GANGGUAN PUBERTASGANGGUAN PUBERTAS

Dr Eka Agustia Rini Sp AKDr Eka Agustia Rini Sp AKSub Bagian Endokrinologi Ilmu Sub Bagian Endokrinologi Ilmu

Kesehatan AnakKesehatan AnakFK-UNAND / RS Dr M. Djamil FK-UNAND / RS Dr M. Djamil

PadangPadang

PRECOCIOUS PUBERTYPRECOCIOUS PUBERTYPRECOCIOUS PUBERTYPRECOCIOUS PUBERTY

Hypothalamus - Pituitary – Gonad Hypothalamus - Pituitary – Gonad axisaxis

INTRODUCTIONINTRODUCTION

EpidemiologyEpidemiology

– Frequency : girls > boysFrequency : girls > boys

– Girls: most have a benign central cause Girls: most have a benign central cause

– Boys: 50% pathologic peripheral cause. Boys: 50% pathologic peripheral cause.

all boys with precocious puberty should all boys with precocious puberty should undergo detailed investigation, but in undergo detailed investigation, but in girls additional investigation can be girls additional investigation can be based on the clinical impressionbased on the clinical impression

Profiles of Girls with Precocious Puberty Profiles of Girls with Precocious Puberty (N=438)(N=438)

Age of onsetAge of onset

between 7-7.9 year oldsbetween 7-7.9 year olds

6 year olds6 year olds

< 6 years old. < 6 years old.

59.6% 59.6%

22.4% 22.4%

18%18%

EtiologyEtiology

Gonadotropin DependentGonadotropin Dependent

Gonadotropin independentGonadotropin independent

97.7% 97.7%

2.3%2.3%

Neurogenic abnormalities Neurogenic abnormalities (MR/CT skull)(MR/CT skull)

18.4%18.4%

Cisternino M, Arrigo T, Pasquino AM, et al. Etiology and Age Incidence of Precocious Puberty in

Girls: A Multicentric Study. J Pediatr Endocrinol Metab. 2000;13(suppl 1):695-701

Precocious PubertyPrecocious Puberty

DefinitionDefinition– Appearance of Appearance of

secondary sexual secondary sexual characteristics : boys characteristics : boys < 9 years and girls < 8 < 9 years and girls < 8 years old (- 2SD)years old (- 2SD)

Sex steroid Sex steroid – Estrogen: femaleEstrogen: female– Testosterone:maleTestosterone:male

Effect of sex steroid Effect of sex steroid

EstroEstrogengen –Accelerated bone maturation and early Accelerated bone maturation and early

epiphyseal fusion (epiphyseal fusion (tall child but short tall child but short adult)adult)

–Uterus, mammary glandUterus, mammary gland

TestosteroneTestosterone

–Genital, Hirsutism, acne, Genital, Hirsutism, acne, male habitusmale habitus

GeneralGeneral::sexual behavior, sexual behavior, aggressivenessaggressiveness

GnRH dependentGnRH dependent (central) : (central) : – premature reactivation hypothalamus-pituitary-premature reactivation hypothalamus-pituitary-

gonad axis gonad axis increased gonadotropin increased gonadotropin increased sex steroids (dependent)increased sex steroids (dependent)

– Usually idiopathicUsually idiopathic

GnRH independentGnRH independent (peripheral): (peripheral): – autonomous sex steroid secretion, autonomous sex steroid secretion,

depressing the hypothalamus-pituitary-gonad depressing the hypothalamus-pituitary-gonad axisaxis

– Usually pathologicUsually pathologic

ClassificationClassification

Classification Classification

Variant

–premature thelarche

–premature adrenarche

–gynecomastia

Etiology GDPP Etiology GDPP

idiopathicidiopathic

CNSCNS

– tumortumor

– non-tumor: post infection, radiation, non-tumor: post infection, radiation, trauma, congenitaltrauma, congenital

iatrogeniciatrogenic

Delayed diagnosis of GIPP Delayed diagnosis of GIPP

Clinical manifestation GDPPClinical manifestation GDPP

Always isosexualAlways isosexual

Normal sequence of pubertyNormal sequence of puberty

Hormonal profile: increased Hormonal profile: increased gonadotropin and sex steroidgonadotropin and sex steroid

