Precocious Puberty

History

• Girls
  • Breast development ^c1
    • Unilateral or bilateral
  • Whitish vaginal discharge is early evidence of uterine estrogen exposure ^c2
  • Bleeding consistent with menarche is typically a late pubertal event ^c3
• Boys
  • Central precocious puberty
    • Increased size of testes is the earliest symptom ^c4
    • Later symptoms include:
      • Growth of penis ^c5
      • Increased frequency of erection ^c6
      • Deepening of voice ^c7
  • Peripheral precocious puberty
    • Testicular size typically does not increase ^c8
      • Testicular growth is primarily mediated by increasing gonadotropin levels; in peripheral precocious puberty, elevated testosterone levels cause some signs of virilization, but gonadotropin levels are suppressed and hence testicular volume does not increase
    • Penile growth, increased frequency of erections, and voice changes occur ^c9c10c11
• Both girls and boys
  • Increased linear growth ^c12
  • Pubic and axillary hair may accompany other puberty changes ^c13c14
    • Development of pubic and axillary hair signals androgen production by adrenal glands, a separate process that may occur simultaneously with precocious puberty in some children
  • Symptoms of anterior or posterior pituitary deficiencies
    • Headache ^c15
    • Vision changes ^c16
    • Fatigue ^c17
    • Polyuria ^c18
    • Polydipsia ^c19
    • Seizures ^c20
• Family history may be significant for familial pattern of idiopathic central precocious puberty ^c21
  • Up to 33% of children with idiopathic central precocious puberty have positive family history;^r3menarche before the age of 10 years in mother and growth spurt before the age of 12 years in father are suggestive ^r10
  • Unexplained early death in a male sibling suggests congenital adrenal hyperplasia ^r3
• Medical history may be significant for any of the following:
  • Frequent fractures and ovarian cysts in girls with McCune-Albright syndrome ^c22c23
  • Head trauma, prior central nervous system irradiation, or prior central nervous system infection in patients with central precocious puberty ^c24c25c26
  • Learning difficulties, short stature, and/or failure to thrive may be present in patients with hypothyroidism ^c27c28c29
• History of child playing with lavender oil, tea tree oil, makeup, or skin creams may be concerning for iatrogenic causes of estrogen exposure ^c30

Physical examination

• Girls
  • Normal breast development is present in 23% of Black, 15% of Hispanic, and 10% of White girls aged 7 to 8 years in the United States ^r9
  • Exposure to estrogen is identified by the following clinical findings:
    • Tanner stage 2 or higher breast development (breast bud or surrounding breast tissue present) ^{r1c31c32c33c34}
    • Vaginal mucosa has a dull pink appearance (in contrast to prepubertal vaginal mucosa that is bright pink or red) ^c35
    • Enlargement of labia minora ^c36
  • Ovarian mass may have palpable ovarian tumors ^c37
  • Hyperpigmented skin lesions (café au lait spots) may be present in patients with McCune-Albright syndrome or neurofibromatosis ^c38
  • Dark pigmentation of nipples and areolae is often noted after ingestion of certain exogenous synthetic estrogen compounds ^c39c40
• Boys
  • Exposure to testosterone is identified by the following clinical findings:
    • Testicular volume greater than 3 mL^r10 or testicular length greater than 25 mm signals onset of puberty^r2c41
    • Growth of phallus ^c42
  • Hyperpigmented skin lesions (café au lait spots) may be present in patients with neurofibromatosis ^c43
• Both girls and boys
  • Acceleration of linear growth is evidence of exposure to sex steroids ^c44
    • Often the first change in children with precocious puberty ^r4
    • Proven by the crossing of linear growth percent channels on growth chart ^r10
  • Pubic hair, axillary hair, and acne may be present because adrenarche (separate process of androgen production by the adrenal cortex) often occurs simultaneously ^c45c46c47
  • Signs of anterior or posterior deficiencies
    • Visual field defects or papilledema if optic chiasm is involved in central nervous system lesion ^c48c49
    • Absence of linear growth acceleration may be present with concomitant growth hormone deficiency or hypothyroidism ^c50
    • Dehydration only if thirst mechanism is not intact with diabetes insipidus ^c51
      • Dry mucous membranes ^c52
      • Sunken eyes ^c53
      • Tachycardia ^c54

