Transcript PCO - Dr. Yaser orief

POLYCYSTIC OVARY SYNDROME
(PCOS)
Yasser Orief M.D.
Fellow , Lübeck University, Germany.
DAOG, Auvergné University, France.
Agenda







Definition
Epidemiology
Pathophysiology
Diagnostic approach
Long term Consequences
Treatment
Follow up
PCOS: History

1721



1935



Dr. Irving Stein and Dr. Michael Leventhal
Coined Stein-Leventhal disorder
1980


Antonio Vallisneri
“…Young peasant woman, married, moderately
plump, infertile, with ovaries larger than normal,
like doves’ eggs, lumpy, shiny and whitish”
Linked to hyperinsulinemia and impaired glucose
tolerance
2006

What causes PCOS?
Lanham 2006
Introduction
Stein and Leventhal
They were the first to recognize an association between the presence of
polycystic ovaries and signs of hirsutism amenorrhea (oligomenorrhea,
obesity)
Polycystic Ovarian Disease
After successful wedge resection of the ovaries in women diagnosed with
Stein-Leventhal syndrome, menstrual cycles become regular and the pati
ents were able to conceive. Primary ovarian disorder come to be known a
s polycystic ovarian disease
Polycystic ovarian syndrome
Biochemical, clinical and endocrinological abnormalities have shown an
array of underlying abnormalities; hence condition known as polycystic ov
arian syndrome( PCOS)
Syndrome O
gets to the real heart of the problem and indicates: Ovarian confusion an
d Ovulation disruption caused primarily by Over nourishment and Overpro
duction of insulin
In reality PCOS, infertility, and other health problems may be all consequence
s of syndrome O
Introduction

Most attention has been paid to the managem
ent of the presenting complaint (infertility, hirs
utism..
etc.)

It has become clear that the polycystic ovary
phenotype is linked to a number of metabolic
disturbances, including type II diabetes and
possibly atherosclerosis

Since PCOS frequently diagnosed by
gynecologists, it is therefore, important that
gynecologists have a good understanding of t
he
Definition
Common names and confused with…






Stein-Leventhal Syndrome
Polycystic ovary disease
Functional ovarian hyperandrogenism
Hyperandrogenic chronic anovulation
Ovarian dysmetabolic syndrome
Polycystic ovarian syndrome
Definition

Stein and Levanthal (1935): association of amenorrhe
a with polycystic ovaries and variably: hirsutism and/
or
obesity

ACOG and NIH (1990): hyperandrogenism and chroni
c anovulation excluding other causes
Criteria of the PCO
National Institutes of Health







Presence of menstrual abnormalities and anovulation
Presence of clinical and/or biochemical
hyperandrogenaemia
Ultrasound examination ?
peripheral cysts (10 or more) less than 10mm in size in
an enlarged ovary with significant increase in the central
stroma
Absence of hyperprolactinaemia or thyroid disease
Absence of late-onset congenital adrenal hyperplasia
Absence of Cushing’s syndrome
2003 ESHRE/ASRM-sponsored PCOS
Consensus workshop

1990 Criteria (both 1 and 2)


1. Chronic anovulation and
2. Clinical and/or biochemical signs of hyperandrogenism
and exclusion of other etiologies.

Revised 2003 criteria (2 out of 3)

1. Oligo- or anovulation
2. Clinical and/or biochemical signs of hyperandrogenism,
3. Polycystic ovaries



and exclusion of other causes of hyperandrogenism (congenital
adrenal hyperplasia, androgen-secreting tumors, Cushing's
syndrome)
PCOS: Diagnostic Criteria

Other concurrent manifestations



Insulin resistance
Features of metabolic syndrome
Increased risk for diabetes mellitus II, cardiovascul
ar disease, endometrial bleeding or cancer
Milnar et al. 2006
Carmina 2006
Pathology
Appearance of ovaries

Polycystic ovaries are enlarged bilaterally and
have a smooth thickened capsule that is
avascular

On cut section, subcapsular follicles in variou
s stages of atresia are seen in the peripheral
part of the ovary

The most striking ovarian features of PCOS is
hyperplasia of the theca stromal cells
surrounding arrested follicles

Microscopically luteinizing theca cells are see
n
increased size and a smooth white
surface reflecting thickening of the
capsule
Showing multiple cysts with diameter <10mm arranged
around the periphery of the ovary.
The stroma is increased, and the ovary enlarged
Prevelance
Epidemiology

Prevalence: 4-6% females
 Probably same world wide

No difference between blacks and whites

75% of women w/ irregularity or infertility
Pathophysiology
PCOS: Pathopysiology
What we think we know.