Etiology GIPP - maleEtiology GIPP - male

IsosexualIsosexual– adrenal: tumor, CAHadrenal: tumor, CAH– testes : cell Leydig tumor, familial testes : cell Leydig tumor, familial

testotoxicosistestotoxicosis– gonadotropin-secreting tumor: gonadotropin-secreting tumor:

non CNS: hepatoma, germinoma, teratomanon CNS: hepatoma, germinoma, teratomaCNS: germinoma, adenoma (LH secreting)CNS: germinoma, adenoma (LH secreting)

heterosexual heterosexual Increased peripheral aromatizationIncreased peripheral aromatization

Etiology GIPP - femaleEtiology GIPP - female

Isosexual)Isosexual)– McCune AlbrightMcCune Albright– Severe Severe

hypothyroidhypothyroid

heterosexualheterosexual– adrenal: tumor, adrenal: tumor,

CAHCAH– tumor ovarium: tumor ovarium:

arrhenoblastomaarrhenoblastoma

Mc Cune Albright SyndromeMc Cune Albright Syndrome

TriasTrias

– Precocious puberty / Precocious puberty / endocrine endocrine hyperactivityhyperactivity

– FibrodysplasiaFibrodysplasia

– Café au laitCafé au lait

Clinical manifestation GIPPClinical manifestation GIPP

Isosexual or heterosexual (late onset Isosexual or heterosexual (late onset CAH, tumor adrenal)CAH, tumor adrenal)

Disconcordant of sexual characteristics Disconcordant of sexual characteristics (testes volume inappropriate with pubertal (testes volume inappropriate with pubertal stage - smaller) stage - smaller)

Low or normal gonadotropin and Low or normal gonadotropin and increased sex steroidincreased sex steroid

Benign Premature AdrenarcheBenign Premature Adrenarche

self-limited condition occurring before six self-limited condition occurring before six years of age years of age characterized by the appearance of pubic characterized by the appearance of pubic and no further secondary sexual and no further secondary sexual development. development. normal growth patternsnormal growth patterns

Benign Premature AdrenarcheBenign Premature Adrenarche

Normal bone age Normal bone age Slight elevation of serum DHEASlight elevation of serum DHEANormal adrenal steroid hormone levels Normal adrenal steroid hormone levels Normal sex hormone levels Normal sex hormone levels ACTH stimulation test: to exclude late-ACTH stimulation test: to exclude late-onset CAH onset CAH GnRH test: prepubertal patternGnRH test: prepubertal patternNormal imaging studies Normal imaging studies No specific treatment required No specific treatment required

Premature AdrenarchePremature Adrenarche

Excude virilizationExcude virilization

– clitoral enlargement, advanced bone clitoral enlargement, advanced bone age, acne, rapid growth, and voice age, acne, rapid growth, and voice change. change.

– rapid progression rapid progression

If virilization present If virilization present

– measure testosterone, 17-OHP and measure testosterone, 17-OHP and DHEA DHEA

– USG: adrenal or ovarian tumorUSG: adrenal or ovarian tumor

– 17-OHP or DHEA17-OHP or DHEA: CAH: CAH

Benign Premature ThelarcheBenign Premature Thelarche

Isolated appearance of unilateral or Isolated appearance of unilateral or bilateral breast aged 6 months to 3 yearsbilateral breast aged 6 months to 3 years

No other signs of puberty or evidence of No other signs of puberty or evidence of excessive estrogen effect (excessive estrogen effect (thickening of thickening of the vaginal secretions or bone age the vaginal secretions or bone age accelerationacceleration). ).

