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

2. PRECOCIOUS PUBERTY

3. Hypothalamus - Pituitary – Gonad axis

4. INTRODUCTION Frequency : girls > boys
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

5. Profiles of Girls with Precocious Puberty (N=438)
Age of onset
between 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%
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):

6. Precocious Puberty Definition
Appearance of secondary sexual characteristics : boys < 9 years and girls < 8 years old (- 2SD)
Sex steroid 
Estrogen: female
Testosterone:male

7. Genital, Hirsutism, acne, male habitus
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

8. 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

9. Classification Variant premature thelarche premature adrenarche
gynecomastia

10. Etiology GDPP idiopathic CNS tumor
non-tumor: post infection, radiation, trauma, congenital
iatrogenic
Delayed diagnosis of GIPP

11. Clinical manifestation GDPP
Always isosexual
Normal sequence of puberty
Hormonal profile: increased gonadotropin and sex steroid

12. 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

13. Etiology GIPP - female Isosexual) McCune Albright Severe hypothyroid
heterosexual
adrenal: tumor, CAH
tumor ovarium: arrhenoblastoma

14. Mc Cune Albright Syndrome
Trias
Precocious puberty / endocrine hyperactivity
Fibrodysplasia
Café au lait

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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.

23. 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

24. 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

25. 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.

26. Diagnostic work up
Gonadotropin dependent or independent?
Etiology?

27. Hypothalamus
GnRH
(-)
Pituitary
LH/FSH
Gonad
E2 or T
H-P-G axis

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

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

30. 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),

31. 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),

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

33. 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  

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

36. DELAYED PUBERTY

37. 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

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

39. Hipergonadotropik hipogonadism
Dengan kelainan kromosom
Dysgenesis gonad
Sindrom Turner
Pure gonadal dysgenesis
Sindrom Klinefelter
Androgen Insensitivity Syndrome *

40. 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

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

42. 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)

43. Hipogonadotropik hipogonadism
Penyakit kronis
endokrin, malnutrisi/anorexia nervosa, kelainan sistemik
Aktivitas fisik berlebihan
Sindrom-sindrom
Prader-Willi; Laurence-Moon-Biedl

44. 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

45. Italian Working Group on Endocrine Complication in non-endocrine diseases, 1993

46. 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

47. Tatalaksana
Anamnesis
Pemeriksaan fisik
Pemeriksaan penunjang
Terapi

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

49. 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)

50. 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

51. Psychological distress?
Pubertal Delay
Any signs of puberty?
YES
Psychological distress? NO
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

52. 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

53. Recommended hormone replacement
When to wait watchfully and when to test and refer are part of the art of medicine
Female patients
chronological age > years
bone age > 11 years
Male patients
chronological age > years
bone age > 12 years

54. 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)

55. 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