Med Clin (Barc).

2019;152(11):450–457

www.elsevier.es/medicinaclinica

Review

Polycystic ovary syndrome in adult women夽

Andrés E. Ortiz-Flores, Manuel Luque-Ramírez, Héctor F. Escobar-Morreale ∗
Grupo de Investigación en Diabetes, Obesidad y Reproducción Humana, Servicio de Endocrinología y Nutrición, Hospital Universitario Ramón y Cajal y Universidad de Alcalá, Instituto
Ramón y Cajal de Investigación Sanitaria (IRYCIS), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Polycystic ovary syndrome is the most prevalent endocrine-metabolic pathology in pre-menopausal
Received 19 September 2018 women. Its etiopathogenesis is complex, multifactorial and heterogeneous, including the interaction
Accepted 4 November 2018 of genetic, epigenetic and environmental factors. Androgenic excess constitutes the disease’s main
Available online 25 March 2019
physiopathological mechanism and results in reproductive, metabolic and cosmetic alterations which
negatively impact these patients’ quality of life. The criteria established in the Rotterdam consensus and
Keywords: their correct application form the necessary basis for this syndrome’s proper diagnosis. In the absence
Ovulatory dysfunction
of an aetiological treatment, the aim is to improve the clinical signs and symptoms derived from hyper-
Hyperandrogenism
Obesity
androgenism, ovarian dysfunction and existing metabolic complications, and, therefore, they must be
Subfertility chronic and individualised.
© 2018 Elsevier España, S.L.U. All rights reserved.

Síndrome de ovario poliquístico en la mujer adulta

r e s u m e n

Palabras clave: El síndrome de ovario poliquístico es la enfermedad endocrinometabólica más prevalente en mujeres pre-
Disfunción ovulatoria menopáusicas. Su etiopatogenia es compleja, multifactorial y heterogénea, incluyendo la interacción de
Hiperandrogenismo factores genéticos, epigenéticos y ambientales. El exceso androgénico constituye el principal mecanismo
Obesidad
fisiopatológico de la enfermedad, resultando en alteraciones reproductivas, metabólicas y cosméticas que
Subfertilidad
impactarán negativamente en la calidad de vida de estas pacientes. Los criterios establecidos en el con-
senso de Róterdam, y su correcta aplicación, constituyen la base necesaria para el correcto diagnóstico de
este síndrome. Ante la inexistencia de un tratamiento etiológico este tiene como objetivo mejorar los sín-
tomas y signos clínicos derivados del hiperandrogenismo, de la disfunción ovárica y de las complicaciones
metabólicas existentes y, por lo tanto, debe ser crónico e individualizado.
© 2018 Elsevier España, S.L.U. Todos los derechos reservados.

Introduction all patients who are overweight and a substantial percentage of

Polycystic ovary syndrome (PCOS) is an endocrinometabolic
disorder whose main pathophysiological basis is an excess of
androgen production of ovarian and adrenal origin, which trans-
lates into dermocosmetic, reproductive and metabolic alterations.
These alterations, a result of adipose tissue dysfunction, is charac-
terised by the presence of resistance to insulin action in virtually
women with normal weight.1,2 Its aetiology is complex, multifac-
torial and heterogeneous, but it is the most frequent metabolic
endocrinopathy in women of childbearing age,1,3 with a worldwide
prevalence ranging between 6% and 15%,4 depending on the criteria
used for its diagnosis.
Definition

Since its initial description by Stein and Leventhal, there has

夽 Please cite this article as: Ortiz-Flores AE, Luque-Ramírez M, Escobar- been certain confusion regarding its definition, both for women
Morreale HF. Síndrome de ovario poliquístico en la mujer adulta. Med Clin (Barc). who suffer from it and for health care professionals not familiar
2019;152:450–457.
∗ Corresponding author. with this entity. The confusion derives in large part from the term
E-mail address: hectorfrancisco.escobar@salud.madrid.org ‘polycystic’, which focuses on one of the consequences of the syn-
(H.F. Escobar-Morreale). drome, the radiological aspect of the gonads, with follicles paused

2387-0206/© 2018 Elsevier España, S.L.U. All rights reserved.

