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    Precocious Puberty

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    Feb.05.2024

    Precocious Puberty

    Synopsis

    Key Points

    • Precocious puberty refers to early activation of the hypothalamic-pituitary-gonadal axis resulting in development of specific secondary sex characteristics and is typically defined as breast development (thelarche) in girls younger than 8 years, menarche in girls younger than 9 years, and testicular enlargement in boys younger than 9 years r1r2r3
    • Presents with early breast development in girls and testicular growth in boys
    • Associated with increased linear growth velocity and advanced bone age; signs of adrenarche such as development of pubic and axillary hair may also be present r4
    • Has a variety of underlying causes; precocious puberty is divided into central (gonadotropin-releasing hormone–dependent) causes and peripheral (gonadotropin-releasing hormone–independent) causes r4
    • Most central precocious puberty in girls is idiopathic; in boys, the cause of central precocious puberty is most often intracranial. Peripheral precocious puberty is most often secondary to a gonadal or adrenal disorder r4
    • Early involvement of an endocrinologist to assist with diagnosis and coordinate therapeutic interventions is important
    • Results of baseline hormone testing can confirm precocious puberty and help differentiate between central and peripheral precocious puberty; stimulation test may be needed if results of baseline testing are within reference range or equivocal r4
    • Imaging tests are the last step to evaluate for cause of precocious puberty; head MRI is indicated for patients with central precocious puberty, and pelvic or testicular ultrasonography is indicated for patients with peripheral precocious puberty r4
    • Central precocious puberty can be treated with gonadotropin-releasing hormone agonists r4
    • Peripheral precocious puberty treatment depends on underlying cause r4
    • Prognosis is good and height outcome is reasonable if treatment is started early r4

    Urgent Action

    • Vision changes in any patient with precocious puberty are concerning for central nervous system lesion with optic nerve involvement; obtain urgent head MRI with pituitary imaging and initiate prompt referral to pediatric neurosurgeon

    Pitfalls

    • Patients may not report exposure to topical hormone creams; it is important to specifically inquire about these products
    • If treatment is not initiated owing to slow progression of precocious pubertal changes, patients require continued close follow-up to evaluate for pubertal acceleration and need for treatment initiation

    Terminology

    Clinical Clarification

    • Precocious puberty refers to early activation of the hypothalamic-pituitary-gonadal axis resulting in development of specific secondary sex characteristics and is typically defined as breast development (thelarche) in girls younger than 8 years,r1 menarche in girls younger than 9 years,r3 and testicular enlargement in boys younger than 9 yearsr2
      • Studies suggest normal onset of puberty has been occurring earlier in the past few decades than previously described; exact age cutoff between normal and precocious development in girls is not universally agreed upon and is dependent on race and BMI r5r6r7r8
        • Onset of breast development may begin between ages 7 and 8 years in White girls
        • Onset of breast development may begin between ages 6 and 8 years in Black girls
        • Overweight girls experience earlier breast development than those of normal weight r9
    • Precocious puberty is different from precocious (or premature) adrenarche, which is characterized by early development of pubic hair (pubarche), axillary hair, body odor, and acne

    Classification

    • Central precocious puberty
      • Gonadotropin-releasing hormone–dependent precocious puberty with premature full activation of hypothalamic-pituitary-gonadal axis representing physiologically normal but chronologically early hypothalamic activation before the age of 8 years in girls and 9 years in boys r4r10
        • Secondary sex characteristics develop in a pattern of normal pubertal progression, leading to normal menses with ovulation and potential for pregnancy
        • Growth is accelerated and bone age is advanced
      • Also referred to as complete or true precocious puberty r4
    • Peripheral precocious puberty
      • Gonadotropin-releasing hormone–independent precocious puberty without activation of hypothalamic-pituitary-gonadal axis in a child of any age r4
        • Premature sexual maturation occurs independent of hypothalamic-pituitary-gonadal axis from an exogenous or endogenous peripheral sex hormone (testosterone or estrogen) source; result is development of secondary sex characteristics and can result in anovulatory cycles with irregular, heavy uterine bleeding
          • Often, the development of secondary sex characteristics occurs in an abnormal pattern, different from normal progression of puberty
        • Growth is accelerated and bone age is advanced
      • Also referred to as incomplete or pseudoprecocious puberty r4
    • Variations on normal puberty
      • Variations of normal growth and development that do not require laboratory testing, radiographs, or specific intervention are common and include benign premature adrenarche and benign premature thelarche
        • Benign premature thelarche is distinguished by nonprogressive breast development observed over a 4- to 6-month period, without rapid linear growth acceleration or accompanying signs of pubertal development; often occurs in girls younger than 2 years r10
        • Benign premature adrenarche is distinguished by early onset of pubic hair (pubarche) and/or body odor (before age 8 years in girls and 9 years in boys) without rapid linear growth acceleration or evidence of clitoromegaly, penile growth, or testicular enlargement; most commonly occurs in Black girls r10
    • Endocrine mediators of sexual development r10
      • Puberty is triggered by an increase in pulsatile secretion of gonadotropin-releasing hormone (ie, gonadarche or activation of the hypothalamic-pituitary-gonadal axis)
        • Gonadotropin-releasing hormone stimulates secretion of the gonadotropins luteinizing hormone and follicle-stimulating hormone
          • Luteinizing hormone stimulates ovaries to secrete estradiol and testes to secrete testosterone
          • Follicle-stimulating hormone promotes development of oocytes or spermatozoa and increases size of gonads
          • Luteinizing hormone and follicle-stimulating hormone work in synergy to stimulate male and female gonads and regulate maturation of sexual and reproductive function
            • Estradiol causes progressive breast enlargement, pubertal growth spurt in girls, and rapid bone age advancement
            • Testosterone causes penile enlargement and pubic hair growth in boys and, by conversion to estradiol, causes pubertal growth spurt in boys
      • Adrenarche is mediated largely by adrenal glands, and effects are secondary to circulating androgens (dehydroepiandrosterone and dehydroepiandrosterone sulfate); unrelated to activation of the hypothalamic-pituitary-gonadal axis

