Polycystic Ovarian

Syndrome & fertility

Dr sundar narayanan
M.D, DIP LAP, DIP ART, DIP US
INTRODUCTION

• The polycystic ovary syndrome is the most

common metabolic abnormality in young
women today of reproductive age.
• Most common cause of infertility in women
• Studies of PCOS in India reported a prevalence
of 3.7% to 22.5%, upto 36% prevalence in
adolescents
Etiology
• A large number of genomic variants has
been associated with PCOS and many of
these associations have not been replicated in
different populations.
• It is believed that the picture is of a
multigenic etiology in which non-genetic
factors such as diet and exercise have strong
influence on the development of the disorder
PCOS
Syndrome characterized by
• Oligoammenorhoea / amenorrhoea
Laboratory criteria of
• Hyperandrogenemia
• Hyperinsulinemia

• Polycystic ovaries on USG

Diagnostic criteria
• Classic syndrome originally described by
Stein and Levanthal (1935)
• Hyperandrogenism
• Menstrual irregularity
• Polycystic ovaries
• Central adiposity

• Few of these original features are now

considered consistent findings in PCOS
NATIONAL INSTITUTES OF HEALTH AND CHILD
HEALTH AND HUMAN DEVELOPMENT(1990)

• Chronic anovulation
• Hyperandrogenemia
• Clinical signs of hyperandrogenism
• Exclusion of other androgenic disorders
ROTTERDAM CRITERIA (2003)

• 2 out of 3
• Polycystic ovaries (>12 peripheral follicles or
increased ovarian volume >10cm3)
• Oligo- or anovulation
• Clinical and/or biochemical signs of
hyperandrogenism
• And exclusion of other etiologies such as
hypothyroidism, hyperprolactinemia, congenital
adrenal hyperplasia, cushing syndrome, androgen
secreting tumors
AE-PCOS SOCIETY 2006
• Hyperandrogenism-hirsutism and/ or
hyperandrogenemia
• And
• Ovarian dysfunction-oligo-anovulation
and/ or polycystic ovaries
• Exclusion of other androgen excess or
related disorders
pathogenesis
Pituitary –ovarian –Adrenal
Inter action
Abnormal Pituitary Function—
Altered Negative Feedback Loop

• Increased GnRH from hypothalamus

• Excessive LH secretion relative to FSH
by pituitary gland
• Ineffective suppression of the LH pulse
frequency by estradiol and
progesterone
• LH stimulated excessive androgen production
• Intraovarian androgen excess results in
excessive growth of small ovarian follicles
• Inhibition of follicular maturation
• Thecal and stromal hyperplasia
Pathogenesis:
Hyperandrogenism
• Reduced sex-hormone-binding globulin
(SHBG)  more free testosterone
• Insulin insensitivity
• Lipid abnormalities
• Abdominal obesity
• Symptoms of androgen excess
HYPERANDROGENISM

• 50-90% patients have elevated serum

androgen levels
• Causes hirsutism, acne, male pattern
balding, alopecia
• Deepening voice, clitoromegaly
Insulin resistance in PCOS:

• Insulin resistance in PCOS is independent of

obesity
• Increased risk for impaired glucose tolerance and
type 2 DM in PCOS women
• Obese women with PCOS tend to be more insulin
resistant than normal-weight counterparts.
• 30-40% prevalence of glucose intolerance
• 7-10% prevalence of type 2 DM in PCOS women
• Insulin resistance worsens over time
 ETIOLOGY OF INSULIN
RESISTANCE
• Unknown largely.
• Genetic link
• Mutation of the insulin receptor gene in the
peripheral target tissues
• Reduced tyrosine auto phosphorylation of
the insulin receptor.
Pathogenesis: Insulin resistance
• Excess insulin production and insulin
resistance
• Favors anovulation, reduced SHBG, IGF-1
BP and androgen excess
• Metabolic syndrome
• Abdominal obesity
IR influencing Hypothalamic-Pituitary-Ovary Axis

Reference: Understanding polycystic ovary syndrome [Internet]. Available

at: http://www.bpac.org.nz/BPJ/2008/April/polycystic.aspx. Accessed on
May 06,
2016.
 Insulin Resistance:
Associated Conditions
Type 2 diabetes
Atherosclerosis

Hypertension
Dyslipidemia

Impaired Glucose
Insulin Resistance tolerance
Decreased
Fibrinolytic
Activity Obesity (central)