 A.E. Ortiz-Flores et al. / Med Clin (Barc). 2019;152(11):450–457
at different maturational states that are not really cysts, displacing
it from its metabolic endocrinopathy nature with not only repro-
ductive implications. In 1992 the US National Institute of Health5
established the bases for an initial unification of diagnostic criteria,
defining the syndrome as the presence of clinical and/or biochem-
ical hyperandrogenism and ovulatory dysfunction, after ruling out
secondary causes that justify the presence of the previous cause, a
definition now known as ‘classic PCOS’.
In an attempt to agree on a more inclusive definition, extend-
ing the spectrum of patients to those women with ovulatory
dysfunction and polycystic ovarian morphology (POM) without
hyperandrogenism, in 2003 the European Society of Human Repro-
duction and the American Society of Reproductive Medicine
published the Rotterdam criteria,6 which is still the criteria rec-
ommended by various scientific and medical societies, endorsed in
a recent US National Institute of Health consensus.3,5 According to
this definition, confirmation of PCOS requires at least two of the
following situations: (1) clinical and/or biochemical hyperandro-
genism; (2) ovulatory dysfunction; and/or (3) POM in transvaginal
ultrasound,6 in the absence of other diseases that could mimic the
clinical symptoms and characteristic of PCOS.1,7,8 This has facili-
tated the identification of four clinical phenotypes of the disease,5
each with a different clinical impact in terms of severity (Table 1).
Additionally, these women have a greater risk of associated
metabolic complications, such as hypertension, dyslipidaemia,
non-alcoholic steatohepatitis, obstructive sleep apnea, insulin
resistance, glucose intolerance, type 2 diabetes mellitus (DM),
and gestational diabetes.8 Those phenotypes that associate ovula-
tory dysfunction and hyperandrogenism, particularly biochemical,
regardless of the existence or absence of POM, present more seri-
ous clinical and metabolic repercussions.9 The phenotype that
follows it in severity is ‘ovulatory phenotype’ (women with hyper-
androgenism and POM), while the least severe from a metabolic
perspective is ‘non-hyperandrogenic phenotype’ (women with
ovulatory dysfunction and POM).1 Thus, a correct diagnosis and
phenotyping of the patient facilitates an approach to the car-
diometabolic risk these women have.
Aetiology and physiopathology
Family aggregation
The presence of familial aggregation in the families of women
with PCOS is well known, suggesting a possible genetic basis in
their aetiopathogenesis.10 Like other metabolic diseases, PCOS is a
complex disorder, resulting from the interaction of environmental
factors with genetic variants in loci related to enzymes involved in
the synthesis, secretion and action of androgens, the metabolism of
carbohydrates and mechanisms of systemic inflammation, which
may predispose, or prevent, the appearance of this process. As a
result of the interaction between genotype and environment, the
phenotypic expression of the disease can be variable.
The search for genes responsible for this syndrome has been
unsuccessful, given that only a few genetic variants and/or muta-
tions have been replicated in women with PCOS from different
populations.10 The main reasons for this failure include the absence
of an adequate clinical phenotyping of the patients, the application
of different diagnostic criteria – which make comparing between
diverse populations difficult – and the possibility that the geno-
typic variants involved vary depending on the ethnic substrate.
In addition, there is the possibility that this family aggregation is
not motivated by genetic factors, but by the non-genetic transmis-
sion of a lifestyle (eating habits, sedentary lifestyle) generating a
continuous harmful environment from the foetal life that, giving
rise to a Metabolic reprogramming, triggers the onset of insulin
451
Table 1
Definition of polycystic ovary syndrome according to criteria established in 2003 by
the European Society of Human Reproduction and Embryology/American Society
for Reproductive Medicine Rotterdam Consensus and endorsed by the US National
Institute of Health working group in 2012.
Ovulation dysfunction
• Oligomenorrhea: cycles >35 days, assessable from the third year after
menarche and even perimenopause
• Fewer than eight menstrual cycles in one year
• Amenorrhea ≥90 days having previously ruled out pregnancy
• Polymenorrhea (menstrual cycles <21 days)
• Regular menstrual cycles (26–35 days) in the absence of ovulation
Clinical and/or biochemical hyperandrogenism
• Clinical data: hirsutism, androgenetic alopecia, acne
• Biochemical data: calculated total and free testosterone elevation and/or
other androgens (4 A, DHEA-S)
Polycystic ovarian morphology (at least in one of the two ovaries)a
• Antral follicle count ≥25, counting all follicles between 2 and 9 mm in each
ovary, in the absence of follicular or corpus luteum cyst
• Ovarian volume >10 ml
Exclusion of other clinical situations that could justify the above symptoms
• Nonclassic congenital adrenal hyperplasia, androgen producing tumour,
hyperprolactinemia, thyroid dysfunction, Cushing’s syndrome, drugs with
androgenic activity
Phenotypes Synonymy Diagnostic criteria Metabolic
associationsb
Phenotype Classic phenotype Hyperandrogenism + Oligo- +++
I ovulation + POM
Phenotype Classic phenotype Hyperandrogenism + Oligo- +++
II ovulation
Phenotype Ovulatory Hyperandrogenism + POM ++
III phenotype
Phenotype Non- Oligo-ovulation + POM ±
IV hyperandrogenic
phenotype
Definition of polycystic ovarian syndrome based on Rotterdam Consensus criteria.
Two of three criteria diagnose the disease, in the absence of other diseases that could
justify the existing symptoms. These criteria allow establishing four clinical pheno-
types of the disease, with a different metabolic repercussion for each one of them.
4 A: 4 androstenedione; DHEA-S: dehydroepiandrosterone sulphate; POM: poly-
cystic ovarian morphology.
a
Access via the transvaginal route using a sonographic transducer with a fre-
quency of ≥8 MHz. If these conditions are not met, applying the ovarian volume
criterion is recommended.
b
Association with metabolic alterations is determined to a greater extent by
hyperandrogenaemia than by clinical hyperandrogenism; the higher the concentra-
tion of circulating androgens, the greater the phenotypic expression and the greater
the correlation with metabolic disorders.
resistance, hyperandrogenism and adipose tissue dysfunction in
adulthood.1,10
However, as also occurs in other metabolic diseases, to a lesser or
greater degree there must be a predisposing genotype, since not all
women exposed to this harmful environment will develop a clinical
PCOS profile.
Relationship between insulin resistance and androgen excess
As mentioned above, when comparing women with PCOS
with healthy controls of similar age and body mass index (BMI),
insulin sensitivity is lower in hyperandrogenic patients with nor-
mal weight, and there is a significant interaction between BMI and
PCOS in those who are overweight, which translates into greater
insulin resistance than that already present as a result of obesity.11
The relationship between insulin resistance and compensatory
hyperinsulinemia with hyperandrogenism is bidirectional. On the
one hand, insulin, either by itself or in conjunction with luteinizing
hormone (LH), stimulates the expression and function of steroido-
genic enzymes involved in the synthesis of androgens at the ovarian
and adrenal levels, favouring hyperandrogenaemia.12 This same
452 A.E. Ortiz-Flores et al. / Med Clin (Barc). 2019;152(11):450–457

