Guideline No.

33
May 2003

LONG-TERM CONSEQUENCES OF POLYCYSTIC OVARY

SYNDROME
1.

Aim

The aim of this guideline is to provide information, based on clinical evidence, to assist clinicians
who manage patients with polycystic ovary syndrome in advising them about the long-term health
consequences of the syndrome.
2.

Introduction

Polycystic ovary syndrome (PCOS) is commonly diagnosed in young women with anovulatory
infertility, oligomenorrhoea or hyperandrogenic problems such as hirsutism and acne. Although
associated with obesity, the syndrome is also frequently seen in women of normal body habitus. While
most attention has been paid to the management of the presenting complaint (infertility, hirsutism,
etc.), it has become clear that the polycystic ovary phenotype is linked to a number of metabolic
disturbances, including type II (non-insulin-dependent) diabetes and possibly atherosclerotic
conditions.1 PCOS is frequently diagnosed by gynaecologists and it is therefore important that
gynaecologists have a good understanding of the long-term implications of the diagnosis.
3.

Identification and assessment of evidence

Original articles considered when writing this guideline were obtained following a computer
search using polycystic ovary as a key phrase, and also in combination with metabolic,
diabetes, cardiovascular and glitazone applied to
i) Medline (PubMed) 1966June 2002
ii) Embase 1980June 2002.
The computer search was complemented by hand searching from original references and reviews.
Where possible, recommendations are based on, and explicitly linked to the evidence that supports
them. Areas lacking evidence are highlighted and annotated as good practice points.
4.

Prevalence of PCOS

PCOS has been diagnosed with increasing frequency following technological developments in
automated hormone assay and in ultrasound. Estimates of the true prevalence of the disorder
must be made with caution, since there is no overall consensus concerning the diagnostic criteria
that must be satisfied in order to make the diagnosis. Most clinical data originates from highly
specialised tertiary clinics, which may not reflect the picture in the population at large. However,
several attempts have been made to quantify the prevalence of polycystic ovaries in communitybased studies,24 suggesting that approximately 20% of women of reproductive age demonstrate
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the ultrasound picture of polycystic ovaries with half that number having clinical or biochemical
signs of anovulation or androgen excess. PCOS is a familial condition. Most studies have focused
exclusively on white populations. The prevalence of PCOS may be higher in other ethnic groups
(e.g. South Asian immigrants to UK),5 although further studies are needed.
5.

Diagnosis of PCOS

The association of the clinical features of truncal obesity, oligo- or amenorrhoea and hirsutism
with biochemical evidence of hyperandrogenaemia, elevated luteinising hormone and suppressed
sex hormone-binding globulin (SHBG) and characteristic ovarian morphology on ultrasound has
formed the basis of the diagnosis of PCOS for some years. However, biochemical abnormalities
are seen in women with regular menstrual cycles and normal ovaries on ultrasound but who
present with hirsutism or acne; and women of normal body mass who present with
oligomenorrhoea will frequently exhibit biochemical and ultrasound signs of PCOS.6,7 The key
underlying abnormality that leads to long-term health risk appears to be insulin resistance
hyperinsulinaemia in the presence of normoglycaemia.8,9 Identification of patients with metabolic
complications of PCOS should therefore focus on biochemical criteria to diagnose the syndrome,
particularly hyperandrogenaemia,10 together with an assessment of fasting glucose and insulin,
lipids and triglycerides.11 This should identify women with PCOS most at risk of long-term
complications of their condition.

Young women diagnosed with PCOS should be informed of the possible longterm risks to health that are associated with their condition. They should be
advised regarding weight and exercise.

6.

Metabolic consequences of PCOS

6.1

PCOS and risk of type II diabetes

Evidence
level III

Insulin resistance in PCOS has been linked to later development of impaired glucose tolerance and
type II diabetes.12 Evidence from small long-term cohort studies, casecontrol studies and case
series, points to a risk of type II diabetes in middle age of 1020%,1214 with a higher rate of
impaired glucose tolerance suggesting that further cases of diabetes will develop later. Increased
body mass, particularly truncal obesity, and a strong family history of diabetes both increase the
risk of developing type II diabetes in the presence of the polycystic ovary phenotype.13 However,
the frequency of type II diabetes is also increased in non-obese PCOS patients (body mass index
less than 27 kg/m2),13,14 suggesting that PCOS is an independent risk factor for type II diabetes in
middle age.

