the 3-mo formulation of Lupron-Depot 11.25 mg, which has not been approved for children, reported that the suppression of LH and FSH levels was nearly as good as Lupron-Depot 7.5 mg administered monthly and that the clinical effectiveness was equivalent (Badaru, 2006). This is obviously more convenient for the family, and further studies on this dosage form are needed.

Dosing

Adult

Pediatric

Depot preparation initial dose: 300 mcg/kg/mo IM; standard kits available as 7.5 mg, 11.25 mg, or 15 mg vials; some children may require even higher doses to completely suppress gonadotropins and sex steroids
Subcutaneous preparation daily dose: 50 mcg/kg/d SC; dosage increases may be required; preparation available as 5 mg/mL (2.8 mL multidose vial)

Interactions

None reported

Contraindications

Documented hypersensitivity; pernicious anemia; approximately 5% of individuals develop an immune response to the encapsulation material of depot preparation; discontinue depot preparation if sterile abscess forms at injection site and/or systemic symptoms develop, including fever and chills; daily SC preparation usually may be substituted without incident, or another daily preparation may be used

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor every 4-6 mo; linear growth rate should slow to reference range for age; initial stimulation of puberty may be seen in first several weeks of therapy, and estrogen withdrawal bleeding may be noted in girls with advanced puberty within 4-6 wk of treatment; demonstrating that the dose used fully suppresses rise in LH and FSH levels normally seen 20-40 min after injecting 100 mcg is suggested in treating girls; testing may not be needed for boys because decline in serum testosterone levels to <20 ng/dL and decrease in size of testes is adequate to assess effectiveness; monitor bone age at least yearly to document slowing of progression and to reassess adult height prediction, which is often subnormal at onset of treatment and improves with therapy

Histrelin (Supprelin LA)

LHRH agonist that is a potent inhibitor of gonadotropin secretion when administered long term. Desensitizes responsiveness of pituitary gonadotropin. Circulating LH and FSH levels initially increase following administration, leading to transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males and estrone and estradiol in premenopausal females). However, long-term administration decreases LH and FSH levels. Implant can provide continuous SC release of histrelin at nominal rate of 50-65 mcg/d over 12 mo. Indicated for CPP (neurogenic or idiopathic).

Dosing

Adult

Not indicated

Pediatric

Supprelin LA: 1 implant/12 mo; each implant contains 50 mg histrelin acetate (delivers about 65 mcg/d); SC insert implant at inner aspect of upper arm; provides continuous release of histrelin for 12 mo
Discontinue at appropriate time of puberty (approximately age 11 y for girls and age 12 y for boys)

Interactions

None reported

Contraindications

Documented hypersensitivity to GnRH or GnRH agonist analogs; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor response by monitoring growth and breast development and measuring basal and GnRH-stimulated LH levels and estradiol by an ultrasensitive assay

Gonadotropin-releasing hormone (GnRH) agonist

These potent long-acting synthetic derivatives of native GnRH suppress pituitary production of gonadotropins because they provide constant stimulus, whereas the pituitary responds only to pulsatile GnRH stimulation. In use since the late 1970s, GnRH agonists are safe and effective.

Nafarelin acetate (Synarel)

Analogue of GnRH that is approximately 200 times more potent than natural endogenous GnRH. Upon long-term administration, suppresses gonadotrope responsiveness to endogenous GnRH, thereby reducing secretion of LH and FSH, which in turn reduces ovarian and testicular steroid production. Administered intranasally to induce gonadotropin suppression. Consider as second-line agent if leuprolide proves difficult to administer. Adherence to a bid intranasal drug regimen may be difficult to achieve. Available as nasal spray; 200 mcg/spray. One 10 mL bottle contains 7-day supply for daily dose of 1600 mcg.

