Delayed puberty ppt

Delayed puberty

1. Delayed puberty Dr.Yassin Alsaleh

2. INTRODUCTION Definitions: Delayed puberty is defined as the lack of pubertal development by 2 SD above the mean age for the general population. An absence of an increase in testicular volume (less than 4 mL ) at 14 yr in a boy or absence of any breast development at 13 yr in a girl. delay in the onset, progression or completion of puberty sufficient to cause concern to the adolescent, parents or physician.

3. In boys, a period of 3.2 +/– 1.8 (mean +/– SD) years is necessary to achieve adult testicular volume after the onset of puberty. In girls, the period from breast budding to menarche is 2.4 +/–1.1 (mean +/– SD) years . Therefore, evaluation is warranted if more than 4–5 yr has elapsed from the onset of puberty to adult testicular size in boys or menarche in girls. Pubertal arrest

4. in girls: lack of breast development by 13 more than five years between breast growth and menstrual period lack of pubic hair by age 14 failure to menstruate by age 15-16 in boys: lack of testicular enlargement by age 14 lack of pubic hair by age 15 more than five years to complete genital enlargement INTRODUCTION

5.  occurs in approximately 3% of children . In boys, delayed puberty is often constitutional and functional. (63 %) In girls, delayed puberty is less common and often organic. Delay of puberty leads to delay in the acquisition of secondary sex characteristics, psychological problems, defect in reproduction function and the reduction of bone mass. INTRODUCTION

6. Normal puberty Normal puberty is initiated by the onset of pulsatile secretion of gonadotropin -releasing hormone ( GnRH ) from the hypothalamus. These pulses cause release of luteinizing hormone (LH) and follicular stimulating hormone (FSH) from the pituitary gland. These pituitary gonadotropins then circulate to the gonads and stimulate production of sex steroids .

7. ATIOLOGY

8. CLASSIFICATION The first group represents temporary delays of puberty that are functional disorders, most commonly, constitutional delay of growth and puberty . Low LH/FSH Low T/E2

9. The second is hypogonadotropic hypogonadism , in which hypothalamic or pituitary failure results in deficiency of circulating gonadotropins . Low LH/FSH Low T/E2 CLASSIFICATION

10. Finally, hypergonadotropic hypogonadism results from primary gonadal failure, resulting in elevated serum gonadotropin levels. High LH/FSH Low T/E2 CLASSIFICATION

11. CONSTITUTIONAL DELAY OF PUBERTY AND GROWTH The the single most common cause in both genders. more often in boys than in girls. It represent the extreme of the normal physiologic variations . CDGP is a diagnosis of exclusion. Children with constitutional delay are more likely to be short for age. with a history of relatively normal growth rate. delays in bone maturation . Delay in adrenarche

12. Frequently, there is a family history of late menarche in the mother or sisters or a delayed growth spurt in the father. sporadic cases are also seen. Puberty is not delayed beyond the chronological age of 16 yr in females and 18 yr in males, the onset of puberty corresponds better with bone age (BA) than chronological age CONSTITUTIONAL DELAY OF PUBERTY AND GROWTH

13. Functional causes Chronic renal disease, cardiac disease, Chronic gastrointestinal disease/malnutrition Sickle cell disease/iron overload Chronic lung disease/cystic fibrosis/asthma Anorexia nervosa Bulimia nervosa Psychogenic/stress Extreme exercise Drugs Poorly controlled diabetes mellitus Hypothyroidism Cushing disease Hyperprolactinemia PCOS AIDS, recurrent infections

14. HYPOGONADOTROPIC Congenital Isolated GnRH deficiency Kallmann syndrome KAL1, FGFR1, PROKR2 Idiopathic hypogonadotropic hypogonadism GnRHR,FGFR1,GPR54,Leptin,FSH β- subunit,LH β- subunit Idiopathic hypogonadotropic hypogonadism associated with obesity Leptin , Leptin receptor, PC1 DAX1 mutation ( Adrenal hypoplasia congenita Pituitary transcription factor deficiency. Panhypopitutirism (e.g. LHX3, PROP1) Septooptic dysplasia ( HESX1) Syndromes Prader-Willi syndrome Noonan syndrome CHARGE syndrome Bardet-Biedl syndrome

15. HYPOGONADOTROPIC Acquired CNS tumors Craniopharyngioma , germinoma , hypothalamic glioma , optic nerve glioma , pituitary tumors Trauma/surgery Pituitary apoplexy Infiltration Hypophysitis Lymphocytic Granulomatous Histiocytosis X Sarcoidosis Infectious— meningoencephalitis radiotherapy

