REVIEWS

Polycystic ovary syndrome: definition,

aetiology, diagnosis and treatment
Héctor F. Escobar-Morreale1,2,3,4
Abstract | Polycystic ovary syndrome (PCOS) is one of the most common endocrine and
metabolic disorders in premenopausal women. Heterogeneous by nature, PCOS is defined by a
combination of signs and symptoms of androgen excess and ovarian dysfunction in the absence
of other specific diagnoses. The aetiology of this syndrome remains largely unknown, but
mounting evidence suggests that PCOS might be a complex multigenic disorder with strong
epigenetic and environmental influences, including diet and lifestyle factors. PCOS is frequently
associated with abdominal adiposity, insulin resistance, obesity, metabolic disorders and
cardiovascular risk factors. The diagnosis and treatment of PCOS are not complicated, requiring
only the judicious application of a few well-standardized diagnostic methods and appropriate
therapeutic approaches addressing hyperandrogenism, the consequences of ovarian dysfunction
and the associated metabolic disorders. This article aims to provide a balanced review of the
latest advances and current limitations in our knowledge about PCOS while also providing a few
clear and simple principles, based on current evidence-based clinical guidelines, for the proper
diagnosis and long-term clinical management of women with PCOS.

1
Department of
Endocrinology and Nutrition,
Hospital Universitario
Ramón y Cajal, Madrid, Spain.
2
Universidad de Alcalá,
Alcalá de Henares, Spain.
3
Centro de Investigación
Biomédica en Red Diabetes y
Enfermedades Metabólicas
Asociadas (CIBERDEM),
Madrid, Spain.
4
Instituto Ramón y Cajal de
Investigación Santiaria
(IRYCIS), Madrid, Spain.
e-mail: hectorfrancisco.
escobar@salud.madrid.org
doi:10.1038/nrendo.2018.24
Published online 23 Mar 2018
Polycystic ovary syndrome (PCOS) is a heterogeneous
disorder that is defined by a combination of signs and
symptoms of androgen excess (hirsutism and/or hyper­
androgenaemia) and ovarian dysfunction (oligo-­ovulation
and/or polycystic ovarian morphology (PCOM)), provided
that other specific diagnoses, such as hyper­prolactinaemia
and non-classic congenital adrenal hyperplasia, have been
excluded1. The prevalence of PCOS in premenopausal
women ranges from ~6% (using the older, more restrictive
criteria) to ~20% (when applying current, more inclusive
definitions)2–5, possibly making this syndrome the most
common endocrine and metabolic disorder in women
of reproductive age6,7.
Unfortunately, the growing interest of the scientific
community in PCOS has not been paralleled by that
of the international and local health authorities8 or, in
particular, of the pharmaceutical industry. PCOS was
first described in 1935 by Stein and Leventhal9 as the
combination of hirsutism (a condition of male-pattern
terminal hair growth in women), amenorrhoea (absence
of menstruation), chronic anovulation and infertility,
obesity and enlarged cystic ovaries9. However, it was
not until 1990 that the WHO included ‘E28.2 Polycystic
ovarian syndrome’ — with sclerocystic ovary syndrome
and Stein–Leventhal syndrome as synonyms — among
the disorders of ovarian dysfunction included in the
International Classification of Diseases, 10th revision
(ICD10)10. Moreover, most of the drugs that are used
to treat the symptoms of PCOS, from oral contraceptive
pills to anti-androgens, insulin sensitizers or aromatase
inhibitors, are used in an off-label fashion because neither
the FDA nor the European Medicines Agency has ever
approved a drug specifically for the treatment of PCOS11.
The limited interest of the pharmaceutical industry in
PCOS is exemplified by the current registration of clin­
ical trials: while 28 commercial studies on PCOS were
registered at ClinicalTrials.gov at the end of August
2017, the number of studies addressing diabetes melli­
tus was 4,632, despite both disorders showing similar
worldwide prevalences5,12. Hence, from the perspective
of pharmacological treatment, PCOS might currently be
considered by far the most prevalent orphan disorder of
adolescent and adult women.
The most likely explanation for the current apparent
lack of interest of health authorities and the pharma­
ceutical industry is that PCOS remains one of the most
poorly understood medical disorders among patients,
physicians13 and even scientists14, and the common
misunderstanding of the syndrome and its long-term
consequences for the health of both patients and their
families has limited the allocation of research and devel­
opment resources into this area of study. Possible reasons
underlying the misunderstanding about PCOS include
the inadequacy of its naming, its heterogeneous nature,

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Key points
• Polycystic ovary syndrome (PCOS) is defined by a combination of signs and
symptoms of androgen excess and ovarian dysfunction in the absence of other
specific diagnoses.
• Heterogeneity, from aetiology to clinical presentation and long-term prognosis, is
intrinsic to PCOS.
• Mounting evidence suggests that PCOS might be a complex multigenic disorder
with strong epigenetic and environmental influences, including diet and other
lifestyle issues.
• The diagnosis of PCOS is uncomplicated, requiring only the careful application of a
few well-standardized diagnostic methods.
• Treatment should be symptom-oriented, long term and dynamic and adapted to the
changing circumstances, personal needs and expectations of the individual patient.
• Therapeutic approaches should target hyperandrogenism, the consequences of
ovarian dysfunction and/or the associated metabolic disorders.
the always controversial issue of its definition and the
many uncertainties remaining about its aetiology and
pathophysiology.
This Review outlines the latest advances and current
limitations in our knowledge about PCOS, with the aim
of providing a few clear and simple principles for its
proper diagnosis and long-term clinical management.
Most of these recommendations rest on and are sup­
ported by current evidence-based clinical guidelines for
the management of PCOS, but in rare cases when the
suggestions are from my own personal experience or
are based on a few individual studies, the lack of actual
evidence supporting them is clearly stated.
The term ‘polycystic ovary syndrome’
PCOS can be anything but polycystic. The ‘polycystic’
appearance of the ovaries frequently found in patients
with PCOS is caused by the accumulation of ovarian fol­
licles in different stages of maturation and/or atresia15.
Ovarian follicles are cellular aggregates that contain a
single oocyte and are not cysts (which, in medical terms,
are membranous sacs or cavities of abnormal charac­
ter containing fluid), and therefore, the name PCOS
could be considered a misnomer. Sadly, this confusion
diverts attention from the actual pathophysiology of the
syndrome16. The name PCOS is perceived as confusing
both by primary health-care physicians and patients,
and it is not unusual for patients and their families to
even express unreasonable concerns about the poten­
tial for malignancy of such ‘cysts’ (REF. 17). Accordingly,
the 2012 National Institutes of Health Office for Disease
Prevention-Sponsored Evidence-Based Methodology
Workshop on Polycystic Ovary Syndrome18 recom­
mended that a new name was needed for PCOS. This
proposal was supported by certain professional associa­
tions, women’s health organizations and a PCOS patient
support group from Australia; these groups strongly
supported this proposal to ensure that “…an alternative
name enhances understanding and recognition of the
syndrome and its complex features” (REF. 16).
Unfortunately, all previously proposed alternative
names to PCOS have not been widely adopted, proba­
bly for the same reasons underlying the endless debate
about which are the most appropriate diagnostic criteria
for PCOS. Given the lack of solid evidence about the
aetiology and pathophysiology of the disorder, the dif­
ferent names proposed reflect the interpretations and
beliefs of the proponents and cause conflict with those
of others. As a result, experts who defend the major part
of androgen excess proposed names such as functional
ovarian hyperandrogenism19, hyperandrogenic-chronic
anovulation20 or female functional hyperandrogen­
ism21,22, whereas those who suggest that insulin resist­
ance and metabolic dysfunction are the most important
factors propose names such as metabolic reproductive
syndrome23, syndrome XX24 or even prevalent cardio­
metabolic ovary syndrome, which would also take the
abbreviation of PCOS.
The problem with these names is that current defi­
nitions of PCOS include women who might not have
androgen excess and that many women with PCOS,
particularly those of normal weight and those with nor­
moandrogenaemic phenotypes25, have no evidence at all
of insulin resistance, metabolic dysfunction or increased
cardiovascular risk. Names such as polyfollicular ovar­
ian syndrome rely on an assessment of altered ovarian
morphology only, which is a criterion that is neither nec­
essary nor sufficient to diagnose the syndrome. Other
names, such as female hormonal imbalance, hormonal
imbalance syndrome or imbalanced hormone syn­
drome, are unspecific and might be inclusive of any kind
of endocrine dysfunction. Finally, there are experts26 and
patient’s associations reluctant about renaming PCOS,
mostly because this name has been finally included by
the WHO as a disease and is increasingly recognized
by the general public as an important health problem
and thus changing its name might draw all previous
efforts in dissemination of knowledge back to square
one. Perhaps the easiest and most elegant solution would
be giving Stein and Leventhal due credit for their original
observations9 and continue to name PCOS after them27.
The term ‘Stein–Leventhal syndrome’ has already been
used to name PCOS for decades17, and it is well known
to health authorities, patients and other organizations.
Definition of PCOS
Even though the 2012 Evidence-Based Methodology
Workshop on Polycystic Ovary Syndrome mentioned
in the previous section18 intended to end the debate on
which are the most appropriate diagnostic criteria for the
definition of PCOS, the report of the steering committee
was not published in a peer-reviewed scientific journal,
reducing its impact and authority. Hence, the recommen­
dation to use the criteria jointly proposed by members
of the European Society of Human Reproduction and
Embryology and the American Society of Reproductive
Medicine in 2003 — the so-called Rotterdam criteria —
has not been universally accepted, and three definitions
for PCOS remain valid at present.
The Rotterdam definition is the most widely used
PCOS classification, and it is currently supported by
most scientific societies and health authorities18,28–31.
The definition proposes that PCOS can be diagnosed
in any woman presenting with at least two of the three

