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Polycystic ovary syndrome controversy: are expanding

disease definitions unnecessarily labelling women with PCOS?

Journal: BMJ

Manuscript ID BMJ.2016.035545

Article Type: Analysis

BMJ Journal: BMJ

Date Submitted by the Author: 09-Nov-2016

Complete List of Authors: Copp, Tessa; University of Sydney, School of Public Health Jansen, Jesse; The University of Sydney, School of Public Health Doust, Jenny; Bond University, Mol, Ben; University of Adelaide, School of Paediatrics and Reproductive Health Dokras, Anuja; University of Pennsylvania, Obstetrics and Gynecology McCaffery, Kirsten; The University of Sydney, School of Public Health

Keywords: PCOS, Overdiagnosis, Disease labels, Psychosocial

https://mc.manuscriptcentral.com/bmj

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Polycystic ovary syndrome controversy: are expanding disease definitions unnecessarily

labelling women with PCOS?

Tessa Copp1,2

PhD student, Jesse Jansen1,2

cognitive psychologist and senior research fellow,

Jenny Doust3 GP and professor of clinical epidemiology, Ben W. J. Mol

4,5 professor of

obstetrics and gynaecology, Anuja Dokras6 professor of obstetrics and gynaecology, Kirsten

McCaffery1,2

health psychologist and professorial research fellow

1. Wiser Healthcare, Sydney School of Public Health, The University of Sydney, NSW 2006,

Australia.

2. Centre for Medical Psychology and Evidence-Based Decision-Making (CeMPED), The

University of Sydney, NSW 2006, Australia.

3. Centre for Research in Evidence-Based Practice, Bond University, QLD 4229, Australia.

4. Robinson Research Institute, School of Paediatrics and Reproductive Health, University of

Adelaide, SA 5005, Australia.

5. The South Australian Health and Medical Research Institute, Adelaide, Australia.

6. Penn PCOS Centre, Department of Obstetrics and Gynaecology, University of Pennsylvania,

Philadelphia, USA.

Word count: 2064

Correspondence to: Dr Jesse Jansen; Sydney School of Public Health, The University of

Sydney, NSW 2006, Australia. (email: [email protected]; phone number: + 61 2

9351 5178)

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This article is part of a series on overdiagnosis looking at the risks and harms to patients of

expanding definitions of disease and increasing use of new diagnostic technologies.

Polycystic Ovary Syndrome (PCOS) is the most commonly diagnosed endocrine disorder

affecting women of reproductive age and is associated with infertility and adverse

reproductive, metabolic, cardiovascular and psychosocial outcomes.1 2

PCOS includes a

range of features, such as anovulation, menstrual irregularities, polycystic appearing ovaries

and signs of androgen excess, which can vary by weight, ethnicity and environmental

factors, and can also change across the lifespan.3 4

These symptoms cluster, forming a

variety of different phenotypes,1 and the heterogeneous presentation of PCOS has been

proposed as one of the factors contributing to significant patient dissatisfaction with

diagnosis and treatment experience.5 Expanding diagnostic criteria has resulted in an

increase in the number of women being diagnosed,6 raising concerns about potential

overdiagnosis through unnecessary disease labelling. This paper will discuss the various

areas of overdiagnosis and consider the evidence and uncertainty surrounding diagnosis and

overdiagnosis of this condition.

Change in diagnostic criteria

PCOS was first described by Stein and Leventhal in 1935, in a case series of seven women

with amenorrhea and infertility associated with multiple cysts in the ovaries.7 There are

currently three different diagnostic criteria for PCOS in use (see Table 1).8-10

Table 1: Diagnostic criteria for PCOS

NIH Diagnostic Criteria

(US, 1990)8

Rotterdam Diagnostic

Criteria

(International, 2003)9

Androgen Excess & PCOS

Society Criteria

(International, 2006)10

Need both:

1) Oligo- or anovulation

2) Clinical and/ or

biochemical signs of

hyperandrogenism

and exclusion of other

aetiologies

Two of the following:


2) Clinical and/ or


hyperandrogenism

3) Polycystic ovaries on

ultrasound


aetiologies

1) Clinical and/ or


hyperandrogenism

and at least one of the following:


and/ or polycystic

ovaries on ultrasound


aetiologies

The National Institute of Health (NIH) criteria were established by consensus in 1990.1 8

