precocious puberty - univ-tlse3.fr precoce nejmag carel 2008.pdf · loss due to precocious puberty...

clinical practice

T h e n e w e ng l a nd j o u r na l o f m e dic i n e

n engl j med 358;22 www.nejm.org may 29, 20082366

Precocious PubertyJean-Claude Carel, M.D., and Juliane Léger, M.D.

From the Department of Pediatric Endo-crinology and Diabetology, INSERM Unité 690, and Centre de Référence des Mala-dies Endocriniennes de la Croissance, Robert Debré Hospital and University of Paris 7 — Denis Diderot, Paris (J.-C.C., J.L.). Address reprint requests to Dr. Carel at Endocrinologie Diabétologie Pédiatrique and INSERM U690, Hôpital Robert Debré, 48, Blvd. Sérurier, 75935 Paris CEDEX 19, France, or at [email protected].

N Engl J Med 2008;358:2366-77.Copyright © 2008 Massachusetts Medical Society.

The parents of a 6-year-old girl bring her to a pediatrician because of breast develop-ment. Her medical history is unremarkable. The parents are of average height, and the mother reports first menstruating when she was 11 years old. At physical exami-nation, the girl is 125 cm tall (in the 97th percentile for her age), weighs 28 kg, and has a body-mass index (the weight in kilograms divided by the square of the height in meters) of 17.9 (90th percentile for her age). Her pubertal development is classified as Tanner stage 3 breast development and Tanner stage 2 pubic hair development. A re-view of her previous growth data indicates that she has grown 8 cm during the past year. How should her condition be evaluated and managed?

The Cl inic a l Problem

Puberty results when pulsatile secretion of gonadotropin-releasing hormone (GnRH) is initiated and the hypothalamo–pituitary–gonadal axis is activated. Tanner stages (Fig. 1) are used to evaluate pubertal development. The onset of puberty is marked by breast development in girls (Tanner stage 2 breast development, best assessed by both inspection and palpation) and testicular enlargement in boys (Tanner stage 2 genital development, assessed as testicular volume greater than 4 ml or testicular length greater than 25 mm).1,2 Physicians evaluating patients with suspected preco-cious puberty should address several questions: Is pubertal development really oc-curring outside the normal temporal range? What is the underlying mechanism, and is it associated with a risk of a serious condition, such as an intracranial lesion? Is pubertal development likely to progress, and if so, would this impair the child’s normal physical and psychosocial development?

Cross-sectional data obtained in the 1960s led to designation of the normal age range of pubertal onset (the age at which 95% of children attain Tanner stage 2) as between 8 and 13 years in girls and between 9 years 6 months and 13 years 6 months in boys.1,2 More recently, cross-sectional data obtained in the United States indicated that pubertal milestones were being reached earlier than previous-ly thought by black girls and to a lesser extent by Mexican-American and white girls.3-6 These observations led to recommendations to classify pubertal development as precocious when it occurs before the ages of 6 years in black girls and 7 years in all other girls.7 However, the validity of these recommendations has been ques-tioned, and most pediatric endocrinologists in the United States use the traditional threshold of 8 years to define precocious pubertal development in girls.8 Although a similar tendency toward earlier puberty was also noted in Europe, the shift was less marked, and there, the lower end of the normal range for the onset of puberty is also 8 years in girls and 9 years 6 months in boys.9

The onset of puberty is affected by many factors in addition to race10; it occurs earlier in girls with early maternal menarche, low birth weight, or excessive weight

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines,

when they exist. The article ends with the authors’ clinical recommendations.

Copyright © 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org by PATRICK GIRAUD MD on May 29, 2008 .

clinical pr actice

n engl j med 358;22 www.nejm.org may 29, 2008 2367

gain or obesity in infancy and early childhood, after international adoption (for unclear reasons, the risk is 10 to 20 times as great for these chil-dren11), and possibly after exposure to estrogen-ic endocrine-disrupting chemicals or when no father is present in the household.10,12 However,

these factors account for only a fraction of the variation in the timing of pubertal onset and are not considered in definitions of normality in practice. It is important to recognize that a “nor-mal” timing of the onset of pubertal develop-ment does not rule out a pathologic condition.13,14

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Author

Fig #Title

ME

DEArtist

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COLOR FIGURE

Version 4Carel1

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Precocious puberty

CSIK

Genital Development and Pubic Hair

Breast Development and Pubic Hair

Stage 5Stage 4Stage 3Stage 2Stage 1

A

B

Breast

Pubic hair

Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

Figure 1. Pubertal Rating According to Tanner Stages.

In girls (Panel A), breast development is rated from 1 (preadolescent) to 5 (mature), and stage 2 (appearance of the breast bud) marks the onset of pubertal development. Pubic hair stages are rated from 1 (preadolescent, no pubic hair) to 5 (adult), and stage 2 marks the onset of pubic hair development.1 In boys (Panel B), genital development is rated from 1 (preadolescent) to 5 (adult); stage 2 marks the onset of pubertal development and is characterized by an enlargement of the scrotum and testis and by a change in the texture and a reddening of the scrotal skin. Pubic hair stages are rated from 1 (preadolescent, no pubic hair) to 5 (adult), and stage 2 marks the onset of pubic hair development.2 Although pubic hair and genital or breast development are represented as synchronous in the illustration, they do not necessarily track together and should be scored separately. In normal boys, stage 2 pubic hair develops at an average of 12 to 20 months after stage 2 genital development.




The prevalence of precocious puberty is about 10 times as high in girls as in boys, with an esti-mated prevalence of 0.2% among girls and less than 0.05% among boys in Denmark.15

The most common mechanism of progressive precocious puberty is the early activation of pul-satile gonadotropin-releasing hormone (GnRH) secretion (central or gonadotropin-dependent pre-cocious puberty), which may result from hypotha-lamic tumors or lesions but in most cases remains unexplained (Table 1).16 Several causes of periph-eral or gonadotropin-independent puberty are rec-ognized, including gonadal and adrenal tumors and tumors producing human chorionic gonado-tropin, activation of mutations in the gonado-tropic pathway, and exposure to exogenous sex steroids (Table 1). Peripheral precocious puberty can lead to activation of pulsatile GnRH secre-tion and to central precocious puberty.