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following characteristics: clinical and/or biochemical
hyperandrogenism, ovulatory dysfunction and PCOM28.
By contrast, the 2006 Androgen Excess and PCOS Society
(AE–PCOS) Position Statement requires the presence
of hyperandrogenism, which must be accompanied by
evidence of ovarian dysfunction in the form of ovula­
tory dysfunction and/or PCOM1,32. Finally, the National
Institute of Child Health and Human Development has
an older definition that requires the presence of both
hyperandrogenism and ovulatory dysfunction but does
not consider ovarian morphology 33. This definition rep­
resents the most severe phenotype of the PCOS spec­
trum, and it is included within both the Rotterdam and
AE–PCOS definitions. Of note, these definitions equally
consider clinical and/or biochemical hyperandrogenism,
even though there is a definite lack of convincing evi­
dence to show that these two forms of androgen excess
have the same health consequences for patients. The
three definitions require exclusion of specific disorders
that might have signs and symptoms that overlap with
those of PCOS, such as non-classic congenital hyper­
plasia, hyperprolactinaemia, thyroid dysfunction,
hypercortisolism and androgen-secreting tumours1,28,33.
As a result of these differing criteria, the dispute con­
tinues regarding whether or not women who present
with ovulatory dysfunction and PCOM but who do not
exhibit any signs of either clinical or biochemical andro­
gen excess actually have PCOS34,35. This debate might
not continue if we change our focus from thinking in
terms of whether the patient has a disease to considering
the exposure to the health risks associated with different
manifestations and phenotypes of PCOS. PCOS is a
hetero­geneous disorder, not only in terms of patho­
physiology 36 but also in the severity of its clinical con­
sequences, as, by definition, not all patients with PCOS
have all the possible manifestations of the disorder nor
are they exposed to the same health risk factors.
Each individual criterion used to define PCOS has
clinical consequences by itself. Androgen excess might
result in cutaneous manifestations, such as hirsutism,
acne and alopecia1; ovulatory dysfunction and chronic oli­
gomenorrhoea might result in infertility and endo­metrial
hyperplasia and/or carcinoma1; and isolated PCOM is
associated with a risk of ovarian hyperstimulation syn­
drome only during ovulation induction37. As a rule of
thumb, the more criteria met by the individual patient
with PCOS, the more severe her particular phenotype is.
As shown in FIG. 1a, the most severe clinical mani­
festation is the classic PCOS phenotype that presents
with both hyperandrogenism and oligo-ovulation, irre­
spective of the presence of PCOM. The next most severe
phenotype is ovulatory PCOS (presents with hyperan­
drogenism and PCOM), and the non-hyperandrogenic
phenotype, which consists of oligo-ovulation and PCOM,
is the least severe phenotype38. The latter category is not
considered PCOS by the AE–PCOS statement1.
Similarly, PCOS is a heterogeneous disorder in terms
of its link with insulin resistance and metabolic dys­
function (FIG. 1b). This association is much stronger in
women with the classic PCOS phenotype than in those

a b
Hyperandrogenism
• Hirsutism
• Acne
• Alopecia Hyperandrogenism
• Seborrhoea

Ovulatory
PCOS ++
Classic +++
PCOS

Oligo-ovulation
• Menstrual PCOM
Ovarian Oligo-ovulation PCOM
dysfunction Non-
• Subfertility hyperstimulation
hyperandrogenic syndrome
• Endometrial phenotype +
–
hyperplasia

Figure 1 | The heterogeneous nature of PCOS. Polycystic ovary syndrome
(PCOS) is a heterogeneous disorder in terms of phenotypes and clinical
manifestations (part a) and in terms of metabolic consequences (part b).
The most severe classic phenotypes (highlighted in dashed outline),
consisting of hyperandrogenism (symptoms include hirsutism, acne,
alopecia and seborrhoea) and oligo-ovulation (symptoms include
menstrual dysfunction, subfertility and endometrial hyperplasia), are
associated with the most severe insulin resistance and metabolic
comorbidities. Ovulatory PCOS consists of hyperandrogenism
Nature and
Reviews | Endocrinology
polycystic ovarian morphology (PCOM; clinical consequences include
ovarian hyperstimulation syndrome), and it is associated with moderate
insulin resistance and metabolic comorbidities. The non-hyperandrogenic
phenotype consists of oligo-ovulation and PCOM and has a weak
association with insulin resistance and metabolic comorbidities. The
strength of the association ranges from weak (±) to strong (+++). Adapted
from REF. 38, Macmillan Publishers Limited.

