Adolescent Gynecology

Update on Precocious Puberty

Katherine A. Lewis, MD; Peter A. Lee, MD, PhD Evaluation and treatment of precocious puberty in girls require thorough understanding of normal pubertal development. Clinicians must be alert to findings that warrant further investigation and treatment while avoiding unnecessary treatment.
aged-based definition is also controversial. Since premature adrenarche (PA) occurs independently of gonadarche, breast development and menarche are not seen with isolated PA.1

FOCUSPOINT
Growth parameters are a crucial evaluation element. Accurate height measurements should be made to determine growth velocity using serial measurements.

Historical Findings

uberty involves 2 separate physiologic processes: gonadarche, the primary process, and adrenarche. Gonadarche, reactivation of the hypothalamic-pituitary-gonadal (HPG) axis, leads to ovarian activation of estradiol production. The first clinical sign of gonadarche is breast development. Adrenarche, activation of the hypothalamicpituitary-adrenal androgen axis, involves increased adrenal androgen levels. Clinical signs include development of adult-type body odor, axillary hair, and pubic hair (pubarche).1 Precocious puberty in girls is commonly defined as breast development before age 8. In the United States, there is continuing debate regarding whether puberty from ages 6 to 8 should be considered normal, since epidemiologic studies demonstrated breast development at these ages, particularly in non-Hispanic black girls and Mexican American girls. Opponents to changing the definition of precocious puberty question the validity of true earlier breast development and note that both significant bone age advancement and pathologic etiologies for precocious sexual development may be found among Caucasian girls ages 7 to 8 and African American girls ages 6 to 8.2,3 Adrenarche is considered premature when onset is noted in girls younger than 8. This
Katherine A. Lewis, MD, is Fellow, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis. Peter A. Lee, MD, PhD, is Professor, Department of Pediatrics, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, PA. Follow The Female Patient on and

In evaluating for precocious puberty, certain historic information should be obtained. Pertinent are timing of onset and progression of pubertal signs, history of growth acceleration, and family history regarding timing of puberty, particularly of immediate family. Symptoms such as headaches, seizures, or visual changes are suggestive of central nervous system (CNS) pathology.4 Inquiry should also be made regarding potential exposures in the home to hormonal products such as estrogen creams, testosterone gels, placental-derived products, lavender oil, and tea tree oil.5

Physical Findings
Growth parameters are a crucial evaluation element. Accurate height measurements should be made to determine growth velocity using serial measurements. A growth velocity greater than 6 cm/year is typically seen in early puberty. Assessment of pubertal findings include Tanner breast staging by inspection plus palpation, as well as pubic hair development. Breast palpation helps distinguish between adipose tissue (adipomastia) and breast tissue. Signs of estrogen stimulation include enlargement and darkening of the nipple-areola complex. The presence of coarse pigmented pubic hair (Tanner stage 2), axillary hair, acne, and adult-type body odor (signs of adrenarche) should also be noted. Other key examination aspects include thyroid examination, skin inspection for hyperpigmenta The Female Patient | Vol 35 January 2010 31

AdolescentGynecology
Update on Precocious Puberty

FOCUSPOINT
Most girls with precocious pubarche, but without breast development or estrogenized vaginal mucosa, have premature adrenarche.

tion, vaginal mucosa visualization, and neurologic examination. Carefully spreading the labia majora allows visualization of vaginal mucosa coloration with pink coloration rather than bright red coloration indicative of estrogen exposure. Vaginal discharge should be described.4

for psychopathology.9 While most girls with isolated PA have normal progression to true puberty and adult height within target range, a subset who had low birth weight may have earlier puberty with a rapid progression to menarche and reduced adult height (Figure).8

Late onset congenital adrenal hyperplasia

In a small minority of cases, late-onset congenital adrenal hyperplasia (LO-CAH) may present with precocious pubarche, most being mild enzymatic deficiency of 21-hydroxylase with excessive adrenal androgen production. LOCAH causes acceleration of skeletal maturity, shortened adult height, hirsutism, and hypofertility. It is therefore important to differentiate PA and LO-CAH in patients presenting with premature pubarche.6

