pubertate precoce

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REVISTAROMNDEPEDIATRIE VOLUMULLX, NR. 3, AN2011214

REFERATE GENERALE

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Adresa de coresponden:Dr. Corina Duncescu, Spitalul Clinic de Urgenpentru Copii Louis urcanu, Str. Dr. Iosif Nemoianu, Nr. 2, Timioara

DEZVOLTAREA SEXUALPRECOCEDr. Corina Duncescu1, Asist. Univ. Dr. Monica Mrzan1,2,

Dr. Adela Chiri-Emandi1, Asist. Univ. Dr. Ramona Stroescu1,2,Prof. Dr. Ioana Micle1,2

1Clinica I Pediatrie, Spitalul Clinic de Urgenpentru Copii Louis urcanu, Timioara2Universitatea de Medicini Farmacie Victor Babe, Timioara

REZUMAT

Pubertatea este un proces biologic ce presupune modificri fizice i psihologice majore, la finele cruiacopilul devine adult. Clinic, debutul pubertii este anunat de apariia caracterelor sexuale secundare ceevolueazspecific pentru sexul feminin, respectiv masculin pnla forma adult, trecnd prin cele 5 stadii

descrise de Tanner. Debutul pubertii variazn funcie de ras, etnie, localizarea geografic, condiii demediu i nutriionale, la populaia caucaziansitundu-se ntre 8 i 12 ani. Dezvoltarea sexualprecoce este

definitarbitrar ca apariia caracterelor sexuale secundare nainte de vrsta de 8 ani la fete, respectiv naintede 9 ani la biei. Pubertatea precoce se clasificn 3 categorii mari: (1) pubertatea precoce gonadodropindependent (central), (2) pubertatea precoce gonadotropin independent (periferic), (3) pubertateaprecoce parial. Lucrarea de fai propune sprezinte sintetic, pentru fiecare categorie n parte, modulspecific de apariie a caracterelor sexuale secundare, modificrile hormonale i posibilitile terapeutice.Urmrirea copiilor longitudinal, anamneza amnunit, nregistrarea cronologic a semnelor pubertare,msurtorile somatometrice i investigaiile hormonale repetate reprezintcheia unui diagnostic corect ipremisa unui tratament precoce i eficient.

Cuvinte cheie: pubertate precoce, gonadotropine, telarha, adrenarha

INTRODUCERE

Pubertatea este un proces biologic ce presupunemodificri fizice i psihologice majore, la finelecruia copilul devine adult.

Aspecte clinice normale ale pubertii

Clinic, debutul pubertii este anunat de apariiacaracterelor sexuale secundare, i anume: apariiamugurelui mamar la fete, creterea n volum a tes-

ticulelor la biei i apariia pilozitii axilare/pu-biene la ambele sexe. Aceste caractere sexuale se-cundare evolueazpnla forma adult, trecnd princele 5 stadii descrise de Tanner (1, 2, 3). Evoluia ca-racterelor sexuale feminine i masculine, conformstadiilor Tanner, este prezentatn Tabelele 1 i 2.

1. Pubertatea la fete

Menstrele debuteazla aproximativ 2-2 ani dela apariia primelor semne ale pubertii, n timpulstadiilor 3-4. Modificri mai puin vizibile sunt:creterea n volum a ovarelor, uterului, labiilor i

clitorisului, ngroarea mucoasei endometriale i acelei vaginale. Cea din urm are, prepuberal, oculoare roiatic, devenind n cursul pubertii rozpal (2, 3, 4).

2. Pubertatea la bieiComponentele cartilaginoase i membranoase

ale corzilor vocale se mresc, ducnd la ngroareavocii. De asemenea, apare pilozitatea facial, iniialdeasupra buzei superioare i n poriunea superioara obrajilor. Concomitent, are loc o cretere n volum

a canalelor seminifere, epididimului, veziculelorseminale i prostatei. La 40-60% dintre biei apareo hipertrofie a esutului mamar bilateral, care n90% dintre cazuri se remite spontan (2, 3).

Att la biei, ct i la fete pot aprea comedoane,acnee i seboreea scalpului, datoritcreterii andro-genilor circulani.

3. Creterea n cursul pubertiiLa ambele sexe, accelerarea creterii debuteaz

timpuriu, fiind maxim n stadiile 3-4. La biei,creterea debuteaz cu 2-3 ani mai trziu fa de


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REVISTAROMNDEPEDIATRIE VOLUMULLX, NR. 3, AN2011 215

fete, continundu-se nc2-3 ani dupce aceasta

s-a oprit la fete (2, 3, 4).4. Debutul pubertiiDebutul pubertii variaz n funcie de ras,

etnie, localizarea geografic, condiii de mediu inutriionale. Astfel, la populaia caucaziandebutulpubertii are loc ntre 8 i 12 ani. Debutul pubertiieste mai timpuriu n prezent fade decadele pre-cedente, fiind influenat de creterea adipozitiicorporale (4-8).

