1. 1 به نام خدا

2. Delayed puberty Mehdi salek MD

3. Delayed puberty Initial physical changes of puberty are not present by age   13 years in girls   14 years in boys

4. Delayed puberty lack of appropriate progression of puberty more than 4.5-5 years  A boy who has’nt completed secondary sexual development within 4.5 years  A girl who does’nt menstruate within 5 years

5. Classification of Delayed Puberty Gonadotropin deficiency Gonadotropin deficiency  CNS tumors  Functional HH  Infiltrative  Trauma   Isolated Gonadotropin  Genetic forms  CDP Hypergonadotropic Hypogonadism Hypergonadotropic Hypogonadism

6. Classification of Delayed Puberty Non-pathologic pathologic

7. Classification of Delayed Puberty Transient Permanent

8. Evaluation

9. History Infertility Anosmia → HH Cryptorchidism → HH Small penis in neonate → HH low Gn in neonatal period → HH

10. Evaluation Family pattern attainment of menarche Family history of delay pubertal Constitutional delay often have a positive family Birth trauma Familial marriage

11. Evaluation   Chemotherapy   Glucocorticoid therapy   Surgery   History of intense exercise   Exposures to irradiation

12. Growth chart   Growth pattern Late onset growth failure CNS mass lesion Organic disease Occasionally MRI IS necessary

13. Growth chart   Normal growth velocity for BA → CDGP Normal growth pattern without growth spurt   With anosmia Kallmann syndrom   Without anosmia ↓ isolated gonadotropin

14. Physical Examination   Neurologic examination   Gynecomastia   midline facial malformations   Size of glandular breast tissue,areolarsize   Testing of sense of smell   Galactorrhea   Turner stigma   Retractile testes

15. Physical Examinatin Height especially HT velocity at least 6 - 12 months upper to lower segment ratio ↑↑U/L → CDG ↓↓U/L → H ypogonadism

16. Physical Examinatin Signs of puberty Testicular location,size, and consistency Prepubertal: Normal size testis <2.0 cc or longer<1.5 cm Early puberty:   Normal size testis >3.0 cc or longer >2.5 cm pubertal-aged A testis ≤1.0cm particularly if unusually firm or soft suggestive of a hypogonadal state.

17. Skeletal age Gonadotropin status initial Approach

18. BA = 11-13 years Gonadotropin measurement High Primary gonadal failure  Girl Turner Boy Klinefelter

19. initial Approach Mild Elevated→ GnRH Test Exaggerated response Primary gonadal failure

20. initial Approach Low or lower limit of normal level   Constitutional Delay   Chronic disease    permanent Gonadotropin

21. initial Approach Low gonadotropin levels and pubertal delay may result from a physiologic delay or a permanent defect

22. General Approach Diagnosis of HH versus CDP is more difficult because of Overlap in physical and laboratory finding

23. General Approach Hypogona Hypogo   FSH and LH are low They haven't a pulsatile LH with↑ bone age

24. General Approach Overlap between HH and an immature hypothalamus if BA<10–11 years for girls BA<12–13 for boys

25. General Approach In older adolescent   Minimal response to GnRH Test suggests Gonadotropin Deficiency   Pubertal rise in the child with delayed puberty suggests CDP

26. General Approach Patients with HH have normal height in early or mid adolescent Patients with CDP have a normal growth rate for BA but are short for CA.

27. Laboratory assessment   CBC   Electrolytes   LFT   ESR   Prolactin   Cortisol   IGF-1   TSH, Free T4   Sex steroids,DHEAS   FSH, LH   MIH,INSL3,PSA

28. Laboratory assessment   Karyotype   Bone age   Brain imaging for HH or hyperprolactinemia   pelvic ultrasound urinary pH,SG urea nitrogen, creatinine

29. Treatment

30. Management   Girls   low dose estrogen therapy started at 13 years or bone age >11 years   Continue 3- to 4-month in CDP

31. Management   0.3mg of conjugated estrogens every other day   5ug of ethinyl estradiol daily   0.025 mg transdermal estrogen twice weekly

32. Management If permanent HH Estrogen can be increased every 6 to 12 months in order to reach full replacement doses after two to three years of therapy

33. Management During 2-3 years Daily doses of 0.6 - 1.25mg of conjugated estrogen or 10 -20ug ethinylestradiol are accepted as full replacement doses Cyclical progesterone 5 to 10mg of daily for 12 days can be added every month to induce monthly menstrual bleeding

34. Management   Boys   The initial dosage should be low to avoid priapism and rapid pubertal development   Dose should be adjusted based on intellectual maturation, and psychological needs Response, age, social

35. Treatment If skeletal age is immature   Risk of accelerating BA, short adult height If it is started at pubertal bone age 12-13   No detrimental effect on adult height   leads to somatic and genital growth

36. Treatment In boys of age 14 Testosterone Dose 50 to 100mg IM every four weeks Three to six months Oxandrolone 2.5mg/day

37. Management After a few months Treatment should be stopped for Differentiation temporary from permanent Then Testosterone level to determine for endogenous androgen production.