Differential Diagnosis
Premature adrenarche

Most girls (80% to 95%) with precocious pubarche, but without breast development or estrogenized vaginal mucosa, have PA.6 Until recently always considered a benign condition, current studies find an association with insulin resistance, hyperinsulinism, and obesity. Girls with PA may share metabolic features of postpubertal females with polycystic ovary syndrome and should be continually monitored.7,8 Also, a recent study demonstrated that girls with PA may be at higher risk

Premature thelarche
Premature thelarche (PT) refers to isolated precocious breast development. It is most prevalent in the first 2 years of life and usually represents a self-limiting condition with breast tissue often regressing or waxing and waning over time. Pos-

Assessment of Early Puberty in Girls

Early Breast Development Premature Thelarche Accelerated Growth Assess for Precocious Puberty Obtain LH, FSH, Estradiol, Skeletal Age X-ray Consider pelvic ultrasound & DHEAS Early Sexual Hair Premature Pubarche

Observe for Progression

Consider DHEAS, 17-hydroxyprogesterone, & skeletal age

If basal LH, FSH, estradiol, bone age & ultrasound consistent, Central Precocious Puberty Consider GnRHa therapy to halt progression & slow growth rate

If basal LH within prepubertal range, conduct GnRH or GnRHa stimulation test

If normal for adrenarche, Premature Adrenarche

If elevated or advanced, consider LO-CAH

Central Precocious Puberty if pubertal response; If lower response, consider slowly progressive PP, Peripheral PP, variant of prepuberty or obesity

Figure. Algorithm for assessment of early puberty in girls.

Abbreviations: DHEAS, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; GnRHa, GnRH analog; LH, luteinizing hormone; LO-CAH, late-onset congenital adrenal hyperplasia; PP, precocious puberty.

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Lewis and Lee

sible causes include increased sensitivity of breast tissue to estrogen, transient estrogen from follicular ovarian cysts, partial HPG axis activation with follicle-stimulating hormone (FSH) secretion predominance, increased dietary estrogen, and increased sex hormone binding globulin. Occasionally girls with PT will progress to central precocious puberty (CPP), so repeat clinical evaluation is indicated.10,11

Basal gonadotropin levels and estradiol

FOCUSPOINT

Central precocious puberty

CPP refers to precocious progressive pubertal maturation from early reactivation of the HPG axis. It is accompanied by growth and skeletal maturation acceleration (Table).12 CPP patients may have an underlying CNS abnormality or history of previous CNS insult. Approximately 92% of girls with CPP do not have evidence of CNS lesion (in contrast to 50% among boys). CPP may also result secondarily after sex steroid exposure.

While previous gonadotropin assays were inadequate to distinguish between prepubertal Since sex steroid and pubertal basal gonadotropin levels, newer third genera- exposure leads to tion assays offer greater speci- advanced epiphyseal ficity and sensitivity. A recent maturation, deterstudy using 2 different third generation assays for luteinizing mination of skeletal hormone (LH) demonstrated maturity is useful. that a single unstimulated LH level was sufficient to diagnose CPP in more than 90% of girls.12 Basal estradiol levels have poor sensitivity in distinguishing between early pubertal and prepubertal levels. A markedly elevated estradiol level, with concomitant low gonadotropins, suggests ovarian cyst or tumor.4

Peripheral precocious puberty

Peripheral precocious puberty (PPP) is rare. One form, McCune-Albright syndrome, with its classic triad of caf au lait macules, gonadotropinindependent precocious puberty, and fibrous dysplasia of the bone, results from a postzygotic activating mutation in the subunit of the G protein gene. Other endocrine hyperfunction or bone pain from fibrous dysplasia may occur. Estrogen-producing autonomous ovarian cysts stimulate rapid progression of breast development and vaginal bleeding.4 Other PPP etiologies include ovarian granulosa cell tumors and exposure to exogenous estrogen. Rarely, untreated profound hypothyroidism can result in early breast development but not accelerated growth.4 Androgen-producing tumors of adrenal or ovarian origin or exogenous androgen may lead to virilizing symptoms.