Fiziologia pubertii

Mecanismele implicate n iniierea i desfura-rea fiziologica pubertii sunt: axul hipotalamo-hipofizo-gonadal, respectiv axul hipotalamo-hipo-fizo-corticosuprarenalian.

1. Axul hipotalamo-hipofizo-gonadal

Pnla debutul pubertii, nivelurile circulantede gonadotropine, hormonul luteinizant hipofizar(LH)i hormonul foliculostimulant (FSH), respectivde hormoni sexuali (estradiol i testosteron) suntnedetectabile. Este clar c aceste mecanisme re-

glatorii sunt dormante, dar modul prin care sunt su-primate este ncpuin neles (2, 3).Iniierea pubertii

Cu unul pnla 3 ani nainte de debutul clinic alpubertii, nivelurile sczute de gonadotropi, cu

predominana LH, devin detectabile n cursul som-

nului. Aceast secreie este iniiat de eliberareaepisodica hormonului hipotalamic gonadotropinreleasing hormone (GnRH) prin mecanisme neuro-hormonale ncneelucidate complet. Secreia pul-satil, nocturn de gonadotropine continu screascatt n amplitudine, ct i n frecven, pemsurce ne apropiem de pubertatea clinic evident.LH i FSH determin creterea i maturarea go-nadelor i secreia de hormoni sexuali (2, 3, 7).

Hormonii sexuali

Hormonii sexuali, estrogenii i androgenii, au

un impact major asupra creterii i maturrii osoase.Androgenii sunt transformai, prin aromatizare, nestrogeni. Astfel, acetia din urmcontroleazcre-terea asociatpubertii. Vrsta de debut a pubertiise coreleazmai bine cu vrsta osoasdect cu ceacronologic(2,3).

2. Axul hipotalamo-hipofizo-corticosuprare-

nalian

Adrenarha

Debutul pubertii este precedat de o cretere a

nivelelor circulante de androgeni corticosuprarena-lieni: androstendion, dihidroepiandrosteron (DHEA)i dihidroepi-androsteron sulfat (DHEAs). Acestproces se numete adrenarh i debuteaz la 6-8ani, paralel cu creterea n dimensiuni a zonei

TABELUL 1. Stadiile pubertare Tanner, fete

Stadiu Tanner Glanda mamar Pilozitate pubian

I Prepubertar: doar papila mamar este vizibiln relief Prepubertar: nu existpilozitate pubian

II Mugurii mamari sunt vizibili sau palpabili; areola se

mretePilozitate pubianrar, ndeosebi la nivelullabiilor; firul de pr este lung, drept/sau uorondulat, slab pigmentat

III Continucreterea n dimensiuni a mugurilor mamari

i a areolei, fro separare neta contururiloracestora

Pilozitatea se extinde pe muntele pubisului, firul

de pr este mai gros i mai nchis la culoare

IV Proiecia papilei i areolei mamare deasupra planuluisnului

Fir de pr gros, de tip adult; pilozitatea nu seextinde spre prile mediale ale coapselor

V Forma adult: proiecia doar a papilei deasupraplanului snului

Fir de pr de tip adult cu distribuie clasicdetriunghi inversat

TABELUL. 2. Stadiile pubertare Tanner, biei

Stadiu Tanner Testicule/penis Pilozitate pubian

I Prepubertar: diametru testicular < 2,5 cm sau volum

testicular < 4 ml

Prepubertar: nu existpilozitate pubian

II Diametru testicular maxim > 2,5 cm sau volum

testicular > 4 ml; scrotul i modificculoarea i sesubiaz

Pilozitate pubianrar, ndeosebi la baza

penisului; firul de pr este lung, uor ondulat, slabpigmentat

III Penisul crete n lungime i grosime; continu cre-terea n dimensiuni a testiculelor

Pilozitatea se extinde pe muntele pubisului, firul

de pr este mai gros i mai nchis la culoare

IV Continucreterea penisului; scrotul devine nchis laculoare

Fir de pr gros, de tip adult; pilozitatea nu seextinde spre prile mediale ale coapselor

V Forma adulta penisului i testiculelor Fir de pr de tip adult; pilozitatea se extinde spreprile mediale ale coapselor i spre linia albmedian, dispoziia fiind triunghiular


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reticulate a corticosuprarenalei. Cu toate acestea,semnele adrenarhei (mirosul specific al transpiraiei,pilozitatea axilar i pubian) nu apar pn lamijlocul pubertii (5, 9, 10, 11).

