Follow The Female Patient on and TheFemalePatient | Vol 35 January 2010 31

Adolescent GynecoloGy

Puberty involves 2 separate physiologic processes: gonadarche, the primary process, and adrenarche. Gonadarche, reactivation of the hypothalamic-pitu-

itary-gonadal (HPG) axis, leads to ovarian activation of estradiol production. The first clin-ical sign of gonadarche is breast development. Adrenarche, activation of the hypothalamic-pituitary-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 epidemio-logic 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 devel-opment and note that both significant bone age advancement and pathologic etiologies for pre-cocious 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

aged-based definition is also controversial. Since prema-ture adrenarche (PA) occurs independently of gonadarche, breast development and men-arche are not seen with iso-lated PA.1

Historical FindinGsIn evaluating for precocious puberty, certain historic infor-mation should be obtained. Pertinent are timing of onset and progression of pubertal signs, history of growth accel-eration, and family history regarding timing of puberty, particularly of immediate family. Symptoms such as headaches, seizures, or visual changes are sug-gestive of central nervous system (CNS) pathol-ogy.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 FindinGsGrowth parameters are a crucial evaluation ele-ment. 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 Tan-ner breast staging by inspection plus palpation, as well as pubic hair development. Breast palpa-tion helps distinguish between adipose tissue (adipomastia) and breast tissue. Signs of estro-gen stimulation include enlargement and dark-ening 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-

Update on Precocious Puberty Katherine A. Lewis, MD; Peter A. Lee, MD, PhD

evaluation and treatment of precocious puberty in girls require thorough under-standing of normal pubertal development. clinicians must be alert to findings that warrant further investigation and treatment while avoiding unnecessary treatment.

Katherine a. lewis, Md, is Fellow, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Chil-dren, Indianapolis. Peter a. lee, Md, Phd, is Professor, Department of Pediatrics, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, PA.

FoCuSPOINT

Growth param- eters are a crucial evaluation element. accurate height mea-surements should be made to determine growth velocity using serial measurements.

AdolescentGynecoloGyUpdate on Precocious Puberty

32 TheFemalePatient | Vol 35 January 2010 all articles are available online at www.femalepatient.com.

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

diFFerential diaGnosis Premature adrenarche Most girls (80% to 95%) with precocious pubarche, but with-out breast development or estrogenized vaginal mucosa, have PA.6 Until recently always

considered a benign condition, current studies find an association with insulin resistance, hyper-insulinism, and obesity. Girls with PA may share metabolic features of postpubertal females with polycystic ovary syndrome and should be con-tinually monitored.7,8 Also, a recent study dem-onstrated that girls with PA may be at higher risk

for psychopathology.9 While most girls with iso-lated 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 hyperplasiaIn a small minority of cases, late-onset congeni-tal adrenal hyperplasia (LO-CAH) may present with precocious pubarche, most being mild enzymatic deficiency of 21-hydroxylase with excessive adrenal androgen production. LO-CAH causes acceleration of skeletal maturity, shortened adult height, hirsutism, and hypofer-tility. It is therefore important to differentiate PA and LO-CAH in patients presenting with pre-mature pubarche.6

Premature thelarchePremature thelarche (PT) refers to isolated pre-cocious 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-

FoCuSPOINT

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

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.

assessment of early Puberty in Girls

accelerated Growth

obtain lH, FsH, estradiol, skeletal age X-ray

Consider pelvic ultrasound & DHEAS

If normal for adrenarche, Premature

adrenarche

early Breast development early sexual Hair

Premature thelarche Premature Pubarche

observe for Progression Consider DHEAS, 17-hydroxyprogesterone,

& skeletal age

assess for Precocious Puberty

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 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

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Follow The Female Patient on and TheFemalePatient | Vol 35 January 2010 33

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

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 ste-roid exposure.

Peripheral precocious puberty Peripheral precocious puberty (PPP) is rare. One form, McCune-Albright syndrome, with its clas-sic triad of café au lait macules, gonadotropin-independent precocious puberty, and fibrous dysplasia of the bone, results from a postzygotic activating mutation in the α subunit of the G pro-tein gene. Other endocrine hyperfunction or bone pain from fibrous dysplasia may occur. Estrogen-producing autonomous ovarian cysts stimulate rapid progression of breast develop-ment and vaginal bleeding.4

Other PPP etiologies include ovarian granu-losa cell tumors and exposure to exogenous estrogen. Rarely, untreated profound hypothy-roidism can result in early breast development but not accelerated growth.4 Androgen-produc-ing tumors of adrenal or ovarian origin or exoge-nous androgen may lead to virilizing symptoms.