16. Hypergonadotropic ( Congenital) Girls Tuner syndrome (45,X) (46XX/45X) Swyer syndrome (46,XY) Mixed gonadal dysgenesis (46,XX/46,XY) Pure ovarian agenesis (46,XX) Galactosemia FSH or LH receptor gene mutations steroidogenic defect (CAH) Boys Mixed gonadal dysgenesis (e.g. 46XY/45X) Testicular dysgenesis (e.g. loss of functional SRY, Sox9, SF1, WT1, DMRT) Klinefelter syndrome Noonan syndrome LH receptor gene mutation Androgen resistance steroidogenic defect (CAH)

17. Hypergonadotropic Acquired Girls Radiation Chemotherapy Trauma/surgery Infections Autoimmunity Idiopathic failure Boys Radiation Chemotherapy Trauma/surgery Infections Vanishing toxin

18. Evaluation of Pubertal Delay

19. Evaluation of Pubertal Delay HISTORY: totally absent or had started but then arrested. family history of constitutional delay of puberty. Family history of infertility . The review of symptoms. Perinatal history prior medical illness. Medication. psychosocial deprivation

20. Nutritional habits, exercise intensity. Neurologic symptoms such as headache, visual disturbances,seizures , and intellectual disability . sense of smell. Hypoglycemia. Cancer history :Radiation, Chemotherapy history compatible with testicular injury (bilateral cryptorchidism , surgery, irradiation, bilateral torsion) Evaluation of Pubertal Delay

21. growth parameter Ht,Wt,BMI .weight for height. The growth velocity ,Arm span. pubertal staging. Systemic exam. dysmorphisim visual field exam. Fundoscopy . Evaluation of the sense of smell. associated congenital abnormalities ( eg , midline defects, cleft lip/palate, cryptorchidism , and microphallus  ) . PHYSICAL EXAMINATION

22. BOYS Increase in testicular size is usually the first sign of puberty in boys testicular size greater than 4 mL in volume or a longitudinal measurement greater than 2.5 cm is consistent with the onset of pubertal development. Scrotal skin also changes in texture and reddens in early puberty. PHYSICAL EXAMINATION

23. PHYSICAL EXAMINATION

24. GIRLS Breast development in girls begins with formation of breast buds. This development is frequently unilateral for several months. Development of axillary and pubic hair may or may not accompany the onset of puberty. the vaginal mucosa changes from a reddish to pink. PHYSICAL EXAMINATION

25. Initial screening should include: complete blood cell count. Electrolytes , renal , liver panel. erythrocyte sedimentation rate . LH,FSH. Testosterone/ estradiol . thyroid function. serum prolactin . Celiac profile. Cortisol /ACTH. LAB

26. Testosterone an 8AM total serum testosterone concentration level greater than 45 ng / dL (1.6 nmol /L ) indicates the inception of puberty LAB

27. estradiol a plasma estradiol of more than 9 pg/ mL (32 pmol /l) is indicative of puberty. Elevations are reassuring for onset of early puberty. but levels below the limit may be seen in early puberty. LAB

28. serum gonadotropin levels (LH and FSH). baseline serum gonadotropin values are typically low in both constitutional delay of puberty and congenital GnRH deficiency. If elevated, the etiology for gonadal failure should be further investigated based on the differential diagnoses. LAB

29. Sleep-associated gonadotropin secretion Normal puberty begins at night with the onset of episodic LH secretion coincident with the onset of sleep. In compare to those with CDGP , Hypogonadotropic children typically do not experience an increase in serum LH during sleep LAB

30. Karyotyping : if physical examination suggest the presence of a genetic syndrome . Also in any short girl. GnRH stimulation testing: limited benifit LAB

31. Bone age : may be obtained at the initial visit to assess skeletal maturation and repeated over time if needed. Skeletal age more closely correlates with sexual development than does chronological age. Bone age more than 13 for girls and 14 for boys less likely to constitutonal . imaging

32. Pelvic /scrotal ultrasound: Indicated when an dysgenesis is suspected to determine the presence or absence of internal organs. imaging

33. MRI: should be obtained in patients with hypogonadotropic hypogonadism . imaging

34. Psychological and reassurance

35. The aim of treatment: Development of age-appropriate secondary sex characteristics . Induction of a growth spurt without  inducing premature epiphyseal closure. achievement of normal muscle mass and bone mineral density for age. improvement in psychosocial wellbeing. in some patient reversal of GnRH defceincy . TREATMENT

36. constitutional delay: conservative management with observation over 6 mo to 1 yr may be warranted. Constitutional delay of growth and puberty can cause significant psychosocial stress, particularly in males. Cases must be evaluated on an individual basis for psychosocial distress, and subsequent need for intervention. TREATMENT

37. in cases of clearly permanent hypogonadism , therapy should be initiated at a normal pubertal age to avoid the delay of growth and psychological effect of pubertal delay. TREATMENT

38. CDGP VS HH Determining the etiology of delayed puberty during initial evaluation can be challenging. clinicians often cannot distinguish constitutional delay of growth and puberty (CDGP) from isolated hypogonadotropic hypogonadism (IHH).