    Diagnosis

    Clinical Presentation

    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 development 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
    • 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 mLr10 or testicular length greater than 25 mm signals onset of pubertyr2c41
        • 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 and Risk Factors

    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
            • DLK1 loss-of-function mutations r15
        • 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 r16c65
              • 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 long-term exposure to sex steroids (eg, McCune-Albright syndrome, congenital adrenal hyperplasia) r17c83c84c85c86
    • 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 r18r19c95c96
          • 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 r20c102
        • 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

    Age
    • In girls older than 4 years with central precocious puberty, cause is more often idiopathic and is rarely identified r4c106
    • In girls aged 4 years or younger with central precocious puberty, a central nervous system lesion is often identified r4c107
    Sex
    • Female to male ratio is 5:1 r21c108c109
    • Approximately 1 in 180 girls in the United States experiences precocious pubertyr4; precocious puberty is much less common in boysr22
    Ethnicity/race
    • 5-fold higher incidence of idiopathic precocious puberty in Black girls r23c110c111
    Other risk factors/associations
    • Higher risk for idiopathic precocious puberty in the following patient populations:
      • Internationally adopted girls r21r24c112
      • Children with early weight gain or obesity in infancy and early childhood r25c113c114
        • Children with low birth weight r26c115

    Diagnostic Procedures

    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 workup 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 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 one linear growth percentile channel on growth chart) is one of the first signs of precocious puberty r10
      • Obtain radiographic bone age estimate for all children with signs of precocious puberty to determine whether additional immediate investigation is necessary r8r10
        • 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 centimeters)
          • For girls: (mother's height in cm + father's height in cm − 13) / 2 r27
          • For boys: (mother's height in cm + father's height in cm + 13) / 2 r27
      • Proceed with workup in the following groups: r8
        • Girls with breast development before age 7 years (White girls) or age 6 years (Black girls) r8
        • Girls with breast development beginning after age 7 years (White girls) or age 6 years (Black girls) with the following: r8
          • Significant bone age advancement (greater than 2 standard deviations ahead of chronological age) and predicted height of 2 standard deviations or more below genetic target height or predicted height less than 150 cm r8
          • New central nervous system findings (eg, headaches, seizures, hydrocephalus) r8
          • Behavioral factors such as maturity level leading to difficulty dealing with effects of pubertal progression r8
        • Boys with onset of pubertal changes before age 9 years r8
    • 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 r10r28c117c118c119c120
      • 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 test results are inconclusive
          • Differentiate between central and peripheral precocious puberty
      • Findings consistent with central and peripheral precocious puberty
        • The 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 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 for patients with precocious puberty include:
        • Brain MRI with special attention to hypothalamus and pituitary glands for patients found to have central cause of precocious puberty
        • Pelvic or testicular ultrasonogram for patients found to have peripheral cause of precocious puberty c122c123
    • For 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) r29c128c129
        • Reference range gonadotropin levels based on Tanner stage or age r30
          • 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 r4r31
            • Luteinizing hormone over 0.3 units/L is the most reliable screen for central precocious puberty r10
            • Gonadotropins are much higher compared with those in 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 than in 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) r30
        • 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 r30
          • 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 for girls for 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 r32
          • Elevated in primary hypothyroidism
          • Normal or low in central hypothyroidism
        • Free thyroxine r32
          • Low in primary and central hypothyroidism