Dosing

Adult

Pediatric

1600 mcg/d intranasally divided as 2 sprays (400 mcg) in each nostril bid, may increase to 1800 mcg/d (3 sprays [600 mcg] into alternating nostrils tid [total of 9 sprays/d]) if necessary for suppression

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Do not administer within 2 h of a nasal decongestant; monitor every 4-9 mo; linear growth rate should slow to reference range for age; initial stimulation of puberty may be seen in first several weeks of therapy; estrogen withdrawal bleeding may be noted in girls with advanced puberty within the first 4-6 wk of treatment
Demonstrating that the dose used fully suppresses rise in LH and FSH levels normally seen 20-40 min after injecting GnRH is suggested in treating girls; testing may not be needed for boys because decline in serum testosterone level to <20 ng/dL and decrease in size of testes is adequate to assess effectiveness; monitor bone age at least yearly to document slowing of progression and to reassess adult height prediction, which is often subnormal at onset of treatment and improves with therapy

Progestin

Before availability of GnRH agonists, these agents were the mainstay of therapy. Progestins work by providing feedback suppression of pituitary gonadotropin secretion. They lack significant androgenic or estrogenic activity.

Medroxyprogesterone acetate (Depo-Provera) 150 mg

Inhibits secretion of pituitary gonadotropin. Inhibits effect of LH. Effective at slowing breast growth and preventing or stopping menses when administered q3mo, although breakthrough bleeding may occur. Less used now due to relative ineffectiveness in reversing rapid advancement of skeletal maturation seen in CPP. Relatively inexpensive; consider when leuprolide cost is a factor and when adult height prediction is close to reference range or is not a major concern.

Dosing

Adult

Pediatric

150 mg IM every 3 mo

Interactions

Aminoglutethimide decreases bioavailability of medroxyprogesterone; may slightly decrease elimination of digitoxin or warfarin

Contraindications

Documented hypersensitivity; thrombophlebitis; cerebral apoplexy; liver dysfunction; undiagnosed vaginal bleeding

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

At higher doses, causes adverse cushingoid effects in some patients; experienced personnel should administer injections as sterile abscess formation has been reported with improper injection technique; other adverse effects are rare in children

Follow-up

Further Outpatient Care

• Patients with precocious puberty treated with gonadotropin-releasing hormone (GnRH) agonists
  • Follow up every 4-6 months to ensure that progression of puberty has been arrested.
  • Favorable signs include normalization of accelerated growth, reduction (or at least no increase) in size of breasts, and suppression of gonadotropin levels after a challenge of GnRH.
  • The ideal testing frequency has not been established. A suggested timeline for girls is to obtain a GnRH test about 4 months after starting the drug to confirm suppression and then no more often than yearly, as long as clinical indicators suggest that the drug is working as intended. Some clinicians advocate dispensing with formal GnRH testing as long as growth has slowed and breasts have decreased in size. In boys, a decrease in the size of the testes and a fall in serum testosterone level to less than 20 ng/dL are good indications of efficacy.
  • Monitor bone age yearly to confirm that the rapid advancement seen in the untreated state has slowed, typically to a half year of bone age per year or less.
• Patients not treated with GnRH agonists: In many cases, the physician may elect to observe the child with central precocious puberty (CPP), either because the age is borderline (ie, 7-8 y) and the child and family are coping well or because the progression of puberty is not rapid and the bone age is only mildly advanced (ie, £ 1 y), so that predicted adult height falls well within the reference range. In these cases, follow-up at 6-month intervals is appropriate. Testing and treatment may be initiated if the tempo of puberty begins to accelerate and predicted adult height deteriorates.

