GANGGUAN PUBERTAS

Dr Eka Agustia Rini Sp AK

Sub Bagian Endokrinologi Ilmu Kesehatan
Anak
FK-UNAND / RS Dr M. Djamil Padang

PRECOCIOUS
PRECOCIOUSPUBERTY
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
6 year olds
< 6 years old.

59.6%
22.4%
18%

Etiology
Gonadotropin Dependent
Gonadotropin independent

97.7%
2.3%

Neurogenic abnormalities
(MR/CT skull)

18.4%

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-pituitarygonad 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
Caf 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 lateonset 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 estrogencontaining 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?

Hypothalamu
Hypothalamu
ss
GnRH

(-)

Pituitar
Pituitar
yy
LH/FSH
Gonad
Gonad

E2 or T
H-P-G
H-P-G axis
axis

Hypothalam
Hypothalam
us
us
GnRH

(-)

Pituitar
Pituitar
yy
LH/FSH
Gonad
Gonad

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

Primary

Hypothalamu
Hypothalamu
ss
GnRH
Pituitar
Pituitar
yy
LH/FSH

(-)

Gonad
Gonad

IM
R
P

Extra Gonadal
Gonadal
Extra

Y
R
A

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, caf au lait),

Diagnostic work up
Laboratory
gonadotropin, HCG, 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

Hipofisis

LHRH

LH/FSH

(-)
Target Organ
(gonad)

Primary defect

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,3HSD) 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

Italian Working Group on Endocrine Complication in nonendocrine 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
Pubertal Delay
Delay

Any
Anysigns
signsof
ofpuberty?
puberty?

YES
YES

Psychological
Psychologicaldistress?
distress?

NO
NO

NO
NO

Check
Check
height,
height, FSH/LH,
FSH/LH,TT4/TSH,
4/TSH,
Prolactin,
Prolactin,Karyotype
Karyotype(girls)
(girls)

YES
YES
Low
LowFSH/LH
FSH/LH

High
HighFSH
FSH

GnRh
GnRh/ /
sex
sexsteroids
steroids

sex
sexsteroids
steroids

oxandrolone
oxandrolone/ /
sex
sexsteroids
steroids

Monitor
Monitorgrowth
growth&&pubertal
pubertal
progress
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 estrogen 0,25 mg daily (6-9
months)
after 9 MOs cyclic therapy 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