hyperinsulinaemia, together with hyperandrogenaemia alters LH Diagnosis

pulsatility in approximately 50% of women with PCOS.11 These
harmful effects of endogenous hyperinsulinism also occur in sit-
uations of exogenous hyperinsulinism, such as that presented by a
significant number of women with type 1 DM.13
Furthermore, the androgen excess that characterises PCOS also
affects the appearance of metabolic alterations, including cen-
tral adiposity, insulin resistance and hydrocarbon metabolism
disorders.14,15 This synergy between excess androgenic and insulin
resistance is supported in a variety of manners including: genetic
aetiopathogenic mechanisms or common enzymatic alterations;
alterations in the insulin receptor (such as hyperphosphorylation of
serine residues in a subgroup of women with PCOS); the predomi-
nantly visceral deposition of adipose tissue as a consequence of the
hyperandrogenic environment, and in the secretion of proinflam-
matory adipocytokines that interfere even more with the normal
action of insulin.11
In short, the physiopathology of PCOS is a vicious circle where an
androgen excess favours the deposition of abdominal and visceral
fatty tissue, which in turn facilitates the synthesis of ovarian and
adrenal androgens, mediated directly through proinflammatory
substances, and indirectly by favouring insulin resistance and com-
pensatory hyperinsulinism (Fig. 1).15
Polycystic ovary syndrome and its heterogeneity
Considering the above, the phenotypic expression of PCOS will
be influenced by the appearance of abdominal obesity and the
severity of insulin resistance. In our interpretation of the available
scientific evidence, PCOS is the result of an interaction of the pri-
mary defect of variable severity in the steroidogenesis resulting in
androgen excess, with other environmental external factors, the
most well-known being excess weight.1,15 According to this the-
ory, when the intrinsic defect is severe enough, the symptoms of
androgen excess can manifest even in thin women, while at the
other extreme, a slight defect in steroidogenesis will only manifest
clinically when other external factors accompany it, such as obesity
or insulin resistance (Fig. 1).
Clinical and biochemical hyperandrogenism
The most frequent clinical manifestation of androgen excess
is hirsutism, which is defined as an excess of terminal hair in
androgen-dependent areas.16 The most frequently used clinical
assessment method is the modified Ferriman-Gallwey scale,17
which establishes a cut-off point for each population and ethnic
group,16 which in Spain corresponds to 10.18 If no local normative
values exist, a cut-off of ≥8 points is recommended for most popu-
lations (except populations in the far east who have a higher limit of
the lower limit of normal[≥2]).16,19 Other manifestations of func-
tional hyperandrogenism, such as a persistence of acne beyond the
age of 20 or androgenetic alopecia have a worse correlation with
circulating levels of androgens.1
Conversely, clinical manifestations of severe hyperandro-
genism, such as defeminisation or virilisation, the sudden and
rapidly progressive onset of signs of hyperandrogenism, or its clin-
ical presentation before or after adolescence – in the absence of
a clear trigger such as a significant increase in weight – are not
common in PCOS and should provoke an immediately suspicion of
tumour-derived androgen excess.
The diagnosis of biochemical hyperandrogenism is a challenge
in our setting, given that the androgen determination methods
available in most clinical laboratories lack the sensitivity and
specificity needed to analyse the very low concentrations char-
acteristic of children and women. The most useful parameter to
define the presence of hyperandrogenaemia is the presence of high
concentrations of free testosterone – according to local normative
limits – in the follicular phase of the menstrual cycle (3.◦ –9.◦ day
of the cycle of a spontaneous menstruation, or after progestogen
deprivation), determined by means of a complex technique not
usually available in the clinical setting. The best alternative to this
technique is the calculation of free testosterone from the concen-
trations of total testosterone and sex hormone-binding globulin
(SHBG).20 This approach requires a reliable technique for the
determination of total testosterone; the current gold standard for

Adiponectin
TNFα IL-6 Glucose
Leptin
Others Glucose
Adipocytes transporter

Target cells
Adiponectin TNFα IL-6 Leptin Others

Resistance to insulin

Excess of androgens

TRIGGERS
Abdominal adiposity Hyperinsulinism
Resistance to insulin Adrenal
Others