Adrenarha i pubertatea

Dei existo legturtemporalntre adrenarh

i debutul pubertii, ntre cele douprocese bio-logice nu exist o relaie de cauzalitate, fapt de-monstrat de disocierea lor n anumite entiti pato-logice cum sunt pubertatea precoce central sauinsuficiena corticosuprarenalian(2, 9, 10, 11).

Dezvoltarea sexualprecoce

Pubertatea precoce este definitarbitrar ca apa-riia caracterelor sexuale secundare nainte de vrstade 8 ani la fete, respectiv nainte de 9 ani la biei(2).

Pubertatea precoce se clasific n 3 categoriimari: (1) pubertatea precoce gonadodropin depen-dent(central), (2) pubertatea precoce gonadotropinindependent (periferic), (3) pubertatea precoceparial.

1. Pubertatea precoce gonadotropin dependentCaracteristici generale

Este ntotdeauna izosexual i presupune oanomalie a axului hipotalamo-hipofizo-gonadal(2). Gonadotropii hipofizari determincreterea n

volum i activitate a gonadelor, rezultnd cretereanivelurilor circulante de hormoni sexuali, respectivmaturarea sexualprogresiv.

Pubertatea precoce gonadotropin dependenteste de 5 pnla 10 ori mai frecventla fete dectla biei. Doar 10% dintre fetele cu pubertate pre-coce central au o anomalie a sistemului nervoscentral (2-6). La biei se poate pune n evidenoastfel de anomalie n 25-75% dintre cazuri (2, 3).S-a gsit o prevalencrescuta pubertii precocecentrale la fetele adoptate din rile n curs de

dezvoltare, cauzele acestei observaii fiind deocam-datnecunoscute (2-6).

Pubertatea precoce urmeazaceleai etape ca icea fiziologic, existnd o concordan n dezvol-tarea tuturor structurilor implicate n pubertate (2,3).

Creterea n pubertatea precoce central

Talia, greutatea i maturarea osoassunt avan-sate. Sub aciunea hormonilor sexuali, cartilajele decretere se nchid, iar 1/3 dintre fete i un procent i

mai mare de biei au o talie adultsub percentila 5.Vrsta osoas se evalueazprin radiografia pum-nului. Se impune o urmrire longitudinala copiilor,diagnosticul nefiind posibil n urma unei singureexaminri (2-6).

Modificri hormonale n pubertatea precoce

gonadotropin dependent

Nivelurile serice de gonadotropi i hormonisexuali (estradiol, testosteron) sunt n concordancu stadiul pubertar. Testul de stimulare cu GnRHdetermino cretere a nivelurilor de LH i FSH, cu

predominana primului. Un raport LH/FSH supra-unitar este marker al pubertii. Astfel, n faasemnelor clinice de pubertate, creterea nivelurilorserice de estradiol la fete, respectiv testosteron labiei, un raport LH/FSH supraunitar n urmatestului de stimulare cu GnRH sugereaz diag-nosticul de pubertate precoce central. Se impuneluarea n calcul, dacsemnele clinice o sugereaz,a unei puberti precoce determinat de un hipo-tiroidism sever, netratat. n acest caz se vor de-termina nivelurile circulante de hormon stimulanttiroidian, tirotropina (TSH) i forma liber atiroxinei (FT4) (2, 3, 12, 13). Testul de stimulare cuGnRH este de importanmaxim.

Investigaii imagistice

n prezent se recomand investigarea prin re-zonanmagneticnucleara unor eventuale leziuniorganice cerebrale ce pot determina pubertate pre-coce centralurmtoarelor categorii de pacieni: lafete cu dezvoltare rapida glandei mamare (14), cuun nivel al estradiolului peste 30 picomoli per litru

(imunometric) sau cu vrsta sub 6 ani, precum i latoi bieii (2, 3).Cauze de pubertate precoce central

Cele mai comune anomalii cerebrale ce pot de-termina pubertate precoce centralsunt hamartoa-mele hipotalamice.

Pubertatea precoce gonadotropin dependentpoateaprea post iradiere cerebralpentru leucemie sau tu-mori cerebrale sau n cazul unor tumori ce secretgonadotropine, de exemplu hepatoblastomul.

