M.Hashemipour Professor in Pediatric Endocrinology Isfahan university of Medical Sciences

2. M.HashemipourProfessor in Pediatric Endocrinology Isfahan university of Medical Sciences

3. Polycystic Ovary SyndromeinAdolescents

4. PCOS is a result of a complex genetic disorder, which often first becomes apparent at the onset of puberty • Heritable and non-heritable factors contribute to the phenotypic expression of PCOS • PCOS appears to be inherited in an autosomal dominant

5. Predisposing factors • Prenatal exposure to androgens • Low birth weight • Premature pubarche • Obesity • Acanthosisnigricans

6. Diagnosing PCOS in adolescents using the above criteria poses several challenges.

7. First, using menstrual irregularity to diagnose PCOS is difficult in adolescents, given that greater than 50% of menstrual cycles are anovulatory in the first 2 years after menarche.

8. Second, nonpathologic acne and mild hirsutismare common in the peripubertal years.

9. Third, children develop physiologic insulin resistance during puberty.

10. Fourth, limited normative data of androgen levels by body mass index (BMI) and pubertal stage exist.

11. Fifth, multifollicular ovaries also can be a normal finding in adolescence. They can be difficult to distinguish from polycystic ovaries .

12. Ovarian size • appears to be maximal in the perimenarchal period • 25% of adolescent girls have multifollicular ovaries, making the differentiation of “normal” versus “abnormal” ovaries difficult for even experienced specialists.

13. Sixth, a transvaginal ultrasound is often inappropriate for pediatric patients, particularly virginal girls, and the use of a transabdominal ultrasound yields limited resolution of ovarian morphology and has been shown to underestimate the presence of the syndrome.

14. According to this proposal, four out of the following five criteria would be required for a PCOS diagnosis in adolescents:

15. (1) Oligo- or amenorrhea 2 years after menarche, (2) Clinical hyperandrogenism (hirsutism, acne, and/or alopecia), (3) Biologic hyperandrogenism (an elevated testosterone concentration), (4) Insulin resistance or hyperinsulinemia (acanthosisnigricans, abdominal obesity, and/or glucose intolerance), and (5) Polycystic ovaries.

16. Oligomenorrhea (defined as missing more than four periods per year, menstrual bleeding that occurs at intervals over 40 days • secondary amenorrhea (defined as >90 days without a menstrual period • Irregular menstrual cycles that persist for six months carry about a 40 percent risk of ongoing menstrual abnormality • menstrual dysfunction that continues for two years after menarche carries approximately a two-thirds probability of ongoing menstrual irregularity

17. DIFFERENTIAL DIAGNOSIS

18. Nonclassic (late-onset CAH) • 5 percent of hyperandrogenism • Affected patients may present with premature pubarche, adolescent- or adult-onset hirsutism, and/or symptoms of anovulation.

19. Nonclassic (late-onsetCAH) • Females with nonclassic CAH may have polycystic ovaries and elevated serum LH levels.

20. Diagnosis • Increase DHEAS,Androstenedion,Testosterone in both condition • Early morning 17OHP<1ng/ml during follicular phase exclude Nonclassic CAH • 17OHP >2 ng/ml in follicular phase suggested Nonclassic CAH

21. Diagnosis • A basal value of 17-OHP above 12ng/mLsuggested virilizing tumor • 17OHP 2-8ng/ml needs ACTH test • 17OHP>10-15ng/ml after ACTH test suggested Nonclassic CAH • Genotype is recommended to confirm the diagnosis

22. Treatment • For women with nonclassicCAH with anovulatory cycles who desire fertility • we suggest glucocorticoids as initial therapy for ovulation induction

23. Ovarian steroidogenic blocks

24. Aromatase Deficiency • Catalyze the conversion of androgens to estrogens • plays a crucial role in synthesis of circulating estrogens from the ovary at the time of puberty

25. Aromatase Deficiency • Clitoromegaly • primary amenorrhea • No pubertal growth spurt. • Breasts remain hypoplastic after initial development during puberty • pubic hairs develop in a normal fashion • Tall stature • Delayed bone maturation • Osteopenia • Maternal virilization in pregnancy

26. Aromatase Deficiency • increased FSH in the absence of ovarian aromatase result in multiple enlarged follicular cysts finally develop polycystic ovaries • Hypergonadotropichypogonadism • progressive virilization. • Plasma androgen are elevated • Estradiollevels are low • They respond to estrogen replacement therapy

27. Cushing's syndrome weight gain Growth arrest Mood change plethora Acne Hirsutism Anovulation cycle PCOS

28. Cushing's syndrome • Glucocorticoid excess inhibit GnRH secretion

29. Cushing's syndrome • Overnight dexamethasone suppression test • low- and high-dose dexamethasone suppression tests confirmed the diagnosis • A single plasma cortisol at midnight<2 μg/dL against disease

30. Virilizing Adrenal tumor • Adrenal carcinomas secrete both cortisol and androgens. • Diagnosis is based on hyperandrogenemia that is non-suppressible by glucocorticoids.