Acanthosis
Nigricans Polycystic ovary
Hyperuricemia disease
Clinical
presentation
Clinical Presentation of Women with PCOS

Obesity

Reference: Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2014;6:1–3.
OBESITY AND INSULIN RESISTANCE
• > 50 % patients with PCOS are obese
• > 80% are hyperinsulinemic and have insulin
resistance
• Hyperinsulinemia contributes to
hyperandrogenism & associated hirsutism
and menstrual irregularities.
• Even 2/3 of lean PCOS (normal BMI) have
excessive body fat and central adiposity
ASSOCIATED MEDICAL
CONDITIONS

• Low HDL and high triglycerides

• Sleep apnea
• Nonalcoholic steatohepatitis
• Metabolic syndrome—43% of PCOS patients
(2 fold higher than age-matched population)
• Elevated CRP and heart disease
• Advanced atherosclerosis
 MENSTRUAL DYSFUNCTION
• Oligo or amenorrhea typically begins in the
peripubertal period
• Reduction in ovulatory events leads to
deficient progesterone secretion
• Chronic estrogen stimulation of the
endometrium with no progesterone
results in intermittent breakthrough
bleeding or DUB
• Increased risk for endometrial hyperplasia
and/or endometrial CA
HIRSUTISM
Hair & sebaceous Follicle Response to
Hyperandrogenism
Acne & baldness
Male Type Hair Growth
Ferriman Gallwey 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
 Chest
 Upper abdomen
 Lower abdomen
 Upper arms
 Thighs

 Score of 6 or above used to define clinical hyperandrogenemia

Modified Ferriman Gallwey score
9 areas
• Score 1-4
• 0-absence of terminal hair
• 4-extensive terminal hair growth

>8 - hirsutism
Modified Ferriman Gallwey score
Acanthosis nigricans
Metabolic Syndrome
• Personal or family history of DM
• Obesity
• Hyperinsulinemia
• Hypertension
• Atherogenic Dyslipidemia
• Atherosclerosis
• Hyperglycemia
• The AACE have already included PCOS as an
important risk factor for diabetes and have
recommended screening for DM by age 30
in all patients with PCOS.
Laboratory
investigations
Hyperandrogenism

 Laboratory features
 Elevated total testosterone
 Most values in PCOS <150 ng/dl (if >200 ng/dl,
consider ovarian or adrenal tumor)
 Free testosterone assays not reliable yet
 Free androgen index > 4.5 (FAI= total testosterone x
100 /SHBG). Considered a better indicator
 DHEA-S
 Most normal or slightly high in PCOS
 If >800 mcg/dl, consider adrenal tumor
 LH/FSH ratio
 Levels vary over menstrual cycle, released in
pulsatile fashion, affected by OCPs
 LH/FSH ratio >2 has little diagnostic sensitivity
and need not be documented
Hyperinsulinemia
• Fasting glucose level of 110-125 mg/dL

• Glucose level of 140-199 mg/dL after

75 gm glucose challenge test

• Stimulated testing with OGTT may be

more sensitive than fasting measurements

• Fasting glucose/insulin ratio (G/I) . A ratio

< 4.5 has in general been shown to be >
90% sensitive
ATP III Clinical Identification
of the Metabolic Syndrome
• Waist circumference:
• Women>88 cm (>35 in)
• Triglycerides >150 mg/dL
• HDL cholesterol:
• Women<50 mg/dL
• Blood pressure 130/ 85 mm Hg
• Fasting glucose >100 mg/dL

Presence of any 2 of 5 criteria

DIFFERENTIAL DIAGNOSIS
1. Hyperprolactinemia/ hypothyroidism
• Prominent menstrual dysfunction
• mild hyperandrogenism

2. Congenital Adrenal Hyperplasia

• morning serum 17-hydroxyprogesterone
concentration greater than 200 ng/dL
in the early follicular phase strongly
suggests the diagnosis
3. Ovarian and adrenal tumors
• serum testosterone concentrations are always
higher than 150 ng/dL
• adrenal tumors: serum DHEA-S concentrations
higher than 800 mcg/dL
• LOW serum LH concentrations

4. Cushing’s syndrome
5. Drugs: danazol; OCPs with high
androgenicity
Polycystic Ovaries - USG

 Criteria by ultrasound
 Increased ovarian area (>5.5 cm2)
or volume (>11 ml) w/ presence of
>12 follicles measuring 2-9 mm in
diameter
 Polycystic ovaries not specific for
PCOS
 > 20% normal women have incidental
polycystic ovaries
 Polycystic VS. Multicystic Ovaries
• Polycystic ovaries • Multicystic ovaries
• Bilateral • Bilateral
• Multiple cysts
• At least 12 follicles
• Cyst diameter usually
• Follicular diameter > 10 mm
2 - 9 mm
• Stroma not
• Stroma increased increased
OVARIAN ABNORMALITIES

