PCOS Evidence-Based Guideline For Assessment and Management Pcos
PCOS Evidence-Based Guideline For Assessment and Management Pcos
PCOS Evidence-Based Guideline For Assessment and Management Pcos
Publication approval
These guidelines were approved by the Chief Executive Officer of the National Health and Medical Research
Council (NHMRC) on 29 July 2011, (with a subsequent amendment approved on 15 June 2015) 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. This approval is valid
for a period of 5 years.
NHMRC is satisfied that they are based on the systematic identification and synthesis of the best available
scientific evidence and make clear recommendations for health professionals practising in an Australian
health care setting.
This publication reflects the views of the authors and not necessarily the views of the Australian
Government.
This guideline reflects the identified key clinical priorities and areas of clinical need, covering assessment of
PCOS, assessment of emotional wellbeing, management of lifestyle and management of infertility in women
with PCOS.
A list of Alliance members can be found in Appendix I.
Acknowledgments
We gratefully acknowledge the volunteers in the Alliance who were involved in the development of the
guideline (see Appendix II for a list of individuals and organisations), the Jean Hailes for Womens Health
team who contributed so much to this project over the past 2 years, the Department of Health and Ageing
and Health Minister Roxon for their support and funding of this guideline and the subsequent translation
program. Finally we acknowledge the commitment and support of the Centre for Clinical Effectiveness for
providing evidence synthesis and guideline development expertise, including guidance from Dr Claire Harris
and Dr Tari Turner during the early planning phase, and to the Australasian Cochrane Centre for appraising
the guidelines (using AGREE II).
AGREE II appraisal
1st independent rater: 6, 2nd independent rater: 6-7 (1=Lowest possible quality and 7=Highest possible
quality) [3]. The full AGREE II appraisal is available upon request, email linda.downes@monash.edu
Domain scores (calculated based on two
independent raters scores)
Domain 1: Scope and Purpose
Domain 2: Stakeholder Involvement
Domain 3: Rigour of Development
Domain 4: Clarity of Presentation
Domain 5: Applicability
Domain 6: Editorial Independence
Obtained
score
42
39
98
41
39
24
Maximum
score
42
42
112
42
56
28
Minimum
score
6
6
16
6
8
4
Scaled domain
score (%)
100%
91.67%
85.42%
97.22%
64.58%
83.33%
Disclaimer
This document is a guide to best practice, designed to provide information to assist decision-making. It is
based on the best available evidence and clinical judgement at the time of development of this publication
and is to be followed subject to the clinicians judgement and patients preference in each individual case.
Copyright information
Jean Hailes for Womens Health on behalf of the PCOS Australian Alliance 2015
Paper-based publication This work is copyright. Apart from any use permitted under the Copyright Act
1968, no part may be reproduced by any process without written permission from Jean Hailes for Womens
Health on behalf of the PCOS Australian Alliance.
ISBN Print: 978-0-646-55470-9
Electronic documents This work is copyright. You may download, display, print and reproduce this material
in unaltered form only (retaining this notice) for your personal, non-commercial use, or use within your
organisation. Apart from any use as permitted under the Copyright Act 1968, all other rights are reserved.
Copies of the guideline can be downloaded from www.managingpcos.org.au
Suggested citation Evidence-based guidelines for the assessment and management of polycystic ovary
syndrome. Jean Hailes for Womens Health on behalf of the PCOS Australian Alliance; Melbourne, 2015.
Contents
Publication approval .................................................................................................................................... 2
PCOS Australian Alliance: A single voice for polycystic ovary syndrome ............................................................ 3
Acknowledgments ....................................................................................................................................... 4
AGREE II appraisal........................................................................................................................................ 4
Disclaimer .................................................................................................................................................... 4
Copyright information ................................................................................................................................. 4
Preface ................................................................................................................................................................. 8
Executive summary ............................................................................................................................................. 9
Recommendations............................................................................................................................................. 11
Algorithms ......................................................................................................................................................... 25
Introduction ....................................................................................................................................................... 31
Background ................................................................................................................................................ 31
Clinical need for this guideline .................................................................................................................. 32
Purpose ...................................................................................................................................................... 34
Patient population ..................................................................................................................................... 34
Setting and audience ................................................................................................................................. 34
Scope ......................................................................................................................................................... 34
Agreed diagnostic criteria for PCOS .......................................................................................................... 36
Funding ...................................................................................................................................................... 38
Editorial independence ............................................................................................................................. 38
Methods used to develop this guideline ........................................................................................................... 39
Multidisciplinary guideline development groups .......................................................................................... 40
Clinical question development and prioritisation ......................................................................................... 41
Search for existing evidence-based guidelines.............................................................................................. 42
Evidence reviews to answer the clinical questions ....................................................................................... 43
Formulation of recommendations ................................................................................................................ 47
Public consultation ........................................................................................................................................ 50
External review .............................................................................................................................................. 51
Piloting of the guideline ................................................................................................................................ 51
Evaluation strategy ........................................................................................................................................ 51
Scheduled review and update of the guideline............................................................................................. 51
CHAPTER ONE
CHAPTER THREE
Preface
This national evidence-based guideline for the assessment and management of polycystic ovary syndrome,
designed to provide clear information to assist clinical decision making and support optimal patient care, is the
culmination of the work of many individuals including women with PCOS. Most gave of their time and expertise
voluntarily and it is important to appreciate the considerable contributions of the guideline development groups
and particularly of the guideline development group chairs: Dr Michael Costello, Dr Amanda Deeks, Dr Lisa Moran
and Clinical Professor Dr Bronwyn Stuckey. We would like to thank the tireless efforts, commitment, dedication
and drive of the Project Director, Professor Helena Teede and Project Manager, Ms Linda Downes, the Senior
Evidence Officer and Guideline Writer, Dr Marie Misso and the Guideline Evidence Team: Ms Angela Melder, Ms
Marie Garrubba and Mr Henry Ko for their contribution to the body of evidence reviews and guideline. Finally we
would like to acknowledge the PCOS Australian Alliance who provided expertise and guidance and Jean Hailes for
Womens Health who auspiced and managed the guideline development process. It is hoped that women with
PCOS, their families, health professionals and policy makers find this useful.
The guideline is based on the best evidence available up to November 2010. Where appropriate, the evidence has
been interpreted with regard to the Australian context in which the guideline will be implemented. It is intended
that the guideline be considered according to the limitations outlined herein and used in conjunction with clinical
judgement and patient preference. The guideline contains the following information:
Recommendations
Algorithms
Introduction including a discussion about the clinical need for the guideline, scope of the guideline and a list
of clinical questions
Discussion chapters covering the clinical need for each question, the evidence to answer each question that
underpins each recommendation and the clinical impact of the recommendation;
Composition of the multidisciplinary guideline development groups
Methods used to develop the guideline
Additional tools and resources
Useful references and supporting information are provided throughout the guideline in clinical practice points.
Janet Michelmore
Director
Chair
Executive summary
This guideline integrates the best available evidence with clinical expertise and
consumer preferences to provide health professionals, consumers and policy makers
with guidance for timely diagnosis, accurate assessment and optimal management of
women with PCOS and promotes consistency of care and prevention of complications.
Polycystic ovary syndrome (PCOS) affects a striking 12-21% of Australian reproductive-aged women,
depending on the population studied and the diagnostic criteria used and is a major public health concern
[4-6]. The clinical implications of PCOS are broad and vary across the lifespan [7]. Whilst reproductive
features are prominent, PCOS has potential for major metabolic consequences including obesity and related
type 2 diabetes (DM2) and cardiovascular disease (CVD), all currently national health priority areas [8, 9]. It
also has significant mental health and psychological impact, impairing quality of life (QoL) [10, 11]. Overall
PCOS has significant health and economic costs. With increasing obesity exacerbating incidence, prevalence
and severity of PCOS and weight loss, improving reproductive, metabolic and psychological features and
lifestyle change should be first-line PCOS therapy. Currently 70% of Australian women with PCOS remain
undiagnosed [5], clinical practice is inconsistent [12], psychological issues are neglected [11] and there is
little focus on lifestyle and prevention with most services targeting infertility and costly assisted reproductive
technology.
Given the clear gaps in care, PCOS is recognised by government and prioritised in funding for this evidencebased guideline. Jean Hailes for Womens Healths efforts in PCOS have been noted in the 2010 national
womens health policy and priority areas including prevention of chronic disease, mental health, sexual and
reproductive health [13]. The PCOS Australian Alliance and this evidence-based guideline have prioritised the
development and evaluation of interdisciplinary models of care integrated with lifestyle intervention for
women with PCOS, with no such services currently available. Interdisciplinary care involves a collaboration
between a woman and her care team with shared goals for total wellbeing. This encompasses a
multidisciplinary team, an agreed care plan, a care coordinator and clear and regular communication.
Implementation of the PCOS evidence-based guideline through development and evaluation of effective,
sustainable community-based interdisciplinary models of care, integrated with lifestyle interventions,
addressing psychological, metabolic and reproductive features of PCOS is now vital.
This guideline provides recommendations on assessment and management in women and adolescents with
PCOS in the reproductive age groups. The guideline begins by providing guidance around assessment
challenges in diagnosing PCOS followed by methods for assessing emotional wellbeing and risk of
cardiometabolic complications. The lifestyle options considered in this guideline include diet, exercise and
behavioural interventions; pharmaceutical options include clomiphene citrate, metformin, gonadotrophins
and aromatase inhibitors; and surgical options include laparoscopic ovarian surgery and bariatric surgery.
Diagnostic criteria were adapted based on current international criteria and were not evaluated in this
guideline. IVF therapy and other areas were beyond the scope of the guideline but may be included in
subsequent updates.
Executive summary
This guideline was developed using internationally agreed methods for the development of evidence-based
guidelines. Multidisciplinary committees included a Project Board, PCOS Australian Alliance Strategic
Advisory Group and four guideline development groups, comprising experts in PCOS and multiple consumer
representatives appointed by the project board and mostly drawn from Alliance members and the consumer
advocacy group Polycystic Ovary Association of Australia (POSAA). These groups determined the clinical
questions that make up the structure of the guideline; the search for existing evidence-based guidelines; and
the development of clinical practice and research recommendations.
This guideline contains 39 recommendations, each of which is assigned a grade. In developing the guideline
recommendations, the guideline development groups placed emphasis on the accurate assessment as well
as the management of PCOS. The recommendations in this guideline are strengthened by the use of
rigorous methodology for evidence review and guideline development including use of: study designs least
susceptible to bias; a priori criteria for inclusion and appraisal of studies, extraction of study data; and metaanalysis where appropriate. The recommendations were formulated using a considered judgement process
which took into account the amount and quality of available evidence as well as its generalisability and
applicability to current practice in Australia. Further points of relevance in the implementation of
recommendations were made in clinical impact statements for each recommendation including
consideration of resource implications.
In formulating the recommendations for this guideline, the guideline development groups recognised and
took into account a number of factors and limitations pertaining to the available evidence. In many areas of
PCOS, there is little or no evidence or the evidence is of poor quality and other potential biases in the trials
resulting from different methods for diagnosis of PCOS, and differing endpoints. As a result of these
limitations, several clinically important questions remain.
Key gaps in the evidence include inadequate study of the natural history of PCOS, its features and its
complications, establishing the optimal model of care, optimal lifestyle intervention (specifically aiming to
increase engagement, adherence and sustainability) and optimal fertility interventions. Another key gap was
inadequate evidence about the role of bariatric surgery for improving fertility in PCOS. Hence wellconsidered research recommendations are made throughout the guideline.
It is intended that the guideline be considered according to the limitations outlined herein and used in
conjunction with clinical judgement and patient preference.
Executive summary
10
Recommendations
This summary section provides a list of the evidence-based recommendations discussed in the text of
chapters one through eight. Each of the evidence-based recommendations is given an overall grading from
A to D based on the volume, consistency, generalisability, applicability and clinical impact of the body of
evidence supporting each recommendation (as outlined in the National Health and Medical Research Council
(NHMRC) levels of evidence and grades of recommendations for guideline developers) [14]. When
insufficient evidence was available but there was consensus among the guideline development group,
clinical consensus recommendations have been developed. Clinical practice points have also been included,
where important issues (such as safety, side effects or risks) arose from discussion of evidence-based or
clinical consensus recommendations. It is not possible to grade consensus recommendations and practice
points according to NHMRC grading; instead a classification has been allocated according to its type of
recommendation, ie.. a clinical consensus recommendation is classified CR and a clinical practice point is
classified PP.
The strength of the recommendations can be identified throughout the guideline with the following grades:
A
Body of evidence provides some support for recommendation but care should be taken
in its application.
PP
Evidence not sought. A practice point has been made by the guideline development
group where important issues arose from discussion of evidence-based or clinical
consensus recommendations.
The words should, could and should not do not directly reflect the grade or classification allocated to a
recommendation and are independent descriptors intended to reflect the judgment of the multidisciplinary
guideline development group on the practical application of the recommendation, balancing benefits and
harms. Where the word should is used in the recommendations, the guideline development group judged
that the benefits of the recommendation (whether evidence-based or clinical consensus) clearly exceed the
harms, and that the recommendation can be trusted to guide practice. Where the word could is used,
either the quality of evidence was underpowered, or the available studies demonstrated little clear
advantage of one approach over another, or the balance of benefits to harm was unclear. Where the words
should not are used, there is either a lack of appropriate evidence, or the harms outweigh the benefits.
Recommendations
11
Page numbers are provided in the table below to direct the reader to a discussion supporting the
recommendation, including the clinical need for the question, the body of evidence identified to answer the
question and the clinical impact of the recommendation, covering issues of applicability (such as potential
changes in care and the way care is organised), organisational barriers and resource implications. The full
evidence tables supporting the recommendations can be found in the supplementary document titled
Evidence report, which can be found at www.managingpcos.org.au/pcos-evidence-based-guidelines.
The Project Board, the PCOS Australian Alliance Strategic Advisory Group and the guideline development
groups support all 39 recommendations and intend that they be used in conjunction with clinical judgement
and patient preferences.
No.
Recommendations
Grade
Page
1.1b
P51
PP
Where the oral contraceptive pill has already been commenced, it should be
withdrawn for at least three months before appropriate hormonal
assessments for diagnosis of polycystic ovary syndrome are undertaken.
Contraception should be otherwise managed during this time.
1.1d
CR
PP
Reference ranges for different methods and different laboratories vary widely
and clinical decisions should be guided by the reference ranges of the
laboratory used.
Recommendations
12
1.2a
In adolescent women (<18 years), after two years of irregular cycles (>35 or
<21 days) following the onset of menarche, polycystic ovary syndrome should
be considered and appropriate assessment should be undertaken.
CR
1.3a
1.3b
After twelve months of irregular cycles (>35 or <21 days) after onset of
menarche, polycystic ovary syndrome should be considered before
commencement of the oral contraceptive pill.
Where the oral contraceptive pill has already been commenced, when
girls are not sexually active, if biochemical hyperandrogenism is needed
for the diagnosis of polycystic ovary syndrome, the oral contraceptive pill
could be withdrawn for three months to facilitate appropriate hormonal
assessments. Withdrawal of the oral contraceptive pill may facilitate
assessment and early diagnosis of polycystic ovary syndrome as diagnosis
can have important implications including optimisation of healthy
lifestyle, regular metabolic screening and proactive fertility planning, with
consideration of planning for conception at an earlier age. However, the
risk of unplanned pregnancy needs to considered and weighed up against
potential benefits of early diagnosis. Contraception may still need to be
otherwise managed during this time.
P53
PP
CR
PP
p54
CR
p57
Recommendations
13
p57
PP
3.1b
CR
P60
All women with polycystic ovary syndrome should be assessed for excess
weight at every visit.
In assessing women with polycystic ovary syndrome < 18 years, age
appropriate and gender appropriate body mass index should be calculated at
every visit.
CR
All women with polycystic ovary syndrome should be assessed for cigarette
smoking.