Causes

• Central precocious puberty
  • Pulsatile release of gonadotropin-releasing hormone from hypothalamus results in activation of hypothalamic-pituitary-gonadal axis; subsequently, estrogen is produced in girls and testosterone is produced in boys ^c55
    • Idiopathic
      • More common in girls (92%) than boys (50%) ^r11c56c57
      • Rare genetic mutations can result in familial idiopathic central precocious puberty
        • KISS1 and KISS1R gain-of-function mutations ^r12r13c58
        • MKRN3 loss-of-function mutations ^r14
    • Central nervous system lesions, insults, or abnormalities involving hypothalamic/pituitary area (including optic chiasm) ^c59
      • Abnormalities disrupt normal hypothalamic-pituitary-gonadal axis and result in release of gonadotropins; disruption of this neurohormonal axis may simultaneously alter other anterior and/or posterior pituitary hormones
        • Tumors ^r4c60
          • Hypothalamic hamartoma ^c61
          • Germinoma ^c62
          • Craniopharyngioma ^c63
          • Glioma ^c64
            • Optic pathway gliomas occur in 15% to 20% of patients with neurofibromatosis 1 ^r15c65
          • Other tumors such as astrocytoma, ependymoma, or pinealoma ^c66c67c68
        • Cerebral malformations in hypothalamic/pituitary area ^c69c70
          • Arachnoid cyst ^c71
          • Septo-optic dysplasia ^c72
          • Hydrocephalus ^r4c73
        • Injury to hypothalamic/pituitary area ^r4c74c75
          • Radiation ^c76
          • Head trauma ^c77
          • Infection (eg, meningitis, encephalitis, tuberculosis) ^c78c79c80c81
          • Perinatal insult ^c82
    • Secondary to longstanding peripheral precocious puberty or chronic exposure to sex steroids (eg, McCune-Albright syndrome, congenital adrenal hyperplasia) ^{r16c83c84c85c86}
• Peripheral precocious puberty
  • Sex hormones (estrogen or testosterone) are produced without activation from hypothalamic-pituitary-gonadal axis or are available from an exogenous peripheral source ^c87c88
    • Isolated ovarian cyst ^r4c89
    • Tumors ^r4
      • Granulosa cell tumor of ovary ^c90
      • Leydig cell tumor of testicle ^c91
      • hCG-producing tumor of liver or mediastinum ^c92c93
        • Produces precocious puberty signs in boys
        • May be associated with Klinefelter syndrome
      • Adrenocortical tumors (feminizing and virilizing) ^c94
    • Exposure to exogenous estrogens or androgens ^r17r18c95c96
      • Ingestion of oral contraceptives or exposure to transdermal estrogen ^r10c97
      • Hormone-containing creams and shampoos ^c98
        • Patients may not report exposure to topical hormone creams; it is important to specifically inquire about these products
      • Hormone-containing herbs (eg, lavender, tea tree oil) ^r10
      • Speculation exists about other potential sources of exposure to hormones or hormonelike substances (eg, hormone-containing foods, soy [phytoestrogens], certain heated plastics), but definitive evidence is lacking
    • McCune-Albright syndrome ^r4c99c100
      • Found mostly in girls
    • Familial male-limited precocious puberty ^c101
    • Severe untreated hypothyroidism in girls ^r19c102
    • Congenital adrenal hyperplasia ^r4c103
      • In most common form of congenital adrenal hyperplasia, 21-hydroxylase deficiency leads to increased testosterone production
        • Contrasexual precocity (virilization) in girls ^c104
        • Isosexual precocity (peripheral precocious puberty) in boys ^c105

