DOI: 10.1111/tog.

12345 2017;19:119–29
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Polycystic ovary syndrome (PCOS)

Adam H Balen MD DSc FRCOG*

Leeds Centre for Reproductive Medicine, Leeds Teaching Hospitals, Leeds, LS14 6UH, UK
*Correspondence: Adam H Balen. Email: a.balen@nhs.net

Accepted on 25 July 2016. Published Online 21 January 2017.

Key content  To appreciate the role of insulin resistance and the long-term
 The symptoms of polycystic ovary syndrome (PCOS) include health implications for women with PCOS.
menstrual cycle disturbance and features of hyperandrogenism  To understand how to manage the issues that may affect a woman
(hirsutism, acne and alopecia), with associated fertility problems, in different ways at different times in her life, namely menstrual
obesity and psychological issues. cycle irregularity, hyperandrogenism and infertility.
 There are ethnic variations in expression of PCOS related to
Ethical issues
differences in insulin metabolism and this may impact upon  A contentious issue is the appropriateness to deny fertility
treatment algorithms.
 Obesity has a major impact on the expression of PCOS and the
treatment based upon a cut-off for body mass index (BMI), when
BMI is a crude measure of metabolic risk and the risks of
efficacy of the management of all aspects of the syndrome, in
conception at a high BMI are not absolute. This also has to be
particular infertility.
 The management of anovulatory infertility involves lifestyle
balanced against the decline in fertility with age which may have an
additional impact.
modification and therapies to induce ovulation, namely clomifene  To what extent should young women who are found to have
citrate, gonadotrophin therapy and laparoscopic
polycystic ovaries on ultrasound scan but without any features of
ovarian diathermy.
the syndrome be advised about the potential for developing
 For those who do not wish to conceive the management of
problems in the future?
menstrual problems requires prevention of endometrial
 Should relatives of individuals with PCOS be screened for either
hyperplasia and adenocarcinoma and consideration of the long
PCOS or metabolic syndrome (the latter may apply to male
term metabolic risks.
relatives too)?
Learning objectives
Keywords: anovulatory infertility / hyperandrogenism / menstrual
 To understand the full spectrum of the syndrome that is PCOS to
irregularity / ovulation induction / polycystic ovary syndrome
include how to make the diagnosis and differentiate from other
causes of menstrual irregularity and androgen excess.

Please cite this paper as: Balen AH. Polycystic ovary syndrome (PCOS). The Obstetrician & Gynaecologist 2017;19:119–29. DOI:10.1111/tog.12345

insulin resistance, which in turn may be promoted by

Introduction
obesity.2 The primary presenting complaint itself is subject to
Polycystic ovary syndrome (PCOS) is a far reaching change depending on the age and needs of the patient; for
condition that has a number of reproductive and general example, acne may be the primary concern during
health implications; furthermore, it is the commonest adolescence, whereas reduced fertility may be the main
endocrine condition to affect women with an estimated concern for an older woman. PCOS may also be associated
prevalence of 10–15% (depending on the population studied with an increased risk of developing type II diabetes,
and the diagnostic criteria used – see below).1 The symptoms metabolic syndrome and endometrial cancer.1,2 The
of PCOS include menstrual cycle disturbance and features of symptoms of PCOS may have a profound impact on
hyperandrogenism (hirsutism, acne and alopecia), with psychological wellbeing.3 Options for treatment include
associated fertility problems, obesity and psychological lifestyle advice and a range of therapies depending upon
issues.1 There is significant heterogeneity of presentation, the constellation of an individual’s problems.
such that signs and symptoms manifest across a spectrum PCOS appears to be underdiagnosed and, as a result,
and their severity may vary (Box 1). Ovarian patients may not be managed appropriately.4 Furthermore,
hyperandrogenism is thought to have genetic origins with management of PCOS may require the collaboration of a
amplification in some by hyperinsulinaemia secondary to variety of healthcare professionals, ranging from primary care