    Imaging

    • Bone age radiograph c132
      • Determine bone age by comparing radiographs of patient's left hand and wrist with standard reference imagesr11 published in an atlas such as Greulich and Pyler33
      • 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 r34
    • 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 among girls older than 6 years (2%) r35
        • Higher prevalence of lesions among boys (40%-90%) r36
        • Obtain head MRI for all boys with central precocious puberty and girls younger than 6 years with central precocious puberty r10r29
          • 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 for 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)r17
        • 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 more than 2 mL or length more than 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 (more than 6 cysts of 4 mm in diameter or greater) is consistent with progressive precocious puberty (a result of sustained increase in estrogen) r17
    • Testicular ultrasonogram for boys c136
      • Evaluates for testicular mass; can detect Leydig cell tumors r37
      • 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

    Leuprolide stimulation test (ie, gonadotropin-releasing hormone–stimulation test) c139
    General explanation
    • Classic test to confirm central precocious puberty r4
      • Needed only if baseline gonadotropins are not in pubertal range (less than 0.3 units/L using ultrasensitive assay) r11
    • Administered subcutaneously
    • Multiple protocols exist, but generally, luteinizing hormone levels are obtained at baseline and then at 3 and 24 hours after leuprolide is given r38
    Indication
    • Suspicion for central precocious puberty that cannot be confirmed using results of baseline laboratory tests
    • To differentiate central from peripheral precious puberty
    Interpretation of results
    • Peak luteinizing hormone greater than 5 to 8 international units/L or basal luteinizing hormone greater than 0.3 units/L is diagnostic of central precocious puberty r29r31
    • Prepubertal gonadotropin status is established by a minimal rise in luteinizing hormone level r4
    • Premature thelarche can result in a follicle-stimulating hormone–predominant response to leuprolide stimulation test (ie, gonadotropin-releasing hormone–stimulation test) r3

    Differential Diagnosis

    Most common

    • Differential diagnosis of premature pubertal changes
      • Nonprogressive precocious puberty r5c140
        • 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 r39
        • Often occurs in girls younger than 2 years,r39r10rarely in girls older than 4 years;r4 self-limiting condition that resolves without treatment within 6 months to 6 years after diagnosisr3
        • Differentiate from precocious puberty by normal growth rate, absence of breast development progression, and normal bone age r17
        • 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 evaluations do 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) r17
      • Isolated precocious menarche c143
        • Vaginal bleeding without breast development, growth rate acceleration, advanced bone age, or any other detectable medical, vaginal, or uterine abnormalities r40
        • Benign, self-limiting, rare cause of vaginal bleeding in a prepubertal child; cause is unclear r40
        • 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 findings r40
      • Premature adrenarche c144c145c146
        • Adrenal maturation event that results in increased production of adrenal androgens (ie, dehydroepiandrosterone sulfate, dehydroepiandrosterone, and androstenedione) r8r23
          • 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 and 6 yearsr3r4
          • More common in girls and in children with central nervous system abnormalities
          • Thought to be due to a relatively 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 r23
        • 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 r10r23
          • Low levels in the preadrenarchal range are reassuring for a nonpathologic process; adrenal androgen levels in the postadrenarchal 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 r41
          • If levels are intermediate and nondiagnostic, ACTH-stimulation test results can help differentiate pathologic from nonpathologic causes 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) r17
    • 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 longstanding, peripherally mediated elevation of sex hormones
        • Can be extremely difficult to differentiate from idiopathic precocious puberty, but there may be clues in history and physical examination findings 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 tumors 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 oilr42), 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 estrogenr4
        • 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 r43
        • 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, asymmetrical ovarian volumes with large autonomously functioning luteinized follicular cysts r4
      • Congenital adrenal hyperplasia c166
        • 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 r17
          • 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 r39
          • Up to 10% of children with premature adrenarche are diagnosed with late-onset congenital adrenal hyperplasia r39
        • Exclude diagnosis of congenital adrenal hyperplasia in children with development of pubic and axillary hair and rapid growth (signs of androgen exposure) with ACTH stimulation testing r17
        • In congenital adrenal hyperplasia, results of ACTH stimulation testing will show high 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 r17
        • 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 dehydroepiandrosterone levels are usually markedly elevated
        • Diagnosis is confirmed by imaging (eg, adrenal ultrasonography, CT, MRI)
      • Hypothyroidism c168d2
        • 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 characteristicr10
        • Differentiate from other causes of peripheral precocious puberty by history and physical examination findings 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 r17
        • Cause is a genetic mutation resulting in activation of the luteinizing hormone receptor
        • Testosterone level is markedly elevated, while gonadotropin levels are low, and gonadotropin-releasing hormone–stimulation test findings are in the prepubertal range r44
        • Genetic analysis can confirm mutations responsible for this rare familial syndrome if the diagnosis remains in question r44