In at least 50% of cases of precocious pubertal development, pubertal manifestations will regress or stop progressing, and no treatment is neces-sary.17 Although the mechanism underlying these cases of nonprogressive precocious puberty is un-known, the gonadotropic axis is not activated. For cases in which precocious puberty progresses, concerns include early menarche in girls and short adult stature due to early epiphyseal fusion and adverse psychosocial outcomes in both sexes.18 Parents often seek treatment in girls because they fear early menarche,19 but it is difficult to predict the age at which menarche will occur after the onset of puberty. In the general population, the time from breast development to menarche is longer for children with an earlier onset of pu-berty, ranging from a mean of 2.8 years when breast development begins at the age of 9 years to 1.4 years when breast development begins at the age of 12.20

Several studies have assessed adult height in people with a history of precocious puberty. In older published series of untreated patients, mean heights ranged from 151 to 156 cm in boys and from 150 to 154 cm in girls, corresponding to a loss of about 20 cm in boys and 12 cm in girls as compared with normal adult height.21 Height loss due to precocious puberty is inversely corre-lated with the age at the onset of puberty, and today, treated patients tend to have a later onset of puberty than did patients in historical se-ries.21 Adverse psychosocial outcomes are also a concern, but the available data that are specific to patients with precocious puberty have serious

limitations.22 Data from surveys of the general population have indicated that a higher propor-tion of early-maturing adolescents engage in exploratory behaviors (sexual intercourse and legal and illegal substance use), and at an earlier age, than adolescents maturing within the normal age range or later.23,24 However, the relevance of these findings to precocious puberty is unclear, and they should not be used to justify inter-vention.

S tr ategies a nd E v idence

Evaluation

The first step in evaluating a child with preco-cious puberty is to obtain a complete family his-tory (age at onset of puberty in parents and sib-lings) and personal history, including the age at onset of puberty and progression of pubertal manifestations, and any evidence suggesting pos-sible central nervous system dysfunction, such as headache, increased head circumference, visual impairment, or seizures. Growth should be eval-uated, because progressive precocious puberty is almost invariably associated with a high growth velocity; a high growth velocity may also precede the onset of pubertal manifestations.25

The stage of pubertal development should be classified as described by Tanner. Careful assess-ment is needed in obese girls to avoid overesti-mating breast development (Fig. 1). The devel-opment of pubic hair results from the effects of androgens, which may be produced by testes or ovaries in central precocious puberty. In girls, pubic hair in the absence of breast development is suggestive of adrenal disorders, premature pubarche, or exposure to androgens (Table 1). In boys, measurement of testicular volume may sug-gest the cause of puberty; volume increases in central precocious puberty as it does in normal puberty (Fig. 1) and in cases of peripheral preco-cious puberty due to testicular disorders (although generally less so); volume remains prepubertal in adrenal disorders, premature pubarche, and other causes of peripheral precocious puberty. The physical examination should include an as-sessment for signs of specific causes of precocious puberty, such as hyperpigmented skin lesions suggesting neurofibromatosis or the McCune–Albright syndrome (Table 1). Precocious puber-tal changes have been associated with high levels of anxiety in girls,19,23 and psychological evalua-tion may be useful.


clinical pr actice


Additional Testing

Although no evidence-based algorithm is avail-able to guide testing, evaluation of the mecha-nism and potential for progression of precocious puberty is generally recommended in all boys with precocious pubertal development and in girls who have precocious breast development at stage 3 or higher or at stage 2 with additional criteria such as increased growth velocity or who have symp-toms or signs suggestive of central nervous system dysfunction or of peripheral precocious puberty. Table 2 summarizes the features identified in cross-sectional and small longitudinal studies as potentially useful in distinguishing between pro-gressive and nonprogressive precocious puberty. Particularly when these features are inconsistent, the best policy is to wait a few months and per-form a reassessment in order to avoid unneces-sary treatment.28

Bone AgeA reference atlas such as the one by Greulich and Pyle can be used to evaluate the effect of sex ste-roids on epiphyseal maturation; the bone age of patients with precocious puberty is generally great-er than their chronologic age. Bone age can also be used to predict adult height, although the pre-cision is low (with a 95% confidence interval of about 6 cm below to 6 cm above the predicted value), and predictions tend to overestimate adult height.29

Hormonal MeasurementsLevels of sex steroids should be determined in the morning, with the use of assays that have detection limits adapted to pediatric values (Ta-ble 3). Most boys with precocious puberty have morning plasma testosterone values in the puber-tal range.30 In girls, serum estradiol levels are highly variable and have a low sensitivity for the diagnosis of precocious puberty. Very high estra-diol levels (above 100 pg per milliliter [367 pmol per liter]) generally indicate an ovarian cyst or tumor (Table 1). Gonadotropin determinations (based on ultrasensitive assays) are central to the diagnosis. The gold standard for evaluation is the measurement of gonadotropins after stimulation by GnRH (which is unavailable in the United States) or a GnRH-releasing hormone agonist. Peak luteinizing hormone levels of 5 to 8 IU per liter suggest progressive central precocious puber-ty, but there is an overlap between prepubertal and early pubertal values.31 Random measure-

ments of luteinizing hormone have been proposed as an alternative; in one study, randomly measured values of 0.3 IU per liter and above were reported to be 100% specific for peak values above 5 IU per liter.32 However, unless levels of luteinizing hormone are clearly elevated, it is advisable to con-firm the diagnosis of progressive central preco-cious puberty with a stimulation test before ini-tiating treatment. Caution should be used when interpreting gonadotropin levels in children young-er than 2 or 3 years old, because gonadotropin levels are normally high in this age group. Random measurements of follicle-stimulating hormone are not useful, since they vary little throughout puber-tal development.

Pelvic or Testicular Ultrasound ScansIn girls, pelvic ultrasonography can reveal ovar-ian cysts or tumors. Uterine changes due to estro-gen exposure can be used as an index of progres-sive puberty, but this approach is used much less frequently in the United States than in Europe. A uterine volume greater than 2.0 ml has been reported to have 89% sensitivity and specificity for precocious puberty.26 Testicular ultrasonog-raphy can detect nonpalpable Leydig-cell tumors and should be performed in cases of asymmetric testicular volume or peripheral precocious pu-berty.33

Brain Magnetic Resonance ImagingIn all cases of progressive central precocious pu-berty, magnetic resonance imaging (MRI) of the brain should be performed to determine whether a hypothalamic lesion is present (Table 1).34 The prevalence of such lesions is higher in boys (40 to 90%) than in girls (8 to 33%) presenting with precocious puberty and is much lower when pu-berty starts after the age of 6 years in girls (about 2% in one series).14,35 It has been suggested that an algorithm based on age and estradiol levels may obviate the need for MRI in one third of girls, but this practice has not been extensively vali-dated.14,34

M a nagemen t

Central Precocious Puberty

GnRH agonists are indicated in progressive cen-tral precocious puberty. They work by providing continuous stimulation of the pituitary gonado-trophs, leading to desensitization and decreases in the release of luteinizing hormone and, to a




Tabl

e 1.