Patients presenting with PCOS, particularly if they are obese, should be offered
measurement of fasting blood glucose and urinalysis for glycosuria. Abnormal
results should be investigated by a glucose tolerance test. Such patients are at
increased risk of developing type II diabetes.

Evidence
level IIb

A sensible approach to ensure early detection of diabetes might be to offer screening to women
with PCOS for glycosuria, and possibly measurement of fasting blood glucose, on a regular basis,
perhaps annually.
6.2

PCOS and cardiovascular risk

Women with PCOS have not been found to have markedly higher than average mortality from
cardiovascular disease,15 despite their cardiovascular risk factors (obesity, hypertension,
hyperandrogenism and hyperinsulinaemia). Women with PCOS frequently have abnormal lipid
profiles, with raised triglycerides and total and low-density lipoprotein cholesterol.1618 The effect
of PCOS on high-density lipoprotein cholesterol (HDL-C), however, is controversial.1517 There is
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evidence that the risk factors in PCOS women are elevated at an earlier age than among women
without PCOS and therefore the risks of developing atherosclerotic conditions, hypertension and
myocardial infarction are greater.12,16,18

7.

Measurement of fasting cholesterol, lipids and triglycerides should be offered

to patients with PCOS, since early detection of abnormal levels might
encourage improvement in diet and exercise.

Evidence
level III

PCOS and pregnancy

Women diagnosed as having PCOS before pregnancy have an increased risk of development of
gestational diabetes.19,20 The risk is believed to be greatest in obese women with PCOS who
required ovulation induction in order to conceive. Such patients should be screened for abnormal
glucose tolerance in pregnancy and, if appropriate referred for antenatal management by an
obstetrician with special interest in pregnancy and diabetes. A single, small, retrospective,
matched-cohort study has suggested that metformin 2.25g taken throughout pregnancy reduces
the chance of women with PCOS developing gestational diabetes.21 However, metformin is not
licensed in the UK for this indication and further larger prospective studies are necessary to
provide adequate evidence of efficacy and safety of insulin-sensitising agents used in this context.
Women who have been diagnosed in pregnancy with gestational diabetes have been found to a
high prevalence of PCOS on subsequent screening. This association is more common in women
with raised body mass index.22,23

8.

Women who have been diagnosed as having PCOS before pregnancy (e.g. those
requiring ovulation induction for conception) should be screened for
gestational diabetes in early pregnancy, with referral to a specialised obstetric
diabetic service if abnormalities are detected.

Evidence
level IIb

PCOS and cancer

It has been known for many years that severe oligo- and amenorrhoea in the presence of
premenopausal levels of oestrogen can lead to endometrial hyperplasia and carcinoma.24 In women
with PCOS intervals between menstruation of more than three months may be associated with
endometrial hyperplasia.25 Regular induction of a withdrawal bleed with cyclical gestogens is
advisable in oligomenorrhoeic women with PCOS. Those with persistently thickened
endometrium when measured by transvaginal ultrasound should be advised to have an
endometrial biopsy and/or hysteroscopy to rule our endometrial hyperplasia.26

Oligo- and amenorrhoeic women with PCOS may develop endometrial

hyperplasia and later carcinoma. It is good practice to recommend treatment with
progestogens to induce a withdrawal bleed at least every three to four months.