• Thickened sclerotic
cortex
• Multiple follicles in
peripheral location
• 80% of women with
PCOS have classic
cysts
laparoscopy

PEARLY WHITE SMOOTH ENLARGED AND THICK WALLED

OVARY ON LAPAROSCOPY
Gross Appearance of Ovaries

• Polycystic ovaries are enlarged and

have a smooth thickened capsule that is
Avascular
• On cut section, subcapsular follicles in various
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
TREATMENT
ADOLESCENT PCOS
• Immediate/Acute issues
• Hirsutism
• obesity
• Regulation of menses
• Long-term issues
• Insulin resistance
• Cardiovascular risk
• Obstructive sleep apnea
• Malignancy risk
Adolescent pcos - management

• Life style modification

• Weight Reduction.
• Diet management.
• Hormone therapy
 Diet and Exercise

• In patients with PCOS who are obese, endocrine-

metabolic parameters markedly improve after 4-12
weeks of dietary restriction.
• Their SHBG levels rise and free testosterone levels fall
by 2-fold.
• Serum insulin and IGF-1 levels also decrease.
• Weight loss in patients with PCOS who are obese is
associated with a reduction of hirsutism and a return
of ovulatory cycles in 30% of women.

Moran LJ, Pasquali R, et all Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome
Society. Fertil Steril. Dec 3 2008;
 Diet and Exercise
• A moderate amount of daily exercise increases of
levels of IGF-1 binding protein and decreases IGF-1
levels by 20%.
• Modest weight loss of 2-5% of total body weight can
help restore ovulatory menstrual periods in obese
patients with PCOS.
• A daily 500-1000 calorie deficit with 150 minutes
of exercise per week can cause ovulation.
• The AE-PCOS recommends lifestyle management as
the primary therapy in overweight and obese women
with PCOS for the treatment of metabolic
complications.
Moran LJ, Pasquali R, et all Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome
Society. Fertil Steril. Dec 3 2008;
Metformin
• Metformin therapy is considered the initial
intervention in most women with PCOS,
particularly in those who are overweight or
obese.
• Metformin improves many metabolic
abnormalities in PCOS and may improve
menstrual cyclicity and the potential for
pregnancy.
 Metformin and
hyperinsulinemia
• This anti-diabetic drug improves insulin resistance
and decreases hyperinsulinemia in patients with
PCOS.

• Metformin also has a beneficial effect on metabolic

syndrome.

• Decreases hepatic glucose production

• Increases peripheral glucose uptake and utilization

• Antilipolytic effect—reduces fatty acid concentrations

and reduces gluconeogenesis

Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. Oct 25 2003;327(7421):951-
3. [Medline].
Metformin and Anovulation

• Patients have a high likelihood of having ovulatory

cycles while taking metformin.
• will restore ovulation and menses in > 50% of
patients
• In addition, pretreatment with metformin has
been shown to enhance the efficacy of clomiphene
for inducing ovulation.
• N-acetylcysteine may also enhance the effect
METFORMIN DOSING
• The usual starting dose is 500 mg given
orally twice a day.
• Target—1500-1800 mg per day
• Clinically significant responses not regularly
observed at doses less than 1000 mg per
day
• Sustained release formulations taken after
dinner have fewer side-effects.
 Adverse effects
• Diarrhea, nausea, vomiting, flatulence,
indigestion, abdominal discomfort
• Caused by lactic acid in the bowel wall
• Minimized by slow increase in dosage

• Lactic acidosis—rare
• Avoid in CHF, renal insufficiency, sepsis
• Discontinue for procedures using contrast (HSG)
• Temporarily suspend for all surgical procedures
that involve fluid restriction
Oligomenorrhea
• Combination estrogen-progestin pill first line
when fertility is not desired
• Decrease in LH secretion and decrease in androgen
production
• Increase in hepatic production of sex-hormone
binding globulin
• Decreased bioavailablity of testosterone
• Decreased adrenal androgen secretion
• Regular withdrawal bleeds
• Prevention of endometrial hyperplasia
Hormone therapy for Adolescent Patients
• Combined OCPs containing estrogen and
Progesterone given cyclically help in controlling
menstrual problem , hirsutism and acne
• Periodic progesterone withdrawal
• Medroxyprogesterone 10 mg/day x 7-10
days
• Anti androgens
• Mechanical hair removal
Plucking/shaving/electrolysis/laser
Pharmacological Profile of natural
progesterone and synthetic progestrogens
Drug Progestrongic Anti Antimineralo
activity androgenic corticoid Glucocorticoid
activity activity activity
Progesterone
(Natural) + ( +) + -
Drosperinone + + + -

