IN THE NAME OF GOD

1. IN THE NAME OF GOD

2. Delayed puberty Ms,Hosseini,Associate Prof Of Endocrinology,Baqiatallah University of Medical Science

3. Agenda • Definition • Etiology • Evaluation • History • Physical Examination • Laboratory tests • Therapy

4. N Engl J Med 2012;366:443-53 .

5. Definition • Delayed puberty is defined as the absence of testicular enlargement in boys or breast development in girls at an age that is 2 to 2.5 SD later than the population mean (traditionally, the age of 14 years in boys and 13 years in girls) • Because of a downward trend in pubertal timing in the United States and other countries and differences in pubertal timing among racial and ethnic groups, some observers have advocated for updated definitions with younger age cutoffs for the general population or perhaps for particular countries or racial or ethnic group Sun SS,Pediatrics 2002;110,911-9 Pediatrics 2002;110:752-7 Pediatrics 2009;123(5):e932-e939 J ClinEndocrinolMetab;2010;95:263-70

6. Definition…… Development of pubic hair is usually not considered in the definition because pubarche may result from maturation of the adrenal glands and the onset of pubic hair can be independent of HPG-axis activation N Engl J Med 2012;366:443-53

7. Etiology

8. Etiology….

11. Idiopathic or Constitutional Delay in Growthand Puberty • Otherwise healthy girls who spontaneously enter puberty after the age of 13 years and boys who begin after 14 years • Affected individual usually are short at evaluation and have been shorter than their classmates for years, although growth velocity and height are usually appropriate for bone age • Family history in as many as 77% of cases reveals a mother who had delayed menarche or a father (or sibling) who entered puberty late • Adrenarche and gonadarchoccure later • Bone age is delayed at presentation • There is no impairment of olfaction, as in Kallmann’s syndrome, and undescended testes are uncommon J ClinEndocrinolMetab.2002;87:1613-1620 ClinEndocrinolMetab. 2002;87:5581-5586 .

13. J Clin Endocrinol Metab 97: 3056–3067, 2012

14. Diagnostic tests • Basal gonadotropin levels • GnRH and GnRH agonist (GnRHa) stimulation tests • Human chorionic gonadotropin test • Genetic tests • Inhibin B

17. Conclusion • Distinguishing IHH from CDGP is an important clinical issue. Basal inhibin B may offer a simple, discriminatory test if results from recent studies are replicated • Current literature does not allow for recommendation of any diagnostic test for routine clinical use, making this an important area for future investigation J Clin Endocrinol Metab 97: 3056–3067, 2012

18. Distinguishing Constitutional Delay of Growth and Puberty from Isolated HypogonadotropicHypogonadism Is an Important Clinical Issue The presence of endogenouse ,progressive pubertal development by age 18 Yr is the gold standard for differentiating J Clin Endocrinol Metab 97: 3056–3067, 2012

19. Evaluation • History: all symptoms of chronic or intermittent illnesses , all details pertaining to growth and development, the patient’s sense of smell,puberty course, abnormality of labor and delivery,familyhistory,history of consanguinity • physical examination :height ,weight,U/L ratio,BMI, signs of puberty, height velocity over a period of at least 6 months, preferably 12 months,neurologicexamination, including examination of the optic discs andvisual field ,determination of olfaction,stigma of gonadal dysgenesis,compelet physical examination including lung,heart,kidney and GI is important in the search for a chronic disorders that may delay puberty

20. Body Segment Ratio

21. Evaluation…. • Laboratory tests : • Plasma testosterone or estradiol • Plasma FSH and LH • Plasma thyroxine (and prolactin) • Radiographic examination: • Bone age and lateral skull roentgenograph • MRI with contrast enhancement • Pelvic ultrasonography • karyotype : • For all short girls, even in the absence of somatic signs of Turne syndrome and for boys with suspected Klinefelter’s syndrome stigma or behavior

22. Evaluation

23. Evaluation….

25. Flow chart for the evaluation of delayed puberty in boys

26. Flow chart for the evaluation of delayed puberty in girls

27. Treatment • Objective: • Determine site and etiology of abnormality • Induce and maintain secondary sexual characteristics • Induce pubertal growth spurt • Prevent the potential short-term and long-term psychological, personality, and social handicaps of delayed puberty • Ensure normal libido and potency • Attain fertility

28. Treatment….. • Concerned But Not Anxious or Socially Handicapped Adolescent Reassurance and follow-up Repeat evaluation (including serum testosterone or estradiol) in 6 mo • Psychosocial Handicaps, Anxiety, Highly Concerned • Therapy for 4 mo • Boys: testosterone enanthate 100 mg IM q4wk at 14-14.5 yr of age, or overnight transdermal testosterone patch • Girls: ethinyl estradiol 5-10 µg/day PO or conjugated estrogens 0.3 mg/day PO or overnight ethinyl estradiol patch at 13 yr of age • No therapy for 4-6 mo; reevaluate status including serum testosterone or estradiol; if indicated repeat treatment regimen ClinEndocrinol (Oxf).2003;58:267-272 HormRes. 2003;59:270-275 J Clin Endocrinol Metab. 2001;86:3039-3044.