“Vicious cycle”
Abnormal gonadotropin secretion
 Excess LH and low, tonic FSH
Hypersecretion of androgens
 Disrupts follicle maturation
 Substrate for peripheral aromatization
Negative feedback on pituitary
 Decreased FSH secreation
Insulin resistance, Elevated insulin levels
PCOS: Current theories of pathopysiology
Downstream
Signal Defect
Autosomal
Dominant Gene
GnRH
E2
LH
Insulin Resistance
A=androgens, E2=estradiol
PCOS
A
functional hyperandrogenism
Theories of the Pathogenesis of PCOS
Salehi M. et al., Metabolism 2004; 53: 358-376
PATHWAYS LEADING TO ANDROGEN EXCESS IN PCOS
Tscichorozidou T et al.., Clin Endocrinol 60: 1-17, 2004
Diagnostic Approach
Manifestations of PCOS
at different ages
Manifestations of PCOS
at different ages
PCOS: Signs and Symptoms
SYMPTOMS
 Menstrual irregularity
 Infertility
 Hirsutism, acne, etc
 Obesity
SIGNS
 Hirsutism, acne
 Obesity
 Ovarian enlargement
 Acanthosis nigricans
PCOS: Signs and Symptoms
Polycystic Ovarian Syndrome

History

Complete a good menstrual history





menarche
duration, frequency, intensity of bleeding
periods always irregular or new onset
Menorrhagia / metrorrhagia
Attempt to determine if irregular bleeding ovulatory or
anovulatory
Polycystic Ovarian Syndrome

History

Ovulatory bleeding suggested by presence of
premenstrual symptoms:




Menstrual regularity more suggestive of ovulatory
Anovulatory
 absence of premenstrual symptoms
 frequently long periods of amenorrhea followed by
irregular bleeding


breast engorgement
pelvic cramping
fluid retention
mood swings
Polycystic Ovarian Syndrome

Life long history of irregular menses, hirsutism, infertil
ity, and obesity is suggestive of PCO

Family Hx of PCO
Polycystic Ovarian Syndrome


Pelvic
 ovarian enlargement-irregularity suggestive of cyst
s
 clitoral hypertrophy
Breasts
 Galactorrhea

Suggestive of hyperprolactinemia
Investigations
(A) Pelvic ultrasound examination

Transvaginal ultrasound is the best imaging mode

Endometrial thickness should always be assessed to
exclude significant endometrial pathology
Ultrasound assessment of the Polycystic ovaries
International consensus definitions

Although the 1990 National Institute of
Health
Conference
on
PCOS
recommended that diagnostic criteria
should
include
evidence
of
hyperandrogenism
and
ovulatory
dysfunction, in the absence of nonclassic adrenal hyperplasia, and that
evidence
of
polycystic
ovarian
morphology was not essential, the
Rotterdam
ESHRE/ASRM-sponsored
PCOS consensus considered that PCO
should be considered as one of the
possible criteria for PCOS.
Ultrasound assessment of the Polycystic ovaries
International consensus definitions
1.
The PCO should have at least one of the
following: either 12 or more follicles measuring
2-9 mm in diameter or increased ovarian volume
(>10 cm3). If there is evidence of a dominant
follicle (>10 mm) or a corpus luteum, the scan
should be repeated during the next cycle.
2.
The subjective appearance of PCOs should not
be substituted for this definition. The follicle
distribution should be omitted as well as the
increase in stromal echogenicity and/or volume.
Although the latter is specific to polycystic ovary,
it has been shown that measurement of the
ovarian volume is a good surrogate for the
quantification of the stroma in clinical practice.
Ultrasound assessment of the Polycystic ovaries
International consensus definitions (continued)
3. Only one ovary fitting this definition or a
single occurrence of one of the above
criteria is sufficient to define the PCO.
The presence of an abnormal cyst or
ovarian asymmetry, which may suggest
a homogeneous cyst, necessitates
further investigation.
4. This definition does not apply to women
taking the oral contraceptive pill, as
ovarian size is reduced, even though the
`polycystic' appearance may persist.
Ultrasound assessment of the Polycystic ovaries
International consensus definitions (continued)
5.
A woman having PCO in the absence of an
ovulation disorder or hyperandrogenism
(`asymptomatic
PCO')
should
not
be
considered as having PCOS, until more is
known about this situation.
6.
In addition to its role in the definition of PCO,
ultrasound is helpful to predict fertility outcome
in patients with PCOS (response to clomiphene
citrate, risk for ovarian hyperstimulation
syndrome (OHSS), decision for in-vitro
maturation of oocytes). It is recognized that the
appearance of PCOs may be seen in women
undergoing ovarian stimulation for IVF in the
absence of overt signs of PCOS. Ultrasound
also provides the opportunity to screen for
endometrial hyperplasia.
Ultrasound assessment of the Polycystic ovaries
International consensus definitions (continued)
7.
The following technical recommendations should
be respected:






State-of-the-art equipment is required and should be
operated by appropriately trained personnel.
The transvaginal approach should be preferred,
particularly in obese patients.
Regularly menstruating women should be scanned in the
early follicular phase (days 3±5). Oligo-/amenorrhoeic
women should be scanned either at random or between
days 3±5 after a progestogen-induced bleed.
If there is evidence of a dominant follicle (>10mm) or a
corpus luteum, the scan should be repeated the next
cycle.
Calculation of ovarian volume is performed using the
simplified formula for a prolate ellipsoid (0.5 3 length 3
width 3 thickness).
Follicle number should be estimated both in longitudinal,
transverse and antero-posterior cross-sections of the
ovaries. Follicle size should be expressed as the mean of
the diameters measured in the three sections.

The usefulness of 3-D ultrasound,
Doppler or MRI for the definition of
PCO has not been sufficiently
ascertained to date, and should be
confined to research studies.
Hormone assays

Blood tests needed to exclude ?

Late-onset congenital adrenal hyperplasia
(17-hydroxyprogesterone)
Thyroid abnormality (TSH)
Hyperprolactinaemia (prolactin)
Cushing’s syndrome
These tests can be omitted if other features are
not suggestive.




Androgens

testosterone (total or adjusted for SHBG) is
helpful to show hyperandrogenaemia and to rule
out an androgen-secreting tumour

Total testosterone concentration greater than 60
ng/dL ; consistent with PCOS

dehydroepiandrosterone sulfate and
androstenedione is not particularly useful.
Insulin resistance

It is essential to exclude glucose intolerance with
glucose tolerance testing

It is doubtful whether insulin measurement is
indicated, as interpretation is clouded by obesity

calculating an index of insulin resistance from
glucose and insulin levels
(eg, the homeostasis model assessment [HOMA] or quantitative
insulin sensitivity check index [QUICKI])

random and fasting glucose levels are usually
normal in women with PCOS, the standard
Australian recommendations for diagnosing
diabetes by measuring these levels are not
applicable, and glucose tolerance testing is
recommended
Lipid status

Assessment of lipid status is justified
- total and HDL cholesterol
- triglyceride levels
Criteria for the metabolic syndrome in women with PCOS*
Risk factor
Cut-off
1. Abdominal obesity(waist circumference)
>88 cm (>35 in)
2. Triglycerides
>150 mg/dl
3. HDL-C
<50 mg/dl
4. Blood pressure
>130/>85 mmHg
5. Fasting and 2 h glucose from OGTT
*Three
110±126 mg/dl and/or2 h
glucose 140±199 mg/dl
out of five qualify for the syndrome
Other investigations

Laparoscopy of the pelvis, computed
tomography and magnetic resonance imaging
are never justifiable for suspected PCOS alone.

Endometrial biopsy and hysteroscopy may be
used to investigate unexplained vaginal bleeding.
Long-term health consequences
of PCOS
Long-term health consequences
of PCOS

There is no doubt that women with
PCOS cluster risk factors for diabetes,
cardiovascular disease and endometrial
cancer.

Women with PCOS are also thought to
be at increased risk for endometrial
cancer through chronic anovulation with
unopposed estrogen exposure of the
endometrium. However, epidemiological
evidence to support this hypothesis is
limited.
Long-term health consequences
of PCOS (continued)

PCOS is associated with an increased risk of
type 2 diabetes. The risk is greater in
anovulatory women with PCO, in obese subjects
and those with a family history of type 2
diabetes.