Primary abnormality in androgen secretion

Ovary

Fig. 1. Metabolic heterogeneity in patients with polycystic ovarian syndrome. Left panel. Polycystic ovary syndrome is the result of the interaction of a primary abnormality
in the synthesis of androgens with other factors, such as abdominal obesity (red and white targets), excess weight and insulin resistance. In the far left (*), the intrinsic defect
is serious enough for the manifestation of polycystic ovary syndrome, even in the absence of other triggers. At the other extreme (†), a mild intrinsic defect in androgen
secretion may be exacerbated by the presence of other coexisting aggravating factors.
Right panel. There is a close link between polycystic ovary syndrome and abdominal obesity, which could be the result of a vicious circle in which the androgen excess
favours the deposition of adipose tissue at the abdominal and visceral levels, in turn leading to a greater secretion of sexual androgens at the ovarian and adrenal levels,
by direct action – through endocrine, paracrine and autocrine mediators, where the tumour necrosis factor alpha, interleukin-6, leptin and adiponectin (grey arrow) play a
fundamental role - and by indirect action – by promoting the excess of plasma insulin, as a consequence of its resistance to the action (black arrows).
Reproduced from Escobar-Morreale and San Millán.15
 A.E. Ortiz-Flores et al. / Med Clin (Barc). 2019;152(11):450–457
the determination of sex steroids is liquid chromatography-mass
spectrometry (LC/MS).
The determination of other circulating androgens such as 4 -
androstendione or ehydroepiandrosterone sulphate (DHEA-S) is
not essential, although it increases the percentage of women with
hyperandrogenaemia by 10% compared to an isolated measure-
ment of testosterone, which is explained by the fact that the adrenal
glands contribute to androgen excess in approximately one third
of patients with PCOS.21 While many texts states that total testos-
terone levels above 200 ng/dl or dehydroepiandrosterone sulphate
levels over 6000 ng/ml should lead to a suspicion of androgen
excess of a neoplastic origin, this may also occur with lower figures,
while very elevated androgen figures may appear in women with
functional forms of hyperandrogenism. Therefore, rather than the
severity of hyperandrogenaemia, the most alarming data, which
should provoke suspicion of tumour-derived hyperandrogenism,
are a rapid onset, progression, and clinical severity of the profile.19
Ovulation dysfunction
Ovulatory dysfunction usually appears after menarche (or in
some cases after gaining a lot of weight) and usually results in
oligomenorrhea – menstrual cycles lasting more than 35 days in
at least six cycles per year, or less than eight menstrual cycles per
year22 – or amenorrhea – absence of menstruation for 90 or more
days with no pregnancy.22 Because occasional ovulatory dysfunc-
tion can be considered a variant of normality within the first two
years after menarche, waiting out this period before using ovula-
tory dysfunction as a diagnostic criterion of PCOS is recommended.7
Ovulatory dysfunction less frequently results in polymenor-
rhea (a menstrual cycle that is shorter than 21 days), which may
even occur in patients with menstrual cycles of normal length
(26–35 days), requiring determining circulating levels of proges-
terone <4 ng/ml for the theoretical luteal phase of the menstrual
cycle for diagnosis.1,8
Polycystic ovarian morphology
Ovarian ultrasound is not essential in women who already have
associated excess androgenic and ovulatory dysfunction, and who
have an associated increased risk of ovarian hyperstimulation in
ovulation induction procedures. In any case, it can only be assessed
if strict criteria are used; inaccurate descriptions and diagnoses
such as ‘polycystic ovaries’, ‘micropolycystic ovaries’ and ‘polycys-
tic ovarian syndrome’, etc., should not be used for the diagnosis of
PCOS.
Diagnosis of POM is based on antral follicle count – between 2
and 9 mm in diameter – and ovarian volume on ultrasound, prefer-
ably transvaginal, conducted during the follicular phase.23 Using
transducers ≥8 MHz, a follicular count of ≥25 in one or two ovaries
is considered pathological. If using a lower frequency transducer,
or a transabdominal ultrasound, the ovarian volume criterion is
recommended (≥10 ml in at least one of the ovaries).23
Metabolic evaluation
Given the cardiometabolic risk associated with PCOS and obe-