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with ovulatory PCOS25,39–41 or in those with the non-­
hyperandrogenic phenotype25,42. The latter group fre­
quently does not have insulin resistance25 or metabolic
dysfunction, although they might have mildly decreased
levels of sex hormone-binding globulin42.
Owing to the phenotypic heterogeneity of PCOS,
when a patient is diagnosed with PCOS, an additional
brief description of the specific PCOS criteria that she
meets would help the patient and the health-care pro­
fessionals involved in her care to understand the health
consequences of such a diagnosis, thereby facilitating
her peace of mind and her correct long-term medical
management. In essence, this improvement in diagnos­
tic information might be accomplished by identifying
the individual’s particular PCOS phenotype as recom­
mended by the 2012 Evidence-Based Methodology
Workshop on Polycystic Ovary Syndrome18 (BOX 1).
However, it is the usual practice of this author to include
even more detailed descriptions in the clinical reports
of his patients, differentiating between clinical and bio­
chemical androgen excess and giving information on
the specific metabolic alterations experienced by each
particular patient.
Aetiology and pathophysiology of PCOS
An evolutionary perspective
A common evolutionary origin based on survival advan­
tage has been suggested for prevalent metabolic dis­
orders such as obesity and diabetes mellitus43; a similar
theory has also been proposed for PCOS21. According to
this theory 44,45, in ancient times, humans were exposed
to extremely stressful environmental conditions char­
acterized by near-continuous physical activity, a diet
rich in complex carbohydrates and proteins yet poor in
fat and long periods of famine, trauma and infection.
In such conditions, the combination of thrifty geno­
types and phenotypes might be essential for survival
and therefore facilitate their selection during evolution.
However, during the past century, food access in many
countries has become unrestricted, the occurrence of
trauma and epidemics has decreased, and life expectancy
has increased markedly; the defensive mechanisms of
the thrifty genotypes and phenotypes were therefore
no longer beneficial, leading to a dramatic increase in
the prevalence of obesity, diabetes mellitus and cardio­
vascular disease21,43–45.
Insulin resistance might have played a major part
in the thrifty genotypes and phenotypes21,43. Moreover,
cosegregation of insulin-resistant genotypes and pheno­
types with those related to PCOS might explain the fre­
quent association of both traits; however, for this to be
plausible, PCOS should have provided advantages in
Box 1 | Phenotypes of polycystic ovary syndrome18
• Hyperandrogenism and ovulatory dysfunction.
• Hyperandrogenism and polycystic ovarian morphology.
• Oligo-ovulation and polycystic ovarian morphology.
• Hyperandrogenism, oligo-ovulation and polycystic
ovarian morphology.
survival during evolution. Such an advantage has been
proposed for carriers of 21-hydroxylase deficiency 46 (the
most common form of congenital adrenal hyperplasia,
which is characterized by adrenal androgen excess),
and the mechanisms underlying this advantage might
also apply to other androgen excess disorders such as
PCOS46–48 (BOX 2).
Familial aggregation
The familial aggregation of PCOS and its related traits,
which suggests a genetic basis for these disorders, has
been recognized for decades49–60. However, despite enor­
mous efforts in targeted21,61 and genome-wide associ­
ation studies62–65, the search for the genes responsible
for such an association has proved mostly fruitless,
and the associations of only a few genetic variants and
mutations have been replicated in different popula­
tions of patients with PCOS, which accounts for ~10%
of the heritability of PCOS66. Similar to other prevalent
metabolic disorders such as type 2 diabetes mellitus67,
PCOS is now considered a complex multigenic disor­
der in terms of aetiology, in which predisposing and
protective genetic variants interact with strong environ­
mental influences to result in the different PCOS phe­
notypes21. These environmental factors possibly include
diet and lifestyle factors that are heavily influenced by
race and/or ethnicity; as such, the genes responsible for
PCOS might differ depending on the population stud­
ied. These differences could at least partly explain the
repeated difficulties in replicating the association of
PCOS with genomic variants and loci in populations
of diverse origin21.
Familial aggregation of PCOS, however, might be
related to certain environmental factors that are present
only in the families affected and not in the families of
unaffected women and might initiate epigenetic mech­
anisms — that is, stably heritable phenotypes resulting
from changes in a chromosome without actual alter­
ations in the DNA sequence68. Epigenetic initiators
include mechanisms during fetal and childhood devel­
opment, exposure to environmental chemicals and cer­
tain drugs, the ageing process and diet 68, most of which
might contribute to PCOS.
For example, insults during pregnancy, such as
maternal hypertension, diabetes or smoking, might
induce intrauterine growth retardation, which has
been proposed to induce a thrifty phenotype in babies
that are born small for gestational age69. These babies
are predisposed to insulin resistance owing to perma­
nent programming of metabolic function and might
be overweight in childhood69. These children might
develop hypertension, glucose intolerance, adrenal axis
hyperactivity with relative cortisol excess, functional
hyperandrogenism or PCOS later in life70, especially
when they are exposed to environmental factors such
as a sedentary lifestyle and a diet rich in saturated fat
(FIG. 2). These factors might cluster in particular fam­
ilies, as parental habits heavily affect the exercise and
dietary habits of offspring. The metabolic abnormali­
ties associated with the thrifty phenotype could induce
further changes during the pregnancies of women who