Risk factors and/or associations

Primary diagnostic tools

• History and physical examination with attention to growth parameters are important to determine need for further evaluation ^c116
  • Early consultation with a pediatric endocrinologist is important to determine need for further work-up to be initiated by primary caregiver or for immediate referral to a specialist for urgent consultation and expedited evaluation ^r10
    • Endocrinologists with experience evaluating children for precocious puberty can help target investigations and assist in interpretation of diagnostic investigations ^r10
    • In general, girls who have breast development before age 8 years that is not attributable to premature thelarche and boys with testicular enlargement before age 9 years require pediatric endocrinology consultation for diagnostic considerations ^r10
      • Carefully note any additional signs of estrogen effect in girls on examination (eg, maturation of nipples and areolae, mucous vaginal discharge)
      • Carefully note any signs of significant androgen effect in boys on examination (eg, voice changes, acne, facial hair)
      • Pubic hair development, apocrine odor, and axillary hair in boys and girls are related to adrenal androgen production and are not reliable signs of puberty
    • Refer to growth chart to determine whether growth has accelerated
      • Accelerated linear growth (eg, crossing of at least 1 linear growth percentile channel on growth chart) is one of the first signs of precocious puberty ^r10
  • Obtain radiographic bone age estimate in all children with signs of precocious puberty to determine whether additional immediate investigation is necessary ^r7r10
    • Children with advanced puberty are more likely to have advanced bone age ^r3
    • Often pediatric endocrinologists prefer to evaluate bone age radiographs directly; readings performed by radiologists less experienced with bone age estimation may differ from readings by clinicians with experience interpreting bone age radiographs ^r10
  • Calculate genetic target height (ie, predicted adult height) based on parents' height to help determine whether further investigation is warranted
    • Genetic target height (in cm)
      • For girls: (mother's height in cm + father's height in cm − 13) / 2 ^r26
      • For boys: (mother's height in cm + father's height in cm + 13) / 2 ^r26
  • Proceed with work-up in the following groups: ^r7
    • Girls with breast development before age 7 years (White girls) or age 6 years (Black girls) ^r7
    • Girls with breast development beginning after age 7 years (White girls) or age 6 years (Black girls) with the following: ^r7
      • Significant bone age advancement (greater than 2 standard deviations ahead of chronologic age), and predicted height of 2 standard deviations or more below genetic target height, or predicted height less than 150 cm ^r7
      • New central nervous system findings (eg, headaches, seizures, hydrocephalus) ^r7
      • Behavioral factors such as maturity level leading to difficulty dealing with effects of pubertal progression ^r7
    • Boys with onset of pubertal changes before age 9 years ^r7
• Diagnosis is made based on laboratory and radiographic findings
  • First step in evaluating precocious puberty is to measure first morning serum luteinizing hormone, follicle-stimulating hormone, and sex steroid (estrogen or testosterone) levels ^{r10r27c117c118c119c120}
  • If any baseline laboratory test results are already in pubertal range, the next step is an imaging study
    • If luteinizing hormone and follicle-stimulating hormone levels are in pubertal range, obtain brain MRI with special attention to hypothalamus and pituitary glands to look for central cause of precocious puberty
    • If luteinizing hormone and follicle-stimulating hormone levels are low and estradiol or testosterone level is in pubertal range, obtain pelvic or testicular ultrasonogram to look for peripheral cause of precocious puberty
  • If baseline laboratory test results (ie, luteinizing hormone, follicle-stimulating hormone, and estradiol or testosterone) are within reference range, the next step is stimulation testing
    • Results of leuprolide stimulation test (ie, gonadotropin-releasing hormone–stimulation test) can achieve the following: ^c121
      • Confirm suspicion for central precocious puberty when baseline tests are inconclusive
      • Differentiate between central and peripheral precocious puberty
  • Findings consistent with central and peripheral precocious puberty
    • The constellation of findings most consistent with central precocious puberty include:
      • Pubertal levels of follicle-stimulating hormone, luteinizing hormone, and sex hormones, and pubertal luteinizing hormone response to gonadotropin-releasing hormone–stimulation test ^r4
      • Growth is accelerated and bone age is advanced
    • The constellation of findings most consistent with peripheral precocious puberty include:
      • High levels of sex hormones (estrogen or testosterone) accompanied by low levels of gonadotropins (eg, luteinizing hormone, follicle-stimulating hormone); luteinizing hormone secretion does not exhibit pubertal response after administration of gonadotropin-releasing hormone agonist ^r4
      • Growth is accelerated and bone age is often advanced
  • Final diagnostic imaging considerations in patients with precocious puberty include:
    • Brain MRI with special attention to hypothalamus and pituitary glands in patients found to have central cause of precocious puberty
    • Pelvic or testicular ultrasonogram in patients found to have peripheral cause of precocious puberty ^c122c123
• In patients with clinical signs of virilization
  • Obtain blood to measure levels of testosterone, 17-hydroxyprogesterone, androstenedione, and dehydroepiandrosterone sulfate to exclude a process causing concomitant pathologic androgen excess (eg, premature adrenarche due to congenital adrenal hyperplasia, adrenal tumors) ^r3
  • Obtain adrenal imaging if virilization is present on physical examination with concomitant increase in laboratory evidence of adrenal excess
• Obtain thyroid studies to exclude hypothyroidism as a cause of peripheral precocious puberty if hypothyroidism is suggested by clinical findings ^r3

