PCOS

Williams Gyn.
August 2013
Samuel Bezabih

PCOS
No universally accepted definition
Many expert dxtic criteria are avilable

PCOS- Dxtic criteria

NIH (1990) def - both of the following (+_ Polycystic
ovaries) are required
I.
II.

Hyperandrogenism/Hyperandrogenimia
Oligo/Anovoulation(oligomenorrhoea/ Amenorhoea

ESHRE/ASRM Definition( Roterdam 2003) replaced the NIH

2 or more of the following are required
I.
II.

III.

Oligo/Anovoulation (oligomenorrhoea/ Amenorhoea)

Hyperandrogenism (clinical Hirsutism , acne and/or biochemical
serum hormone level)
Polycystic Ovaries on US ( >12, 2-9mmD or/and increased ovarian
volume,>10ml)

Androgen Excess society 2006

Hyperandrogenism Plus one of the following
Oligomenorhoea/Amenorhoea
Polycystic Ovaries by US

NB: Other disorders should be excluded before dxing PCOS Eg Late

onset CAH, Hyperprolactinemia,Androgen secreting neoplasms)

PCOS Incdence and P- ACOG 2009

Incidence
~7% of reproductive age women with
hyperandrogenic chronic anovulation (Acc to NIH
criteria)
Prevalence of PCOS in normogonadotropic
anovulatory woman according to :
Roterdam- 91%
NIH- 55%
AES in b/n the above

Roterdam criteria- broader, criticized for ing

prevalence of PCOS by including more mild
phenotypes

PCOS
The most common endocrine disorder of
reproductive-aged women
Incidence~ 4 to 12%

One of the most frequent causes of infertility in

couples
The most common cause (80-85%) of androgen
excess in women

Etiology
the underlying cause of PCOS is unknown.
However, a genetic basis that is both
multifactorial and polygenic is suspected, as
there is a well-documented aggregation of the
syndrome within families

Etiology of PCOS
Candidate genes in PCOS:
Steroid biosynthesis and action
(CYP17, CYP11A, AR-androgen receptor, SHBG,
CYP21)
Gonadotrophic action and regulation
(Follistatin, LH -subunit, FSH -subunit, FSH
receptor)
Insulin secretion and metabolism
(Insulin receptor, IRS1, IRS2, PPARG, IGF2)
Cardiovascular disease (PAI-1, IL6, Adiponectin)

Consequences of Polycystic Ovarian Syndrome

Short-term consequences
1.
2.
3.
4.
5.
6.

Irregular menses
Hirsutism/acne/androgenic alopecia
Infertility
Obesity
Metabolic disturbances
Abnormal lipid levels/glucose intolerance

Long-term consequences
1. Diabetes mellitus
2. Cardiovascular disease
3. Endometrial cancer

Pathophysiology
Altered GnRH pusatility (?Hypothalamic vs 20)
more LH secretion than FSH
50% PCOS- elevated serum LH
60% LH:FSH > 2

Affected ovaries secrete elevated levels of

androgens (testosterone and androstenedione).
Specifically,
elevated free T levels in 70 to 80% of women with
PCOS,
elevated levels of DHEAS in 25 to 65%

Pathogenesis of PCOS (2)

Liver

Ovary

LH

Insuline, IGF

+
SHBG
free-Testost.

+
+

2%

95%
T-SHBG
normal

free-Testost.

20%

80%
T-SHBG
in PCOS

2Follicle
cell theory bild?
Theca
cells

Granulosa cells

Aromatization

Diffusion of
Testosterone

Excess
Testosterone
binds to SHBG

Estradiol

T-SHBG

Functionalhyperandrogenemia
Inhibition of
follicle growth
Low estradiol
with poor -ve
feed back
LH high

Pathophysiology
Elevated androgen level may result from
High LH and low FSH level (LH: FSH)
stimulation of Theca Cells by LH , androgen synthesis in
the face of low granulasa cell aromatase activity
Decreased androgen conversion to E increased
intrafollicular androgen ( and serum level too)

Hyperinsulinemia 20 to insulin resistance

suppression of liver production of SHBG by insulin
increased circulating free androgens

Adrenal secretion

Patophysiology
Effects of ed androgen level ( IF and serum)
ed intrafollicular androgen
follicular atresia

ed circulating androgens
Dyslipidemia, Acne, Hirsuitism , Alopecia
Suppression of SHBG synthesis (ed free androgens )
ed peripheral conversion of androstenidione to
Estrone (E2)??E1??
chronic unopposed exposure of endometrium to
Estrogen E. hyperplasia , Eca
Chronic ve feedback on pitutary and
hypothalamusAnovulation