3.1c
Body mass index should be assessed in all women with polycystic ovary
syndrome using the following criteria:
PP
Recommendations
14
A complete lipid profile should be measured every two years in women with
polycystic ovary syndrome who have normal lipid profiles.
CR
3.1f
3.1g
3.1h
P60
PP
CR
CR
In women with polycystic ovary syndrome who are at high risk of type 2
PP
Recommendations
15
diabetes, the ideal day time blood pressure should not exceed 135 mmHg
systolic and 85 mmHg diastolic [19].
3.2a
Age
Gender
Ethnicity
Parental history of diabetes
History of high blood glucose level
Use of antihypertensive medications
Smoking
Physical inactivity
Waist circumference
3.2b
An oral glucose tolerance test should be performed every second year in all
women with polycystic ovary syndrome and annually in those found to have
additional risk factors for developing type 2 diabetes as outlined in 3.2a.
3.2c
CR
CR
P62
PP
Ideally 150 grams of carbohydrate per day should be consumed for three days
before, and women should then fast for 8 hours immediately prior to the oral
glucose tolerance test since low carbohydrate intake may lead to false
positive glucose tolerance tests.
CR
P66
PP
1) During the last month, have you often been bothered by feeling down,
Recommendations
16
depressed, or hopeless?
2) During the last month, have you often been bothered by having little
interest or pleasure in doing things?
3) During the last month, have you been bothered by feeling excessively
worried or concerned?
If any of the screening questions are positive further depression and/or
anxiety assessment could be by either:
a) Referring the patient to an appropriate professional if they do not feel
competent to perform a further mental health assessment. If the health
professional is not the patients usual GP, inform the GP of the referral.
P66
4.2a
CR
To screen for negative body image, the following questions could be asked:
1) Do you worry a lot about the way you look and wish you could think about
it less?
P68
2) On a typical day, do you spend more than 1 hour per day worrying about
your appearance? (More than 1 hour a day is considered excessive)
3) What specific concerns do you have about your appearance?
PP
Recommendations
17
P68
CR
To screen for disordered eating and eating disorders, the following questions
could be asked:
1) Do you worry you have lost control over your eating?
2) Do you ever feel disgusted, depressed, or guilty about eating?
3) Have you tried fasting or skipping meals in an attempt to lose weight?
P70
PP
If a woman with polycystic ovary syndrome answers yes to any of the above
questions the practitioner should further assess for the diagnosis of an eating
disorder by either:
a) Referring the patient to an appropriate professional to perform a further
mental health assessment.
b) If the practitioner feels competent, performing a clinical interview which
may be supplemented with standardised assessment tools (e.g. Eating
Assessment Tool (EAT 26) www.eat-26.com).
c) Assessing the level of depression and/or anxiety (see 4.1a).
4.4a
CR
P71
Disordered eating refers to eating and weight related symptoms commonly associated with an eating disorder; this
can include behavioural (e.g. bingeing, restriction), cognitive (e.g. dietary restraint, negative body image), and
emotional (e.g. emotional eating) factors.
2
Psychosexual dysfunction refers to sexual problems or difficulties that have a psychological origin based in cognitions
and/or emotions such as depression, low self-esteem and negative body image.
Recommendations
18
offered.
4.4b
PP
P71
5.2a
Lifestyle management targeting weight loss (in women with a body mass
index 25kg/m2 (overweight)) and prevention of weight gain (in women with a
body mass index 25kg/m2 (lean)) should include both reduced dietary energy
(caloric) intake and exercise and should be first-line therapy for all women
with polycystic ovary syndrome.
C
P76
5.2b
5.3a
Weight loss should be targeted in all women with polycystic ovary syndrome
and body mass index 25kg/m2 (overweight) through reducing dietary energy
(caloric) intake in the setting of healthy food choices, irrespective of diet
composition.
5.3b
P74
PP
P78
Recommendations
19
5.3c
Weight loss (in women with a body mass index 25kg/m2 (overweight)) and
prevention of weight gain (in women with a body mass index 25kg/m2 (lean))
is the joint responsibility of all health professionals, partnering with women
with polycystic ovary syndrome. Where complex dietary issues arise (or
obesity is present), referral to a dietitian should be considered as part of an
enhanced primary care plan.
P78
PP
5.4b
5.4c
PP
PP
5.5a
5.5b
CR
P80
P83
P83
Recommendations
20
In women with polycystic ovary syndrome and body mass index 30kg/m2
with due consideration given to age-related infertility, intensive (frequent
multidisciplinary contact) lifestyle modification alone (and not in combination
with pharmacological ovulation induction therapy) should be first-line therapy
for 3 to 6 months to determine if ovulation is induced.
6.1d
6.1e
Morbid obesity (body mass index 35kg/m2) increases risks during pregnancy
and should be regarded as a relative contraindication to assisted fertility.
PP
6.1f
PP
6.1b
6.1c
P87
7.1b
The risk of multiple pregnancy is increased with clomiphene citrate use and
therefore monitoring is recommended.
PP
7.2a
P90
P94
Recommendations
21
7.2b
Metformin could be used alone to improve ovulation rate and pregnancy rate
in women with polycystic ovary syndrome who are anovulatory, have a body
mass index 30kg/m2 and are infertile with no other infertility factors.
7.2c
7.3a
7.3b
7.3c
P96
PP
7.4a
7.4b
7.4c
P99
PP
Need for patient explanation and consent for off label use.
Recommendations
22
8.1b
PP
8.1c
CR
8.1d
8.2a
8.2b
P103
PP
CR
P105
PP
Recommendations
23
P105
PP
Recommendations
24
Algorithms
The algorithms summarise the recommendations of the guideline and provide an accessible desktop tool.
There are five algorithms:
1)
A detailed flow chart covering challenges in diagnostic assessment of PCOS and assessment of
cardiometabolic risk
2)
3)
4)
5)
Algorithms
25
ALGORITHM 1:
DIAGNOSTIC AND METABOLIC RISK ASSESSMENT FOR ALL WOMEN WITH POLYCYSTIC OVARY SYNDROME
The 2003 Rotterdam criteria for diagnosis of Polycystic Ovary Syndrome (PCOS) requires two of the following three criteria:
1) Oligo- or anovulation 2) Clinical and/or biochemical signs of hyperandrogenism 3) Polycystic ovaries, exclusion of other aetiologies such as congenital adrenal hyperplasia, androgen-secreting tumours, Cushings syndrome
CHALLENGES IN DIAGNOSTIC ASSESSMENT
Calculated bioavailable testosterone, calculated free testosterone or free androgen index should be first
line investigation for biochemical determination of hyperandrogenism in PCOS.
The addition of androstenedione and dehydroepiandrosterone sulfate could be second line
investigation for biochemical determination of hyperandrogenism in PCOS. [C]
In adolescent women (<18 years), after two years of irregular cycles (35 or <21 days) following the
onset of menarche, PCOS should be considered and appropriate assessment should be undertaken.
As polycystic ovary syndrome is a diagnosis of exclusion, other causes of irregular cycles (such as
thyroid dysfunction or hyperprolactinaemia) need to be considered and excluded prior to the diagnosis
of polycystic ovary syndrome. [CR]
GOOD PRACTICE POINT
If oral contraceptive pill therapy is being considered or has commenced in adolescents (<18 years), the
following are recommended:
*After twelve months of irregular cycles (>35 or <21 days) after onset of menarche, PCOS should be
considered before commencement of the oral contraceptive pill.
* Where the oral contraceptive pill has already been commenced, when girls are not sexually active, if
biochemical hyperandrogenism is needed for the diagnosis of PCOS, the oral contraceptive pill could
be withdrawn for three months to facilitate appropriate hormonal assessments. Withdrawal of the oral
contraceptive pill may facilitate assessment and early diagnosis of PCOS as diagnosis can have
important implications including optimisation of healthy lifestyle, regular metabolic screening and
proactive fertility planning, with consideration of planning for conception at an earlier age. However,
the risk of unplanned pregnancy needs to considered and weighed up against potential benefits of
early diagnosis. Contraception may still need to be otherwise managed during this time.
Given the apparent lack of specificity of polycystic ovaries on ultrasound in adolescents, generally,
ultrasound should not be recommended first line in this age group for diagnosis of polycystic ovary
syndrome pending further research. If pelvic ultrasounds are to be ordered in adolescents, the results
should be interpreted with caution. [CR]
GOOD PRACTICE POINT
Vaginal ultrasound is not appropriate in adolescents who have not been sexually active. [PP]
All women with PCOS should be assessed for excess weight at every visit. In assessing women with PCOS < 8
years, age appropriate and gender appropriate body mass index should be calculated at every visit. All women
with polycystic ovary syndrome should be assessed for cigarette smoking.[CR]
RISK OF CARDIOVASCULAR DISEASE
POLYCYSTIC OVARIES
IN ADOLESCENTS
All women with PCOS should be assessed for cardiovascular disease risk by assessing individual cardiovascular
disease risk factors.
If screening in women with polycystic ovary syndrome shows that any of the following cardiovascular disease risk
factors are present, these women with polycystic ovary syndrome should be considered at increased relative risk
of cardiovascular disease (obesity, cigarette smoking, dyslipidemia, hypertension, impaired glucose tolerance,
lack of physical activity) and those with metabolic syndrome and/or type 2 diabetes, at even greater risk. [CR]
RISK OF DIABETES
HYPERANDROGENISM
Late-onset congenital adrenal hyperplasia, although rare, needs to be considered before the diagnosis
of polycystic ovary syndrome is confirmed. In more severe clinical cases of hyperandrogenism, 21hydroxylase deficiency, the most common form of congenital adrenal hyperplasia, can be excluded by
measuring serum 17-hydroxyprogesterone in the follicular phase to explore this diagnosis. [CR]
To assess for risk of type 2 diabetes, in addition to PCOS status, the following diabetes risk factors should be
considered: age, gender, ethnicity, parental history of diabetes, history of high blood glucose level, use of
antihypertensive medications, smoking, physical inactivity, waist circumference. [CR]
An oral glucose tolerance test should be performed every second year in all women with polycystic ovary
syndrome and annually in those found to have additional risk factors for developing type 2 diabetes as outlined in
3.2a. [CR]
GOOD PRACTICE POINT
Reference ranges for: Impaired fasting glucose - fasting plasma glucose: 6.1 - 6.9 mmol/L. Impaired glucose
tolerance - 2 hour glucose level: 7.8-11 mmol/L. Type 2 diabetes - fasting plasma glucose: 7.0 mmol/L or 2
hour oral glucose tolerance test: 11.1 mmol/L. Ideally 150 grams of carbohydrate per day should be consumed
for three days before, and women should then fast for 8 hours immediately prior to the oral glucose tolerance test
since low carbohydrate intake may lead to false positive glucose tolerance tests. [PP]
Algorithms
26
ALGORITHM 2:
ASSESSMENT FOR EMOTIONAL WELLBEING FOR ALL WOMEN WITH POLYCYSTIC OVARY SYNDROME
INTERDISCIPLINARY CARE [CR]
Interdisciplinary care, with multiple health professionals involved, should be offered to women with PCOS, where appropriate based on the chronic and complex nature of the disease.
An interdisciplinary care model is the collaboration between a woman with PCOS and a care team who have shared goals for her total wellbeing. It should have the following integral components:
*
*
*
*
A care team, comprised of and representation from, varied health disciplines (eg. may include dietetics, psychology, endocrinology, gynaecology, exercise physiology, general practice)
A care plan which has been developed and agreed with the woman, and if relevant, the carer
A designated care coordinator, who oversees the care plan and monitors and evaluates outcomes, which is often the general practitioner
Clear and regular communication (eg. information sharing via different forms of media, including internet, letters, case conferencing, email, teleconference)
The complexity of the womans need will determine the extent of interdisciplinary care required.
GOOD PRACTICE POINT
When referring a woman with PCOS to other health professionals ie. psychologists, a resource has been developed (Appendix IV) to inform the professional about PCOS.
STEP 2: ASSESSMENT
STEP 1: SCREENING
Depression and/or anxiety should be routinely screened and assessed by all appropriately
qualified health professionals in women with PCOS.
If a woman with PCOS is positive on screening, the practitioner should further assess for
depression and/or anxiety.
If depression and/or anxiety are detected, appropriate management should be offered.
The following questions could be asked:
1. During the last month, have you often been bothered by feeling down, depressed, or hopeless?
2. During the last month, have you often been bothered by having little interest or pleasure in
doing things?
3. During the last month, have you been bothered by feeling excessively worried or concerned?
The following areas should be considered for further screening according to presented clinical symptoms:
If issues of
depression and/or
anxiety, body image,
disordered eating or
psychosexual
dysfunction are
identified on
screening explore
the assessment
further by
undertaking a clinical
interview using one
of the recommended
tools.
STEP 3: MANAGEMENT
Step 2:
The choice of scale selected should be at the discretion of the
clinician, based on specific sexual problem, accessibility and
expertise of the practitioner.
Algorithms
27
ALGORITHM 3:
MANAGEMENT OF LIFESTYLE FOR ALL WOMEN WITH POLYCYSTIC OVARY SYNDROME
DIET
Weight loss should be targeted in all women with PCOS and body mass index 25kg/m2 (overweight) through
reducing dietary energy (caloric) intake in the setting of healthy food choices, irrespective of diet composition. [C]
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. [D]
EXERCISE
Exercise participation of at least 150 minutes per week should be recommended in all women with PCOS,
especially those with a body mass index dvykgsm2 (overweight), given the metabolic risks of PCOS and the
long term metabolic benefits of exercise. [D]
Of this, 90 minutes per week should be aerobic activity at moderate to high intensity (60% - 90% of maximum
heart rate) to optimise clinical outcomes. [D]
Weight loss (in women with a body mass index vykgsm2 (overweight)) and prevention of weight gain (in
women with a body mass index vykgsm2 (lean)) is the joint responsibility of all health professionals, partnering
with women with polycystic ovary syndrome. Where complex dietary issues arise (or obesity is present), referral
to a dietitian should be considered as part of an enhanced primary care plan.
Tools such as Lifescripts could be used for engagement in dietary change: www.health.gov.au/lifescripts
Tools such as Lifescripts could be used for engagement in physical activity: www.health.gov.au/lifescripts
Algorithms
28
ALGORITHM 4:
Algorithms
29
ALGORITHM 5:
Algorithms
30
Introduction
Background
Polycystic ovary syndrome (PCOS) is one of the most common conditions in Australian women affecting 12-21%
of reproductive-aged women [5, 26, 27] with 70% of these affected women with PCOS remaining undiagnosed
[5]. In Indigenous 3 Australian women the prevalence is 21% [6]. Women with PCOS can present with a range of
features including psychological (poor self-esteem, anxiety, depression) [11, 28, 29], reproductive (menstrual
irregularity, hirsutism, infertility and pregnancy complications) [30], and metabolic features (insulin resistance
(IR), metabolic syndrome, prediabetes, type 2 diabetes (DM2) and cardiovascular disease (CVD)) [31, 32](Figure
1). Not all women demonstrate all symptoms and there is considerable heterogeneity. Presentation can also
vary across the lifecycle. PCOS is a chronic condition with manifestations that begin most commonly in
adolescence with menstrual irregularity and hyperandrogenism with transition over time into problems
including infertility and metabolic complications. PCOS is the most common cause of anovulatory infertility, and
once pregnant, these women have higher risks of pregnancy-related diabetes and pregnancy complications.
Figure 1. Published with permission from the Royal Australian College of General Practitioners [33].
Screening in unselected women with obesity showed 28% had PCOS, compared to 5% of women who were
lean [34]. The prevalence of PCOS will likely increase in line with the increasing prevalence of obesity in
Australia. Other important long-term implications include a 4-7 fold increased risk of DM2 and CVD [21, 35].
Challenges to feminine identity and body image due to obesity, acne and excess hair compromise quality of
life (QoL) in women with PCOS and social stigmas around symptoms adversely impact on self efficacy [10].
Increased rates of depression and anxiety are found in women with PCOS [28].
