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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
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
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
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
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