29. Treatment….. • If during the 3 to 6 months after discontinuing gonadal steroid therapy spontaneous puberty does not ensue or the concentrations of plasma gonadotropins and plasma testosterone in boys or plasma estradiol in girls do not increase, the treatment may be repeated • Only one or two courses of therapy usually are necessary • When treatment is discontinued after bone age has advanced(to 12 to 13 years in girls or 13 or 14 years in boys),patients with constitutional delay usually continue pubertal development on their own, whereas those with gonadotropin deficiency do not progress Horm Res 2003 ;60(suppl):74-77

30. Treatment: Functional hypogonadotropichypogonadism • Functional hypogonadotropichypogonadism associated with chronic disease is treated by alleviating the underlying problem • Delayed puberty in this situation is usually a result of inadequate nutrition and low weight or excessive energy expenditure • When weight returns to normal values, puberty usually occurs spontaneously • Treatment with T4 allows normal pubertal development in hypothyroid patients with delayed puberty

31. Treatment:permanenthypogonadism • Boys • Goal: to approximate normal adolescent development when diagnosis is established • Initial therapy: at 13 yr of age, testosterone enanthate50 mg IM every month for about 9 mo (6-12 mo) • Over the next 3-4 yr: gradually increase dose to adult replacement dose of 200 mg q2-3 wk • To induce fertility at appropriate time in hypogonadotropichypogonadism: pulsatile GnRH or FSH and hCG therapy

32. Treatment:permanenthypogonadism • Girls • Goal: to approximate normal adolescent development when diagnosis is stablished • Initial therapy: at 12-13 Yr of age: ethinyl estradiol 5 µg by mouth or conjugated estrogen 0.3 mg (or less) by mouth daily for 4-6 mo or preferably estradiol transdermally • After 6 mo of therapy (or sooner if breakthrough bleeding occurs), begin cyclic therapy: Estrogen: first 21 days of month Progestagen: 12th to21st day of month Gradually increase dose of estrogen over next 2-3 yr to conjugated estrogen 0.6- 1.25 mg or ethinyl estradiol 10-20µ g daily for first 21days of month or estradiol patch • In hypogonadotropichypogonadism, to induce ovulation at appropriate time: pulsatile GnRH or FSH and hCG therapy

33. Treatment with GH • Although the Food and Drug Administration has approved the use of growth hormone for the treatment of idiopathic short and height is 2-2.5 SD below average for age, this therapy has at best a modest effect on adult height in adolescents with CDGP, and its use in CDGP is not recommended N Engl J Med 2012;366:443-53

34. Treatment with aromatase inhibitor • Aromatase inhibitors, can prolong linear growth and potentially increase adult height • In controlled trials in boys with short stature or delayed puberty, aromatase inhibitors delayed bone maturation and appeared to increase adult height • However, the amount of height gained as well as the optimal timing dose, and duration of therapy with aromatase inhibitors remain uncertain • Moreover, potentially adverse effects must be considered • This treatment requires further study before it should be incorporated into routine practice • J Clin Endocrinol Metab 2005;90:6396-402 • Lancet 2001;357:1743-8 • Pediatrics 2008;121(4):e975-e983

35. Medications used for the treatment of constitutional delay of growth and puberty and permanent hypogonadism

36. European Journal of Endocrinology(2014) 170, R229–R239

37. Areas of Uncertainty • Further research is needed to establish: • Appropriate age cutoffs for delayed puberty in different racial and ethnic groups • The psychosocial distress among children with delayed puberty, whether this distress has long term sequelae, and what effect sex-steroid supplementation has on these outcomes • whether adult bone mass is adversely affected by pubertal delay J ClinEndocrinolMetab2006 J Pediatr 2010;156:308-12 J Pediatr 2011; 158:100-5.

38. Areas of Uncertainty….. • Distinguishing between CDGP and IHH remains difficult in many cases • The role of inhibin B or other markers for this purpose is needed • To compare different estrogen formulations, routes of administration and drug regimens to determine optimal therapy for girls • To identify genes that cause CDGP, which would also elucidate factors that regulate the timing of puberty

39. Conclusions and Recommendations • The patient in the vignette has delayed puberty. Given that he is male and has a family history of late pubertal development, CDGP is the most likely • Before making this diagnosis, a careful evaluation is required to rule out other causes • In CDGP, in which pubertal delay is transient, the decision regarding whether to treat should be made by the patient • If spontaneous puberty has not occurred after 1 year, other diagnoses, should be considered and MRI of the brain is indicated N Engl J Med 2012;366:443-53

40. با تشكر از توجه شما