The

Cau

ses

of P

reco

ciou

s Pu

bert

y.*

Dis

orde

rC

hara

cter

isti

c Sy

mpt

oms

and

Sign

sTe

st R

esul

ts

Prog

ress

ive

cent

ral o

r gon

adot

ropi

n-de

pend

ent p

reco

ciou

s pu

bert

y

Ove

rvie

wB

reas

t dev

elop

men

t or

test

icul

ar e

nlar

gem

ent w

ith o

r w

ithou

t pu

bic

hair

dev

elop

men

t; in

crea

sed

grow

th v

eloc

ity; p

ossi

-bl

e ac

ne, o

ily s

kin

and

hair

, and

em

otio

nal c

hang

es

Hig

h se

rum

test

oste

rone

in b

oys,

var

iabl

e se

rum

est

radi

ol in

girl

s;

peak

ser

um L

H le

vel a

fter

GnR

H s

timul

atio

n in

the

pube

rtal

ra

nge;

adv

ance

d bo

ne a

ge; d

evel

oped

ute

rus

on u

ltras

ound

ex

amin

atio

n

No

CN

S le

sion

Poss

ible

his

tory

of f

amili

al p

reco

ciou

s pu

bert

y or

ado

ptio

n; n

o C

NS

lesi

on in

app

roxi

mat

ely

92%

of g

irls

and

appr

oxim

atel

y 50

% o

f boy

s; c

an a

lso

be p

art o

f a d

evel

opm

enta

l syn

drom

e su

ch a

s W

illia

ms–

Beu

ren

synd

rom

e or

mat

erna

l uni

pare

n-ta

l dis

omy

of c

hrom

osom

e 14

No

hypo

thal

amic

abn

orm

ality

foun

d on

MR

I of b

rain

; pos

sibl

e en

larg

emen

t of p

ituita

ry

CN

S le

sion

Hyp

otha

lam

ic h

amar

tom

aPo

ssib

le a

ssoc

iatio

n of

lesi

on w

ith g

elas

tic (

laug

hing

), fo

cal,

or

toni

c–cl

onic

sei

zure

sM

ass

in fl

oor

of th

ird

vent

ricl

e fo

und

on M

RI,

isoi

nten

se in

rel

a-tio

n to

nor

mal

tiss

ue w

ithou

t con

tras

t enh

ance

men

t

Oth

er h

ypot

hala

mic

tum

or (

e.g.

, glio

ma

in-

volv

ing

the

hypo

thal

amus

or

optic

chi

asm

, as

troc

ytom

a, e

pend

ymom

a, p

inea

lom

a, o

r ge

rm-c

ell t

umor

)

Poss

ible

hea

dach

e, v

isua

l cha

nges

, cog

nitiv

e ch

ange

s, s

ymp-

tom

s or

sig

ns o

f ant

erio

r or p

oste

rior p

ituita

ry d

efic

ienc

y (e

.g.,

decr

ease

d gr

owth

vel

ocity

, pol

yuri

a or

pol

ydip

sia)

, fat

igue

, an

d vi

sual

-fiel

d de

fect

s; if

CN

S tu

mor

is a

ssoc

iate

d w

ith

neur

ofib

rom

atos

is, o

ther

feat

ures

of n

euro

fibro

mat

osis

(e

.g.,

cuta

neou

s ne

urof

ibro

mas

, caf

é au

lait

spot

s, L

isch

no

dule

s)

Poss

ible

con

tras

t-en

hanc

ed m

ass

foun

d on

MR

I inv

olvi

ng o

ptic

pa

thw

ays

(chi

asm

, ner

ve, t

ract

) or

hyp

otha

lam

us a

lone

(in

the

case

of a

stro

cyto

ma

or g

liom

a) o

r hy

poth

alam

us a

nd p

ituita

ry

stal

k (i

n th

e ca

se o

f a g

erm

-cel

l tum

or);

pos

sibl

e ev

iden

ce o

f in

trac

rani

al h

yper

tens

ion;

pos

sibl

e si

gns

of a

nter

ior

or p

oste

-ri

or p

ituita

ry d

efic

ienc

y (e

.g.,

hype

rnat

rem

ia);

with

ger

m-c

ell

tum

or, c

an d

etec

t β-h

CG

in b

lood

or

CSF

Cer

ebra

l mal

form

atio

ns in

volv

ing

the

hypo

thal

-am

us —

sup

rase

llar

arac

hnoi

d cy

st, h

ydro

-ce

phal

us, s

epto

-opt

ic d

yspl

asia

, mye

lom

e-ni

ngoc

ele,

ect

opic

neu

rohy

poph

ysis

Poss

ible

neu

rode

velo

pmen

tal d

efic

its, m

acro

cran

ia, v

isua

l im

-pa

irm

ent,

nyst

agm

us, o

besi

ty, p

olyu

ria

or p

olyd

ipsi

a, o

r de

crea

sed

grow

th v

eloc

ity

Poss

ible

sig

ns o

f ant

erio

r or

pos

teri

or p

ituita

ry d

efic

ienc

y (e

.g.,

hype

rnat

rem

ia)

or h

yper

prol

actin

emia

Inju

ry —

cra

nial

irra

diat

ion,

hea

d tr

aum

a,

infe

ctio

n, p

erin

atal

insu

ltR

elev

ant h

isto

ry o

f inj

ury;

pos

sibl

e sy

mpt

oms

and

sign

s of

an-

teri

or o

r po

ster

ior

pitu

itary

def

icie

ncy

Poss

ible

find

ing

on M

RI o

f con

ditio

n-sp

ecifi

c se

quel

ae —

or

may

be

nor

mal

Earl

y ex

posu

re to

sex

ste

roid

s (a

fter

cur

e of

gon

ado-

trop

in-in

depe

nden

t pre

coci

ous

pube

rty)

