POLYCYSTIC OVARIAN

SYNDROME

Wg Cdr G S Sandhu
 PCOS
Criteria
Aetiogenesis
Consequences
Presentation
Evaluation
Treatment
 PCOS
Syndrome : Cluster of abnormalities
Complex heterogeneous endocrine
disorder
It encompasses a spectrum of conditions
rather than a single discrete disease
Affects 5 -10% women in the reproductive
age group
 Revised 2003 consensus on
diagnostic criteria related to PCOS
 Polycystic ovarian syndrome
A syndrome of
Ovarian dysfunction
Hyperandrogenism
Polcystic ovarian morphology
Common associations
Hyperinsulinemia
Elevated LH levels
 Requisites for ovulation
Functional Hypothalamic Pituitary axis
Feedback signals
Negative
Positive
Local Paracrine / Autocrine intra-ovarian
responses
Coordination / Synchronization of the
above
Ovulatory cycle
 Chronic anovulation
6 or less ovulatory cycles in 12 months

Up to 25% of women with PCOS may

have regular cycles
 Hyperandrogenism vs
Hyperandrogenemia
Hyperandrogenism is the clinical
manifestation of hyperandrogenemia

Hyperandrogenism can exist in absence of

hyperandrogenemia (enhanced tissue
sensitivity to androgens)

Hyperandrogenemia may not always be

associated with Hyperandrogenism
 PCOS : Hirsutism
Differences in end organ sensitivities can
prevent physical manifestations of
Hyperandrogenism in some women

Because of variations in end organ

sensitivities some obviously hirsute
women may not have detectable
Hyperandrogenemia
 Hyperandrogenism
Hirsutism
Patient perception of hirsutism depends upon
Personal, cultural, ethnic factors
Target tissue sensitivity

Acne
 Virilization
Clitoromegaly
Voice changes
muscle mass
Frontal crown baldness
 Ferriman Gallway score
Extent of terminal (coarse pigmented) hair growth at each
of the following 11 hormonally sensitive sites
Upper lip
Sideburn area
Chin
Jaw & Neck
Upper back
Lower back
Upper arms
Thighs
Chest
Upper abdomen
Lower abdomen
Score of 6 or above used to define clinical
hyperandrogenemia
 PCOS : Hyperandrogenism
Ovaries are the primary source of
androgens
Disturbances in Gonadotrophin secretion
and Hyperinsulinemia contribute to
Hyperandrogenism
Testosterone levels > 60 ng / dl abnormal
DHEAS levels > 700gm / dl abnormal
 PCOS : Role of Adrenals
Dynamic testing with ACTH suggests that
50 60% of women with PCOS
demonstrate exaggerated release of
Androstenedione or DHEA
Adrenals may contribute to the
Hyperandrogenism in PCOS
 Ultrasonic Criteria of PCO
At least one of the following
12 or more follicles measuring 29 mm in diameter
increased ovarian volume (>10 cm 3).
If there is a follicle >10 mm in diameter, the
scan should be repeated at a time of ovarian
quiescence in order to calculate volume
The presence of a single PCO is sufficient for
diagnosis
The distribution of follicles and a description of
the stroma (volume & echogenicity) are not
required for diagnosis
 Polycystic VS. Multicystic Ovaries
Polycystic ovaries Multicystic ovaries
Bilateral Bilateral
At least 12 follicles Multiple cysts
Follicular diameter Cyst diameter usually
2 - 9 mm > 10 mm
Stroma increased Stroma not increased

Polyfollicular syndrome may be a more

appropriate terminology
 Pitfalls Rotterdam Definition

Doubts regarding borderline groups of

patients (hirsute oligo-ovulatory / ovulatory
normoandrogenic women)
Neglects role of Insulin Resistance
 Etiology

Speculation
Complex interaction of genetic, hormonal and
environmental factors
Linkages among the abnormal parameters
may be self perpetuating
Initiating event?
 PCOS : Genetic factors
Pattern of inheritance suggestive of
autosomal dominant with limited penetrance

