At a Glance

The normal pubertal onset occurs between 8 and 13 years of age for girls and 9.5 and 13.5 years of age for boys. Precocious puberty (PP) is defined as the development of secondary sexual characteristics in girls younger than 8 years of age and boys younger than 9 years of age. It is estimated that the incidence of PP is 10- to 20-fold higher in girls than in boys. It is associated with accelerated growth, advanced bone age, and early closure of epiphysis.

For both boys and girls, rapid growth, appearance of pubic and underarm hairs, and the presence of acne at an early age are the presenting symptoms of PP. In addition, girls may present with breast budding or menstruation, whereas boys may present with increased testicles and penis size and deepening voices.

PP can be classified into gonadotropin dependent (central/true PP) or gonadotropin independent (peripheral/pseudo PP). Central precocious puberty (CPP) is caused by abnormality in the hypothalamus-pituitary-gonadal axis. Most cases of CPP are idiopathic, and, in rare situations, central nervous system (CNS) tumors, such as hypothalamic hamartoma, astrocytoma, optical glioma, ependymoma, or craniopharyngioma, may be the cause of CPP. Other CNS lesions that may cause CPP include abscess, encephalitis, hydrocephalus, arachnoid cysts, or trauma.

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Peripheral precocious puberty (PPP) is much less common than CPP and is caused by early secretion of sex steroids independent of pituitary gonadotropins. The sources of the sex steroids could be either endogenous, such as adrenal hyperplasia, adrenal, or gonadal tumors, or exposure to exogenous sex steroids. PPP can be subcategorized into congenital and acquired. Congenital PPP includes congenital adrenal hyperplasia (CAH), McCune-Albright syndrome (MAS), and familial male-limited precocious puberty (FMPP).

CAH is a common congenital disorder transmitted in an autosomal recessive fashion. It is caused by 21-hydroxylase deficiency (in 90% of the cases) due to mutations in the CYP21A2 gene, which results in impairment of cortisol biosynthesis and accumulation of 17-hydroxyprogesterone (17-OHP), progesterone, and androstenedione (see chapter on Congenital Adrenal Hyperplasia).

MAS is characterized by a triad of fibrous dysplasia of bone, café au lait skin pigmentation, and PP. The syndrome is commonly diagnosed in girls presenting with PP between 2 to 6 years of age. It usually presents with sudden onset of painless vaginal bleeding accompanied by subtle breast enlargement. The etiology of the disorder is caused by a somatic mutation in GNAS gene, which encodes for the stimulatory subunit Gsα. The activating mutation of GNAS results in constitutive activation of G-protein signaling. This results in the development of estrogen-producing ovarian cysts. Resolution of the cysts causes a fall in estrogen followed by withdraw-bleeding. MAS is extremely rare in boys.

FMPP is caused by activating mutation in luteinizing hormone (LH) receptor gene, resulting in increased secretion of testosterone by Leydig cells at early age. The increase in testosterone is gonadotropin independent. Although it is transmitted in an autosomal dominant fashion, FMPP only occurs in boys and heterozygous girls are completely asymptomatic. This male restriction has been contributed to the requirement of both LH and follicle stimulating hormone (FSH) for ovarian steroidogenesis. Affected boys usually undergo rapid growth, bone age maturation, and progressive virilization as early as 2-4 years of age. Testosterone level is in the pubertal range, and gonadotropin level is markedly decreased or undetectable. A total of 15 mutations have currently been identified.

Acquired PPP usually results from exposure of either endogenous or exogenous sex hormones. The endogenous sex hormones could be produced by tumors, such as ovarian granulosa cell tumors, testicular Leydig cell tumors, adrenocortical tumors, or hCG producing germ cell tumors. In girls, one of the most common etiologies of PPP is ovarian follicular cysts. Finally, in patients with chronic primary hypothyroidism, significant increase of TSH may cause an increase in FSH and result in appearance of pubertal signs in children.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Test for CPP

Gonadotropins (FSH and LH) and related sex steroids (testosterone or estradiol) should be measured first. LH is the dominant gonadotropin in CPP patients. If the LH and FSH are at prepubertal levels, a Leuprolide (GnRH) stimulation test is necessary to determine if LH levels rise 30 minutes after administration of leuprolide. Pubertal levels of basal or stimulated LH are consistent with the diagnosis of CPP. Suppressed levels of FSH and LH are suggestive of PPP. In boys, the testosterone level is increased both in CPP and in PPP, but the testosterone level is much higher in PPP than in CPP patients.

Test for PPP

As mentioned, sex steroids increase with suppressed pituitary gonadotropins is diagnostic of PPP. In patients with CAH, cortisols (glucocorticoid and mineralocorticoids) are decreased with elevation of 17-OHP, testosterone, and DHEA-S levels. Adrenocorticotropic hormone (ACTH) is usually elevated because of loss of negative feedback from cortisols. An ACTH stimulation test is necessary for borderline cases of CAH.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

The practical procedure for GnRH stimulation test varies among different institutions. The agent used, route of administration (intravenous or subcutaneous), and dosing vary in different studies, making it difficult to set consistent cut-off values. Results should always be interpreted in the context of clinical situation and specific cut-offs determined.

What Lab Results Are Absolutely Confirmatory?

The diagnosis of central precocious puberty is confirmed by a pubertal level of LH at baseline or in response to GnRH stimulation in a girl younger than 8 years of age and a boy younger than 9 years of age.

For congenital peripheral precocious puberty, detection of specific mutations is absolutely confirmatory. Detection of CYP21A2 gene mutation is confirmatory of CAH. Finding known activating mutation of LH receptor genes in a boy is confirmatory for FMPP.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The diagnosis of central PP should not be solely based on hormonal data, and it must be correlated with clinical history. For patients suspicious for both CPP and PPP, a bone scan should be performed to determine the bone age. Some studies use pelvic ultrasonography to determine the maturation of ovaries and uterine structure. Increased ovarian and uterine volumes are important signs for CPP patients.

Since a minority of CPP is due to CNS lesions, imaging study, such as magnetic resonance imaging (MRI), may be performed to exclude space occupying lesions in brain, adrenals, and ovaries.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Measurement of 17-OHP is important in the diagnosis of CAH due to 21-hydroxylase deficiency. Normal newborns have high concentration of Δ5-steroids conjugated as sulfates, which have a markedly prolonged half-life and potentially interfere with the 17-OHP assay. The interference becomes minimal by 2-4 months of age; however, a propanol/heptane serum extraction is recommended to avoid interference when analyzing 17-OHP in a pediatric population.

The placenta secretes large amounts of progesterone and 17-OHP. These steroids cross the placenta to the fetus, resulting in higher concentrations in newborns. Measurement of these hormones in newborns younger than 3 days of age may not represent the infant’s own secretion of steroids.

Androgens can arise from the fetus with CAH or from the mother. Assay of samples in the first 6 months of life may result in spurious data.