Tratament

Pubertatea precoce central beneficiazde tra-tament cu analogi de GnRH sub forme farmaceuticecu eliberare lent. Efectele adverse sunt rare, trata-mentul fiind, n general, bine tolerat. Evoluia pu-bertii este ntrerupt, menstrele se opresc, iarglandele mamare, volumul testicular pot regresasub tratament. Pilozitatea nu se remite sub tratament,uneori putnd chiar progresa. Creterea i maturareaosoassunt stopate.

Terapia va fi monitorizat la 4-6 luni i va fi

ntreruptn momentul n care predicia pentru taliaadult este n limite acceptabile sau pn cndcopilul ajunge la vrsta pubertii fiziologice pentrugrupul populaional din care face parte (12, 15-19).


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2. Pubertatea precoce gonadotropin indepen-

dentCaracteristici generale

Poate fi izosexual sau heterosexual i secaracterizeazprin apariia unor caractere sexualesecundare, n lipsa activrii axului hipotalamo-

hipofizo-gonadal. Creterea i maturarea osoassunt avansate (2, 3, 10).De cele mai multe ori pubertatea precoce

periferic este determinat de secreia crescut aunui hormon din periferie (estrogen sau androgen)ce poate induce feminizare sau masculinizareindiferent de sexul copilului. Diferite tipuri detumori ale glandei corticosuprarenale (inclusivhiperplazia glandei ce determinsindromul adreno-genital) sau ale gonadelor pot produce o astfel desecreie (2, 3, 21-24).

Pubertatea precoce perifericla sexul femininForma izosexual

n faa unor semne clinice de pubertateizosexual, un nivel crescut de estradiol, nivelurisupresate de LH i FSH dupstimularea cu GnRH,sugereaz pubertate precoce periferic i impuneinvestigarea cauzelor prin ultrasonografia ovarelor,ficatului, glandei suprarenale (2, 21-24).

Forma heterosexual

Dacexistsemne de virilizare, se impune deter-minarea 17OH progesteronului i a androgenilor

corticosuprarenalieni, DHEA i DHEAs pentrudiagnosticarea sindromului adreno-genital (2, 3).Pubertatea precoce perifericla sexul masculinForma izosexual

n cazul semnelor de pubertate precoce izo-sexual, un nivel crescut de testosteron cu nivelurisczute de gonadotropi dupstimularea cu GnRHsugereazpubertatea precoce de cauzperiferic.Sursa corticosuprarenaliana androgenilor poate fipus n evidenprin determinarea 17OH proges-teronului, DHEA i DHEAs (2, 3).

Forma heterosexualGinecomastia izolat va fievaluatprin deter-

minarea de testosteron, prolactin, estradiol, gona-dotrofin corionic uman (hCG) i LH. Niveluricrescute de estradiol i/sau hCG sugereaztumoritesticulare sau extragonadale secretoare de estrogen.Prolactinoamele sunt foarte rare n copilrie. Dacestradiolul este uor crescut sau toate testele maisus menionate sunt normale, existo aromatizareextraglandular a testosteronului n estrogen, deobicei, prin exces de esut adipos (2, 3, 26-18).

Pubertatea precoce periferic beneficiaz detratament specific fiecrei cauze.3. Pubertatea precoce parialn practic ntlnim destul de des dezvoltarea

unor caractere sexuale izolate, att la fete, ct i la

biei, fralte semne pubertare. Cel mai frecventapare dezvoltarea glandelor mamare la fete (telarhaprecoce), respectiv apariia pilozitii axilare i/saupubiene la ambele sexe (adrenarha/pubarha precoce).

Telarha precoce

Este o condiie tranzitorie, caracterizatprin dez-

voltarea izolata glandelor mamare la fete, ce aparecel mai frecvent n primii 2 ani de via. n unelecazuri, dezvoltarea mamareste prezentdin perioadaneonatal i persist pentru o perioad variabil detimp. Dezvoltarea mamarpoate fiuni- sau bilaterali poate fluctua n dimensiuni (2, 3, 28).

Creterea i dezvoltarea osoas sunt normalesau uor accelerate, iar organele genitale nu prezintmaturare sexual. Nivelul seric de estradiol estenedetectabil, dar existo uoarcretere a nivelurilorLH i FSH dup stimularea cu GnRH, cu o pre-

dominan a FSH (2,13-16). Ecografia pelvinpoate releva microchiste ovariene (< 9 mm) (2).

Telarha precoce este n general benign, darpoate fi i primul semn de pubertate precoce, deaceea urmrirea longitudinalse impune.