sity, carrying out a correct clinical and anthropometric assessment
in each medical visits, and a complete physical examination in
search of clinical findings that suggest a possible metabolic compli-
cations is essential,24 such as the presence of acanthosis nigricans,
a clinical sign of insulin resistance. Patients’ dietary habits and
physical activity must be taken into account, especially in women
with ovulatory dysfunction and suspicion of a possible functional
hypothalamic amenorrhea as an alternative diagnosis to PCOS.1
Finally, a clinical screening of the apnea-hypoventilation-obesity
453
syndrome, Cushing’s syndrome or thyroid dysfunction should be
carried out, in addition to directed explorations in case of com-
patible symptoms. In the case of a family history of venous
thromboembolic disease, ruling out congenital thrombophilias is
advisable, especially if the possibility of using exogenous oestro-
gens as a treatment is being considered.
At the time of initial diagnosis of PCOS, a complete biochemical
profile should be obtained, including liver and lipid profile.22,24 The
test of choice for screening for alterations in glucose metabolism is
still a 75 g oral glucose tolerance test (OGTT). It is recommended
at diagnosis and then every two years, unless the patients presents
pre-diabetes, history of gestational diabetes, or significant weight
gain, in which case it should be carried out on an annual basis.8
Even when the prevalence of impaired glucose tolerance is very
low (<5%), in young patients with normal weight, OGTT is still the
test of choice when there are no problems of cost or availability.24
Fig. 2 outlines a summary of the diagnostic approach of the OGTT.
Treatment
Treatment of PCOS must be personalised according to the needs
of each patient, in order to reduce the psycho-emotional impact
of dermocutaneous manifestations derived from androgen excess,
prevent endometrial hyperplasia in women with severe ovulatory
dysfunction, increase fertility in women with reproductive desires
and to prevent or treat metabolic complications.1,21
As a general rule, hygienic-dietetic measures should be recom-
mended to all patients whose aim is to prevent or treat excess
weight, a sedentary lifestyle and smoking.25 In those mild variants
of the disease, patients may simply require a clinical follow-up,
ensuring that they have more than 4–6 menstrual cycles per year
as an effective measure of endometrial protection.1,7 On the con-
trary, moderate or severe symptoms and signs will require chronic
pharmacological treatment to ensure satisfactory control. Table 2
and Fig. 3 summarise the treatment of ovulatory dysfunction and
hyperandrogenism.
Treatment of androgen excess
In general terms, using dermocosmetic measures is advisable,
associated or not with pharmacological treatment, a decision that
will depend on the severity of the symptoms and the patient’s psy-
chological response to the symptoms.
Dermocosmetic treatment for hirsutism includes methods
aimed at eliminating excess terminal hair by whitening or
removal with tweezers, shaving, waxing, laser photodepilation
or electrolysis.19,22 Symptomatic treatment may use retinoids or
antibiotics to control acne, topical minoxidil in the case of andro-
genetic alopecia and eflornithine for the control of facial hirsutism.
The systemic treatment of choice is oral contraceptives (OC)
containing progestagen with low affinity for the androgen receptor
(dienogest, norgestimate, desogestrel or gestodene) or antian-
drogenic profile (cyproterone acetate, chlormadinone acetate,
drospirenone). The progestogens associated with a lower risk of
thrombosis within this group are norgestimate and dienogest. The
use of the lowest possible dose of oestrogen, but sufficient to avoid
the appearance of intermenstrual staining, will reduce possible
adverse effects of the treatment, provided that bone health is not a
concern. Thus, in the case of adolescents who have not yet reached
their bone mass peak, doses of ethinylestradiol at 30–35 ␮g/day, or
the equivalent in case of using another oestrogen, is recommended.
In cases of moderate-severe, or refractory, hirsutism, adding
an antiandrogenic drug to the OC after 6–12 months of treatment
with OC should be considered. Cyproterone acetate, spironolactone
and 5-alpha-reductase inhibitors are the antiandrogens available
454 A.E. Ortiz-Flores et al. / Med Clin (Barc). 2019;152(11):450–457