Pathophysiology-IR
Positive correlation between insulin resistance (IR) and
hyperandrogenism
Women with PCOS display greater degrees of IR and
compensatory hyperinsulinemia than non affected
women
Icreased rate of IR in both lean and obese women with
PCOS, compared with weight matched unaffected
controls
-cell dysfunction that is independent of obesity reported
in PCOS

The mechanism of this decreased insulin sensitivity

appears to be due to a post binding abnormality in
insulin receptor-mediated signal transduction

Insulin Resistance
IR hyperinsulinemia , Effects of insulin
Suppression of SHBG production of liver
Stimulation of Androgen production by theca cell
Stimulation of LH-secretion
Acanthosis nigricans
Contribution to follicular atresia

IR is associated with high risk of

Type ll DM,
hypertension,
dyslipidemia and
CV diseases

Insulin sensitivity in obese and Non-obese, normal (NL) and

affected(PCOS) women

Impaired Glucose Tolerance and Type 2 DM

women with PCOS are at increased risk for IGT and

type 2 DM.
Based on OGT , the prevalence of IGT and DM is
approximately 30% and 7 %, respectively .
Similar findings were reported in a group of obese
adolescents with PCOS (Palmert, 2002).
Over time, IGT in PCOs worsens , with a reported
conversion rate of about 2% per year to type 2 DM
In addition, -cell dysfunction that is independent
of obesity has been reported in patients with PCOS

Sex Hormone-Binding Globulin

Glycoprotein, produced in the liver, binds most sex
steroids.
Only~1% of sex steroids are unbound and thus free and
bioavailable.
The synthesis of SHBG is suppressed by Insulin as well
as Androgens, Corticoids, Progestins, and growth
hormone (Estrogen and thyroxine stimulate SHBG synthesis )
Suppressed SHBG liver production free androgen to
bind with end-organ receptors

Women with PCOS display decreased levels of SHBG.

Clinical hyperandrogenism in the face of normal total
serum T level ( because of Elevated free T levels)

Dyslipidemia
The classic atherogenic lipoprotein profile seen in
PCOS is characterized by
Elevated LDL& TG
Depressed HDL levels ,
Elevated total cholesterol:HDL ratios

These changes may increase the risk of CV

disease in women with PCOS independent of
total cholesterol levels.
Following criteria of the National Cholesterol
Education Program, the prevalence of
dyslipidemia in PCOS approaches 70%

Ovarian Hyperthecosis
Ovarian Hyperthecosis
is a rare condition characterized by nests of
luteinized theca cells distributed throughout the
ovarian stroma with increased production of
testosterone
Often Hx of gradual onset of hirsutism and frank
virilization
Affected women exhibit severe hyperandrogenism,
and may occasionally display frank virilization signs
such as clitoromegaly, temporal balding, and
deepening of the voice

It is still unclear if hyperthecosis is a distinct

disorder or is part of the spectrum of PCOS

HAIRAN syndromeHyperanderogenic Insulin Resistant Acanthosis Nigricans

Uncommon and consists of
marked Hyperandrogenism,
severe IR and
Acanthosis Nigricans (Barbieri, 1994).

Etiology -unclear, and

HAIRAN syndrome may represent either a variant
of PCOS or a distinct genetic syndrome.

Metabolic Syndrome
MS is associated with an increased risk of CV
disease and type 2 DM
characterized by:Insulin Resistance,Atherogenic
dyslipedimia,Obesity Hypertension
Dxtic criteria (Adult Treatment Panel III)

BP (> 130/85)
Waist circumference > 35 inches
FBS > 100mg/dl
HDL < 50mg/dl,
TG > 150mg?dl

Prevalence of MS ~45% in women with PCOS

Signs and Symptoms of PCOS

Signs and Symptoms

Various endocrine effectsVarious
complaints
Symptoms classically become apparent within
a few years of puberty
Symptoms may include
menstrual irregularities,
infertility,
manifestations of androgen excess, or
other endocrine dysfunction.

Menstrual Dysfunction
Range from amenorrhoea to oligomenorhoea and
menometroragia with anemia
Effect of unopposed estrogen unpredictable bleeding
Androgens counteract against E endometrial atrophy
and amenorrhoea

women with oligo-ovulation or anovulation typically

have
fewer than eight menses per year,
often skip menses for several months at a time,
or simply have amenorrhea.
Flow may be scanty or very long and heavy, resulting in
anemia.

