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

3. Polycystic Ovary Syndrome in Adolescents

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
Acanthosis nigricans

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 hirsutism are 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 (acanthosis nigricans, 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 17OHP 2-8ng/ml needs ACTH test
A basal value of 17-OHP above 12ng/mL suggested 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 nonclassic CAH 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
Hypergonadotropic hypogonadism
progressive virilization.
Plasma androgen are elevated
Estradiol levels 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, acanthosis nigricans, 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

51. Obesity insulin resistance
Hyperinsulinemia acts in conjunction with LH to increase androgen production by ovarian theca cells
Increase Testosterone and DHEAS
precocious puberty
Accelerated bone age
Tall stature
premature adrenarche
PCOS

52. Hypothyroidism
Menstrual irregularity,anovulation
impaired LH surge,increase prolactin and low SHBG
Secretion of progesterone is inadequate, and endometrial proliferation persists, resulting in excessive and irregular breakthrough menstrual bleeding.
Decreased testosterone and estradiol

53. Androgenic drugs
Anabolic steroids for body building

54. Epilepsy Temporal lobe epilepsy is 20–25% PCOS Hypersecretion of LH
Hypothalamic amenorrhea
premature menopause
Hyperprolactinemia

55. Anti-epileptic drugs valproate
Obesity, hyerinsulinemia, IGFBP-1 have a role in the development of PCOS.
Augments the transcription of the steroidogenic gene cytochrome P450c17
PCOS and hyperandrogenism if the treatment was started before 20 years

56. Type 1 diabetes mellitus
PCOS –18%
Mild hirsutism and biochemical hyperandrogenism %
polycystic ovarian morphology %

57. Disorders of sex developmen
phenotypic females have mixed ovarian and testicular tissue
The development of the internal and external genitalia in these children can be quite variable depending upon androgen production and exposure

58. Portohepatic shunting
PCOS phenotype can occur as a complication of portal hypertension or portosystemic shunting
This has been attributed to impaired steroid metabolism.

59. Finding of PCOS has been observed in
AIDS
Epilepsy
20% of normal women

60. INDICATIONS FOR EVALUATION
Girls with a sole finding of moderate or severe hirsutism, or a hirsutism equivalent, including treatment-resistant acne vulgaris, or male pattern alopecia.
Girls with mild hirsutism or obesity with any other feature of PCOS (eg, menstrual abnormality).

61. Adolescent girls with menstrual irregularity that persists more than two years or who have severe dysfunctional uterine bleeding.
Adolescent girls with intractable obesity whether or not hirsutism, hirsutism equivalents, or menstrual irregularity are present.

62. DIAGNOSTIC APPROACH Evaluation for hyperandrogenism Prolactin
Insulin-like growth factor-I
Serum cortisol
Thyroid function tests
Early-morning 17-hydroxyprogesterone

63. Testosterone The key androgen to measure is testosterone.
Plasma total and free testosterone are best assessed in the early morning, on days 4 through 10 of the menstrual cycle in regularly cycling women.
The normal upper limit for plasma total testosterone in women varies from about 0.7 to 0.9 ng/ml .

64. A total testosterone > 2 ng/ml increases the likelihood of a virilizing neoplasm.
In girls with laboratory-confirmed testosterone elevation, ultrasonography is recommended primarily to exclude the rare but serious adrenal or ovarian tumor.

65. Dehydroepiandrosterone sulfate (DHEAS)
DHEAS is a marker for adrenal hyperandrogenism.
Measurement is not necessary in the initial evaluation of PCOS in most girls.
Girls with a virilizing tumor usually present with a rapid onset of virilizing features and DHEAS levels are often markedly elevated (> µg/dL) if the tumor is of adrenal origin.

66. Ultrasonography
A polycystic ovary in adolescents is similar in size to that of adults, with increased volume defined as >10.8 mL.

67. Ultrasonography
Multiple follicles (>10 per maximum plane or >12 per ovary) are a feature of polycystic ovaries.
increased volume defined as >10.8 cubic mL
in the absence of ovarian enlargement, up to 10 follicles is defined as a multifollicular ovary and the distinction from polycystic ovary is problematic.

69. About 75% of all anovulatory women will have polycystic-appearing ovaries as determined by ultrasonography.
There are numerous causes of anovulation, and there are numerous reasons for polycystic ovaries.

70. Additional evaluation
Once a diagnosis of PCOS has been established, identifying abnormal glucose tolerance or other features of the metabolic syndrome is important because PCOS is a risk factor for the early development of type 2 diabetes mellitus, metabolic syndrome, and their associated cardiovascular risk sequelae.

71. An elevated LH/FSH ratio supports the diagnosis of PCOS and may be useful in differentiating mild cases of nonobese PCOS without prominent androgen excess from hypothalamic anovulation.
However, failure to exhibit an elevated LH level is of no diagnostic value.

