Polycystic ovarian syndrome – an
update
Dr. Eeson Sinthamoney
MD(Malaysia), MRCOG(London), DFFP(UK)
Fellowship in Reproductive Medicine (Singapore/UK)
Consultant Obstetrician, Gynaecologist and Fertility Specialist
Pantai Hospital Kuala Lumpur
• Is polycystic ovary syndrome (PCOS) an
ancient disorder?
• Or is it a disorder of recent development, the
consequence of rising metabolic stress in an
increasingly obese society?
• And if it is ancient, why has it persisted
despite its reproductive disadvantage?
From the ancient scripts…..
“But those women whose menstruation is less
than three days or is meagre, are robust, with
a healthy complexion and a masculine
appearance, yet they are not concerned about
bearing children nor do they become
pregnant” Diseases of women 1.6 –
Hippocrates (460-377B.C)
An ancient disorder?
• Observations suggest PCOS is an ancient disorder,
arising from ancestral gene variants selected and
maintained over the past 10,000 years
• Such ancient genes likely transmitted transgenerationally through offspring conceived between
fertile carrier males and sub-fertile affected females;
• The reduced fecundity of affected women potentially
would have been offset, at least in part, by their
greater sturdiness and improved energy utilization, a
rearing advantage for their children and kin, and a
reduction in the risk of maternal mortality
Is anything new?
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•
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PCO versus PCOS
Is metformin useful?
Role of ovarian diathermy / drilling
Is weight loss useful?
Fertility treatment and OHSS risk
Revised diagnostic criteria for PCOS
1999 criteria (both 1 and 2)
1. Chronic anovulation
2. Clinical and/or biochemical signs of hyperandrogenism,
and exclusion of other aetiologies
Revised 2003 criteria (2 out of 3)
1. Oligo- and/or anovulation
2. Clinical and/or biochemical signs of hyperandrogenism
3. Polycystic ovaries
and exclusion of other aetiologies (congenital adrenal
hyperplasias, androgen-secreting tumours, Cushing's
syndrome)
PCO ,IR
IGF – 1 and II –
important
regulators of
ovarian follicular
maturation and
steroidogenesis
Prolonged exp. to
androgens causes
foll. suppression
and stromal
hypertrophy
Pathophysiology of PCOS
Insulin interferes with
follicular development
and may affect LH sec
PCO versus PCOS
• Up to 23% of normal volunteer women meet
the sonographic criteria for polycystic ovaries
• Ovarian morphological changes considered a
sign and not a disease
• Diagnosis of disease based on criteria
• However:
Metabolic similarities including degree of IR
Significantly increased risk of OHSS in IVF
Insulin resistance
• Although not included in diagnostic criteria, IR is
regarded as a major / pivotal pathophysiological
feature
• 40-70% of women with PCOS have IR
• Defined as reduced glucose response to a given
amount of insulin
• Common in obese and non-obese PCOS
• Obese PCOS more IR than non-obese PCOS
• Indications that IR in PCOS independent of
obesity
Measuring IR
• No standard definition and assessment
• A unique defect in insulin action and secretion
• Possible mechanisms:
Peripheral target tissue resistance
Decreased hepatic clearance
Increased pancreatic sensitivity
The pathophysiology of polycystic ovary syndrome. Tsilchorozidou T et al. Clinical Endocrinology
(2004)60,1-17
Metformin
• Does metformin (or other insulin sensitizing
agents) improve
clinical features – hirsuitism and acne?
reproductive outcomes – OI, ART?
• Does metformin help with weight loss?
Metformin
Reduces
hepatic
glucose
production
Inhibits
intestinal
glucose
absorption
Increases
peripheral
glucose
uptake by the
liver, skeletal
muscle and
adipose
tissue
Improves insulin
sensitivity
Stimulates
glycolysis in
liver
Reduces
lipolysis in
adipose
tissue
Metformin
• Menstrual irregularity: Improves menstrual
cyclicity in normal weight and over-weight
PCOS patients
• Hirsuitism: metformin improves hirsuitism in
normal weight PCOS patients
In obese patients – long term (2 years)
therapy may be helpful
Hirsutism and acne in polycystic ovary syndrome. Archer JS et al. Best practice and research
clinical obstetrics and gynaecology 18(5) 2004
Metformin in ovulation induction
• Metformin is beneficial in improving clinical
pregnancy rates and ovulation rates
• No evidence it improves live birth rates (either
alone, in comparison or combination with CC)
Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for
women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Tang T et al.
Cochrane Database Syst Rev. 2010 Jan 20;(1):CD003053.
Metformin in ART
• In Non-obese PCOS patient (BMI < 28)
undergoing IVF/ICSI, metformin treatment
(2000mg/day) for  12 weeks prior to and
during long protocol
• Significantly increased pregnancy and LBRs
compared to placebo
Use of metformin before and during assisted reproductive technology in non-obese young
infertile women with polycystic ovary syndrome: a prospective, randomized, double-blind,
multi-centre study. Kjøtrød SB et al. Hum Reprod. 2011 May 23.
Metformin in ART
• In obese patients
Metformin in ART
• In women with PCO morphology but no other
features of PCOS
• Appears to be no benefit of metformin cotreatment before and during IVF in women
with PCO without any other features of PCOS
Do women with ovaries of polycystic morphology without any other features of PCOS
benefit from short-term metformin co-treatment during IVF? A double-blind, placebocontrolled, randomized trial. Swanton A, et al. Hum Reprod. 2011 May 27.
Metformin and infertility - summary
1.
