Prof Robert Norman presented this to the Adelaide Northern Division of General Practice on 24th July 2012.

1. Evidence based guidelines
for the assessment and
management of fertility in
polycystic ovary syndrome
Prof Helena Teede Norman
Prof Robert

2. Disclosure
• Funding from MSD and Merck Serono
• Employed by the University of Adelaide
• Work at FertilitySA
• On NHMRC Research Committee

3. Background
• Prevalence of PCOS traditionally estimated at
4-8% (NIH) - Greece, Spain, USA 1,2,3
• Australian (Rotterdam) prevalence 12-18% 4
• Indigenous populations ~21%
• Costs >$400 million/yr in Australia 5,6
• Major health and economic burden6
1) Diamanti-Kandarakis et al JCEM 1999 2) Knochenhauer ES et al JCEM 1998, 3) Asuncion M et al JCEM
2000, 4) March et al Human Reprod 2010 6 5) Azziz et al JCEM 2005, 6) Teede et al MJA 2007

4. Perspective is everything

5. Clinical perspectives on PCOS
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 (350 gynaecologists, 350 endocrinologists)
Cussons et al 2007 : Survey of Australian gynaecologists and endocrinologists

6. Laboratory perspectives on PCOS
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 Cussons et al 2007

7. Types of PCOS
Hyperandrogenism, normal cycles,
PCO ultrasound
Hyperandrogenism, oligo-
anovulation, PCO ultrasound (NIH)
Normal androgens 16%
oligo-anovulation, PCO
17%
61%
7%
Hyperandrogenism, oligo-
anovulation, normal ultrasound N= 380
(NIH) Prevalence of PCO around 20%
Prevalence of PCOS 12-17%
Prevalence in Indigenous women 21%

8. A changing paradigm in PCOS
Human Reproduction 27:14-24 (2012)

9. Diagnosis
Rotterdam diagnostic criteria requires two of:
1. Oligo- or anovulation;
2. Clinical and/or biochemical signs of hyperandrogenism;
3. Polycystic ovaries;
and exclusion of other aetiologies such as hypothydoidism,
Rotterdam
hyperprolactinemia, congenital adrenal hyperplasia, androgen-
secreting tumours and Cushing’s syndrome.
NIH diagnostic criteria requires:
1. Oligo- or anovulation; and
2. Clinical and/or biochemical signs of hyperandrogenism;
NIH
and exclusion of other aetiologies such as congenital adrenal
hyperplasia, androgen-secreting tumours and Cushing’s
syndrome.
Teede et al MJA 2011

10. PCOS: Complex clinical syndrome
Norman et al Lancet 2007

11. PCOS– lifelong consequences
Peripuberty Adolescence
In utero Aging
Adulthood
PCOS Metabolic syndrome
Growth issues Early puberty
Long-term health Precocious puberty Reproductive disorders Metabolic

12. Psychological features
Anxiety & depression
Poor
Eating body
disorders image
Psychosexual
dysfunction
Teede et al MJA 2011, Deeks et al Fertil Steril 2010

13. Gaps in clinical PCOS guidance
• No accessible evidence-based guidelines (EBG)
internationally, no Australian EBG
• Current information often opinion based or
included as small part of broader guidelines
(Obesity and type II diabetes)
• Recent position statements by international
bodies (AEPCOS Society) on diagnosis, glucose
intolerance, CVD risk and lifestyle
treatment, but no evidence based rigorously
developed guidelines

14. Evidence based practice
is integration
Patient of best research evidence
Clinical preference
judgment with clinical expertise
Evidence and patient values
from
research Sackett et al. 2000. Evidence based medicine. How to
practice and teach EBM. Second edition. Churchill
Livingstone. London
Evidence Based
Practice

15. PCOS Australian Alliance

16. International /NHMRC grading
A Body of evidence can be trusted to guide practice.
B Body of evidence can be trusted to guide practice in most situations.
Body of evidence provides some support for recommendation but care
C should be taken in its application.
Body of evidence is weak and recommendation must be applied with
D
caution.
Classifications where NHMRC grading cannot be applied:
In the absence of evidence, a clinical consensus recommendation has been
CR
made by the guideline development group.
Evidence not sought. A practice point has been made by the guideline
PP development group where important issues arose from discussion of
evidence based or clinical consensus recommendations.