Ingestion or application of estrogen-Ingestion or application of estrogen-containing compounds must be excluded containing compounds must be excluded as etiologyas etiology

Benign Premature ThelarcheBenign Premature Thelarche

Normal growth rate and bone age Normal growth rate and bone age Normal levels of gonadotropins and Normal levels of gonadotropins and estradiolestradiolUSG: normal ovaries, prepubertal uterus USG: normal ovaries, prepubertal uterus Usually resolves spontaneously and Usually resolves spontaneously and requires no treatment requires no treatment re-evaluation at intervals of 6-12 months to re-evaluation at intervals of 6-12 months to ensure that premaure thelarche is not the ensure that premaure thelarche is not the beginning of isosexual precocious pubertybeginning of isosexual precocious puberty

GynecomastiaGynecomastia

Breast enlargement in malesBreast enlargement in males

common in teenage years, lasting 2 yearscommon in teenage years, lasting 2 years

differentiate with obese boys differentiate with obese boys

– lipomastialipomastia

– no mammae diskno mammae disk

Pathological causes must be soughtPathological causes must be sought

Pubertal Gynecomastia Pubertal Gynecomastia

Incidence: 50-60% of boys during early Incidence: 50-60% of boys during early adolescenceadolescencebreast tissue usually asymmetric and often breast tissue usually asymmetric and often tender. tender. If history and physical examination, If history and physical examination, including palpation of the testicles, are including palpation of the testicles, are unremarkable, reassurance and periodic unremarkable, reassurance and periodic reevaluation are all that is necessary. Most reevaluation are all that is necessary. Most cases resolve in one to two years.cases resolve in one to two years.

GynecomastiaGynecomastiaDrugsDrugs

– sex steroids, hCG, sex steroids, hCG, psychoactive (phenotiazine), psychoactive (phenotiazine), antituberculosis, antituberculosis, testosterone antagonist testosterone antagonist (ketoconazole, cimetidine, (ketoconazole, cimetidine, spironolactone)spironolactone)

Malnutrition Malnutrition

Idiopathic (most common)Idiopathic (most common)

Tumor producing diseaseTumor producing disease– hepatoma, adrenal, testes, LH hepatoma, adrenal, testes, LH

and hCG producing tumorsand hCG producing tumors

Pubertal Gynecomastia Pubertal Gynecomastia

Familial gynecomastiaFamilial gynecomastia

– X-linked recessive trait or a sex-limited X-linked recessive trait or a sex-limited dominant traitdominant trait

– unless associated with hypogonadism no unless associated with hypogonadism no further evaluation in an otherwise normal boyfurther evaluation in an otherwise normal boy

– If severe, gynecomastia If severe, gynecomastia cosmetic surgery. cosmetic surgery.

Pathologic gynecomastiaPathologic gynecomastia

– Klinefelter's syndrome: high risk for breast Klinefelter's syndrome: high risk for breast cancercancer

– prolactin-secreting adenomataprolactin-secreting adenomata

Pubertal GynecomastiaPubertal GynecomastiaPathologic gynecomastiaPathologic gynecomastia

– hormone-secreting tumors (testes, hormone-secreting tumors (testes, hepatoma), cirrhosis, hypo- and hepatoma), cirrhosis, hypo- and hyperthyroidism. hyperthyroidism.

– Drug induced (marijuana, phenothiazines, Drug induced (marijuana, phenothiazines, opiates, amphetamines, digitalis, estrogens, opiates, amphetamines, digitalis, estrogens, ketoconazole, spironolactone, isoniazid, ketoconazole, spironolactone, isoniazid, tricyclic antidepressants, cimetidine, etc).tricyclic antidepressants, cimetidine, etc).

If worsens and associated with psychologic If worsens and associated with psychologic morbidity morbidity bromocriptine, tamoxifen bromocriptine, tamoxifen

reduction mammoplasty rarely indicatedreduction mammoplasty rarely indicated..

Diagnostic work upDiagnostic work up

Gonadotropin dependent or independent?Gonadotropin dependent or independent?

Etiology?Etiology?