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Box 2 | Causes of survival advantage in women with PCOS and their progeny46–48
• Rapid maturation of the reproductive axis.
• Increased androgen secretion results in assertive behaviour.
• Subfertility could increase the interval between pregnancies, decreasing the birth
rate and favouring maternal and infant survival.
• Oligo-ovulation leads to pregnancies occurring at older ages, favouring the survival
of these women and their progeny.
were born small for gestational age, thus passing on
the pheno­type to another generation without a genetic
change occurring 21. Therefore, instead of being the result
of genetic factors, the presence of more than one small
for gestational age baby in a family might be the result
of the exposure of mothers and their fetuses to the same
unfavourable environmental conditions.
Although the effect of intrauterine growth restriction
on the subsequent development of PCOS is debatable, as
polycystic ovaries have also been seen in women born at
an above-average birthweight with mothers with andro­
gen excess and obesity 71–73, a large body of evidence,
mostly from animal models, suggests that early prena­
tal exposure to androgen excess leads to a permanent
PCOS-like phenotype in the progeny 74,75. This perma­
nent PCOS-like phenotype is characterized by hyper­
secretion of luteinizing hormone as a result of reduced
hypothalamic sensitivity to steroid negative feedback
and relative insulin resistance from increased abdom­
inal adiposity 74,75. Hence, androgen excess might have
a negative effect on women affected by this condition
during their whole life, from the fetal period and early
childhood to adulthood and extending into the meno­
pausal years. In this regard, current evidence suggests
that androgen excess and insulin resistance persist in
women with PCOS after menopause76–78, but these traits
might be attenuated during these years following the
decline of ovarian function79,80.
In addition, exposure to environmental toxins, such
as endocrine-disrupting chemicals that mimic endo­
genous hormones and advanced glycation end prod­
ucts, might programme reproductive and metabolic
function, leading to PCOS and its associated metabolic
dysfunctions, especially if such exposure is persistent
and occurs during developmental periods such as fetal
life, infancy or childhood81. The same consequences
might result from exposure to certain pharmaceutical
drugs during critical developmental windows, especially
the anti-epileptic and mood stabilizer valproate82, which
is frequently associated with a PCOS-like phenotype in
premenopausal women and induces a genomic and
molecular signature in theca cell cultures that is similar
to that of PCOS83,84.
It is important to highlight that avoidance of epi­
genetic initiators and maintenance of healthy habits in
women with PCOS might ameliorate insulin resistance
and its consequences and that, at least in theory, their
fetuses will be exposed to a less unfavourable metabolic
milieu during pregnancy, which would to some extent
prevent the non-genetic inheritance of PCOS and its
metabolic comorbidities (FIG. 2).
Androgen excess and insulin resistance
Insulin resistance and compensatory hyperinsulinism
contribute to androgen excess in PCOS because,
according to animal and human studies, insulin acts
as a cogonadotropin on the ovary 85,86, facilitates andro­
gen secretion from the adrenal glands87,88 and modu­
lates luteinizing hormone pulsatility 89,90. Accordingly,
patients with any disorder characterized by systemic
hyperinsulinism have an increased prevalence of
PCOS. The systemic hyperinsulinism can either be
endogenous (such as in obesity 91, gestational diabe­
tes mellitus92, type 2 diabetes mellitus93,94, syndromes
of extreme insulin resistance caused by mutations in
the gene that encodes the insulin receptor 95 or from
autoantibodies against the insulin receptor 96, portosys­
temic shunts97, or even insulinomas98,99) or exogenous
(such as in type 1 diabetes mellitus100). Of note, PCOS
frequently remains undiagnosed in premenopau­
sal women who present with some of the previously
described disorders because screening for PCOS is
seldom included in current guidelines for their man­
agement (particularly obesity 91 and type 1 diabetes
mellitus 100), exposing these women to the negative
consequences of this syndrome.
These associations might suggest that insulin resist­
ance and hyperinsulinism are the major pathophysio­
logical mechanisms underlying PCOS. However, the
fact that PCOS is not universal in women presenting
with insulin resistance and hyperinsulinism and the
fact that insulin resistance is not universal in PCOS25,101
argue strongly against this interpretation. These facts
suggest that a primary defect that favours andro­
gen excess102 is essential for the development of the
syndrome in response to insulin or other triggering
factors36.
Conversely, as PCOS is mainly a hyperandro­
genic disorder 32, mounting evidence suggests that
androgen excess not only is a major mechanism in
the oligo-­ovulation and cutaneous manifestations of
the syndrome but also facilitates insulin resistance
and metabolic dysfunction in women with PCOS by
favouring abdominal and visceral adiposity 36,103,104.
Moreover, non-targeted and targeted studies suggest
that the genomic, transcriptomic and proteomic pro­
files105–107 of visceral adipose tissue from women with
PCOS are quite different from those of healthy women
and resemble those of men, indicating that androgen
excess contributes to their adipose tissue dysfunction.
In light of these considerations, my colleagues and
I have hypothesized that PCOS results from a vicious
circle of androgen excess favouring abdominal adipose
tissue deposition and visceral adiposity by inducing
insulin resistance and compensatory hyperinsulin­
ism, which further facilitates androgen secretion by
the ovaries and adrenal glands in women with PCOS36
(FIG. 3). According to this theory, women presenting
with a more severe ovarian dysfunction, both in terms
of androgen excess and ovulatory and menstrual dys­
function, are expected to have more severe insulin
resistance, which corresponds exactly to what has been
reported by most studies to date25,108–111.

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Insult to feto-
placental unit

Intrauterine • Hypertension Normal

growth • PCOS (insulin Healthy intrauterine
restriction resistance, adrenal pregnancy growth
hyperactivity and
hyperandrogenism)
Permanent
programming
of metabolic Unhealthy habits Healthy habits
function

Overweight Normal weight in

in childhood childhood
Small for Normal
gestational age birthweight

Thrifty
phenotype

Unhealthy habits Healthy habits

• High-fat, low-fibre diet

• Adequate diet
• Sedentary lifestyle
• Active lifestyle
• Smoking
• No toxic habits
• Alcohol consumption

Figure 2 | Environmental factors influencing PCOS. Intrauterine growth retardation andNature

insulinReviews
resistance as examples
| Endocrinology
of non-genetic inheritance are markedly influenced by environmental factors. Insults during pregnancy might result in
intrauterine growth retardation, inducing a thrifty phenotype in small for gestational age babies (red). The insulin
resistance characteristic of this phenotype is an example of permanent programming of metabolic function and could
lead to overweight issues in childhood. These children might develop hypertension, glucose intolerance and polycystic
ovary syndrome (PCOS) later in life (especially if these individuals are exposed to environmental risk factors such as a
sedentary lifestyle, a diet rich in saturated fat, smoking and excessive alcohol consumption), which might also cluster in
certain families because exercising and diet are heavily influenced by parental habits. However, if the unhealthy
environment changes to healthier options (adequate diet, active lifestyle and no toxic habits), then the non-genetic
inheritance might be prevented, at least in theory (blue). Adapted with permission from REF. 21, Oxford University Press.

Heterogeneity is intrinsic to PCOS
From a pathophysiological perspective, the most
important factors responsible for the heterogeneity
of PCOS are perhaps obesity, abdominal adiposity
and insulin resistance. For example, metabolomic
data published in 2012 indicate that, although central
(hepatic) insulin resistance might be present (even in
women with PCOS who do not have obesity), periph­
eral (muscle and adipose tissue) insulin resistance is
actually characteristic of patients with obesity 112. My
colleagues and I proposed a unifying hypothesis36 that
explains that PCOS results from a primary defect in
steroidogenesis, which leads to androgen excess, the
severity of which is quite variable and might be trig­
gered by several factors, among which the best known
are those related to excess weight (FIG. 4).
In some cases, the hyperandrogenic abnormality
alone is severe enough to cause PCOS without the
contribution of any other factors (such as lean women
without any evidence of visceral adiposity or insulin
resistance). In other cases, PCOS fully manifests only
when obesity, abdominal adiposity, insulin resistance
and/or hyperinsulinism trigger a very mild alteration
in steroidogenesis. These patients might represent
secondary 113 forms of PCOS, as the PCOS phenotype
in these patients frequently resolves once the trigger­
ing factor is removed98,99,114. Between these described
extremes lies a spectrum of varying severity of the
androgen secretion abnormality, which explains the
heterogeneity of PCOS symptoms in patients with dif­
fering contributions of obesity and insulin resistance
(FIG. 4). Obviously, the most severe PCOS phenotype
develops in women with marked obesity or another
factor that aggravates a substantial pre-existing steroi­
dogenic abnormality. However, some women who
exhibit extreme obesity and insulin resistance do not
develop PCOS114; therefore, a prerequisite for develop­
ing PCOS would be an excess of androgen secretion102.
A genetic predisposition might also underlie both the
primary steroidogenic abnormality and the triggering
factors, which explains the frequent familial aggregation
of PCOS49–60.
Diagnosis of PCOS
Establishing the presence of PCOS
Determining whether a patient has PCOS must be a
straightforward process (FIG. 5), as the criteria used in
all current classifications are the same, and it is only the