In 2006, the estimated health care costs of PCOS in the US were $6 billion/year. This equated to $400 million
in Australia (anovulation 31%, infertility 12% and PCOS related DM2 40% of total costs), representing a major
health and economic burden [36].
With acknowledgment that different terms are used, in this context, the word Indigenous refers to all Aboriginal or
Torres Straight Islanders.
Introduction
31
Long term metabolic complications of PCOS: Prediabetes, type 2 diabetes and cardiovascular disease
In PCOS, prospective trials have shown a 35% prevalence of prediabetes, a 10% prevalence of DM2, a 5-10 fold
risk of progression from prediabetes to DM2 and a 4-7 fold higher risk of DM2. CVD appears increased in PCOS
despite inadequate long-term studies to appropriately address this question [35]. It is proposed in the
international Androgen Excess and PCOS Society (AE-PCOS) consensus statement [17] that those with PCOS and
obesity, cigarette smoking, dyslipidemia, hypertension, impaired glucose tolerance, and subclinical vascular
disease are at increased relative CVD risk, and those with metabolic syndrome and/or DM2 are at even greater
relative risk. In the general population IR is a predictor of CVD [42, 43]. Women with PCOS also have an
increased prevalence of metabolic syndrome (associated with an increased risk for DM2 and CVD) [31], risk
factors for CVD and clinical signs of atherosclerosis [44, 45] which are all exacerbated by obesity. Women with
PCOS are therefore a population with a high relative risk of developing DM2 and CVD with this predisposition
greatly worsened by obesity. It is acknowledged that data on absolute risk of CVD in women with PCOS suggests
Introduction
32
an increase, however data in this area is limited. As DM2 and subsequent CVD are the primary cause of death in
Australian women, any increase in prevalence will have significant public health implications.
Introduction
33
Purpose
The purpose of this guideline is to integrate the best available evidence with clinical expertise and consumer
preferences to provide health professionals, consumers and policy makers with guidance on timely
diagnosis, accurate assessment and optimal management of women with PCOS and to promote consistency
of care and prevention of complications in primary care and specialist settings.
Patient population
This guideline is relevant to the assessment and management of adolescents of reproductive age and
women who have PCOS, including women with PCOS who are also infertile.
Scope
The scope of this guideline was driven by the clinical priorities identified by the PCOS Australian Alliance during
a two day workshop in 2008 4. The clinical priorities were:
Development of evidence-based guidelines for the care of women with PCOS in order to facilitate:
a. Early diagnosis of PCOS
b. Early detection and treatment of depression, anxiety and mood disorders
c. Early detection and diagnosis of risk factors for pre-diabetes, DM2 and CVD
d. Early detection and treatment of fertility problems and prevention of pregnancy complications.
Interdisciplinary co-ordinated care. Effective care for chronic conditions cannot take place unless there
are well trained health professionals to ensure appropriate assessment and treatment. The features of
PCOS require an interdisciplinary approach to care potentially including general practitioners, dietitians,
This workshop was funded by the Helen McPherson Smith Trust as a competitive grant.
Introduction
34
Using these clinical priorities, the Alliance identified the four key clinical areas and corresponding clinical
questions to be addressed in the guideline:
1.
2.
In this guideline, the term screen refers to identifying whether the condition exists and is the first step in
offering appropriate management; and the term assess refers to identifying the severity of the condition.
3.
Introduction
35
4.
In women with PCOS, what is the effectiveness of diet compared to exercise for improving weight loss,
metabolic, reproductive, fertility, QoL and emotional wellbeing outcomes? (See 5.2 Type of lifestyle
modification: Diet or exercise)
In women with PCOS, are diet interventions (compared to no diet or different diets) effective for
improving weight loss, metabolic, fertility, and emotional wellbeing outcomes? (See 5.3 Diet)
In women with PCOS, what is the most effective method to deliver dietary information for improving
weight loss, QoL and emotional wellbeing outcomes? (See 5.4 Diet delivery)
In women with PCOS, are exercise interventions (compared to no exercise or different exercises)
effective for improving weight loss, metabolic, reproductive, fertility, QoL and emotional wellbeing
outcomes? (See 5.5 Exercise)
This additional question was identified as important when the evidence review to answer the original question In
women with PCOS, is metformin effective for improving fertility outcomes? and subsequent recommendations were
discussed. It is apparent from the original evidence review that the effectiveness of metformin may be different
according to BMI in women with PCOS. However the guideline development group is unable to rely on the available
synthesized evidence identified for the original, more general question and more specific analysis of primary evidence
was required to explore the effectiveness of metformin in women with PCOS and a BMI<30-32.
Introduction
36
Rotterdam criteria
The 2003 Rotterdam consensus workshop concluded that PCOS is a syndrome of ovarian dysfunction along
with the cardinal features of hyperandrogenism and polycystic ovary (PCO) morphology. PCOS remains a
syndrome, and as such no single diagnostic criterion is sufficient for diagnosis. Clinical manifestations may
include menstrual irregularities, infertility, signs of androgen excess, obesity and psychological features. IR
and/or hyperandrogenism underpin the features of PCOS in the majority of cases.
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 congenital adrenal hyperplasia,
androgen-secreting tumours and Cushings syndrome [2].
NIH diagnostic criteria requires:
1. Oligo- or anovulation; and
2. Clinical and/or biochemical signs of hyperandrogenism;
and exclusion of other aetiologies such as congenital adrenal
hyperplasia, androgen-secreting tumours and Cushings syndrome [1].
Figure 2. Rotterdam criteria for diagnosis of PCOS is inclusive of NIH criteria, in that a woman diagnosed with PCOS
using the NIH criteria will also meet Rotterdam criteria, however a woman diagnosed with PCOS using Rotterdam
criteria may not meet NIH criteria.
This guideline does not address all aspects of PCOS, such as IVF therapy. Other factors may impact on the
psychosocial wellbeing of women with PCOS including but not limited to compromised infertility, health
related QoL and further depressive disorders such as bipolar disorder. These were beyond the resources
and capacity of this guideline but may be addressed in future updates.
This guideline does not seek to provide full safety and usage information on pharmacological and surgical
interventions. The pharmacological and surgical interventions recommended in the guideline should not be
applied without consideration to the patients clinical profile and personal preferences. It is recommended
that the reader consults the Therapeutic Guidelines (www.tg.com.au) and the National Prescribing Service
(www.nps.org.au) for detailed prescribing information including:
indications
drug dosage
method and route of administration
contraindications
supervision and monitoring
product characteristics
adverse effects.
Introduction
37
This guideline does not include a formal analysis of cost effectiveness of recommended practice versus
current/established practice. Consideration of cost did occur in guideline development group meetings and
did impact on recommendations. These considerations are discussed in the clinical impact of the
recommendation sections in each chapter. It also does not cover the economic feasibility of the
recommendations.
Funding
The development of this guideline was funded by the Australian Government Department of Health and
Ageing, through the national Jean Hailes for Womens Health on behalf of the PCOS Australian Alliance.
Editorial independence
This guideline is editorially independent. The funders, the Australian Government Department of Health and
Ageing, were not involved in the development of the guideline and have not influenced the scope or
recommendations of this guideline.
Introduction
38
Development of evidence-based guidelines for the care of women with PCOS in order to facilitate:
a. early diagnosis of PCOS
b. early detection and treatment of depression, anxiety and mood disorders
c. early detection and diagnosis of risk factors for pre-diabetes, DM2 and CVD
d. early detection and treatment of fertility problems and prevention of pregnancy complications.
Interdisciplinary co-ordinated care. Effective care for chronic conditions cannot take place unless there are
well trained health professionals to ensure appropriate assessment and treatment. The features of PCOS
require an interdisciplinary approach to care potentially including general practitioners, dietitians,
psychologists, exercise physiologists and nurse practitioners, endocrinologists, obstetricians and
gynaecologists. Optimally trained practitioners, armed with evidence-based guidance, need to take an
integrated approach to care in women with PCOS to improve outcomes.
Decisional support and education is needed to translate evidence into practice, including a website,
webcasts, CHECK program (continuing education for general practitioners), Active Learning Modules (ALM),
video conference case support, outreach services with advice, clinical attachments, clinical nurse support.
This will be addressed in guideline translation activities currently underway.
Self management and training, particularly around treatment options including lifestyle management is
needed in PCOS (ie. dietary, exercise and behavioural advice).
Using these clinical priorities, the Alliance identified the four key clinical areas:
1.
2.
3.
4.
The scope of the guideline was reviewed and approved by the Project Board, PCOS Australian Alliance
Strategic Advisory Group and the guideline development groups.
39
Consumer participation
The peak consumer body in PCOS, Polycystic Ovary Syndrome Association Australia (POSAA) provided
consumer representatives who participated in the PCOS Australian Alliance Strategic Advisory Group and the
guideline development groups. The President of POSAA is a member of the Project Board and the PCOS
Australian Alliance. Consumers have been involved in every stage including formation of the Alliance,
proposal to the Department of Health and Ageing for funding, development of the scope, public consultation
of the scope and developing and refining the clinical questions and recommendations as part of the
guideline development groups. Consumer representatives will also be extensively involved in the translation
activities of the guidelines.
Indigenous representation
Indigenous representation was present on the PCOS Australian Alliance Strategic Advisory Group (a member
of the Australian Indigenous Doctors Association) and the guideline development groups comprised
clinicians with experience working with Indigenous communities. The Program Manager for Jean Hailes for
Womens Health National Indigenous Womens Health Program provided oversight for Indigenous issues and
considerations across all recommendations in the guideline.
Training of guideline development groups in evidence review and guideline development methods
The chairs of each guideline development group attended a one day workshop, facilitated by Jean Hailes for
Womens Health and the Centre for Clinical Effectiveness, where the methods of reviewing evidence and
guideline development were described in detail. The purpose of this workshop was to familiarise the chairs
with:
40
the process of identifying, appraising and synthesising evidence in a format to facilitate the formulation
of evidence-based recommendations
grading the strength of evidence and its suitability to support evidence-based recommendations
when to facilitate discussion and clinical judgement to formulate clinical consensus recommendations in
the absence of evidence.
At this workshop the chairs also participated in an exercise to generate potential clinical questions.
In addition, at the beginning of the first guideline development group monthly meeting, the evidence advisor
briefly described the processes for evidence-based guideline development and these processes were
reiterated as the evidence reviews were presented each month.
1.
2.
41
3.
4.
This additional question was identified as important when the evidence review to answer the original question In
women with PCOS, is metformin effective for improving fertility outcomes? and subsequent recommendations were
discussed. It is apparent from the original evidence review that the effectiveness of metformin may be different
according to BMI in women with PCOS. However the guideline development group are unable to rely on the available
synthesized evidence identified for the original, more general question and more specific analysis of primary evidence
was required to explore the effectiveness of metformin in women with PCOS and a BMI<30-32.
Methods used to develop this guideline
42
(((polycystic AND (ovary OR ovarian)) AND (disease OR syndrome)) OR PCOS OR PCOD) AND (professional OR
association OR organisation OR organization OR college OR society OR academy OR peak)
Selection criteria
The PICO (Population, Intervention, Comparison, Outcome) framework was used by the guideline
development group to explore the components of each clinical question. These components were used to
include and exclude studies in the evidence review. Details of the selection criteria for each question can be
found in the supporting document titled Evidence report, which can be found at
www.managingpcos.org.au/pcos-evidence-based-guidelines.
43
studies addressing women with PCOS in all cultural, geographical and socioeconomic backgrounds and
settings would be identified by the search. The search strategy was limited to English language articles and
there were no limits on year of publication. The literature was searched until November 2010.
In keeping with the outlined schedule to update the guideline (page 50), and to reflect recently published
evidence on the effectiveness of aromatase inhibitors (Section 7.4) that had potential for significant clinical
impact with change in practice, the systematic search for this section was searched until January 2015.
The following electronic databases were employed to identify relevant literature:
We also searched the bibliographies of relevant studies identified by the search strategy and relevant
reviews/meta-analysis for identification of additional studies. Details of the search strategies and search
results for each evidence review can be found in the supporting document titled Evidence report, which
can be found at www.managingpcos.org.au/pcos-evidence-based-guidelines.
Where no evidence was found in women with PCOS (in emotional wellbeing evidence reviews), the
emotional wellbeing guideline development group requested additional support to help frame their
recommendations. The evidence officer for the emotional wellbeing guideline development group
undertook an additional search for evidence-based clinical practice guidelines that included
recommendations for the following in the general population: assessment of interdisciplinary models of
care; assessment of body image; assessment of disordered eating; assessment of psychosexual dysfunction.
The following methodology and inclusion criteria were applied:
Search known guideline service websites listed below for guidelines relevant to topic area in the general
population (not in women with PCOS)
Guidelines must not be more than 4 years old
Guidelines must pass the following AGREE benchmark criteria:
o Systematic methods were used to search for evidence
o There is an explicit link between the recommendations and the supporting evidence
The evidence officer provided any guidelines identified in this search to the guideline development
group for consideration.
44
Inclusion of studies
To determine the literature to be assessed further, a reviewer scanned the titles, abstract sections and
keywords of every record retrieved by the search strategy. Full articles were retrieved for further assessment
if the information given suggested that the study met the inclusion criteria. Studies were selected and
appraised by one reviewer in consultation with colleagues, using study selection (according to the PICO) and
appraisal criteria established a priori. Where there was any doubt regarding these criteria from the
information given in the title and abstract, the full article was retrieved for clarification.
Level
Intervention studies
II
III-1
III-2
III-3
IV
45
Table 1b. NHMRC levels of evidence for accuracy studies (adapted from NHMRC levels of evidence and
grades for recommendations for developers of guidelines [14]).
Level
Accuracy studies
II
A study of test accuracy with: an independent, blinded comparison with a valid reference
standard, among consecutive persons with a defined clinical presentation.
III-1
A study of test accuracy with: an independent, blinded comparison with a valid reference
standard, among non-consecutive persons with a defined clinical presentation.
III-2
A comparison with reference standard that does not meet the criteria required for
Level II and III-1 evidence.
III-3
IV
Table 1c. NHMRC levels of evidence for prognosis studies (adapted from NHMRC levels of evidence and
grades for recommendations for developers of guidelines [14]).
Level
Prognosis studies
II
III-1
All or none.
III-2
III-3
IV
46
Rating
Description
Low
All of the criteria have been fulfilled or where criteria have not been fulfilled
it is very unlikely the conclusions of the study would be affected.
Moderate
Some of the criteria have been fulfilled and those criteria that have not
been fulfilled may affect the conclusions of the study.
High
Few or no criteria fulfilled or the conclusions of the study are likely or very
likely to be affected.
Insufficient information
Data extraction
Data, according to the selection criteria, was extracted from included studies using a specially developed
data extraction form [52]. Information was collected on general details (title, authors, reference/source,
country, year of publication, setting), participants (age, sex, inclusion/exclusion criteria, withdrawals/losses
to follow-up, subgroups), results (point estimates and measures of variability, frequency counts for
dichotomous variables, number of participants, intention-to-treat analysis) and validity results. Quality
appraisal and data extraction tables for each evidence review can be found in the supporting document
titled Evidence report, which can be found at www.managingpcos.org.au
Data synthesis
Data was presented in summary form and descriptively, in tables or narratively in the evidence reviews for
each clinical question. Where appropriate, meta-analyses were conducted. These can be found in the
supporting document titled Evidence report, which can be found at www.managingpcos.org.au
Formulation of recommendations
Each of the four guideline development groups considered a new evidence review each month and drafted
corresponding evidence-based recommendations as outlined in NHMRC levels of evidence and grades for
recommendations for developers of guidelines [14].
The body of evidence supporting each recommendation was assessed in an NHMRC Evidence Statement
form (Appendix III) and for each of the following components, a grade was assigned: the volume,
consistency, generalisability, applicability and clinical impact of the body of evidence (see Table 3).
47
Table 3. Body of evidence assessment matrix (adapted from NHMRC levels of evidence and grades for
recommendations for developers of guidelines [14]).