Male relatives may show Hyperandrogenism

(early balding) and Glucose intolerance
 Etiology

Primary Hypothalamic pituitary

dysfunction?
GnRH pulse generator abnormalities
may lead to Gonadotrophin
abnormalities
Possible mediatory role of ghrelin in
abnormal gonadotrophin secretion
(gastric peptide which is orexigenic and
adipogenic)
 PCOS : Gonadotrophin
abnormalities
There is LH pulse frequency and pulse
amplitude
FSH levels are generally in the normal
range but lack the normal cycle variation
Net result is elevated levels of LH and
relative deficiency of FSH
Abnormal LH / FSH levels seen in upto
95% patients with PCOS
 Etiology
Central role of Hyperinsulinemia
(Insulin resistance in PCOS upto 50%
both in obese and non-obese women)
 Insulin signaling cascade
Binding of insulin to its receptor on the cell
surface
Auto-phosphorylation of tyrosine residues on
the intra-cytoplasmic portion of the receptor
Activation of Insulin Receptor substrates
(IRSs) which act as intermediate activators for
insulin induced Glucose and amino acid
uptake, glycogenesis, lipogenesis and
mitogenic action
Insulin signaling cascade : Glucose
uptake
Phosphorylation of second messenger
(phospho inositide 3 kinase / PI-3
kinase)
Release of GLUT 4 from intracytoplasmic
vesicles
Transport of Glucose into the cell
Primary targets for insulin stimulated
glucose uptake : Muscle cells
Secondary targets : Adipocytes
 Insulin resistance
A biologic response to insulin less than
normal
Decreased insulin mediated glucose
utilization
 How Insulin Resistance Can Be
Assessed ??
Oral GTT
Fasting plasma glucose to fasting insulin
ratio < 4.5
( Hyperinsulinemic euglycemic profile)
Hyperinsulinemic Euglycemic clamp
technique
Fixed dose insulin infusion
Fixed euglycemic target level
Glucose infusion in titrating doses to maintain
target glycemic levels
 Insulin resistance states
Syndrome X / Metabolic syndrome
Insulin resistance, Hypertension, Dyslipidemia
(low HDL), Obesity
HAIR-AN (Hyperandrogenism, Insulin
resistance, Acanthosis nigricans*)
* Hyperpigmented velvety areas in the inter-
triginous areas)
 Insulin resistance
Type A syndrome
Due to genetic mutations of the insulin
receptor
Type B syndrome
Due to antibodies directed against the insulin
receptor
Due to post receptor signaling defects
 PCOS : Insulin resistance -
Hyperandrogenism pathogenesis

While PCOS is associated with Insulin

resistance & Hyperinsulinemia, the ovary
itself is not insulin resistant
 PCOS : Insulin resistance -
Hyperandrogenism pathogenesis
Post receptor defect in signal transduction
Serine phosphorylation instead of tyrosine
phosphorylation
Impaired activation of second messenger and
release of GLUT4. Therefore defective glucose
transport into cell
activity of P450c17 enzymes (17 hydroxylase,
17,20 lyase) therefore androgen synthesis
 PCOS : Hyperinsulinemia
Hyperinsulinemia contributes to
Hyperandrogenemia
Direct stimulation of ovarian thecal cell androgen
production through its own and IGF-1 receptors
Suppression of SHBG synthesis
Sensitizing gonadotrophes to action of GnRH
thereby LH levels
Inhibition of hepatic production of IGFBP-1,
resulting in locally ovarian IGF-1 which amplifies
LH action on thecal cells
Prevalence of IGT and NIDDM is greatly
increased in women with PCOS
 PCOS : Hyperinsulinemia
Increased intra-ovarian androgens
Elevated systemic androgens
Altered gonadotrophin levels
 Role of obesity
Obesity aggravates the key biochemical
features of the disease
Adipocytes produce TNF which
Inhibits PPAR mRNA expression
Inhibits insulin action within adipocytes and
muscle cells
Potential consequences of PCOS
 Long term risks in PCOS