In

2003 at a meeting of experts in Rotterdam, sonographic presence of polycystic ovaries was

added to the NIH criteria (see Table 1).1 9

In 2006 an Androgen Excess and PCOS Society

taskforce recommended the third diagnostic criteria stating that clinical or biochemical

evidence of hyperandrogenism was essential for the diagnosis to be made, as the link

between the different PCOS phenotypes and independent morbidity is not equal.10

In 2012,

an NIH evidence-based workshop reviewed the evidence and recommended maintaining

the broad Rotterdam criteria, however also suggested identifying the PCOS phenotype (see

Table 2 for possible PCOS phenotypes).11

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Table 2. Possible PCOS phenotypes by diagnostic criteria11 12

All possible potential PCOS phenotypes

Features A B C D E F G H I J

Hyperandrogenemia

(biochemical

androgen excess)

+ - + + - + + - + -

Hirsutism

(androgen excess)

+ + - + + - + + - -

Oligo-anovulation

(irregular ovulation)

+ + + + + + - - - +

Polycystic Ovaries + + + - - - + + + +

Diagnostic Criteria

NIH (1990) X X X X X X

Rotterdam (2003) X X X X X X X X X X

AE-PCOS (2006) X X X X X X X X X

Modified from: Azziz et al. AE-PCOS Society report on PCOS phenotype. Fertil Steril 2009, and; NIH

Evidence-based Methodology Workshop on PCOS, 2012.

Evidence of overdiagnosis

Impact on prevalence and controversy over criteria

The widening of the diagnostic criteria by the Rotterdam definition has contributed to an

increase in PCOS prevalence from the estimate of 4-6.6% (using NIH criteria)13 14

to up to

21% of reproductive aged women (using Rotterdam criteria)6 15

, depending on the

population studied (Table 3). However, the inclusion of polycystic ovaries as one of the

three key diagnostic criteria has been criticised,16

as polycystic ovaries are also frequently

found in women without PCOS.1 16

In the general population, ultrasound features of

polycystic ovaries have been found in 62-84% of women aged 18-30 years, and this

decreases to 7% of women aged 41-45 years.16 17

This highlights the need for age-specific

cut-off points for follicle count when using modern ultrasound equipment, as 12 or more

follicles (Rotterdam criteria) may be normal in adolescence and early adulthood.16

In 2014,

an expert panel recommended increasing the threshold for defining polycystic ovaries to

>24 follicles per ovary due to advancements in imaging technology,1 18 19

but this

recommendation has not yet been adopted in current international PCOS guidelines.20

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Confidential: For Review Only 4

Table 3: Prevalence of PCOS across various countries using different diagnostic criteria

Source

(first author

and year)

Country Age

range

(years)

Population/ setting Sample

size

1990 NIH

criteria

2003 Rotterdam

criteria (Current

global standard)

2006 Androgen

excess & PCOS

society criteria

March,

201021

Australia

27 – 34

Women born during 1973-1975 from a

single maternity hospital

728 8.7% 17.8%* 12.0%*

Tehrani,

201122

Iran 18 – 45 Women randomly selected from

different geographic regions of Iran

using Health Department lists

929 7.1% 14.6% 11.7%

Mehrabian,

201123

Iran 17 – 34 Women referred to a mandatory pre-

marriage screening clinic in Isfahan

829 7.0% 15.2% 7.9%

Yildiz,

201224

Turkey 18 – 45 Women completing a pre-employment

medical assessment in a government-

based institute in Ankara, Turkey

392 6.1% 19.9% 15.3%

Rashidi,

201425

Iran 18 – 45

Women randomly selected from

different geographic regions of Iran

using Health Department lists

646 4.8% 14.1% 12%

Lauritsen,

201426

Denmark 20 – 40 Employees at Copenhagen University

Hospital

447 Not assessed 16.6% 13.9%

Zhuang,

20143

China 12 – 44 Residents of Chengdu selected using

cluster-randomised sampling

1,645 7.1% 11.2% 7.4%

Joshi,

201427

India 15 – 24 Young girls were selected using random

sampling of a census block of Mumbai

of every 10th

household

600 Not assessed 22.5% 10.7%

*Not all women consented to having an ultrasound. The presence of polycystic ovaries in those that did not consent to the ultrasound were imputed by subdividing women

into PCOS phenotypes per the Rotterdam criteria. For each phenotype, the proportion imputed to have polycystic ovaries was calculated by multiplying the proportion with

polycystic ovaries in the group who had an ultrasound by the number who did not have an ultrasound.