Evidence
level IIa

The possible association of PCOS (at least in its most severe manifestation as SteinLeventhal
syndrome) with risk of postmenopausal breast cancer has also been investigated in a large cohort
study.27 Women with SteinLeventhal syndrome were not more likely to develop breast cancer than
non-PCOS controls (RR 1.2; 95% CI 0.72.0), suggesting that postmenopausal women with PCOS
do not require surveillance over and above that offered by the National Breast Screening Programme.
9.
9.1

Strategies for reduction of risk

Exercise and weight control

The impact of exercise and reduction in body mass by hypocaloric dieting on ovarian function in
PCOS is well characterised. Adoption of simple methods for reduction of body fat and
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improvement in physical fitness will result in resumption of ovulation and increase in fertility in a
high proportion of anovulatory obese PCOS women.28 The demonstration that improvement in
diet and exercise in obese young women with PCOS is accompanied by a normalisation in glucose
metabolism suggests that lifestyle alteration will reduce the likelihood of developing type II
diabetes later in life.29 There is no clear evidence of an effect of diet or exercise on the long-term
health of women with PCOS who have normal body habitus, although it seems prudent to advise
such patients to maintain their body weight within the normal range.
9.2

Drug therapy

The demonstration of the long-term health consequences of PCOS has been accompanied by
renewed interest in the use of drugs, particularly insulin-sensitising agents such as metformin and
troglitazone, to reduce insulin resistance and thereby reduce risk of developing diabetes and other
metabolic sequelae. Both metformin30,31 and troglitazone32,33 have been shown to have beneficial
short-term effects on both reproductive function and insulin resistance in non-diabetic women
with PCOS. Anxieties concerning adverse effects of troglitazone on hepatic function have led to
its withdrawal in UK, although newer insulin-sensitising agents are currently under development.
To date, there have been no published long-term studies on the effects of insulin-sensitising agents
on polycystic ovary insulin resistance or on reduction in incidence of impaired glucose tolerance,
type II diabetes or dyslipidaemia. Although many internet sites advise consideration of metformin
in such circumstances, evidence for long-term safety and efficacy in non-diabetic patients with
PCOS is lacking. Studies to date have only assessed the impact of insulin-sensitising agents in the
short-term, and well-designed randomised controlled trials in this area are urgently needed.

9.3

Insulin-sensitising agents have not been licensed in the UK for use in nondiabetic patients. Nevertheless, a body of evidence has accumulated
demonstrating both their safety and, in some studies, efficacy in the
management of short-term complications of PCOS, particularly anovulation.
Long-term use of insulin-sensitising agents for avoidance of metabolic
complications of PCOS cannot as yet be recommended.

Evidence
level IV

Surgery

Anovulation associated with PCOS has long been known to be amenable to surgical treatment, and
a recent long-term cohort study up to 20 years after laparoscopic ovarian electrocautery has shown
persistence of ovulation and normalisation of serum androgens and SHBG over many years in over
60% of subjects.34 Insulin resistance and serum lipids were not assessed, but women with PCOS
treated with ovarian diathermy for reproductive reasons might obtain long-term benefit over and
above resumption of ovulation and menses. The long-term benefits of ovarian drilling, including
alterations in endocrine profile, have recently been confirmed in a second publication.35 However,
at present, the risks of surgery do not justify recommendation of this treatment purely in an attempt
to ameliorate the chances of developing diabetes or coronary artery disease in later life.
10. Screening young PCOS patients for long-term health risk
Epidemiological and experimental studies suggest that young women with PCOS are at increased
risk of developing type II diabetes and disorders secondary to hyperlipidaemia, when compared
with women who do not have PCOS.18 However, evidence that these metabolic complications lead
to an increased risk of early death is lacking. A retrospective cohort study has shown an increased
prevalence of non-fatal cardiovascular disease and cardiovascular disease risk factors among
women with PCOS.36 In order to encourage compliance with a regimen of diet and exercise
designed to maintain a normal body habitus, it seems reasonable to offer measurement of glucose
in a fasting blood sample, along with measurement of lipids and triglycerides. A 75-gram oral

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glucose tolerance test with measurement of glucose at 0 and 2 hours (with consideration of
including measurement of insulin concentrations) should be performed if fasting glucose is
elevated at the time of diagnosis,37 and may be advisable even if fasting glucose is normal. This
advice is particularly relevant for obese patients with PCOS (body mass index greater than 30 for
white race groups, with adjustment for other ethnic groups) and if there is a family history of
diabetes or heart disease. However, adverse lipid profiles are seen even in thin women with PCOS
and and non-obese women with PCOS might also benefit from this information.8,14,38 Women with
PCOS who are found to have abnormal glucose tolerance, hyperinsulinemia or an adverse lipid
profile should be referred appropriately for further advice and management.