2.
3.
4.
For OI
In IVF/ICSI (non-obese patients)
In IVF/ICSI (obese patients)
In women with PCO appearance only
Metformin and weight loss
• Treatment with metformin showed a statistically
significant decrease in BMI compared with placebo
• Some indication of greater effect with high-dose
metformin (>1500 mg/day) and longer duration of
therapy (>8 weeks).
• A structured lifestyle modification programme to
achieve weight loss should still be the first line
treatment in obese women with or without PCOS.
• Adequately powered RCTs are required.
Insulin sensitizing drugs for weight loss in women of reproductive age who are overweight or
obese: systematic review and meta-analysis. Nieuwenhuis-Ruifrok AE et al. Hum Reprod Update.
2009 Jan-Feb;15(1):57-68.
Ovarian drilling
• Number of punctures?
• Mechanism of action?
• Laparoscopic versus newer options?
LOD – first line?
• When compared to CC as a method of OI in
PCOS, LOD is not superior to CC
• Therefore, what is the role if any of LOD?
Randomized controlled trial comparing laparoscopic ovarian diathermy with clomiphene
citrate as a first-line method of ovulation induction in women with polycystic ovary syndrome.
Amer SA. Hum Reprod. 2009 Jan;24(1):219-25
,
LOD – in ‘CC resistant’ patients
• When compared to Gn for OI, pregnancy rates
are comparable
• Avoids risk of OHSS and multiple pregnancy
• More cost effective (?) and better tolerated
• Improves ovarian response to CC in at least 1/3 of
CC resistant patients
• Long term – increases chances of second
pregnancy
• Side effects – no evidence
Ovarian drilling for surgical treatment of polycystic ovarian syndrome: a comprehensive review. Fernandez
H et al. Reprod Biomed Online. 2011 Jun;22(6)
Long-term outcomes in women with polycystic ovary syndrome initially randomized to receive laparoscopic
electrocautery of the ovaries or ovulation induction with gonadotrophins. Nahuis MJ et al. Hum Reprod.
2011 Jul;26(7)
Obesity in PCOS
• 40-60% of women with PCOS are overweight
or obese
• 40-70% have insulin resistance
• Widespread variability in degree of adiposity
by geographical location and ethinicity
• Spain: 20%, China: 43%, US: 69%
• What is best method to manage?
Obesity in PCOS
• In morbidly obese women
with PCOS – sustained
weight loss and complete
resolution of all features
defining PCOS, including
hirsuitism,
hyperandrogenism,
menstrual irregularity,
anovulation, IR and
metabolic abnormalilities
The higher the weight loss, the
greater the benefit achieved
NHI advocates when BMI 3540kg/m2
Obesity in PCOS – weight loss
• Studies demonstrate fairly uniform
improvements in many key features of PCOS
with modest weight loss (5% to 15%)
• Improvements in biochemical
hyperandrogenism, menstrual cyclicity,
ovulation, and fasting insulin and glucose as
well as glucose tolerance.
Obesity in PCOS – exercise
• Studies examining the effects of exercise in
PCOS suggest that exercise improves
reproductive hormones, menstrual cyclicity or
ovulation and metabolic features.
• Remaining research questions -optimal
amount, type, duration, and mechanisms of
action of exercise.
Key features
• Lifestyle modification is first form of therapy
• ↓500-1000 kcal/day 7-10% weight loss over
6-12 months
• Alternative dietary options?
• Structure and support
• Exercise important  >30mins/day
Letrozole versus CC
• Letrozole is as effective as CC for OI in patients
with PCOS
Sex steroid synthesis
PCOS and IVF
• High risk of OHSS
Strategies to prevent OHSS
1.
2.
3.
4.
5.
6.
7.
8.
9.
Cycle cancellation
Coasting
IV albumin at OR
Antagonist cycles versus agonist (long protocol)
GnRH agonist trigger in antagonist cycle
Natural cycle
IVM
Dopamine agonist
GnRH antagonist in agonist cycles (antogonist
rescue protocol)
10. Dual trigger
Antagonist cycles versus Agonist cycles
• The use of antagonist compared with long
GnRH agonist protocols are associated with a
large reduction in OHSS and there was no
evidence of a difference in live birth rates
Al-Inany HG et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive
technology. Cochrane Database Syst Rev. 2011 May 11;15:CD001750
GnRH agonist trigger in antagonist
cycle
• In fresh autologous cycles, the moderate and severe OHSS
incidence was significantly lower in the GnRH agonists group
compared to the the hcg group but was also less effective than
hcg in terms of live birth rate and on-going pregnancy rates.
• Therefore, not recommended for routine use as final oocyte
maturation trigger in fresh cycles except in high risk women,
after counselling
Youssef MA et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering
in antagonist assisted reproductive technology cycles. Cochrane Database Syst Rev. 2011,
Jan 19;(1):CD008046
Dopamine agonists for prevention of
OHSS
• Significantly reduces the chances of
developing OHSS in IVF and ICSI cycles
• No difference in live birth rate, on-going
pregnancy rate, clinical pregnancy rate or
miscarriage rate
• NNT = 9
• Acts by reversing VEGFR-2 dependent
increased vascular permeability
Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ ICSI treatment cycles? A systematic
review and meta-analysis. Mohamed A.F.M. Youssef et al.
Human Reproduction Update, Vol.16, No.5 pp. 459–466, 2010
Summary
• Metformin for clinical features, weight loss
and fertility
• Drilling
• Managing obesity in PCOS
• Preventing OHSS
Thank you