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Diagnosis during adolescence

Diagnosis of PCOS during adolescence is challenging.28 29

Symptoms tend to first appear

during pubertal development, and as the syndrome is associated with glucose intolerance30

and increased risk of type 2 diabetes mellitus, it is suggested early diagnosis may be

beneficial in reducing long-term implications.31

However, there is limited evidence

indicating any benefit of identifying and managing PCOS in this age group.28 29 32

Importantly, none of the current diagnostic criteria in use take into consideration the

adolescent population.10 28 33

Many symptoms of PCOS, such as acne and oligomenorrhea,

overlap with common features of pubertal development.29 33

Cut-off points for abnormal

androgen levels during adolescence have not been established, and using adult cut-off

points may be inappropriate.34

There are several guidelines for diagnosing adolescents, and

stricter adolescent criteria have been proposed by specialists in attempts to limit

inappropriate diagnosis (such as all three Rotterdam criteria being required, see Figure 1),29

34 but there is not enough high quality evidence to support these models in clinical practice.

6

28 35 In fact, it has been suggested to note adolescents ‘at risk’ and refrain from establishing

the diagnosis.28

As a result, it may be preferable to not diagnose PCOS and instead treat the

symptoms without the diagnostic label for this age group.

Figure 2. Prevalence of PCOS by age group and phenotype of a community sample from Chengdu,

China (12-44 years).3

Widening the definition to include non-hyperandrogenic phenotypes

The Rotterdam criteria widened the NIH definition by including non-hyperandrogenic

phenotypes (such as women with menstrual irregularity and polycystic appearing ovaries)

that have been found to not have the same associated long-term consequences as in

women with hyperandrogenism.1 6 12 36-38

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This reduced risk, however, may not be being communicated by doctors to women. The

wide spectrum of women with different combinations of symptoms and vastly different

levels of risk are not well understood or explained in the scientific literature, and therefore

may not be well explained to patients. Along with the readily available information about

PCOS on social media (often of low quality), women are frequently unaware of their milder

phenotype and believe they have an increased risk for metabolic and cardiovascular

outcomes, despite evidence demonstrating otherwise.37

As before, it may be possible to

avoid diagnosing PCOS in women with non-hyperandrogenic phenotypes, and for clinicians

to treat the presenting symptoms of concern. It has also been suggested that these women

do not represent the syndrome, and may overlap with women with hypothalamic

amenorrhea.6 12

.

Potential benefits of diagnosis

PCOS is associated with long term implications such as infertility, endometrial carcinoma,

obesity, type 2 diabetes mellitus, hypertension, and possibly cardiovascular disease (CVD).10

31 For some women, such as those with the classic phenotype, early diagnosis and

management of PCOS may slow progression of comorbidities by prompting early

intervention and prevent long-term harms. For example, a PCOS label may help women

undergo regular screening for comorbidities and make dietary and lifestyle changes, such as

weight reduction and CVD/ diabetes risk reduction (see Table 4 for treatment guidelines).39

40 The diagnosis may also enable medication, such as oral contraceptive pills to regulate

menstrual cycle, reduce hirsutism and reduce risk of endometrial cancer, or metformin to

improve insulin sensitivity and potentially decrease risk of impaired glucose tolerance (IGT)

and diabetes.41

However, evidence of treatment benefit regarding lifestyle modification and metformin has

been extrapolated from the effects of lifestyle interventions in pre-diabetes populations.42

It

is uncertain whether these interventions provide long-term benefit in the PCOS population,

due to inconsistent findings and open-labelled studies with small sample sizes of primarily

clinical populations (patients from fertility, gynaecology or endocrinology clinics who may

have more severe symptoms) and no long-term follow up.29

It is also unknown how the

evidence applies to the different PCOS phenotypes and various grades of severity.6 39 43

Women with PCOS who are seeking pregnancy may benefit from knowledge of their

ovulatory dysfunction (WHO group 2 ovulatory dysfunction) to assist them with family

planning and increase awareness of treatment options including ovulation induction

medications, such as clomiphene citrate, letrozole and/ or metformin.4 44

Pre-pregnancy

interventions aimed at weight loss also improve pregnancy and live birth rates in women

with PCOS.45

PCOS is also associated with an increased risk of pregnancy complications, such

as gestational diabetes mellitus and preeclampsia.2 46

However, it is currently unclear

whether all phenotypes are at risk and long term studies on impact of pre-pregnancy

interventions on obstetric and neonatal outcomes are lacking.2

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Further reasons for caution: Uncertain areas of potential overdiagnosis

Scepticism of PCOS as a useful clinical diagnosis: Is a diagnosis always necessary to treat

symptoms or reduce future risk?