Definite
Type 2 Diabetes

Dyslipidemia (Hypercholesterolemia with

diminished HDL and increased LDL)

Endometrial cancer
 Long term risks in PCOS
Possible

Hypertension
Cardiovascular disease
Gestational diabetes mellitus
Pregnancy-induced hypertension
Ovarian cancer
 Diagnosis
Primarily clinical
Early recognition vital
PCOS, starts in adolescence.
But

Unfortunately, not always

diagnosed at that age
 Spectrum of phenotypes

Ovulatory dysfunction present or not

Features of androgen excess present or
not
Obese or non-obese
 Symptomatic PCOS
Increased BMI ( severity of the PCOS)
Any or all of these symptoms may be
present
Irregular menstrual cycles
Weight gain
Abnormal hair growth on the face or
the body
Infertility
 Insulin Resistance
Phenotype : PCOS
Usually Obese

Acanthosis Nigricans

Hirsutism

May exhibit resistance to CC

 PCOS Without Insulin
Resistance

May be Non obese

Euinsulinemic/ Euglycemic
Enhanced Ovarian Sensitivity to insulin
(although no Hyperinsulinemia)
 Hyperthecosis
Hyperthecosis is a pathologic diagnosis
Luteinized theca cells are found in the
ovarian stroma distant from follicles
It represents a more severe form of PCOS
 Evaluation of PCOS patients

Body weight
Body Mass Index (BMI)
Waist Hip Ratio (WHR)
Blood pressure
Cutaneous markers of Insulin resistance
Lipid profile
Fasting blood glucose /Fasting insulin levels
Oral GTT
 LH / FSH ratio in PCOS
It is an insensitive indicator of PCOS
Normal variations during the menstrual cycle
Differences between Bioactivity and
Immunoactivity
Sporadic ovulation may normalize LH levels
for a few weeks
Overlap with normal values
Lack of agreement over what constitutes an
abnormal ratio (2, 2.5, 3)
Abnormally elevated levels of LH seen in
approx 60% of patients with PCOS
 LH / FSH ratio in PCOS
High LH / FSH ratios more likely in non
obese
Low LH / FSH ratio may suggest
Hyperthecosis and low likelihood of
response to Clomiphene
Unexpectedly high FSH values suggest
diminished ovarian reserve
High LH levels could have detrimental
effect on oocyte maturity & fertilization,
though some workers have questioned this
 PCOS : USG exam
Criteria
At least 12 follicles per ovary ranging between 2
9 mm in diameter
Ovarian volume > 10 ml
Findings even in one ovary define the syndrome
Not part of criteria
Distribution of follicles / Pearl necklace
configuration
Increased ovarian stromal volume or echogenicity
Stromal Hyperplasia
Ratio of Mean stromal area / Total ovarian area
> 0.4
Use of OC pills may modify PCO morphology
 PCOS : USG exam
14% of women with clinical / biochemical
features of PCOS may not have
characteristic USG findings
22% of normal women may have some
USG features suggestive of PCOS
PCOS : Role of endometrial biopsy
To rule out endometrial Hyperplasia
Laparoscopic features of PCOS
 Exclusion of other disorders
Androgen producing tumors of the ovary
Late onset Congenital Adrenal hyperplasia
Adrenal tumors
Hypothyroidism
Hyperprolactinemia
Cushings syndrome
Exogenous androgen use
hCG producing tumors outside the reproductive
tract
PCOS : Other hormonal assays
DHEAS < 700ugm /dl rules out Adrenal
tumors
Total testosterone < 200 ng/dl rules out
Ovarian tumors
8 am 17 OH Progesterone < 200 ng / dl
rules out Congenital Adrenal Hyperplasia
8 am Plasma cortisol < 5gm /dl after
overnight Dexamethasone (1mg)
suppression rules out Cushings syndrome
Targets for treatment PCOS
 Treatment Goals
Traditional Targets
Infertility
Menstrual irregularities
Androgenic cosmetic manifestations
Unopposed estrogen action
New Goals
Insulin resistance
Metabolic dysfunction
 Potential strategies for prevention /
treatment of metabolic derangements
in PCOS
Weight reduction and exercise
Screening for and treatment of
conventional vascular risk factors
Glucose intolerance and diabetes mellitus
Hyperlipidaemia
Hypertension
Primary treatment of insulin resistance
Metformin
Thiazolidenediones
 Life- style modifications
(Improve Insulin Resistance)
Diet modification
Weight loss
Exercise
Psychosocial support