Adrenarha (pubarha) precoce

Este caracterizatprin apariia iniiala pilozitiipubiene, urmatde cea axilar. De asemenea, poateaprea acnee sau un miros specific al transpiraiei.Este mai frecventla fete, fiind determinatde ma-turarea precoce a zonei reticulare a corticosupra-renalei, respectiv de secreia de hormoni androgenicorticosuprarenalieni (2,3,11,29-31). Vrsta osoaseste uor avansat, dar nu existcretere staturalaccelerat.

Adrenarha precoce este o condiie benignce nunecesit tratament. i n acest caz, se impuneurmrirea pe termen lung a copiilor. Studii longi-tudinale au evideniat c aproximativ 50% dintrefetele cu adrenarh precoce au risc crescut de adezvolta sindrom de ovar polichistic i complicaii

metabolice (2). De asemenea, copiii nscui micipentru vrsta gestaionalau risc crescut de a dez-volta adrenarhprecoce.

CONCLUZIE

Pubertatea precoce reprezinto patologie com-plexa copilriei. Cauzele sunt multiple, variind dela forme benigne, la forme rapid progresive cuimpact asupra taliei definitive sau chiar asupraprognosticului vital. Urmrirea copiilor longitudi-

nal, anamneza amnunit, nregistrarea cronologica semnelor pubertare, msurtorile somatometricei investigaiile hormonale repetate reprezintcheiaunui diagnostic corect i premisa unui tratamentprecoce i eficient.


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Puberty is a biological process that involvesmajor physical and psychological changes at theend of which the child becomes an adult.

Clinical aspects of normal puberty

Clinically, the onset of puberty is announced bythe appearance of secondary sexual characteristics:breast buds in girls, growth of the testes in boys andappearance axillary / pubic hair in both sexes. Thesesecondary sexual characters evolve to the adultform, through the five stages described by Tanner(1, 2, 3). The appearance of male and female sexualcharacteristics, according to Tanner stages is shownin Tables 1 and 2.

1. Puberty in girls

Menses start around 2-2 years after the firstsigns of puberty, during stages 3-4. Less visiblechanges are: increase in the volume of the ovaries,uterus, labia and clitoris, thickening of theendometrial and vaginal mucosa. The latter is redin pre-puberty, becoming pale pink during puberty(2, 3, 4).

2. Puberty in boys

Membranous and cartilaginous components of

the vocal cords grow, leading to deepening of thevoice. Also, facial hair appears, initially above theupper lip and upper portion of the cheeks.Simultaneously, there is an increase in the volumeof seminifere channels, epididymis, seminal vesicles

Early sexual development

Corina Duncescu1, Monica Marazan1,2, Adela Chirita-Emandi1,

Ramona Stroescu1,2, Ioana Micle1,2

11stPediatric Clinic, Louis Turcanu Emergency Hospital for Children, Timisoara2Victor Babes, University of Medicine and Pharmacy, Timisoara

ABSTRACT

Puberty is a biological process that involves major physical and psychological changes at the end of which

the child becomes an adult. Clinically, the onset of puberty is announced by the appearance of secondary

sexual character that develops specific females, respectively to form the adult male, going through the five

stages described by Tanner. The onset of puberty varies by race, ethnicity, geographic location, environmental

and nutritional conditions, in the Caucasian population ranging from 8 to 12 years. Early sexual development

is arbitrarily defined as the occurrence of secondary sexual characteristics before age 8 in girls and before

age 9 in boys, respectively. Precocious puberty is classified into three broad categories: (1) gonadotropin

dependent precocious puberty (central), (2) gonadotropin independent precocious puberty (peripheral), (3)

partial precocious puberty. This paper aims to present the particular appearance of secondary sexualcharacteristics, the hormonal changes and the therapeutic possibilities of each category. Close follow-up of

children, detailed medical history, chronological record of pubertal signs, repeated anthropometric and

hormonal measurement are the key to a correct diagnosis and an early and effective treatment.

Key words: precocious puberty, gonadotropin, thelarche, adrenarche

and prostate. In 40-60% of the boys we may find abilateral hypertrophy of the breast tissue, which in90% of cases resolves spontaneously (2, 3).

Both boys and girls may develop acne andseborrhea of the scalp, due to increased circulatingandrogens.

3. Growth during puberty

In both sexes, there is an early onset of acceleratedgrowth, most visible in stages 3-4. In boys, growthbegins 2-3 years later compared to girls, and is stillcontinuing for 2-3 years after it stopped in girls (2,3, 4).