72. Treatment Change of life style Metformine Ovulation induction
Hirsutism

73. iugr
The adaptation
of the fetus to conditions of undernutrition in utero involves an
alteration in the endocrine setpoint of insulin, insulin-like growth
factor, growth hormone pathways and probably the pituitary–
gonadal axes. pattern with higher LH : FSH ratio and higher estradiol and 17-OH
progesterone (17-OHP) than AGA girls

74. prematurepubarche ovarian androgen
synthesis throughout puberty, based on both peak after
gonadotropin releasing hormone (GnRH) test and incremental
increases of 17-pregnenolone and DHEA throughout puberty
and of 17-OHP and androstenedione in late puberty which were
signifi cantly higher in premature pubarche girls than in controls
in a selected population

75. diabets
that exogenous hyperinsulinism at the onset of ovarian function
during puberty reprograms ovarian function towards increased
androgen secretion, leading to hyperandrogenism [38].

76. Oligomenorrhea: menstrual bleeding that occurs at intervals
over 40 days or fewer than 9 periods per yearabsence of menses for at least 3
months.

77. include 12 or more follicles measuring 2–9 mm in diameter or
increased ovarian volume (>10 cm3

78. Some progestins have more androgenic activity
than others. Desogestrel, gestodene and norgestimate are
considered to have low androgenic potential and are preferred by
pediatric endocrinologi

79. Metformin acts by
inhibiting hepatic glucose output and increasing insulin sensitivity
in peripheral tissues. Decreased insulin concentrations lead to
increased SHBG concentrations, lower free testosterone, improved
androgen excess and ovulation

80. In adult women, a score of <8 is normal, 8 to 15 indicates mild hirsutism, and >15 indicates moderate to severe hirsutism.
A polycystic ovary may not develop until two or more years after menarche
Dysfunctional uterine bleeding (defined as bleeding at intervals of less than 21 days, bleeding for more than seven days, or bleeding requiring pad or tampon changes more than every one to two hours

81. Atypical PCOS
Hyperandrogenic patients who lack menstrual irregularity or hirsutism
Abnormal testing due to ovarian or adrenal dysfunction
17-OHP hyperresponsiveness to gonadotropin stimulation

82. Both nonclassic and classic CAH often are associated with nonclassic PCOS (hyperandrogenism without ultrasonographic evidence of ovarian dysfunction), which causes persistent menstrual irregularity and insulin resistance in patients who are well-controlled on glucocorticoid therapy [19,22,23] . This secondary PCOS may result from in-utero virilization [24] . In rare cases of CAH, adrenal rests of the ovaries seem responsible for functional ovarian hyperandrogenism (FOH)

83. Differential diagnosis of PCOS in adolescents
Congenital adrenal hyperplasia
Nonclassical 21hydroxylase deficiency
Classical 21hydroxylase deficiency
Ovarian steroidogenic blocks
Cushing Syndrome
Cortisol resistance
Apparent cortisone reductase deficiency
Hyperprolactinemia
Acromegaly

84. Differential diagnosis of PCOS in adolescents
Insulin resistance syndrome
Virilizing ovarian or adrenal tumor
Thyroid dysfunction
Androgenic drugs
Valproic acid
Hermaphroditism
Portohepatic shunting
Idiopathic
Obesity

85. f both androgen excess and cortisol are not suppressed, Cushing's syndrome, adrenal tumors, and other adrenal disorders must be considered. If the levels of androgen suggest an adrenal tumor, imaging, such as computed tomography, is indicated.

86. If testosterone excess is not suppressed but cortisol and DHEAS are suppressed, the diagnosis of PCOS is virtually assured
- If androgen excess is suppressed, then further evaluation with a cosyntropin (ACTH) test for CAH is indicate
n patients with PCOS, a normal fasting glucose concentration or hemoglobin A1C is insufficient to exclude impaired glucose tolerance

87. In addition, about two-thirds of fathers and one-third of mothers of PCOS adolescents have been reported to have the metabolic syndrome [11] . Over half of parents have abnormal glucose tolerance, many with asymptomatic type 2 diabetes. Thus, it may be reasonable to suggest that immediate family members should also be screened for diabetes and other features of the metabolic syndrome. It should also be kept in mind that about 25 percent of sisters are reported to have PCOS, so consideration should be given to determining whether sisters have symptoms of or risk factors for the disorder [64]

