In there a consensus

on what is PCOS ?
Robert Norman
Research Centre for
Reproductive Health
University of Adelaide
PCOS is more than a reproductive disease

In utero Peripuberty Adolescence

Adulthood Aging

Growth Early puberty PCOS Syndrome X

issues

Long-term health Precocious puberty Reproductive disorders Metabolic

The definition of PCOS becomes more important
 PCOS – a problem of perspective
Vase Testosterone

LH:FSH ratio
Anovulation
Insulin resistance

Face Ultrasound
 What is this condition?

Ovulatory Status Ovulation Anovulation

Ovarian Morphology Normal Hyperandrogenemia

Androgen Levels Normal Polycystic Ovaries

Insulin Levels Normal Hyperinsulinemia

Concept by David Ehrmann, MD.

 Different diagnostic perspectives

Endocrinologist Gynaecologist
Menstrual problems 70% 47% <0.001

Androgenisation 81% 59% <0.001

Obesity 11% 8% NS

PCO ultrasound 14% 61% <0.001

Increased LH:FSH 24% 47% <0.001

Insulin resistance 6% 11% NS

Cussons et al 2006 (350 gynaecologists, 350 endocrinologists)

 Different perspectives on investigations

Endocrinologist Gynaecologist

LH,FSH 91% 94% NS

Estradiol 64% 56% NS

Testosterone 99% 92% NS

17OHP 70% 46% <0.001

DHEAS 80% 58% <0.001

Glucose 89% 79% 0.02

Lipids 67% 34% <0.001

Ovarian ultrasound 44% 91% <0.001

Cussons et al 2004
 Cardinal features of PCOS

• Hyperandrogenism
• Hirsutism
• Abnormal menstrual cycles
• Polycystic ovaries
 WHO II Anovulatory Infertility:Paradigm Shift

Where does Laven,

Ob Gyn Surv 2002
PCOS fit? Irregular Cycles
WHO II

PCO

LH

Androgens
Insulin
&
Obesity

Fauser 2004
 PCOS definition NIH 1992

• Both criteria required

• Chronic irregular periods

• Excess hair or high testosterone

Exclusion of other causes

 NIH criteria

Irregular Cycles
WHO II

PCOS

Androgens
 Rotterdam consensus on PCOS
• ESHRE/ASRM meeting
• 20 people with expertise on PCOS
• Discussed diagnostic criteria for PCOS
• Consensus reached – published 2004
 PCOS definition Rotterdam 2003

• 2 of 3 criteria required

• Chronic irregular periods

• Excess hair or high testosterone
• Polycystic ovaries on ultrasound

Exclusion of other causes

 PCOS Rotterdam

Irregular Cycles
WHO II

PCO

Androgens
 PCOS definition AES

• Both criteria required

• Ovarian dysfunction
Oligo-anovulation and/or polycystic ovary syndrome

• Hyperandrogenism
•Hirsutism and/or hyperandrogenaemia

• Exclusion of other causes

 PCOS definition AES

Irregular Cycles
WHO II

PCO

Androgens
 PCOS definition in Japanese women

• Chronic anovulation
• High LH levels
• Polycystic ovaries
Hyperandrogenism taken into
consideration

• Exclusion of other causes

(Japanese Society of Obstetrics and Gynaecology criteria)

Reported in English by Iwasa et al 2006
 Japanese definition

Irregular Cycles
WHO II

PCO

LH

Androgens
 Cardinal features of PCOS

• Androgens and measurement

– Assay differences
– Reference ranges
– Skill in interpretation
• Assessment of hirsutism
– Difficulties and sites
• Menstrual cycles
– Can be very difficult and role of progesterone
• Polycystic ovaries
– Skill and availability of ultrasound
 Androgens

• Different assay methods and kits used

• Direct testosterone close to useless
• Reference ranges not done for most assays
• SHBG frequently not measured
• Huge differences between laboratories
• Question of whether worth measuring at all
 Immunoassays for testosterone are unreliable

• Women (n=15) with normal, high and low SHBG

• 6 commercial kits used and 1 in-house method
• 57-115% variation in methods (average 77%)
“These data strongly suggest that the
measurement of total serum
testosterone using commercial kits
may have limited utility, particularly
for the detection of
hyperandrogenemia”

Fertility and Sterility 69:286 (1998) Boots et al

 Immunoassays for testosterone are unreliable

• Plasma from 15 women

• 4 laboratories (2 academic, 2 commercial)
• Testosterone extraction, chromatography and RIA
• Assay CVs 9-26%
• “Use of testosterone assays is problematic”

Fears et al (2000)

Cancer epidemiology, biomarkers and prevention 9:403 (2000)

 Immunoassays for testosterone are unreliable

“Laboratory professionals should not be

associated with a test where an educated
guess would provide an equivalent or
better result”

Clinical Chemistry 49:1250, 2003

 Taieb et al (2003)

• Gold standard
– equilibrium dialysis
• Next best
– LC/MS method
• Best practical
– Free androgen index
– Bioavailable T
• Usual practical
– Automated T
– RIA for T
• Worst
– “free T”
Testosterone variability - Australia
 Hirsutism is a diagnostic feature in PCOS