4. The onset of puberty

The onset of puberty varies by race, ethnicity,

geographic location, environmental and nutritionalconditions. Thus, the onset of puberty in theCaucasian population is between 8 and 12 years.Compared to previous decades, the onset of pubertyis nowadays more precocious, being influenced bythe increase in body fat (4-8).

The physiology of puberty

Mechanisms involved in the initiation anddevelopment of physiological puberty are the hypo-

thalamic-pituitary-gonadal axis and hypothalamic-pituitary-adrenal axis.1. Hypothalamic-pituitary-gonadal axis

Until the onset of puberty, circulating levels ofgonadotropins, pituitary luteinizing hormone (LH)


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and follicle stimulating hormone (FSH) and sexhormones (estradiol and testosterone) areundetectable. It is clear that these mechanisms are

dormant, but the way in which they are suppressedis still poorly understood (2, 3).

Initiation of puberty

With one to three years before the clinical onset ofpuberty, low levels of gonadotropins with LH do-minance, become detectable during sleep. This secretionis initiated by episodic release of hypothalamic gona-dotropin hormone releasing hormone (GnRH) by ne-urohormonal mechanisms, not yet fully elucidated. Thenocturnal, pulsatile secretion of the gonadotropins con-

tinues to grow both in magnitude and frequency as weapproach clinically evident puberty. LH and FSH areresponsible for the growth and maturation of gonadsand sex hormone secretion (2, 3, 7).

Sex hormones

Sex hormones, estrogen and androgens have amajor impact on growth and bone maturation. Andro-gens are converted by aromatization to estrogen. Thus,the latter controls the accelerated growth during pu-berty. Onset age of puberty correlates better with boneage than with chronological age (2, 3).

2. Hypothalamic-pituitary-adrenal axisAdrenarche

The onset of puberty is preceded by an increasein the circulating levels of adrenal androgens:androstendione, dihidroepiandrosterone (DHEA)

and dihidroepi-androsterone sulfate (DHEAS).This process is called adrenarche and starts at 6-8years, in parallel with the increase in size of the

reticulated area of the adrenal glands. However, thesigns of adrenarche (adult sweat odor, axillary andpubic hair growth) do not appear until mid-puberty(5, 9, 10, 11).

Adrenarche and puberty

Although there is a temporal link between theonset of puberty and adrenarche, there is not a causalrelationship between the two biological processes,as demonstrated by their dissociation in certainpathological entities such as central precociouspuberty or adrenal insufficiency (2, 9, 10, 11).

Early sexual development

Precocious puberty is defined arbitrarily as theappearance of secondary sexual characteristics be-fore age 8 in girls and before 9 years in boys,respectively (2).

Precocious puberty is classified into three broadcategories: (1) gonadodropin dependent precociouspuberty (central), (2) gonadotropin independentprecocious puberty (peripheral), (3) partial preco-

cious puberty.1. Gonadotropin-dependent precocious puberty

General Features

It is always isosexual and involves an abnorma-lity of the hypothalamic-pituitary-gonadal axis (2).

TABLE 1. Tanner stages in girls

Tanner stage Breast development Pubic hair

I Prepubertal: areola follows the skin contours of the

chest

Prepubertal: no pubic hair

II Breast buds are visible or palpable; areola begins to

widen

Sparse pubic hair, especially on the labia; the hair

is long, straight/ slightly curvy, slightly pigmented

III Breast buds and areola continue to grow, without a

definite separation of their contours

Hair extends to mount pubis; hair is more coarse

and darkens in colorIV Areola and papilla form a secondary mound

projecting from the contour of the surrounding breast

Adult type hair, it does not extend to the medial

sides of the thighs

V Adult form: only the papilla is projecting from the

contour of the surrounding breast

Adult type hair with classical reverse triangle

distribution

TABLE 2. Tanner stages in boys

Tanner stage Testes Pubic hair

I Prepubertal: testicular diameter< 2,5 cm or testicular

volume < 4 ml

Prepubertal: no pubic hair

II Maximal testicular diameter > 2,5 cm or testicular

volume > 4 ml; scrotum changes in color, becomes

thinner

Sparse pubic hair, especially on the labia; the hair

is long, straight/ slightly curvy, slightly pigmented

III Penis grows in length and girth; testes continue to

grow in size

Hair extends to mount pubis; hair is more coarse

and darkens in color

IV Penis continues to grow; scrotum becomes darker Adult type hair, it does not extend to the medial

sides of the thighs

V Adult form of testes and penis Adult type hair; hair extends to medial sides

of thighs and to the median white line, triangle

distribution


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Pituitary gonadotropins increase the volume andactivity of the gonads, resulting in increasedcirculating levels of sex hormones and progressivesexual maturation.