Laboratory

• Hormone testing ^c124
  • Random serum gonadotropin and sex hormone levels may not always be helpful, but do provide some information about pubertal status ^c125
    • Gonadotropins are secreted from the pituitary gland in a pulsatile manner, so overlap in values can exist between prepubertal and pubertal levels obtained during random testing of luteinizing hormone and follicle-stimulating hormone ^r3
    • Testosterone and estrogen production vary with time of day; additionally, in females, postpubertal estrogen level varies by day with monthly cycle phase (luteal, follicular, or midcycle) ^c126c127
  • Measure levels of luteinizing hormone and follicle-stimulating hormone by ultrasensitive assay (has detection limit near 0.1 units/L) ^r28c128c129
    • Reference range gonadotropin levels based on Tanner stage or age ^r29
      • Luteinizing hormone for males
        • Tanner 1: 0.52 international units/L or lower
        • Tanner 2: 1.76 international units/L or lower
        • Tanner 3: 4.06 international units/L or lower
        • Tanner 4 to 5: 0.06 to 4.77 international units/L
      • Luteinizing hormone for females
        • Tanner 1: 0.15 international units/L or lower
        • Tanner 2: 2.91 international units/L or lower
        • Tanner 3: 7.01 international units/L or lower
        • Tanner 4 to 5: 0.1 to 14.7 international units/L
      • Follicle-stimulating hormone for boys
        • 0 to 4 years: not established
        • 5 to 9 years: 0.21 to 4.33 international units/L
        • 10 to 13 years: 0.53 to 4.92 international units/L
        • 14 to 17 years: 0.85 to 8.74 international units/L
      • Follicle-stimulating hormone for girls
        • 0 to 4 years: not established
        • 5 to 9 years: 0.72 to 5.33 international units/L
        • 10 to 13 years: 0.87 to 9.16 international units/L
        • 14 to 17 years: 0.64 to 10.98 international units/L
    • Findings consistent with pubertal gonadotropin status (central precocious puberty)
      • Usually luteinizing hormone and follicle-stimulating hormone are in pubertal range (luteinizing hormone over 0.3 units/L) or higher, but may be in prepubertal range ^r4r30
        • Luteinizing hormone over 0.3 units/L is the most reliable screen for central precocious puberty ^r10
        • Gonadotropins are much higher compared with cases of peripheral precocious puberty, typically in Tanner 2 to adult ranges
      • Luteinizing hormone to follicle-stimulating hormone ratio of more than 1 ^r4
    • Findings suggestive of prepubertal gonadotropin status (and peripheral precocious puberty)
      • Luteinizing hormone and follicle-stimulating hormone levels are low or below the detectable limits of the assay ^r4
        • Gonadotropins are much lower in peripheral precocious puberty compared to central precocious puberty
      • Luteinizing hormone to follicle-stimulating hormone ratio of less than 1 ^r4
  • Estradiol in girls
    • Prepubertal estradiol level is less than 92 pmol/mL (25 pg/mL) ^r29
    • Findings consistent with central precocious puberty
      • Estradiol is most often in pubertal range, but may be in prepubertal range ^r4
    • Findings consistent with peripheral precocious puberty
      • Estradiol is in pubertal range (or higher) ^r4
  • Testosterone in boys
    • Reference range free testosterone level for boys based on Tanner stage ^r29
      • Tanner 1: 0.2 nmol/L (5 ng/dL) or lower
      • Tanner 2: 5.8 nmol/L (167 ng/dL) or lower
      • Tanner 3: 0.7 to 24.9 nmol/L (21 to 719 ng/dL)
      • Tanner 4: 0.9 to 31.7 nmol/L (25 to 912 ng/dL)
      • Tanner 5: 3.8 to 33.8 nmol/L (110 to 975 ng/dL)
    • Findings consistent with central precocious puberty
      • Testosterone is most often in pubertal range, but may be in prepubertal range
    • Findings consistent with peripheral precocious puberty
      • Testosterone is in pubertal range (or higher)
  • Obtain thyroid testing in girls in whom other clinical findings suggest hypothyroidism (eg, poor linear growth, weight gain, fatigue); specific guidance on when to obtain thyroid screening is not standardized ^c130c131
    • TSH ^r31
      • Elevated in primary hypothyroidism
      • Normal or low in central hypothyroidism
    • Free thyroxine ^r31
      • Low in primary and central hypothyroidism