17. Proposed Infertility treatments for PCOS
1. Ovulation induction
• Lifestyle intervention including diet
• Clomiphene citrate
• Laparoscopic drilling
• Aromatase inhibitors
• Gastric banding
2. IVF/ICSI

18. Obesity
• Prevalence of obesity is increasing and has an
important bearing on the phenotype of PCOS
(level B)
• Higher BMI related to greater prevalence of
menstrual irregularity, hyperandrogenaemia and
hirsutism (level B)
• Increased BMI and visceral adiposity associated
with greater insulin resistance (level B)
• Lifestyle management results in weight loss and
improves surrogate markers of metabolic
disease/syndrome (level B)
Human Reproduction 27:14-24 (2012)

19. IR and metabolic syndrome
• PCOS associated metabolic disorders major
predictors of prediabetes, diabetes and metabolic
syndrome (level B)
• Patient with metabolic syndrome are an important
subset of women with PCOS (level B)
• Not all PCOS has similar metabolic risk.
Hyperandrogenaemia and oligoamenorrhoea pose
the worst risk (level B)
• It is critical to stratify women for metabolic risk in
PCOS. It would be helpful to have a new name for
this subset (GPP)
Human Reproduction 27:14-24 (2012)

20. Type 2 diabetes and PCOS
• PCOS is a major risk factor for IGT and T2D (level A)
• Obesity is an exacerbating factor (level B)
• Obesity predicts further T2D (level B)
• Screening for IGT/T2D should be done by OGTT
(level B)
• Measuring insulin is meaningless (level C)
• Screening important in : hyperandrogenaemia and
anovulation, acanthosis nigricans, high BMI, family
history T2D (level C)
• Metformin may be used for IGT/T2D (GPP)
Human Reproduction 27:14-24 (2012)

21. Clinical questions relating to
lifestyle management of PCOS
Dietary • Effectiveness of lifestyle interventions
intervention • Comparative effectiveness of individual
lifestyle intervention components
• How best to deliver lifestyle interventions
Exercise • Amount of weight loss required for
intervention improvements
• Specific strategies for prevention of
weight gain or weight maintenance
Behavioural • Lifestyle intervention compared to
intervention pharmacological or surgical interventions

22. Are lifestyle interventions effective?
• Evidence-based recommendation
• Lifestyle management (single or combined
approaches of diet, exercise and/or behavioural
interventions) for weight loss, prevention of weight
gain, or for general health benefits should be
recommended in women with PCOS

23. Effectiveness of diet versus exercise
• Evidence-based recommendation
• Lifestyle management targeting weight loss (BMI ≥ 25
kg/m2 (overweight)) and prevention of weight gain
(BMI < 25 kg/m2 (lean)) should include both reduced
dietary energy (caloric) intake and exercise and should
be first line therapy for all women with PCOS

24. Type of dietary interventions
• Evidence-based recommendation
• Weight loss should be targeted in all women with
PCOS and BMI ≥ 25 kg/m2 (overweight) through
reducing dietary energy (caloric) intake in the setting
of healthy food choices, irrespective of diet
composition
• Prevention of weight gain should be targeted in all
women with PCOS through monitored caloric
intake, in the setting of healthy food
choices, irrespective of diet composition

25. Delivery of diet information
• Evidence-based recommendation
• Face to face, tailored dietary advice, including
education, behavioural change techniques and
ongoing support should be provided to women with
PCOS and BMI ≥ 25 kg/m2 (overweight).
– Dietary modification is the joint responsibility of all health
professionals, partnering with women with PCOS
• Behaviour change techniques should target
prevention of weight gain in all women with PCOS
including those with BMI < 25 kg/m2 (lean)

26. Clomiphene Citrate

27. Clomiphene Citrate (CC)
Comparison Clomiphene citrate vs Placebo in PCOS
Results Increased ovulation per woman(OR = 7.5; 3 RCTs)
Increased pregnancy rate per woman (OR = 5.5;
3 RCTs)
Recommendation CC should be first line pharmacological therapy
(Grade A) to improve fertility outcomes in women with
PCOS and anovulatory infertility
CC resistance = CCR
CC failure = CCF

28. Metformin (Met)

29. Metformin
Comparison Metformin vs Placebo/no Treatment
in PCOS♀
Results Increased ovulation rate per woman(OR=2.12; 13
RCTs; 875♀)
Increased pregnancy rate per woman(OR=3.86; 6
RCTs; 479♀)
Equivalent live birth rate per woman(OR=1.0; 95%CI
0.16-6.39; 2 RCTs; 50♀)
Recommendation See later (interpret with other evidence)
(Grade)

30. Metformin versus CC

31. Metformin versus CC
Comparison Metformin vs clomiphene citrate in PCOS♀
Results Overall ♀ (3RCTs): Decreased ovulation rate + decreased pregnancy
rate and equivalent live birth rate with metformin
BMI > 30 ♀ (2RCTs): Decreased ovulation rate + decreased pregnancy
rate and decreased live birth rate with metformin
BMI < 30 ♀ (1RCT): Equivalent ovulation rate + decreased pregnancy
rate and equivalent live birth rate with metformin
Overall lower BMI better response to metformin
Recommendation See later (interpret with other evidence)
(Grade)