Gonadotropin-dependent precocious puberty is5 to 10 times more common in girls than in boys.

Only 10% of girls with central precocious pubertyhave an abnormality of central nervous system(2-6). In boys we may find such an anomaly in 25-75% of cases (2, 3). There is a high prevalence ofcentral precocious puberty in girls adopted fromdeveloping countries, of yet unknown causes(2-6).

Precocious puberty follows the same stages asphysiological puberty, with a concordance in all of thestructures involved in pubertal development (2, 3).

Growth in central precocious puberty

Height, weight and bone maturation are ad-vanced. Under the action of sex hormones, growthcartilage close, and one third of girls and a greaterproportion of boys have an adult height below the5thcentile. Bone age is assessed by wrist radiography.It requires a longitudinal follow-up, the diagnosisnot being possible after a single examination (2-6).

Hormonal changes in gonadotropin-dependent

precocious puberty

Serum levels of gonadotropins and sex hormones(estradiol, testosterone) are consistent with pubertalstage. The GnRH stimulation test increases thelevels of LH and FSH, with the predominance ofthe former. A LH / FSH ratio above 1 is a marker ofpuberty. Thus, faced with clinical signs of puberty,increased serum levels of estradiol in girls,testosterone in boys and a LH / FSH ratio above 1after GnRH stimulation test suggests the diagnosisof central precocious puberty. We must take intoaccount, if clinical signs suggest a precociouspuberty caused by severe, untreated hypothyroidism.

In this case we will determine the circulating levelsof thyroid stimulating hormone, tirotropin (TSH)and the free form of thyroxin (FT4) (2, 3, 12, 13).GnRH stimulation test is of utmost importance.

Imaging

It is now recommended to investigate by mag-netic resonance imaging a possible organic braindamage that may cause central precocious pubertyin the following categories of patients: girls withrapid breast development (14), estradiol levelsabove 30 picomoli per liter (immunometric) or

younger than 6 years and in boys (2, 3).Causes of central precocious puberty

The most common brain abnormalities that cancause central precocious puberty are hypothalamichamartomas.

Gonadotropin-dependent precocious pubertymay occur after brain irradiation for leukemia orbrain tumors or in the case of gonadotropin-secreting tumors, for example hepatoblastoma.

Treatment

Central precocious puberty is treated with GnRH

analogues in slow-release formulations. Side effectsare rare, treatment is generally well tolerated. Inevolution, puberty is interrupted; menses stop,breast development and testicular volume mayreverse with treatment. Hair does not disappearwith treatment, sometimes may even worsen.Growth and bone maturation are stopped.

Therapy will be monitored every 4-6 monthsand will be discontinued when the prediction forthe adult size is within acceptable limits or until thechild reaches the age of physiological puberty in

the population group to which he/she belongs (12,15-19).2. Gonadotropin independent precocious pu-

berty

General Features

It may be isosexual or heterosexual and ischaracterized by the appearance of secondarysexual characteristics, in the absence of the acti-vation of the hypothalamic-pituitary-gonadal axis.Bone growth and maturation are well advanced (2,3, 10).

In most cases peripheral precocious puberty iscaused by increased secretion of a hormone in theperiphery (estrogen or androgen) and may inducefeminization or masculinization regardless of sex.Different types of tumors of the adrenal gland(including congenital adrenal hyperplasia CAH)or of the gonads may produce such a secretion (2,3, 21-24).

Peripheral precocious puberty in females

Isosexual form

Faced with clinical signs of isosexual puberty,

high levels of estradiol and suppressed LH and FSHlevels after GnRH stimulation, suggests peripheralprecocious puberty and require ultrasound imagingof the ovaries, liver and adrenal gland (2, 21-24).

Heterosexual form

If virilizing signs are present, it is necessary todetermine the 17 OH progesterone and adrenalandrogens, DHEA and DHEAS for CAH (2, 3).

Peripheral precocious puberty in males

Isosexual form

If isosexual signs of precocious puberty are

present, increased testosterone levels and low levelsof gonadotropins after GnRH stimulation suggestsperipheral precocious puberty. Source of adrenalandrogens may be pinpointed by testing for 17 OHprogesterone, DHEA and DHEAS (2, 3).


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Heterosexual form

Isolated gynecomastia will be assessed by deter-mining testosterone, prolactin, estradiol, humanchorionic gonadotrophin (hCG) and LH. Highlevels of estradiol and/or hCG suggest estrogen-secreting testicular or extra gonadal tumors. Pro-

lactinoma are very rare in childhood. If estradiol isslightly increased or all of the above tests arenormal, there is an extra glandular aromatization oftestosterone to estrogen, usually in excess adiposetissue (2, 3, 26-18).

