AAP offers guidance on evaluating early puberty

Early signs of puberty can be concerning for parents, and pediatricians may not always know which signs warrant further testing and referral and which are benign.

In new guidance, the American Academy of Pediatrics (AAP) outlines methods for evaluating and referring to specialists children with early pubertal development.

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Paul Kaplowitz, MD, PhD, endocrinologist at Children’s National Health System, in Washington, DC, helped develop the guidance and says pediatricians should be able to recognize the common and benign scenarios that look like precocious puberty but are not-particularly pubic hair and body odor development before age 8 years and breast development before age 2 years.

“In most cases, they can avoid ordering tests and try to reassure rather than worry parents,” Kaplowitz says. “[Pediatricians] should be able to monitor many of these benign cases in their practice and refer to the specialist the ones that are atypical (eg, if there is rapid progression or growth acceleration) or when the parents are very anxious.”

Early pubertal development is a common source of parental anxiety and a leading cause of referrals to pediatric endocrinologists, but only a small number of children truly have disorders that warrant testing and treatment. The majority of cases are benign and can be handled within the pediatric primary care office without immediate action, according to the report.

“Although there is a chance of finding pathology in girls with signs of puberty before 8 years of age and in boys before 9 years of age, the vast majority of these children
with signs of apparent puberty have variations of normal growth and physical development and do not require laboratory testing, bone age radiographs, or intervention,” according to the report.

Commonly, early puberty manifests as premature adrenarche (early onset of pubic hair and/or body odor), premature thelarche (non-progressive breast development, usually occurring before 2 years of age), and lipomastia, in which girls have apparent breast development which, on careful palpation, is determined to be adipose tissue.

Sign that sexual maturation may in fact be taking place include progressive breast development over 4 to 6 months, or progressive penis and testicular enlargement-particularly when accompanied by rapid linear growth.

Children exhibiting these signs of early puberty need evaluation by pediatric medical subspecialists and may require therapy with gonadotropin-releasing hormone (GnRH) agonists, according to the report.

As more studies confirm that the onset of puberty is occurring earlier than was previously considered normal, many primary care physicians are facing confusion about the timing of puberty and benign normal variants versus central precocious puberty (CPP).

Puberty is triggered by increased secretion of peptide GnRH by the hypothalamus. The GnRH stimulates the production of the 2 gonadotropins-follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

Follicle-stimulating hormone promotes the development of oocytes and spermatozoa, and increases the size of gonads, while LH causes the ovaries to secrete estradiol resulting in breast enlargement, growth spurts, and bone advancement; and the testes to secrete testosterone resulting in pensile enlargement, pubic hair growth, and growth spurts. These processes activate the hypothalamic-pituitary- gonadal (HPG) axis, referred to
as gonadarche.

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“It is important 
to note that pubic hair in girls and adult axillary odor in boys and girls is related to the increase in secretion of weak adrenal androgens (primarily dehydroepiandrosterone-sulfate [DHEA-S]), referred to as adrenarche, and is unrelated to activation of the HPG axis,” the study notes. “[Therefore], it is not unusual for a child to have pubic hair and/or axillary odor a few years before the onset of true, central puberty.”

When assessing a patient that presents with possible early pubertal development, physicians must understand the historic trends. While research has revealed a decrease in the age of menarche over the past 2 centuries, the report notes that the trend stabilized in the 1950s with little subsequent change. The standard cutoff is that puberty is considered precocious when it occurs before age 8 years in girls and age 9 years in boys, and those standards are still generally accepted by specialists despite more recent research challenging those ages.

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Benign variants of early pubertal development can present in many ways. One of these is premature adrenarche, which is associated with an increase in the secretion of DHEA and DHEA-S. This can result in the appearance of pubic hair, axillary hair, body odor, and mild acne. When these signs appear alongside normal growth rates, and there is no evidence of genital enlargement, the diagnosis is generally premature adrenarche (PA), according to the report.