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 Polycystic ovary syndrome

physicians, gynaecologists, reproductive specialists, may be precipitated by various factors, most predominantly
endocrinologists, diabetologists, dermatologists, dieticians an increase in body weight. We tend to take a pragmatic
and psychologists. In some clinics, important components approach to the management of an individual’s symptoms
of the syndrome may not be considered; for example, and needs; hence an argument could be made that a
gynaecological problems in a dermatology clinic or metabolic precise definition of the condition does not help when
problems in a gynaecology clinic.4 In a recent study of providing therapy. Yet, we feel that, while having practical
women presenting with features of PCOS in clinics outwith relevance, this argument is flawed, because it is necessary
reproductive medicine in a large teaching hospital it was to evaluate scientifically the outcomes of treatment based
found that 34% had previously undiagnosed impaired on clear diagnostic criteria. It is then only possible to
glucose tolerance (IGT) and 9% were diabetic.4 compare outcomes if the same starting points
are employed.
Debate continues regarding the reliability and
Definition and diagnosis
reproducibility of the various tests that we have at our
In 2003, the European Society for Human Reproduction disposal, whether ultrasound- or biochemical-based.5
and Embryology (ESHRE) and the American Society of Raised serum levels of luteinising hormone (LH),
Reproductive Medicine (ASRM) held a consensus meeting testosterone and androstenedione, in association with low
in Rotterdam and proposed that a diagnosis of PCOS or normal levels of follicle stimulating hormone (FSH) and
should be made if two out of three criteria are met: the abnormalities of estrogen secretion, are variable findings
presence of (1) clinical or biochemical features of and sometimes the endocrine profile may be normal
hyperandrogenism, (2) oligo-ovulation or anovulation (i.e. (Box 2). It is thought that the ovarian hyperandrogenism
menstrual cycle disturbance) and/or (3) polycystic ovaries is driven by LH in slim women and in overweight women
on ultrasound, once appropriate investigations have been by insulin, which acts as a ‘co-gonadotrophin’ and
performed to exclude other causes of menstrual disturbance amplifies the effect of LH.
and androgen excess.1 The ESHRE/ASRM Rotterdam
criteria have now gained widespread acceptance. The Ultrasound
diagnosis requires the exclusion of specific underlying Polycystic ovaries are commonly detected by pelvic
diseases of the adrenal or pituitary glands (e.g. ultrasound, with estimates of the prevalence in the general
hyperprolactinemia, acromegaly, congenital adrenal population being in the order of 20–33%.6 The morphology
hyperplasia, Cushing’s syndrome and androgen-secreting of the polycystic ovary was also defined in the ESHRE/
tumours of the ovary or adrenal gland), which could ASRM consensus as an ovary with 12 or more follicles
predispose to similar ultrasound and biochemical features measuring 2–9 mm in diameter and/or an increased ovarian
and also the exclusion of other causes of menstrual cycle volume (>10 cm3) (Figure 1).7 With improvements in the
irregularity secondary to hypothalamic, pituitary or resolution of ultrasound technology, it has more recently
ovarian dysfunction. been suggested that the threshold number of follicles to
There is considerable heterogeneity of symptoms and define a polycystic ovary should be 25,8 and that the
signs amongst women with PCOS and for an individual biochemical marker of anti-m€ullerian hormone (AMH) may
these may change over time. Polycystic ovaries can exist be even more precise than ultrasound, with a threshold
without clinical signs of the syndrome, expression of which serum concentration of >35 pmol/l. However, this figure has

Box 1. The spectrum of clinical manifestations of polycystic ovary

syndrome
Box 2. Serum endocrinology in PCOS
Symptoms
↑ or normal androgens (testosterone (T) and androstenedione)
 Hyperandrogenism (hirsutism, acne, alopecia) ↑ or normal luteinising hormone (LH) - elevated in 40%, usually slim
 Menstrual disturbance women
 Infertility
 Obesity Normal follicle stimulating hormone (FSH)

Possible late sequelae ↑ or normal fasting insulin (not routinely measured; insulin resistance
assessed by glucose tolerance test, GTT)
 Type II diabetes mellitus ↓ or normal sex hormone binding globulin (SHBG), results in elevated
 Dyslipidaemia “free androgen index” calculated by [(T 9 100)  SHBG]
 Hypertension ↑ or normal estradiol
 Cardiovascular disease ↑ Anti-müllerian hormone (AMH)
 Endometrial carcinoma
Prolactin usually normal, occasionally slightly elevated

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(a) (b)

(c) (d)

(e)

Figure 1. (a) Transabdominal ultrasound scan of a normal ovary. (b) Transabdominal ultrasound scan of a polycystic ovary. (c) Transvaginal
ultrasound scan of a polycystic ovary. (d) Transabdominal ultrasound scan of a multicystic ovary. (e) Magnetic resonance imaging of the pelvis,
demonstrating two polycystic ovaries (closed arrows) and a hyperplastic endometrium (open arrow). Reproduced with permission.36

not been universally accepted, and the use of AMH as a have been performed to attempt to determine the prevalence
surrogate for follicle number is currently being debated.9 of polycystic ovaries in the general population, as detected by
ultrasound alone, and have found remarkably similar
prevalence rates in the order of 20–30%.6 In a UK study of
Epidemiology and ethnic variations
224 female volunteers between the ages of 18 and 25 years,
The prevalence of PCOS in the general population has not polycystic ovaries were identified by ultrasound in 33%, and
been definitively determined and appears to vary the prevalence of PCOS was 26%.10
considerably between populations that have been studied PCOS is probably the same worldwide, although there may
and the diagnostic criteria being employed. Several studies be factors that affect expression and presentation – whether