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Biochemical hyperandrogenism. Diagnosing biochemical

Androgen excess
+ ficity needed to accurately measure the very low androgen
Adrenal
glands
Adipocytes
Ovary +
Abdominal visceral adiposity
+ must not be used)119,120. A perfectly valid alternative is the
+ spectrometry (LC/MS) should be used; however, some
Hyperinsulinism ↓ Adiponectin
↑ TNF
↑ IL-6
Glucose ↑ Leptin
transporter
Target cell
+ characteristic of women and children119; however, these
Insulin resistance
Figure 3 | Abdominal adiposity and PCOS. The interplay between
Nature Reviewspolycystic ovary
| Endocrinology
syndrome (PCOS) and abdominal adiposity might be the result of a vicious circle
(represented by the black arrows) of androgen excess favouring abdominal visceral
adiposity, which facilitates androgen excess of ovarian and/or adrenal origin by the
direct effects (grey arrow) of several autocrine, paracrine and endocrine mediators
(downregulation of adiponectin and upregulation of tumour necrosis factor (TNF), IL‑6
and leptin) or indirectly by the induction of insulin resistance and hyperinsulinism.
Adapted with permission from REF. 36, Elsevier.
combination of criteria that is disputed1,28,32,33. However,
the accuracy of the diagnosis of PCOS is equal to the
accuracy of the evaluation methods used to assess the
individual criteria, and no efforts should be spared to
use the most appropriate methods available.
Clinical hyperandrogenism. This feature of PCOS usu­
ally has peripubertal onset and progresses slowly during
adolescence. The most reliable clinical marker of andro­
gen excess is hirsutism115, because isolated acne (in the
absence of biochemical hyperandrogenism) is not asso­
ciated with menstrual dysfunction and does not have
reproductive consequences in women from the gen­
eral population116,117. In addition, alopecia is fairly rare
in women with functional causes of androgen excess,
such as PCOS, and has a range of aetiologies unrelated
to androgen excess disorders116,117. Hirsutism should be
quantified according to the modified Ferriman–Gallwey
score using available charts115,118, and the cut-off value
should be established for the population under study 118.
If this is not possible, a cut-off value of ≥8 points is
recommended for most populations, with the notable
exception of women from the Far East, in whom a ≥2
cut-off value is recommended115.
hyperandrogenism is a critical issue because many com­
mercially available methods lack the sensitivity and speci­
concentrations characteristic of women119. A consensus
has now been reached that serum concentrations of free
testosterone are the most sensitive measure of hyperan­
drogenaemia, provided that reliable methods such as equi­
librium dialysis are used for its determination (the grossly
inaccurate direct radioimmunoassay analogue method
calculation of free testosterone concentrations from cir­
culating concentrations of sex hormone-binding globulin
and total testosterone121, provided that total testosterone
is properly assayed. Ideally, liquid chromatography/mass
extraction or chromatography radioimmunoassays119 and
a few direct radioimmunoassays1,122 might be reliable. All
these assays are technically complex, might involve the use
of radioactivity and are expensive and/or time consum­
ing, which limit their broad use. By contrast, almost all
immunochemiluminescence assays currently used cannot
accurately measure the low testosterone concentrations
are precisely the assays currently available for most clinical
practitioners. This situation will hopefully change in the
near future as an updated direct immunochemilumines­
cence assay for total testosterone was certified in 2016 by
the Centers for Disease Control and Prevention (CDC)
Laboratory/Manufacturer Hormone Standardization
(HoSt) programme. The assay could detect testosterone
levels of 8–1,000 ng/dl, which might be adequate for
measuring levels of testosterone in women123. However,
the actual performance of this particular immunoassay
in clinical practice remains to be determined.
The usefulness of the additional assessment of the levels
of androstenedione and dehydroepiandrosterone sulfate
to total and free testosterone measurements is debatable
because only a few patients with PCOS show increased
levels of these androgens in the presence of normal con­
centrations of free testosterone1. Again, the assays used to
measure these steroids must be accurate, and data from a
2016 study suggest that, using a LC/MS-based steroid pro­
file, hyperandrogenaemia is present in as many as 90% of
women with PCOS124. However, as important as the accu­
racy of the androgen detection assays are the reference val­
ues used as comparators, which must be established from
healthy women from the general local population119.
Hence, the relative importance given to hyper­
androgenaemia for the diagnosis of PCOS should inevitably
take into account the performance of the androgen detec­
tion assays available to a particular clinic or practitioner.
Such a diagnosis should never rely on a dubious result
that suggests increased androgen levels, especially for hor­
mones that show substantial intraindividual variation125.
Ovulatory dysfunction. Hirsutism and ovulatory dys­
function start early after menarche and might present
clearly in the form of severe oligomenorrhoea or amen­
orrhoea, which ameliorates in the years preceding
menopause in some women with PCOS1. In women

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evidence of hyperandrogenism and ovulatory dysfunc­