    Treatment

    Goals

    • Reduce sex steroid effects and maximize eventual adult height r4
    • Counsel to address emotional problems and explain physical changes to child; provide contraception advice if needed r4
    • Central precocious puberty
      • Eliminate gonadotropin secretion to halt progression of puberty r4
      • Address primary cause if central nervous system lesion is present
    • Peripheral precocious puberty
      • Address underlying cause
        • Surgical resection for gonadal or adrenal tumors
        • Discontinue any external exposure to exogenous source
        • Medical treatment may be helpful for McCune-Albright syndrome and familial male-limited precocious puberty r45

    Disposition

    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 r28
      • 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

    Treatment Options

    Treat all patients with precocious puberty in consultation with a subspecialist with expertise treating disease (eg, endocrinologist)

    Timely referral is important to ensure children can benefit from treatment, but be clear with patients about the uncertainty of benefits over harms from investigation and treatment

    Vision changes in any patient with precocious puberty are concerning for central nervous system lesion with optic nerve involvement; obtain urgent head MRI with pituitary imaging and initiate prompt referral to pediatric neurosurgeon

    Central precocious puberty

    • Gonadotropin-releasing hormone agonists
      • Suppresses hypothalamic-pituitary-gonadal axis to halt pubertal progression and pubertal growth spurt r4
        • Continuous exposure to a gonadotropin-releasing hormone analog results in subsequent downregulation 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
      • Benefits of gonadotropin-releasing hormone–agonist therapy are debated, and girls may be at risk for overtreatment r28
      • Treatment has a role in preserving adult height potential for children with precocious puberty aged 6 years and younger; there is limited evidence of benefit in idiopathic precocious puberty that is not rapidly progressing before age 7 years r28
      • Indications for treatment
        • Predicted height is less than 152.4 cm for girls or less than 165.1 cm for boys, especially if younger than 7 years r10
        • Bone age more than 2 years older than chronological age r4
        • Progressive thelarche and pubarche,r4especially if younger than 6 yearsr29
        • Menarche before age 8 years r4
      • Treatment is individualized and determined by patient's age, rate of progression of pubertal changes, rate of growth acceleration, degree of anticipated decrease in final adult height, and degree of psychological distress associated with early pubertal changes r17
        • Choice of treatment depends on patient's individual needs, but depot formulations are preferred because of improved adherence r29
        • Long-acting formulations include leuprolide intramuscular depot, histrelin subcutaneous implant, and triptorelin intramuscular suspension
          • Must be administered by a health care professional
        • Short-acting option limited to nafarelin nasal spray
          • Useful for patients who cannot tolerate depot forms
          • FDA approval of leuprolide subcutaneous injection for daily use for patients with pediatric central precocious puberty has been removed
      • Duration of treatment varies but usually continues until the average age of typical puberty r46
        • Gonadotropin secretion resumes approximately 4 months after discontinuation of therapy r3
          • Girls often begin menstruation within about 1 year r3
    • Rarely, treatment of central precocious puberty requires resection of tumor, chemotherapy, and/or radiation therapy r17
      • Management of central nervous system lesions has no effect on progression of pubertal development r11
      • Medical treatment is preferred for pedunculated hamartomas (a more common cause) r17

    Peripheral precocious puberty

    • Treatment depends on the cause
      • May require surgical resection of gonadal or adrenal tumor, possibly chemotherapy or radiation therapy r4
      • Discontinue any identified iatrogenic source of sex hormone r4
      • Use tamoxifen or letrozole to treat McCune-Albright syndrome r4
      • Use either ketoconazole or a combination of an aromatase inhibitor and spironolactone for familial male-limited precocious puberty r17
        • Ketoconazole inhibits testosterone biosynthesis
        • Aromatase inhibitors decrease serum estrogen levels to mitigate skeletal maturation
        • Spironolactone blocks androgen receptors
      • Provide thyroid replacement for patients with hypothyroidism r4