Since the PCOS label may not change the type or intensity of treatment, the critical question

remains whether a PCOS label contributes to effective treatment of symptoms or reduces

the risk of diabetes or CVD? For example, for women who are overweight with menstrual

irregularity and signs of hyperandrogenism, the label is not needed to recommend healthy

lifestyle changes, use of the oral contraceptive pill or to give fertility counselling. Similarly, in

women with WHO group 2 anovulation actively seeking pregnancy, does the diagnosis of

PCOS need to be made above the identification of WHO group 2 anovulation, as the

treatment is likely to be the same with or without a PCOS label?32

Importantly, although experts often believe a PCOS diagnosis conveys a sense of urgency

and motivation for doctors and patients to comply with recommendations; there is evidence

of low compliance with regular screening recommendations for metabolic comorbidities in

physicians,47

and a recent review on communication of a genetic risk diagnosis showed no

improvements in health related behaviour.48

Limited evidence supporting diagnostic criteria

Both the NIH and Rotterdam criteria are based on expert majority opinion, and have come

under criticism due to insufficient high quality evidence on long-term follow-up or

therapeutic benefit to derive an evidence-based definition of the syndrome.6 9

Studies that

report associations between PCOS and increased risk of metabolic complications do not

distinguish between the different phenotypes.46

The data is also over-represented by small

convenience samples of women recruited from outpatient clinics or hospital settings, and

therefore may include women with more severe symptoms (more hirsute, more

hyperandrogenaemic and more likely to have the classic NIH phenotypes).49

This potentially

overestimates long-term morbidities and introduces substantial referral bias.6 50

It can be further argued that the original NIH criteria also introduced the potential for

overdiagnosis, as it classifies women with milder symptoms of PCOS, who may not require a

disease label or benefit from treatment.3 For example, women who have menstrual

irregularity and elevated free testosterone at one assessment. A significant proportion of

younger women may meet this definition, and can experience spontaneous resolution over

time, suggesting they were incorrectly diagnosed (see Figure 2).3 More high quality studies

of PCOS prevalence by age group and phenotype that control for BMI and other cofounders

are crucial to investigate this further.

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Figure 2. Prevalence of PCOS by age group and diagnostic criteria of a community sample from

Chengdu, China (12-44 years).3

Psychological burden of diagnosis

Women diagnosed with PCOS have higher levels of depression and anxiety, poorer self-

esteem, negative body image, disordered eating and decreased sexual satisfaction in various

clinical and community samples.51-54

. However, the association between timing of diagnosis

and psychological symptoms is unclear,55-57

and it is unknown whether these findings vary

between the different phenotypes.

It is also unclear whether these negative consequences are due to the condition, its

symptoms, or from the psychological effect of being labelled as having PCOS and the

perceived long-term implications.49

Unnecessarily labelling healthy people as patients can

negatively impact their health and wellbeing.58 59

The PCOS label may induce fear and

anxiety as it has no cure, and is associated with fertility implications,57

an obligation for

screening for comorbidities,12

implementing dietary and lifestyle changes, and taking long

term medications.29

Thus, for each individual woman these potential harms need to be

weighed against the benefits of a PCOS diagnosis and early intervention, taking into account

the limitations around the evidence.

Groups at risk of underdiagnosis

Some women with PCOS at high risk of long-term harms may be undiagnosed. Populations

with limited access to healthcare or at high risk of obesity and diabetes, such as Indigenous

populations and Hispanic Americans, are less likely to be diagnosed.15 60

A lower threshold

for screening for PCOS has been suggested for these groups in order to provide early access

to healthcare and implement lifestyle interventions.4 However, overall, evidence of

increased prevalence in these populations is scant.

Pre

va

len

ce o

f P

CO

S

Age (years)

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How to move forward

In PCOS, disease definitions have expanded without clear evidence of benefits for the

women receiving a diagnosis. More adequately powered, carefully phenotyped and

multiethnic longitudinal research among unbiased PCOS adolescent and adult populations is

needed to validate any associations of adverse long-term implications, along with double-

blinded RCTs of long duration with placebo controlled arms to investigate the value of early

intervention and treatment benefit.