The risk of cardiovascular disease is uncertain
at present. Limited epidemiological data have
shown no increase in cardiovascular events, but
two factors need to be borne in mind: The young
age of the cohorts studied so far (~55 years) and
the possibility that unknown factor(s) may be
present in PCOS which protect the heart in the
face of other risk factors.
Treatment
Treatment Plans

What are your goals?

Treat short-term problems?

Prevent long-term risks?

Pregnancy?

Have other options failed?
 Short-term
 Infertility
 Hirsutism
 Acne
 Obesity
 Miscarriage
management
Treatment
Treatment




Patient's height and weight to calculate her body
mass index
BP at the first visit
Fasting lipid panel to evaluate cardiovascular risk
Fasting glucose concentration to evlauate the
possibility of IGT or non-insulin-dependent diabetes
mellitus
 2-hour oral glucose tolerance test is preferable
Treatment

In overweight patient (body mass index 26 or
higher),
major component of any treatment should be
directed at weight reduction
 Best weight loss strategy - integrated behavioral
program
 Include exercise, moderate caloric restriction
 Result in significant favorable impact on insulin,
androgens, and ovulation
 No data on long-term outcomes of such lifestyle
modification programs
 Metformin - not sliver bullet for all aspects of
PCOS treatment
Treatment

Irregular menstruation

Without the additional concerns of hirsutism or
infertility



OCs remain an excellent choice
Progestins (eg, medroxyprogesterone acetate or
norethisterone)
Present hirsutism

OCs plus spironolactone, at a dose of 200 mg/d is
standard choice
Treatment

Several clear benefits in the treatment of irregular
menstrual cycles in women with PCOS






1.Regular withdrawal bleeding
2. Reduction in the risk of endometrial hyperplasia or cancer
because of progestin opposition of estrogen
3. Reduction in LH secretion and consequent reduction of
ovarian androgens
4. Increased sex hormone binding globulin production and
consequent reduction in free testosterone
5. Improvement in hirsutism and acne
Measruable decline in hirsutism after 6 months of
treatment, while no effect on hirsutism was seen with
metformin
Treatment

Common reason for a physician consultation ;
infertility

Assuming a normal semen analysis, ovulation
induction

Hysterosalpingography to confirm a normal genital
tract if history of PID, endometriosis, or previous
abdominal surgery
Treatment
Treatment

Most physiologic approach to ovulation induction ;
weight loss

Failing that -> clomiphene citrate


Excellent initial pharmacologic strategy
Use the lowest clomiphene citrate dose that will
initiate the smallest number of ovulatory
follicles(hopefully, only one!)


Starting dose ; 50 mg/d for 5 days(usually days 5-9)
approximately 50% ovulation on 50 mg
Treatment




Ultrasound on day 13 to assess follicle development
 More than 2 preovulatory follicles on day 13 ;
reduced to 25 mg/d in subsequent cycles
 No follicle development ; dose and duration of
treatment increased
Never exceed 150 mg/d for 5 days
Once regimen that induces ovulation if there is no
pregnancy
 Should repeat that regimen and not increase the
dose in subsequent cycles
-> Goal is ovulation, not superovulation
Overall, approximately 80% of women with PCOS ovulate on clomiphene citrate
Treatment

How should ovulation be induced in the 20% of
women who are refractory to clomiphene citrate?

Use of metformin hydrochloride





Common and effective strategy
Used extensively in the treatment of non-insulin-dependent
diabetes mellitus
Helps with glycemic control by reducing hepatic glucose
output and by increasing peripheral uptake of glucose
Kidney or liver ds., alcoholism, heart failure treated with
furosemide should not take metformin
∵ lactic acidosis risk ↑
Begun at a dose of 500 mg/d to minimize
gastrointestinal side effects and increased gradually
as tolerated
Postulated role for insulin-sensitising agents
Harborne L et al.,Lancet2003; 361:894-1901
Treatment



Small percentage of women with PCOS (about 510%) who are refractory to clomiphene citrate alone
and to metformin plus clomiphene citrate or who
cannot tolerate these medications
Laparoscopic ovarian drilling
Gonadotropins
 Hypersensitive to exogenous FSH