“Levels of DHEA-S are typically increased for age, usually in the range of 30 to 150 μg/dL. There
is no activation of the HPG axis,
and thus, FSH, LH, and estradiol or testosterone concentrations are at prepubertal levels,” the report notes. “In 3% to 5% of cases of apparently benign PA, a mild, non-classic form of congenital adrenal hyperplasia can present with similar features, but there is no consensus that such mild cases benefit from treatment.”

Non-classic congenital adrenal hyperplasia is often seen in children with Ashkenazi Jewish and Hispanic backgrounds, but is uncommon in black children despite evidence that black children are prone to earlier pubic hair development.

In rare cases, virilizing adrenal or gonadal tumors accompany early pubic hair, but these cases are distinguished by concurrent clitoral enlargement or progressive penis growth and marked linear growth acceleration.

Although many physicians elect to have radiographs performed in these cases to determine bone age, the diagnostic value of such tests is uncertain. Hormonal testing is preferred by specialists because it can rule out non-classic forms of congenital adrenal hyperplasia in children who present with rapid growth and other symptoms of CPP.

In cases involving premature thelarche (PT)-or the appearance of palpable glandular tissue in girls aged under 2 years without progressive growth-the etiology is unclear, but may be caused by small ovarian cysts that product small, transient amounts of estrogen, according to the report.

“There is some controversy as to how often PT with onset before 2 years of
age progresses to CPP, the extent
of testing that is needed, and how closely such girls should be followed,” the study authors note.

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In a recent study of 450 Italian girls referred for PT before age 2 years, only 2% were found to have CPP and less than 1% had peripheral precocious puberty. However, no single test was useful in determining which girls developed CPP, and the study authors conclude that it is therefore reasonable to hold off on hormonal testing and pelvic ultrasound in most cases with additional intervention needed only in cases where breast size increases over a 4- to 6-month period or is accompanied by rapid growth.

In cases of genital hair appearing in infancy-which was once considered a rare finding but has increased over the last 2 decades-the report notes that hormonal concentrations normal for their age plus a possible elevation of DHEA-S can result in fine, straight hair over the labia or scrotum, as opposed to the thicker, curlier hair over the pubic symphysis found in older children with PA. This hair growth is generally benign in the absence of genital enlargement or abnormal growth patterns, and does not usually require hormonal testing or intervention, according to the report.

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Lipomastia is most common in girls who are overweight or obese, and is often a source of referral over concern of early puberty. Upon detailed assessment, however, physicians will usually find no evidence of glandular tissue under the areolae, along with a lack of estrogenic stimulation of the nipples and areola.

“At times, even endocrinologists may have trouble determining whether there
is a small amount of breast tissue
or not,” the report authors note. “If the breast examination is inconclusive, the patient is unlikely to have progressive precocious puberty. Observation over a period of 4 to 6 months is, in most cases, reassuring.”

For prepubertal vaginal bleeding, or premature menarche, 1 or 2 brief episodes without breast development are generally benign. More concerning is recurrent or continuous bleeding, and those cases should be referred to a specialist. Most cases, however, resolve after 1 to 6 episodes, according to the report.

A typical assessment to confirm CPP includes a family history, possible ingestion of exogenous sex steroids including ingestions of contraceptive pills or exposure to estrogen or testosterone creams or gels, assessment of any central nervous system (CNS) symptoms such as headaches or vision changes, or a history of disorders associated with CPP including brain tumors, meningitis, CNS trauma, cranial irradiation, hypoxic-ischemic injury, histiocytosis, and neurofibromatosis. Physical examination in girls should also include a review of their place in the Tanner stage of breast development. In boys, voice changes, facial hair, or other signs of androgen effect may be noted. Pubic hair, apocrine odor, and axillary
hair in both boys and girls are typically related to adrenal androgen production, and are not reliable signs of CPP, according to the report. Severe hypothyroidism is a rare cause of CPP, but should be ruled out, particularly is growth rates are slow alongside other CPP symptoms.

Other hormonal tests include FSH, LH, and either estradiol or testosterone. Luteinizing hormone of >0.3 IU/L is the most reliable screening test for CPP on a random blood sample, according to the report.

Once a diagnosis of CPP is made, a computed tomography or magnetic resonance imaging scan may be performed to rule out other structural abnormalities.