Ewing and Rouse (1978) showed that women in the USA from a
Chinese background had less hair than women from a Caucasian
background but identical free and total testosterone levels
 Hirsutism in East Asian women with PCOS

Ethnic group City Hirsutism Raised Reference

(per cent) testosterone
Chinese Guangzhou 30% not stated Li et al 2007

Chinese Hong Kong 35% 48% Lam et al 2006

Chinese Jinan 48% not stated Zhionghua et

al
Chinese Taipei 30% 59% Hsu et al 2007

Shandong University (2007) Lip, chest and lower belly best to

diagnose hirsutism
Many studies have shown acne and hirsutism is less in East Asians
 PCO and anovulation

• Conway et al (1989)
– Only 3% had no biochemical features of PCOS (androgens, LH)
• Gilling-Smith et al (1997)
– Abnormal response to hCG injection
• Norman et al (1995)
– Increased insulin response to glucose
• General experience
– Increased response to FSH stimulation
 Ultrasound reproducibility

• Elter et al 2005 Gynecol Endocrinol

Reasonably good correlation between scans and scanners
• Merce et al 2005 J Ultrasound Med 24:1279
– Excellent correlation between scans and scanners >90%
• Amer et al 2002
– Poor correlation - Intra-observer variation 69%, inter-observer
51%
Allemand et al (2006)

Fertility and Sterility 85:214 (2006)

 Diagnostic criteria for East Asian PCOS

90 patients seen in gynaecological endocrinology unit at Prince of Wales

Hospital, Hong Kong over a one year period. Thorough examination and
endocrine and ultrasound testing performed

Rotterdam criteria best

Lam PM et al Hong Kong Med J 2006 11:336
 Diagnostic criteria for East Asian PCOS

• 170 patients with PCOS from Taipei Medical University

reproductive endocrine clinic
• 61% met NIH criteria for PCOS as well as Rotterdam
• An additional 39% had PCOS only by Rotterdam criteria
• NIH only were more severe and had longer duration
• PCO found in 91% of Rotterdam diagnosed and 85% of
NIH diagnosed
• Rotterdam seems more appropriate for East Asian
PCOS
Hsu et al 2007
 Definition and frequency of PCOS - Taipei

Hyperandrogenism, normal cycles,

PCO GROUP C Hyperandrogenism, oligo-anovulation,
PCO ultrasound GROUPA
Normal androgens oligo-
anovulation, PCO ultrasound
18%
GROUP D
21% 52%
9%

Hyperandrogenism, oligo-
anovulation, normal ultrasound N=170
GROUP B
Hsu et al 2007
 Definition and frequency of PCOS - France
Hyperandrogenism, normal cycles,
PCO GROUP C Hyperandrogenism, oligo-anovulation,
PCO ultrasound GROUPA
Normal androgens oligo-
anovulation, PCO ultrasound 16%
GROUP D
17% 61%
7%

Hyperandrogenism, oligo-
anovulation, normal ultrasound N= 380
GROUP B

Dewailley et al 2006
 Why does metabolic syndrome matter?

• Potential long-term consequences

• Patient information
• Lifestyle change encouraged
• Appropriate monitoring
• Appropriate therapy
 Meta-analysis of mortality in metabolic syndrome

Definition Numbers All-cause CVD mortality

mortality
Two components 1488 1.23 (0.96-1.57) 1.56 (0.93-2.60)

Three or more 534 1.41 (1.03-1.92) 2.17 (1.13-4.19)

components
Hyperinsulinaemia plus 727 1.38 (1.02-1.87) 2.78 (1.57-4.94)
2 or more components
Hyperinsulinaemia plus 330 1.49 (1.02-2.31) 2.74 (1.21-6.20)
3 or more components

DECODE study Hu et al Arch Int Med 164:1066 (2004)

 Comparison of current metabolic definitions
IDF criteria ATPIII criteria

Central obesity: waist >80cm >88 cm

Hypertriglyceridaemia > 1.7 mmol/l > 1.7 mmol/l

Low HDL cholesterol <1.29 mmol/l < 1.3 mmol/l

Hypertension: BP > 130/85 > 135/85

Fasting plasma glucose >5.6 mmol/l > 6.1 mmol/l

 Prevalence of metabolic syndrome in PCOS

Features of Glueck Apridonidze Pasquali Weerak

metabolic USA USA Italy iet et al
syndrome
No criteria 18%

2 or less 57% 51%

Three or more 46% 43% 31% 35%

 Metabolic syndrome and PCOS in Hong Kong

295 Chinese women with PCOS from Hong Kong studied for
metabolic syndrome assessed by ATP III criteria

Cheung et al 2008
Metabolic syndrome and PCOS in Hong Kong

Cheung et al 2008
 Tests needed

• Medical history and examination

• Tests for the diagnosis
– Testosterone and pelvis ultrasound
– Exclusion of other conditions
• Tests for reproduction
– Various reproductive hormones
• Tests for metabolism
– Glucose tolerance test. cholesterol, HDL cholesterol,
triglycerides
– Possibly insulin
 First International
Asia Pacific meeting on
Polycystic Ovary Syndrome
organized by Department of Obstetrics and
Gynaecology, the University of Hong Kong
and Androgen Excess Society
17-18 January 2009
HONG KONG