Clinically, more recognition of the uncertainties that exist in the diagnosis, progression and

treatment of PCOS is required. Although women with certain PCOS phenotypes (e.g. classic

PCOS) may benefit from the disease label, for some women the PCOS label may not be

needed to effectively and rapidly treat the presenting symptoms. Until we have adequate

data, it may be best to provide symptomatic treatment and avoid making a diagnosis,

particularly for adolescents and women with the non-hyperandrogenic phenotypes, as

women may experience prolonged distress and psychological anguish. At a minimum we

suggest carefully weighing up the benefits and harms for each individual women,32

and that

a slower, stepped or delayed approach to diagnosis could be a way forward to optimise

benefits and reduce harm from disease labelling.

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Table 4: International guideline recommendations for PCOS in Adult women

International guideline recommendations for

investigation and management of PCOS*

Important considerations and caveats

Diagnostic criteria: The Rotterdam criteria (see

Table 1)

Communication around PCOS diagnosis

• Inform women of possible long-term risks of

PCOS and positive effect of lifestyle

modification (e.g. weight loss), especially for

those who are overweight

Screening for comorbidities: assessment of BMI,

waist circumference, blood pressure, oral glucose

tolerance, CVD risk factors and psychological issues

Treatment: Should target presenting complaints.

First line treatment: lifestyle modification (weight

loss, diet, exercise) As required: targeted medical

therapy

• Oligomenorrhea/amenorrhoea: lifestyle

modification, OCPs

• Hirsutism: OCPs, waxing and laser hair

removal

• Acne: OCPs, topical creams, Roaccutane

• Infertility: lifestyle intervention, smoking

cessation, clomiphene citrate, metformin,

gonadotrophins, surgery and in-vitro

fertilisation

• Cardiometabolic risk: lifestyle change,

optimise CVD risk factors (smoking cessation

etc.), metformin4 (not licenced for use in UK,

due not lack of evidence of long-term

benefit)

Communication around diagnosis

• We recommend caution when

informing about risks associated with

PCOS as not all phenotypes/

manifestations of PCOS are at

increased risk

• Inform women of their phenotype

Screening for comorbidities

• Consider if the diagnostic label is

necessary to screen for comorbidities

• Frequency of screening is not based

on long-term evidence

• There is limited evidence in PCOS

populations that early identification

improves health outcomes.

Treatment:

• The best evidence comes from an

extrapolation of impaired glucose/

diabetes prevention studies,

suggesting lifestyle modification and

metformin will decrease risk of

diabetes mellitus in women with

PCOS.

• Most studies look at

clinical/biochemical markers (e.g.

insulin levels), not patient relevant

outcomes (e.g. menstrual irregularity)

Note: * US Endocrine Society, UK Nice-accredited RCOG Green-top guideline, and Australian evidence-based

guideline for assessment and management of polycystic ovary syndrome.20 33 61

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Summary Box

Clinical context – PCOS is the most commonly diagnosed endocrine disorder affecting

reproductive aged women, and is associated with adverse reproductive, metabolic and

cardiovascular outcomes.

Diagnostic change – The Rotterdam consensus expanded the NIH criteria to include

polycystic ovaries, introducing a number of different PCOS phenotypes.

Rationale for change – Early identification, diagnosis and management of PCOS could

prevent the adverse long-term implications by implementing lifestyle modifications and

screening for comorbidities

Leap of faith – a diagnosis will provide relief to symptom burden and allow

implementation of lifestyle changes to improve cardiovascular risk and increase fertility

Increase in disease – Number of diagnoses increased from NIH criteria based estimates of

4-6.6% to up to Rotterdam criteria based 21% of reproductive aged women, depending

on the population studied

Evidence of overdiagnosis – Diagnoses have rapidly increased, the criteria are of

questionable use in adolescent populations, and the milder phenotypes of PCOS do not

have the same associated adverse implications as the hyperandrogenic phenotypes.

Harms from overdiagnosis – Along with taking long-term medications, labelling healthy

women with PCOS may negatively impact their psychological health and wellbeing,

inducing fear and anxiety about future fertility and long-term health.

Uncertainties – Suggestion of overdiagnosis is based upon the rise of diagnoses and the

uncertainties that exist in the diagnosis, progression and treatment of PCOS

Conclusion/ way forward- A PCOS label may not be needed to effectively treat many

symptoms of PCOS as the label does not change the type or intensity of the intervention.

We suggest carefully weighing up the benefits and harms for each individual women, and

that a slower, stepped or delayed approach to diagnosis may be a method to optimise

benefits and reduce harm from disease labelling.