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because of racial differences in the color and distribution of pancreatic sensitivity. Both obese and non-obese women
hair or variations in hormone production and receptor with PCOS are more insulin resistant than age- and weight-
activity; for example, Japanese women with little bodily hair matched women with normal ovaries. Thus, there appear to
compared with Mediterranean women, who may have a be factors in women with PCOS that promote insulin
greater degree of hirsutism with similar circulating androgen resistance and that are independent of obesity. Women with
levels.10 It has been shown that South Asian women in the PCOS who are oligomenorrheic are also more likely to be
UK with anovulatory PCOS have greater insulin resistance insulin resistant than are those with regular cycles,
and more severe symptoms of the syndrome than irrespective of their body mass index (BMI).
anovulatory white Caucasians with PCOS.11 Indeed, it is Fasting insulin levels are not measured in routine practice,
the genetic variations in the control of insulin metabolism in so instead we suggest that a 75 g oral glucose tolerance test
different populations that is thought to have a profound (GTT) be performed in women with a BMI >30 kg/m2
effect on the expression of the syndrome, which is further (Table 1). It has been suggested that South Asian women
influenced by environmental factors. There have now been should have an assessment of glucose tolerance if their BMI is
many studies from around the world exploring ethnic greater than 25 kg/m2 because of the greater risk of insulin
variations in presentation, metabolic associations and resistance at a lower BMI.12 A measurement of glycosylated
effects on quality of life that have recently been reviewed.10 haemaglobin (HbA1c) may also be useful.
Type II diabetes and insulin resistance have a high Although the insulin resistance may occur irrespective of
prevalence among indigenous populations in South Asia, BMI, the common association of PCOS and obesity has a
with a rising prevalence among women. Ethnic variations in synergistic deleterious impact on glucose homeostasis and
the overt features of PCOS in women of South Asian descent can worsen both hyperandrogenism and anovulation.
may therefore be linked with the higher prevalence and Insulin decreases synthesis of sex hormone binding globulin
degree of insulin resistance in this population.11 (SHBG) by the liver, thereby increasing the serum free-
PCOS also appears to run in families, with approximately testosterone concentration, and consequent peripheral
50% of first degree female relatives being affected and an androgen action.
increased risk of metabolic problems in male relatives. An assessment of BMI alone is not thought to provide a
There have been numerous studies attempting to ascertain reliable prediction of cardiovascular risk. It has been
the gene(s) involved, which are beyond the scope of this suggested that, rather than BMI itself it is the distribution
review, but have reached no clear conclusions to date. of fat that is important, with android obesity being more of a
risk factor than gynecoid obesity.13 Hence the value of
measuring waist circumference, which detects abdominal
PCOS and metabolic abnormalities
visceral fat rather than subcutaneous fat. It is the visceral fat
The presence of insulin resistance, central obesity, and which is metabolically active and when increased results in
dyslipidaemia appears to place women with PCOS at increased rates of insulin resistance, type II diabetes,
higher risk of developing diabetes and cardiovascular dyslipidaemia, hypertension and left ventricular
disease. A plausible hypothesis for the survival of PCOS in enlargement. Waist circumference should ideally be less
the population is that of the ‘thrifty phenotype/genotype’ than 80 cm, while a measurement that is greater than 87 cm
whereby in times of famine, individuals who have a tendency carries a significant risk. Exercise has a significant effect on
to obesity preserve the population by maintaining fertility, reducing visceral fat and reducing cardiovascular risk; indeed,
while those of normal body weight fall below the threshold a 10% reduction of body weight may equate with a 30%
body weight for fertility. This might explain the greater reduction in visceral fat.
prevalence of PCOS among South Asians in the UK, where
there is relatively greater nutrition and thus the right
environment to express PCOS. In addition, the ‘thrifty
phenotype’ hypothesis suggests that in utero insulin Table 1. Definitions of glucose tolerance after the 75 g glucose
tolerance test.
resistance results as an adaptation to impaired nutrition
and then persists through to adult life and is then amplified Impaired Impaired
by over-nutrition (obesity). Diabetes glucose fasting
mellitus tolerance glycaemia
Women who are obese, and also many slim women with
PCOS will have insulin resistance and elevated serum
Fasting glucose ≥7.0 <7.0 ≥6.1 and <7.0
concentrations of insulin. Insulin resistance is defined as a (mmol/l)
reduced glucose response to a given amount of insulin and 2-hour glucose ≥11.1 ≥7.8 and ≤11.1 <7.8
may occur secondary to resistance at the insulin receptor, (mmol/l)
decreased hepatic clearance of insulin and/or increased

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Health consequences of PCOS PCOS in adolescence