31. Virilizing ovarian and Adrenal tumor Woman • Frank virilization,baldness, deep voice,clitoromegaly,anovulation

32. Virilizing Adrenal tumor Children<7years • Advance bone age, growth accelerated,pubic hair, Cushingoid changes, and/or abdominal or pelvic masses, rapid onset of hirsutism

33. Biochemical evaluation • Diagnosis by measurement of serum cortisol, DHEAS ,testosterone ,androstendione, 17OHP, estradiol, renin, aldosterone and 11 deoxycortisol. • Testosterone >2ng/ml ovarian tumors • DHEAS> 8ug/ml Adrenal tumors

34. Diagnostic imaging • Ultrasound is the examination of first choice • MRI, CT • FDG-PET

35. Treatment • The treatment is surgical, Mitotane therapy, Chemotherapy, Radiotherapy

36. Glucocorticoid resistance • Caused by mutations in the glucocorticoid receptor. • Decreased glucocorticoid action results in increased ACTH secretion which stimulations production of cortisol, androgens and deoxycorticosterone • Resistant to suppression of cortisol with Low DST but respond to high doses.

37. Glucocorticoid resistance • Fatigue, hypertension and hypokalemic alkalosis, • Hyperandrogenism • without the stigmata of Cushing's syndrom • A useful clinical discriminatory test to differentiate this condition from Cushing's syndrome is to measure bone mineral density • Preserved in patients with glucocorticoid resistance • Circadian rhythm for ACTH and cortisol is preserved in patients with glucocorticoid resistance.

38. Apparent cortisone reductase deficiency • Defect in cortisol metabolism • Defect in the conversion of cortisone to cortisol • inhibition of 11β-HSD1 • Cortisol clearance is increased • As a consequence ACTH secretion is elevated to maintain normal cortisol but at the expense of adrenal androgen excess

39. Apparent cortisone reductase deficiency • female present with hirsutism, menstrual irregularity, and/or androgenic alopecia • . Dexamethasone treatment suppress ACTH and hyperandrogenism • Urinary ratio tetrahydrometabolites of cortisol to cortisone <0.05, reference range 0.8 to 1.3

40. Prolactinoma • present in children older than 12 years • Excess prolactin is a distant second cause of hyperandrogenism to CAH • Headache • visual disturbance • Growth failure • Amenorrhea or menstrual irregularities • pubertal arrest and galactorrhea. • Additional pituitary hormone deficiencies.

41. Prolactinoma • Diagnosis to obtain both MRI and biochemical evidence of sustained hyperprolactinemia • Differential diagnosis should include secondary hyperprolactinemia resulting from impaired hypothalamic production of dopamine • stalk compression • medication phenothiazines, metoclopramide) • presence of macroprolactin

42. Prolactinoma • Normal range for serum prolactin is 5 to 20 ng/mL • prolactin between 20 and 200 ng/mL can be found in patients with any cause of hyperprolactinemia. • serum prolactin values above 200 ng/mL usually indicate the presence of a lactotroph adenoma

43. Treatment of Prolactinoma • Surgery for visual loss, hydrocephalus • Treatment of choice is Bromocriptine • Cabergoline • Irrespective of the type of treatment, the reduction of tumor size, by dopamine agonists or surgery, may result in restoration of normal pituitary function

44. Acromegaly • soft tissue swelling, enlargement of the nose, ears, and jaw with coarsening of the facial features • pronounced increases in hand and foot size • Galactorrhea, and menstrual irregularity,PCOS • Cranial nerve palsy,    Headache ,   Pituitary enlargement    ,Visual field defects • Cardiomyopathy ,hypertension

45. Diagnosis of Acromegaly • Serum IGF-I levels are elevated • Random GH greater than 0.4 μg/L • serum GH is not suppressed by administration of glucose (1.75 g/kg body weight, up to a maximum of 100 g(greater than 1 μg/L) • Hypothalamus and pituitary MRI or CT

46. Treatment of Acromegaly • surgical ablation of the tumor. • use of somatostatin analogues • Dopamine agonists • GH-receptor antagonists

47. Insulin resistance syndrome • Leprechaunism • Type A insulin resistance syndrome • Rabson–Mendenhall syndrome • Inherited lipoatrophic diabetes

48. Insulin resistance • inability of a known quantity of exogenous or endogenous insulin to increase glucose uptake and utilization in an individual as much as it does in a normal population.

49. Insulin resistance syndrome presents in thin young women with • Extreme hyperinsulinism, acanthosisnigricans, glycosuria, hyperandrogenism • virilization and polycystic ovarian syndrome • normal glucose levels ,impaired glucose tolerance to frank NIDDM • Dyslipidemia, hypertension

50. Treatment of Insulin Resistance • Metformin • Thiazolidinediones • Weight loss