Abdominal adiposity
– +
+ –
Androgen excess
* Triggering factors
• Abdominal adiposity
• Insulin resistance
• Obesity
Primary abnormality in androgen secretion
**
Figure 4 | Pathophysiological heterogeneity in patients with PCOS. Polycystic
Nature Reviews | Endocrinology
ovary syndrome (PCOS) is the result of the interaction of a primary abnormality in
androgen synthesis (manifesting as androgen excess) with other factors, such as
abdominal adiposity (red and white targets), obesity and insulin resistance. At one
extreme (*), the disorder in some patients is severe enough to result in PCOS even in
the absence of triggering factors (light-blue-shaded woman on the left). At the other
extreme (**), a very mild defect in androgen secretion is amplified by the coexistence
of abdominal adiposity, obesity and/or insulin resistance (pink-shaded woman on the
right). Between the two extremes, there is a spectrum in the severity (range of
blue-shaded to pink-shaded women in the middle) of the primary defect in androgen
secretion, providing an explanation for the heterogeneity of patients with PCOS with
regards to the presence of obesity and metabolic comorbidities. However, all patients
share a primary defect in androgen secretion. Adapted with permission from
REFS 36,114, Elsevier and Oxford University Press, respectively.
presenting with amenorrhoea, it is prudent practice
to obtain a pregnancy test before assuming that PCOS
is the actual cause of the present absence of menses1.
More rarely, oligo-ovulation leads to polymenorrhoea
(menstrual cycle length <21 days), and it must be high­
lighted that oligo-ovulation might be present even in
women with regular menstrual cycles of normal length
(26–35 days)1. In these patients, demonstration of oligo-
ovulation might be best achieved by the use of body
temperature charts or the testing of low serum or sal­
ivary concentrations of progesterone during the luteal
phase of the menstrual cycle1. Finally, in selected cases,
a progestin withdrawal test might be needed to differen­
tiate non-hyperandrogenic phenotypes of PCOS from
functional hypothalamic amenorrhoea, especially in
the increasingly frequent patients presenting with low
weight, including those in the low range of the normal
BMI spectrum and/or those who exercise vigorously 126.
Polycystic ovarian morphology. Ultrasonography eval­
uation of ovarian morphology might not be required
for diagnosis in women already presenting with clinical
tion127. Even so, PCOM must be defined using strict crite­
ria, as other non-standard descriptions such as poly­cystic,
multicystic or polyfollicular ovaries might be frequently
present in otherwise healthy women, especially during
adolescence15. The use of the strict criteria for PCOM is
especially important in order to avoid the overdiagnosis
of PCOS, given the potential negative psychosocial con­
sequences of such labelling 128. The definition of PCOM
was updated in 2014 (REF. 15) to take into account the
improved resolution of modern ultrasonography equip­
ment compared with the earlier machines used at the
time of the establishment of the Rotterdam definition129.
Currently, the diagnosis of PCOM requires the presence
of an ovarian volume ≥10 ml (preferred criterion when
using transducer frequencies <8 mHz) and/or 25 folli­
cles per ovary (criterion preferred when using transduc­
ers with frequencies ≥8 mHz)15. The role of circulating
concentrations of anti-Mullërian hormone as a surrogate
marker of PCOM is still a matter of debate because of
the lack of standardization and appropriate cut-offs for
the different assays available7,15,130, even though current
data suggest that such measurements, when accurately
quantified, might predict ovarian follicle counts both in
patients with PCOS and in healthy women131.
Exclusion of secondary aetiologies. The most impor­
tant aetiologies to exclude are the fortunately rare but
life-threatening adrenal and ovarian androgen-­secreting
tumours. Suspicion of such a diagnosis should arise
when symptoms and signs of androgen excess start at
any time other than the peripubertal period, are accom­
panied by signs of virilization or defeminization and/or
progress rapidly, as these signs are atypical in functional
causes of androgen excess such as PCOS, non-­classic
congenital hyperplasia or idiopathic hirsutism1. In
patients with a suspected androgen-secreting tumour,
imaging of the adrenal glands and ovaries must be per­
formed immediately 1,115. Selective venous catheterization
and sampling, laparoscopy and/or laparotomy might be
needed in uncertain cases, with the concentrations of
androgen being less important in the diagnosis of these
neoplasms115. Other disorders might be excluded by
clinical judgement (namely, Cushing syndrome) or by
appropriate sampling — levels of serum 17-hydroxy­
progesterone for non-classic congenital adrenal hyper­
plasia132, prolactin for hyperprolactinaemia, TSH for
thyroid dysfunction and follicle-stimulating hormone
for premature ovarian failure1.
Assessment of cardiometabolic risk
Clinical evaluation and anthropometrics. Considering
the major impact that abdominal adiposity and obesity
exert on insulin resistance and the cardiometabolic
comorbidities of PCOS, BMI, waist circumference (a
reliable marker that accurately predicts objective meas­
urements of abdominal adiposity) and office blood pres­
sure must be measured at every appointment in these
patients133. The finding of acanthosis nigricans (patches
of darkened, thickened skin usually found in the skin
folds of the armpit and around the groin and neck) is

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Clinical history and physical examination

• Sudden onset • Peripubertal onset

• Rapid progression • Slow progression
• Virilization • Absence of virilization

• Quantify hirsutism and look for acne

• Adrenal CT or MRI scan
• Ovarian ultrasonography
Tumour or hyperplasia
Consider combined adrenal
Normal and ovarian venous sampling,
imaging
laparotomy or laparoscopy
or alopecia
• Calculate free testosterone levels
• Monitor ovulation
• Obtain ovarian imaging
• Exclude secondary aetiologies

• ✓ Hirsutism and/or • ✓ Hirsutism • ✓ Hirsutism • ✓ ↑ Basal 17-OHP levels

↑ free testosterone
• ✓ Oligo-ovulation
and/or polycystic ovaries
• ✓ NCCAH excluded
• ✓ ↑ Free testosterone • × Normal free testosterone confirmed by 17-OHP
• × Regular ovulation • × Regular ovulation and levels >10 ng/ml after 1–24 ACTH
and normal ovaries normal ovaries or
• ✓ NCCAH excluded • ✓ NCCAH excluded • ✓ ↑ Basal and 1–24 ACTH-stimulated
11-deoxycortisol levels

PCOS Idiopathic Idiopathic hirsutism NCCAH

hyperandrogenism

Figure 5 | Algorithm for the aetiological diagnosis of women thought to have PCOS. Nature An unusual clinical
Reviews presentation
| Endocrinology
should immediately be suspected to be an androgen-secreting neoplasm that must be ruled out by appropriate adrenal
and ovarian imaging techniques and might even require venous sampling (left arm of diagram). A typical peripubertal,
slow and progressive presentation requires careful assessment of clinical hyperandrogenism, hyperandrogenaemia,
ovulatory function and ovarian morphology and exclusion of secondary aetiologies such as non-classic congenital adrenal
hyperplasia (NCCAH) or hyperprolactinaemia. (Please note that the Androgen Excess and Polycystic Ovary Syndrome
Society (AE–PCOS) definition of PCOS preferred by the author has been used for this algorithm, but the reader might
combine individual criteria according to other diagnostic classifications as appropriate.) 1–24 ACTH, cosyntropin; 17OHP,
17-hydroxyprogesterone. Adapted with permission from REF. 115, Oxford University Press.

a strong indicator of insulin resistance but is rare in
patients without obesity 1. In selected cases, monitoring
ambulatory blood pressure might be needed to detect
subtle abnormalities in regulation of blood pressure134,
whereas in others, bioimpedanciometry (the measure of
relative body fat and lean body mass) or even a proges­
terone withdrawal test (to clarify the hypogonadotropic
or normogonadotropic mechanism of oligo-ovulation)
might help in the differential diagnosis between non-­
hyperandrogenic PCOS and functional hypothalamic
amenorrhoea126. Although such a differential diagnosis
was rarely needed in the past, at least in my experience,
the occurrence of functional hypothalamic amenorrhoea
in non-athlete, normal-weight women is currently rap­
idly increasing in frequency in women who exercise
daily and have reduced body fat mass. However, these
tests and techniques are not required on a routine basis.
Testing for insulin resistance, glucose tolerance and
cardiovascular risk factors. A truly accurate estima­
tion of insulin resistance and compensatory hyper­
glycaemia requires a euglycaemic hyperinsulinaemic
clamp, a technically complex test that is rarely available
for routine clinical practice and should be reserved for
research studies1. Alternatively, a standard oral glucose
tolerance test that includes measurement of glucose
and insulin levels might provide a reasonably accurate
estimation of insulin resistance1,135 while at the same
time providing the most complete information about
glucose tolerance1,136. It must be highlighted, however,
that the accurate measurement of serum concentra­
tions of insulin requires the use of reliable immuno­
assays and that the establishment of a normative range
for detecting hyperinsulinaemia during an oral glucose
tolerance test usually entails studying sufficient num­
bers of well-characterized healthy control individuals
with BMIs similar to those of the patients with PCOS
being evaluated1.
Together with a complete lipid profile, an oral glu­
cose tolerance test for plasma concentrations of glucose
is recommended at diagnosis and then every 2 years in
patients with PCOS who have obesity and in women
who do not have obesity but are at high risk of dia­betes
mellitus (such as those with advanced age, personal his­
tory of gestational diabetes mellitus or family history
of type 2 diabetes mellitus)133. Whether these recom­
mendations should be extended to other women with
PCOS depends on the availability of the tests and the
concerns expressed by the patients, because metabolic
comorbidities are uncommon in these patients133.