Obesity and metabolic abnormalities are recognised risk There is no agreement concerning how to diagnose PCOS in
factors for the development of ischemic heart disease in the adolescence.16 In fact, during the transition of girls into
general population, and these are also recognised features of adulthood, several features may be in evolution or may only
PCOS. The questions are whether women with PCOS are at an be transitory findings. It has therefore been suggested that the
increased risk of ischaemic heart disease, and whether diagnosis of PCOS should not be made until 2 years after
ischaemic heart disease will occur at an earlier age than menarche.16,17 It has also been proposed that all elements of the
women with normal ovaries. Cardiovascular risk factors Rotterdam consensus are required for diagnosing PCOS during
include insulin resistance, obesity (especially an increase in adolescence (and not just two out of three).17 Acne is common
waist circumference), glucose intolerance, diabetes, during the adolescent years and in most subjects is a transitory
hypertension and dyslipidaemia (in particular raised phenomenon. Hirsutism may be a better marker of
serum triglycerides). hyperandrogenism, and some authors have reported that
A study of women with PCOS and a mean age of 39 years, progressive hirsutism during the adolescent years may be an
followed over a period of 6 years, found that 9% of those important sign of PCOS.18 It is important to exclude non-
with normal glucose tolerance developed impaired glucose classical (late onset) congenital adrenal hyperplasia, particularly
tolerance (IGT) and 8% developed type II diabetes while 54% in those populations where it is more prevalent. Menstrual
of women with IGT at the start of the study had type II irregularities are also very common in adolescence, with up to
diabetes at follow-up.14 The risk of disease progression, not 65% having anovulatory cycles. There is a natural progression
surprisingly, was greatest in those who were overweight. towards more ovulatory cycles with increasing age.19 When the
In a large retrospective study the mortality rate was diagnosis of PCOS cannot be confirmed, careful follow-up is
assessed in 1028 women diagnosed as having PCOS in the UK required and the diagnosis re-considered if the symptoms
between 1930 and 1979.15 There was an increased, though persist. Nonetheless, it may be useful to start treatment during
non-significant risk of death due to diabetes but no increased the adolescent years for those with troublesome problems.
long-term coronary heart disease mortality, although there
was evidence of increased stroke-related mortality even after
Management of hyperandrogenism
adjustment for BMI.15 The epidemiology of the long-term
risks of PCOS is therefore somewhat conflicting, and further The bioavailability of testosterone is affected by the serum
prospective studies are required.16 concentration of SHBG. High levels of insulin lower the
production of SHBG and so increase the free fraction of
androgen. Elevated serum androgen concentrations stimulate
Effect on quality of life
peripheral androgen receptors, resulting in an increase in
The symptoms typically associated with PCOS have also been 5-alpha reductase activity, directly increasing the conversion of
shown to lead to a significant reduction in health-related testosterone to the more potent metabolite
quality of life (HRQoL). HRQoL is a multi-dimensional, dihydrotestosterone. Women with PCOS do not become
dynamic concept that encompasses physical, psychological, virilised (that is, they do not develop deepening of the voice,
and social aspects that are associated with a particular disease increased muscle mass, breast atrophy or clitoromegaly). A total
or its treatment. Therefore, any management of the woman testosterone level of greater than 5 nmol/l (depending upon the
with PCOS needs to consider and understand the negative assay) or rapid onset of signs of hyperandrogenism requires
impact this condition may have upon these psychosocial further investigation. Non-classic (late onset) congenital
parameters.3 For example, although the management of adrenal hyperplasia (CAH) is not common in the UK but is
hirsuitism may be considered a purely cosmetic issue, more prevalent in certain ethnic groups (e.g. Mediterranean,
excessive facial hair has been shown to be one of the major South American and some Jewish populations).
causes of marked psychological stress in women with PCOS, Hirsutism is characterised by terminal hair growth in a male
often caused by the ‘embarrassment’ about the excessive hair pattern of distribution, including the chin, upper lip, chest,
growth. Infertility and weight issues have also been found to upper and lower back, upper and lower abdomen, upper arm,
affect other social and psychological parameters. Infertility thigh and buttocks. A standardised scoring system, such as the
can cause tensions within the family, altered self-perception modified Ferriman and Gallwey score, may be used to evaluate
and problems at work.3 While obesity worsens the symptoms, the degree of hirsutism before and during treatments. Many
the metabolic scenario conspires against weight loss and many women attend having already tried cosmetic techniques and so
women experience ‘frustration’ in attempts to lose weight and it may be difficult to obtain a baseline assessment.
suffer from low self-esteem and poor body image, which also Drug therapy may take 6–9 months or longer before any
impacts on their ability to exercise in public places. improvement of hirsutism is perceived. Physical treatments