    Drug therapy

    • For treatment of central precocious puberty c170
      • Gonadotropin-releasing hormone agonists
        • Long-acting formulations
          • Leuprolide acetate suspension depot injection c171
            • Every 4 weeks regimen
              • Leuprolide Acetate Suspension for injection [Precocious Puberty]; Children weighing 25 kg or less: 7.5 mg IM every 4 weeks. Increase the dose to the next available higher dose at next monthly injection if inadequate hormonal and clinical suppression. May adjust dose if changes in body weight occur. Max: 15 mg/dose.
              • Leuprolide Acetate Suspension for injection [Precocious Puberty]; Children weighing more than 25 kg to 37.5 kg: 11.25 mg IM every 4 weeks. Increase the dose to the next available higher dose at next monthly injection if inadequate hormonal and clinical suppression. May adjust dose if changes in body weight occur. Max: 15 mg/dose.
              • Leuprolide Acetate Suspension for injection [Precocious Puberty]; Children weighing more than 37.5 kg: 15 mg IM every 4 weeks. May adjust dose if changes in body weight occur. Max: 15 mg/dose.
            • Every 12 weeks regimen
              • Leuprolide Acetate Suspension for injection [Precocious Puberty]; Children: 11.25 or 30 mg IM every 12 weeks.
            • Every 24 weeks regimen
              • Intramuscular
                • Leuprolide Acetate Suspension for injection [Precocious Puberty]; Children: 45 mg IM every 6 months.
              • Subcutaneous
                • Leuprolide Acetate Suspension for injection [Precocious Puberty]; Children 2 to 12 years: 45 mg subcutaneously every 6 months.
          • Histrelin acetate implant r47c172
            • Histrelin Acetate Implant [Precocious puberty]; Children 2 to 12 years: 50 mg subcutaneously every 12 months. Remove and replace the implant after 12 months to continue therapy.
          • Triptorelin suspension injection
            • Triptorelin Suspension for injection, Extended Release [Precocious Puberty]; Children 2 to 12 years: 22.5 mg IM every 24 weeks.
        • Short-acting formulation
          • Nafarelin nasal spray c173
            • Nafarelin Acetate Nasal spray, solution; Children: 400 mcg in each nostril twice daily. May increase the dose to 600 mcg in alternating nostrils 3 times daily if inadequate suppression. Max: 1,800 mcg/day.
    • Peripheral precocious puberty c174
      • No drugs approved for treatment, but there have been small studies showing effectiveness in some conditions
        • McCune-Albright syndrome
          • Selective estrogen receptor modulator r45c175
            • Tamoxifen
              • Tamoxifen Citrate Oral solution; Children and Adolescents 2 to 13 years: 10 to 20 mg PO once daily.
          • Aromatase inhibitor r48c176
            • Letrozole c177
              • Letrozole Oral tablet; Children: 2.5 mg PO once daily. Alternatively, 0.5 mg/m2/day PO divided every 12 hours for 7 days, then 1 mg/m2/day PO divided every 12 hours for 7 days, and then 1.5 mg/m2/day PO divided every 12 hours. May reduce or increase dose if pubertal regression or progression, respectively, occurs during therapy. Max: 2 mg/m2/day.
        • Familial male-limited precocious puberty
          • Antiandrogen therapy
            • Ketoconazole r49c178
              • Ketoconazole Oral tablet; Children and Adolescents: 10 to 20 mg/kg/day PO divided every 8 to 12 hours, or alternatively, 200 mg PO every 8 to 12 hours, initially. May increase the dose by 100 mg/day for testosterone concentration more than 0.5 ng/mL. Max: 700 mg/day.
            • Spironolactone r50c179
              • Spironolactone Oral suspension; Children and Adolescents: 1.5 mg/kg/day divided every 12 hours for 7 days, then 3 mg/kg/day divided every 12 hours for 7 days, then 5.7 mg/kg/day divided every 12 hours. Max: 500 mg/day.
          • Aromatase inhibitor
            • Letrozole
              • Letrozole Oral tablet; Children: 2.5 mg PO once daily. Alternatively, 0.5 mg/m2/day PO divided every 12 hours for 7 days, then 1 mg/m2/day PO divided every 12 hours for 7 days, and then 1.5 mg/m2/day PO divided every 12 hours. May reduce or increase dose if pubertal regression or progression, respectively, occurs during therapy. Max: 2 mg/m2/day.

    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 to any hormone-containing creams, shampoos, or other products