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Contributors: TC is a PhD student the School of Public Health, University of Sydney. JJ is a

cognitive psychologist at the School of Public Health, University of Sydney. JD is a general

practitioner and professor of clinical epidemiology at the Centre for Research in Evidence-

Based Practice, Bond University. BM is a professor of obstetrics and gynaecology at

Robinson Research Institute, School of Paediatrics and Reproductive Health, University of

Adelaide. AD is a professor of obstetrics and gynaecology at the Department of Obstetrics

and Gynaecology, University of Pennsylvania. KM is a health psychologist at the School of

Public Health, University of Sydney. All authors contributed to the concepts and structure of

this manuscript. JJ is the guarantor.

Competing interests: All authors have completed the Unified Competing Interest form at

www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author)

and declare: no financial relationships with any organisations that might have an interest in

the submitted work in the previous three years, and no other relationships or activities that

could appear to have influenced the submitted work.

LICENCE: The Corresponding Author has the right to grant on behalf of all authors and does

grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in

perpetuity, in all forms, formats and media (whether known now or created in the future),

to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the

Contribution into other languages, create adaptations, reprints, include within collections

and create summaries, extracts and/or, abstracts of the Contribution, iii) create any other

derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the

Contribution, v) the inclusion of electronic links from the Contribution to third party

material where-ever it may be located; and, vi) licence any third party to do any or all of the

above.

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References

1. Dumesic DA, Oberfield SE, Stener-Victorin E, et al. Scientific Statement on the Diagnostic

Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary

Syndrome. Endocr Rev 2015;36(5):487-525.

2. Palomba S, de Wilde MA, Falbo A, et al. Pregnancy complications in women with

polycystic ovary syndrome. Hum Reprod Update 2015;21(5):575-92.

3. Zhuang J, Liu Y, Xu L, et al. Prevalence of the polycystic ovary syndrome in female

residents of Chengdu, China. Gynecol Obstet Invest 2014;77(4):217-23.

4. Teede HJ, Misso ML, Deeks AA, et al. Assessment and management of polycystic ovary

syndrome: summary of an evidence-based guideline. Med J Aust 2011;195(6):S65-

112.

5. Gibson-Helm ME, Lucas IM, Boyle JA, et al. Women's experiences of polycystic ovary

syndrome diagnosis. Fam Pract 2014;31(5):545-9.

6. Lizneva D, Suturina L, Walker W, et al. Criteria, prevalence, and phenotypes of polycystic

ovary syndrome. Fertil Steril 2016

7. Stein IFL, M. L. . Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet

Gynecol 1935:181-91.

8. Zawadzki JD, A. . Diagnostic criteria for polycystic ovary syndrome: towards a rational

approach. In: Dunaif AG, J.R. Haseltine, F. , ed. Polycystic Ovary Syndrome. Boston:

Blackwell Scientific 1992:377-84.

9. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003

consensus on diagnostic criteria and long-term health risks related to polycystic

ovary syndrome (PCOS). Hum Reprod 2004;19:41-47.

10. Azziz R, Carmina E, Dewailly D, et al. Positions statement: criteria for defining polycystic

ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess

Society guideline. J Clin Endocrinol Metab 2006;91(11):4237-45.

11. National Institute of Health. Evidence-based Methodology Workshop on Polycystic

Ovary Syndrome. 2012

12. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for

the polycystic ovary syndrome: the complete task force report. Fertil Steril

2009;91(2):456-88.

13. Azziz R, Woods KS, Reyna R, et al. The prevalence and features of the polycystic ovary

syndrome in an unselected population. J Clin Endocrinol Metab 2004;89(6):2745-9.

14. Knochenhauer ES, Key TJ, Kahsar-Miller M, et al. Prevalence of the polycystic ovary

syndrome in unselected black and white women of the southeastern United States: a

prospective study. J Clin Endocrinol Metab 1998;83(9):3078-82.

15. Boyle JA, Cunningham J, O'Dea K, et al. Prevalence of polycystic ovary syndrome in a

sample of Indigenous women in Darwin, Australia. Med J Aust 2012;196(1):62-6.

16. Johnstone EB, Rosen MP, Neril R, et al. The polycystic ovary post-rotterdam: a common,

age-dependent finding in ovulatory women without metabolic significance. J Clin

Endocrinol Metab 2010;95(11):4965-72.

17. Duijkers IJ, Klipping C. Polycystic ovaries, as defined by the 2003 Rotterdam consensus

criteria, are found to be very common in young healthy women. Gynecol Endocrinol

2010;26(3):152-60.