No clear consensus has yet emerged concerning regular screening of women

with PCOS for later development of diabetes and dyslipidemia,13,37 but obese
women with a strong family history of cardiac disease or diabetes should be
assessed regularly in a general practice or hospital outpatient setting. Local
protocols should be developed and adapted as new evidence emerges.

Evidence
level IV

References
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Polson DW, Adams J, Wadsworth J, Franks S. Polycystic ovaries a common finding in
normal women. Lancet 1988;i:8702.
Clayton RN, Ogden V, Hodgkinson V, Worswick L, Rodin DA, Dyer S et al. How common
are polycystic ovaries in normal women and what is their significance for fertility of the
population? Clin Endocrinol 1992;37:12734.
Farquhar CM, Birdsall M, Manning P, Mitchell JM, France JT. The prevalence of polycystic
ovaries on ultrasound scanning in a population of randomly selected women. Aust NZ J
Obstet Gynaecol 1994;34:6772.
Wijeyaratne CN, Balen A, Barth JH, Belchetz PE. Clinical manifestations and insulin
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is there a difference? Clin Endocrinol (Oxf) 2002;57:34350.
Franks S. Polycystic ovary syndrome. New Engl J Med 1995;333:85361.
Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for
distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes
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Mather KJ, Kwan F, Corenblum B. Hyperinsulinemia in polycystic ovary syndrome correlates
with increased cardiovascular risk independent of obesity. Fertil Steril 2000;73:15056.
Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and
implications for pathogenesis. Endocr Rev 1997;18:774800.
Consensus Development Conference on Insulin Resistance (American Diabetes Association).
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Legro RS, Kunselman AR, Dodson WC, Dunaif A. 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 Endocr Metab 1999;84:1659.
Dahlgren E, Janson PO, Johansson S, Lapidus L, Oden A. Polycystic ovary syndrome and
risk for myocardial infarction. Acta Obstet Gynecol Scand 1992;71:599604.
Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired
glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care
1999;22:1416.
Dunaif A, Finegood D. Beta-cell dysfunction independent of obesity and glucose intolerance
in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:9427.
Wild S, Pierpoint T, McKeigue P, Jacobs H. Cardiovascular disease in women with
polycystic ovary syndrome at long-termfollow up: a retrospective cohort study. Clin
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Talbot E, Guzick D, Clerici A, Berga S, Detre K, Weimer K et al. Coronary heart disease risk
factors in women with polycystic ovary syndrome. Arterioscler Thromb Vasc Biol
1995;15:8216.
Conway GS, Agrawal R, Betteridge DJ, Jacobs HS. Risk factors for coronary artery disease
in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol
1992;37:11925.
Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women
with polycystic ovary syndrome. Am J Med 2001;111:60713.
Radon PA, McMahon MJ, Meyer WR. Impaired glucose tolerance in pregnant women with
polycystic ovary syndrome. Obstet Gyaecol 1999;94:1947.
Vollenhoven B, Clark S, Kovacs G, Burger H, Healy D. Prevalence of gestational diabetes
mellitus in polycystic ovarian syndrome (PCOS) patients pregnant after ovulation induction
with gonadotrophins. Aust N Z J Obstet Gynaecol 2000;40:548.
Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L. Metformin therapy throughout
pregnancy reduces the development of gestational diabetes in women with polycystic ovary
syndrome. Fertil Steril 2002;77:5205.
Holte J, Gennarelli G, Wide L, Lithell H, Berne C. High prevalence of polycystic ovaries and
associated clinical, endocrine and metabolic features in women with previous gestational
diabetes mellitus. J Clin Endocrinol Metabol 1998;83:114350.
Koutsa E, Cela E, Lawrence NJ, Penny A, Millauer BA, White DM et al. The prevalence of
polycystic ovaries in women with a history of gestational diabetes mellitus. Clin Endocrinol
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Chamlian DL, Taylor HB. Endometrial hyperplasia in young women. Obstet Gynecol
1970;36:65966.
Cheung AP. Ultrasound and menstrual history in predicting endometrial hyperplasia in
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Balen AH. Polycystic ovary syndrome and cancer. Hum Reprod Update 2001;7:5225.
Anderson KE, Sellers TA, Chen PL, Rich SS, Hong CP, Folsom AR. Association of Stein-Leventhal syndrome with the incidence of postmenopausal breast carcinoma in a large
prospective study of women in Iowa. Cancer 1997;79:4949.
Clark AM, Ledger W, Galletly C, Tomlinson L, Blaney F, Wang X, et al. Weight loss results
in significant improvement in pregnancy and ovulation rates in anovulatory obese women.
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Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, et al. Improvement
in endocrine and ovarian function during dietary treatment of obese women with polycystic
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Velasquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic
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Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and
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Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin sensitizing agent
troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary
syndrome. J Clin Endocrinol Metab 1996;81:3299306.
Ehrmann DA, Schneider DJ, Sobel BE, Cavaghan MK, Imperial J, Rosenfield RL, et al.
Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis
and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab
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Gjonnaess H. Late endocrine effects of ovarian electrocautery in women with polycystic
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APPENDIX
Clinical guidelines are: systematically developed statements which assist clinicians and patients in
making decisions about appropriate treatment for specific conditions. Each guideline is
systematically developed using a standardised methodology. Exact details of this process can be
found in Clinical Governance Advice No. 1: Guidance for the Development of RCOG Green-top
Guidelines (available on the RCOG website at www.rcog.org.uk/clingov1). These
recommendations are not intended to dictate an exclusive course of management or treatment.
They must be evaluated with reference to individual patient needs, resources and limitations
unique to the institution and variations in local populations. It is hoped that this process of local
ownership will help to incorporate these guidelines into routine practice. Attention is drawn to
areas of clinical uncertainty where further research may be indicated.
The evidence used in this guideline was graded using the scheme below and the recommendations
formulated in a similar fashion with a standardised grading scheme.
Classification of evidence levels
Ia
Ib
IIa
IIb
III
IV