Imaging

• Bone age radiograph ^c132
  • Determine bone age by comparing radiographs of patient's left hand and wrist to standard reference images^r11 published in an atlas such as Greulich and Pyle^r32
  • Bone age advanced beyond 96th percentile for chronological age suggests significant peripheral sex steroid effects on bone maturation ^r4
  • Bone age advanced more than 2 standard deviations above chronological age is consistent with precocious puberty ^r4
    • Bone age may not be accelerated with hypothyroidism ^r4
  • Can assist with estimated final height calculation using published standards
    • This estimate can determine whether treatment is indicated
    • Low precision with 95% confidence interval of plus or minus 6 cm ^r33
• Head MRI with and without gadolinium ^c133c134
  • Evaluates for presence of lesion in hypothalamic and pituitary area
  • Include special pituitary and hypothalamic protocol for adequate imaging of that area
  • Recommended when central precocious puberty has been confirmed and when precocious puberty is associated with neurologic signs or symptoms ^r3
    • Low likelihood of lesions in girls older than age 6 years (2%) ^r34
    • Higher prevalence of lesions in boys (40%-90%) ^r35
    • Obtain head MRI on all boys with central precocious puberty and girls younger than 6 years with central precocious puberty ^r10r28
      • Whether girls between ages 6 and 8 years should have head MRI is controversial, but this imaging is indicated if neurologic findings are present in the setting of rapid pubertal progress
• Transabdominal pelvic ultrasonogram in girls ^r11c135
  • Assess ovarian and uterine size and evaluate for abnormalities
  • Indicated for primary evaluation of peripheral precocious puberty as a baseline assessment to monitor efficacy of treatment in girls with central precocious puberty and as an adjunct when needed to clarify whether child is having sustained exposure to estrogen (ie, borderline cases of presumed isolated thelarche)^r16
    • Evaluates for peripheral (ovarian) source of estrogen in girls
      • Helpful in absence of central precocious puberty
      • Can detect presence of ovarian mass
    • Evaluates for sustained exposure of uterus to estrogen
      • Uterine volume over 2 mL or length over 34 mm, pear-shaped uterus, and endometrial thickening suggestive of progressive precocious puberty (a result of sustained increase in estrogen) ^r11
    • Evaluates for sustained exposure of ovaries to estrogen
      • Multicystic morphology (over 6 cysts of 4 mm in diameter or greater) is consistent with progressive precocious puberty (a result of sustained increase in estrogen) ^r16
• Testicular ultrasonogram in boys ^c136
  • Evaluates for testicular mass; can detect Leydig cell tumors ^r36
  • Indicated if there is testicular asymmetry or evidence of peripheral precocious puberty
• Adrenal imaging (ultrasonogram or CT) ^r11c137c138
  • Indicated if virilization is present, dehydroepiandrosterone sulfate or adrenal steroid precursors are elevated, or precocious adrenarche is suspected
  • Can detect adrenal tumors

