Approach Considerations
If the history, physical examination, and laboratory data suggest that a child exhibits early and sustained pubertal maturation, the clinician must differentiate CPP from precocious pseudopuberty. In CPP, which is gonadotropin-dependent, early maturation of the entire hypothalamic-pituitary-gonadal (HPG) axis occurs, with the full spectrum of physical and hormonal changes of puberty. Precocious pseudopuberty is much less common and refers to conditions in which increased production of sex steroids is gonadotropin-independent (see Precocious Pseudopuberty). Correct diagnosis of the etiology of sexual precocity is critical because the evaluation and treatment of patients with precocious pseudopuberty are quite different from those of patients with CPP.
Laboratory Studies
Sex steroid levels
Measurement of serum testosterone is useful in boys with suspected precocious puberty. Early morning testosterone levels in boys in early puberty are higher than afternoon levels because luteinizing hormone (LH) and testosterone levels rise with sleep onset in early puberty.
The stages of puberty as indicated by serum testosterone levels are as follows:
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Testosterone level less than 30 ng/dL - Generally prepubertal (Depending on the laboratory, testosterone levels of 20-30 ng/dL may represent early puberty)
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Testosterone level of 30-100 ng/dL - Early pubertal
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Testosterone level of 100-300 ng/dL - Mid-to-late pubertal
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Testosterone level of more than 300 ng/dL - Adult
For girls, estradiol measurements are less reliable indicators of the stage of puberty. Many commercial assays are not sufficiently specific or sensitive enough to demonstrate an increase during early puberty. Levels that exceed 20 pg/mL usually indicate puberty, but some girls who are clearly pubertal may have levels of less than 20 pg/mL. In addition, estradiol levels may fluctuate from week to week. Girls who have ovarian tumors or cysts often have estradiol levels that exceed 100 pg/mL.
Levels of adrenal androgens (dehydroepiandrosterone [DHEA] and dehydroepiandrosterone sulfate [DHEA-S]) are usually elevated in boys and girls with premature adrenarche. DHEA-S, the storage form of DHEA, is the preferred steroid to measure because its levels are much higher and vary much less during the day. In most children with premature pubarche, DHEA-S levels are 20-100 mcg/dL, whereas in rare patients with virilizing adrenal tumors, levels may exceed 500 mcg/dL.
Consider obtaining a 17-hydroxyprogesterone (17-OH progesterone) serum study if mild or nonclassic congenital adrenal hyperplasia is suspected, which is more likely in children of Hispanic or Ashkenazi Jewish origin. One study from Paris found that if a basal level is below 200 ng/dL, the diagnosis of nonclassic congenital adrenal hyperplasia can be excluded; however, if the random 17-OH progesterone level is elevated, a corticotropin (ie, Cortrosyn)–stimulation test provides the greatest diagnostic accuracy, with a post-corticotropin 17-OH progesterone level of greater than 1000 ng/dL being diagnostic. [40]
Gonadotropins
Because of the development of more sensitive third-generation assays for LH, which can detect levels as low as 0.1 IU/L or below, random LH is now considered a good screening test for CPP, with levels of 0.3 IU/L or above considered diagnostic. However, many children with CPP have prepubertal basal LH levels but will respond to a challenge with GnRH with an increase to 5 IU/L or above, which is considered pubertal.
The immunochemiluminometric assay (ICMA) method for LH assessment seems more specific than the immunofluorometric assay (IFMA) method. An LH level of less than 0.1 IU/L is generally prepubertal, and one study suggested an upper reference range limit for IMCA-measured LH of 0.2 IU/L in both boys and girls, with no overlap between prepubertal and pubertal levels in boys and a 10% overlap in girls. [41] Another study found that a basal LH level measured by two different ICMA assays was sufficient to document CPP in 90% of girls, with levels of more than 0.83 IU/L in all but one patient; 29 of 34 prepubertal girls had undetectable values (< 0.15 IU/L to < 0.2 IU/L). [42]
A study by Carel et al stated that the peak LH level measured by ICMA that defines CPP is 4.1 IU/L in boys and 3.3 IU/L in girls. [23]
Random follicle-stimulating hormone (FSH) levels do not discriminate between prepubertal and pubertal children. Suppressed levels of LH and FSH accompanied by highly elevated testosterone or estradiol levels suggest precocious pseudopuberty rather than CPP.