Menstrual Dysfunction
Menstrual abnormality in PCOS begins at
menarchae
difficult to differentiate from anovulatory cycles
common in postmenarchal girls (50%) due to H-P-O axis
immaturity
Girls with PCOS continue to have M irregularity in the
mid teenage years while the unaffected etstablish
regular ovulatory cycles

Menses may become more regular with age( in 30s

and 40s ) as the no of antral follicle cohort
decrease in androgen production

SS of Hyperandrogenism
Androgen excess symptoms and signs vary b/n
races/ ethnicities
SS HA Typical in PCOS are
Hirsutism
Acne
Androgenic Alopecia

Virillization is uncommon in pcos ( muscle mass,

cliteromegally, frontal balding, voice deepening)

sign of highly elevated androgen levels from androgen

secreting adrenal or ovarian tumors

SS of Hyperandrogenism
Hirsuitism
Terminal hair (Coarse, dark pigmented) in male
like pattern i.e. On androgen sensitive regions
upper lip, chin, chest, thighs, lower abdomen
Distinct from Hypertechosis- generalized increase
in lanugo hairs( soft, lightly pigmented) usually 20
to drugs, malignancy--

PCOS is the commonest cause of hirsuitism (7080% of cases)

Women with PCOS typically report hirsutism
beginning in late adolescence or the early 20s.

SS of Hyperandrogenism-Hirsuitism
5 alpha reductase converts testestorone to DHT in the
hair follicles
Sexual Hair androgen dependent( face, pubic,
chest,back, thigh, breast-----)
Vellus hair (short soft,downy, unpigmented) converted to
terminal hair (coarse, pigmented ) by the action of DHT( to
some extent Testosterone) in the hair follicles
Hirsuitism is a vellus to terminal hair transformation
Irreversible even after androgen withdrawal

DHT has reverse effect on scalp hair ( non sexual)

conversion of TH to VH and balding

SS of Hyperandrogenism-Hirsuitism
IGF 1 stimulate 5 alpha Reductase activity
Anovulatory hyperandrogenic women with IR and
Hyperinsulinemia have ed IGF1 activity
Intensified Hirsuit response
Extent of hirsuitism varies with race or ethnicity (
concentration of hair follicles)
Asians-low HF concentration/unit area less
likely to have overt hirsuitism

Hirsuitism
Ferriman-Gallwey scoring system of hirsuitism

SS of Hyperandrogenism-Acne vulgaris
Acne that is particularly persistent or of late onset
should suggest PCOS
Hyperandogenism overstimulation of androgen receptors in the
pilosebaceous unit increased sebum production that eventually
leads to inflammation and comedone formation

Type 1 5-alpha-reductase in sebacious glands is

implicated ( high DHT production in the glands)
Pathogenesis

blockage of Hair follicle openings by hyperkeratosis

Excessive sebum production
Proliferation of propionibacetrium acne
inflammation

SS of Hyperandrogenism-Alopecia
Female androgenic alopecia is a less common finding in
women with PCOS.
Hair loss progresses slowly and is characterized either by
diffuse thinning at the crown with preservation of the
frontal hairline or by bitemporal recession .
Its pathogenesis involves an excess of 5-alpha-reductase
activity in the hair follicle leading to a rise in DHT levels.
In addition, there is an increased expression of androgen
receptors in these individuals .
Under the influence of androgens, terminal hairs that were not
previously dependent on androgens revert to a vellus form and
balding results

Alopecia, however, may reflect other serious disease. For

this reason, affected women should also be evaluated to
exclude thyroid dysfunction, anemia, or other chronic
illness.

Acanthosis Nigricans
Thickened, gray-brown velvety plaques seen in areas of
flexure such as the back of the neck, the axillae, the crease
beneath the breast, the waist, and the groin .
May be found in individuals with or without PCOS
Thought to be a cutaneous marker of insulin resistance,
IR leads to hyperinsulinemia, which is believed to stimulate
keratinocyte and dermal fibroblast growth, producing the
characteristic skin changes .
Among women with PCOS, AN is more common in obese
women (50 %incidence) than in those with normal weight
(5 -10 %).
Less commonly, it is seen with genetic syndromes or
malignancy of the GI tract, such as adenocarcinoma of the
stomach or pancreas

Obesity
Compared with age-matched controls, women
with PCOS are more likely to be obese, as reflected
by an elevated BMI and Waist:Hip ratio
Pear shaped vs. Apple shaped .
This ratio reflects an android or central pattern of
obesity, which itself is an independent risk factor
for cardiovascular disease
However women with PCOS donot necessarily
present with obesity `
~ 20% of women with PCOS are not obese (ACOG 2009)

Anovulation
Unknown Precise mechanism
Indirect evidences attribute anovulation to the
Large number of antral follicle cohort and IR
resumption of fertility/regular menses after
wedge resection/ laparascopic ovarian drilling and
metformin treatment