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 Polycystic ovary syndrome

including electrolysis, waxing and bleaching may be helpful

Management of menstrual problems
while waiting for medical treatments to work. Electrolysis is
time-consuming, painful and expensive and should be Women with unpredictable, irregular and heavy periods are
performed by an expert practitioner. Regrowth is not likely to benefit from cyclical hormone therapy. Furthermore,
uncommon, and there is no really permanent cosmetic women with PCOS who experience amenorrhea have
treatment. Laser and photothermolysis techniques are more unopposed estrogen production from the conversion of
expensive, but may have a longer duration of effect. Repeated androgens and the absence of postovulatory secretion of
treatments are required for a near-permanent effect because progesterone. Therefore, the induction of artificial
only hair follicles in the growing phase are obliterated at each withdrawal bleeds to prevent endometrial hyperplasia is
treatment. Hair growth occurs in three cycles, so 6–9 months prudent management.16
of regular treatments are typical. The topical use of eflornithine The risk of developing endometrial cancer has been shown
may be effective. It works by inhibiting the enzyme ornithine to be adversely influenced by a number of factors including
decarboxylase in hair follicles and may be a useful therapy for obesity, long-term use of unopposed estrogens, nulliparity
those who wish to avoid hormonal treatments, but may also be and infertility. Endometrial hyperplasia may be a precursor
used in conjunction with hormonal therapy. Eflornithine may to adenocarcinoma, with cystic glandular hyperplasia
cause some thinning of the skin and so high-factor sun block is progressing in perhaps 0.4% of cases and adenomatous
recommended when exposed to the sun. hyperplasia in up to 18% of cases over 2–10 years. Precise
Medical regimens should stop further progression of estimation of the rate of progression is impossible to
hirsutism and decrease the rate of hair growth. Adequate determine. Some authors have reported conservative
contraception is important in women of reproductive age as management of endometrial adenocarcinoma in women
transplacental passage of anti-androgens may disturb the with PCOS with a combination of curettage and high-dose
genital development of a male fetus. First-line therapy has progestogens. The rationale is that cancer of the
traditionally been the preparation Dianette (Bayer PLC, endometrium often presents at an early stage, is well
Newbury, Berkshire, UK), which contains ethinyloestradiol differentiated, of low risk of metastasis, and therefore is not
(35 lg) in combination with cyproterone acetate (2 mg). The perceived as being life-threatening, while poorly
addition of higher doses of cyproterone acetate (50–100 mg) differentiated adenocarcinoma in a young woman has a
does not appear to confer additional benefit. The effect on acne worse prognosis and warrants hysterectomy. In general,
and seborrhoea is usually evident within a couple of months. however, the literature on women with PCOS and
Sometimes additional topical antibiotic and anti- endometrial hyperplasia or adenocarcinoma suggests that
inflammatory preparations may be helpful. this group has a poor prognosis for fertility. This may be
Spironolactone is a weak diuretic with antiandrogenic because of the factors that predisposed to the endometrial
properties that may be used in women in whom the combined pathology – chronic anovulation often combined with severe
oral contraceptive pill is contraindicated at a daily dose of 25– obesity – or secondary to the endometrial pathology
100 mg. Drosperinone is a derivative of spironolactone and is disrupting potential embryonic implantation. Thus a more
contained in the combined oral contraceptive pill Yasmin traditional and radical surgical approach (i.e. hysterectomy)
(Bayer PLC, Newbury, Berkshire, UK), which may also be is suggested as the safest way to prevent progression of the
beneficial for women with PCOS. In reality all combined oral cancer. Early-stage disease may permit ovarian conservation
contraceptive preparations should benefit both the control of and the possibility of pregnancy by surrogacy.
the menstrual cycle and suppress hyperandrogenism. It is therefore important that women with PCOS shed their
Consideration should be made of the risk of endometrium at least every 3 months. For those women with
thromboembolism, particularly for those with PCOS who oligo/amenorrhea who do not wish to use cyclical hormone
may be overweight. therapy, we recommend an ultrasound scan to measure
Other antiandrogens such as finasteride and flutamide endometrial thickness and morphology every 6–12 months
have been tried, but are not widely used in the UK for the (depending on menstrual history). An endometrial thickness
treatment of hirsutism owing to their adverse side effects and greater than 10 mm in an amenorrheic woman warrants an
they do not appear to be any more effective. artificially induced bleed, which should be followed by a
The management of alopecia is difficult but may be repeat ultrasound scan and endometrial biopsy if the
stabilised by the anti-androgen preparations mentioned endometrium has not been shed. Another option is to
above. Iron deficiency may have an impact on hair loss and consider a progestogen-secreting intrauterine system, such as
so ferritin levels should be assessed. the Mirena (Bayer PLC, Newbury, Berkshire, UK).16

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are no medications that have been shown to assist with

