Central Precocious Puberty Guideline Resources

Recommendation 1

In girls who present with thelarche (Tanner B2) between ages 7.0 and 8.0 years, we suggest watchful waiting via periodic physical examinations rather than immediately performing evaluation with laboratory testing and/or radiologic imaging. (2 | ⊕OOO)

Technical remarks:

• Thelarche is defined as Tanner B2 (i.e., Tanner stage II) breast development and should be distinguished from lipomastia (i.e., the accumulation of fatty tissue) on physical exam by palpation in girls with overweight or obesity.
• In this context, “additional evaluation” means laboratory testing (e.g., serum LH and sex steroid concentrations) and a bone age assessment (i.e., hand and wrist radiography), with subsequent evaluation (e.g., GnRH/GnRHa stimulation test) performed when indicated.
• In this context, “watchful waiting” means conducting periodic physical examinations (every 4-6 months), including reassessment of growth and Tanner staging, to identify rapid growth and pubertal progression to Tanner B3 or greater.
• The panel judged that immediate additional diagnostic evaluation would be appropriate for girls younger than 8 years who present with Tanner B3 or higher, who progress to Tanner B3 under observation, and/or who have documented growth acceleration (i.e., increasing height percentiles, pubertal growth velocity >6 cm/year).
• This recommendation does not apply to girls with early thelarche who also exhibit CNS findings (e.g., headaches, seizures, visual field deficits, etc.). The guideline-development panel assumed that such girls should be promptly evaluated by a pediatric endocrinologist and other appropriate specialists.
• This recommendation is not intended to discourage primary care providers from referring these patients to pediatric endocrinologists as needed.

Recommendation 2

In girls younger than age 7 years with initial breast development (Tanner B2), we suggest a 4- to 6-month period of observation to differentiate unsustained or slowly progressive puberty from rapidly progressive puberty before starting diagnostic evaluation. (2 | ⊕OOO)

Technical remarks:

“A period of observation” refers to periodic physical examinations (i.e., reassessment of growth velocity and Tanner staging) every 4 to 6 months.

• The panel judged that immediate additional diagnostic evaluation would be appropriate for girls younger than 7 years who present with Tanner B3 or higher, who progress to Tanner B3 before age 8 years, and/or have documented growth acceleration (i.e., increasing height percentiles, pubertal growth velocity >6 cm/year). Rapid progression can be defined by progression to B3 within six months of the onset of thelarche.
• This recommendation does not apply to girls with early thelarche who also exhibit CNS findings (e.g., headaches, seizures, visual field deficits, etc.). The guideline-development panel assumed that such girls should be promptly evaluated by a pediatric endocrinologist and other appropriate specialists.

Recommendation 3

In girls and boys with evidence of precocious puberty, we suggest an initial evaluation with a basal luteinizing hormone concentration by ultrasensitive assay, rather than initially performing a gonadotropin-releasing hormone / gonadotropin-releasing hormone agonist stimulation test, in order to distinguish those with central precocious puberty from those without. (2 | ⊕OOO)

Technical remarks:

• An ultrasensitive LH assay should reliably detect very low LH concentrations (e.g., <0.05–0.1 IU/L).
• While first morning (8:00-10:00 am) basal LH testing may be optimal, especially in early puberty, the guideline-development panel judged that it is acceptable to measure basal LH at any time of the day.
• When ultrasensitive basal LH concentrations are low in the presence of clinical evidence of precocious puberty, a GnRH/GnRH agonist stimulation test would generally be the next step in diagnostic evaluation, particularly when the index of suspicion for CPP is high and/or when a rapid diagnosis is needed (e.g., in the setting of rapidly progressive puberty). Otherwise, another option is to repeat an ultrasensitive basal LH concentration, preferably in the early morning (8:00-10:00 am).

Recommendation 4

In girls ages 6.0 to 8.0 years and boys ages 8.0 to 9.0 years with central precocious puberty and without central nervous system findings, we suggest that brain MRI should not be routinely performed. (2 | ⊕OOO)

Technical remark:

• This recommendation does not apply to younger patients or to patients of any age who present with CNS findings (e.g., headaches, seizures, visual field deficits, etc.).