Component
Excellent
Good
Satisfactory
Poor
Volume of
evidence
several level I or II
studies with low
risk of bias
level IV studies, or
level I to III studies
with high risk of
bias
Consistency
all studies
consistent
most studies
consistent and
inconsistency may
be explained
some inconsistency
reflecting genuine
uncertainty around
clinical question
evidence is
inconsistent
Clinical impact
very large
substantial
moderate
slight or restricted
Generalisability
population/s
studied in body of
evidence are the
same as the target
population for the
guideline
population/s
studied in the body
of evidence are
similar to the
target population
for the guideline
population/s
studied in body of
evidence different
to target
population for
guideline but it is
clinically sensible
to apply this
evidence to target
population
population/s
studied in body of
evidence different
to target
population and
hard to judge
whether it is
sensible to
generalise to target
population
Applicability
directly applicable
to Australian
healthcare context
applicable to
Australian
healthcare context
with few caveats
probably applicable
to Australian
healthcare context
with some caveats
not applicable to
Australian
healthcare context
These component grades were then compiled and an overall grade was assigned to the recommendation.
The overall grade reflects the strength of the recommendation in terms of trust or confidence practitioners
can have in the recommendation when applied in a clinical situation (see Table 4).
Where there was insufficient or no evidence to make an evidence-based recommendation, a clinical
consensus or research recommendation was made based on the clinical expertise of the multidisciplinary
guideline development group. Where important issues arose from discussion of evidence-based or clinical
consensus recommendations, and thus evidence was not sought, clinical practice points have been provided.
They are essential tips on how to safely and effectively implement the recommendations. Clinical consensus
48
recommendations, clinical practice points and research recommendations, which are not based on a body of
evidence but rather clinical expertise, are therefore not suitable for grading as outlined in NHMRC levels of
evidence and grades for recommendations for developers of guidelines [14]. Instead, a classification has
been allocated according to its type of recommendation ie. a clinical consensus recommendation is classified
CR and a clinical practice point is classified PP (see Table 5).
Table 4. The strength of the recommendations can be identified throughout the guideline with the following
grades (from NHMRC levels of evidence and grades for recommendations for developers of guidelines [14]):
Grade
Description
Body of evidence provides some support for recommendation but care should be taken
in its application.
Classification Description
CR
PP
Evidence not sought. A practice point is made by the guideline development group where
important issues arose from discussion of evidence-based or clinical consensus
recommendations.
The words should, could and should not do not directly reflect the grade or classification allocated to a
recommendation and are independent descriptors intended to reflect the judgment of the multidisciplinary
guideline development group about the practical application of the recommendation, balancing benefits and
harms. Where the word should is used in the recommendations, the guideline development group judged
that the benefits of the recommendation (whether evidence-based or clinical consensus) clearly exceed the
harms, and that the recommendation can be trusted to guide practice. Where the word could is used,
either the quality of evidence was underpowered, or the available studies demonstrated little clear
advantage of one approach over another, or the balance of benefits to harm was unclear. Where the words
should not are used, there is either a lack of appropriate evidence, or the harms outweigh the benefits.
All recommendations formulated from each evidence review were reviewed three times to ensure
consensus among the guideline development group: 1) a first draft recommendation(s) was suggested by the
evidence team and sent to the chair for input; 2) a second draft, formulated by the evidence team and the
guideline development group chair, was sent to the guideline development group; 3) the second draft of the
Methods used to develop this guideline
49
recommendation(s) was discussed and revised in the monthly guideline development group meeting; 4) the
revised recommendation was revisited and finalised upon consensus using a vote technique within the
guideline development group in the following monthly guideline development group meeting.
Each recommendation is supported by a discussion (in the chapters of this document) about the clinical need
for the question, the body of evidence identified to answer the question and the clinical impact of the
resulting recommendation(s), including potential changes in usual care and the way care is organised,
organisational barriers and resource implications. Such organisational issues are difficult to quantify without
conducting methodologically rigorous assessments of relevant services and resources, therefore the clinical
experience of the multidisciplinary guideline development groups was drawn upon for these discussions.
The Project Board, the PCOS Australian Alliance Strategic Advisory Group and the guideline development
groups support all 38 recommendations and intend they be used in conjunction with clinical judgement and
patient preferences. The guideline development groups acknowledge that lack of evidence is not evidence
of lack of effect and have attempted to reflect this in the strength of the grading given to recommendations
on interventions that are not supported by evidence. In addition, some interventions were not supported by
evidence in the recommendations due to lack of evidence of effect. The guideline development groups
acknowledge that this refers to lack of evidence of effect over placebo; that is, patients may receive some
beneficial outcomes from the intervention but these do not exceed the beneficial effects that can be
expected from a placebo therapy [53].
Public consultation
Public and targeted consultation was conducted for a period of 30 days commencing 5th March 2011 in
accordance with the legislative requirements set out in section 14A of the National Health and Medical
Research Council Act 1992 as outlined in the NHMRC standards and procedures for externally developed
guidelines (2007) [51]. Public consultation was invited via an advertisement in 'The Australian' which
directed the reader to content on the Jean Hailes for Women's Health website and a contact phone number.
The organisations approached for targeted consultation were:
50
Details of submissions arising from public consultation and the response of the guideline development
groups as well as how the guidelines were altered as a result of their inclusion are available upon request
(linda.downes@monash.edu).
In keeping with the outlined schedule to update the guideline (page 50), and to reflect recently published
evidence on the effectiveness of aromatase inhibitors (Section 7.4) that had potential for significant clinical
impact with change in practice, the evidence review for this section was updated. Public and targeted
consultation was invited for a period of 30 days commencing 21st February 2015. Public consultation was
invited via an advertisement in 'The Australian' which directed the reader to content on the Monash Centre
for Health Research and Implementation website and a contact phone number. Details of submissions
arising from public consultation and the response of the guideline development groups as well as how the
guidelines were altered as a result of their inclusion are available upon request, email
linda.downes@monash.edu.
External review
This guideline has been reviewed by the PCOS Australian Alliance Strategic Advisory Group, and
independently by the Australasian Cochrane Centre, relevant professional colleges and societies and through
public consultation.
Evaluation strategy
For an outline of the evaluation strategy, see Translation and implementation.
a change in the indications registered by the Therapeutic Goods Administration for any drug included in
this guideline; or
publication of any new major randomised controlled trials or systematic reviews that potentially have a
bearing on the safety of the recommendations in this guideline.
51
CHAPTER ONE
52
testosterone for diagnosis of PCOS and that the free androgen index (FAI) was better than androstenedione
and SHBG for diagnosis of PCOS [59]. The same study also found that calculated free testosterone and total
testosterone were better than androstenedione for diagnosis of PCOS.
There is supporting evidence from one medium quality, level III-2 study with a moderate risk of bias that FAI
was better than calculated free testosterone for diagnosis of PCOS [58]. However, the authors note that
their study did not have the statistical power to detect this small difference.
There was insufficient evidence from one low quality, level III-2 study with a high risk of bias to support any
differences between total testosterone, SHBG and androstenedione [60].
A diagnostic study (level III-2) with high risk of bias compared the diagnostic accuracy of gas
chromatographic mass spectrometry and radio-immunoassay to detect PCOS using serum reproductive
hormone markers [61]. The authors reported that the FAI had a higher area under the receiver operating
curve (AUC) than free testosterone, however they acknowledged that their study did not have the statistical
power to detect such small differences. No other direct comparisons between techniques were made.
The evidence obtained from the included studies is generalisable to patient population in terms of age and
BMI. The studies were conducted in Germany, Spain, Finland and Sweden and may be applied in the
Australian setting as the tests addressed in the studies are available and routinely used in Australia.
Recommendations
CLINICAL CONSENSUS RECOMMENDATION
1.1a Late-onset congenital adrenal hyperplasia, although rare, needs to be considered, before the
diagnosis of polycystic ovary syndrome is confirmed. In more severe clinical cases of
hyperandrogenism, 21-hydroxylase deficiency, the most common form of congenital adrenal
hyperplasia can be excluded by measuring serum 17-hydroxyprogesterone in the follicular phase to
explore this diagnosis.
EVIDENCE-BASED RECOMMENDATION
1.1b Calculated bioavailable testosterone, calculated free testosterone or free androgen index
should be first line investigation for biochemical determination of hyperandrogenism in
polycystic ovary syndrome.
The addition of androstenedione and dehydroepiandrosterone sulfate could be second line
investigation for biochemical determination of hyperandrogenism in polycystic ovary
syndrome.
It is difficult to assess androgen status in women on the oral contraceptive pill as effects include
oestrogen mediated increases in sex hormone-binding globulin and reduction in androgens.
Where the oral contraceptive pill has already been commenced, it should be withdrawn for at least
three months before appropriate hormonal assessments for diagnosis of polycystic ovary syndrome
are undertaken. Contraception should be otherwise managed during this time.
53
54
Recommendations
CLINICAL CONSENSUS RECOMMENDATION
1.2a
In adolescent women (<18 years), after two years of irregular cycles (>35 or <21 days) following the
onset of menarche, polycystic ovary syndrome should be considered and appropriate assessment
should be undertaken.
As polycystic ovary syndrome is a diagnosis of exclusion, other causes of irregular cycles (such as
thyroid dysfunction or hyperprolactinemia) need to be considered and excluded prior to the
diagnosis of polycystic ovary syndrome.
After twelve months of irregular cycles (>35 or <21 days) after onset of menarche, polycystic
ovary syndrome should be considered before commencement of the oral contraceptive pill.
Where the oral contraceptive pill has already been commenced, when girls are not sexually
55
56
consensus recommendation has been made based on the clinical expertise of the multidisciplinary guideline
development group.
Recommendations
CLINICAL CONSENSUS RECOMMENDATION
1.3a
Given the apparent lack of specificity of polycystic ovaries on ultrasound in adolescents, generally,
ultrasound should not be recommended first line in this age group for diagnosis of polycystic ovary
syndrome pending further research. If pelvic ultrasounds are to be ordered in adolescents, the
results should be interpreted with caution.
RESEARCH RECOMMENDATION
Further methodologically rigorous trials are important to determine:
1) Natural history of menstrual cycles in PCOS compared to non-PCOS adolescents
2) Age-appropriate normal ranges for sonographic features of polycystic ovaries and for clinical and
biochemical features of PCOS in adolescents (<18 years)
3) Accuracy of ovarian volume to diagnose polycystic ovary syndrome in adolescents (<18 years).
57
CHAPTER TWO
58
Recommendations
CLINICAL CONSENSUS RECOMMENDATION
2.1a
Interdisciplinary care, with multiple health professionals involved, should be offered to women with
polycystic ovary syndrome, where appropriate based on the chronic and complex nature of the
disease.
An interdisciplinary care model is the collaboration between a woman with polycystic ovary
syndrome and a care team who have shared goals for her total wellbeing. It should have the
following integral components:
A care team, comprised of representation from varied health disciplines (e.g. may include
dietetics, psychology, endocrinology, gynaecology, exercise physiology, general practice)
A care plan which has been developed and agreed with the woman, and if relevant, the carer
A designated care coordinator, who oversees the care plan and monitors and evaluates
outcomes, which is often the general practitioner
Clear and regular communication (e.g. information sharing via different forms of media,
including internet, letters, case conferencing, email, teleconference)
The complexity of the womans need will determine the extent of interdisciplinary care required.
CLINICAL PRACTICE POINT
2.1b When referring a woman with polycystic ovary syndrome to other health professionals ie..
psychologists, a resource has been developed (Appendix IV) to inform the professional about
polycystic ovary syndrome.
RESEARCH RECOMMENDATION
Further methodologically rigorous trials are important to address implementation and evaluation of
interdisciplinary models of care in polycystic ovary syndrome, where an evaluation strategy for a service
model needs to be designed from the outset of the interdisciplinary service. Implementation
research/evaluation of health service models requires resources.
59
and often women with PCOS need to see multiple health professionals frequently. Although current care
plans do facilitate chronic PCOS care, funding models need to be adapted for chronic, complex health
problems like PCOS.
Whilst there are organisational changes that need to take place, there is also a need to change the cultural
mindset and philosophy of clinicians. The single and multidisciplinary care models have been well
established, where clinicians tend to work autonomously. The interdisciplinary model of care requires a
considerable change in culture and in health service delivery. Clinicians need to shift to a philosophy of
collaboration, trust and respect for all professional competences and recognise complementary skills and
knowledge. This may require an education strategy aiming to break down impedance to this model of care.
60
CHAPTER THREE
61
Recommendations
CLINICAL CONSENSUS RECOMMENDATION - CARDIOVASCULAR RISK
3.1a
All women with polycystic ovary syndrome should be assessed for cardiovascular disease risk by
assessing individual cardiovascular disease risk factors.
If screening in women with polycystic ovary syndrome shows that any of the following
cardiovascular disease risk factors are present, these women with polycystic ovary syndrome should
be considered at increased relative risk of cardiovascular disease (obesity, cigarette smoking,
dyslipidemia, hypertension, impaired glucose tolerance, lack of physical activity) and those with
metabolic syndrome and/or type 2 diabetes, at even greater risk.
Body mass index should be assessed in all women with polycystic ovary syndrome using the
following criteria [15]:
Body mass index <18.5kg/m2 = underweight
Body mass index 18.5 24.9kg/m2 = lean
Body mass index 25.0 29.9kg/m2 = overweight
Body mass index 30.0-34.9kg/m2 = obese
Body mass index 35kg/m2 = morbidly obese
Significant benefits have been demonstrated with 5-10% weight loss in overweight women with
polycystic ovary syndrome and is a feasible initial target (see 5.4c).
BMI doesnt always reflect adverse body fat stores and waist circumference will be useful.
Waist circumference should be assessed using the following criteria [15]:
Waist circumference >80cm = increased risk of metabolic complications
Waist circumference >88cm = substantially increased risk of metabolic complications
62
High density lipoprotein cholesterol (HDL-C) - HDL-C levels should be > 1.0 mmol/L [18]
Prediabetes and/or type 2 diabetes should be assessed in all women with polycystic ovary syndrome
(see 3.2a and 3.2b).
Blood pressure should be measured annually in women with polycystic ovary syndrome and a body
mass index 25kg/m2 (lean).
Blood pressure should be routinely measured at each visit in women with polycystic ovary syndrome
and a body mass index 25kg/m2 (overweight/obese).
63
Recommendations
CLINICAL CONSENSUS RECOMMENDATION
3.2a
To assess for risk of type 2 diabetes, in addition to polycystic ovary syndrome status, the following
diabetes risk factors should be considered [20, 21]:
Age
Gender
Ethnicity
Parental history of diabetes
History of high blood glucose levels
Use of antihypertensive medications
64
Smoking
Physical inactivity
Waist circumference
Ideally 150 grams of carbohydrate per day should be consumed for three days before, and women
should then fast for 8 hours immediately prior to the oral glucose tolerance test since low
carbohydrate intake may lead to false positive glucose tolerance tests.
RESEARCH RECOMMENDATIONS
Further methodologically rigorous trials in women with polycystic ovary syndrome are important to
determine:
1) absolute risk of CVD in women with polycystic ovary syndrome across age ranges
2) the most appropriate way of identifying those with polycystic ovary syndrome at highest risk of
developing type 2 diabetes and the value of utilising existing scores such as the AUSDiab risk score in
women with polycystic ovary syndrome
3) the most effective method to prevent the development of type 2 diabetes.
65
to DM2 and CVD. It is acknowledged that oral glucose tolerance tests increase inconvenience for patients
and may impact on compliance. In some populations where cardiometabolic and DM2 risk is high, the
impact of weight gain appears to be more significant than in Caucasian populations and this needs to be
considered when assessing and managing women with PCOS. In these populations consideration should be
given to potentially lower BMI limits in high risk ethnic groups. It is important to note that assessment of
insulin resistance has no current role in clinically assessing for risk of DM2.
66
CHAPTER FOUR
The treatment and management of depression in adults with chronic physical health problems, NICE,
2009 [23].