Pharmacologic interventions
 The ACOG notes that interventions to
improve insulin sensitivity, such as weight
loss and the use of insulin-sensitizing
agents, are beneficial in improving the
frequency of ovulation in women with
PCOS
 Role of exercise
Activation of 5 AMP kinase in cells by
exercise
Release of GLUT 4 from intracytoplasmic
vesicles
Transport of Glucose into the cell
 Metformin
Action
Inhibits Glycogenolysis & Gluconeogenesis
Improves peripheral insulin sensitivity by
enhancement of insulin stimulated glucose
transport
Increases non oxidative Glucose metabolism
Poor response
Extreme obesity
Suboptimal doses (< 1000 mg/day)
 Metformin
Advantages
Long term administration (> 12 mths)
increases HDL levels
Decreased risk of ovarian hyperstimulation
during ovulation induction with
Gonadotrophins
 Thiazolidenediones
Action
Activation of Gamma Peroxisome Proliferation
Activator receptor (PPAR )
Activation of genes that encode for insulin
action
Increased GLUT 4 synthesis within target
cells
Improved peripheral Glucose uptake
Decreased Hyperinsulinemia
 Thiazolidenediones
Reduction in release of FFAs and TNF
from adipose tissue
No direct effect on Lipid profile
improvement
Dose dependent weight gain has been
observed
Adipogenesis / fluid retention
Reduction in Waist Hip ratio (signifying shift
from visceral to peripheral distribution of fat)
 D Chiro Inositol
D Chiro inositol is a synthetic sugar which gets
incorporated into cell membrane phospholipid
Inositol phosphoglycan
Hydrolysis of inositol phoshoglycan provides
substrates for the formation of intracellular insulin
signal transduction mediators
Phospho inositide-3 kinase is the second
messenger for insulin action
It is essential for the release of GLUT 4 from
intracytoplasmic vesicles
Used in a dosage of 1200 mg / day
 Ovulation induction
For women desiring fertility
Clomiphene + Insulin sensitizers (Metformin)
recommended
80 percent ovulate and one half of these patients
conceive
Gonadotrophins for clomiphene resistance /
failure
ACOG recommends low-dose, rather than high-
dose, gonadotropin therapy
Concerns about Multi-follicular development
& OHSS
 Combined OC pills
For cycle control and prevention of
Endometrial carcinoma

Hirsutism
The combination of an antiandrogen and an
ovarian suppression agent appears to be
effective in women with PCOS, although the
best oral contraceptive pill or antiandrogen
agent is not known (recommendations based
primarily on consensus and expert opinion)
Cyproterone containing pills preferred
(Personal)
Combined OC pills : Mechanism of
action
Decreased gonadotrophin stimulation of
ovary
Decreased ovarian androgen production
Increased SHBG levels
Decreased androgen receptor binding

Caution : Effects on Insulin resistance

Medroxy Progesterone Acetate
The ACOG notes that the optimal
progestin and the optimal duration and
frequency of treatment to prevent
endometrial cancer in women with PCOS
is not known.
 GnRH agonists
For severe ovarian Hyperandrogenism
Role in infertility management
Long protocols
Prevention of premature LH surge
Reduction of OHSS
 Gn RH antagonists
In Stimulation protocols
To decrease LH secretion and normalize
LH / FSH ratios
Reduced incidence of premature LH
action and oocyte abnormalities
Reduced incidence of OHSS
 Laparoscopic ovarian drilling

ACOG indicates that the benefit and role

of surgery (laparoscopic ovarian drilling by
laser or diathermy) are undetermined in
women who have PCOS
Thank you