Recommendation 5

For children with central precocious puberty, we suggest against routine genetic testing (e.g., to identify loss-of-function mutations in MKRN3, DLK1, and/or MECP2). (2 | ⊕OOO)

Technical remarks

• This recommendation relates to targeted genetic testing (including genes such as MKRN3, DLK1, and/or MECP2) as opposed to unbiased genomic sequencing.
• In patients with familial CPP, genetic testing should be considered based on shared decision-making with the family.

Recommendation 6

For many children with central precocious puberty, we suggest gonadotropin-releasing hormone agonist treatment, although certain patient subgroups may not achieve net benefit with such treatment. (2 | ⊕OOO)

Technical remarks:

• Because this recommendation was predominantly driven by the adult height outcome, it may not apply to certain patient subgroups who are not expected to derive an important height benefit, including:
  • Girls ages 7.0 to 8.0 years who have slowly progressive CPP.
  • Girls and boys who are at or beyond the peak of their pubertal growth spurt (this will be concordant with their bone age assessment).
• The recommendation is for both girls and boys; however, the available evidence was from studies of girls only, as evidence in boys was lacking.
• The guideline-development panel emphasizes the importance of shared-decision making for all patients with CPP, which should include a careful weighing of anticipated benefits and potential harms of GnRH agonist use in the context of each patient's clinical presentation, patient/caretaker values, etc.

Recommendation 7

In patients with central precocious puberty who will use a long-acting gonadotropin-releasing hormone agonist in the long term, we suggest initiating therapy with the long-acting gonadotropin-releasing hormone agonist preparation rather than initiating therapy with a monthly gonadotropin-releasing hormone agonist. (2 | ⊕⊕OO)

Technical remarks:

• Long-acting GnRH agonist preparations refer to those with ≥3-month duration of action (e.g., 3-month and 6-month injectable formulations and the 12-month subcutaneous implant).
• Patients and families who anticipate using monthly GnRH agonist preparations in the long term should begin with a monthly GnRH agonist preparation.

Recommendation 8

In children being treated for central precocious puberty with a gonadotropin-releasing hormone agonist, we suggest against routine biochemical testing (e.g., luteinizing hormone and sex steroid concentrations) to monitor pubertal suppression. (2 | ⊕OOO)

Technical remarks:

• The guideline-development panel assumed that interval clinical assessment and monitoring (e.g., growth velocity, Tanner staging, annual bone age assessments) would be performed routinely for all children with CPP receiving GnRH agonist treatment.
• This recommendation pertains specifically to children without clinical evidence to suggest GnRH agonist treatment failure. Evidence of potential treatment failure may include progression in breast development or testicular size, acceleration in growth velocity, and/or persistent pubertal growth velocity.
• The guideline-development panel emphasized the importance of assessing GnRH agonist treatment adherence and administration technique in all patients with concern for treatment failure.
• The panel assumed that most pediatric endocrinologists would perform biochemical testing when treatment failure is suspected clinically, before implementing changes in the dose, duration, and/or formulation of GnRH agonist therapy.

Recommendation 9

In children with central precocious puberty, we suggest against the routine addition of growth hormone to gonadotropin-releasing hormone agonist therapy. (2 | ⊕OOO)

Technical remarks:

• This recommendation does not pertain to children with CPP who also have a distinct, well-established indication for growth hormone therapy.

Recommendation 10

In children being treated for central precocious puberty, we suggest against routinely continuing gonadotropin-releasing hormone agonist treatment beyond chronological age 10.0-11.0 years (girls) or 11.0-12.0 years (boys) and/or bone age 11.0-12.0 years (girls) or 12.0-13.0 years (boys). (2 | ⊕OOO)

Technical remark:

• The potential reasons to consider GnRH agonist continuation beyond these recommended ages are highly individualized and may relate to growth trajectory, psychosocial considerations, and/or neurocognitive impairment (e.g., developmental delay).