Infertility
Infertility or subfertility is a frequent
complaint in women with PCOS
results from anovulatory cycles.
PCOS is the most common cause of infertility
secondary to anovulation 80 to 90 percent
of cases

Pregnancy Complications- Will Gyn 2

nd

Several pregnancy and neonatal complications have been

associated with PCOS.
One large metaanalysis found women with PCOS to have a 23x higher risk of GDM, PIH, preterm birth, and PNM,
unrelated to multifetal gestations (Boomsma, 2006).
Metformin has been studied as a tool to mitigate these
complications.
However, investigators in one study found that metformin
treatment during pregnancy did not reduce rates of these
complications (Vanky, 2010).
Many women with PCOS require the use of ovulation
induction medications or in vitro fertilization to conceive.
These practices substantially increase the risk of multifetal
gestations, which are associated with increased rates of
maternal and neonatal complications

DIAGNOSIS

Diagnosis Of PCOS
PCOS is a diagnosis of exclusion
other disorders that have clinical appearance
similar to PCOS need to be routinely ruled out
DDX

PCOS DDX ACOG 2009

Androgen secreting tumors

Exogenous androgens
Cushng Syndrome
NC CAH
Acromegally
Insulin action genetic defects
10 hypothalamic amenorrhea
10 ovarian failure
Thyroid disease
Prolactin disorders

PCOS DDx
Anovulation/Menstrual dysfunction
Hypo/hyperthyroidism -- or TSH levels
Hyperprolactinemia-- Prolactin level
Hypogonadotropic hypogonadism -- FSH, LH, E2
POF--FSH and LH ,E2
PCOS LH:FSH> 2
LH and FSH levels have little additive value to the diagnosis
of PCOS. Although classically LH levels measure at least
twofold higher than FSH levels, this is not found in all
women with PCOS. Specifically, one third of women with
PCOS have circulating LH levels in the normal range, a
finding more common in obese patients (Arroyo, 1997; Taylor, 1997).
Moreover, serum LH levels are affected by sample timing
within a menstrual cycle, use of oral contraceptive pills,
and body mass index

Hyperandrogenism
Late onset CAH

PCOS DDx

17ydroxyprogesteroneP(>200ng/dl)

Androgen secreting tumors*

Ovarian tumor-- t T(>200ng/dl),
Adrenal tumor-- DHEAS(>200ng/dl)

Exogenous androgens-- A in toxicology screen

Cushings Syndrome
cortisol level (24hr urine cortisol >300micg),DMST

PCOS
Testosterone- usually elevated
DHEAS- may be mildly elevated
LH:FSH ratio typically > 2

*women with an abrupt onset, typically within several months, or sudden worsening of virilizing signs should
prompt concern for a hormone-producing ovarian or adrenal tumor

Patient Evaluation

Clinical Evaluation ACOG 2009

Hx Onset and duration of hperandrogenic SS
Menstrual hx
Medication hx ( exogenous androgens)
Family Hx of DM,CV diseases
PE- BP, BMI,
Waist circumference (fat distribution) >35inches abnormal
Hyperandrogenism stigmata
Hirsuitism,Acne, Androgenic alopecia, clteromegaly

IR signs HTN, Obesity, centripetal fat distribution, Acanthosis nigricans

Workup ACOG 2009

Laboratory
Biochemical Hyperandrogenism
(HA)
Total and Free T, SHBG
Other HyperA causes

TSH
Prolactin
17OH progestrone (CAH)
Cushing S screening

Metabolic abnormalities
OGTT
Fasting lipid and lipoprotein level

US
Polycystic ovaries, Em
abnormalities

Optional tests
LH,FSH (cause of amenorrhea)
Fasting insulin level (young with
severe stigmata of IR, HA or on
Ovuation Induction)
24hr urine free cortisol/ low dose
DST for late onset PCO symptoms
and stigmata suggesting Cushing
Syndrome)

Imaging for Hyperandrogenism

Pelvic sonography is the preferred method to
exclude an ovarian neoplasm in a female with
very high androgen levels.
Alternatively, CT or MRI may also be used in
this setting.
Adrenal imaging with abdominal CT or MRI is
indicated for any patient with DHEAS levels
that exceed 700ng/dl

Sonography
Sonographic criteria for polycystic ovaries from the
2003 Rotterdam conference include > 12 small cysts (2
to 9 mm in diameter) or an increased ovarian volume
(>10 mL) or both
Only one ovary with these findings is sufficient to
define PCOS.
However, criteria do not apply to women taking
combination oral contraceptive pills
Sonography is particularly important for women with
PCOS seeking fertility and in women with signs of
virilization.
TVUS is superior to TABUS
TABUS-preferable for virgin adolescents

Sonography
studies using sonography have shown that at
least 23% of young women have ovaries that
exhibit PCO morphology, yet many of these
women have no other symptoms of PCOS .
In addition, a polycystic appearance of the ovaries
can often be found in other conditions of
androgen excess, such as CAH, Cushing syndrome,
and exogenous use of androgenic medications.
For this reason, PCO morphology found during
sonographic examination is not used solely to
make the diagnosis of PCOS.