88. Recognizing and treating PCOS in adolescents are important beyond management of the presenting symptoms because PCOS increases the risk of developing endometrial hyperplasia and carcinoma, type 2 diabetes mellitus, metabolic syndrome, infertility, and possibly cardiovascular disease. PCOS is characterized by hyperandrogenism (eg, hirsutism, severe acne, pattern alopecia), and/or menstrual irregularity (eg, oligo- or amenorrhea, irregular bleeding), or polycystic ovaries. However, standard diagnostic criteria in women are more difficult to apply to adolescents who are normally oligo-ovulatory and are less likely to have polycystic ovaries. As a result, we define PCOS as chronic, confirmed hyperandrogenemia of ovarian or adrenal origin that is otherwise unexplained. (See "Diagnostic criteria" above). PCOS should be considered in any adolescent girl with hirsutism or hirsutism equivalents, menstrual irregularity, and/or obesity. These patients should be tested for androgen excess. (See "Androgen testing" above and see "Indications for evaluation" above). Once androgen excess has been confirmed by laboratory testing, other hyperandrogenic disorders are excluded by the combination of ultrasonography and endocrine testing (show algorithm 1 and show table 3). (See "Evaluation for causes of hyperandrogenemia" above and see "Differential diagnosis" above). Once a diagnosis of PCOS has been established, it is important to identify and monitor for abnormal glucose tolerance and other features of the metabolic syndrome, because PCOS is a risk factor for the early development of type 2 diabetes mellitus and metabolic syndrome, and their associated morbidity. (See "Additional evaluation" above

89. Progestin inhibits endometrial proliferation, preventing hyperplasia
. Progestin inhibits endometrial proliferation, preventing hyperplasia. Estrogen inhibits the activity of the hypothalamic-pituitary-gonadal axis, reducing ovarian androgen production as well as increasing serum sex hormone binding protein levels. This results in decreased concentrations of unbound testosterone. OCP therapy also will normalize androgen levels in most cases within 18 to 21 day

90. Norgestimate is a newer, potent progestin with low androgenic
Drospirenone, an analogue of spironolactone with weakly anti-androgenic and anti-mineralocorticoid properties, is combined with ethinyl estradiol: 30 mcg (in Yasmin®) [3] . It may be particularly well suited for patients with PCOS, as it addresses both menstrual irregularity and hirsutis

91. fter three months, the efficacy of treatment is assessed by evaluating clinical symptoms and androgen levels. If the treatment is effective, as a general rule, OCPs should be continued until the patient is gynecologically mature (five years postmenarcheal) or has lost a substantial amount of excess weight. At that point, withholding treatment for a few months to allow recovery of suppression of pituitary-gonadal function and to ascertain whether the menstrual abnormality is persistent is advisable. In doing so, however, one must keep in mind that the anovulatory cycles of PCOS lead to relative infertility, not absolute infertility. The need for continued use of the OCP for contraceptive purposes must be considered

92. If treatment is not successful in reducing androgen levels, the patient either has an unusually prominent component of functional adrenal hyperandrogenism (FAH) to the PCOS or the diagnosis of PCOS should be questioned
Glucocorticoid therapy does not result in consistent ovulation in patients with PCOS, even in those with a prominent component of functional adrenal hyperandrogenism (FAH

93. . A three month trial of glucocorticoid therapy seems sufficient to determine efficac
Significant suppression can be excluded if the cortisol level is ≥ 10 mcg/dL (276 nmol/L) at 8:00 AM or ≥ 13 mcg/dL (359 nmol/liter) 30 minutes after administering ACTH
GnRH therapy is generally not recommended in adolescents younger than 16 years of age because of concerns regarding bone mineral accrual.

94. The 2008 Endocrine Society Clinical Guidelines suggest adding an antiandrogen in patients taking OCPs who feel that their cosmetic response is suboptimal after six months. . Thus, the effects of these agents usually are not appreciated for 9 to 12 months because of the long growth cycles of sexual hair follicles.

95. — Metformin in adolescent PCOS is used as an adjunct to management of obesity and the related insulin-resistant metabolic abnormalities. In adults, it also is used in promoting ovulation in patients who are resistant to fertility therapy. (See "Metformin for treatment of the polycystic ovary syndrome").
Metformin tends to suppress appetite and enhance weight loss. It also reduces insulin levels primarily by directly inhibiting hepatic glucose output [16] . Its effectiveness is minimized in the absence of weight control [25] , which may be why insulin levels are inconsistently lowered ncreases the frequency of menses and ovulation (by about 50 percent), and lowers testosterone levels (by about 20 percent). However, the decrease in testosterone level is not enough to appreciably improve hirsutism [20,26,27] . The body mass index is modestly decreased, if at all. A small increase in high-density lipoprotein cholesterol levels also is reported.

96. Thiazolidinediones increase insulin sensitivity primarily by promoting fat mobilization from the bloodstream. Troglitazone, the initial thiazolidinedione, decreased androgen levels in women with PCOS but has been withdrawn from the market in the United States and the United Kingdom because of the risk of hepatotoxicity. The new generation of thiazolidinediones (eg, rosiglitazone, pioglitazone) is FDA approved for treatment of type 2 diabetes mellitus. In small, randomized trials, they appear to increase ovulation and decrease androgen levels. Unfortunately, these drugs also increase weight gain. Although less toxic than troglitazone, there are rare case reports of reversible hepatic toxicity. Because of the limited data and concern for weight gain and hepatic toxicity, we do not recommend the use of thiazolidinediones in adolescents with PCOS who are not diabet