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Finally, even though non-classic cardiovascular risk
factors (such as increased levels of inflammatory medi­
ators137–139, advanced glycation end products140, carotid
intima–media thickness 141,142, endothelial dysfunc­
tion139,141,143 or subclinical cardiac dysfunction144) might
cluster in women with PCOS, particularly in those with
obesity, the clinical utility of such determinants remains
to be established. Currently, not enough evidence is
available to justify their inclusion in the routine clinical
workup of PCOS.
Mood disorders
Mood disturbances, particularly depression, are prev­
alent in adolescent and adult women with PCOS145–147.
However, even though current guidelines7,133 suggest
that mood and health-related quality of life should be
addressed at diagnosis and during follow-up in women
with PCOS using general and/or specific questionnaires,
such as the PCOSQ (PCOS questionnaire)148, the evi­
dence indicating improvements in mood and psycho­
logical well-being in response to available interventions
for PCOS is scarce7.
Reporting the diagnosis of PCOS
An isolated diagnosis of PCOS is mostly meaningless
because of the broad spectrum of clinical manifestations
and consequences of the syndrome. Unless a broad con­
sensus is finally reached on how to term the different
phenotypes of PCOS, a reasonable alternative might
consist of including a complete description of the spe­
cific PCOS criteria matched by the individual patient
and of the comorbidities present in her particular case.
For example, the consequences of a diagnosis of ‘PCOS
(hirsutism, hyperandrogenaemia and oligo-ovulation)
with obesity, insulin resistance, impaired glucose toler­
ance and hypercholesterolaemia’ are entirely different
from those of a diagnosis of ‘PCOS (mild oligomenor­
rhoea and PCOM with no evidence of androgen excess)
without obesity or metabolic complications’, and patients
with either diagnosis meet the PCOS diagnostic criteria.
This approach might help patients to achieve realistic
expectations about their disorders and help practitioners
guide patients’ long-term management.
Treatment of PCOS
Principles of treatment
Importantly, no universal treatment for PCOS is avail­
able, and therefore, treatment must always be individu­
alized and adapted to the actual needs of the individual
patient 7 (BOX 3). Treatment is symptom-oriented and
might not be needed at all in mild cases that require only
adequate follow-up of the patient’s symptoms (namely,
in a patient presenting with PCOM and mild oligomen­
orrhoea)1. In fact, there are currently no drugs approved
for the indication of PCOS11. Targets for pharmacolog­
ical treatment might include androgen excess, oligo-
ovulation and insulin resistance, but lifestyle counselling
should be provided in all cases in order to prevent or treat
obesity 7 (BOX 3). Considering that PCOS is a lifelong dis­
order, with the exception of the specific secondary cases
in which the syndrome might resolve after resolution
Box 3 | Principles of the treatment of PCOS
• No universal treatment for PCOS exists.
• Treatment is symptom-oriented.
• Other than lifestyle recommendations, patients with
mild symptoms might not require any intervention.
• No drugs are currently approved specifically for PCOS.
• Targets for pharmacological treatment should consider
androgen excess, oligo-ovulation and insulin
resistance.
• Treatment should be chronic and dynamic and adapted
to the changing circumstances, personal needs and
expectations of the individual patient.
of the triggering aetiological factor, treatment should be
long term, dynamic and adapted to the changing circum­
stances, personal needs and expectations of the individual
patient7 (BOX 3).
Targeting androgen excess in PCOS
The dermocutaneous manifestations of androgen excess
in women with PCOS frequently require a combination
of cosmetic techniques with topical and/or oral drugs,
depending on their severity and their psychological
repercussions115 (FIG. 6). Cosmetic methods for managing
hirsutism include bleaching, plucking, shaving, waxing,
chemical treatment, photoepilation and electrolysis115.
Acne can be managed with dermocosmetics149, derm­
abrasion150, laser or light therapy 151 or cosmetic surgery
for severe scarring, and the effect of alopecia might be
ameliorated with hairstyling, hair replacement and addi­
tions, hair transplantation152 or new techniques such as
growth factors from platelet-rich plasma153,154 or stem-
cell-based therapies155. However, the effectiveness of
most of these approaches for acne and alopecia remains
to be fully evaluated in women, as no evidence-based
data actually support their use156–159.
Drugs might be considered only in women who
are not attempting to conceive115. Effective topical
drugs might include eflornithine (which might be ter­
atogenic)160 for facial hirsutism115, retinoids161 and anti­
biotics156 for acne and minoxidil for alopecia159. However,
an oral drug is frequently needed in order to obtain satis­
factory results (FIG. 6). As such, oral contraceptive pills
containing a neutral or anti-androgenic progestin and/or
anti-androgens — androgen receptor blockers such as
cyproterone acetate (approved for hirsutism, acne and
seborrhoea in some countries), spironolactone or fluta­
mide and 5α-reductase inhibitors — remain the drugs of
choice for hirsutism115 and might help with severe cases
of alopecia and acne7; however, retinoids are the most
effective approved drugs for acne156. The particularities
pertaining to the use of these drugs for treating symp­
toms of androgen excess in women with PCOS (specific
drugs, doses, monitoring and potential adverse effects)
have been covered in great detail by guidelines published
in the past 6 years7,115. Moreover, amelioration of sys­
temic hyperandrogenism improves body fat distribution
in women with PCOS and hyperandrogenism162, which
might explain the fact that, in my experience, metabolic