    Comorbidities c182

    Monitoring

    • Monitoring with gonadotropin-releasing hormone–agonist treatment
      • Primary monitoring
        • Often, monitoring is clinical; some endocrinologists obtain laboratory test results after initiation of treatment
        • Levels of serum gonadotropins and sex steroids are sometimes obtained c183
          • Goal levels are within prepubertal range r4
            • Long-acting leuprolide formulation r51
              • After initiation of therapy, interval for monitoring response is based on selected regimen
                • 1-month regimen: 1 to 2 months
                • 3-month regimen: months 2 to 3 and month 6
                • 6-month regimen: months 5 to 6
          • A single gonadotropin measurement after gonadotropin-releasing hormone–agonist dose can replace gonadotropin-releasing hormone–stimulation testing; leuprolide injection itself functions as a gonadotropin-releasing hormone–stimulation test r52r53
        • Bone age and linear growth c184
          • Bone age is monitored in children with precocious puberty at 6-month intervals to evaluate rate of skeletal maturation and effectiveness of treatment;r4deceleration of skeletal age maturation is apparent after 6 months of effective treatment
          • Goal rate of linear growth slows to a prepubertal rater41(eg, slowing of growth velocity to less than 7 cm/year)r10
        • Pubertal changes on physical examination c185
          • Breast size will stabilize or decrease slightly, and menses will cease within the first 6 months of effective therapy r4
          • Testicular size will stabilize or decrease slightly with effective therapy r3
          • Gonadotropin-releasing hormone–agonist therapy does not affect adrenal androgen production
            • Pubic hair stage is primarily influenced by adrenal androgen production; therefore, any pubic hair changes may slowly advance in certain patients despite effective treatment owing to the separate endocrinologic process of adrenarche
        • Medication adverse reactions r51
          • During initiation of therapy (eg, the first 4 weeks or after subsequent doses), gonadotropins and sex steroids may increase due to initial stimulatory effect of the medication, resulting in an increase in signs and symptoms of pubertal progression (eg, vaginal bleeding)
            • Patients should be evaluated if these signs or symptoms continue after the second month of treatment or dose change
          • Caregivers and patients should be instructed to monitor for psychiatric events (eg, emotional lability, irritability, aggression), convulsions, and idiopathic intracranial hypertension (pseudotumor cerebri)
          • The Pediatric Endocrine Society Drug and Therapeutics Committee has reported that, in some patient populations, gonadotropin-releasing hormone agonists may cause prolonged QT interval. Before starting therapy, the following should occur: r54
            • Inquire about other medications the patient may be taking or any symptoms concerning for an arrhythmia
            • A screening ECG should be obtained if the patient is receiving other medications that prolong the QT interval; has a history of congenital heart disease, arrhythmia, or long QT syndrome; has any family history of sudden cardiac death or long QT syndrome; or has symptoms concerning for long QT syndrome (eg, syncope)
              • Obtain a repeat ECG when the gonadotropin-releasing hormone agonist medication is at steady state
            • A cardiology consult should be obtained if patient has long QT syndrome, any ECG abnormalities (eg, prolonged QTc interval), or symptoms or family history of sudden cardiac death or long QT syndrome
            • Counsel the patient about arrhythmia symptoms (eg, palpitations, syncope)
            • Continue to ask periodically about any new medications during ongoing treatment
        • No further biochemical monitoring is necessary if serum gonadotropin and sex steroid levels are prepubertal and gonadotropin suppression is achieved as demonstrated by diminished acceleration in growth velocity and skeletal maturation and arrested clinical pubertal progression r17
      • Secondary monitoring is indicated if primary measures are inconclusive or if there is concern about continued progression of puberty during treatment
        • Ultrasonography of uterus and ovaries
          • Uterine and ovarian changes can be monitored to determine clinical response to treatment r4
          • With effective treatment of central precocious puberty, ovarian and uterine size and dimensions regress
        • Gonadotropin-releasing hormone–stimulation test
          • Gonadotropin-releasing hormone–stimulation test is sometimes necessary if there is concern about progression of puberty for patients with a histrelin implant because random luteinizing hormone often remains pubertal r55
          • Luteinizing hormone levels are blunted, exhibiting a prepubertal response with effective therapy r41
      • Monitoring of children who do not require immediate treatment
        • If treatment is not initiated owing to slow progression of precocious pubertal changes, presumed isolated benign thelarche or adrenarche, or absence of increased linear growth and skeletal maturation, patients require continued close clinical follow-up to evaluate for pubertal acceleration and need for treatment initiation
          • Initially follow up children at 3- to 6-month intervals to clinically assess for pubertal progression r17
          • Further evaluation is indicated if child develops pubertal progression or accelerated linear growth associated with advanced bone age r17

    Complications and Prognosis

    Complications

    • Untreated precocious puberty may lead to early growth plate fusion and subsequent short stature c186
      • However, girls with borderline early-onset puberty (between ages 6 and 8 years) usually reach normal adult height (and treatment may not be indicated) r8
    • Precocious puberty can lead to psychosocial difficulties c187
      • Mood changes associated with early puberty are perceived by some families as disruptive r3
      • Differences among children with precocious puberty (eg, early sexual development, menses, erections) can lead to embarrassment, disruptive behavior at school, teasing from peers, and difficulty in social adjustment r3
      • Precocious puberty can lead to unwanted sexual advances and early sexual activity r3
    • Central nervous system lesions that cause precocious puberty can cause other pituitary dysfunction and optic nerve abnormalities
      • Diabetes insipidus c188
      • Growth hormone deficiency c189
      • Hypothyroidism c190
      • Adrenal insufficiency c191
      • Visual defects c192