Risk of multiple pregnancy and hyperstimulation
Should be used in conjunction with in vitro fertilization
; Number of embryos that are transferred to the uterine
cavity controlled
Follow-Up

Women with PCOS who are being seen for infertility
 Followed closely with regards to ovulation
induction

If no pregnancy after 6 months of documented
ovulation


If no pregnancy after 9-12 months of documented
ovulation, and if no other infertility factors



Additional infertility evaluation
Blend with unexplained infertility
Intrauterine insemination is added
If lack of pregnancy despite multiple cycles of
ovulation induction and intrauterine insemination
Follow-Up

For women with PCOS who are not interested in
pregnancy

Follow-up at 6 month intervals
Hirsutism

oral contraceptive pill
(eg, ethinyloestradiol 35 μg + cyproterone acetate
2mg daily for 21 of 28 days)

cosmetic measures
(eg, laser electrolysis, bleaching, waxing or shaving)

oral oestrogen and cyproterone acetate
(oestradiol valerate 2mg daily
and cyproterone acetate 50 mg for 14 days a month)

spironolactone (75–200mg daily)
other drugs


reduce androgen production / inhibit androgen-binding to
the receptor
- antiandrogen flutamide
- antifungal agent ketoconazole
Response times for drugs can be up to 3 months
TABLE 2 -- THERAPEUTIC OPTIONS FOR HIRSUTISM
Hormonal Suppression
Antiandrogens
Physical Methods
Oral contraceptives
Spironolactone
Temporary depilation
Cyproterone acetate (not availabl
e in US)
Shaving
Dexamethasone
GnRH agonists
Chemical depilatories
Bromocriptine
Flutamide
Temporary epilation
Ketoconazole
Finasteride
Plucking
Weight reduction
Insulin-sensitizing agents
Metformin
Troglitazone
Surgery
GnRH = gonadotropin-releasing hormone.
Waxing
Permanent hair removal
Electrolysis
Endometrial hyperplasia

Ultrasound examination

Endometrial biopsy

Hysteroscopy

Hormonal therapy
(oral contraceptive pill or progestins)
RCOG Guidelines
(May 2003)
Evidence based guidelines for reduction of long-te
rm PCOS consequences
Guidelines (RCOG, May 2003)


1- Patients presenting with PCOS particularly if they
are obese, should be offered measurement of fastin
g blood glucose and urine analysis for glycosuria. A
bnormal
results should be investigated by a gluc
ose tolerance
test. Such patients are at increased risk of develo
ping type II diabetes (Evidence level IIb[C])
2- Women who have been diagnosed as having PC
OS before pregnancy (those requiring ovulation indu
ction for conception) should be screened for gest
ational diabetes in early pregnancy, with referral to a
specialized obstetric diabetic service if abnormalities
are detected (evidence level IIb[B])
Guidelines (RCOG, May 2003)
3- Measurement of fasting cholesterol, lipids and trig
lycerides should be offered to patients with PCOS, si
nce early detection of abnormal levels might encoura
ge improvement in diet and exercise (Evidence level I
II[C])


4- Olig- and amenorrhoeic women with PCOS may
develop endometrial hyperplasia and later carcinom
a. It is good practice to recommend treatment with
progestogens to induce withdrawal bleed at least ev
ery 3-4 months (Evidence level IIa[B])
Guidelines (RCOG, May 2003)

5- A body of evidence has accumulated demonstrati
ng safety and in some studies efficacy of insulin-se
nsitizing agents in the management of short-term co
mplications of PCOS, particularly anovulation. Longterm use of these agents for avoidance of metabolic
complications of PCOS can not as yet be recommen
ded (Evidence level IV[B])

6- No clear consensus has yet emerged concerned r
egular screening of women with PCOS for later devel
opment of diabetes and dyslipidemia but obese wom
en with a strong family history of cardiac disease or
diabetes should be assessed regularly in a general pr
actice or hospital outpatient setting. Local protocols
should be developed and adapted as new evidence e
merges (Evidence level IV[C])
Guidelines (RCOG, May 2003)

Young women diagnosed with PCOS should be infor
med of the possible long-term risks to health that are
associated with their condition. They should be advis
ed regarding weight and exercise (Evidence level III[
C])