Stimulation tests using GnRH or GnRHa

Where basal gonadotropin levels are insufficient to evaluate CPP, a gonadotropin-releasing hormone (GnRH) or GnRH analog (GnRHa) stimulation test measuring gonadotropin levels is indicated. Of note, there is significant overlap between FSH responses in prepubescence and in those with CPP; therefore, stimulated LH is most useful in the diagnostic evaluation of CPP.12

Pelvic ultrasound
Pelvic ultrasonography may be a complementary tool in CPP evaluation. A recent study comparing normal girls and girls with CPP , PT, and PA found ovarian volume to be the best parameter of CPP, while uterine length was best to distinguish between patients with CPP and PT. Girls with CPP more frequently had multicystic and macrocystic ovaries compared with other groups.13

Further Evaluation
Bone age x-ray
Since sex steroid exposure leads to advanced epiphyseal maturation, determination of skeletal maturity is useful. Skeletal age higher than 2 SD above chronological age suggests significant sex steroid exposure. While a less-mature bone age suggests a self-limiting process such as isolated premature thelarche or adrenarche, patients with early CPP may not initially have significant bone age advancement. Projected adult height can also be estimated, which is useful when discussing treatment options.
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Brain MRI
Patients with CPP should be evaluated with a brain MRI to look for any CNS pathology. Findings associated with CPP include hypothalamic hamartoma, other hypothalamic tumors, cerebral malformations, or evidence of sequelae of previous CNS insults.4

Other hormone evaluations

In girls with significant androgenic signs, measurement of serum dehydroepiandrosterone sulfate (DHEA-S), testosterone, androstenedi The Female Patient | Vol 35 January 2010 33

AdolescentGynecology
Update on Precocious Puberty

Table. Forms of Early Puberty

Premature Premature Thelarche Adrenarche Onset of Breast Development Early, minimal or Not present no progression Early, varying rates of progression Peripheral Precocious Central Precocious Puberty Puberty at Diagnosis on Treatment Early with progression May or may not accompany breast growth Early with progression May or may not accompany breast growth No progression or regression Not expected to regress Regression of growth rates to 4-6 cm/y Deceleration toward normal Prepubertal/ minimal rise Low/undetectable

Onset of Pubic Not present Hair Development Accelerated Growth Rate Absent or minimal acceleration

Absent May occur at Occurs at or minimal onset, >6 cm/y onset, >6 cm/y acceleration Advanced related to duration/intensity Below/within prepubertal range Within/above early pubertal range Variable, may be asymmetrical Advanced related to duration/intensity Often above prepubertal range/ pubertal rise May be in pubertal range Pubertal size

Advanced No or minimal No or minimal Bone Age advancement advancement LH Level-Basal Prepubertal Prepubertal /GnRH Stimulation minimal rise minimal rise Estradiol Level Low/ Low/ undetectable undetectable Ovarian Volume Prepubertal Prepubertal

Decreases

one, and 17-hydroxyprogesterone may be useful. DHEA-S should be in the range of normal adrenarche in isolated PA. Markedly elevated levels may be seen in an adrenal enzymatic defect or with an adrenal tumor. Elevated androstenedione and testosterone suggest an adrenal disorder. 17-Hydroxyprogesterone obtained as a morning value or a stimulated value after corticotropin stimulation is used to evaluate for LO-CAH.4 Thyroid function tests should be obtained in patients with clinical findings of hypothyroidism, including poor linear growth.

Treatment

GnRHa therapy
GnRH analogs are standard treatment for CPP . These down-regulate the HPG axis and effectively halt pubertal progression. A recent consensus statement regarding the use of GnRHa in children summarizes some key data and offers recommendations.14 Reasons for treatment with GnRHa in CPP include preservation of adult height potential and delay of puberty and menarche for psychosocial reasons. Some patients have a slowly progressive form of CPP and will
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reach normal adult heights without intervention. Hence, it is recommended that pubertal development and growth be monitored over 3 to 6 months unless patients have pubertal development beyond Tanner stage III breast development or have a markedly advanced bone age at presentation.14 GnRH analogs are generally well tolerated and effective. They are most commonly given as a depot formulation. There is also an implant using the GnRHa histrelin, which is effective for at least a year. Girls treated with GnRHa in a timely fashion generally reach a normal adult height, with greatest benefit when therapy begins before age 6. Follow-up studies find no impairment of ovarian function; menses generally occur within 2 years after cessation of therapy. While body mass index (BMI) may be elevated at diagnosis of CPP , GnRHa therapy does not seem to worsen BMI. Peak bone mass does not seem to be affected by GnRHa therapy.14 Adult height is associated with growth after discontinuation of treatment, with skeletal age explaining 60% of this growth; however, the lack of predictability of growth after treatment