His

tory

of s

uch

expo

sure

Perip

hera

l or g

onad

otro

pin-

inde

pend

ent p

reco

ciou

s pu

bert

y

Ove

rvie

wV

arie

d pu

bert

al s

ympt

oms

depe

ndin

g on

nat

ure

of s

ex s

tero

id

prod

uced

; typ

ical

ly, s

mal

ler t

estic

ular

vol

ume

than

in c

entr

al

prec

ocio

us p

uber

ty

Hig

h se

rum

test

oste

rone

in b

oys,

gen

eral

ly h

igh

and

occa

sion

ally

m

arke

dly

elev

ated

ser

um e

stra

diol

in g

irls

; low

(su

ppre

ssed

) pe

ak s

erum

LH

aft

er G

nRH

stim

ulat

ion;

adv

ance

d bo

ne a

ge;

deve

lope

d ut

erus

on

ultr

asou

nd e

xam

inat

ion

Aut

onom

ous

gona

dal a

ctiv

atio

n

McC

une–

Alb

righ

t syn

drom

e an

d re

curr

ent

auto

nom

ous

ovar

ian

cyst

s du

e to

som

atic

ac

tivat

ing

mut

atio

n of

the

GN

AS

gene

re-

sulti

ng in

incr

ease

d si

gnal

tran

sduc

tion

in

the

Gs

path

way

Foun

d m

ostly

in g

irls

; typ

ical

ly r

apid

pro

gres

sion

of b

reas

t de-

velo

pmen

t and

ear

ly o

ccur

renc

e of

vag

inal

ble

edin

g (b

efor

e or

with

in a

few

mon

ths

afte

r the

sta

rt o

f bre

ast d

evel

opm

ent)

; pr

ecoc

ious

pub

erty

isol

ated

or

asso

ciat

ed w

ith c

afé

au la

it sk

in le

sion

s or

bon

e pa

in d

ue to

pol

yost

otic

fibr

ous

dysp

la-

sia;

in ra

re c

ases

oth

er s

igns

of e

ndoc

rine

hype

rfun

ctio

n (e

.g.,

hype

rcor

tisol

ism

, hyp

erth

yroi

dism

), li

ver

chol

esta

sis,

or

card

iac

rhyt

hm a

bnor

mal

ities

Typi

cally

larg

e ov

aria

n cy

st o

r cy

sts

on p

elvi

c ul

tras

ound

exa

min

a-tio

n; b

one

lesi

ons

of fi

brou

s dy

spla

sia;

pos

sibl

e la

bora

tory

ev-

iden

ce o

f hyp

erco

rtis

olis

m, h

yper

thyr

oidi

sm, i

ncre

ased

GH

se

cret

ion,

hyp

opho

spha

tem

ia, o

r liv

er c

hole

stas

is

Ger

m-li

ne m

utat

ion

of G

NA

S ge

ne r

esul

ting

in

dual

loss

and

gai

n of

func

tion

(rar

e)Fe

atur

es o

f gon

adot

ropi

n-in

depe

nden

t pre

coci

ous

pube

rty

an

d ps

eudo

hypo

para

thyr

oidi

sm ty

pe 1

a in

boy

sTe

mpe

ratu

re-s

ensi

tive

poin

t mut

atio

n in

the

GN

AS

gene

res

ult-

ing

in a

ctiv

atio

n at

test

is te

mpe

ratu

re a

nd lo

ss o

f fun

ctio

n at

bo

dy te

mpe

ratu

re


clinical pr actice


Fam

ilial

mal

e-lim

ited

prec

ocio

us p

uber

ty d

ue

to g

erm

inal

act

ivat

ing

mut

atio

ns o

f the

LH

re

cept

or g

ene

Poss

ible

fam

ilial

his

tory

of d

omin

ant p

reco

ciou

s pu

bert

y in

boy

s (c

an b

e tr

ansm

itted

by

mot

hers

), w

ith s

ome

spor

adic

cas

esA

ctiv

atin

g m

utat

ion

of L

H r

ecep

tor

gene

.

Tum

ors

Gra

nulo

sa-c

ell t

umor

of t

he o

vary

Rap

id p

rogr

essi

on o

f bre

ast d

evel

opm

ent a

nd p

ossi

ble

abdo

mi-

nal p

ain;

tum

or m

ay b

e pa

lpab

le o

n ab

dom

inal

exa

min

atio

nTu

mor

det

ectio

n on

ultr

asou

nd o

r C

T sc

an

And

roge

n-pr

oduc

ing

ovar

ian

tum

orPr

ogre

ssiv

e vi

riliz

atio

nTu

mor

det

ectio

n on

ultr

asou

nd o

r C

T sc

an

Test

icul

ar L

eydi

g-ce

ll tu

mor

Prog

ress

ive

viri

lizat

ion;

test

icul

ar a

sym

met

ry; t

umor

pal

pabl

e in

rar

e ca

ses

Tum

or d

etec

tion

on te

stic

ular

ultr

asou

nd

hCG

-pro

duci

ng tu

mor

Tum

ors

can

orig

inat

e in

the

liver

or

med

iast

inum

; pub

erta

l sy

mpt

oms

in b

oys

only

; may

be

asso

ciat

ed w

ith

Klin

efel

ter’

s sy

ndro

me

Elev

ated

ser

um h

CG

; tum

or d

etec

tion

on u

ltras

ound

or

CT

scan

Adr

enal

dis

orde

rs

Con

geni

tal a

dren

al h

yper

plas

iaIn

crea

sed

andr

ogen

pro

duct

ion,

lead

ing

to v

irili

zatio

n in

boy

s an

d gi

rls

Incr

ease

d ad

rena

l ste

roid

pre

curs

ors

in s

erum

, mai

nly

17-h

ydro

xy-

prog

este

rone

(ba

sal o

r af

ter

a co

rtic

otro

pin

stim

ulat

ion

test

)