Chapter 4: Assessment of emotional wellbeing in PCOS
67
Depression: the treatment and management of depression in adults, NICE, 2009 [130].
Beyondblue Depression in Adolescents and Young Adults, Beyond Blue, 2010 [131].
Anxiety: management of generalised anxiety disorder and panic disorder (with or without agoraphobia)
in adults in primary, secondary and community care partial update, 2011 [132].
The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [133] also informed the clinical
consensus recommendation.
Recommendation
CLINICAL CONSENSUS RECOMMENDATION
4.1a Depression and/or anxiety should be routinely screened and assessed by all appropriately qualified
health professionals in women with polycystic ovary syndrome.
If a woman with polycystic ovary syndrome is positive on screening, the practitioner should further
assess for depression and/or anxiety.
If depression and/or anxiety are detected, appropriate management should be offered.
CLINICAL PRACTICE POINT
4.1b To screen for depression and/or anxiety, the following questions could be asked [23]:
1) During the last month, have you often been bothered by feeling down, depressed, or hopeless?
2) During the last month, have you often been bothered by having little interest or pleasure in
doing things?
3) During the last month, have you been bothered by feeling excessively worried or concerned?
If any of the screening questions are positive further depression and/or anxiety assessment could be
by either:
a) Referring the patient to an appropriate professional if they do not feel competent to perform a
further mental health assessment. If the health professional is not the patients usual GP, inform
the GP of the referral.
b) If they feel competent, perform a clinical interview and according to level of competence,
choose from one or more of the following :
68
69
for the general population and the clinical expertise of the multidisciplinary guideline development group.
The guideline development group has consulted the following guidelines:
NICE Guideline 31 Obsessive Compulsive Disorder: Core interventions in the treatment of obsessive
compulsive disorder and body dysmorphic disorder [142].
Australian Medical Association Position Statement: Body Image and Health 2002 [143].
Recommendation
CLINICAL CONSENSUS RECOMMENDATION
4.2a Negative body image should be considered in women with polycystic ovary syndrome.
If a woman with polycystic ovary syndrome is positive on screening, the practitioner should further
assess for negative body image.
If negative body image is detected, appropriate management should be offered.
CLINICAL PRACTICE POINT
4.2b To screen for negative body image, the following questions could be asked:
1) Do you worry a lot about the way you look and wish you could think about it less?
2) On a typical day, do you spend more than 1 hour per day worrying about your appearance?
(More than 1 hour a day is considered excessive)
3) What specific concerns do you have about your appearance?
4) What effect does it have on your life?
5) Does it make it hard to do your work or be with your friends and family?
If an issue is identified, the practitioner could further assess negative body image by:
a) Identifying any focus of concern of the patient and respond appropriately
b) Assessing the level of depression and/or anxiety (if they have not done so already) (see 4.1a)
c) Identifying if there is any distortion of body image (e.g. presence of anorexia nervosa (see 4.3) or
body dysmorphic disorder)
70
other tools recommended here. Intervention may require referral to other health practitioners. Where
needed, access to appropriately trained and experienced health professionals is required. A shift in cultural
mindset may be required to ensure the clinical impact of negative body image is understood.
71
Recommendation
CLINICAL CONSENSUS RECOMMENDATION
4.3a Disordered eating, including eating disorders, should be considered in women with polycystic ovary
syndrome.
If a woman with polycystic ovary syndrome is positive on screening, the practitioner should further
assess for disordered eating and eating disorders.
If disordered eating, or an eating disorder is detected, appropriate management should be offered.
CLINICAL PRACTICE POINT
4.3b To screen for disordered eating and eating disorders, the following questions could be asked:
1) Do you worry you have lost control over your eating?
2) Do you ever feel disgusted, depressed, or guilty about eating?
3) Have you tried fasting or skipping meals in an attempt to lose weight?
4) Have you tried vomiting, laxatives or diuretics in an attempt to lose weight?
5) Have you had significant (e.g. >5-7%), recurrent fluctuation in body weight?
If a woman with polycystic ovary syndrome answers yes to any of the above questions the
practitioner should further assess for the diagnosis of an eating disorder by either:
a) Referring the patient to an appropriate professional to perform a further mental health
assessment.
b) If the practitioner feels competent, performing a clinical interview which may be supplemented
with standardised assessment tools (e.g. Eating Assessment Tool (EAT 26) www.eat-26.com).
c) Assessing the level of depression and/or anxiety (see 4.1a).
72
required. A shift in cultural mindset may be required to ensure the clinical impact of eating disorders is
understood.
Recommendation
CLINICAL CONSENSUS RECOMMENDATION
4.4a Psychosexual dysfunction should be considered in women with polycystic ovary syndrome.
If a woman with polycystic ovary syndrome is positive on screening, the practitioner should further
assess for psychosexual dysfunction.
If psychosexual dysfunction is detected, appropriate management should be offered.
CLINICAL PRACTICE POINT
4.4b To screen for psychosexual dysfunction, the following questions could be asked:
1) During the last few months, have you often been bothered by problems with your sex life such
as reduced satisfaction, diminished desire, pain, or any other problems?
73
2) Do you feel that polycystic ovary syndrome affects your sex life?
3) (If relevant) Do sexual problems affect your current relationship and/or have sexual problems
affected your past relationships?
If a woman with polycystic ovary syndrome answers yes to any of the above questions or where
sexual function is a concern, the practitioner should assess this through more detailed clinical
interview, and in particular screen for depression and/or anxiety if not already done (see 4.1) and
negative body image (see 4.2) or refer to a more appropriately qualified health practitioner.
Specific validated scales could be used as outcome measures at baseline to monitor progress over
time. The choice of scale should be selected by the discretion of the clinician, based on the specific
sexual problem, accessibility and expertise of the practitioner.
RESEARCH RECOMMENDATIONS
Further methodologically rigorous trials in women with polycystic ovary syndrome are important to
determine the most effective tool to assess and optimal approaches to manage:
74
This body of research should consider emotional wellbeing across the different cultural and age groups
affected by PCOS.
75
CHAPTER FIVE
76
Recommendations
EVIDENCE-BASED RECOMMENDATION
5.1a 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 polycystic ovary syndrome.
RESEARCH RECOMMENDATION
Further methodologically rigorous trials in women with polycystic ovary syndrome are important to
address:
1) The extent of the benefits of lifestyle management compared to no or minimal therapy for all clinically
relevant outcomes
2) Comparing efficacy of different types of lifestyle management (diet alone, exercise alone, behavioural
modification alone, or combinations of the three)
3) The effect of lifestyle management in prevention of weight gain/weight maintenance compared to
weight loss
4) The effect of lifestyle management for women who are both overweight and not overweight and
specific reproductive outcomes such as menstrual regularity, ovulation and fertility and the relative
efficacy of lifestyle management either compared to or in combination with pharmacological therapy.
77
recommendation will reduce variation in practice and ensure lifestyle advice is prescribed to all women with
PCOS, targeting prevention of weight gain and promoting weight loss, where appropriate. The
recommendation may result in increased consultation times, increased utilisation of care plans and
increased referral to allied health professionals and as such, higher associated healthcare costs, however
long term benefits of lifestyle change are anticipated to reduce the health and economic burden of PCOS.
Barriers to implementation of these recommendations include the engagement of health practitioners,
access to allied health professionals and financial barriers. Insufficient consultation time allocated by general
practitioners and other health professionals may also be a barrier and a shift in cultural mindset may be
required to focus on lifestyle interventions especially around prevention of weight gain which is not
traditionally a focus of health professionals. In high risk populations where cardiometabolic and DM2 risk is
increased, the impact of weight gain appears to be more significant than in Caucasian populations and this
needs to be considered when assessing and managing women with PCOS.
78
increased ovulation rate (SET: 28 ovulatory cycles/113 observed cycles (24.8%), HCHP: 18 ovulatory
cycles/119 observed cycles (15.1%), p=0.032) and increased cumulative ovulation rate (SET: 13 ovulatory
patients/20 patients (65.0%), HCHP: 5 ovulatory patients/20 patients (25.0%), p=0.011). In the SET group,
there were thirteen ovulatory women, compared to the diet group of just three ovulatory women. There
was no difference between the interventions for anthropometric, metabolic, non-fertility or QoL outcomes,
however upon subgroup analysis in women who were ovulatory, SET was better than diet for fasting insulin
(SET: -23.4 10.0, HCHP: -13.1 8.6, p<0.05), fasting glucose-to-insulin ratio (SET: 37.5 19.6, HCHP: 19.0
10.1, p<0.05), homeostasis model of assessment-insulin resistance (HOMA-IR) (SET: -41.0 15.9, HCHP: -9.1
4.1, p<0.05), SHBG (SET: 82.5 30.6, HCHP: 41.9 19.1, p<0.05) and FAI (SET: -27.2 9.2, HCHP: -18.1
9.7, p<0.05). Diet was better than SET for weight (SET: -5.6 1.6, HCHP: -10.5 4.1, p<0.05) and BMI (SET:
10.0 3.7, HCHP: -15.4 3.9, p<0.05). The evidence from the included study is directly generalisable to the
patient population of women with PCOS, particularly to women who have BMI 33kg/m2.
There may be limitations to generalising these findings to other ethnic groups, especially to non-European
populations. The usability of the evidence is limited to the particular exercise (bicycling) and diet (high
protein, low carbohydrate) interventions used in this study.
Recommendation
EVIDENCE-BASED RECOMMENDATIONS
5.2a Lifestyle management targeting weight loss (in women with a body mass index 25kg/m2
(overweight)) and prevention of weight gain (in women with a body mass index 25kg/m2
(lean)) should include both reduced dietary energy (caloric) intake and exercise and should
be first line therapy for all women with polycystic ovary syndrome.
79
Recommendations
EVIDENCE-BASED RECOMMENDATIONS
5.3a
Weight loss should be targeted in all women with polycystic ovary syndrome and body
mass index 25kg/m2 (overweight) through reducing dietary energy (caloric) intake in the
setting of healthy food choices, irrespective of diet composition.
C
80
5.3b Prevention of weight gain should be targeted in all women with polycystic ovary syndrome
through monitored caloric intake, in the setting of healthy food choices, irrespective of
diet composition.
Weight loss (in women with a body mass index 25kg/m2 (overweight)) and prevention of weight
gain (in women with a body mass index 25kg/m2 (lean)) is the joint responsibility of all health
professionals, partnering with women with polycystic ovary syndrome. Where complex dietary
issues arise (or obesity is present), referral to a dietitian should be considered as part of an
enhanced primary care plan.
Tools such as Lifescripts could be used for engagement in dietary change:
www.health.gov.au/lifescripts
RESEARCH RECOMMENDATION
Further methodologically rigorous trials in women with polycystic ovary syndrome are important to
address:
1) A range of diet compositions including low glycaemic index for both prevention of weight gain/weight
maintenance and weight loss in women who are overweight and in women who are lean
2) Monitoring of safety and harms of diets and longer follow-up
3) Increasing engagement and compliance with intervention studies.
81
short term, combined with lack of access to services in rural and remote areas, implementation of the
dietary recommendations may be difficult in some settings.
82
study where only breakfast was altered [214]. Exercise was only increased in two studies [170, 203]. Other
studies reported participants having regular exercise [189, 205], or having no change in exercise levels [193,
214]. One study offered participants other lifestyle support mechanisms such as menu plans, emails,
newsletters, articles, recipes, and motivational support [189, 205].
There was no difference between the diet delivery methods for the majority of the anthropometric, QoL,
and emotional wellbeing outcomes. Two studies reported differences for anthropometric outcomes [204,
214] and another study reported a difference in an emotional wellbeing outcome [205], however the studies
varied by the diet delivery regime and by degree of dietary support, so it is difficult to make a
recommendation about the use of one method over another.
The evidence from the included studies is directly generalisable to the patient population of women with
PCOS, particularly to women >30 years of age and who have BMI 30kg/m2. However, the majority of the
women in the studies were European Caucasian, so there may be limitations to generalising these findings to
other ethnic groups. The multidisciplinary guideline development group included evidence comparing diet
compositions as different diets have inherent differences in the method of their delivery and on the
behaviour of the participant.
Overall, the diet delivery approaches that were consistently reported included face to face advice and
education about diet composition, food types and practical approaches to healthy eating, including
behaviour change techniques.
Recommendations
EVIDENCE-BASED RECOMMENDATION
5.4a Face to face, tailored dietary advice, including education, behavioural change techniques
and ongoing support should be provided to women with polycystic ovary syndrome and a
body mass index 25kg/m2 (overweight). Dietary modification is the joint responsibility of
all health professionals, partnering with women with polycystic ovary syndrome.
83
RESEARCH RECOMMENDATION
Further methodologically rigorous trials in women with polycystic ovary syndrome are important to
address:
1) the types of diet delivery methods and diet support and tools that are effective - an initial study would
be to have diet compositions the same and vary the delivery method or support tools between the
groups
2) comparison of the delivery methods for lifestyle interventions including comparing settings and
providers.
84
groups to reduce DM2 risk [223, 224] and improve cardiovascular risk factors (ie. weight, lipid profiles and
blood pressure) [225, 226]. Similarly, resistance or weight-bearing exercise either alone or in combination
with aerobic exercise has been shown to improve health outcomes in high risk groups [227-230]. When
combined with dietary changes, exercise has been shown to potentiate the effects of diet on insulin
sensitivity in obese DM2 patients [231].
Whilst diet and exercise should be combined in PCOS lifestyle interventions, there is significant evidence to
support the role of exercise alone for improving overall health and insulin sensitivity, independent of any
weight loss [174, 232]. Thus, it is important to determine whether the inclusion of moderate to high intensity
exercise and different types of exercise may be effective in management of PCOS and its associated comorbidities.
85
It is important to note that while exercise has benefits for overweight women with PCOS, the evidence is
limited, inconsistent and of low quality.
Recommendations
EVIDENCE-BASED RECOMMENDATION
5.5a
Exercise participation of at least 150 minutes per week should be recommended to all
women with polycystic ovary syndrome, especially those with a body mass index
25kg/m2 (overweight), given the metabolic risks of polycystic ovary syndrome and the
long term metabolic benefits of exercise. Of this, 90 minutes per week should be aerobic
activity at moderate to high intensity (60% - 90% of maximum heart rate) to optimise
clinical outcomes.
RESEARCH RECOMMENDATION
Further methodologically rigorous trials in women with polycystic ovary syndrome are important to help
define what types, intensities and delivery methods of exercise strategies are optimal for lean and
overweight women for improved clinical outcomes.
86
health professionals including insufficient consultation time allocated by general practitioners, may be
barriers. Drop-out or non-adherence to exercise programmes by patients may be a problem, but if there is
adequate allied health and clinical support, then this issue may be reduced. A shift in cultural mindset may
be required to ensure clinicians and women with PCOS understand the importance of exercise in PCOS
management.
To find an exercise physiologist, follow the links on the Exercise and Sports Science Australia website:
www.essa.org.au
87
CHAPTER SIX
88
menstrual frequency (p<0.05) [259]. There was no difference between lifestyle (diet) therapy (with or
without placebo) and pharmacological therapy.
When comparing lifestyle (diet) therapy (with or without placebo) to pharmacological therapy plus lifestyle
(diet) therapy, five out of the eight studies reported that there was no difference between the interventions.
Gambineri et al. reported that metformin was better than placebo plus diet for menstrual pattern after six
months (p=0.03) and 12 months (p=0.003) [182, 260] and frequency of menstruation at both baseline to six
months (p=0.05) and baseline to 12 months (p=0.01). Pasquali et al. reported that metformin plus diet was
better than placebo plus diet (p<0.05) for menstruation frequency [191]. Another study reported that
lifestyle plus clomiphene citrate was better than lifestyle alone for ovulation rate and menstrual frequency
(p<0.05) [259].