FUrtHer evalUationBone age x-raySince sex steroid exposure leads to advanced epiphyseal maturation, determination of skel-etal maturity is useful. Skeletal age higher than 2 SD above chronological age suggests signifi-cant 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.

Basal gonadotropin levels and estradiolWhile previous gonadotropin assays were inadequate to dis-tinguish between prepubertal and pubertal basal gonadotro-pin levels, newer third genera-tion assays offer greater speci- ficity and sensitivity. A recent study using 2 different third generation assays for luteinizing hormone (LH) demonstrated 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 distinguish-ing between early pubertal and prepubertal levels. A markedly elevated estradiol level, with concomitant low gonadotropins, suggests ovar-ian cyst or tumor.4

Stimulation tests using GnRH or GnRHaWhere basal gonadotropin levels are insuffi-cient to evaluate CPP, a gonadotropin-releas-ing hormone (GnRH) or GnRH analog (GnRHa) stimulation test measuring gonadotropin lev-els is indicated. Of note, there is significant overlap between FSH responses in prepubes-cence and in those with CPP; therefore, stimu-lated LH is most useful in the diagnostic evaluation of CPP.12

Pelvic ultrasoundPelvic 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

Brain MRIPatients with CPP should be evaluated with a brain MRI to look for any CNS pathology. Find-ings associated with CPP include hypothalamic hamartoma, other hypothalamic tumors, cere-bral malformations, or evidence of sequelae of previous CNS insults.4

Other hormone evaluationsIn girls with significant androgenic signs, mea-surement of serum dehydroepiandrosterone sulfate (DHEA-S), testosterone, androstenedi-

FoCuSPOINT

since sex steroid exposure leads to advanced epiphyseal maturation, deter- mination of skeletal maturity is useful.

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34 TheFemalePatient | Vol 35 January 2010 all articles are available online at www.femalepatient.com.

one, and 17-hydroxyprogesterone may be use-ful. 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 andro-stenedione and testosterone suggest an adrenal disorder. 17-Hydroxyprogesterone obtained as a morning value or a stimulated value after cor-ticotropin 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.

treatMentGnRHa therapyGnRH analogs are standard treatment for CPP. These down-regulate the HPG axis and effec-tively halt pubertal progression. A recent con-sensus 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 men-arche for psychosocial reasons. Some patients have a slowly progressive form of CPP and will

reach normal adult heights without interven-tion. 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 gener-ally occur within 2 years after cessation of ther-apy. 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 ther-apy.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

taBle. Forms of early Puberty

Peripheral Premature Premature Precocious central Precocious Puberty thelarche adrenarche Puberty at diagnosis on treatment

onset of Breast Early, minimal or Not present Early with Early with No progression development no progression progression progression or regression

onset of Pubic Not present Early, varying May or may not May or may not Not expected Hair development rates of accompany accompany to regress progression breast growth breast growth

accelerated Absent Absent May occur at Occurs at Regression of Growth rate or minimal or minimal onset, >6 cm/y onset, >6 cm/y growth rates acceleration acceleration to 4-6 cm/y

advanced No or minimal No or minimal Advanced Advanced Deceleration Bone age advancement advancement related to related to toward normal duration/intensity duration/intensity

lH level-Basal Prepubertal Prepubertal Below/within Often above Prepubertal/ /GnrH stimulation minimal rise minimal rise prepubertal prepubertal range/ minimal rise range pubertal rise

estradiol level Low/ Low/ Within/above May be in Low/undetectable undetectable undetectable early pubertal pubertal range range

ovarian volume Prepubertal Prepubertal Variable, may be Pubertal size Decreases asymmetrical

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Follow The Female Patient on and TheFemalePatient | Vol 35 January 2010 35

suggests the decision to discontinue treatment should be individualized.15

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

conclUsionCareful 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 con-flicts of interest in relation to this article.

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premature adrenarche. Womens Health Issues. 2004;14(6): 177-183.

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3. Rosenfield RL, Lipton RB, Drum ML. Thelarche, pubarche, and menarche attainment in children with normal and ele-vated body mass index. Pediatrics. 2009;123(1):84-88.

4. Carel JC, Léger J. Clinical practice: Precocious puberty. N Engl J Med. 2008;358(22):2366-2377.

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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.

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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.

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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 diag-nosis 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 chil-dren. 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 preco-cious 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 pre-cocious puberty in girls with McCune-Albright syndrome. J Clin Endocrinol Metab. 2008;93(7):2751-2754.