Adr

enal

tum

orIn

crea

sed

andr

ogen

pro

duct

ion,

lead

ing

to v

irili

zatio

n in

boy

s an

d gi

rls;

in r

are

case

s es

trog

en-p

rodu

cing

adr

enal

tum

orTu

mor

on

abdo

min

al u

ltras

ound

or

CT

scan

; ele

vate

d D

HEA

S or

ad

rena

l ste

roid

pre

curs

ors

Con

ditio

n du

e to

exp

osur

e to

exo

geno

us a

gent

s

Sex

ster

oids

Var

ied

man

ifest

atio

ns d

epen

ding

on

type

of p

repa

ratio

n (a

n-dr

ogen

ic o

r es

trog

enic

); m

ost c

omm

only

des

crib

ed a

fter

to

pica

l exp

osur

e to

and

roge

ns; p

ossi

ble

diffi

culty

trac

ing

sour

ce o

f exp

osur

e

Mis

lead

ing

endo

crin

e ev

alua

tion

poss

ible

due

to v

aria

ble

seru

m

leve

ls o

f sex

ste

roid

s

Estr

ogen

ic e

ndoc

rine

-dis

rupt

ing

chem

ical

sA

lthou

gh u

npro

ven,

pos

sibl

e ro

le o

f exp

osur

e in

pre

coci

ous

pube

rty

amon

g ad

opte

d ch

ildre

n (b

y m

odul

atin

g tim

ing

of

activ

atio

n of

pub

erta

l gon

adot

ropi

c ax

is)

No

valid

ated

bio

chem

ical

test

Seve

re, u

ntre

ated

pri

mar

y hy

poth

yroi

dism

Sign

s of

hyp

othy

roid

ism

; no

incr

ease

in g

row

th v

eloc

ityEl

evat

ed s

erum

leve

ls o

f thy

rotr

opin

, low

leve

ls o

f fre

e th

yrox

ine;

no

adv

ance

men

t in

bone

age

Ben

ign

vari

ants

of p

reco

ciou

s pu

bert

al d

evel

opm

ent

Ove

rvie

wU

sual

ly is

olat

ed s

econ

dary

sex

ual c

hara

cter

istic

; no

or s

light

ly

incr

ease

d gr

owth

vel

ocity

Bon

e ag

e w

ithin

two

stan

dard

dev

iatio

ns o

f nor

mal

for

age;

low

se

rum

leve

ls o

f sex

ste

roid

s; p

eak

seru

m L

H le

vels

aft

er G

nRH

st

imul

atio

n in

pre

pube

rtal

ran

ge; n

orm

al p

elvi

c ul

tras

ound

ex

amin

atio

n

Non

prog

ress

ive

prec

ocio

us p

uber

tySt

abili

zatio

n or

reg

ress

ion

of p

uber

tal s

igns

, nor

mal

gro

wth

ve-

loci

ty; f

ollo

w-u

p is

war

rant

ed s

ince

pro

gres

sion

can

occ

urN

orm

al b

one

age

and

prep

uber

tal u

teru

s on

ultr

asou

nd e

xam

inat

ion

Isol

ated

pre

coci

ous

thel

arch

eU

nila

tera

l or

bila

tera

l bre

ast d

evel

opm

ent;

part

icul

arly

freq

uent

be

fore

the

age

of 2

yr

No

furt

her

eval

uatio

n ne

eded

in m

ost c

ases

Isol

ated

pre

coci

ous

puba

rche

Pubi

c ha

ir d

evel

opm

ent,

som

etim

es a

ssoc

iate

d w

ith a

dult

body

odo

r, a

xilla

ry h

air,

or

mild

acn

e N

orm

al c

ortis

ol p

recu

rsor

s in

ser

um, i

nclu

ding

nor

mal

leve

ls o

f 17

-hyd

roxy

pro

gest

eron

e af

ter

cort

icot

ropi

n st

imul

atio

n

Isol

ated

pre

coci

ous

men

arch

eIs

olat

ed v

agin

al b

leed

ing

with

out b

reas

t or p

ubic

-hai

r dev

elop

-m

ent a

nd w

ithou

t gen

ital t

raum

a; im

port

ant t

o ev

alua

te c

lin-

ical

ly fo

r a v

agin

al le

sion

(se

xual

abu

se, f

orei

gn b

ody,

tum

or)

Nor

mal

bon

e ag

e an

d pr

epub

erta

l ute

rus

on u

ltras

ound

exa

min

atio

n

* C

NS

deno

tes

cent

ral n

ervo

us s

yste

m, C

SF c

ereb

rosp

inal

flui

d, C

T co

mpu

ted

tom

ogra

phy,

DH

EAS

dehy

droe

pian

dros

tero

ne s

ulfa

te, G

H g

row

th h

orm

one,

GN

AS

guan

ine

nucl

eotid

e–bi

nd-

ing

prot

ein

alph

a su

buni

t, G

nRH

gon

adot

ropi

n-re

leas

ing

horm

one,

Gs

stim

ulat

ory

guan

ine

nucl

eotid

e-bi

ndin

g pr

otei

n, h

CG

hum

an c

hori

onic

gon

adot

ropi

n, L

H lu

tein

izin

g ho

rmon

e, a

nd

MR

I m

agne

tic r

eson

ance

imag

ing.




lesser extent, follicle-stimulating hormone.36 Sev-eral GnRH agonists are available in depot forms (Table 4). In open-label, noncomparative, longitu-dinal studies, the use of GnRH agonists consis-tently resulted in the regression or stabilization of pubertal symptoms.41,42 A suppressed lutein-izing hormone response to GnRH or a GnRH agonist or a suppressed response after an injec-tion of the depot preparation (which contains a fraction of free GnRH agonist) indicates that the therapy is having the desired effect.43

There are no data from randomized controlled trials assessing long-term outcomes of GnRH therapy for central precocious puberty. Among approximately 400 girls who received such treat-ment until the age of 11 years on average, the mean adult height was about 160 cm; mean gains over predicted height in several series of patients ranged from 3 to 10 cm.21 Individual height gains varied considerably but were calculated on the basis of predicted height, which is unreliable. Fac-tors affecting height gains include baseline bone age (with markedly advanced bone age associat-ed with shorter adult height) and, in some series, duration of treatment (with a younger age at the

start of treatment and a longer duration of treat-ment associated with greater height44,45). The optimal time to stop treatment has not been established, but retrospective analyses suggest that discontinuation at the age of 11 years is as-sociated with optimal height outcomes (i.e., no appreciable further gains with continued treat-ment).46 Pubertal manifestations generally re-appear within months after GnRH-agonist treat-ment has been stopped, with a mean time to menarche of 16 months.47 Long-term fertility has not been fully evaluated, but preliminary observa-tions are reassuring.47