Adverse events were not consistently reported. Two patients had adverse events in the metformin group
[261] and Qublan et al. [192] reported that 11 women withdrew due to side-effects in the metformin plus
diet group. Six women withdrew from the placebo plus diet group due to side effects within the first 2
months of the study, however the side effects were not defined.
It is important to note that there was inconsistency in the components of lifestyle (diet) therapy and
therefore a recommendation cannot be made about a specific intervention; however given that there is no
difference between lifestyle and pharmacological therapy overall, the guideline development group deemed
that there are clear benefits in using lifestyle interventions over pharmacological interventions.
Recommendations
EVIDENCE-BASED RECOMMENDATIONS
6.1a
Lifestyle management, including diet and exercise programs, should be used throughout
the lifespan in women with polycystic ovary syndrome to optimise health generally and to
alleviate polycystic ovary syndrome clinical severity including infertility.
6.1b In women with polycystic ovary syndrome and body mass index 30kg/m2 with due
consideration given to age-related infertility, intensive (frequent multidisciplinary contact)
lifestyle modification alone (and not in combination with pharmacological ovulation
induction therapy) should be first line therapy for 3 to 6 months to determine if ovulation
is induced.
6.1c
Pharmacological ovulation induction should not be recommended for first line therapy in
women with polycystic ovary syndrome who are morbidly obese (body mass index
35kg/m2) until appropriate weight loss has occurred either through diet, exercise,
bariatric surgery, or other appropriate means.
6.1d Pharmacological ovulation induction could be second line therapy, after intensive lifestyle
modification has been undertaken.
C
C
Morbid obesity (body mass index 35kg/m2) increases risks during pregnancy and should be
regarded as a relative contraindication to assisted fertility.
6.1f
Psychological factors should be considered and managed in infertile women with polycystic ovary
89
RESEARCH RECOMMENDATIONS
Further methodologically rigorous trials are important to investigate the impact of lifestyle improvement
on fertility outcomes including live birth. Implementation research into the optimal engagement,
adherence and delivery of lifestyle intervention is needed to inform consumers, health professionals and
policy makers.
90
CHAPTER SEVEN
91
Recommendations
EVIDENCE-BASED RECOMMENDATION
7.1a
7.2 Metformin
In women with PCOS, is metformin effective for improving fertility outcomes?
92
is a biguanide which is used as an oral antihyperglycaemic agent in the treatment of DM2 [274]. The first
published report on the use of metformin as a treatment for PCOS was in 1994 [275]. The early studies
examining the reproductive system effects of metformin in women with PCOS showed promising results but
most of the studies had relatively small sample sizes [272].
Metformin is available in two formulations: immediate and extended-release. Therapeutic regimens of
metformin administration in PCOS are not well standardized in clinical practice, and various protocols have
been used in the studies available in literature with an extremely variable target dose of 1500 to 2550 mg
per day having been proposed [258].
Metformin was better than placebo for ovulation rate in overall women with PCOS 7 (OR 2.12 [1.50,3.00]
I2=69% p=0.000019; 13 studies, 875 participants) [257], women with PCOS and a BMI 30kg/m2 (OR 2.33
[1.433.81] I2=88% p=0.00071; 4 studies, 417 participants) [257], women with PCOS and a BMI 30kg/m2
(OR 1.94 [1.203.15] I2=39% p=0.0073; 9 studies, 458 participants)[257] and women with nonclomiphene citrate resistant (non-CCR 8) PCOS (OR 3.55 [1.468.65]; 6 studies, 401 participants) [276].
However, there was significant statistical heterogeneity in overall women with PCOS and women with
PCOS and a BMI 30kg/m2. There was no difference in ovulation rate between metformin and placebo
in women with CCR PCOS.
Metformin was better than placebo for pregnancy rate in overall women with PCOS (OR 3.86 [2.18, 6.84]
I2=0% p<0.00001; 6 studies, 479 participants) [257] and women with PCOS and a BMI 30kg/m2 (OR 4.41
[2.248.66] I2=40% p=0.000017; 3 studies, 250 participants) [257] but no difference in women with PCOS
and a BMI 30kg/m2, women with clomiphene citrate nave PCOS, women with CCR PCOS or women
with non-CCR PCOS.
There was no difference between metformin and placebo for live birth rate in overall women with PCOS,
women with CCR PCOS and women with PCOS and a BMI 30kg/m2.
There was no difference between metformin and placebo for miscarriage rate in overall women with
PCOS.
Metformin had a higher incidence of gastrointestinal related adverse events compared to placebo (OR
9.23 [4.18, 20.37] I2=25% p<0.00001; 5 studies, 253 participants) in women with PCOS [257].
Two systematic reviews (one high quality systematic review (level I) with low risk of bias [257] and a medium
quality systematic review (level I) with moderate risk of bias [277]) and two RCTs (one high quality RCT (level
II) with low risk of bias [278] and a medium quality RCT (level II) with moderate risk of bias [262] (both RCTs
were published after publication of the most current systematic review) found that:
7
Overall women with PCOS is defined as all the women with PCOS in the relevant study or studies regardless of BMI
or clomiphene citrate exposure or sensitivity.
8
Non-CCR PCOS is defined as clomiphene citrate sensitive or unknown clomiphene citrate sensitivity.
Chapter 7: Pharmacological management of infertility in PCOS
93
Clomiphene citrate was better than metformin for ovulation rate in overall women with PCOS (OR 0.48
[0.41, 0.57] I2=78% p<0.00001; 3 studies, 2470 participants) [257] and women with PCOS and a BMI
30kg/m2 (OR 0.43 [0.360.51] I2=0% p<0.00001; 2 studies, 2044 participants) [257]. However, there
was significant statistical heterogeneity seen in overall women with PCOS. There was no difference in
ovulation rate between metformin and clomiphene citrate in women with PCOS and a BMI 30kg/m2.
Clomiphene citrate was better than metformin for pregnancy rate in overall women with PCOS (OR 0.63
[0.43, 0.92] I2=91% p=0.018; 3 studies, 600 participants) [257] and women with PCOS and a BMI
30kg/m2 (OR 0.34 [0.210.55] I2=0% p=0.000011; 2 studies, 500 participants) [257]. However, there
was significant statistical heterogeneity seen in overall women with PCOS. Metformin was better than
clomiphene citrate for pregnancy rate in women with PCOS and a BMI 30kg/m2, however this was
based on a single study (OR 3.47 [1.527.90] I2=NA p=0.0031; 1 study, 100 participants) [257].
There was no difference in live birth rate between metformin and clomiphene citrate in overall women
with PCOS with statistical heterogeneity. Clomiphene citrate was better than metformin for live birth
rate in women with PCOS and a BMI 30kg/m2 without statistical heterogeneity (OR 0.30 [0.170.52]
I2=0% p=0.000021; 2 studies, 500 participants) [257]. Metformin was better than clomiphene citrate for
live birth rate in women with PCOS and a BMI 30kg/m2, however this was based on a single study (OR
4.94 [1.9912.26] I2=NA p=0.00059; 1 study, 100 participants) [257].
There was no difference in multiple pregnancy rate (without statistical heterogeneity) and miscarriage
rate (with statistical heterogeneity) between metformin and clomiphene citrate in overall women with
PCOS.
Three systematic reviews (two high quality systematic reviews (level I) with low risk of bias [257, 276] and a
medium quality systematic review (level I) with moderate risk of bias [277]) and five RCTs (three high quality
RCT (level II) with low risk of bias [278-280], a medium quality RCT (level II) with moderate risk of bias [262]
and a low quality RCT (level II) with high risk of bias [281]) (all RCTs were published after publication of the
most current systematic review) found that:
Metformin plus clomiphene citrate was better than clomiphene citrate alone for ovulation rate in overall
women with PCOS (OR 1.76 [1.51, 2.06] I2=74% p<0.00001; 11 studies, 2668 participants) [257], women
with PCOS and a BMI 30kg/m2 (OR 1.61 [1.132.31] I2=65% p=0.0091; 5 studies, 525 participants) [257],
women with PCOS and a BMI 30kg/m2 (OR 1.80 [1.512.14] I2=81% p<0.00001; 6 studies, 2143
participants) [257], women with CCR PCOS (OR 4.86 [2.43, 9.74] I2=0% p<0.00001; 5 studies, 179
participants) [257], women with non-CCR PCOS (OR 3.84 [1.3810.68]; 5 studies, 832 participants) [276],
and women with unknown clomiphene citrate sensitivity PCOS (ie. clomiphene citrate sensitivity not
defined) (OR 1.65 [1.40, 1.94] I2=85% p<0.00001; 5 studies, 2433 participants) [257]. However, there
was significant statistical heterogeneity seen in all these types of PCOS women except in the women
with CCR PCOS. There was no difference in ovulation rate between metformin plus clomiphene citrate
and clomiphene citrate alone in women with clomiphene citrate sensitive PCOS.
Metformin plus clomiphene citrate was better than clomiphene citrate alone for pregnancy rate in
overall women with PCOS (OR 1.48 [1.12, 1.95] I2=58% p=0.0058; 7 studies, 976 participants) [257],
women with PCOS and a BMI 30kg/m2 (OR 1.67 [1.182.36] I2=41% p=0.0038; 5 studies, 643
participants) [257], women with clomiphene citrate nave PCOS (RR 1.5 [1.21.8] I2=78% p<0.0001; 7
studies, 985 participants) [277] and women with CCR PCOS (RR 5.6 [2.313] I2=0% p=0.0001; 5 studies,
212 participants) [277]. However, there was significant statistical heterogeneity seen in all these types
of PCOS women except in women with PCOS and a BMI 30kg/m2 and women with CCR PCOS. There
was no difference in pregnancy rate between metformin plus clomiphene citrate and clomiphene citrate
94
alone in women with PCOS and a BMI 30kg/m2, women with non-CCR PCOS and women with unknown
clomiphene citrate sensitivity PCOS.
Metformin plus clomiphene citrate was better than clomiphene citrate alone for live birth rate in women
with CCR PCOS, without significant statistical heterogeneity (RR 6.4 [1.234] I2=0% p=0.03; 2 studies, 107
participants) [277]. There was no difference in live birth rate between metformin plus clomiphene
citrate and clomiphene citrate alone in overall women with PCOS women, women with PCOS and a BMI
30kg/m2, women with PCOS and a BMI 30kg/m2, or women with clomiphene citrate nave PCOS.
There was no difference between metformin plus clomiphene citrate and clomiphene citrate alone for
miscarriage rate in overall women with PCOS and women with PCOS and a BMI 30kg/m2.
There was no difference between metformin plus clomiphene citrate and clomiphene citrate alone for
multiple pregnancy rate in overall women with PCOS, women with PCOS and a BMI 30kg/m2 and
women with unknown clomiphene citrate sensitivity PCOS.
Clomiphene citrate alone had fewer gastrointestinal related adverse events compared to metformin plus
clomiphene citrate in overall women with PCOS.
One high quality systematic review (level I) with low risk of bias evaluating two RCTs with a mean BMI 30
kg/m2 [282] and two RCTs (one high quality RCT (level II) with low risk of bias [278] and one medium quality
RCT (level II) with moderate risk of bias [262] (both RCTs were published after publication of the most
current systematic review)) and found that:
Metformin plus clomiphene citrate was better than metformin alone for ovulation rate (OR 0.23 [0.15,
0.34] Q=0.948 (p=0.330 test for heterogeneity) p<0.0001 (for test of overall effect); 2 studies, 741
participants), pregnancy rate (OR 0.23 [0.14, 0.37] Q=0.244 (p=0.622 test for heterogeneity) p<0.0001
(for test of overall effect); 2 studies, 741 participants) and live birth rate (OR 0.23 [0.13, 0.40] Q=0.533
(p=0.465 test for heterogeneity) p<0.0001 (for test of overall effect); 2 studies, 741 participants) in
overall women with PCOS [282].
There was no difference between metformin plus clomiphene citrate and metformin alone for
miscarriage rate or adverse events in overall women with PCOS.
The included studies provide supporting evidence for the use of metformin alone as well as for the use of
metformin combined with clomiphene citrate. The included studies also provide supporting evidence for the
use of clomiphene citrate over metformin, therefore we suggest that metformin be used (alone or in
combination with clomiphene citrate) only in women with PCOS who have not responded to clomiphene
citrate as first line therapy either in terms of ovulation or pregnancy. There is evidence that the use of
metformin may be associated with gastrointestinal related adverse events and therefore women with PCOS
who are prescribed metformin (alone or in combination with clomiphene citrate) to improve fertility
outcomes should be informed about associated gastrointestinal related side effects.
There is heterogeneity in the evidence about efficacy of metformin for rates of ovulation, pregnancy and live
birth across the subgroups, including BMI ( or 30kg/m2) and sensitivity to clomiphene citrate.
Additionally, we conducted a meta-analysis of four RCTs (level II) comparing metformin and clomiphene
citrate in women with PCOS and a BMI 30-32kg/m2 [262, 278, 283, 284], since this was not performed in
any of the included systematic reviews. There was no difference between metformin and clomiphene
citrate in women with PCOS and a BMI30-32kg/m2. Due to significant heterogeneity across the RCTs and
wide confidence intervals in the results, we were unable to make an evidence-based recommendation. For
more detail about this evidence review and analysis, see section 7.2b in the Evidence report
(www.managingpcos.org.au/pcos-evidence-based-guidelines).
Chapter 7: Pharmacological management of infertility in PCOS
95
The evidence is generalisable to patient population in terms of age and BMI. The setting was varied and only
one of the RCTs within one systematic review was conducted in New Zealand which may be generalisable to
the Australian setting but may not be generalisable to Indigenous populations.
Recommendations
EVIDENCE-BASED RECOMMENDATIONS
7.2a
7.2b Metformin could be used alone to improve ovulation rate and pregnancy rate in women
with polycystic ovary syndrome who are anovulatory, have a body mass index 30kg/m2
and are infertile with no other infertility factors.
7.2c
If one is considering using metformin alone to treat women with polycystic ovary
syndrome who are anovulatory, have a body mass index 30kg/m2, and are infertile with
no other infertility factors, clomiphene citrate should be added to improve fertility
outcomes.
B
A
RESEARCH RECOMMENDATIONS
Further methodologically rigorous trials are important to address:
1) whether the addition of metformin to clomiphene citrate improves live birth rate in anovulatory PCOS
women with no other infertility factors
2) whether there is a difference in effectiveness between clomiphene citrate and metformin in PCOS
anovulatory, infertile women with a body mass index 30kg/m2 to improve fertility outcomes.
96
hence it is not approved for use in PCOS 9. Whilst use is evidence-based, patient explanation and consent is
appropriate.
7.3 Gonadotrophins
In women with PCOS, are gonadotrophins effective for improving fertility outcomes?
For TGA approval, industry must propose metformin for approval and as metformin is generic and produced by many
companies, no one company will fund and support an application to TGA. This technical challenge is independent of
effectiveness or evidence.
Chapter 7: Pharmacological management of infertility in PCOS
97
review (in the supporting document titled Evidence report, which can be found at
www.managingpcos.org.au/pcos-evidence-based-guidelines).
The evidence obtained from the included studies is generalisable to patient population in terms of age and
BMI. Where reported, studies were conducted in Spain and India. These studies may be applied in the
Australian setting, but may not address issues of special importance, such as generalisability to Indigenous
populations.
Recommendations
EVIDENCE-BASED RECOMMENDATIONS
7.3a
7.3b Gonadotrophins could be considered as first line pharmacological therapy in women with
polycystic ovary syndrome who are therapy nave, anovulatory and infertile, with no other
infertility factors.
Where gonadotrophins or laparoscopic ovarian surgery (see 8.1) are to be prescribed, the following
should be considered:
RESEARCH RECOMMENDATION
Further methodologically rigorous trials are important to address the role of gonadotrophins in ovulation
induction in polycystic ovary syndrome.
98
99
the identified systematic reviews contains the meta-analyses conducted in the initial Australian PCOS
guideline and thus will not be referred to further [299]. The remaining three systematic reviews will only be
referred to where they provide evidence not already addressed in this evidence review [300-302].