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REVIEWS

Lifestyle modification changes, and anti-obesity drugs are seldom effective

Cosmetic procedures
Seeking fertility Not seeking fertility
Delay drug treatment Contraindication for oral
until delivery contraceptive pills?
No Yes
Oral contraceptive pill containing: Anti-androgens with
• Cyproterone secure contraception
• Chlormadinone
• Drospirenon
• Neutral progestin
• Moderate or severe hirsutism
• Unsatisfactory result
Add cyproterone, finasteride
or spironolactone
Figure 6 | Algorithm for the management of clinical hyperandrogenism. Lifestyle
Nature Reviews |can
Endocrinology
recommendations might benefit all patients, and cosmetic procedures be freely
used for all patients. By contrast, drug treatment must be restricted to women not
seeking to conceive, and this restriction applies even to topical drugs, such as
eflornithine, which might be teratogenic. For women not seeking to conceive, clinical
hyperandrogenism is best treated through the use of an oral contraceptive pill
containing an anti-androgenic or neutral progestin. When the response to oral
contraceptive pills is unsatisfactory or these drugs are contraindicated, anti-androgens
might be added to oral contraceptive pills or used as single agents (provided that
secure contraception is warranted), respectively. Adapted with permission from
REF. 115, Oxford University Press.
function does not deteriorate with the use of oral contra­
ceptives and spironolactone in these women163, in con­
trast to what might happen in women from the general
population164. Finally, the improvement in dermocuta­
neous manifestation following treatment with oral con­
traceptive pills might also result in an improvement in
health-related quality of life165.
Targeting insulin resistance and obesity
Lifestyle modification (changes to diet and/or physical
activity levels) should be recommended to every woman
with PCOS, given the deleterious effect of abdominal
adiposity and obesity on their cardiometabolic risk
profile7,133 (FIG. 6). Lifestyle intervention improves body
composition, hyperandrogenism and insulin resistance
in women with PCOS, yet its effects on improving glu­
cose tolerance or lipid profiles, clinical reproductive out­
comes, mood, quality of life and treatment satisfaction
are currently unclear 166,167. Of note, weight loss improved
the features of PCOS regardless of dietary composition
in the majority of studies168. Several anti-obesity drugs
resulted in initial positive changes in signs and symp­
toms of PCOS169–172; however, their long-term effec­
tiveness remains to be established173, and some of them
are no longer available because of adverse effects174.
Unfortunately, lifestyle modifications, including diet
in the long run175; therefore, bariatric surgery is a very
attractive alternative for women with severe obesity and
PCOS. A meta-analysis published in 2017 indicated that
surgically induced weight loss in women with severe obe­
sity and PCOS resulted in marked decreases in serum
levels of total and free testosterone and the resolution of
hirsutism and menstrual dysfunction in as many as 53%
and 96% of the patients, respectively, leading to a striking
PCOS resolution rate of 96% (95% CI, 88–100%)114; how­
ever, whether PCOS might reappear in the patients who
regain weight is currently unknown. The indications for
bariatric surgery are not different in women with PCOS
compared with those in the general population (BMI
≥40 kg/m2 or ≥35 kg/m2 and the presence of any severe
comorbidity that might improve with weight loss)176.
The most common strategy targeting insulin resist­
ance in PCOS consists of the use of insulin-sensitizer
drugs, particularly metformin. Metformin has similar
effects to lifestyle interventions in terms of decreasing
body weight but is superior in its effects on decreasing
androgen concentrations177. The combination of lifestyle
modification and metformin is associated with lower BMI
and subcutaneous adipose tissue and improved men­
struation than with lifestyle changes alone177. Moreover,
the combination of metformin with oral contraceptive
pills might prevent any deterioration in metabolic func­
tion with the latter, especially in women with the non-­
hyperandrogenic phenotypes of PCOS178. However, oral
contraceptive pills are superior to metformin for amelio­
rating the signs and symptoms of PCOS163 because met­
formin has very little or no effect on the dermocutaneous
manifestations of the syndrome7,115. Furthermore, current
recommendations indicate that metformin should mostly
be used in patients with documented abnormalities in
glucose tolerance133. The evidence supporting the use of
other insulin sensitizers, such as thiazolidinediones179,
berberine180 or inositols181, in patients with PCOS is lim­
ited and/or needs to be clarified, and the same might
apply to the new incretin-based therapies182. Finally,
other metabolic disorders, such as hypertension or dys­
lipidaemia, should receive standard therapy, but because
of the fairly young age of women with PCOS at the onset
of these metabolic derangements, treatment must start
as soon as these disorders are diagnosed to avoid long-
term exposure to these cardiovascular risk factors133. Of
note, the potential for teratogenicity of most drugs used
at present to treat hypertension183 and dyslipidaemia184
must be considered carefully, and the need for secure
contraception must be explained to these women.
Targeting oligo-ovulation in PCOS
The clinical consequences of oligo-ovulation in women
with PCOS include menstrual dysfunction and sub­
fertility of variable severity. Of note, severe menstrual
dysfunction means that these women are at risk of endo­
metrial hyperplasia and cancer and might also cause
infertility 1. Hence, treatment for oligo-ovulation and
its consequences must be individualized, taking into
account the patient’s expectations and the severity of
her symptoms (BOX 3).

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For women not seeking immediate fertility, menstrual
dysfunction might require specific interventions to pre­
vent endometrial hyperplasia when menstrual bleeding
occurs less than four times per year 185, whereas yearly fol­
low-up would suffice for milder cases. These interventions
include the use of oral contraceptive pills for endometrial
protection (which might also improve hyperandrogen­
ism)186, cyclic or continuous progestin administration186 or
the use of a levonorgestrel-releasing intrauterine device187.
For women who express the desire for fertility, the first
step would be addressing the fertility of her partner, and if
a male factor is present, these women should be referred
for assisted reproductive technology without further delay.
If undergoing in vitro fertilization, safer gonadotropin-
releasing hormone antagonist protocols should be con­
sidered, or if agonists are used, the addition of metformin
might help with the prevention of ovarian hyperstimula­
tion syndrome188. By contrast, when only a female factor is
suspected and only mild to moderate menstrual dysfunc­
tion is present, ovulation needs to be evaluated carefully
before starting fertility drugs because these women might
become pregnant with something as simple as appropriate
advice about the most fertile days of their menstrual cycle.
When ovulation is unpredictable or absent, ovulation
induction is advised1. Even though metformin might
improve ovulation and pregnancy rates compared with
placebo, there is no evidence that this drug improves
live birth rates189, and accordingly, clomiphene citrate
or letrozole should be considered the first-line drugs
for ovulation induction188. Metformin might, however,
reduce the risk of ovarian hyperstimulation syndrome
secondary to stimulation with exogenous gonadotropins,
which, together with ovarian laparoscopic surgery, could
be used as second-line treatment188.
Unfortunately, it is still not unusual for women
presenting with moderate or severe obesity (BMI
>35 kg/m2) to find their access to fertility-related ser­
vices restricted regardless of PCOS190, even though such
a recommendation is not supported by convincing evi­
dence indicating that the outcomes of fertility techniques
are poorer in women with obesity than in those without
obesity 191. Alternatively, these women might benefit from
bariatric surgery because, as stated earlier, marked weight
loss frequently resolves oligo-ovulation and restores
fertility 114,192. Provided that pregnancy is delayed until
after the initial postsurgical rapid weight loss phase and
proper nutritional and obstetric support is given during
follow-up, the risks of pregnancy after bariatric sur­
gery (intrauterine growth restriction, prematurity and
complications of surgery, such as internal hernia) are
counterbalanced by the prevention of comorbidities of
severe obesity in pregnancy, such as gestational diabetes
mellitus, pre-eclampsia and fetal macrosomy 193.
Conclusions
PCOS is a common endocrine and reproductive disor­
der that is frequently associated with abdominal adi­
posity, insulin resistance, obesity, metabolic disorders
and cardiovascular risk factors. The aetiology of this
syndrome remains largely unknown, but mounting
evidence suggests that PCOS might be a complex multi­
genic disorder with strong epigenetic and environmen­
tal influences, such as diet and other lifestyle factors.
The diagnosis and treatment of PCOS are uncompli­
cated, requiring only the judicious application of a
few clear and simple principles based on current evi­
dence-based clinical guidelines for its proper diagnosis
and long-term clinical management.

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Acknowledgements
This paper was supported by grants PI1501686 and
PIE1600050 from the Instituto de Salud Carlos III, Spanish
Ministry of Economy and Competitiveness. CIBERDEM and
IRYCIS are also initiatives of the Instituto de Salud Carlos III,
supported in part by Fondo Europeo de Desarrollo Regional
FEDER.
Competing interests
The author declares no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
Reviewer information
Nature Reviews Endocrinology thanks D. Glintborg, and the
other anonymous reviewer(s), for their contribution to the
peer review of this work.

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