Cyproterone + + - ( + )
Acetate
Desogestrel + - - -

Dienogest + + - -

Gestodene + - ( +) -

Levonorgestrel + - - -

Norgestimate + - - -

+ Effct (+) negligible - No effct

Long-Term Issues

• Cardiovascular Risk
• Increased prevalence of HTN
• Dyslipidemia (↑ TG, ↓ HDL, ↑ LDL)
• Predisposition to macrovascular disease and
thrombosis
• Multidisciplinary management
Long-Term Issues

• Obstructive Sleep Apnea

• 30-fold increased risk of OSA, not
explained by obesity alone.
• Insulin resistance strongest predictor
of OSA (not BMI, age, testosterone)
• Consider polysomnography if at risk
Long-Term Issues
• Risk for malignancy
• 3 fold increased risk endometrial
carcinoma in PCOS
• Increased risk of ovarian and breast
cancer
• Warrants regular screening
MESSAGE TO THE YOUNG GIRLS
Young girls should be advised to adopt healthy life
style in the form of balanced diet having locally
available food articles like all cereals, pulses, green
leafy vegetables, seasonal fruits, fish, jaggery and
dairy products in appropriate amount.

They should avoid soft drinks, chocolates and junk

food.

They should be advised to play out door games and

do regular physical exercises like cycling, skipping,
jogging, swimming etc.

This will go long way to prepare a girl to let her

develop as a perfect adolescent with minimal
menstrual dysfunction..
Infertility in pcos
 PCOS & INFERTILITY

Approx. 85–90% of women with

oligomenorrhea have PCOS
>80% of women having
symptoms of androgen
excess present with PCOS 30–40% of women with
amenorrhea will have PCOS

Hirsutism occurs in up to
70% of women with PCOS PCOS Approx. 15–30% of adult women
having PCOS manifest acne

Infertility is seen in 40% of Approx. 90–95% of anovulatory women

women with PCOS reporting to infertility clinics have PCOS

Spontaneous abortion is seen more

frequently in PCOS with incidences
ranging from 42–73%

Reference: Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome.Clin Epidemiol. 2014;6:1–3.
 PCOS and infertility
Ovulation
Poor Oocyte
Quality

Fertilization
Endometrial
Abnormality

Implantation
Effects
Hyperinsulinemia

Fetal Viability
?Effects gestational
Diabetes and
hypertension
Healthy Live born

Ref : Hum Reprod 2004: 19

Treatment modalities

• Lifestyle Modifications
• Insulin Sensitizing Agents
• Clomiphene Citrate
• Gonadotrophins
• Laparoscopic Ovarian Drilling
• Ovulation Induction and IUI
• IVF
Consensus on infertility treatment
related to PCOS
R
E
S
FIRST LINE
I
S
CLOMIPHENE CITRATE
T
A
N F
C A
E
I
SECOND LINE L
R LOD/GONADOTROPINS U
E R
S
I
E
S
T
A
N
C THIRD LINE
E
IVF

The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group March

2–3, 2007, Thessaloniki, Greece. Human Reproduction 2008
INFERTILITY TREATMENT
• Clomid
• 50 mg from cycle days 2-6 for 3 months
• Incremental 50 mg every 3 months up to 150 mg.
• Most women with PCOS do not respond to normal
dose—20% ovulation rate!
• Clomid: 80% will ovulate, 50% will conceive
• Combined metformin+clomiphene better conception
rate compared to clomiphene alone
• FSH injections
Letrozole

• Release the pituitary/hypothalamic axis from

the estrogenic negative feedback, increase Gnt
secretion, stimulate ovarian follicle development

• Locally in the ovary: increase the follicular

sensitivity to FSH

• Letrozole associated with fewer birth defects

than clomiphene but this is not statistically
significant.