Aromatase inhibitors compared to placebo
Our search did not identify any studies addressing the effectiveness of letrozole as first line therapy in
women with PCOS (ie. letrozole versus placebo in treatment nave patients).
Studies identified by our search addressed the effectiveness of letrozole as second line therapy in women
with PCOS. One high quality RCT (level II) with a low risk of bias compared letrozole to placebo in women
with CCR PCOS and found that letrozole was better than placebo for ovulation rate per patient but there was
no difference between letrozole and placebo for pregnancy rate per patient or live birth rate per patient
[303].
Type, duration and dose of aromatase inhibitors
One high quality RCT with low risk of bias found that there was no statistical difference between letrozole
and anastrozole for ovulation rate per cycle, pregnancy rate per cycle and miscarriage rate per pregnancy in
clomiphene-resistant women with PCOS [304]. A low quality RCT with high risk of bias (Al-Omari 2004)
addressing this comparison and outcomes found that letrozole is better than anastrazole for ovulation rate
per cycle (p=0.05) and pregnancy rate per cycle (p = 0.05), however it is possible that the effect may be
overestimated in a study with high risk of bias and therefore the results should be interpreted with caution.
One high quality RCT with low risk of bias found that long term therapy (10 days) of letrozole may be better
than short term therapy (5 days) for pregnancy rate per cycle in clomiphene-resistant women with PCOS (p
= 0.03) but that there is no statistical difference between short and long term therapy for ovulation rate per
patient and miscarriage rate per pregnancy [305]. This is the only study identified addressing the duration
and dose of letrozole and the 10 day protocol using 2.5mg per day appeared optimal.
One low quality RCT with low risk of bias found that there was no statistical difference between 5mg/day
and 7.5mg/day of letrozole for ovulation rate per patient and per cycle, pregnancy per patient and per cycle,
miscarriage rate per pregnancy and multiple pregnancies per pregnancy [306]. No OHSS was reported in
either group.
Aromatase inhibitors compared to clomiphene citrate
Thirteen RCTs (level II) compared letrozole with clomiphene citrate. Seven of these RCTs had a high risk of
bias [307-313], two had a moderate risk of bias [298, 314] and four had a low risk of bias [315-318]. Upon
meta-analysis, we found that letrozole was better than clomiphene citrate for ovulation rate per patient
[298, 307, 308, 310, 312, 314, 317, 318]; pregnancy rate per patient [298, 307-318]; and per cycle [310, 311,
318]; and live birth rate per patient [298, 308, 315, 317, 318]. There was no difference between letrozole
and clomiphene citrate for ovulation rate per cycle [310, 311, 315, 316, 318]; multiple pregnancy rate per
patient [298, 307, 309, 310, 313, 316-318]; and miscarriage rate per patient [298, 308-310, 314-318]. When
subgroup analysis was conducted for studies that included women with PCOS who were therapy nave, there
was no difference between the two interventions for any outcome though we note that for pregnancy rate
per patient the OR 1.68 [95% CI 0.96, 2.94] had an I2 of 0% and a p value of 0.07.
100
Outcome
RCTs*
PCOS &**
Effect estimate***
Favours
2L 2M 5H
TN CCR U
letrozole
3L 2H
TN U
ND
4L 2M 7H
TN CCR U
letrozole
1L 2H
TN CCR U
letrozole
3L 1M 1H
TN CCR U
letrozole
Multiple pregnancy
rate per patient
3L 1M 4H
TN CCR U
ND
4L 2M 3H
TN CCR U
ND
*Risk of bias: L, low risk of bias, high quality; M, moderate risk of bias, medium quality; H, high risk of bias, low
quality.
**Includes women with PCOS and one or more of: TN, therapy nave; CCR, clomiphene citrate-resistant; U,
unknown whether therapy nave or clomiphene citrate-resistant.
***OR, odds ratio
101
The evidence obtained from the included studies is generalisable to patient population in terms of age and
BMI. Detail about the study setting was often not reported but studies were conducted in Egypt, Iraq,
Bangladesh, Iran, India, Saudi Arabia, Turkey and the USA. These studies may be applied in the Australian
setting, but may not address issues of special importance, such as generalisability to Indigenous populations
and those of ethnicities not yet studied. It should also be noted that the evidence does not provide clear
guidance on the role of aromatase inhibitors across the different treatment subgroups (eg. Treatment nave
and clomiphene citrate-resistant women) or ethnic groups.
Recommendations
EVIDENCE BASED RECOMMENDATIONS
7.4a
7.4b Letrozole, under caution, could be considered as a first line pharmacological treatment for
ovulation induction in therapy naive, infertile anovulatory women with polycystic ovary
syndrome with no other infertility factors
A
B
10
The Council of Australian Therapeutic Advisory Groups (CATAG) includes the following recommendation with regard
to "off-label" prescribing: An in-depth discussion with the patient/carer about potential benefits and risks is necessary
when making the decision to use a medicine off-label. This is particularly important when the use of a medicine offlabel is being considered on the wishes of the patient/carer. In general, the off-label use of a medicine should only be
considered when the approved use of a registered medicine does not address the clinical needs of patients [322].
Chapter 7: Pharmacological management of infertility in PCOS
102
RESEARCH RECOMMENDATION
Further methodologically rigorous trials are important to address the role of aromatase inhibitors in
ovulation induction in polycystic ovary syndrome. In particular, the comparison of letrozole and clomiphene
citrate in population subgroups according to BMI and prior therapy or not is important to explore. The
impact on birth defects should also be investigated.
103
CHAPTER EIGHT
104
laparoscopic ovarian surgery was better than gonadotrophins for multiple pregnancy rate (OR 0.13 [0.03 to
0.59] I2 = 0%, 4 studies, 303 participants) [327].
One high quality RCT (level II) with a low risk of bias compared laparoscopic ovarian surgery to clomiphene
citrate plus metformin and found that clomiphene citrate plus metformin (CC+M) was better than
laparoscopic ovarian surgery for ovulation rate per cycle (LOS: 77/107 (72%), CC+M: 52/92 (56.5%),
p=0.023), but there was no difference for live birth rate per cycle, pregnancy rate per cycle and miscarriage
rate per pregnancy [328].
Two medium quality RCTs (level II) with a moderate risk of bias compared laparoscopic ovarian surgery to
metformin and found that there was insufficient evidence to make a recommendation about laparoscopic
ovarian surgery compared to metformin for live birth rate per patient, ovulation rate per cycle, pregnancy
rate per cycle, pregnancy rate per patient and miscarriage rate per pregnancy [329-331] because the
evidence was conflicting. One RCT reported that laparoscopic ovarian surgery was better than metformin
for ovulation (OR 2.05; [1.42.9] p=0.001) and pregnancy rate (per cycle: OR 2.19 [1.034.63] p=0.03; per
patient: OR 2.47 [1.055.81] p=0.03) [329] and the other study reported that metformin was better than
laparoscopic ovarian surgery for live birth rate (metformin: 82.1%, LOS: 64.5%, p<0.05), pregnancy rate per
cycle (metformin: 18.6%, LOS: 13.4%, p<0.05), and miscarriage rate (metformin: 15.4%, LOS:29.0%, p<0.05)
[330, 331]. Both medium quality single centre studies had a small sample size and moderate risk of bias and
therefore need to be interpreted with caution.
One high quality RCT (level II) with a low risk of bias compared laparoscopic ovarian surgery to clomiphene
citrate [332] and one high quality systematic review of RCTs (level I) with low risk of bias found that
laparoscopic ovarian surgery was better than gonadotrophins for multiple pregnancy rate (OR 0.13 [0.03 to
0.59] I2 = 0%, 4 studies, 303 participants) [327]. These studies found that there was no difference between
laparoscopic ovarian surgery, clomiphene citrate and gonadotrophins for live birth rate per patient and
pregnancy rate per patient, ovulation rate per patient and miscarriage rate per pregnancy [327, 332].
There was insufficient evidence to support or refute the use of laparoscopic ovarian surgery over metformin
or clomiphene citrate or clomiphene citrate plus metformin for multiple pregnancies [329-332] and there
was insufficient evidence to support or refute the use of laparoscopic ovarian surgery over any intervention
for adverse effects and QoL.
The evidence obtained from the included studies is generalisable to the patient population in terms of age
and BMI. Detail about the study setting was often not reported but studies were conducted in New Zealand,
Italy, UK and Egypt. While the studies conducted in Europe and Egypt may not be directly generalisable to
the Australian setting, it is possible that the RCT [333] included in the systematic review by Farquar et al.
[327], conducted in New Zealand, may address issues of special importance, such as generalisability to
Indigenous populations.
105
Recommendations
EVIDENCE-BASED RECOMMENDATION
8.1a
Laparoscopic ovarian surgery should be second line therapy in women with polycystic
ovary syndrome who are clomiphene citrate resistant, anovulatory, and infertile, with no
other infertility factors.
Where ovulation induction would be considered appropriate, laparoscopic ovarian surgery can be
used as first line treatment if laparoscopy is indicated for another reason in infertile women with
PCOS.
106
107
complications. Average energy intake is around 1600kcals/day following bariatric surgery [343] and nutrient
density therefore becomes an issue affecting nutritional status. Women may be at particular risk of
deficiencies in iron, folate and iodine in addition to other nutrients as the recommended daily intake
increases in pregnancy. While supplement use is widely recommended following bariatric surgery and for
pregnant women, there are reports of poor compliance with supplement use in the general population of
pregnant women with only 10% taking adequate folate [344]. This may be further compromised because of
poor food tolerance in bariatric patients, particularly of foods fortified with iodine and folate such as bread.
Assisting women with a BMI 35kg/m2 through standard infertility is not appropriate (see recommendation
6.1c). In severe obesity, lifestyle interventions have very limited efficacy but given the substantial efficacy of
bariatric surgery in women who are severely obese, including in women with PCOS, it is important to
determine the impact of bariatric surgery on infertility in women with PCOS. The potential benefits also need
to be balanced with the risks of bariatric surgery.
Recommendations
CLINICAL CONSENSUS RECOMMENDATION
8.2a
Bariatric surgery could be considered second line therapy to improve fertility outcomes in adult
women with polycystic ovary syndrome who are anovulatory, have a body mass index 35kg/m2, and
who remain infertile despite undertaking an intensive (frequent multidisciplinary contact) structured
lifestyle management program involving reducing dietary energy (caloric) intake, exercise,
behavioural and/or drug interventions for a minimum of 6 months.
A structured weight management program involving diet, physical activity and interventions to
improve psychological, musculoskeletal and cardiovascular health should continue postoperatively.
The patient should be made aware of the risk of pre-and post-operative nutritional deficiencies
and should be managed in a specialist interdisciplinary care setting, including a bariatric surgeon,
a dietitian and/or other multidisciplinary staff trained to work with patients who have had
bariatric surgery.
108
Bariatric surgery should not be conducted in patients who are known to be pregnant [24]
Pregnancy should be avoided during periods of rapid weight loss
Patients should be counselled to avoid pregnancy for at least 12-18 months after bariatric
surgery [24, 25]
Contraception should be discussed prior to surgery
If pregnancy occurs, the patient should be made aware of the risk of pre-and post-operative
nutritional deficiencies and should ideally be managed in a specialist interdisciplinary care
setting which includes an obstetrician, bariatric surgeon and a dietitian and/or other
multidisciplinary staff trained to work with patients who have had bariatric surgery to ensure
that nutritional deficiencies and complications are avoided
Fetal growth should be monitored during pregnancy
A structured weight management program involving diet, physical activity and interventions to
improve psychological, musculoskeletal and cardiovascular health should continue postoperatively.
RESEARCH RECOMMENDATIONS
Further methodologically rigorous trials are important to address the efficacy, safety and role of bariatric
surgery in polycystic ovary syndrome including to improve fertility.
109
3
4
5
6
7
Impacts of implementation of recommendations, including costs, have been considered throughout the guideline by
the guideline development groups. Recommendations on challenges in diagnostic assessment of PCOS impact primarily
through increased investigations. Metabolic tests on CVD risk factors and glycaemic status would be expected to
increase in response to guideline implementation, with cost implications, whereas more limited androgen testing and
less usage of ultrasounds in adolescents may reduce costs.
8
9
10
11
12
In assessment of emotional wellbeing, screening may increase consultation time, however initial screening time can be
minimised by the use of the devised general emotional wellbeing screening tool developed with this guideline
(Appendix V) that can be completed outside consultation times and has been trialled and used in clinical practice. The
primary challenges here are the cost implications when psychological dysfunction is detected, potentially requiring
additional consultation time and referral to other health professionals and utilisation of care plans may be required.
13
14
15
16
17
18
Likewise, in lifestyle management of PCOS, recommendations may increase consultation times, utilisation of care plans
and referral to allied health professionals and as such, higher associated healthcare costs. However long term benefits
of lifestyle change are anticipated to reduce the health and economic burden of PCOS. Whilst in the overall
management of infertility, lifestyle intervention and bariatric surgery have cost implications, which may be offset by
reduced medical intervention to induce fertility, overall the fertility recommendations are not expected to have major
resource implications.
19
110
Age-appropriate normal ranges for sonographic features of polycystic ovaries and for clinical and
biochemical features of PCOS in adolescents (<18 years)
Accuracy of ovarian volume to diagnose PCOS in adolescents (<18 years)
Implementation and evaluation of an interdisciplinary model of care in PCOS, where an evaluation
strategy for a service model needs to be designed from the outset of the interdisciplinary service.
Evaluation of health service models requires resources
Absolute risk of CVD in women with polycystic ovary syndrome across age ranges
The most appropriate way of identifying those with PCOS at highest risk of developing DM2 and the
value of utilising existing scores such as the AUSDiab risk score
The most effective method to prevent the development of DM2
Further methodologically rigorous trials in women with PCOS are important to determine the most
effective tool to assess and optimal approaches to manage:
o depression and/or anxiety
o psychosexual dysfunction
o eating disorders and disordered eating
o negative body image
o overall health related quality of life
This body of research should consider emotional wellbeing across the different cultural and age groups
affected by PCOS.
The extent of the benefits of lifestyle management compared to no or minimal treatment for all clinically
relevant outcomes
Comparing efficacy of different types of lifestyle management (diet alone, exercise alone, behavioural
modification alone, or combinations of the three)
The effect of lifestyle management in prevention of weight gain/weight maintenance compared to
weight loss
The effect of lifestyle management for women who are both overweight and not overweight and specific
reproductive outcomes such as menstrual regularity, ovulation and fertility and the relative efficacy of
lifestyle management either compared to or in combination with pharmacological therapy
A range of diet compositions including low GI for both prevention of weight gain/weight maintenance
and weight loss in women who are overweight and in women who are lean
Monitoring of safety and harms of diets and longer follow-up
Increasing engagement and compliance with intervention studies
The types of diet delivery methods and diet support and tools that are effective - an initial study would
be to have diet compositions the same and vary the delivery method or support tools between the
groups
Comparison of the delivery methods for lifestyle interventions including comparing settings and
providers
The types, intensities and delivery methods of exercise strategies that are optimal for lean and
overweight women for improved clinical outcomes
111
112
indications
drug dosage
method and route of administration
contraindications
supervision and monitoring
product characteristics
adverse effects.
This guideline does not include a formal analysis of cost effectiveness of recommended practice compared to
current/established practice, nor does it cover economic feasibility of the recommendations. Consideration
of cost did occur in guideline development group meetings and did impact on recommendations. These
considerations are discussed in the clinical impact of the recommendation sections in each chapter.
The guideline is based on the best evidence available up to November 2010. Evidence published after this
date has not been reviewed for the guideline. Development of technology and pharmacological intervention
progresses rapidly and so the guideline may become outdated. However steps are in place to ensure that the
guideline is updated in a timely manner, such as upon publication of new evidence that has any bearing on
the safety of the recommendations or if there are changes in the indications registered by the Therapeutic
Goods Administration for any drug included in the guideline. For more information about scheduled review
and update, see Scheduled review and update of the guideline.