Anamnesis
- Ovulatory dysfunction: age of menarche, menstrual rhythm, presence of amenorrheic spots
- Hyperandrogenic symptoms: age of onset, rhythm of progression,psycho-emotional impact
- Personal and family history of known metabolic diseases.History of VTD
- Eating habits and physical exercise carried out

Physical exploration of devices and systems, including

- Vital signs and anthropometric data.Weight, size. Abdominal perimeter, blood pressure and heart rate
- Ferriman-Gallwey scales to assess hirsutism and Ludwig scale for androgenic alopecia.
- Signs that guide the presence of resistance to insulin action: acanthosis nigricans
- Evaluation of syndromic phenotypes: lipodystrophic, cushinoid,acromegaloide.Discard galactorrhea

Complementary tests:
- General analytical tests that includes complete liver and lipid profile
- Determination of sexual androgens: total testosterone calculated total and free testosterone, SHBG, DHEA-S, D4A
- Screening for NCAH (17-OH-progesterone), hyperprolactinemia,thyroid dysfunction
- Serum progesterone in the luteal phase (in cases of regular menstrual cycles)
- Transvaginal ovarian ultrasound during follicular phase*
- Adrenal CT only in the case of suspected tumour pathology

Screening of metabolic complications

• Oral overload with 75 g of glucose
• 24-hour ambulatory blood pressure monitoring (ABPM)**
• Confirm alterations of the lipid profile

Fig. 2. Initial management of patients with polycystic ovarian syndrome. Carrying out a complete clinical history is essential, including an assessment of each patient’s
menstrual rhythm, the detection of signs and symptoms related to hyperandrogenism, the request for complementary tests aimed at establishing a diagnosis of PCOS and
screening for other diseases that may cause similar clinical symptoms. Once the diagnosis is made, the patient’s metabolic risk should be established, especially in those
phenotypes that associate hyperandrogenism and ovulatory dysfunction.
4 A: 4 -androstendione;DHEAS: dehydroepiandrosterone sulphate; VTD: venous thromboembolic disease; NCAH: nonclassic congenital adrenal hyperplasia; ABPM: ambu-
latory blood pressure monitoring; SHBG: sex hormone binding globulin.
* In case of ovulatory dysfunction and clinical and/or biochemical hyperandrogenism this test can be omitted.
** Consider this test, especially for overweight patients.

Table 2
Hormonal drug treatment available in Spain for polycystic ovarian syndrome.

