eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Precocious Puberty: Differential Diagnoses & Workup

Author: Paul B Kaplowitz, MD, PhD, Professor of Pediatrics, George Washington University School of Medicine and Health Sciences; Chief of Endocrinology, Children's National Medical Center
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Updated: Jun 30, 2009

Differential Diagnoses

Precocious Pseudopuberty

Other Problems to Be Considered

Premature pubarche

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

Premature thelarche

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

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

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

Workup

Laboratory Studies

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

Imaging Studies

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

Histologic Findings

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

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