39. A family history of delayed puberty is strongly suggestive of CDGP (seen in 50–75%). Adolescents with CDGP may have delayed adrenarche and pubarche along with delayed gonadal development. The presence of progressive pubertal development by age 18 yr in boys or 16 yr in girls is the “gold standard” for differentiating CDGP from HH. CDGP VS HH

40. Constitutional Delay of Growth and Puberty VS Permanent Hypogonadotropic Hypogonadism No single test

41. most physicians advocate a period of “watchful waiting”. including periodic evaluation, reassurance, and psychological counseling . short course of testosterone therapy may be initiated . A low dose of testosterone enanthate (50–100 mg given intramuscularly every 4 wk) for 4–6 mo will stimulate linear growth and secondary sexual characteristics without inappropriately accelerating bone age. TREATMENT of constitutional delay of growth and puberty in boys

42. Testosterone enanthate , administered by intramuscular injection, is the most common method of pubertal induction and maintenance . Various schemes have been proposed, but most authors advocate a starting dose of 50 mg every 4 wk. When the pubertal growth spurt is well established, the dose should be gradually increased to a full adult dose of 200 mg every 2 wk. When hypogonadism is diagnosed at a prepubertal age, testosterone therapy may be started as early as a bone age of 11–12 yr . TREATMENT of permanent hypogonadal state in boys

43. Testosterone: Testosterone therapy is utilized for induction of puberty in boys with constitutional delay of puberty, hypogonadotropic hypogonadism , and hypergonadotropic hypogonadism . testosterone esters Intramuscularly are the most commonly used. Testosterone enanthate and cypionate are preferred over testosterone propionate TREATMENT (MALE)

44. testosterone esters, such as enanthate 50 mg monthly given IM for 4–12 months. Thereafter, the doses are gradually increased with 50 mg every 6 to 12 months. After reaching 100-150 mg monthly ,decrease interval to every 2 weeks. Then adult dose 200 mg every 2 weeks. TREATMENT (MALE)

45. The following schedule also may be proposed : first year: 25 mg every 2 weeks; second year: 50 mg every 2 weeks; third year: 100 mg every 2 weeks; fourth year onward: 200 mg every 2 weeks . TREATMENT (MALE)

46. Transdermal Testosterone: a scrotal patch and a nongenital patch. When applied daily, result in similar testosterone concentrations to those seen in normal young men in magnitude and diurnal variation. TREATMENT (MALE)

47. Transdermal Testosterone: substantially more expensive than testosterone esters . can produce skin reaction . not yet approved in males younger than age 18 years their effectiveness in induction of puberty remains unclear TREATMENT (MALE)

48. Side effect: acne, and gynecomastia . fast skeletal maturation leading to impaired adult height. excessive aggressiveness. excessive stimulation of libido, priapism , polycythemia , obstructive sleep apnea mainly in obese subjects TREATMENT (MALE)

49. Beneficial effects: decline in total plasma cholesterol and LDL concentrations, increased lean body mass. decreased risk of osteoporosis . TREATMENT (MALE)

50. Testosterone Not for use in boys with bone age <10 years. Erythrocytosis , weight gain, prostate hyperplasia. Premature epiphyseal closure . Local side effects (pain, erythema ) Initiate after age 12 years of age at 50 mg every 4 weeks. Increase with 50 mg every 6 to 12 months. After reaching 100-150 mg monthly ,decrease interval to every 2 weeks. adult dose 200 mg every 2 weeks Testoserone enathate , cypionate and propionate. IM Can cause POME Adult dose 1000 mg every 10-14 weeks. Testosterone undecanoate.IM Local irritation. Avoid contact with other Can be started when 50% adult dose with intramuscular testosterone achieved. Testosterone gel TREATMENT (MALE)

51. Testosterone the levels of testosterone seem to be slightly more erratic. hepatotoxic at the starting dose of 40 mg/daily in the morning. Oral testosterone undecanoate Gum irritation 30 mg per buccal system. 30 mg twice a day trans- buccal testosterone TREATMENT (MALE)

52. TREATMENT (MALE)

53. TREATMENT (male) Oxandrolone : Can be used for Induction of a pubertal growth spurt in CDGP . the mechanism of action is unclear. it is anabolic steroid that increases growth velocity without promoting excessive skeletal maturation Doses of (0.1 mg/kg/day, 1.25 or 2.5 mg/d for 3–12 months).