18. Dewailly D. Diagnostic criteria for PCOS: Is there a need for a rethink? Best Pract Res Clin

Obstet Gynaecol 2016

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19. Dewailly D, Lujan ME, Carmina E, et al. Definition and significance of polycystic ovarian

morphology: a task force report from the Androgen Excess and Polycystic Ovary

Syndrome Society. Hum Reprod Update 2014;20(3):334-52.

20. Evidence-based guidelines for the assessment and management of polycystic ovary

syndrome. Jean Hailes for Women's Health on behalf of the PCOS Australian Alliance.

Melbourne 2015.

21. March WA, Moore VM, Willson KJ, et al. The prevalence of polycystic ovary syndrome in

a community sample assessed under contrasting diagnostic criteria. Hum Reprod

2010;25(2):544-51.

22. Tehrani FR, Simbar M, Tohidi M, et al. The prevalence of polycystic ovary syndrome in a

community sample of Iranian population: Iranian PCOS prevalence study. Reprod Biol

Endocrinol 2011;9:39.

23. Mehrabian F, Khani B, Kelishadi R, et al. The prevalence of polycystic ovary syndrome in

Iranian women based on different diagnostic criteria. Endokrynol Pol 2011;62(3):238-

42.

24. Yildiz BO, Bozdag G, Yapici Z, et al. Prevalence, phenotype and cardiometabolic risk of

polycystic ovary syndrome under different diagnostic criteria. Hum Reprod

2012;27(10):3067-73.

25. Rashidi H, Ramezani Tehrani F, Bahri Khomami M, et al. To what extent does the use of

the Rotterdam criteria affect the prevalence of polycystic ovary syndrome? A

community-based study from the Southwest of Iran. Eur J Obstet Gynecol Reprod

Biol 2014;174:100-5.

26. Lauritsen MP, Bentzen JG, Pinborg A, et al. The prevalence of polycystic ovary syndrome

in a normal population according to the Rotterdam criteria versus revised criteria

including anti-Mullerian hormone. Hum Reprod 2014;29(4):791-801.

27. Joshi B, Mukherjee S, Patil A, et al. A cross-sectional study of polycystic ovarian

syndrome among adolescent and young girls in Mumbai, India. Indian J Endocrinol

Metab 2014;18(3):317-24.

28. Morris S, Grover S, Sabin MA. What does a diagnostic label of 'polycystic ovary

syndrome' really mean in adolescence? A review of current practice

recommendations. Clin Obes 2016;6(1):1-18.

29. Witchel SF, Oberfield S, Rosenfield RL, et al. The Diagnosis of Polycystic Ovary Syndrome

during Adolescence. Horm Res Paediatr 2015

30. Legro RS, Kunselman AR, Dodson WC, et al. Prevalence and predictors of risk for type 2

diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a

prospective, controlled study in 254 affected women. J Clin Endocrinol Metab

1999;84(1):165-9.

31. Dokras A, Witchel SF. Are young adult women with polycystic ovary syndrome slipping

through the healthcare cracks? J Clin Endocrinol Metab 2014;99(5):1583-5.

32. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women's health aspects of

polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd

PCOS Consensus Workshop Group. Fertil Steril 2012;97(1):28-38 e25.

33. Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treatment of polycystic ovary

syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab

2013;98(12):4565-92.

34. Carmina E, Oberfield SE, Lobo RA. The diagnosis of polycystic ovary syndrome in

adolescents. Am J Obstet Gynecol 2010;203(3):201 e1-5.

Page 14 of 16


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nly

15

35. Roe AH, Dokras A. The diagnosis of polycystic ovary syndrome in adolescents. Rev Obstet

Gynecol 2011;4(2):45-51.

36. Carmina E, Chu MC, Longo RA, et al. Phenotypic variation in hyperandrogenic women

influences the findings of abnormal metabolic and cardiovascular risk parameters. J

Clin Endocrinol Metab 2005;90(5):2545-9.

37. Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome:

the Rotterdam criteria are premature. J Clin Endocrinol Metab 2006;91(3):781-5.

38. Daan NM, Louwers YV, Koster MP, et al. Cardiovascular and metabolic profiles amongst

different polycystic ovary syndrome phenotypes: who is really at risk? Fertil Steril

2014;102(5):1444-51 e3.

39. Naderpoor N, Shorakae S, de Courten B, et al. Metformin and lifestyle modification in

polycystic ovary syndrome: systematic review and meta-analysis. Hum Reprod

Update 2015;21(5):560-74.