Hypothalamus

Hypothalamus

Pituitary

Pituitary

GnRH

GonadGonad

LH/FSH

E2 or T

(-)

H-P-G axisH-P-G axis

Hypothalamus

Hypothalamus

Pituitary

Pituitary

GnRH

GonadGonad

LH/FSH

Sex steroid

(-)

H-P-G axis in GDPPH-P-G axis in GDPP

Primary

Hypothalamus

Hypothalamus

Pituitary

Pituitary

GnRH

GonadGonad

LH/FSH

(-)

Extra GonadalExtra Gonadal

H-P-G axis in GIPP

Sex steroid PRIM

ARY

Diagnostic work upDiagnostic work up

HistoryHistoryage of onset, progressivity, family history, age of onset, progressivity, family history, growth, symptoms extragonadal cause growth, symptoms extragonadal cause (adrenal), CNS complaints, gelactic laughter (adrenal), CNS complaints, gelactic laughter (hamartoma), previous history: encephalitis, (hamartoma), previous history: encephalitis, meningitis TBmeningitis TB

Physical examinationPhysical examinationpubertal stage, signs of virilisation, height, pubertal stage, signs of virilisation, height, testes size (small indicative of perpheral testes size (small indicative of perpheral cause), CNS signs, skin (acne, café au lait), cause), CNS signs, skin (acne, café au lait),

Diagnostic work upDiagnostic work up

LaboratoryLaboratorygonadotropin, gonadotropin, HCG, 17-OHProgesterone HCG, 17-OHProgesterone (CAH), cortisol (Cushing syndrome, (CAH), cortisol (Cushing syndrome, adrenal tumor)adrenal tumor)

ImagingImagingBone age, pelvic ultrasound, skull x-ray, Bone age, pelvic ultrasound, skull x-ray, CT/MRI, bone survey (McCune Albright), CT/MRI, bone survey (McCune Albright),

TherapyTherapy

According to the etiologyAccording to the etiology

GDPP idiopathic: GnRH agonisGDPP idiopathic: GnRH agonis

GIPP : medroxy-progesteron, GIPP : medroxy-progesteron, ketoconazole, dllketoconazole, dll

Variant: observationVariant: observation

PrognosisPrognosis

According to etiologyAccording to etiology

GDPP idiopathic: GnRH agonisGDPP idiopathic: GnRH agonis– Final height = potential genetic heightFinal height = potential genetic height– Preserved fertilityPreserved fertility– Psychosocial minimal, regression of Psychosocial minimal, regression of

secondary sexsecondary sex

GIPP : medical GIPP : medical – Potential genetic height Potential genetic height – Regression of secondary sex Regression of secondary sex

ConclusionConclusion

Not all pubertal disorders are pathologicNot all pubertal disorders are pathologic

Early increase of sex steroid should be Early increase of sex steroid should be thoroughly investigatedthoroughly investigated

GnRH agonist = drug of choice for GnRH agonist = drug of choice for GDPPGDPP

DELAYED PUBERTYDELAYED PUBERTY

DefinisiDefinisi

Pubertas terlambat bila tidak adanya Pubertas terlambat bila tidak adanya tanda-tanda pubertas tanda-tanda pubertas – laki-laki pada usia 14 tahunlaki-laki pada usia 14 tahun– perempuan pada usia 13 tahunperempuan pada usia 13 tahunKlasifikasiKlasifikasi– hipergonadotropik hipogonadismhipergonadotropik hipogonadism– hipogonadotropik hipogonadismhipogonadotropik hipogonadismAmmenorrhoe primerAmmenorrhoe primerAmmenorrhoe sekunderAmmenorrhoe sekunder

hipogonadismhipogonadism

LHRHLHRH

LH/FSHLH/FSH

HipotalamusHipotalamus

HipofisisHipofisis

Target Organ(gonad)

Sex SteroidSex Steroid

Primary defectPrimary defect

HipergonadotropikHipergonadotropik

(-)