38. Management   Testosterone <50 ng/dl   Give another course After a few months Treatment should be stopped for Differentiation temporary from permanent Given 1-2 course

39. Management   If testosterone remain low→  Gona   Continue treatment with androgen   Dosages gradually increase to full replacement after three to four years   100 mg/wk, 200 mg/ two wk or 300mg three week intervals

40. Management The skin gel preparation 50, 75, or 100 mg Absorption over a 24-hours Recommended sites are the shoulders, upper arms and abdomen

41. Management Testosterone >50 ng/dl → CDP Treatment should be stop To assess progression of puberty Hypothalamic-pituitary-testicular function can be assumed if Testosterone > 275 ng/dl Testicular examination is normal

42. Management Bone age 12 to 13 years in girls 13 or 14 years in boys patients with CDP usually continue pubertal development patients with gonadotropin deficiency do not progress and may regress.

43. Management when fertility is desired Biosynthetic LH and FSH administration is utilized Episodic administration of LHRH Portable pumps to administer LHRH in episodic fashion over prolonged periods

45. Case History   15yr old boy   Shortest in his class   No problem at school   Always a small boy   No chronic disease   Father didn’t grow till he entered college

47. Case physical   No dysmorphic features   CVS, Resp, Abd Exam normal   Normal development   Ht= 135cm   Wt= 30kg   U/l = near one   Testicular volume =2.5ml

48. Case physical   Testicular length = 1.5cm   Penis = 4cm   Normal Testicular consistency   No gynecomastia   Arm span – height span= 2cm   GV =5cm/yr   PH=1

49. Hormonal and biochemical studies   Normal BUN /ESR   Normal T4 &TSH   Low IGF1& IGFBP3 for age   Normal IGF1& IGFBP3 for BA   Decreased FSH& LH

50. Hormonal and biochemical studies   Testosterone= 0/15ng / ml   Celiac test= ok   Cortisol levels = ok   LHRH shows not yet in puberty   Normal prolactin

51. Case treatment   Oxandrolon for 6 month  12.5 mg/day  Zinc 12.5 mg/day   Iron 12mg/day for 3 mo   Vitamin A = 6000IU/week for 3 mo   But Testicular volume &Testicular length   Didn’t change

52. Case imaging   BA=12yr

53. Diagnosis? Any treatment ?

54. Case treatment Testosteron 1mg/kg for 4 month Letrozol 2.5mg

55. Case treatment Six month after stopping of Testosteron   Testosteron level was 0/8ng/ml   Testicular volume =5ml   Testicular length = 3cm

58. Discussion Discussion

59. Constitutional Delay Puberty   Multifactorial   Fathers has similar pattern   often in boys   Normal size at birth.. - -.

60. Constitutional Delay Puberty By three years of age Decrease height,BA, growth velocity By usual age of puberty immaturity become more noticeable as the approaches with somatic and sexual pubertal At older age than typical Puberty occurring spontaneously

61. 61 Constitutional Delay Puberty No history of systemic illness. Normal nutrition. Normal P/E. Normal hormones

62. 62 Constitutional Delay Puberty Delayed puberty. Delayed bone age. a short adolescent with bone age delay greater than three years is more likely to have a pathologic problem.

63. Constitutional Delay Puberty Growth velocity and height are usually appropriate for bone age Delay in the reactivation of the GnRH pulse generator Adrenarche and gonadarche occur later

64. Constitutional Delay Puberty   Outcome is benign   Normal physical development, sexual and reproductive function

65. Constitutional Delay Puberty Not one test yet distinguishes between CDP and HH, so watchful waiting is usually in order

66. Constitutional Delay Puberty Hypogonadotropin hypogonadism Adrenarche at a normal age Higher DHEAS than CDG Failure of a rise in Gonadotropin or sex steroid by age 18

67. Treatment Assurance to family GH treatment Treatment for BA>12y Don’t Treatment for BA<10y or CA<12 Oxandrolon Transdermal patch and gel preparations of testosterone