M.Hashemipour
Professor in Pediatric Endocrinology
Isfahan university of Medical Sciences
2
Polycystic Ovary
Syndrome
in
Adolescents
3
• 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
4
Predisposing factors
•
•
•
•
•
Prenatal exposure to androgens
Low birth weight
Premature pubarche
Obesity
Acanthosis nigricans
5
• Diagnosing PCOS in adolescents using the
above criteria poses several challenges.
6
• 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.
7
• Second, nonpathologic acne and mild
hirsutism are common in the peripubertal
years.
8
• Third, children develop physiologic insulin
resistance during puberty.
9
• Fourth, limited normative data of
androgen levels by body mass index (BMI)
and pubertal stage exist.
10
• Fifth, multifollicular ovaries also can be a
normal finding in adolescence. They can be
difficult to distinguish from polycystic ovaries .
11
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.
12
• 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.
13
• According to this proposal, four out of the
following five criteria would be required for a
PCOS diagnosis in adolescents:
14
(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.
15
• 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
16
DIFFERENTIAL DIAGNOSIS
17
Nonclassic (late-onset CAH)
5 percent of hyperandrogenism
Affected patients may present with
premature pubarche, adolescent- or adultonset hirsutism, and/or symptoms of
anovulation.
18
Nonclassic (late-onsetCAH)
• Females with nonclassic CAH may have
polycystic ovaries and elevated serum LH
levels.
19
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
20
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
21
Treatment
For women with nonclassic CAH with
anovulatory cycles who desire fertility
we suggest glucocorticoids as initial therapy
for ovulation induction
22
Ovarian steroidogenic blocks
23
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
24
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
25
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
26
Cushing's syndrome
weight gain
Growth arrest
Mood change
plethora
Acne
Hirsutism
Anovulation cycle
PCOS
27
Cushing's syndrome
• Glucocorticoid excess inhibit GnRH secretion
28
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
29
Virilizing Adrenal tumor
• Adrenal carcinomas secrete both cortisol and
androgens.
• Diagnosis is based on hyperandrogenemia
that is non-suppressible by glucocorticoids.
•
30
Virilizing ovarian and Adrenal tumor
Woman
• Frank virilization,baldness, deep
voice,clitoromegaly,anovulation
31
Virilizing Adrenal tumor
Children<7years
• Advance bone age, growth accelerated,pubic
hair, Cushingoid changes, and/or abdominal or
pelvic masses, rapid onset of hirsutism
32
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
33
Diagnostic imaging
• Ultrasound is the examination of first choice
• MRI, CT
• FDG-PET
34
Treatment
• The treatment is surgical, Mitotane therapy,
Chemotherapy, Radiotherapy
35
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.
36
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.
•
37
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
38
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
39
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.
40
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
41
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
42
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
43
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
44
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
45
Treatment of Acromegaly
•
•
•
•
surgical ablation of the tumor.
use of somatostatin analogues
Dopamine agonists
GH-receptor antagonists
46
Insulin resistance syndrome
•
•
•
•
Leprechaunism
Type A insulin resistance syndrome
Rabson–Mendenhall syndrome
Inherited lipoatrophic diabetes
47
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.
48
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
49
Treatment of Insulin Resistance
• Metformin
• Thiazolidinediones
• Weight loss
50
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
51
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
52
Androgenic drugs
• Anabolic steroids for body building
53
Epilepsy
Temporal lobe epilepsy is 20–25%
• PCOS
• Hypersecretion of LH
• Hypothalamic amenorrhea
• premature menopause
• Hyperprolactinemia
54
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
55
Type 1 diabetes mellitus
• PCOS
12–18%
• Mild hirsutism and biochemical hyperandrogenism 30%
• polycystic ovarian morphology
50%
56
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
57
Portohepatic shunting
• PCOS phenotype can occur as a complication of
portal hypertension or portosystemic shunting
• This has been attributed to impaired steroid
metabolism.
58
Finding of PCOS has been observed in
• AIDS
• Epilepsy
• 20% of normal women
59
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).
60
• 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.
61
DIAGNOSTIC APPROACH
•
•
•
•
•
•
Evaluation for hyperandrogenism
Prolactin
Insulin-like growth factor-I
Serum cortisol
Thyroid function tests
Early-morning 17-hydroxyprogesterone
62
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 .
63
• 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.
64
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.
65
Ultrasonography
• A polycystic ovary in adolescents is similar in
size to that of adults, with increased volume
defined as >10.8 mL.
66
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.
67
• 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.
69
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.
70
• 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.
71
Treatment
•
•
•
•
Change of life style
Metformine
Ovulation induction
Hirsutism
72
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
73
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
74
diabets
• that exogenous hyperinsulinism at the onset
of ovarian function
• during puberty reprograms ovarian function
towards increased
• androgen secretion, leading to
hyperandrogenism [38].
75
• Oligomenorrhea: menstrual bleeding that
occurs at intervals
• over 40 days or fewer than 9 periods per
yearabsence of menses for at least 3
• months.
76
• include 12 or more follicles measuring 2–9
mm in diameter or
• increased ovarian volume (>10 cm3
77
• 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
78
• 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
79
• 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
80
Atypical PCOS
• Hyperandrogenic patients who lack menstrual
irregularity or hirsutism
• Abnormal testing due to ovarian or adrenal
dysfunction
• 17-OHP hyperresponsiveness to gonadotropin
stimulation
81
• 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)
82
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
83
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
84
• 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.
85
• 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
86
• 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]
87
• 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
88
• . 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
89
• Norgestimate is a newer, potent progestin
with low androgenic
• Drospirenone, an analogue of spironolactone
with weakly anti-androgenic and antimineralocorticoid 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
90
• 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 pituitarygonadal 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
91
• 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
92
• . 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.
93
• 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.
94
•
— 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.
95
• 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
96