54. Human chorionic gonadotropin hCG can be used to induce puberty in CDGP. hCG 1500 U twice weekly, either SC or IM, for 6 months. The use of hCG appears to be more physiologic and potentially safer than Testesterone However, HCG is more expensive and requires multiple injections. TREATMENT (male)

55. aromatase inhibitor An aromatase inhibitor, e.g., letrozole (2.5 mg/PO) in addition to Testosterone. appears to increase the final Ht to approach mid-parental. TREATMENT (male)

56. Dihydrotestosterone (DHT) 50 mg IM every 2 weeks, for 4 months. is associated with appearance of secondary sex characteristics increased lean body mass and decreased body fat with no change in IGF-I. may increase the potential for final Ht. TREATMENT (male)

57. Estrogen : either long-term low doses, or gradual increases in dose providing adequate time for pubertal growth, and gradual breast development. For constitutional : conjugated estrogen 0.3 mg po daily for 3-6 months TREATMENT (GIRLS)

58. For other indications: Premarin (conjugated estrogen) may be used at a dose of: 0.3 mg every other day for 6 months followed by an increase to every day for 6 months then 0.625 mg daily for 6 months, followed by 1.2 mg. TREATMENT (GIRLS)

59. A progesterone should be added after two years of estrogen , after full breast development or if spotting occurs. This is usually administered as: Provera ( medroxyprogesterone ) at a dose of 5–10 mg or micronized progesteroneat 200 mg/day ( eg , Prometrium ) for 10–14 d TREATMENT (GIRLS)

60. After adult doses of estradiol and medroxyprogesterone are reached, oral contraceptive pill may be substituted for separate preparations of these compounds. TREATMENT (GIRLS)

61. In girls without a uterus, such as in androgen insensitivity or XY gonadal dysgenesis , the same guidelines for estrogen replacement can be used, but there is no need for the addition of progesterone. TREATMENT (GIRLS)

62. GNRH THERAPY In some cases of hypogonadotropic hypogonadism , pulsatile administration of gonadotropin releasing hormone has resulted in induction of puberty . frequently used for stimulation of spermatogenesis or induction of ovulation in infertile adult patients.

63. Patients of either sex with hypogonadotropic hypogonadism are potentially fertile to initiate gametogenesis , the typical approach to fertility induction is pump-administered GnRH therapy (assuming an intact pituitary gland) or parenteral combination gonadotropin treatment (synthetic LH/ hCG and recombinant FSH) . further TREATMENT

64. follow-up and monitoring regular clinical follow-up assessing growth and pubertal progression every 3-6 months bone age assessment.

65. Testesterone : 1. therapy should restore serum testosterone levels into the mid-normal range for pubertal stage. 2. measurement of testosterone should be: - testosterone enanthate or cypionate : midway between injections. - i.m . long-acting testosterone undecanoate : before the new injection. - transdermal testosterone patch: 3-12 hours after application. - transdermal testosterone gel application : after 1-2 weeks independently from application. - buccal testosterone tablet : immediately before the application of new tablet. follow-up and monitoring

66. Haematocritus . the discontinuation of therapy is required if hematocrit is greater than 54% until it decreases to a safer level). follow-up and monitoring

67. LH and FSH : the assessment of LH and FSH has poor clinical value follow-up and monitoring

68. references 1- Ines L.sedlmeyeri . Delayed Puberty: Analysis of a Large Case Series from an Academic Center. J Clin Endocrinol Metab 87: 1613–1620, 2002 2- Jennifer Harrington. Distinguishing Constitutional Delay of Growth and Puberty from Isolated Hypogonadotropic Hypogonadism : Critical Appraisal of Available Diagnostic Tests. J Clin Endocrinol Metab 97: 3056–3067, 2012

69. 3-Ines L.sedlmeyeri . Pedigree Analysis of Constitutional Delay of Growth and Maturation: Determination of Familial Aggregation and Inheritance Patterns. (J Clin Endocrinol Metabolism 87(12):5581–5586, 2002 4-Taneli Raivio , Reversal of Idiopathic Hypogonadotropic Hypogonadism . N Engl J Med 2007;357:863-73. references

70. 5-Jürgen Brämswig , Disorders of Pubertal Development Dtsch Arztebl Int 2009; 106(17): 295–304 6- Vidhya viswanathan .Etiology and Treatment of Hypogonadism in Adolescents.  Pediatric Clin North Am. 2011 Oct;58(5):1181-200 7-Shalender Bhasin . Testosterone Therapy in Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. (J Clin Endocrinol Metab 95: 2536 –2559, 2010 references

71. 8- Ashraf T. Soliman , An approach to constitutional delay of growth and puberty. Indian Journal of Endocrinology and Metabolism / Sep-Oct 2012 / Vol 16 | Issue 5 9- Ibrahim AlAlwan . Puberty Onset Among Boys in Riyadh, Saudi Arabia. Clinical Medicine Insights: Pediatrics 2010:4 19–24 references