Treatment may be associated with headaches and menopausal symptoms (e.g., hot f lushes). Local complications, including sterile abscesses at injection sites, occur in 3 to 13% of patients.48 Fat mass tends to increase with treatment, where-as lean mass and bone density tend to decrease. Concerns have been raised about possible risks of obesity and osteoporosis,49,50 but longitudinal studies indicate that the prevalence of obesity does not increase during or after treatment and that bone density is normal after the cessation of treatment.50,51

Table 2. Criteria for Differentiating Progressive from Nonprogressive Forms of Precocious Puberty in Girls.*

Criterion Progressive Central Precocious Puberty Nonprogressive Precocious Puberty

Clinical

Progression through pubertal stages

Progression from one stage to the next in 3–6 mo Stabilization or regression of pubertal signs

Growth velocity Accelerated (> about 6 cm per yr) Usually normal for age

Bone age Usually advanced by at least 1 yr Usually within 1 yr of chronologic age

Predicted adult height Below target height range or declining on serial determinations

Within target height range

Uterine development†

Pelvic ultrasound scan Uterine volume >2.0 ml or length >34 mm, pear-shaped uterus, endometrial thickening (endo-metrial echo)

Uterine volume ≤2.0 ml or length ≤34 mm; prepubertal, tubular-shaped uterus

Hormone levels

Estradiol Usually measurable estradiol level with advanc-ing pubertal development

Estradiol not detectable or close to the detection limit

LH peak after GnRH or GnRH agonist‡

In the pubertal range In the prepubertal range

* These criteria were developed to distinguish progressive central precocious puberty (characterized by a sustained activa-tion of the gonadotropic axis) from nonprogressive precocious puberty (in which the gonadotropic axis is not activated) and were obtained in cross-sectional and small longitudinal studies; their reliability has not been fully evaluated.18,26,27 GnRH denotes gonadotropin-releasing hormone, and LH luteinizing hormone.

† Pelvic ultrasonography is used much more frequently in Europe than in the United States. Uterine development reflects sustained exposure to estrogens and is a marker of progressive puberty.

‡ GnRH is not available in the United States for use in testing.


clinical pr actice


Tabl

e 3.

Hor

mon

al E

valu

atio

n fo

r Pr

ecoc

ious

Pub

erty

.*

Var

iabl

eTe

chni

cal R

equi

rem

ents

Sign

ifica

nce

Lim

itatio

nsR

ecom

men

datio

ns fo

r U

se

Seru

m e

stra

diol

(g

irls

)U

se m

orni

ng v

alue

s an

d an

ass

ay

with

a

low

er li

mit

of d

etec

tion

of

appr

oxim

atel

y 5

pg/m

l (18

pm

ol/l

iter)

or

low

er

Elev

ated

leve

ls a

re in

dica

tive

of e

stro

gen

prod

uctio

n or

exp

osur

e; m

arke

dly

ele-

vate

d le

vels

(>

abou

t 100

pg/

ml [

367

pmol

/lite

r])

sugg

est a

n ov

aria

n cy

st o

r a

tum

or

Leve

ls c

an b

e no

rmal

in p

rogr

essi

ve c

en-

tral

pre

coci

ous

pube

rty;

ther

e ar

e di

ffi-

culti

es in

inte

rpre

ting

valu

es m

easu

red

with

imm

unoe

nzym

atic

met

hods

Use

as

a fir

st-li

ne te

st w

ith b

asal

LH

in

gir

ls, b

ut n

ote

poor

sen

sitiv

ity

in d

iscr

imin

atin

g be

twee

n ea

rly

pube

rtal

and

pre

pube

rtal

leve

ls

Seru

m te

stos

tero

neU

se m

orni

ng v

alue

s an

d an

ass

ay

with

a lo

wer

lim

it of

det

ectio

n

of a

ppro

xim

atel

y 10

ng/

dl

(0.3

5 nm

ol/l

iter)

Elev

ated

leve

ls a

re a

rel

iabl

e m

arke

r of

te

stic

ular

act

ivat

ion

in b

oys;

in g

irls

,

elev

ated

test

oste

rone

leve

ls s

ugge

st

an a

dren

al d

isor

der

Ther

e ar

e di

fficu

lties

in in

terp

retin

g va

lues

m

easu

red

with

imm

unoe

nzym

atic

m

etho

ds

Use

as

a fir

st-li

ne te

st w

ith b

asal

LH

in

boy

s —

hig

h se

nsiti

vity

for

conf

irm

ing

prec

ocio

us p

uber

ty;

for

girl

s, m

easu

re o

nly

if th

ere

are

sign

s of

hyp

eran

drog

enis

m

Seru

m L

HU

se m

orni

ng v

alue

s an

d ul

tra-

sens

itive

ass

ays

with

a d

e-

tect

ion

limit

of a

ppro

xim

atel

y 0.

1 IU

/lite

r or

low

er

Bas

al L

H m

easu

rem

ents

poo

rly

disc

rim

i-na

te b

etw

een

prep

uber

tal a

nd e

arly

pu

bert

al c

hild

ren;

val

ues

>0.3

–0.4

IU/

liter

are

indi

cativ

e of

cen

tral

pre

co-

ciou

s pu

bert

y, w

ith a

hig

h sp

ecifi

city

an

d a

low

sen

sitiv

ity

Ther

e ar

e w

ide

inte

rass

ay v

aria

tions

; ass

ay

char

acte

rist

ics

mus

t be

take

n in

to a

c-co

unt i

n in

terp

retin

g th

e re

sults

Use

as

a fir

st-li

ne s

cree

ning

test

in

asso

ciat

ion

with

est

radi

ol o

r te

s-to

ster

one

mea

sure

men

t; cl

early

el

evat

ed le

vels

can

obv

iate

the

need

for

a st

imul

atio

n te

st

Peak

LH

aft

er s

timu-

latio

n w

ith G

nRH

or

GnR

H a

goni

st†

Leve

l can

be

chec

ked

at a

ny ti

me

of

the

day;