Management of anovulatory infertility
long-term weight reduction. Bariatric surgery is used
PCOS accounts for approximately 80–90% of women with increasingly because of the global epidemic of obesity and
anovulatory infertility, which in turn comprise about a third certainly has a role in the management of obese women
of those attending the infertility clinic. A number of with PCOS.24 It is recommended by some that anyone with
guidelines have been written for the management of a BMI of greater than 40 kg/m2 should be referred for
anovulatory PCOS,20 the most recent by the World consideration of bariatric surgery. If there are comorbidities,
Health Organization.21 such as diabetes, then the BMI cut-off for surgery may be
The principles of the management of anovulatory lower (35 kg/m2). It is also reasonable to consider PCOS as
infertility are first to optimise health before commencing a comorbidity.
therapy (e.g. lose weight in those who are overweight) and
then to induce regular unifollicular ovulation. Folic acid Ovulation induction therapies
should be taken at a daily dose of 400 micrograms or, in Strategies to induce ovulation include oral anti-estrogens
those who are obese, 5 mg. A semen analysis should be (principally clomifene citrate [CC]), parenteral
performed before ovulation induction therapy is gonadotrophin therapy and laparoscopic ovarian surgery.
commenced. To ensure a cost-effective approach to There have been no adequately powered randomised studies
treatment, an assessment of tubal patency is appropriate in to determine which of these therapies provides the best
every woman before commencing therapy. overall chance of an ongoing pregnancy when used as first-
line therapy. Women with PCOS are at risk of ovarian
Obesity and lifestyle hyperstimulation syndrome (OHSS) and multiple pregnancy
Various factors influence ovarian function and fertility, the which is why ovulation induction therapy should be carefully
most important being obesity. Monitoring treatment is also monitored with serial ultrasound scans.20,21 Good cumulative
harder in obese women because their ovaries are more conception rates can be achieved and multiple pregnancy
difficult to see on ultrasound scans, thus raising the risk of rates can be minimised with strict adherence to criteria that
missing multiple ovulation and multiple pregnancy. There is limit the number of follicles that are permitted to ovulate.
debate about the restriction of fertility treatment to women
who are overweight, although there is no doubt that obesity Clomifene citrate (CC) therapy
has a significant adverse impact on reproductive outcome. It The anti-estrogen CC has traditionally been used as first-line
influences not only the chance of conception but also the therapy for anovulatory PCOS.25 CC therapy is usually
response to fertility treatment and increases the risk of commenced on days 2–5 of the menstrual cycle and given for
miscarriage, congenital anomalies and pregnancy 5 days. If the patient has oligo/amenorrhea, it is necessary to
complications. The British Fertility Society guidance exclude pregnancy and then induce a withdrawal bleed with a
suggests that treatment should be deferred until the BMI is short course of a progestogen, such as medroxyprogesterone
less than 35 kg/m2, although in those with more time (e.g. acetate 20 mg/day for 5–10 days. The starting dose of CC is
less than 37 years, normal ovarian reserve) a weight reduction 50 mg/day. If the patient has not menstruated by day 35 and
to a BMI of less than 30 kg/m2 is preferable.22 Even a she is not pregnant, a progestogen-induced withdrawal bleed
moderate weight loss of 5–10% of body weight can be should be initiated. The dose of CC may be increased to
sufficient to restore fertility and improve 100 mg if there is no response. Doses of 150 mg/day or more
metabolic parameters. do not appear to be of benefit. If there is an exuberant
There is no evidence that women with PCOS benefit response to 50 mg/day, as in some women with PCOS, the
from a specific diet compared with obese women without dose can be decreased to 25 mg/day. If the patient is
PCOS.23 The right diet for an individual is one that is ovulating, conception is expected to occur at a rate
practical, sustainable and compatible with her lifestyle. It is determined by factors such as the patient’s age. CC induces
sensible to reduce glycaemic load by lowering sugar content ovulation in approximately 70–85% of patients and
in favour of more complex carbohydrates and to avoid fatty approximately 60–70% should be pregnant by six ovulatory
foods. Meal replacement therapy or low-calorie diets may cycles of therapy.26
be appropriate, and it is often helpful to refer to a dietitian. Hypersecretion of LH is found in 40% of women with
An increase in physical activity is essential, preferably as PCOS and is associated with a reduced chance of conception
part of a daily routine. Thirty minutes per day of brisk and an increased risk of miscarriage, possibly through an
exercise is encouraged to maintain health, but to lose adverse effect of LH on oocyte maturation. Elevated LH
weight, or sustain weight loss, 60 to 90 minutes per day is concentrations are more often found in slim women with
advised. Concurrent behavioural therapy improves the PCOS. Clomifene citrate may cause an exaggeration in the
chances of success of any method of weight loss. There hypersecretion of LH and have anti-estrogenic effects on the

