GANGGUAN PUBERTAS

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 • 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

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

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

30. 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),

31. 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),

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