ass

ay r

equi

rem

ents

si

mila

r to

thos

e fo

r ba

selin

e m

easu

rem

ents

Peak

LH

leve

l abo

ve th

e pu

bert

al c

utof

f w

ith e

leva

ted

sex

ster

oid

leve

ls in

di-

cate

pro

gres

sive

cen

tral

pub

erty

; sup

-pr

esse

d pe

ak L

H le

vel w

ith e

leva

ted

sex

ster

oid

leve

ls in

dica

te p

erip

hera

l pr

ecoc

ious

pub

erty

LH le

vels

var

y ac

cord

ing

to th

e as

say

used

; pa

ucity

of n

orm

ativ

e va

lues

to d

efin

e cu

toffs

; val

ues

of 5

to 8

IU/l

iter o

ften

co

nsid

ered

hig

h in

chi

ldre

n 3

to 8

yr o

ld;

high

er c

utof

fs s

houl

d be

use

d in

chi

ldre

n yo

unge

r tha

n 2

yr o

ld b

ecau

se o

f tra

n-si

ent a

ctiv

atio

n of

gon

adot

ropi

c ax

is;

peak

val

ues

vary

with

the

stim

ulat

ing

agen

t use

d (G

nRH

or G

nRH

ago

nist

)

Use

to d

iagn

ose

cent

ral p

reco

ciou

s pu

bert

y

Peak

FSH

aft

er s

timul

a-tio

n w

ith G

nRH

or

GnR

H a

goni

st†

Peak

LH

:FSH

ratio

typi

cally

incr

ease

s du

r-in

g pu

bert

y; h

igh

ratio

s ha

ve b

een

used

as

a c

rite

rion

for

prog

ress

ive

cent

ral

pube

rty;

not

in c

omm

on u

se n

ow th

at

mor

e se

nsiti

ve L

H a

ssay

s ar

e av

aila

ble

This

mea

sure

is p

oorl

y va

lidat

ed, i

n pa

r-tic

ular

with

san

dwic

h an

tibod

y as

says

fo

r go

nado

trop

in m

easu

rem

ents

Use

as

an a

dditi

onal

cri

teri

on w

hen

a G

nRH

or

GnR

H-a

goni

st te

st is

pe

rfor

med

Seru

m β

-hC

GPr

oduc

ed b

y ge

rm-c

ell t

umor

s; d

etec

tion

in s

erum

is in

dica

tive

of p

erip

hera

l or

intr

acra

nial

tum

ors,

in C

SF in

dica

tive

of in

trac

rani

al tu

mor

s

Peri

pher

al p

rodu

ctio

n of

β-h

CG

lead

s to

pu

bert

al d

evel

opm

ent o

nly

in b

oys

Mea

sure

ser

um le

vel i

n bo

ys w

ith

peri

pher

al p

reco

ciou

s pu

bert

y to

iden

tify

a ge

rm-c

ell t

umor

; m

easu

re in

the

CSF

whe

n a

le-

sion

com

patib

le w

ith a

ger

m-

cell

tum

or is

det

ecte

d on

MR

I

Seru

m D

HEA

SPr

oduc

ed b

y ad

rena

ls; d

etec

tion

is a

mar

k-er

of a

ndro

gen-

prod

ucin

g ad

rena

l tu-

mor

s or

of a

dren

al e

nzym

atic

def

ect

Leve

l is

also

incr

ease

d in

pre

coci

ous

puba

rche

Mea

sure

if a

ndro

geni

c si

gns

(pub

ic

hair

) pr

edom

inat

e

Seru

m 1

7-hy

drox

y pr

oges

tero

neU

se m

orni

ng v

alue

s or

mea

sure

af

ter c

ortic

otro

pin

stim

ulat

ion

Elev

ated

leve

ls a

re a

mar

ker

of a

dren

al

enzy

mat

ic d

efec

ts (

cong

enita

l adr

enal

hy

perp

lasi

a); l

evel

s ar

e oc

casi

onal

ly e

le-

vate

d w

ith a

dren

al tu

mor

s

Bor

derl

ine

elev

atio

ns a

re fr

eque

nt in

un-

affe

cted

car

rier

s of

non

clas

sic

con-

geni

tal a

dren

al h

yper

plas

ia

Mea

sure

if a

ndro

geni

c si

gns

(pub

ic

hair

) pr

edom

inat

e

* C

SF d

enot

es c

ereb

rosp

inal

flui

d, D

HEA

S de

hydr

oepi

andr

oste

rone

sul

fate

, FSH

folli

cle-

stim

ulat

ing

horm

one,

GnR

H g

onad

otro

pin-

rele

asin

g ho

rmon

e, h

CG

hum

an c

hori

onic

gon

adot

ro-

pin,

and

LH

lute

iniz

ing

horm

one.

Mor

ning

val

ues

are

reco

mm

ende

d w

hen

test

ing

leve

ls o

f sex

ste

roid

s an

d LH

bec

ause

of c

irca

dian

rhy

thm

s.†

GnR

H is

not

ava

ilabl

e in

the

Uni

ted

Stat

es fo

r us

e in

tes

ting.




Table 4. Medications Used for the Treatment of Precocious Puberty.*

Drug Formulation and Usually Recommended Dose Side Effects and Cautions

For treatment of central or gonadotropin-dependent precocious puberty

Depot GnRH agonists†

Overview Local side effects include pain, erythema, inflam-matory reaction, sterile abscess, implant-site reaction; other side effects include headaches and menopausal-like symptoms (hot flushes, asthenia); decreased bone density during treatment but no long-term impairment doc-umented after treatment is discontinued

Leuprorelin leuprolide (Enantone [Takeda], Lupron Depot [TAP], Lupron Depot-PED [TAP]‡)

4-wk and 12-wk preparations (subcuta-neous or intramuscular); United States — 0.3 mg/kg of body weight every 4 wk (1-mo depot); Europe — 3.75 mg every 4 wk (4-wk depot) or 11.25 mg every 12 wk (12-wk depot)

Triptorelin (Decapeptyl [Ipsen, Ferring], Gonapeptyl [Ferring])§

4-wk and 12-wk preparations (intramus-cular); Europe — 3.00–3.75 mg every 4 wk (1-mo depot) or 11.25 mg every 12 wk (3-mo depot)

Goserelin (Zoladex [AstraZeneca], 3.6 mg or 10.8 mg)

4-wk and 12-wk implants

Histrelin (Supprelin LA [Indevus]‡) 12-mo implantsUnited States — 50-mg implant every

