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Precocious Puberty

Nick DeBlasio, MD and Nancy Crimmins, MD
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32:32

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You have an overweight child in your office for her well child checkup that seems more developed than she should be...is it precocious puberty? Or obesity? When should you be worried? When should you start a workup? What should you order and when do you refer to endocrinology? We discuss these things and more with our pediatric endocrine consultant.

 

Highlights:

  • Precocious puberty is defined by breast development before the age of 8 years in girls and testicular enlargement before the age of 9 years in boys.

  • Precocious puberty is 10-15 times more common in girls, but the majority of cases in girls are benign.

    • When precocious puberty occurs in boys, while more rare, up to 50% of cases may be pathologic.

  • There are two causes of precocious puberty, central and peripheral.  The two are worked up and managed differently.

 

Introduction:

  • Precocious puberty is 10-15 times more common in girls, but the majority of cases in girls are benign.

  • When precocious puberty occurs in boys, while more rare, up to 50% of cases may be pathologic.

    • To help remember this, “think of it like UTIs!” That is, the condition is more common in females but, when it occurs in males, it may require further investigation.

  • There are two types of precocious puberty: central and peripheral.

    • Central causes include: CNS tumors, CNS injury (inflammation, surgery, trauma, radiation), congenital CNS abnormalities (hydrocephalus, arachnoid or suprasellar cyst).

    • Peripheral causes include: Peripheral tumors (adrenal, ovarian, testicular), endocrinopathies (thyroid disease, Cushing’s syndrome), exposure to hormone containing skin or hair products.

  • The clinician should be cognizant of the potential effects of precocious puberty.

    • Short adult stature (because of premature fusion of the growth plates).

    • Premature breast development and premature menses in girls, both likely undesirable.

    • Testicular enlargement and increased libido in boys (albeit, can be hard to tell what behavior is just a variant of normal development).

    • Psychosocial stress associated with early puberty.

 

Precocious Puberty

Precocious puberty is defined by breast development before the age of 8 years in girls and testicular enlargement before the age of 9 years in boys.

  • With precocious puberty, the clinician is assessing for signs of gonadal activation.

    • Are the ovaries producing estrogen?

      • Clinical correlate: breast development (thelarche).

    • Are the testes producing testosterone?

      • Clinical correlate: testicular enlargement (as males go through puberty, precocious or otherwise, the testes become more rounded and less tubular).

 

Case:  A 7-year-old obese boy presents to your primary care office with pubic hair.  The rest of his physical exam is unremarkable.  What do you do?

  • Crimmins recommends starting with obtaining a bone age study.

  • If the bone age is not advanced, this suggests that there is not enough hormonal activation to signify signs of puberty.

    • Usually the pubic hair just represents benign adrenal activation, possibly secondary to obesity.

  • If the bone age is advanced (>2 standard deviations above the mean), further evaluation by endocrinology is warranted, as this suggests there is abnormal sex steroid production.

 

For the general pediatrician: Workup for patient with signs of premature puberty.

  • For girls, Crimmins recommends ordering serum LH, FSH, and estradiol, as well as a bone age study.

    • If these are all within the normal range, observation is appropriate with a follow-up visit in 6 months.

      • If in 6 months the labs are abnormal, refer to endocrinology, who will likely perform a GnRH stimulation test.

      • Practical caveat: If it is going to take a prolonged period of time to see a pediatric endocrinologist, it might be prudent to obtain a bone age study and refer to endocrine before any lab draw, especially if bone age advanced.

    • In girls with central precocious puberty, obtaining brain-imaging to rule out CNS lesions is controversial, with >95% of cases being idiopathic. Dr. Crimmins  will obtain brain MRI’s on girls who have central precocious puberty younger than 6 years of age, or girls with rapidly progressing puberty.

  • For boys, Crimmins recommends ordering serum LH, FSH, and testosterone, as well as a bone age study.

  • If central precocious puberty is diagnosed in a male (advanced bone age, elevated LH/FSH & testosterone), image the brain to rule out pathologic CNS lesions (common in boys, rarer in girls).

*Editor’s note: Random serum LH and FSH may be normal, even in cases of true central precocious puberty, due to the pulsatile nature of the elevations of these hormones. However, if LH and FSH are elevated in the setting of high estrogen (in girls) or testosterone (in boys) and advanced bone age, this confirms the diagnosis of central precocious puberty. Conversely, elevated testosterone (boys) or estrogen (girls) with very low levels of LSH and FSH should raise your suspicion for a peripheral cause of precocious puberty (e.g.  hormone secreting tumor, exogenous hormone, among others).