Prognosis

• Without treatment
  • Most girls with early puberty who are aged 6-8 years at the onset of puberty achieve an adult height within the reference range. Treatment with GnRH analogues such as Lupron is usually associated with only a modest gain in final height in this age group.
  • Consider therapy following initial evaluation for girls who then have predicted heights less than 4 ft 11 in or who are well below their target height (ie, average of parents' heights, less 2.5 in) when the patient also has very advanced bone age, a height below the 25th percentile, or both.
  • Controversy surrounds the significance of several studies (mostly with small numbers of patients with no control group) that appear to indicate that girls with CPP are at increased risk for significant behavior problems, such as poor self-esteem and higher anxiety, irritability, or withdrawal. Other studies have not shown such problems. A recent review of this topic by Walvoord and Mazur concluded that CPP may become a risk factor for psychosocial problems, mainly in the setting of other risk factors; they cautioned against medical therapy in order to avoid presumed negative psychological consequences of precocious puberty.¹⁵
• With treatment
  • Most studies show significant improvement in adult height compared with height predicted at the start of therapy, but the extent of this improvement depends to some extent on the age of onset of CPP.
  • A recent study from Israel showed that height gained in girls after discontinuation of GnRH analogue therapy at age 11-12 years (and bone age 12-12.5 y) is greater for girls with onset of CPP before age 6 years than at age 6-8 years or after age 8 years. Mean final height was better than genetic target height in the younger group and less-than-target height in the group whose puberty started after age 8 years.¹⁶ This supports the view that the benefit of treatment in terms of increased adult height is the greatest in patients who are diagnosed with CPP and started on GnRH analogues at younger ages.
  • Normal adult height can be achieved in most cases if treatment is started before bone maturation is too advanced (>12 y in girls, >13 y in boys) and if good gonadal suppression is maintained for several years. Treatment allows growth to continue while dramatically slowing the rate of bone maturation.

Patient Education

• Guidelines for sexuality education for children and adolescents have been established by the American Academy of Pediatrics.¹⁷

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose a CNS tumor
  • In girls, most cases of central precocious puberty (CPP) are idiopathic; however, the risk of a tumor or other CNS abnormality is greater in girls younger than 6 years who have rapid progression of puberty or any CNS signs or symptoms (eg, headaches, visual disturbances, seizures). Because some of these tumors are malignant (eg, gliomas, astrocytomas), failure to consider this possibility and to perform CT scanning or MRI in high-risk cases could result in delayed diagnosis, increased morbidity, and poorer chance of a cure.
  • In boys, organic causes of precocious puberty are more likely. CT scanning or MRI should be part of the evaluation once the child is diagnosed with CPP.

Multimedia

Media file 1: Graph represents the prevalence of breast development at Tanner stage 2 or greater by age and race.

Media file 2: Graph represents the prevalence of pubic hair at Tanner stage 2 or greater by age and race.

References

1. Chalumeau M, Chemaitilly W, Trivin C, et al. Central precocious puberty in girls: an evidence-based diagnosis tree to predict central nervous system abnormalities. Pediatrics. Jan 2002;109(1):61-7. [Medline]. [Full Text].

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Keywords

precocious puberty, early puberty, central precocious puberty, CPP, premature thelarche, premature pubarche, precocious pseudopuberty, hyperovarianism, early onset of puberty, sexual precocity, precocious puberty, idiopathic CPP, inappropriate sexual behaviors, increased masturbation, short stature, breast enlargement, clitoral enlargement, enlarged testes, congenital adrenal hyperplasia, familial male precocious puberty, Leydig-cell tumors, HCG-secreting tumors, premature adrenarche, increased body fat, astrocytomas, gliomas, germ cell tumors secreting human chorionic gonadotropin, germ cell tumors secreting HCG, hypothalamic hamartomas, hydrocephalus, arachnoid cysts, suprasellar cysts, treatment, diagnosis

Contributor Information and Disclosures

Author

Paul B Kaplowitz, MD, PhD, Professor of Pediatrics, George Washington University School of Medicine and Health Sciences; Chief of Endocrinology, Children's National Medical Center
Paul B Kaplowitz, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Indevus Consulting fee Review panel membership

Medical Editor

Phyllis W Speiser, MD, Chief of Pediatric Endocrinology, Schneider Children's Hospital; Professor of Pediatrics, New York University School of Medicine
Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
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Managing Editor

Lynne Lipton Levitsky, MD, Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor, Department of Pediatrics, Harvard University Medical School
Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds PI, also occasional consultant

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfizer, Inc. Honoraria Consulting

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