M.HashemipourProfessor in Pediatric Endocrinology

Isfahan university of Medical Sciences

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Polycystic Ovary Syndrome

inAdolescents

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• 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

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Predisposing factors

• Prenatal exposure to androgens• Low birth weight• Premature pubarche• Obesity• Acanthosis nigricans

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

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• 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.

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• Second, nonpathologic acne and mild hirsutism are common in the peripubertal years.

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• Third, children develop physiologic insulin resistance during puberty.

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

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

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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.

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• 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.

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

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(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.

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• 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

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DIFFERENTIAL DIAGNOSIS

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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.

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Nonclassic (late-onsetCAH)

• Females with nonclassic CAH may have polycystic ovaries and elevated serum LH levels.

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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

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Diagnosis• 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

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Treatment

For women with nonclassic CAH with anovulatory cycles who desire fertility

we suggest glucocorticoids as initial therapy for ovulation induction

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Ovarian steroidogenic blocks

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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

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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

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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 elevatedEstradiol levels are lowThey respond to estrogen replacement therapy

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Cushing's syndrome

weight gainGrowth arrestMood change plethoraAcneHirsutismAnovulation cyclePCOS

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Cushing's syndrome

• Glucocorticoid excess inhibit GnRH secretion

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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

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Virilizing Adrenal tumor

• Adrenal carcinomas secrete both cortisol and androgens.

• Diagnosis is based on hyperandrogenemia that is non-suppressible by glucocorticoids.

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Virilizing ovarian and Adrenal tumor

Woman• Frank virilization,baldness, deep

voice,clitoromegaly,anovulation

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Virilizing Adrenal tumor

Children<7years• Advance bone age, growth accelerated,pubic

hair, Cushingoid changes, and/or abdominal or pelvic masses, rapid onset of hirsutism

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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

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Diagnostic imaging

• Ultrasound is the examination of first choice• MRI, CT• FDG-PET

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Treatment

• The treatment is surgical, Mitotane therapy, Chemotherapy, Radiotherapy

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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.

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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.

•

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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

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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

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Prolactinoma

• present in children older than 12 years• Excess prolactin is a distant second cause of

hyperandrogenism to CAHHeadachevisual disturbance Growth failure Amenorrhea or menstrual irregularitiespubertal arrest and galactorrhea. Additional pituitary hormone deficiencies.

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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

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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

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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

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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

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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

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Treatment of Acromegaly

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

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Insulin resistance syndrome

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

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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.

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Insulin resistance syndrome

presents in thin young women withExtreme hyperinsulinism, acanthosis nigricans,

glycosuria, hyperandrogenismvirilization and polycystic ovarian syndromenormal glucose levels ,impaired glucose

tolerance to frank NIDDMDyslipidemia, hypertension

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Treatment of Insulin Resistance

• Metformin• Thiazolidinediones• Weight loss

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Obesity insulin resistanceHyperinsulinemia acts in conjunction with LH to

increase androgen production by ovarian theca cells Increase Testosterone and DHEASprecocious puberty Accelerated bone age Tall staturepremature adrenarche PCOS

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Hypothyroidism

Menstrual irregularity,anovulation impaired LH surge,increase prolactin and low SHBGSecretion of progesterone is inadequate, and

endometrial proliferation persists, resulting in excessive and irregular breakthrough menstrual bleeding.

Decreased testosterone and estradiol

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Androgenic drugs

• Anabolic steroids for body building

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Epilepsy

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

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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

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Type 1 diabetes mellitus

• PCOS 12–18%• Mild hirsutism and biochemical hyperandrogenism 30% • polycystic ovarian morphology 50%

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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

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Portohepatic shunting

• PCOS phenotype can occur as a complication of portal hypertension or portosystemic shunting

• This has been attributed to impaired steroid metabolism.

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Finding of PCOS has been observed in

• AIDS• Epilepsy• 20% of normal women

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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).

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• 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.

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DIAGNOSTIC APPROACH

• Evaluation for hyperandrogenism • Prolactin • Insulin-like growth factor-I• Serum cortisol • Thyroid function tests • Early-morning 17-hydroxyprogesterone

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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 .

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• 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.

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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 (>700 - 800 µg/dL) if the tumor is of adrenal origin.

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Ultrasonography

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

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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.

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• 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.

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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.

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• 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.

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Treatment

• Change of life style• Metformine • Ovulation induction• Hirsutism

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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

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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

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diabets

• that exogenous hyperinsulinism at the onset of ovarian function

• during puberty reprograms ovarian function towards increased

• androgen secretion, leading to hyperandrogenism [38].

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• Oligomenorrhea: menstrual bleeding that occurs at intervals

• over 40 days or fewer than 9 periods per yearabsence of menses for at least 3

• months.

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• include 12 or more follicles measuring 2–9 mm in diameter or

• increased ovarian volume (>10 cm3

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• 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

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• 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

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• 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

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Atypical PCOS

• Hyperandrogenic patients who lack menstrual irregularity or hirsutism

• Abnormal testing due to ovarian or adrenal dysfunction

• 17-OHP hyperresponsiveness to gonadotropin stimulation

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• 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)

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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 •

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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

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• 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.

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• 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

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• 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]

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• 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" abo ve

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• . 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

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• 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

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• 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

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• 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

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• . 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.

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• 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.

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• — 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.

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• 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