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Lewis and Lee

suggests the decision to discontinue treatment should be individualized.15

Other treatments
Treatment for other forms of precocious puberty is limited. Indicated therapies include discontinuing implicated substances, surgery for tumors, and thyroid replacement therapy when due to hypothyroidism. Tamoxifen or third generation aromatase inhibitors have not shown clear treatment benefit in girls who have McCune-Albright syndrome.16

Conclusion
Careful evaluation of precocious pubertal development in girls is necessary for proper diagnosis and treatment. Further study of the underlying physiology of normal puberty and investigations of treatment options for forms of PPP are crucial for ongoing improvement of care for these patients. The authors report no actual or potential conflicts of interest in relation to this article.

References

1.  Dorn LD, Rotenstein D. Early puberty in girls: the case of premature adrenarche. Womens Health Issues. 2004;14(6): 177-183. 2.  Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari J, Bourguignon JP . The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr Rev. 2003; 24(5):668-693. 3.  Rosenfield RL, Lipton RB, Drum ML. Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index. Pediatrics. 2009;123(1):84-88.

4.  Carel JC, Lger J. Clinical practice: Precocious puberty. N Engl J Med. 2008;358(22):2366-2377. 5.  Henley DV, Lipson N, Korach KS, Bloch CA. Prepubertal gynecomastia linked to lavender and tea tree oils. N Engl J Med. 2007;356(5):479-485. 6.  Armengaud JB, Charkaluk ML, Trivin C, et al. Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. J Clin Endocrinol Metab. 2009;94(8):2835-2840. 7.  Belgorosky A, Baquedano MS, Guercio G, Rivarola MA. Adrenarche: postnatal adrenal zonation and hormonal and metabolic regulation. Horm Res. 2008;70(5):257-267. 8.  Ibez L, Daz R, Lpez-Bermejo A, Marcos MV. Clinical spectrum of premature pubarche: links to metabolic syndrome and ovarian hyperandrogenism. Rev Endocr Metab Disord. 2009;10(1):63-76. 9.  Dorn LD, Rose SR, Rotenstein D, et al. Differences in endocrine parameters and psychopathology in girls with premature adrenarche versus on-time adrenarche. J Pediatr Endocrinol Metab. 2008;21(5):439-448. 10.  Crofton PM, Evans NE, Wardhaugh B, Groome NP , Kelnar CJ. Evidence for increased ovarian follicular activity in girls with premature thelarche. Clin Endocrinol (Oxf). 2005;62(2): 205-209. 11.  Borges MF, Pacheco KD, Oliveira AA, et al. Premature thelarche: clinical and laboratorial assessment by immunochemiluminescent assay. Arq Bras Endocrinol Metabol. 2008; 52(1):93-100. 12.  Houk CP , Kunselman AR, Lee PA. Adequacy of a single unstimulated luteinizing hormone level to diagnose central precocious puberty in girls. Pediatrics. 2009;123(6): e1059-e1063. 13.  Badouraki M, Christoforidis A, Economou I, Dimitriadis AS, Katzos G. Evaluation of pelvic ultrasonography in the diagnosis and differentiation of various forms of sexual precocity in girls. Ultrasound Obstet Gynecol. 2008;32(6):819-827. 14.  Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009;123(4):e752-e762. 15.  Nabhan ZM, Feezle LK, Kunselman AR, Johnson NB, Lee PA. Normal adult height among girls treated for central precocious puberty with gonadotropin-releasing hormone analog therapy. J Pediatr Endocrinol Metab. 2009;22(4):309-316. 16.  Mieszczak J, Lowe ES, Plourde P , Eugster EA. The aromatase inhibitor anastrozole is ineffective in the treatment of precocious puberty in girls with McCune-Albright syndrome. J Clin Endocrinol Metab. 2008;93(7):2751-2754.

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