Evidence obtained from meta-analysis of randomised controlled trials.

Evidence obtained from at least one randomised controlled trial.
Evidence obtained from at least one well-designed controlled study without randomisation.
Evidence obtained from at least one other type of well-designed quasi-experimental study.
Evidence obtained from well-designed non-experimental descriptive studies, such as
comparative studies, correlation studies and case studies.
Evidence obtained from expert committee reports or opinions and/or clinical experience of
respected authorities.

Grades of recommendations

Requires at least one randomised controlled trial as part of a body of literature of overall
good quality and consistency addressing the specific recommendation. (Evidence levels Ia, Ib)

Requires the availability of well controlled clinical studies but no randomised clinical trials
on the topic of recommendations. (Evidence levels IIa, IIb, III)

Requires evidence obtained from expert committee reports or opinions and/or clinical
experiences of respected authorities. Indicates an absence of directly applicable clinical studies
of good quality. (Evidence level IV)

Good practice point

Recommended best practice based on the clinical experience of the guideline development
group.

This Guideline was produced on behalf of the Royal College of Obstetricians and Gynaecologists by:
Professor WL Ledger FRCOG, Sheffield and Ms T Clark, Sheffield.
and peer reviewed by:
Dr AH Balen MRCOG, Leeds; Professor S Franks FRCOG, London; Professor N Haites, geneticist, Aberdeen Royal Infirmary,
Aberdeen; Dr WJ Jeffcoate, endocrinologist, Nottingham City Hospital, Nottingham; Dr J McManus MRCOG, Belfast; RCOG
Consumers Forum.

The final version is the responsibility of the Guidelines and Audit Committee of the RCOG

Valid until May 2006

unless otherwise indicated
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