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 Polycystic ovary syndrome

endometrium and cervical mucus. The author suggests conception (e.g. persistent hypersecretion of LH, or anti-
measuring LH on day 8 of the cycle and if persistently estrogenic effect on endometrium). In order to prevent the
elevated then move on to alternative therapy as the chance of risks of overstimulation and multiple pregnancy, a low-dose
conception is reduced and the risk of miscarriage step-up regimen should be used with a daily starting dose of
increased.26,27 All women who are prescribed CC should be 25–50 IU of FSH or human menopausal gonadotrophin. This
carefully monitored with ultrasonographic assessment of is only increased after 14 days if there is no response and then
follicular growth because of the risk of multiple pregnancy, by only half of the starting dose every 7 days. Treatment
which is approximately 10%. Therefore, CC therapy should cycles using this approach can be quite long – up to 28–35
be prescribed and managed by specialists in days – but the risk of multiple follicular growth is low and the
reproductive medicine. multiple pregnancy rate should be less than 5%. It can be
If pregnancy has not occurred after 6–9 normal ovulatory extremely difficult to predict the response to stimulation. The
cycles, it is then reasonable to offer the couple assisted polycystic ovary is characteristically quiescent, at least when
conception (that is in vitro fertilisation [IVF]). Women with viewed by ultrasound, before often exhibiting an exuberant
anovulatory infertility who are resistant to anti-estrogens and explosive response to stimulation. It can be very
may be prescribed parenteral gonadotrophin therapy or challenging to stimulate the development of a single
treated with laparoscopic ovarian surgery. The term dominant follicle.
‘clomifene resistance’ strictly speaking refers to a failure to Ovulation is triggered with a single subcutaneous injection
ovulate rather than failure to conceive despite ovulation, of human chorionic gonadotropin (hCG) 5000 units, when
which should be termed ‘clomifene failure’. there has been the development of at least one follicle of at
least 17 mm in its largest diameter. In order to reduce the
Aromatase inhibitors risks of multiple pregnancy and OHSS, the exclusion criteria
For completeness we need to consider the use of aromatase for hCG administration are the development of a total of two
inhibitors such as letrozole. Inhibition of the aromatase or more follicles larger than 14 mm in diameter. In
enzyme decreases the aromatisation of androgens to overstimulated cycles hCG is withheld, and the patient is
estrogens that in turn releases the hypothalamic–pituitary counselled about the risks and advised to refrain from sexual
axis from negative feedback of estrogen. Adverse effects intercourse. The cumulative conception and live birth rates
on the endometrium and cervical mucus are considerably less after 6 months should be 65–70% and 55–60%, respectively.
than with CC and there are reports of good pregnancy rates If conception has failed to occur after six ovulatory cycles in a
with a lower incidence of multiple pregnancy.28 woman younger than 25 years or after 12 ovulatory cycles in
Despite the potential advantages over CC, the use of women older than 25 years, it can be assumed that
letrozole was discouraged following a report at a meeting anovulation is unlikely to be the cause of the couple’s
(that has not been published in a peer-reviewed journal) that infertility, and assisted conception (usually IVF) is
suggested a significant increase in congenital malformations now indicated.21
in newborns in letrozole-treated pregnancies. However, more
recent studies have not supported the teratogenic effect of Insulin-sensitising agents
letrozole and a recent randomised controlled trial It is logical to assume that therapy that achieves a fall in
demonstrated a significantly higher live birth rate when serum insulin concentrations should improve the symptoms
compared with CC.29 A recent Cochrane review also of PCOS. The biguanide metformin both inhibits the
demonstrated a greater chance of live birth with letrozole production of hepatic glucose, thereby decreasing insulin
(odds ratio (OR) 1.64, 95% CI 1.32–2.04) and a lower rate of secretion, and also enhances insulin sensitivity at the cellular
multiple pregnancy (OR 0.38, 95% CI 0.17–0.84).30 level. Many studies have now been carried out to evaluate the
Therefore, the World Health Organization guidance has reproductive effects of metformin in patients with PCOS.
supported the use of letrozole as first-line therapy in those Initial studies appeared to be promising, suggesting that
countries where its use is permitted for this indication (which metformin could improve fertility in women with PCOS;
currently does not include the UK).21 It is still prudent to however, more recent large randomised controlled trials have
perform more research to assess the safety and efficacy of observed limited benefit from metformin, as either a first-line
aromatase inhibitors for ovulation induction. therapy or in combination with other drugs, in enhancing the
chance of a live birth.31
Gonadotrophin therapy The latest update of the Cochrane review of insulin-
Gonadotrophin therapy is indicated for women with sensitising agents and PCOS included 46 trials with a total of
anovulatory PCOS who have been treated with anti- 4227 participants.31 The median daily dose of metformin was
estrogens if they have failed to ovulate or if they have a 1500 mg with durations ranging from 4 to 60 weeks. This
response to CC that is likely to reduce their chance of systematic review concluded that metformin may improve