Procedures

Most common

• Differential diagnosis of premature pubertal changes
  • Nonprogressive precocious puberty ^r8c140
    • Puberty changes begin, but then either regress or stabilize without progression
    • Normal bone age and prepubertal uterus on ultrasonogram
    • Differentiate from progressive precocious puberty with observation over time
  • Isolated premature thelarche in girls ^c141c142
    • Unilateral or bilateral breast development (usually Tanner 2 or early 3) without other pubertal changes, growth acceleration, or advanced bone age ^r38
    • Often occurs in girls younger than 2 years,^r38r10rarely in girls older than 4 years;^r4 self-limiting condition that resolves without treatment within 6 months to 6 years after diagnosis^r3
    • Differentiate from precocious puberty by normal growth rate, absence of breast development progression, and normal bone age ^r16
    • If there is progression or growth acceleration, obtain bone age radiograph and results of laboratory testing (ie, luteinizing hormone, follicle-stimulating hormone, estradiol, and TSH) to definitively exclude early precocious pubertal changes; radiographic and biochemical evaluation does not show any evidence of precocious puberty
    • If the diagnosis is still in question, obtain pelvic ultrasonogram of ovaries and uterus; no pubertal changes affecting uterus or ovaries are evident with isolated premature thelarche
    • Children with isolated premature thelarche require clinical re-evaluation initially every 3 to 6 months to ensure sexual development is indeed isolated and not progressive (excluding early changes associated with progressive precocious pubertal process) ^r16
  • Isolated precocious menarche ^c143
    • Vaginal bleeding without breast development, growth rate acceleration, advanced bone age, or any other detectable medical, vaginal, or uterine abnormalities ^r39
    • Benign, self-limiting, rare cause of vaginal bleeding in a prepubertal child; cause is unclear ^r39
    • Often characterized by 1 to 6 episodes of vaginal bleeding; recurrent, continuous, or heavy bleeding is of greater concern for pathologic causes requiring evaluation in consultation with a pediatric endocrinologist, gynecologist, or urologist ^r10
    • Must exclude other diagnoses that cause prepubertal vaginal bleeding (eg, sexual abuse, arteriovenous malformation, foreign body, vaginal or uterine tumor, trauma, infection); may require imaging or examination under anesthesia
    • Precocious menarche is rarely an initial presentation of central precocious puberty or hypothyroidism
    • Differentiate from precocious puberty with test results showing reference range levels of luteinizing hormone, follicle-stimulating hormone, estradiol, and gonadotropin-releasing hormone stimulation; normal bone age radiography; and normal pelvic ultrasonography ^r39
  • Premature adrenarche ^c144c145c146
    • Adrenal maturation event that results in increased production of adrenal androgens (ie, dehydroepiandrosterone sulfate, dehydroepiandrosterone, and androstenedione) ^r7r22
      • Occurs before age 7 to 8 years in White girls, 6 to 7 years in Black girls, and 9 years in boys
    • Results in physical signs of androgen action (eg, adult-type body odor, oily skin and hair, acne, growth of axillary and pubic hair) without development of true pubertal signs (eg, testicular growth, penile growth, clitoromegaly, breast development, menarche)
    • Adrenarche is a separate process from puberty that occurs around the same time as puberty
    • Isolated premature pubarche (development of pubic hair without secondary sex characteristics or accelerated bone growth and maturation) usually develops in children between ages 4 to 6 years;^r3r4
      • More common in girls and in children with central nervous system abnormalities
      • Thought to be due to a relative mild increase in adrenal androgen production and is nonprogressive
    • Benign idiopathic premature adrenarche is most common in Black girls; levels of dehydroepiandrosterone sulfate are slightly elevated for age (eg, in the range of 30-150 mcg/dL) without activation of the hypothalamic-pituitary-gonadal axis (ie, luteinizing hormone, follicle-stimulating hormone, estradiol, or testosterone concentrations are in the prepubertal range) ^r10
    • Benign idiopathic premature adrenarche (initially characterized by premature pubarche) is a diagnosis of exclusion as certain pathologic processes (eg, milder and nonclassic variants of congenital adrenal hyperplasia, virilizing adrenal or gonadal tumors) must be excluded if child exhibits premature signs of androgen excess on physical examination ^r22
    • Pathologic causes of premature adrenarche typically result in clinically observed, rapidly progressive virilization; accelerated linear growth; and advanced bone age
    • Levels of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, 17α-hydroxyprogesterone, and testosterone obtained in consultation with a pediatric endocrinologist help differentiate pathologic causes of premature adrenarche from idiopathic premature adrenarche when children present with rapid growth, accelerated bone age, rapidly progressing virilization, or atypical signs ^r10r22
      • Low levels in the preadrenarchal range are reassuring for a nonpathologic process; adrenal androgen levels in the postadrenarche range (ie, dehydroepiandrosterone sulfate over 95 mcg/dL, dehydroepiandrosterone over 451.1 nmol/L, and androstenedione over 1.75 nmol/L) are concerning for a pathologic process ^r40
      • If levels are intermediate and nondiagnostic, adrenocorticotropic hormone–stimulation test results can help differentiate pathologic from nonpathologic cause of adrenarche
    • Children with benign idiopathic premature adrenarche initially require re-evaluation every 3 to 6 months to ensure the precocious development is indeed isolated and not progressive or associated with accelerated growth or advancing bone age (excluding early changes associated with a progressive precocious pubertal process or early pathologic premature adrenarche) ^r16
• Differential diagnosis and common causes of nonidiopathic, centrally mediated precocious puberty
  • Benign hypothalamic hamartoma ^c147
    • Nonneoplastic congenital malformation of ectopic gonadotropin-releasing hormone neurosecretory cells usually positioned on the floor of the third ventricle; these cells act as ectopic gonadotropin-releasing hormone pulse generators that produce central precocious puberty ^r4
    • Classically associated with gelastic (laughing) seizures that are often resistant to anticonvulsant therapy; absence or generalized tonic-clonic seizures may also be present ^r4
    • Many patients exhibit behavioral disturbances and mental retardation
    • Identified by central nervous system MRI imaging; consultation with a pediatric neuroradiologist is sometimes necessary because these lesions do not usually enhance with MRI imaging and smaller lesions may be difficult to detect on routine imaging ^r4
  • Other central nervous system tumors ^c148
    • Less common tumors that are positioned near the hypothalamus and impinge on or invade ventral hypothalamic nuclei can alter the normal inhibitory pathways for gonadotropin secretion, producing central precocious puberty ^r4
