GANGGUAN PUBERTAS

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GANGGUAN PUBERTAS

• Dr Eka Agustia Rini Sp AK
• Sub Bagian Endokrinologi Ilmu Kesehatan Anak
• FK-UNAND / RS Dr M. Djamil Padang

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PRECOCIOUS PUBERTY
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Hypothalamus - Pituitary Gonad axis
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INTRODUCTION

• Epidemiology
• Frequency girls gt boys
• Girls most have a benign central cause
• Boys 50 pathologic peripheral cause.
• ? all boys with precocious puberty should undergo
  detailed investigation, but in girls additional
  investigation can be based on the clinical
  impression

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Profiles of Girls with Precocious Puberty (N438) Profiles of Girls with Precocious Puberty (N438)
Age of onset between 7-7.9 year olds 6 year olds lt 6 years old. 59.6 22.4 18
Etiology Gonadotropin Dependent Gonadotropin independent 97.7 2.3
Neurogenic abnormalities (MR/CT skull) 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. 200013(suppl 1)695-701 Cisternino M, Arrigo T, Pasquino AM, et al. Etiology and Age Incidence of Precocious Puberty in Girls A Multicentric Study. J Pediatr Endocrinol Metab. 200013(suppl 1)695-701
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Precocious Puberty

• Definition
• Appearance of secondary sexual characteristics
  boys lt 9 years and girls lt 8 years old (- 2SD)
• Sex steroid ?
• Estrogen female
• Testosteronemale

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Effect of sex steroid

• Estrogen ?
• Accelerated bone maturation and early epiphyseal
  fusion (tall child but short adult)
• Uterus, mammary gland
• Testosterone
• Genital, Hirsutism, acne, male habitus
• Generalsexual behavior, aggressiveness

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Classification

• GnRH dependent (central)
• premature reactivation hypothalamus-pituitary-gona
  d axis ? increased gonadotropin ? increased sex
  steroids (dependent)
• Usually idiopathic
• GnRH independent (peripheral)
• autonomous sex steroid secretion, ? depressing
  the hypothalamus-pituitary-gonad axis
• Usually pathologic

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Classification

• Variant
• premature thelarche
• premature adrenarche
• gynecomastia

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Etiology GDPP

• idiopathic
• CNS
• tumor
• non-tumor post infection, radiation, trauma,
  congenital
• iatrogenic
• Delayed diagnosis of GIPP

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Clinical manifestation GDPP

• Always isosexual
• Normal sequence of puberty
• Hormonal profile increased gonadotropin and sex
  steroid

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Etiology GIPP - male

• Isosexual
• adrenal tumor, CAH
• testes cell Leydig tumor, familial
  testotoxicosis
• gonadotropin-secreting tumor
• non CNS hepatoma, germinoma, teratoma
• CNS germinoma, adenoma (LH secreting)
• heterosexual
• Increased peripheral aromatization

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Etiology GIPP - female

• Isosexual)
• McCune Albright
• Severe hypothyroid
• heterosexual
• adrenal tumor, CAH
• tumor ovarium arrhenoblastoma

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Mc Cune Albright Syndrome

• Trias
• Precocious puberty / endocrine hyperactivity
• Fibrodysplasia
• Café au lait

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Clinical manifestation GIPP

• Isosexual or heterosexual (late onset CAH, tumor
  adrenal)
• Disconcordant of sexual characteristics (testes
  volume inappropriate with pubertal stage -
  smaller)
• Low or normal gonadotropin and increased sex
  steroid

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Benign Premature Adrenarche

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

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Benign Premature Adrenarche

• Normal bone age
• Slight elevation of serum DHEA
• Normal adrenal steroid hormone levels
• Normal sex hormone levels
• ACTH stimulation test to exclude late-onset CAH
• GnRH test prepubertal pattern
• Normal imaging studies
• No specific treatment required

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Premature Adrenarche

• Excude virilization
• clitoral enlargement, advanced bone age, acne,
  rapid growth, and voice change.
• rapid progression
• If virilization present
• measure testosterone, 17-OHP and DHEA
• USG adrenal or ovarian tumor
• 17-OHP or DHEA? CAH

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Benign Premature Thelarche

• Isolated appearance of unilateral or bilateral
  breast aged 6 months to 3 years
• No other signs of puberty or evidence of
  excessive estrogen effect (thickening of the
  vaginal secretions or bone age acceleration).
• Ingestion or application of estrogen-containing
  compounds must be excluded as etiology