32. Met versus CC: BMI < 30-32: Meta-analysis (4RCTs, 465♀)

33. Metformin +clomiphene citrate (CC) versus CC
Comparison
Metformin + clomiphene citrate vs
clomiphene citrate in PCOS♀ (all[overall],
CCR or not, BMI < or > 30)
Results Increased ovulation rate + increased pregnancy rate and
increased live birth rate with Metformin +CC seen only in “CCR
PCOS ♀”
Recommendation See later (interpret with other evidence)
(Grade)

34. Metformin: Recommendations
Evidence-based recommendations
•
7.2a Metformin should be combined with clomiphene citrate to improve fertility A
outcomes rather than persisting with further treatment with clomiphene
citrate alone in women with PCOS who are clomiphene citrate resistant,
anovulatory and infertile with no other infertility factors.
7.2b Metformin could be used alone to improve ovulation rate and pregnancy B
rates in women with PCOS who are anovulatory, have a BMI ≤30kg/m2 and
are infertile with no other infertility factors.
Research recommendation
Whether there is a difference in effectiveness between clomiphene citrate and metformin
in women with PCOS who are anovulatory, infertile and have BMI ≤30kg/m2 to improve
fertility outcomes

35. Gonadotrophins

36. Gonadotrophins
Comparison
Gonadotrophin ovulation induction versus
placebo/no Rx in PCOS♀
Evidence No randomised trials
Large body of observational evidence supporting gonadotrophin
ovulation induction in CCR/CCF PCOS
Recommendation Gonadotrophins should be 2nd line pharmacological therapy in
(Grade B) women with PCOS who have clomiphene citrate resistance and/or
failure, are anovulatory and infertile, with no other
infertility factors

37. Gonadotrophins (Gn)
Comparison
rFSH ovulation induction vs clomiphene
citrate ovulation induction in therapy
naïve PCOS ♀
Results cumulative PR per ♀ (42% v 24%; p=0.09; RR=1.78; 95%CI 0.92-3.54)
cumulative LBR per ♀ (29% v 16%; p=0.17; RR=1.83; 95% CI 0.79-4.0)
Homburg RCT 2009:
cumulative PR per ♀ (56% v 41%; p=0.03)
Recommendation Gonadotrophins could be considered as first line pharmacological
(Grade C) therapy in women with PCOS who are therapy naive, anovulatory
and infertile, with no other infertility factors.

38. Laparoscopic Ovarian Drilling (LOD)

39. Laparoscopic Ovarian Drilling
Comparison
Laparoscopic drilling vs FSH ovulation rate
Results Equivalent live birth rate, ongoing pregnancy rate, ovulation rate
and miscarriage rate per woman
Decreased multiple pregnancy rate per ongoing pregnancy (1% vs
17%; OR=0.13; 95%CI 0.03-0.59)
Recommendation Laparoscopic Ovarian Drilling should be 2nd line therapy in women
(Grade B) with PCOS who are clomiphene citrate resistant , anovulatory, and
infertile, with no other infertility factors

40. Bariatric Surgery

41. Bariatric Surgery
Comparison
Bariatric Surgery Vs placebo/no Rx or
other infertility treatments in PCOS♀
Results Nil
Clinical Bariatric surgery could be considered 2nd line therapy to
Consensus improve fertility outcomes in adult women with PCOS who
Recommendation are anovulatory, have a BMI ≥35kg/m2, and who remain
infertile despite undertaking an intensive (frequent
multidisciplinary contact) structured lifestyle management
programme involving reducing dietary energy (caloric) intake,
exercise, behavioural and/or drug interventions for a
minimum of 6 months.

42. The role of IVF
• Not usually needed
• If required needs skill to handle cycle
• Risks of hyperstimulation
• Risks of multiple pregnancy
• Problems of pregnancy

44. Models of care
Specialists: Allied Health:
Endocrinologist Psychologist
Gynaecologist Dietitian
Dermatologist Exercise Physiologist
Patient central to
care and holds
management plan
Reputable education sources and General Practitioner:
consumer support group:
www.managingpcos.org.au
Central to ongoing care
POSAA: www.main.posaa.asn.au and co-ordination

45. Where to get advice
• Internet – Jean Hailes/FertilitySA site
• Booklets – Merck Serono/PCOS Alliance
• Hirsutism and metabolic – reproductive/medical
endocrinologist
• Ovulation induction – gynaecologist/fertility
specialist ie FertilitySA
• Other fertility – reproductive endocrinologist ie
FertilitySA

46. Guideline
“These guidelines were approved by
the Chief Executive Officer of the
National Health and Medical
Research Council (NHMRC) under
Section 14A of the National Health
and Medical Research Council Act
1992. In approving these guidelines
the NHMRC considers that they meet
the NHMRC standard for clinical
practice guidelines.”