    Prognosis

    • In 400 girls receiving gonadotropin-releasing hormone until age 11 years, mean adult height was 160 cm r56
      • Gains of 3 cm to 10 cm over predicted height
    • Treatment initiated at a younger age and of longer duration is associated with greater height r57
    • After stopping gonadotropin-releasing hormone–agonist treatment, puberty progresses and menarche occurs, on average, 16 months later r11
      • Most females with history of precocious puberty have normal menstrual cycles and normal external appearance and do not experience premature menopause r4
      • Most people with history of precocious puberty have normal fertility r4
    • Majority have normal psychological outcomes r4
      • Minority will experience longer-lasting psychological difficulties (eg, depression, moodiness, social withdrawal, hyperactivity)

    Screening and Prevention

    Screening c193

    Prevention

    • Avoid use of estrogen- or androgen-containing topical products for children r18r19c194
    Marshall WA et al: Variations in pattern of pubertal changes in girls. Arch Dis Child. 44(235):291-303, 19695785179Marshall WA et al: Variations in the pattern of pubertal changes in boys. Arch Dis Child. 45(239):13-23, 19705440182Dixon JR et al: Precocious puberty. Paediatr Child Health.17(9):343-8, 2007http://www.sciencedirect.com/science/article/pii/S1751722207001473Hines CM et al: The clinical evaluation and treatment of female precocious puberty. Primary Care Update for OB/GYNS. 10(1):44–50, 2003http://www.sciencedirect.com/science/article/pii/S1068607X02001452Kaplowitz P: Clinical characteristics of 104 children referred for evaluation of precocious puberty. J Clin Endocrinol Metab. 89(8):3644-50, 200415292280Biro FM et al: Puberty in girls of the 21st century. J Pediatr Adolesc Gynecol. 25(5):289-94, 201222841372Herman-Giddens ME et al: Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics. 99(4):505-12, 19979093289Kaplowitz PB et al: Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics. 104(4 Pt 1):936-41, 199910506238Biro FM et al: Onset of breast development in a longitudinal cohort. Pediatrics. 132(6):1019-27, 201324190685Kaplowitz P et al: Evaluation and referral of children with signs of early puberty. Pediatrics. 137(1), 201626668298Carel JC et al: Clinical practice: precocious puberty. N Engl J Med. 358(22):2366-77, 200818509122Silveira LG et al: Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab. 95(5):2276-80, 201020237166Teles MG et al: A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med. 358(7):709-15, 200818272894Macedo DB et al: Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J Clin Endocrinol Metab. 99(6):E1097-103, 201424628548Maione L et al: Central precocious puberty: Recent advances in understanding the aetiology and in the clinical approach. Clin Endocrinol (Oxf). 95(4):542-555, 202133797780Listernick R et al: Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 61(3):189-98, 200717387725Merke DP et al: Evaluation and management of precocious puberty. Arch Dis Child. 75(4):269-71, 19968984908Stephen MD et al: Sexual precocity in a 2-year-old boy caused by indirect exposure to testosterone cream. Endocr Pract. 14(8):1027-30, 200819095605Guarneri MP et al: Estrogen exposure in a child from hair lotion used by her mother: clinical and hair analysis data. Clin Toxicol (Phila). 46(8):762-4, 200818763154Christens A et al: Van Wyk and Grumbach syndrome: an unusual form of precocious puberty. Gynecol Endocrinol. 30(4):272-6, 201424568556Teilmann G et al: Early puberty in internationally adopted girls: hormonal and clinical markers of puberty in 276 girls examined biannually over two years. Horm Res. 72(4):236-46, 200919786795Teilmann G et al: Prevalence and incidence of precocious pubertal development in Denmark: an epidemiologic study based on national registries. Pediatrics. 116(6):1323-8, 200516322154Idkowiak J et al: Premature adrenarche: novel lessons from early onset androgen excess. Eur J Endocrinol. 165(2):189-207, 201121622478Teilmann G et al: Increased risk of precocious puberty in internationally adopted children in Denmark. Pediatrics. 118(2):e391-9, 200616882780Ahmed ML et al: Childhood obesity and the timing of puberty. Trends Endocrinol Metab. 20(5):237-42, 200919541497Ibáñez L et al: Early puberty-menarche after precocious pubarche: relation to prenatal growth. Pediatrics. 117(1):117-21, 200616396868Tanner JM et al: Standards for children's height at ages 2-9 years allowing for heights of parents. Arch Dis Child. 45(244):755-62, 19705491878Bradley SH et al: Precocious puberty. BMJ. 368:l6597, 202031932347Carel JC et al: Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 123(4):e752-62, 200919332438Atteih S et al: Endocrinology. In: Kleinman K et al, eds: The Harriet Lane Handbook. 