 

How do you differentiate between breast development and fatty tissue?

  • If Dr. Crimmins is unable to tell the difference based on physical exam, she will obtain a bone age study.

  • Obesity can increase bone age by about 1 year, and this is not necessarily a sign of precocious puberty.

Treatment for central precocious puberty.

  • A GnRH agonist (monthly IM leuprolide commonly)  is prescribed at high levels to blunt the pulsing that is thought to start off puberty.

    • Given in form of an injection (by endocrinologists) or implant (by surgeons).

    • The GnRH agonist is usually used for at least two years or until bone age is similar to chronological age.  If there is limited benefit in  height potential (i.e. the physes are already closed or closing), therapy may be discontinued sooner than usual.

Case:  A 9-year-old female who has started menstruating is brought to your general pediatric practice.  Would you treat her with leuprolide?

  • Do a bone age study to assess whether or not growth plates have fused. If growth plates have not fused, it may be worth trying to stop the progression of puberty with depot leuprolide acetate (Lupron).

  • This should be done in consultation with an endocrinologist.

 

Case:  A 7-year-old boy with testicular enlargement and increased height velocity presents to your general pediatrics clinic.  You refer the patient to a pediatric endocrinologist for evaluation of precocious puberty.  Do you obtain any imaging?

  • This patient has an exam and bone age concerning for (but not limited to) central  precocious puberty.

  • Further lab workup may be done by the endocrinologist.

  • Crimmins feels as though ordering a brain MRI would be prudent in this case, to evaluate for pathology that may be contributing to the clinical presentation.

 

Is there an association between diet and precocious puberty?

  • As one would imagine, a randomized controlled trial on this subject is hard to perform.

  • Crimmins’ opinion, however, is that puberty is occurring earlier, probably secondary to obesity.

Editor’s note: There are an abundance of reports of peripheral precocious puberty resulting from exogenous hormone exposures, but none we could find of central precocious puberty. Though human studies are indeed lacking, animal studies may support the concept of obesity contributing to earlier onset puberty, though there is not a lot of literature on the subject. Among rhesus monkeys fed more calories and with higher BMI’s, they showed earlier menses compared with controls. Among pigs fed steroid hormone-containing beef, there was no change in onset of estrus in prepubescent pigs.

Terasawa E, et al. Body weight impact on puberty: effects of high-calorie diet on puberty onset in female rhesus monkeys. Endocrinology. 2012;153(4):1696-705. [Open access link]

Magolski JD, et al. Consumption of ground beef obtained from cattle that had received steroidal growth promotants does not trigger early onset of estrus in prepubertal pigs. J Nutr. 2014;144(11):1718-24. [Open access link]

 

A note about patient with cerebral palsy and other neurologic insults.

  • Crimmins remarks that these patients may have premature puberty and premature adrenarche.

Premature adrenarche

  • With precocious adrenarche (same age cut-offs as for precocious puberty), the clinician is assessing for signs of adrenal activation.

  • Clinical correlate: pubic hair, axillary hair, virilization, body odor.

  • Interestingly, 10-15% of kids will show signs of adrenarche as the first sign of puberty.

  • If a bone age study is obtained and normal, Crimmins recommends following the patient up in 6 months to assess for evidence of ongoing virilization: if progression is noted, then referral to endocrinologist is warranted.

    • The same guidelines exist for premature thelarche.

Editor’s Note: Premature adrenarche is simply excess adrenal hormone causing body hair/virilization/body odor, absent hypothalamic-pituitary axis (HPA) activation or testicular enlargement. You need HPA activation, which includes elevated LH/FSH from regular pulses of GnRH to enter true puberty, resulting in testicular enlargement and advanced bone age. Very high levels of testosterone and other adrenal hormones (e.g. dihydroepiandosterone) and no HPA axis activation is seen in virilizing disorders (e.g. congenital adrenal hyperplasia, hormone secreting tumor). Premature thelarche is the same idea in girls: breast development without HPA activation or advanced bone age. Both premature adrenarche and premature thelarche are forms of incomplete precocious puberty. Both can be normal variants of puberty, while some progress to true precocious puberty.

 

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Neonates to Precocious Puberty & Everything in Between Full episode audio for MD edition 214:58 min - 101 MB - M4AHippo Peds RAP April 2015 Summary 543 KB - PDF