    • Various tumors responsible include craniopharyngiomas, astrocytomas, gliomas, neurofibromas, ependymomas, and suprasellar teratomas ^{r4c149c150c151c152c153c154}
    • Identified by central nervous system imaging; definitive diagnosis may require surgical resection and histopathologic identification
  • Secondary central precocious puberty from any cause of longstanding peripheral precocious puberty ^r4
    • Prolonged elevation of sex steroid levels can result in secondary activation of hypothalamic-pituitary-gonadal axis from any cause of peripheral precocious puberty
    • End result is central precocious puberty superimposed on peripheral precocious puberty as a result of long-standing, peripherally mediated elevation of sex hormones
    • Can be extremely difficult to differentiate from idiopathic precocious puberty, but there may be clues on history and physical examination that suggest peripheral cause
• Differential diagnosis and common causes of peripherally mediated precocious puberty
  • Ovarian tumors ^c155
    • Most common cause of peripheral precocious puberty in girls; account for 11% of all cases of precocious puberty in girls ^r4
    • Granulosa cell tumors are most common ^r4c156
      • Tumors that present with precocious puberty are usually more than 8 cm in diameter and 80% are palpable on abdominal examination ^r4
      • Often appear on ultrasonogram as complex cystic or solid structures, differentiating granulosa cell tumor from simple functioning ovarian cysts ^r4
    • Less common ovarian tumors associated with precocious puberty include thecomas, luteomas, Sertoli-Leydig cell tumors, teratomas, benign follicular cysts, and choriocarcinomas ^{r4c157c158c159c160c161c162}
    • Ovarian tumors are diagnosed by ultrasonography; definitive diagnosis may require surgical resection and histopathologic identification
  • Iatrogenic causes ^r4
    • Common cause of peripheral precocious puberty in girls
    • Common sources of peripheral exogenous estrogen include facial and cosmetic creams, shampoos, hormone-containing herbs (eg, lavender, tea tree oil^r41), oral contraceptives, and transdermal estrogen creams ^c163
    • Common sources of peripheral exogenous testosterone are gels containing testosterone ^r10c164
    • Hormones used on parents' skin can be transferred to a child with close contact
    • Careful history can separate exposure to exogenous estrogen or testosterone from other causes of peripheral precocious puberty
  • McCune-Albright syndrome ^c165d1
    • Sporadic disorder characterized by peripheral precocious puberty, café au lait spots, and polycystic fibrous dysplasia of the skull and long bones; accounts for about 5% of all cases of precocious puberty in girls ^r4
    • Somatic activating mutations of GNAS gene result in recurrent, autonomous ovarian cysts that autonomously produce estrogen^r4
    • Global defect in cellular regulation in various endocrine tissues is responsible for this disorder, so multiple endocrinopathies characterize this syndrome (eg, hyperthyroidism, adrenal nodules with Cushing syndrome, growth hormone–secreting pituitary adenomas, hyperparathyroidism, hypophosphatemic rickets) ^r4
    • History is sometimes significant for frequent bone fractures, as affected bones are fragile and prone to fracture ^r4
    • McCune-Albright syndrome is diagnosed clinically by the presence of at least 2 of the 3 classic findings: skin lesions, fibrous dysplasia, and endocrinopathy ^r42
    • If this syndrome is suspected, a skeletal survey and bone scan can aid in identification of lesions of bony fibrous dysplasia; ovarian ultrasonogram characteristically shows very large, asymmetric ovarian volumes with large autonomously functioning luteinized follicular cysts ^r4
  • Congenital adrenal hyperplasia ^c166d2
    • Classic form (21-hydroxylase deficiency) causes growth acceleration, accelerated bone maturation, and virilization, and it is associated with potentially life-threatening adrenal insufficiency and salt wasting ^r16
      • Diagnosis is made in infancy because of either abnormal state newborn screen, ambiguous genitalia noted at birth (clitoromegaly in female infants), or salt-wasting crisis in neonates (usual presentation in boys weeks after birth)
    • Clinical effects are predominately secondary to androgen exposure (eg, axillary hair, pubic hair, acne); boys do not typically have testicular enlargement and girls do not typically have breast development
    • Nonclassic form presents in childhood or adolescence with early pubic hair development and acne; may present in early adulthood with hirsutism, menstrual irregularity, or infertility ^r38
      • Up to 10% of children with premature adrenarche are diagnosed with late onset congenital adrenal hyperplasia ^r38
    • Exclude diagnosis of congenital adrenal hyperplasia in children with development of pubic and axillary hair and rapid growth (signs of androgen exposure) with adrenocorticotropic hormone stimulation testing ^r16
    • In congenital adrenal hyperplasia, results of adrenocorticotropic hormone stimulation testing will show large levels of precursor steroid that accumulate owing to a specific enzyme deficiency (eg, 17-hydroxyprogesterone level is high in 21-hydroxylase deficiency)
  • Adrenal neoplasms ^c167
    • Adrenal neoplasms present with rapidly progressing peripheral precocious puberty ^r16
    • Adrenal neoplasms can present with either isosexual or heterosexual precocious pubertal changes, but virilizing tumors are more common than feminizing tumors ^r4
    • Both testosterone and dihydroepiandrosterone are usually markedly elevated
    • Diagnosis is confirmed by imaging (eg, adrenal ultrasonography, CT, MRI)
  • Hypothyroidism ^c168d3
    • Longstanding, untreated, severe hypothyroidism uncommonly presents with peripheral precocious puberty; Hashimoto thyroiditis is usually the cause of the hypothyroidism ^r4
    • High levels of TSH may activate follicle-stimulating hormone receptors and cause gonadal enlargement ^r3
    • High levels of TSH, gonadotropins, and prolactin characterize this condition ^r4
    • Short stature, growth retardation, and delayed bone age distinguish this form of peripheral precocious puberty from other causes;^r4slow, as opposed to rapid, acceleration of growth velocity is characteristic^r10
    • Differentiate from other causes of peripheral precocious puberty by history and physical examination along with laboratory findings suggestive of high TSH and low free thyroxine levels; puberty is reversible with thyroid hormone replacement ^r4
  • Familial male-limited precocious puberty (testotoxicosis) ^c169
    • Autosomal dominant disease in boys exclusively, presenting with signs of puberty and accelerated growth around age 2 years ^r16
    • Cause is a genetic mutation resulting in activation of the luteinizing hormone receptor
    • Testosterone level is markedly elevated while gonadotropins levels are low and gonadotropin-releasing hormone–stimulation test findings are in the prepubertal range ^r43
    • Genetic analysis can confirm mutations responsible for this rare familial syndrome if the diagnosis remains in question ^r43