22nd ed. Elsevier; 2021:228-60.e3Fuqua JS: Treatment and outcomes of precocious puberty: an update. J Clin Endocrinol Metab. 98(6):2198-207, 201323515450Kaplowitz PB: Subclinical hypothyroidism in children: normal variation or sign of a failing thyroid gland? Int J Pediatr Endocrinol. 2010:281453, 201020628588Greulich W et al: Radiographic Atlas of Skeletal Development of the Hand and Wrist. Stanford University Press; 1959Bar A et al: Bayley-Pinneau method of height prediction in girls with central precocious puberty: correlation with adult height. J Pediatr. 126(6):955-8, 19957776106Chalumeau M et al: Selecting girls with precocious puberty for brain imaging: validation of European evidence-based diagnosis rule. J Pediatr. 143(4):445-50, 200314571217De Sanctis V et al: Etiology of central precocious puberty in males: the results of the Italian Study Group for Physiopathology of Puberty. J Pediatr Endocrinol Metab. 13(Suppl 1):687-93, 200010969910Liu G et al: Leydig-cell tumors caused by an activating mutation of the gene encoding the luteinizing hormone receptor. N Engl J Med. 341(23):1731-6, 199910580072Ibáñez L et al: Use of leuprolide acetate response patterns in the early diagnosis of pubertal disorders: comparison with the gonadotropin-releasing hormone test. J Clin Endocrinol Metab. 78(1):30-5, 19947507123Muir A: Precocious puberty. Pediatr Rev. 27(10):373-81, 200617012487Pinto SM et al: Prepubertal menarche: a defined clinical entity. Am J Obstet Gynecol. 195(1):327-9, 200616813762Lee PA: Central precocious puberty: an overview of diagnosis, treatment, and outcome. Endocrinol Metab Clin North Am. 28(4):901-18, xi, 199910609126Henley DV et al: Physiological effects and mechanisms of action of endocrine disrupting chemicals that alter estrogen signaling. Hormones (Athens). 9(3):191-205, 201020688617Lietman SA et al: Genetic and molecular aspects of McCune-Albright syndrome. Pediatr Endocrinol Rev. 4(Suppl 4):380-5, 200717982384Clark PA et al: Testotoxicosis: an unusual presentation and novel gene mutation. Clin Pediatr (Phila). 34(5):271-4, 19957628171Eugster EA et al: Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. J Pediatr. 143(1):60-6, 200312915825Carel JC et al: Final height after long-term treatment with triptorelin slow release for central precocious puberty: importance of statural growth after interruption of treatment. French study group of Decapeptyl in precocious puberty. J Clin Endocrinol Metab. 84(6):1973-8, 199910372696Eugster EA et al: Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial. J Clin Endocrinol Metab. 92(5):1697-704, 200717327379Feuillan P et al: Letrozole treatment of precocious puberty in girls with the McCune-Albright syndrome: a pilot study. J Clin Endocrinol Metab. 92(6):2100-6, 200717405850Soriano-Guillén L et al: Adult height after ketoconazole treatment in patients with familial male-limited precocious puberty. J Clin Endocrinol Metab. 90(1):147-51, 200515522928Leschek EW et al: Six-year results of spironolactone and testolactone treatment of familial male-limited precocious puberty with addition of deslorelin after central puberty onset. J Clin Endocrinol Metab. 84(1):175-8, 19999920079Lupron Depot-Ped (leuprolide acetate for depot suspension) package insert. North Chicago, IL: Abbott Laboratories; 2023 April. Accessed January 15, 2024.https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/020263s053lbl.pdfAcharya SV et al: Utility of single luteinizing hormone determination 3 h after depot leuprolide in monitoring therapy of gonadotropin-dependent precocious puberty. Pituitary. 12(4):335-8, 200919396631Bhatia S et al: Serum luteinizing hormone rises within minutes after depot leuprolide injection: implications for monitoring therapy. Pediatrics. 109(2):e30, 200211826240Drug and Therapeutics Committee of the Pediatric Endocrine Society: Risk of Prolonged QT Interval with Gonadotropin Releasing Hormone Agonists. PES website. Published October 18, 2017. Accessed November 15, 2023. https://pedsendo.org/clinical-resource/revised-dt-statement-on-gnrha-and-prolonged-qt-2017/https://pedsendo.org/clinical-resource/revised-dt-statement-on-gnrha-and-prolonged-qt-2017/Lewis KA et al: Random luteinizing hormone often remains pubertal in children treated with the histrelin implant for central precocious puberty. J Pediatr. 162(3):562-5, 201323040793Carel JC et al: Precocious puberty and statural growth. Hum Reprod Update. 10(2):135-47, 200415073143Klein KO et al: Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience. J Clin Endocrinol Metab. 86(10):4711-6, 200111600530
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