Tulandi T. Fertil Steril 85:1761, 2006

Gonadotrophins
Chronic low-dose regimen
• Starting dose: 37.5 IU
• Duration of starting dose:14 d
• The weekly dose increment of 37.5 IU till
ovulation followed by IUI.
Overall ovulation induction (CC/ CC+
GN/chronic low dose regimen) with IUI
results in singleton live birth with marked
reduction of OHSS
Adjuvants
Surgical Management

• Should be used only as a method of induction of ovulation

not for treatment of PCOS symptoms.

• Laparoscopic drilling using electrocautery or laser is

universally accepted procedure now, aimed with the goal
of creating focal areas of damage in the ovarian cortex
and stroma.

• LOD is usually effective in 50% of women and additional

ovulation induction may be required.

• Potential complications include formation of

adhesions & long-term effects of tissue damage
on ovarian function.
Surgical induction of ovulation
Wedge resection LOD
by LT
Publications 18 11

Patients 1766 729

Ovulation 74.6 84.2

Pregnancy 58.8 55.7
Adhesions Moderate to Minimal to mild
severe
From Urman and Yakin JRM 2006
IVF
• Failure to conceive on Gonodotrophin therapy
alone/ IUI after 6 ovulatory cycles (Araki, 2011)

• Associated male factor or tubal factor infertility

• Failure of wt reduction, antiestrogen therapy or

LOD in long standing infertility & advanced age,
Gnt may be omitted and replaced by ovarian
stimulation and IVF (Eijkemans et al., 2005)

• High response to FSH despite low dose to

prevent OHSS and to eliminate the chances of
multiple pregnancy
Challenges of treating infertility
with IVF in the PCOS patient
• Propensity for an exaggerated ovarian response
• Difficulties in titrating gonadotropin dose
• Increased risk of cycle cancellation
• Increased incidence of early and late OHSS
• Increased risk of spontaneous pregnancy loss
PreIVF considerations
• Weight loss in overweight women
• Metformin
• LOD
• All these above measures increase IVF
outcome and reduces incidence of OHSS.
Cycle management in the PCOS
patient
• Antagonist protocol preferred
• Careful titration of the gonadotropin dose
• Measures to prevent OHSS
• GnRHa for triggering final oocyte maturation
• Single Blast transfer
• Cryopreservation of all embryos (segmentation of IVF)
• Cabergoline
Conclusions
• PCOS patient is the most difficult to treat
with IVF
• Cycle cancellation rates and risk of OHSS
are higher
• Fine tailoring of ovarian stimulation is
necessary to avoid complications
• Treating physicians should be well aware of
the difficulties and remedies/solutions
Recommendations

ACOG 2009
The following recommendations and conclusions are based
on good and consistent scientific evidence (Level A):

• An increase in exercise combined with dietary change

has consistently been shown to reduce diabetes risk
comparable to or better than medication.

• Improving insulin sensitivity with insulin-sensitizing

agents is associated with a decrease in circulating
androgen levels, improved ovulation rate, and
improved glucose tolerance.

• The recommended first-line treatment for ovulation

induction remains the antiestrogen clomiphene
citrate.
The following recommendations and conclusions are based
on limited and inconsistent scientific evidence (Level B):

• Women with a diagnosis of polycystic ovary syndrome

(PCOS) should be screened for impaired glucose tolerance
with a fasting glucose level followed by a 2-hour glucose
level after a 75-g glucose load.

• Women with PCOS should be screened for cardiovascular

risk by determination of BMI, fasting lipid and
lipoprotein levels, and metabolic syndrome risk factors.

• There may be an increase in pregnancy rates by adding

clomiphene to metformin, particularly in obese women
with PCOS.

• If clomiphene citrate use fails to result in pregnancy, the

recommended second-line intervention is either
exogenous gonadotropins or laparoscopic ovarian surgery.
The following recommendations and conclusions are based
primarily on consensus and expert opinion (Level C):

• Combination low-dose hormonal contraceptives are

most frequently used for long-term management
though no evidence favors the same.

• A chronic low-dose step up gonadotropin regimen is

still recommended in women with PCOS though better
protocols are available now a days.

• There is no clear primary treatment for hirsutism

in PCOS though anti androgens and or laser may be
helpful.
Conclusions
• The comprehensive management of PCOS
requires:
• A patient-centered approach
• Significant time dedicated to thorough education and
counseling
• Prudent use of referrals and local resources to tackle
metabolic syndrome.
• Remaining up-to-date on newest advances in the
literature.
• Improvement in health of the PCOS woman in
pregnancy could help “prevent” disease in the next
generation
Thank you