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Benign Premature Thelarche

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

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Gynecomastia

• Breast enlargement in males
• common in teenage years, lasting 2 years
• differentiate with obese boys
• lipomastia
• no mammae disk
• Pathological causes must be sought

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Pubertal Gynecomastia

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

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Gynecomastia

• Drugs
• sex steroids, hCG, psychoactive (phenotiazine),
  antituberculosis, testosterone antagonist
  (ketoconazole, cimetidine, spironolactone)
• Malnutrition
• Idiopathic (most common)
• Tumor producing disease
• hepatoma, adrenal, testes, LH and hCG producing
  tumors

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Pubertal Gynecomastia

• Familial gynecomastia
• X-linked recessive trait or a sex-limited
  dominant trait
• unless associated with hypogonadism no further
  evaluation in an otherwise normal boy
• If severe, gynecomastia ? cosmetic surgery.
• Pathologic gynecomastia
• Klinefelter's syndrome high risk for breast
  cancer
• prolactin-secreting adenomata

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Pubertal Gynecomastia

• Pathologic gynecomastia
• hormone-secreting tumors (testes, hepatoma),
  cirrhosis, hypo- and hyperthyroidism.
• Drug induced (marijuana, phenothiazines, opiates,
  amphetamines, digitalis, estrogens, ketoconazole,
  spironolactone, isoniazid, tricyclic
  antidepressants, cimetidine, etc).
• If worsens and associated with psychologic
  morbidity ? bromocriptine, tamoxifen
• reduction mammoplasty rarely indicated.

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Diagnostic work up

• Gonadotropin dependent or independent?
• Etiology?

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Hypothalamus
GnRH
Pituitary
(-)
LH/FSH
Gonad
E2 or T
H-P-G axis
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Hypothalamus
Primary
GnRH
Pituitary
(-)
LH/FSH
Gonad
Sex steroid ?
H-P-G axis in GDPP
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Hypothalamus
GnRH
Pituitary
(-)
LH/FSH
Gonad
Extra Gonadal
PRIMARY
Sex steroid ?
H-P-G axis in GIPP
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Diagnostic work up

• Historyage of onset, progressivity, family
  history, growth, symptoms extragonadal cause
  (adrenal), CNS complaints, gelactic laughter
  (hamartoma), previous history encephalitis,
  meningitis TB
• Physical examinationpubertal stage, signs of
  virilisation, height, testes size (small
  indicative of perpheral cause), CNS signs, skin
  (acne, café au lait),

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Diagnostic work up

• Laboratorygonadotropin, bHCG, 17-OHProgesterone
  (CAH), cortisol (Cushing syndrome, adrenal tumor)
• ImagingBone age, pelvic ultrasound, skull x-ray,
  CT/MRI, bone survey (McCune Albright),

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Therapy

• According to the etiology
• GDPP idiopathic GnRH agonis
• GIPP medroxy-progesteron, ketoconazole, dll
• Variant observation

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Prognosis

• According to etiology
• GDPP idiopathic GnRH agonis
• Final height potential genetic height
• Preserved fertility
• Psychosocial minimal, regression of secondary sex
• GIPP medical
• Potential genetic height ?
• Regression of secondary sex ? ?

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Conclusion

• Not all pubertal disorders are pathologic
• Early increase of sex steroid should be
  thoroughly investigated
• GnRH agonist drug of choice for GDPP

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DELAYED PUBERTY
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Definisi

• Pubertas terlambat bila tidak adanya tanda-tanda
  pubertas
• laki-laki pada usia 14 tahun
• perempuan pada usia 13 tahun
• Klasifikasi
• hipergonadotropik hipogonadism
• hipogonadotropik hipogonadism
• Ammenorrhoe primer
• Ammenorrhoe sekunder

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hipogonadism
Hipergonadotropik
Hipotalamus
LHRH
LH/FSH
Hipofisis
(-)
Target Organ (gonad)
Primary defect
Sex Steroid
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Hipergonadotropik hipogonadism

• Dengan kelainan kromosom
• Dysgenesis gonad
• Sindrom Turner
• Pure gonadal dysgenesis
• Sindrom Klinefelter
• Androgen Insensitivity Syndrome