Hipergonadotropik hipogonadismHipergonadotropik hipogonadism

Dengan kelainan kromosomDengan kelainan kromosom

– Dysgenesis gonadDysgenesis gonad

Sindrom TurnerSindrom Turner

Pure gonadal dysgenesisPure gonadal dysgenesis

– Sindrom KlinefelterSindrom Klinefelter

– Androgen Insensitivity Syndrome *Androgen Insensitivity Syndrome *

Hipergonadotropik hipogonadismHipergonadotropik hipogonadism

Tanpa kelainan kromosomTanpa kelainan kromosom

– kongenitalkongenital

gangguan biosintesis steroid adrenal gangguan biosintesis steroid adrenal (P450c17,P450scc,3(P450c17,P450scc,3HSD) dan HSD) dan gonad (17-KS, P450 aromatase)gonad (17-KS, P450 aromatase)

anorchia, anorchia, ovary resistant syndrome, ovary resistant syndrome, LH resistanceLH resistance

– didapatdidapat

radiasi, chemotherapy, proses radiasi, chemotherapy, proses autoimunautoimun

hipogonadismhipogonadism

LHRHLHRH

LH/FSHLH/FSH

HipotalamusHipotalamus

HipofisisHipofisis

Target Organ(gonad)

Sex SteroidSex Steroid

Primary defectPrimary defect

HipogonadotropikHipogonadotropik

(-)

Hipogonadotropik hipogonadismHipogonadotropik hipogonadism

Constitutional delayConstitutional delayKelainan Susunan Syaraf PusatKelainan Susunan Syaraf Pusat– Tumor (craniopharyngioma, germinoma, Tumor (craniopharyngioma, germinoma,

optic glioma, histiocytosis X)optic glioma, histiocytosis X)– Struktural (Struktural (mid line defectmid line defect))– Sindrom KallmannSindrom Kallmann– hipopituitarism idiopathichipopituitarism idiopathic– pasca tindakan (radiasi, khemoterapi pasca tindakan (radiasi, khemoterapi

inflamasi, infiltrasi - hemosiderosis)inflamasi, infiltrasi - hemosiderosis)

Hipogonadotropik hipogonadismHipogonadotropik hipogonadism

Penyakit kronisPenyakit kronis

– endokrin, malnutrisi/anorexia nervosa, endokrin, malnutrisi/anorexia nervosa, kelainan sistemikkelainan sistemik

Aktivitas fisik berlebihanAktivitas fisik berlebihan

Sindrom-sindromSindrom-sindrom

– Prader-Willi; Laurence-Moon-BiedlPrader-Willi; Laurence-Moon-Biedl

Hypothalamic and pituitary causes of Hypothalamic and pituitary causes of pubertal failure-low gonadotrophinspubertal failure-low gonadotrophins

Congenital defectsCongenital defects– Kalmann syndromeKalmann syndrome– Congenital adrenal hypoplasiaCongenital adrenal hypoplasia– Septoptic dysplasiaSeptoptic dysplasia– Development defect of pituitaryDevelopment defect of pituitary

Tumors, direct effects or following Tumors, direct effects or following radiotherapy or surgeryradiotherapy or surgery

HaemochromatosisHaemochromatosis

Thalassemia and endocrinopathy. A multicenter study (N=3092)

6%4% 3% 7%

80%

Delayed puberty HypothyroidismIDDM HypoparathyroidismOthers

Italian Working Group on Endocrine Complication in non-endocrine diseases, 1993

Delayed puberty in Thalassamia patientDelayed puberty in Thalassamia patient

Italian Multicenter Thalassemia study Italian Multicenter Thalassemia study 1993, (29 centers), 3092 patients : 1993, (29 centers), 3092 patients :

Puberty failure: Puberty failure:

males 41 %males 41 %

females 39,5 %females 39,5 %

All patient with hemachromatosis need All patient with hemachromatosis need periodic careful endocrine evaluationperiodic careful endocrine evaluation

TatalaksanaTatalaksana

AnamnesisAnamnesis

Pemeriksaan fisikPemeriksaan fisik

Pemeriksaan penunjangPemeriksaan penunjang

TerapiTerapi

AnamnesisAnamnesis

Riwayat perkembangan pubertas di dalam Riwayat perkembangan pubertas di dalam keluargakeluarga