Peripheral precocious puberty is treatedspecifically for each particular case.

3. Partial precocious puberty

In practice we encounter quite often isolateddevelopment of sexual characteristics, both in girlsand boys, without other signs of puberty. Breast

development occurs more frequently in girls (pre-cocious telarche) and appearance of axillary and/orpubis hair in both sexes (precocious adrenarch/pubarche).

Precocious telarche

It is a transient condition characterized by iso-lated breast development in girls, which occursmost frequently in the first two years of life. Insome cases, breast development is present in theneonatal period and persists for a variable period oftime. Breast development may be unilateral orbilateral and may fluctuate in size (2, 3, 28).

Growth and bone development are normal orslightly accelerated and there is no sexual matu-ration. Serum levels of estradiol are undetectable,but there is a slight increase in LH and FSH levelsafter GnRH stimulation, with a predominance ofFSH (2, 13-16). Pelvic ultrasound may revealovarian cysts (< 9 mm) (2).

Precocious telarche is generally benign, but maybe the first sign of precocious puberty, and thereforerequires the longitudinal follow-up.

Precocious adrenarche (pubarche)

It is characterized by the appearance of pubichair initially, followed by axillary hair. Acne may

also occur or an adult odor of the sweat. It is morecommon in girls, and is determined by earlymaturation of the adrenal reticular area, and adrenalandrogen secretion, respectively (2, 3, 11, 29-31).Bone age is slightly advanced, but there is noaccelerated growth.

Precocious adrenarche is a benign condition thatdoes not require treatment. Long term follow-up ofthe children is necessary. Longitudinal studies haveshown that approximately 50% of girls with earlyadrenarche have an increased risk of developing

polycystic ovary syndrome and metaboliccomplications (2). Also, children born small forgestational age have an increased risk of developingearly adrenarche.

CONCLUSION

Precocious puberty is a complex childhooddisease. The causes are multiple, ranging frombenign forms, to rapidly progressive forms thatinfluence final adult height or the vital prognosis.Longitudinal tracking of children, detailed medicalhistory, and chronological record of pubertal signs,hormonal measurements and repeated somatometricmeasurements are the key to a correct diagnosisand an early and effective treatment.

Tanner J.M.1. Growth at Adolescence. Springfield, IL: Charles C

Thomas, 1962.

Luigi Garibaldi2. Physiology of Puberty, Disorders of Pubertal

Development. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF

Kasper DL, eds. Nelson Textbook of Pediatrics. 18th ed.Philadelphia,

PA: Elsevier; 2007:2308:2316.

Grumbach M.M., Styne D.M.3. Puberty: ontogeny, neuroendocrinology,

physiology, and disorders. In:Wilson JD, Foster DW, Kronenberg HM,

Larsen PR, eds. Williams Textbook of Endocrinology 9th Edition. WB

Saunders Company; 1998: 1509-1625.

Herman-Giddens M.E., Slora E.J., Wasserman R.C., et al.4.

Secondary sexual characteristics and menses in young girls seen in

office practice: a study from the pediatric research in office settings

network.Pediatrics1997; 99: 505-512.

Kaplowitz P.5. Clinical characteristics of 104 children referred for

evaluation of precocious puberty. J Clin Endocrinol Metab2004; 89:

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Kapl6. owitz P.B. Oberfield SE and the Drug and Therapeutics andExecutive Committees of the Lawson Wilkins Pediatric EndocrineSociety. Reexamination of the Age limit for defining when puberty isprecocious in girls in the United States: implications for evaluation andtreatment. Pediatrics1999; 104: 936-941.Toppari J., Juul A.7. Trends in puberty timing in humans and environ-mental modifiers. Mol Cell Endocrinol. 2010 Aug 5;324(1-2):39-44.Himes J.H.8. Examining the evidence for recent secular changes in thetiming of puberty in US children in light of increases in the prevalence ofobesity. Mol Cell Endocrinol.2006 Jul 25;254-255:13-21.Ebling F.J.P., Cronin A.S.9. The neurobiology of reproductive

development. Neuroreport 2000; 11: R23-33.Biason-Lauber A., Zachmann M., Schoenle E.J.10. Effect of leptin onCYP17 enzymatic activities in human adrenal cells: new insight in theonset of adrenarche. Endocrinology. 2000; 141: 1446-1454.Belgorosky A., Baquedano M.S., Guercio G., Rivarola M.A.11.

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