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

Hypothalamus - Pituitary – Gonad axis

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
59.6%
22.4%
< 6 years old.
Etiology
Gonadotropin Dependent
Gonadotropin independent
18%
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:

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
Estro gen

–Accelerated bone maturation and early epiphyseal fusion ( tall child but short adult)
–Uterus, mammary gland
Testosterone
–Genital, Hirsutism, acne, male habitus
General :
aggressiveness

GnRH dependent (central) :
– premature reactivation hypothalamuspituitary-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

Variant
–premature thelarche
–premature adrenarche
–gynecomastia

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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 .

Gonadotropin dependent or independent?
Etiology?

(-)
Hypothalamus
Pituitary
GnRH
LH/FSH
Gonad
E
2 or T
H-P-G axis

(-)
Hypothalamus
Pituitary
GnRH
LH/FSH
Gonad
Primary
Sex steroid 
H-P-G axis in GDPP

(-)
Hypothalamus
Pituitary
GnRH
LH/FSH
Gonad
Extra Gonadal
Sex steroid 
H-P-G axis in GIPP

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),

Laboratory gonadotropin, b
HCG, 17-OHProgesterone
(CAH), cortisol (Cushing syndrome, adrenal tumor)
Imaging
Bone age, pelvic ultrasound, skull x-ray,
CT/MRI, bone survey (McCune Albright),

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

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
 

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

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
(-)
Target Organ
(gonad)
LH/FSH
Sex Steroid
Primary defect

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,3 b
HSD) dan gonad (17-KS, P450 aromatase) anorchia, ovary resistant syndrome,
LH resistance
– didapat radiasi, chemotherapy, proses autoimun

Hipogonadotropik hipogonadism
Hipotalamus LHRH
Primary defect
LH/FSH Hipofisis
(-)
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%
6%
4% 3%
Delayed puberty
IDDM
Others
80%
Hypothyroidism
Hypoparathyroidism
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

Anamnesis
Pemeriksaan fisik
Pemeriksaan penunjang
Terapi

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

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)

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

YES
NO
Psychological distress?
YES
Pubertal Delay
Any signs of puberty?
NO
Check
• height, FSH/LH, T
4
/TSH,
•
Prolactin, Karyotype (girls)
Low FSH/LH High FSH oxandrolone / sex steroids
GnRh / sex steroids sex steroids
Monitor growth & pubertal progress

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

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)

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