Data pertumbuhan & perkembanganData pertumbuhan & perkembangan

Riwayat penyakit/pengobatan dahuluRiwayat penyakit/pengobatan dahulu

Fungsi penciumanFungsi penciuman

Pemeriksaan fisikPemeriksaan fisik

Pemeriksaan fisik secara umumPemeriksaan fisik secara umum

Pemeriksaan neurologis (funduskopi) dPemeriksaan neurologis (funduskopi) d

Antropometri (TB, BB, rasio segmen atas Antropometri (TB, BB, rasio segmen atas dan bawah, rentang lengan)dan bawah, rentang lengan)

Status pubertasStatus pubertas

Stigmata suatu sindrom (pendek, obese, Stigmata suatu sindrom (pendek, obese, retardasi mental, retardasi mental, webbed neckwebbed neck dll) dll)

Pemeriksaan PenunjangPemeriksaan Penunjang

PencitraanPencitraan: : – usia tulang, CT scan/MRI kepala & USG usia tulang, CT scan/MRI kepala & USG

genitalia interna (atas indikasi), genitalia interna (atas indikasi),

HormonalHormonal (basal/ uji GnRH) (basal/ uji GnRH)– LH,FSH,Prolactin, Estrogen atau testosteroneLH,FSH,Prolactin, Estrogen atau testosterone

Dan lain-lainDan lain-lain– analisis kromosom (atas indikasi)analisis kromosom (atas indikasi)– uji fungsi penciumanuji fungsi penciuman

Any signs of puberty?Any signs of puberty?

Pubertal Delay Pubertal Delay

YESYES

Psychological distress?Psychological distress?

NONO

YESYES

oxandrolone /sex steroids

oxandrolone /sex steroids

Monitor growth & pubertal progress

Monitor growth & pubertal progress

NONO

Check• height, FSH/LH, T4/TSH, • Prolactin, Karyotype (girls)

Check• height, FSH/LH, T4/TSH, • Prolactin, Karyotype (girls)

Low FSH/LHLow FSH/LH High FSHHigh FSH

GnRh /sex steroids

GnRh /sex steroids sex steroids sex steroids

Hormonal replacementHormonal replacement

Discrepancies exist concerningDiscrepancies exist concerning– the age of initiationthe age of initiation– dosagedosage

Some authors : postponing treatment until the Some authors : postponing treatment until the age when arrested sexual maturation in easily age when arrested sexual maturation in easily diagnoseddiagnosed

Early treatment supporters: Insist on the Early treatment supporters: Insist on the psychological benefits treatmentpsychological benefits treatment

Sexual development should be induce at an Sexual development should be induce at an appropriate age appropriate age

Recommended hormone replacementRecommended hormone replacement

When to wait watchfully and when to test When to wait watchfully and when to test and refer are part of the art of medicineand refer are part of the art of medicine

– Female patients Female patients chronological age > 13-14 yearschronological age > 13-14 yearsbone age > 11 yearsbone age > 11 years

– Male patientsMale patientschronological age > 14-15 yearschronological age > 14-15 yearsbone age > 12 yearsbone age > 12 years

Hormonal replacementHormonal replacement

Females : Females : – start ŵ estrogen 0,25 mg daily (6-9 start ŵ estrogen 0,25 mg daily (6-9

months)months)– after 9 MOs cyclic therapy ŵ estrogen after 9 MOs cyclic therapy ŵ estrogen

for 1st 21 daysfor 1st 21 daysMales:Males:– testosterone enanthate 50 mg IM/ testosterone enanthate 50 mg IM/

monthlymonthly– after 6-9 MOs, dose gradually increased after 6-9 MOs, dose gradually increased

to 200 mg/3 weeks (2-3 years) to 200 mg/3 weeks (2-3 years)

KESIMPULANKESIMPULAN

Pubertas berlangsung menurut Pubertas berlangsung menurut stadium, umur tertentustadium, umur tertentu

Pubertas harus selalu menjadi Pubertas harus selalu menjadi perhatian orangtua / tenaga perhatian orangtua / tenaga kesehatankesehatan

Setiap tenaga kesehatan dapat Setiap tenaga kesehatan dapat mendeteksi kelainan pubertas secara mendeteksi kelainan pubertas secara dini dan segera melakukan rujukandini dan segera melakukan rujukan