All recommendations are limited by their applicability to a particular population and setting, therefore use of
the recommendations need to be guided by clinical judgement. For example, high risk populations where
cardiometabolic and DM2 risk is increased, the impact of weight gain appears to be more significant than in
Caucasian populations and this needs to be considered when assessing and managing women with PCOS.
Finally, a guideline is only useful if it has been translated and implemented into practice appropriately. In
doing so, cultural barriers may be experienced.
113
training health professionals in diagnosis and treatment of specific conditions and diseases
producing multi-media presentations that health services and agencies can use to educate their staff and
clients
maintaining a sophisticated, data-rich website with health education resources for women and health
professionals on a variety of topics relating to women, in multiple languages and for all regions of
Australia
responding to requests for information from all sectors by phone, as well as through face-to-face
seminars, presentations and briefings for women and health professionals throughout Australia
extending health promotion messages through the media.
A deliverable of the funding for this guideline is a comprehensive 18 month translation program,
commenced as of February 2011. This program includes dissemination of the guideline and translation of
the guideline into a range of practice enhancement and education tools (e.g. algorithms, facts sheets),
targeting a diverse range of end-users. A comprehensive evaluation of the translation tools is integrated
into the dissemination and translation program. The evaluation is also ongoing through the funded PCOS
Service of Excellence at Jean Hailes for Womens Health which is underpinned by this guideline.
Translation of the updated Section 7.4 Aromatase inhibitors will be facilitated through Jean Hailes for
Womens Health channels, through the fertility-related networks of Alliance and guideline development
group members and through publication of the updated evidence review.
Below are the proposed resources to be developed and translation activities to be undertaken.
114
Resources
Date
Dissemination/use
To begin November
2011 (ongoing)
November 2011
(ongoing)
As above
November 2011
(ongoing)
April 2011
115
Education Programs/Activities
Date
Comments/Further Detail
At least 1 education session to be delivered in each capital city (in Australia).
Sessions to be delivered in partnership with local general practice networks
and with the support of members from the
PCOS Alliance
June 2012
By Nov 2012
By Feb 2012
Public seminars
116
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He, D. and F. Jiang, Meta-analysis of letrozole versus clomiphene citrate in polycystic ovary
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Franik, S., et al., Aromatase inhibitors for subfertile women with polycystic ovary syndrome.
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Title
First
name
Organisation/ State
Doctor
Jacqueline
Boyle
Doctor
Leah
Brennan
Doctor
Grant
Brinkworth
Obstetrician/
Gynaecologist
Clinical and Health
Psychologist and Senior
Research Fellow
Research Scientist
Associate
Professor
Professor
Wendy
Brown
General Surgeon
Henry
Burger
Endocrinologist
Professor
Iain
Clarke
Academic
Doctor
Anne
Corbould
Endocrinologist
Doctor
Michael
Costello
Doctor
Andrea
Cussons
Obstetrician/Gynaecologist
Reproductive
Endocrinologist
Endocrinologist
Associate
Professor
Doctor
Michael
Davies
Amanda
Deeks
Associate
Professor
John
Eden
Doctor
Meredith
Frearson
Professor
Roger
Hart
Doctor
Theresa
Hickey
Doctor
Prudence
Johnstone
Doctor
Warren
Kidson
Doctor
Rachael
Knight
134
Doctor
Ee Mun
Lim
Doctor
Cate
Lombard
Dietitian
Doctor
Wendy
March
Epidemiologist
Doctor
Kate
Marsh
Dietitian/ Diabetes
Educator
Mrs
Veryan
McAllister
Mrs
Janet
Michelmore
Doctor
Lisa
Moran
Associate
Professor
Manny
Noakes
Research Scientist/
Dietitian
Professor
Robert
Norman
Professor
Raymond
Rodgers
Obstetrician/
Gynaecologist
Pathologist
Reproductive
Endocrinologist
Research Fellow
Professor
Peter
Rogers
Researcher
Doctor
Luk
Rombauts
Doctor
Deborah
Sloboda
Obstetrician/
Gynaecologist
Reproductive
Endocrinologist
Scientist
Doctor
Nigel
Stepto
Clinical
Professor
Bronwyn
Stuckey
Endocrinologist
Doctor
Mac
Talbot
Professor
Helena
Teede
Obstetrician/
Gynaecologist
Endocrinologist
Doctor
Mala
Thondan
General Practitioner
Associate
Professor
Beverley
Vollenhoven
Reproductive
Endocrinologist
Doctor
Jennifer
Wong
Endocrinologist
135
Name
Discipline
Technical team
Project Director
Endocrinologist
Project Manager
Guideline Developer
Evidence Advisor
Ms Linda Downes
Dr Marie Misso
Ms Angela Melder
Dr Henry Ko
Ms Marie Garrubba
Project Manager
Senior Evidence Officer
Evidence Service Manager
Senior Project Officer
Senior Project Officer
Evidence Officers
Project board
Chair
Members
Endocrinologist
Reproductive Endocrinologist
Consumer
Organisational affiliation
Director of Research, Jean Hailes for Womens Health; Head of
Diabetes, Monash Health; Professor of Womens Health and
Monash Site Director, School of Public Health, Monash
University
Jean Hailes for Womens Health
Jean Hailes for Womens Health
Centre for Clinical Effectiveness, Monash Health
Centre for Clinical Effectiveness, Monash Health
Centre for Clinical Effectiveness, Monash Health
Chief Executive Officer, Jean Hailes for Womens Health
Director of Research, Jean Hailes for Womens Health; Head of
Diabetes, Monash Health; Professor of Womens Health and
Monash Site Director, School of Public Health, Monash
University
Director, The Robinson Institute, University of Adelaide
President, Polycystic Ovary Syndrome Association Australia
(the peak consumer organisation in PCOS)
136
Members
Reproductive Endocrinologist
Consumer
Endocrinologist
Ms Angela Melder
General Practitioner
Dr Michael Costello
Obstetrician
Gynaecologist
Reproductive Endocrinologist
Epidemiologist
Obstetrician
Gynaecologist
Reproductive Endocrinologist
Dr Meredith Frearson
General Practitioner
137
Members
Endocrinologist
Endocrinologist
Psychiatrist
Dr Jennifer Wong
Dr Leah Brennan
Associate Professor Beverley
Vollenhoven
Dr Mala Thondan
Ms Irene Apostolopoulos
Ms Angela Melder
Ms Marie Garrubba
Endocrinologist
Clinical and Health Psychologist
Dietitian,
Senior Research Fellow
Obstetrician
Gynaecologist
General Practitioner
Consumer
Evidence Service Manager
Senior Project Officer
Dr Lisa Moran
Endocrinologist
Dr Kate Marsh
Associate Professor Manny
Noakes
Dr Mac Talbot
Dietitian
Obstetrician
Monash IVF
Dr Cate Lombard
Evidence team
Members
Dr Amanda Deeks
138
Evidence team
Dr Meredith Frearson
Dr Mala Thondan
Ms Irene Apostolopoulos
Gynaecologist
General Practitioner
General Practitioner
Consumer
Dr Nigel Stepto
Exercise Physiologist
Ms Angela Melder
Dr Henry Ko
Members
Endocrinologist
Endocrinologist
Dr Ee Mun Lim
Chemical Pathologist
Endocrinologist
Obstetrician
Gynaecologist
Dr Elizabeth Davis
Paediatric Endocrinologist
Dr Jacqueline Boyle
Evidence team
Dr Meredith Frearson
Mrs Kedra Egan
Ms Angela Melder
Dr Marie Misso
Dr Michael Costello
Obstetrician
Gynaecologist
General Practitioner
Consumer
Evidence Service Manager
Senior Evidence Officer
Obstetrician
Gynaecologist
139
Reproductive Endocrinologist
Endocrinologist
Obstetrician
Gynaecologist
Reproductive Endocrinologist
Obstetrician
Gynaecologist
Reproductive Endocrinologist
Endocrinologist
Obstetrician
Gynaecologist
Consumer
NSW
Clinical Academic, Department of Reproductive Medicine, the
Royal Hospital for Women
Director of Research, Jean Hailes for Womens Health; Head of
Diabetes, Monash Health; Professor of Womens Health and
Monash Site Director, School of Public Health, Monash
University
Director, The Robinson Institute, University of Adelaide
Researcher
Surgeon
Physician
140
Dr Cate Lombard
Dietitian
Senior Research Fellow
Dr Lisa Moran
Dr Nigel Stepto
Exercise Physiologist
Dr Amanda Vincent
Endocrinologist
141
One or more level I studies with a low risk of bias or several level II studies with a
low risk of bias
One or two Level II studies with a low risk of bias or SR/several Level III studies with a
low risk of bias
One or two Level III studies with a low risk of bias or Level I or II studies with a
moderate risk of bias
Evidence is inconsistent
2. Consistency (if only one study was available, rank this component as not applicable)
NA
3. Clinical impact (Indicate in the space below if the study results varied according to some unknown factor (not simply study quality or sample size) and thus the clinical impact of the intervention could not be
determined)
Very large
Moderate
Slight
Restricted
4. Generalisability (How well does the body of evidence match the population and clinical settings being targeted by the Guideline?)
A
Evidence not directly generalisable to the target population but could be sensibly
applied
Evidence not directly generalisable to target population and hard to judge whether it
142
is sensible to apply
5. Applicability (Is the body of evidence relevant to the Australian healthcare context in terms of health services/delivery of care and cultural factors?)
A
Descriptor
Grade
Volume of Evidence
Consistency
Clinical impact
Generalisability
Applicability
Other Factors (Indicate here any other factors that you took into account when assessing the evidence base (for example, issues that might cause the group to downgrade or upgrade the recommendation)
Recommendations
What recommendation(s) does the guideline development group draw from this evidence? Use action statements where possible.
Grade of Recommendation
Unresolved Issues (If needed, keep note of specific issues that arise when each recommendation is formulated and that require follow-up.)
Implementation of Recommendation
Please indicate yes or no to the following questions. Where the answer is yes please provide explanatory information about this. This information will be used to develop the
implementation plan for the guidelines.
143
YES/NO
Are there any resource implications associated with implementing this recommendation?
YES/NO
Will the implementation of this recommendation require changes in the way care is currently organised?
YES/NO
Are the guideline development group aware of any barriers to the implementation of this recommendation?
YES/NO
144
Body Image
1. Do you worry a lot about the way you look and wish you could think about it less?
2. On a typical day, do you spend more than 1 hour day worrying about your appearance?
(More than 1 hour a day is considered excessive)
3. What specific concerns do you have about your appearance?
4. What effect does it have on your life?
5. Does it make it hard to do your work or be with your friends and family?
145
Disordered Eating
1.
2.
3.
4.
5.
Psychosexual Dysfunction
1. During the last few months, have you often been bothered by problems with your sex life such as reduced
satisfaction, desire, pain, or any other problems?
2. Do you feel that PCOS affects your sex life?
3. Do sexual problems affect your current relationship and/ or have sexual problems affected your past
relationships?
If you require any additional information regarding PCOS and emotional health please contact the Jean
Hailes PCOS Service on 03 9562 7555 and ask to speak with the PCOS Service Coordinator.
You can also visit the Jean Hailes for Womens Health website www.jeanhailes.org.au and the
www.managingpcos.org.au website, which contain professional development webcasts and extensive
information on PCOS and other womens health conditions.
Dr Mandy Deeks
Psychologist
Chair
Emotional wellbeing in PCOS
Guideline development group
Project Director
PCOS evidence-based guidelines project
146
No
Maybe
Yes
No
Maybe
During the last month, have you often been bothered by feeling down, depressed, anxious
or hopeless?
During the last month, have you often been bothered by having little interest or pleasure in
doing things?
During the last month, have you often been bothered by feeling excessively worried or
concerned?
Do you worry a lot about the way you look and wish you could think about it less?
On a typical day, do you spend more than 1 hour day worrying about your appearance?
(More than 1 hour a day is considered excessive)
What specific concerns do you have about your appearance?
Does it make it hard to do your work or be with your friends and family?
Do you worry you have lost control over your eating?
Do you ever feel disgusted, depressed, or guilty about eating?
Have you tried fasting or skipping meals in an attempt to lose weight?
Have you tried vomiting. laxatives or diuretics in an attempt to lose weight?
Have you had significant (e.g. >5-7%), recurrent fluctuation in body weight?
During the last few months, have you often been bothered by problems with your sex life
such as reduced satisfaction, desire, pain, or any other problems?
Do you feel that PCOS affects your sex life?
Do sexual problems affect your current relationship and/or have sexual problems affected
your past relationships?
None of
the time
1.
In the past 4 weeks, about how often did you feel tired
out for no good reason?
2.
3.
4.
5.
6.
7.
8.
In the past 4 weeks, about how often did you feel that
everything was an effort?
9.
10.
A little of
the time
Some of
the time
Most of
the time
All of the
time
Source: http://www.beyondblue.org.au/index.aspx?link_id=89.678
For more information about its use in Australia, visit: http://www.abs.gov.au/ausstats/abs@.nsf/mf/4817.0.55.001
148
DASS21
Name:
Date:
Please read each statement and circle a number 0, 1, 2 or 3 which indicates how much the statement applied to
you over the past week. There are no right or wrong answers. Do not spend too much time on any statement.
The rating scale is as follows:
0
1
2
3
10
11
12
13
14
15
16
17
18
19
149
20
21
Remember when using the DASS21 to multiply the obtained scale scores by 2, so that they can be compared to the DASS
normative data and to other published DASS data.
150
151
152
GAD-7 total score for the seven items ranges from 0 to 21.
Scores represent:
0-5 mild
6-10 moderate
11-15 moderately severe anxiety
15-21 severe anxiety.
153
154
155
BMI
CI
CVD
Cardiovascular disease
CCR
Dietitian
DM2
FBG
FSH
HDL-C
HOMA-IR
IR
Insulin resistance
LDL-C
NICE
NIH
Non-CCR
OCP
OGTT
OR
Odds ratio
PCO
Polycystic ovary
PCOS
PICO
156
POSAA
QoL
Quality of life
RCT
RR
Relative risk
SHBG
TGA
P-value
157
Aerobic exercise/activity
AGREE II
Algorithm
Anovulation
Anxiety
Assess
Blood pressure
Body image
The way a person may feel, think and view their body including
their appearance.
158
BMI = (weight/height)2
Cardiometabolic
Clinical impact
Cochrane review
Co-morbidity
Compliance
Confidence interval
159
Consensus methods
Contraindication
Depression
Diagnostic accuracy
Disordered eating
Dosage
Eating disorder
Heterogeneity
160
Hyperandrogenism
When fasting morning blood glucose levels are higher than normal
but not high enough to diagnose diabetes.
Incidence
Infertility (women)
Interdisciplinary care
Intervention
161
Irregular cycles/oligomenorrhea
Laparoscopy
Lean
BMI 25kg/m2
Lipid profile
Menarche
The onset of the first period of the menstrual cycle, which occurs
on average between the ages of 11 and 14 years.
Meta-analysis
Morbidly obese
BMI 35kg/m2
Non-clomiphene citrate
resistant (Non-CCR)
Obese
BMI 30-35kg/m2
Oligo-anovulation
Oligomenorrhea/irregular cycles When the duration of menstrual cycles is >35 or <21 days.
Oral glucose tolerance test
(OGTT)
Ovarian hyperstimulation
162
syndrome (OHSS)
Overweight
BMI 25.1-30kg/m2
Ovulation
Ovulation induction
Polycystic ovaries
Placebo
Post-operative
Prediabetes
Where blood glucose levels are higher than normal, but not high
enough to be classified as diabetes. Pre-diabetes includes impaired
fasting glucose and impaired glucose tolerance.
Pre-operative
Psychosexual dysfunction
P value
Randomisation
163
(RCT)
Resource implication
Risk of bias
Screen
Selection criteria
Stakeholder
Statistical power
Systematic review
Therapy naive
A patient who has not been administered prior treatment for the
condition.
164
165
166
167