IR and Dyslipidemia
a 2-hr GTT is frequently used to exclude
impaired glucose tolerance (IGT) and type 2
DM
a fasting lipid profile is used to evaluate any
signs of dyslipidemia.
Abnormal values
Total cholestrol, HDL < 50 mg/dl
TG > 150 mg/dl
LDL are alculated using Fridewald equation

PCOS TREATMENT

Laser drilling of ovary for surgical treatment of polycystic ovarian disease- Telinde

Treatment
The choice of treatment for each symptom of
PCOS depends on a woman's goals and the
severity of endocrine dysfunction
Observation
women with PCOS who have fairly regular cycle
intervals (8 to 12 menses/ year) and mild
hyperandrogenism may choose not to be treated.
In these women, however, periodic screening for
dyslipidemia and DM is warranted.

Treatment of PCOS-General
Weight Loss- (by obese women) life style/diet modification
Wt loss lowers circulating androgen levels and
improves reproductive and metabolic abnormalities
Improved pregnancy rate, hirsutism, glucose and lipid
profile
Even a modest amount of weight loss (5% of body
weight) can result in restoration of normal ovulatory
cycles in some women.
This improvement results from reductions in insulin
and androgen levels, the latter mediated through
increases in SHBG levels
Effect of wt loss in women with PCOS and normal wt is
unknown

Wt Loss
Phamacologic wt loss agents show improved
ovarian function
Orlistat- intestinal lipid absorption inhibitor
Sibutramine- anorexic agent

Insulin sensitizers
Biguanides and Thiazolidinediones
Lower androgen level
Improve ovulation rate
Improve glucose tolerance

Effects on body wt
Biguanides (Metformin) decrease body wt
TZ increase body wt

Insulin sensitizers:
Metformin (used off label in PCOS)
Low circulating insulin levels increased SHBG level
Decreased androgen levels
Regular cycles
Increased ovulation rate (Cochrane Review, Lord 2003)
Improves hirsutism
Improved results of CC- or FSH-stimulation
Lord 2003

Ovulation
NNT

Placebo

Metformin

Clomiphene
citrate (CC)

Metformin +
CC

26%

46% (OR 3.88)

42%

76% (OR 4.41)

4.4

Insulin sensitizers:
Metformin in pregnancy:
reduces LH and androgen concentration
enhances uterine vascularity (Jakubowicz et al, 2001)
reduces PAI-I and endothelin-I (Palomba et al., 2005; Orio et al.,
2005)

seems to be safe during pregnancy (Glueck et al. 2004)

beneficial effect on gestational diabetes?
decrease rate of early abortions
miscarriage rate in 328 pregnancies with metformin
20% vs. 65% in 319 previous pregnancies without
metformin (Glueck et al., 2002)

Insulin sensitizers
Note: off-label use for metformin in PCOS patients (pregnant and
non-pregnant)!!!

Thiazolidinediones: (troglitazone, rosiglitazone,

pioglitazone)
- enhances glucose uptake in adipocytes and muscle
- promissing results in patients with PCOS
- limited data for rosiglitazone, pioglitazone
- liver toxicity for troglitazone (not available)
Acarbose:
- promising results in patients with insulin resistance
- limited data

Treatment of menstrual dysfunction

COC pills ( alternatively patch or vaginal ring)
1st line rx for menstrual irregularities
Lower androgen level through
Supression of gonadotropin release
ing SHBG level due to the E component

The P component risk of Em hyperplasia

Withdrawal bleeding is induced by progesterone
before initiation of COC

Treatment of menstrual dysfunction

Cyclic Progestins
in patients who are not candidates for COCs ,
progesterone withdrawal is recommended every
1 to 3 months.
Examples of regimens used include:
MPA, 5- 10 mg PO/Day for 12 days, or
micronized progesterone, 200 mg po/evening for 12
days.

Patients should be counseled that intermittent

progestins will not reduce symptoms of acne or
hirsutism nor provide contraception.

Treatment- Hirsuitism

Acne treatment

Infertility Treatment