GANGGUAN PUBERTAS

Dr Eka Agustia Rini Sp AK

Sub Bagian Endokrinologi Ilmu Kesehatan
Anak
FK-UNAND / RS Dr M. Djamil Padang
PRECOCIOUS PUBERTY
Hypothalamus - Pituitary – Gonad axis
INTRODUCTION
• Epidemiology
• Frequency : girls > 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
 Profiles of Girls with Precocious Puberty
(N=438)
Age of onset
between 7-7.9 year olds 59.6%
6 year olds 22.4%
< 6 years old. 18%
Etiology
Gonadotropin Dependent 97.7%
Gonadotropin independent 2.3%
Neurogenic abnormalities 18.4%
(MR/CT skull)
Precocious Puberty
• Definition
• Appearance of
secondary sexual
characteristics : boys <
9 years and girls < 8
years old (- 2SD)
• Sex steroid 
• Estrogen: female
• Testosterone:male
 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
• General:sexual behavior, aggressiveness
 Classification
• GnRH dependent (central) :
• premature reactivation hypothalamus-pituitary-
gonad axis  increased gonadotropin 
increased sex steroids (dependent)
• Usually idiopathic
• GnRH independent (peripheral):
• autonomous sex steroid secretion,  depressing
the hypothalamus-pituitary-gonad axis
• Usually pathologic
Classification
• Variant
• premature thelarche
• premature adrenarche
• gynecomastia
Etiology GDPP
• idiopathic
• CNS
• tumor
• non-tumor: post infection, radiation,
trauma, congenital
• iatrogenic
• Delayed diagnosis of GIPP
Clinical manifestation GDPP
• Always isosexual
• Normal sequence of puberty
• Hormonal profile: increased
gonadotropin and sex steroid
 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
Etiology GIPP - female
• Isosexual)
• McCune Albright
• Severe
hypothyroid
• heterosexual
• adrenal: tumor,
CAH
• tumor ovarium:
arrhenoblastoma
Mc Cune Albright Syndrome
• Trias
• Precocious puberty /
endocrine hyperactivity
• Fibrodysplasia
• Café au lait
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
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
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
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
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
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
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
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.
 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
 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
 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.
Diagnostic work up
• Gonadotropin dependent or independent?
• Etiology?
 Hypothalamus

GnRH

(-) Pituitary

LH/FSH

Gonad

E2 or T

H-P-G axis
 Hypothalamus

GnRH
Primary
(-) Pituitary

LH/FSH

Gonad

Sex steroid 
H-P-G axis in GDPP
 Hypothalamus

GnRH

(-) Pituitary

LH/FSH

Gonad
Extra Gonadal

Sex steroid 

H-P-G axis in GIPP

Diagnostic work up
• History
age of onset, progressivity, family history, growth,
symptoms extragonadal cause (adrenal), CNS
complaints, gelactic laughter (hamartoma),
previous history: encephalitis, meningitis TB
• Physical examination
pubertal stage, signs of virilisation, height, testes
size (small indicative of perpheral cause), CNS
signs, skin (acne, café au lait),
Diagnostic work up
• Laboratory
gonadotropin, bHCG, 17-OHProgesterone (CAH),
cortisol (Cushing syndrome, adrenal tumor)
• Imaging
Bone age, pelvic ultrasound, skull x-ray, CT/MRI,
bone survey (McCune Albright),
Therapy
• According to the etiology
• GDPP idiopathic: GnRH agonis
• GIPP : medroxy-progesteron, ketoconazole, dll
• Variant: observation
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  
Conclusion
• Not all pubertal disorders are pathologic
• Early increase of sex steroid should be thoroughly
investigated
• GnRH agonist = drug of choice for GDPP
DELAYED PUBERTY
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
Hipergonadotropik hipogonadism

Hipotalamus LHRH

Hipofisis LH/FSH

(-)
Target Organ Primary defect
(gonad)

Sex Steroid
Hipergonadotropik hipogonadism

• Dengan kelainan kromosom

• Dysgenesis gonad
• Sindrom Turner
• Pure gonadal dysgenesis
• Sindrom Klinefelter
• Androgen Insensitivity Syndrome *
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
Hipogonadotropik hipogonadism

Hipotalamus LHRH

Primary defect

Hipofisis LH/FSH

(-)
Target Organ
(gonad)

Sex Steroid
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)
Hipogonadotropik hipogonadism

• Penyakit kronis
• endokrin, malnutrisi/anorexia nervosa,
kelainan sistemik
• Aktivitas fisik berlebihan
• Sindrom-sindrom
• Prader-Willi; Laurence-Moon-Biedl
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
 Thalassemia and endocrinopathy. A
multicenter study (N=3092)
7%
4% 3%
6%

80%

Delayed puberty Hypothyroidism

IDDM Hypoparathyroidism
Others

Italian Working Group on Endocrine Complication in non-

endocrine diseases, 1993
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
Tatalaksana
• Anamnesis
• Pemeriksaan fisik
• Pemeriksaan penunjang
• Terapi
Anamnesis
• Riwayat perkembangan pubertas di dalam keluarga
• Data pertumbuhan & perkembangan
• Riwayat penyakit/pengobatan dahulu
• Fungsi penciuman
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)
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
 Pubertal Delay

Any signs of puberty?

YES NO

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

NO YES

Low FSH/LH High FSH

oxandrolone /
sex steroids
GnRh /
sex steroids sex steroids

Monitor growth & pubertal

progress
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
Recommended hormone replacement
• When to wait watchfully and when to test and refer
are part of the art of medicine

• Female patients
• chronological age > 13-14 years
• bone age > 11 years
• Male patients
• chronological age > 14-15 years
• bone age > 12 years
 Hormonal replacement
• Females :
• start ŵ estrogen 0,25 mg daily (6-9 months)
• after 9 MOs cyclic therapy ŵ 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)
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