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 Balen

menstrual frequency and ovulation rate, which may result in formation is far less after LOD (10–20% of cases) than after
a marginal improvement in live birth rate when compared wedge resection (100% in some series), and the adhesions
with placebo. This review update includes a recent large that do form are usually fine and of limited clinical
Scandinavian study of 329 women, who received metformin significance. The instillation of 500–1000 ml of an isotonic
(1500–2000 mg/day) or placebo for 3 months prior to solution into the pouch of Douglas cools the ovaries to
fertility treatment and then for a further 9 months during prevent heat injury to adjacent tissues and reduce the risk of
treatment and up to 12 weeks of gestation. They showed an adhesion formation.
increase in pregnancy rate from 40.4% to 53.6% (OR 1.61, The largest randomised controlled trial to date is a
95% CI 1.13–2.29), with the greatest benefit seen in obese multicentre study performed in the Netherlands, in which
women.32 While there was no reduction in the miscarriage 168 CC-resistant women were randomised to either LOD
rate, the live birth rate was increased in those who received (n=83) or ovulation induction with recombinant FSH (rFSH,
metformin (41.9% versus 28.8%, P = 0.014).32 n=65).34 The initial cumulative pregnancy rate after
When metformin is added to CC in women with CC- 6 months was 34% in the LOD arm versus 67% in the
resistance, clinical pregnancy rate is increased in both obese rFSH arm. Those who did not ovulate in response to LOD
and non-obese patients but there is no improvement in live were then given first CC and then rFSH so by 12 months, the
birth rates.31 In summary, metformin has limited value in the cumulative pregnancy rate was similar in each group at
management of anovulatory PCOS but could be used alone 67%.34 Thus, those treated with LOD took longer to conceive
to improve ovulation rate and pregnancy rate, if facilities are and 54% required additional medical ovulation induction
not available for monitoring of CC or gonadotrophins, which therapy. Furthermore, the duration of the effect may be
are more effective. Furthermore, a recent systematic review limited to a few months, although some report more
indicated that metformin therapy combined with lifestyle prolonged efficacy.
modification in women with PCOS may improve body
weight.33 For those women with PCOS and impaired glucose Complications of ovulation induction
tolerance or type II diabetes, metformin has a better defined Multiple pregnancy and OHSS are the most serious
role combined, of course, with lifestyle modification. complications that should be avoided in ovulation
induction treatment. Multiple pregnancy, even twins, is
Surgical ovulation induction undesirable due to increased risk of perinatal mortality and
An alternative to gonadotrophin therapy for CC-resistant morbidity. Women with PCOS are at an increased risk of
PCOS is laparoscopic ovarian diathermy (LOD) (often developing OHSS. This occurs if many follicles are
referred to as ‘ovarian drilling’ or laparoscopic stimulated, leading to ascites and pleural and sometimes
electrocautery), which has replaced the more invasive and pericardial effusions, with symptoms of abdominal
damaging technique of ovarian wedge resection. distension, discomfort, nausea, vomiting and difficulty
Laparoscopic ovarian surgery is free of multiple pregnancy breathing. Hospitalisation is sometimes necessary in order
risk and OHSS and does not require intensive ultrasound for intravenous fluids (colloids preferable to crystalloids) and
monitoring. In addition laparoscopic ovarian surgery is a heparin to be given to prevent dehydration and
useful therapy for anovulatory women with PCOS who fail to thromboembolism. Although this condition is rare, it is a
respond to CC and who persistently hypersecrete LH, need a potentially fatal complication and should be avoidable with
laparoscopic assessment of their pelvis or who live too far appropriate monitoring of treatment.
away from the clinic to be able to attend for the intensive
monitoring required of gonadotrophin therapy. Only fully IVF in women with polycystic ovaries
trained laparoscopic surgeons should perform laparoscopic IVF is not the first-line treatment for PCOS, but many
ovarian surgery. patients with the syndrome may be referred for IVF, either
After LOD, with restoration of ovarian activity, serum because there is another reason for their infertility or because
concentrations of LH and testosterone fall. Response depends they fail to conceive despite ovulating (whether
on pretreatment characteristics, with those who are slim and spontaneously or with assistance); i.e. their infertility
with high basal LH concentrations having a better clinical remains unexplained. Furthermore, approximately 25–30%
and endocrine response. Commonly employed methods for of women have polycystic ovaries as detected by ultrasound
laparoscopic surgery include monopolar or bipolar scan. Many will have little in the way of symptoms and may
electrocautery (diathermy) and laser surgery. The larger present for assisted conception treatment because of other
amount of damage to the surface of the ovary, the greater the reasons (for example tubal factor or male factor). When
risk of peri-ovarian adhesion formation. This has led to stimulated these women with asymptomatic polycystic
strategies to minimise the number of diathermy points to ovaries have a tendency to respond sensitively and are at
four per ovary for 4 seconds at 40 watts. The risk of adhesion increased risk of developing OHSS. Care must therefore be

ª 2017 Royal College of Obstetricians and Gynaecologists 127

 Polycystic ovary syndrome

taken and there is evidence of reduced risk if protocols using on the management of PCOS. He was an editor of BJOG: An
a GnRH antagonist are employed. International Journal of Obstetrics & Gynaecology and has had
a number of committee roles in the past at the RCOG but
Pregnancy outcomes none currently. He co-chaired the SSG on PCOS and has
In addition to anovulation there may be other factors that written books, Green-top guidelines, SAC papers and other
contribute to subfertility in women with PCOS including the papers for the RCOG. None of the above conflict with the
effects of obesity, metabolic, inflammatory and endocrine content of the manuscript. Full disclosures are available
abnormalities on oocyte quality and fetal development. online as supporting information.
Women who are obese are also more likely to experience
miscarriage and pregnancy complications. A number of Further reading
studies have compared pregnancy outcomes in women with Balen A, Franks S, Homburg R, Kehoe S, editors. Current
PCOS compared with controls and have found that women management of polycystic ovary syndrome. Proceedings of the
with PCOS demonstrated a significantly higher risk of 59th RCOG Study Group. London: RCOG Press; 2010.
developing gestational diabetes, pregnancy-induced
hypertension, pre-eclampsia, adverse neonatal outcomes
and preterm birth.35 Their babies had a significantly higher References
risk of admission to a neonatal intensive care unit and a
1 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.
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uterine blood flow, and so careful monitoring of pregnancy
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3 Jones GL, Hall JM, Balen AH, Ledger W. Health-related quality of life
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boards for Ferring Pharmaceuticals, Astra Zeneca,
in south Asian women: a case control study. Clin Endocrinol 2002;
Pharmasure, Merck Serono, Gideon Richter, OvaScience 57:343–50.
and Uteron Pharma. Professor Balen’s research is largely 13 Lord J, Wilkin T. Polycystic ovary syndrome and fat distribution: the central
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funded by public bodies in the UK and European Union,
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member of the WHO Global Infertility Guidelines with polycystic ovary syndrome at long-term follow-up: a retrospective
Committee and Chair of the WHO Expert Working Group cohort study. Clin Endocrinol 2000;52:595–600.

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