Recommendations for specialist referral

• Refer to the following specialists as appropriate:
  • Pediatric endocrinologist for evaluation and treatment recommendations ^r4
    • Precocious puberty in males represents a substantial risk of underlying pathology and requires urgent referral to a pediatric endocrinologist ^r27
  • Psychologist for counseling ^r4
  • Pediatric neurosurgeon if there is evidence of central nervous system lesion
  • Pediatric oncologist if there is evidence of central nervous system tumor
  • Appropriate pediatric surgical specialist (eg, gynecologist, urologist, surgeon) if there is evidence of ovarian, testicular, or adrenal mass

Drug therapy

• Gonadotropin-releasing hormone agonists ^c170
  • The Pediatric Endocrine Society Drug and Therapeutics Committee has reported that, in some patient populations, gonadotropin-releasing hormone agonists may cause prolonged QT interval; they released several recommendations for patients receiving gonadotropin-releasing hormone–agonist therapy ^r46
    • Recommendations include inquiring about other medications, conducting screening ECG in certain patients, and cardiologist referral for some patients
  • For treatment of central precocious puberty
    • Continuous exposure to a gonadotropin-releasing hormone analog results in subsequent down-regulation of gonadotropin-releasing hormone receptors and cessation of luteinizing hormone and follicle-stimulating hormone secretion in the anterior pituitary ^r3
    • With luteinizing hormone suppression, sex steroid levels return to prepubertal levels, halting progression of puberty and pubertal growth spurt
  • Choice of treatment depends on patient's individual needs, but depot forms are preferred because of improved adherence ^r28
    • Leuprolide depot injection ^c171
      • Given intramuscularly monthly or every 3 months
    • Histrelin implant ^c172
      • Capsule is inserted subcutaneously into upper arm
      • Suppression lasts for 12 to 24 months ^r47
    • Nafarelin ^c173
      • Nasal spray given twice per day
      • Useful in patients who cannot tolerate depot forms
• Peripheral precocious puberty ^c174
  • No drugs approved for treatment, but there have been small studies showing effectiveness in some conditions
    • McCune-Albright syndrome
      • Tamoxifen (selective estrogen receptor modulator) ^r44c175
      • Letrozole (aromatase antagonist) ^r48c176
      • Testolactone (aromatase inhibitor that prevents peripheral conversion of estrogen precursors to active estrogen) has been used historically to treat girls with disease ^r4c177
        • Off market; no aromatase inhibitors are approved or proven effective for treatment ^r49
    • Familial male-limited precocious puberty
      • Testolactone (blocks conversion of androgens to estrogen) and spironolactone (blocks action of androgens) ^r50c178
      • Ketoconazole (inhibits testosterone biosynthesis) ^r51c179

Nondrug and supportive care

• Counseling ^r4c180
  • Important for child and family
    • Address emotional problems that arise as a result of child's early sexual development; teasing from peers is common
    • Explain physical changes to child and provide sex education if needed
    • Foster emotional support network by involving pediatrician, psychologist, family, and teachers for best results
• Discontinue potential exogenous source of sex steroid exposure ^r18c181
  • Eliminate exposure from any hormone-containing creams, shampoos, or other products

Comorbidities ^c182