40. Moran LJ, Hutchison SK, Norman RJ, et al. Lifestyle changes in women with polycystic

ovary syndrome. Cochrane Database Syst Rev 2011(2):CD007506.

41. Tang T, Lord JM, Norman RJ, et al. Insulin-sensitising drugs (metformin, rosiglitazone,

pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo

amenorrhoea and subfertility. Cochrane Database Syst Rev 2010(1):CD003053.

42. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2

diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346(6):393-

403.

43. Tang T, Glanville J, Hayden CJ, et al. Combined lifestyle modification and metformin in

obese patients with polycystic ovary syndrome. A randomized, placebo-controlled,

double-blind multicentre study. Hum Reprod 2006;21(1):80-9.

44. Bhagavath B, Carson SA. Ovulation induction in women with polycystic ovary syndrome:

an update. Am J Obstet Gynecol 2012;206(3):195-8.

45. Legro RS, Dodson WC, Kunselman AR, et al. Benefit of Delayed Fertility Therapy With

Preconception Weight Loss Over Immediate Therapy in Obese Women With PCOS. J

Clin Endocrinol Metab 2016;101(7):2658-66.

46. Boomsma CM, Eijkemans MJ, Hughes EG, et al. A meta-analysis of pregnancy outcomes

in women with polycystic ovary syndrome. Hum Reprod Update 2006;12(6):673-83.

47. Dhesi AS, Murtough KL, Lim JK, et al. Metabolic screening in patients with polycystic

ovary syndrome is largely underutilized among obstetrician-gynecologists. Am J

Obstet Gynecol 2016

48. Hollands GJ, French DP, Griffin SJ, et al. The impact of communicating genetic risks of

disease on risk-reducing health behaviour: systematic review with meta-analysis.

BMJ 2016;352:i1102.

49. Azziz R, Carmina E, Chen Z, et al. Polycystic ovary syndrome. Nat Rev Dis Primers

2016;2:16057.

50. Lizneva D, Kirubakaran R, Mykhalchenko K, et al. Phenotypes and body mass in women

with polycystic ovary syndrome identified in referral versus unselected populations:

systematic review and meta-analysis. Fertil Steril 2016

51. Deeks AA, Gibson-Helm ME, Teede HJ. Anxiety and depression in polycystic ovary

syndrome: a comprehensive investigation. Fertil Steril 2010;93(7):2421-3.

52. Bazarganipour F, Ziaei S, Montazeri A, et al. Body image satisfaction and self-esteem

status among the patients with polycystic ovary syndrome. Iran J Reprod Med

2013;11(10):829-36.

Page 15 of 16


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


nly

16

53. Dokras A, Clifton S, Futterweit W, et al. Increased prevalence of anxiety symptoms in

women with polycystic ovary syndrome: systematic review and meta-analysis. Fertil

Steril 2012;97(1):225-30 e2.

54. Dokras A, Clifton S, Futterweit W, et al. Increased risk for abnormal depression scores in

women with polycystic ovary syndrome: a systematic review and meta-analysis.

Obstet Gynecol 2011;117(1):145-52.

55. Rowlands IJ, Teede H, Lucke J, et al. Young women's psychological distress after a

diagnosis of polycystic ovary syndrome or endometriosis. Hum Reprod 2016

56. Deeks AA, Gibson-Helm ME, Paul E, et al. Is having polycystic ovary syndrome a predictor

of poor psychological function including anxiety and depression? Hum Reprod

2011;26(6):1399-407.

57. Jones GL, Hall JM, Lashen HL, et al. Health-related quality of life among adolescents with

polycystic ovary syndrome. J Obstet Gynecol Neonatal Nurs 2011;40(5):577-88.

58. Jorgensen P, Langhammer A, Krokstad S, et al. Diagnostic labelling influences self-rated

health. A prospective cohort study: the HUNT Study, Norway. Fam Pract

2015;32(5):492-9.

59. Ogedegbe G. Labeling and hypertension: it is time to intervene on its negative

consequences. Hypertension 2010;56(3):344-5.

60. Goodarzi MO, Quinones MJ, Azziz R, et al. Polycystic ovary syndrome in Mexican-

Americans: prevalence and association with the severity of insulin resistance. Fertil

Steril 2005;84(3):766-9.

61. Royal College of Obstetricians & Gynaecologists. Long-term Consequences of Polycystic

Ovary Syndrome: Green-top Guideline No. 33, . Royal College of Obstetricians &

Gynaecologists 2014

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