A definitive diagnosis of CPP may be confirmed by measuring LH and FSH levels 30-60 minutes after stimulation with GnRH at 100 mcg or with a GnRH analogue. Because native GnRH is no longer available, most centers are using the analogue leuprolide (aqueous form) at a dose of 20 mcg/kg, up to a maximum of 500 mcg. An increase in FSH levels much greater than the increase in LH levels suggests that the child is prepubertal.
Another study suggested that when the baseline LH level is prepubertal, an increase in LH level to 5 IU/L or more after leuprolide correlates well with progression of pubertal signs during a 6-month period of observation. [43] No increase in LH and FSH levels after the infusion of GnRH suggests precocious pseudopuberty.
Thyroid
Thyroid tests are not a routine requirement in the evaluation of precocious puberty. Mild to moderate hypothyroidism does not lead to early puberty, and severe hypothyroidism only rarely does, in a phenomenon known as Van Wyk-Grumbach syndrome. Major clues suggesting severe hypothyroidism include growth arrest instead of growth acceleration, goiter, and symptoms of thyroid hormone deficiency (fatigue, cold intolerance).
Other
A study by Chen et al indicated that in girls, serum anti-Müllerian hormone and inhibin B offer markers for differentiating progressive CPP from slowly progressive CPP, with anti-Müllerian hormone levels being lower and inhibin-B levels being higher in girls with the progressive form of the condition. [44]
Imaging Studies
Radiography
As used to determine bone age, radiography of the hand and wrist is a quick and helpful means of estimating the likelihood of precocious puberty and its speed of progression. If bone age is within 1 year of chronologic age, puberty either has not started or the duration of the pubertal process has been relatively brief. If bone age is advanced by 2 years or more, puberty likely has been present for a year or more or is progressing more rapidly.
Head MRI
Many authors have recommended that a brain MRI be performed to look for a tumor or a hamartoma in any child after hormonal studies indicate a diagnosis of CPP. [45] However, subsequent studies have suggested that the finding of tumors or hamartomas in girls between the ages of 6 an 8 years is very low, while incidental findings are more common. [2] Thus, many now advise limiting such studies to girls younger than age 6 years at the onset of puberty, unless there are signs and symptoms suggestive of a CNS tumor or mass. [46] In such cases, consultation is suggested with a pediatric endocrinologist who can order the study, if indicated, and ask the radiologist to obtain a high-resolution study that focuses on the hypothalamic-pituitary area.
For boys younger than 9 years, the incidence of CNS findings is much higher than in girls, and MRI should be part of the evaluation.
Pelvic ultrasonography
Ultrasonography is unnecessary for girls with a definite diagnosis of CPP. If performed, however, ultrasonography usually reveals bilaterally enlarged ovaries, often with multiple small follicular cysts, and an enlarged uterus with an endometrial stripe.
Pelvic ultrasonography is essential when precocious pseudopuberty is suspected in girls (based on examination or hormone levels), because an ovarian tumor or cyst may be detected.
Histologic Findings
If CPP is caused by a tumor in the hypothalamic-pituitary area, the histology of the tumor can be important to the patient's prognosis. Gliomas tend to grow more rapidly than astrocytomas, whereas hamartomas are benign.
Treatment of precocious puberty associated with a hamartoma suppresses gonadotropin production by the pituitary without affecting the hamartoma itself.
For information on different non-CNS tumors associated with precocious puberty, see Precocious Pseudopuberty.
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Graph represents the prevalence of breast development at Tanner stage 2 or greater by age and race.
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Graph represents the prevalence of pubic hair at Tanner stage 2 or greater by age and race.