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Hipergonadotropik hipogonadism

• Tanpa kelainan kromosom
• kongenital
• gangguan biosintesis steroid adrenal
  (P450c17,P450scc,3bHSD) dan gonad (17-KS, P450
  aromatase)
• anorchia, ovary resistant syndrome, LH resistance
• didapat
• radiasi, chemotherapy, proses autoimun

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hipogonadism
Hipogonadotropik
LHRH
Hipotalamus
Primary defect
LH/FSH
Hipofisis
(-)
Target Organ (gonad)
Sex Steroid
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Hipogonadotropik hipogonadism

• Constitutional delay
• Kelainan Susunan Syaraf Pusat
• Tumor (craniopharyngioma, germinoma, optic
  glioma, histiocytosis X)
• Struktural (mid line defect)
• Sindrom Kallmann
• hipopituitarism idiopathic
• pasca tindakan (radiasi, khemoterapi inflamasi,
  infiltrasi - hemosiderosis)

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Hipogonadotropik hipogonadism

• Penyakit kronis
• endokrin, malnutrisi/anorexia nervosa, kelainan
  sistemik
• Aktivitas fisik berlebihan
• Sindrom-sindrom
• Prader-Willi Laurence-Moon-Biedl

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Hypothalamic and pituitary causes of pubertal
failure-low gonadotrophins

• Congenital defects
• Kalmann syndrome
• Congenital adrenal hypoplasia
• Septoptic dysplasia
• Development defect of pituitary
• Tumors, direct effects or following radiotherapy
  or surgery
• Haemochromatosis

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Italian Working Group on Endocrine Complication
in non-endocrine diseases, 1993
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Delayed puberty in Thalassamia patient

• Italian Multicenter Thalassemia study 1993, (29
  centers), 3092 patients
• Puberty failure
• males 41
• females 39,5
• All patient with hemachromatosis need periodic
  careful endocrine evaluation

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Tatalaksana

• Anamnesis
• Pemeriksaan fisik
• Pemeriksaan penunjang
• Terapi

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Anamnesis

• Riwayat perkembangan pubertas di dalam keluarga
• Data pertumbuhan perkembangan
• Riwayat penyakit/pengobatan dahulu
• Fungsi penciuman

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Pemeriksaan fisik

• Pemeriksaan fisik secara umum
• Pemeriksaan neurologis (funduskopi) d
• Antropometri (TB, BB, rasio segmen atas dan
  bawah, rentang lengan)
• Status pubertas
• Stigmata suatu sindrom (pendek, obese, retardasi
  mental, webbed neck dll)

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Pemeriksaan Penunjang

• Pencitraan
• usia tulang, CT scan/MRI kepala USG genitalia
  interna (atas indikasi),
• Hormonal (basal/ uji GnRH)
• LH,FSH,Prolactin, Estrogen atau testosterone
• Dan lain-lain
• analisis kromosom (atas indikasi)
• uji fungsi penciuman

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Pubertal Delay
Any signs of puberty?

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

YES
NO
Low FSH/LH
High FSH
oxandrolone / sex steroids
GnRh / sex steroids
sex steroids
Monitor growth pubertal progress
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Hormonal replacement

• Discrepancies exist concerning
• the age of initiation
• dosage
• Some authors postponing treatment until the age
  when arrested sexual maturation in easily
  diagnosed
• Early treatment supporters Insist on the
  psychological benefits treatment
• Sexual development should be induce at an
  appropriate age

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Recommended hormone replacement

• When to wait watchfully and when to test and
  refer are part of the art of medicine
• Female patients
• chronological age gt 13-14 years
• bone age gt 11 years
• Male patients
• chronological age gt 14-15 years
• bone age gt 12 years

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Hormonal replacement

• Females
• start w estrogen 0,25 mg daily (6-9 months)
• after 9 MOs cyclic therapy w estrogen for 1st 21
  days
• Males
• testosterone enanthate 50 mg IM/ monthly
• after 6-9 MOs, dose gradually increased to 200
  mg/3 weeks (2-3 years)

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KESIMPULAN

• Pubertas berlangsung menurut stadium, umur
  tertentu
• Pubertas harus selalu menjadi perhatian orangtua
  / tenaga kesehatan
• Setiap tenaga kesehatan dapat mendeteksi kelainan
  pubertas secara dini dan segera melakukan rujukan

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