12 mo

Rapid-acting GnRH agonists — buserelin, deslorelin, histrelin, leuprorelin, leupro-lide, nafarelin, triptorelin

Nasal spray or subcutaneous injections 1–3 times daily

Difficulties with compliance; use usually limited to patients with sterile abscesses from depot injections

For treatment of peripheral or gonadotropin-independent precocious puberty¶

Aromatase inhibitors

Testolactone (Teslac [Bristol-Myers Squibb]) 40 mg/kg of body weight/day orally, 4–6 times daily

Data from small, uncontrolled trials in McCune–Albright syndrome; also used in association with spironolactone for familial male-limit-ed precocious puberty37

Letrozole (Femara [Novartis]) 2.5 mg orally once daily Menopause-like symptoms; data from small, uncontrolled trial in McCune–Albright syn-drome38

Anastrozole (Arimidex [AstraZeneca]) 1 mg orally once daily Data from case reports

SERM — Tamoxifen (Nolvadex [AstraZeneca]) 20 mg orally once daily Data from small, uncontrolled trials in McCune–Albright syndrome39

Androgen-synthesis inhibitor — ketoconazole (Nizoral [Janssen-Cilag])

20 mg/kg of body weight/day orally Side effects include liver toxicity and adrenal de-ficiency; data from small, uncontrolled trials in familial male-limited precocious puberty40

* Drugs used for the treatment of adrenal disorders (congenital adrenal hyperplasia) are not included in this table. SERM denotes selective estrogen-receptor modulators.

† The availability, approval for use, and recommended dosages of depot GnRH agonists for the treatment of precocious puberty vary through-out the world.

‡ The Food and Drug Administration has approved Lupron Depot-PED and Supprelin LA for the treatment of central precocious puberty. Histrelin implants are available only in the United States.

§ Triptorelin is not available in the United States.¶ None of these drugs have been approved for use in the treatment of precocious puberty.


clinical pr actice


For cases in which precocious puberty is caused by a central lesion (e.g., a mass or malfor-mation), management of the causal lesion gener-ally has no effect on the course of pubertal de-velopment. Hypothalamic hamartomas should not be removed surgically for the purpose of manag-ing precocious puberty. When precocious puberty is associated with the presence of a hypothalamic lesion, there may be progression to gonadotro-pin deficiency.

Peripheral Precocious Puberty

Surgery is indicated for gonadal tumors. The roles of postoperative chemotherapy and radiotherapy in granulosa-cell tumors of the ovary at stage I or after complete resection have not been defined.52 For large ovarian cysts (those that are greater than 20 ml in volume [3.4 cm in diameter] and particularly those that are more than 75 ml in volume [5.2 cm in diameter]), puncture should be considered because of the risk of adnexal tor-sion.53 If there is exposure to exogenous sex ste-roids, it should be withdrawn.

Aromatase inhibitors38 have been used to in-hibit the production of estrogens, and selective estrogen-receptor modulators39 have been used to interfere with the action of estrogens in the McCune–Albright syndrome. Limited data from uncontrolled studies suggest that these strategies have been effective in some cases.

A r e a s of Uncerta in t y

The appropriate age threshold for the definition of precocious puberty remains controversial; well-performed longitudinal assessments of normally developing children are needed to inform these criteria. The best approach for differentiating pro-gressive from nonprogressive forms of precocious puberty remains unclear. The decision about whether to provide treatment is therefore often difficult, particularly for girls with an onset of puberty between the ages of 6 and 8 years. The most appropriate age for stopping treatment also remains uncertain. The addition of growth hor-mone54 or oxandrolone55 has been proposed when growth velocity decreases or if the prognosis for adult height appears to be unsatisfactory, but data are limited on the efficacy and safety of these

drugs in children with precocious puberty. Causal mechanisms underlying idiopathic precocious pu-berty also remain uncertain.16

Guidel ines

A consensus statement on the use of GnRH ago-nists in children is currently being prepared by the European Society for Paediatric Endocrinology and its American counterpart, the Lawson Wilkins Pediatric Endocrine Society.

Conclusions a nd R ecommendations

In the case described in the vignette, advanced breast development (Tanner stage 3), pubic hair development, higher-than-expected height given parental height, and increased growth velocity at 6 years of age suggest progressive precocious pu-berty. Evidence of possible causes of precocious puberty should be sought by means of a thor-ough history taking and careful examination, but this search is often unrevealing. Further eval-uation should include measurements of bone age (which would probably be advanced) and levels of estradiol and luteinizing hormone. If a randomly measured level of luteinizing hormone is in the pubertal range, an MRI scan of the brain should be obtained, and it would be useful to perform a GnRH-agonist stimulation test to confirm pro-gressive central precocious puberty before con-sidering treatment with a GnRH agonist. If the randomly measured level of luteinizing hormone is in the prepubertal range, a pelvic ultrasound scan is needed to rule out an ovarian tumor or cyst, particularly if the estradiol level is elevated. If randomly measured levels of both estradiol and luteinizing hormone are in the prepubertal range, we recommend performing a GnRH or GnRH-agonist stimulation test to further evalu-ate the activation of the gonadotropic axis and the potential for progression of puberty. If the results suggest nonprogressive precocious pu-berty, we recommend follow-up every 3 to 6 months between the ages of 6 and 7 years to as-sess the child clinically for progression. If pro-gressive central precocious puberty is confirmed, treatment with a depot GnRH agonist is recom-




mended and is generally continued until the child is 11 years old, although the optimal duration of therapy is uncertain. [Educational information for families can be found at http://eurospe.org/patient/English/index.html or at www.hormone.org/Public/factsheets.cfm.]

Dr. Carel reports receiving grant funding from Ipsen and

Takeda; having been part of the organizing committee of a pediatric endocrinology consensus meeting supported in part by Indevus, Ipsen, Ferring, and TAP; and receiving lecture fees from Ferring. No other potential conflict of interest relevant to this article was reported.

We thank Drs. Jean-Louis Chaussain, Najiba Lahlou, and Marc Roger for their longstanding contributions to the field of preco-cious puberty.An audio version of this article is available at www.nejm.org.

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collections of articles on the journal’s web site

The Journal’s Web site (www.nejm.org) sorts published articles into more than 50 distinct clinical collections, which can be used as convenient

entry points to clinical content. In each collection, articles are cited in reverse chronologic order, with the most recent first.


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