Pharmacological group Medication Dosage/administration

Endometrial protection and control of hyperandrogenism

Combined oral contraceptives

Synthetic oestrogens + progestogen with Synthetic oestrogen: 0.02–0.035 mg Daily administration of 21 active tablets and 7
antiandrogenic properties ethinylestradiol days off, or daily administration of 28 tablets
Progestogen: cyproterone acetate, (21 active + 7 placebo)
drospirenone, chlormadinone
Synthetic oestrogens + low affinity Progestogen: dienogesta , norgestimatea ,
progestogen for the androgen receptor desogestrel, levonorgestrel, gestodene
Natural oestrogens + progestogen Natural oestrogen: estradiol valerate Daily administration of 28 tablets (21 active + 7
Progestogen: cyproterone acetate, dienogest, placebo)
norgestrel
Vaginal ringb Synthetic oestrogen: Ethinyl estradiol: The ring is inserted for 3 weeks and removed
0.015 mg for 1 week; a new vaginal ring is then inserted
Progestogen: etonogestrel: 0.12 mg
Cyclic progestins
Progesterone Micronised progesterone 200 mg/day/10 days
Medroxyprogesterone acetate 10 mg/day/10 days

Continuous progestogens
Oral route Desogestrel, levonorgestrel
Subcutaneous implant Levonorgestrel 75 mg Duration up to 5 years
Intrauterine device Levonorgestrel (0.02 mg sustained release) Duration up to 5 years

Antiandrogensb
Androgen receptor antagonists Cyproterone Acetate 50–100 mg the first 10 days of the cycle
Mineralocorticoid receptor antagonistsc Spironolactone 100–200 mg/day
Inhibitors of 5-alpha-reductasec Finasteride 5 mg/day
Dutasteride 0.15–0.5 mg/day

Other drugs for hirsutism

Ornithine decarboxylase inhibitor Eflornithine 0.15% topical cream Apply twice daily on the facial region
a
They are associated with a lower risk of venous thrombosis.
b
An effective contraceptive method should always be used given the risk of feminisation of a male foetus in case of pregnancy.
Used off-label.
 A.E. Ortiz-Flores et al. / Med Clin (Barc). 2019;152(11):450–457 455

Lifestyle factors

Clinical hyperandrogenism Ovulation dysfunction

Gestational desire No gestational desire No gestational desire Gestational desire

Cosmetic measures OC cosmetic measures Moderate/

Mild Fertile couple Subfertile couple
severe

Contraindication/ Assisted
Absence of clinical improvement OC Observation Ovulatory rhythm
Rejection reproduction
and scheduled
coitus techniques

Add antiandrogenic drug

- Cyproterone Cyclic progestins†
Continuous progestogens Induction of
- Spironolactone
IUD levonorgestrel ovulation
- Finasteride

Endometrial protection > four

menstrual cycles year

Fig. 3. Treatment of clinical hyperandrogenism and ovulatory dysfunction. Schematic representation of the symptomatic treatment of PCOS, which must be variable and
personalised according to the needs of each patient. In all cases we will always recommend hygienic-dietetic measures designed to maintain a normal weight. OC provide
the benefit of endometrial protection and improve symptoms of androgen excess. *When an antiandrogen is used, a safe method of contraception must be also used in all
cases.
†
In the case of women who do not experience psycho-emotional impact from hyperandrogenism, are not sexually active or/and do not want contraception, cyclic progestogens
will be the first therapeutic option.
‡
To determine the ovulatory rhythm, the patient should first determine their basal temperature, rectally, as soon as they wake up and before getting out of bed (there will
be an elevation of 0.3 to 0.5 ◦ C on the days immediately following ovulation); this should be carried out for at least three to four months to accurately estimate the patient’s
fertile days and schedule intercourse dates. If there is a certain regularity in ovulation, intercourse will be recommended on alternate days for at least one week, starting two
or three days before the theoretical date of the ovulatory peak.
OC: oral contraceptives; IUD: intrauterine device.

in Europe, also used to treat severe or refractory cases of acne or
androgenetic alopecia, although the only one that has technical
specifications approval for this purpose it is cyproterone acetate.
In regard to acne, we must point out that the drugs of choice
are retinoids, as they are the most effective.19,26 Although in the
general population certain OC can worsen cardiometabolic risk, in
women with PCOS, treatment with OC is usually associated with
an improvement in the lipid profile – increase in HDL-cholesterol
– although in cases of familial dyslipidemia triglyceride concentra-
tions may increase.27,28
Treatment of ovulatory dysfunction
Treatment of the symptoms derived from the oligoanovulation
should be personalised according to the individual needs of each
patient, and should consider menstrual dysfunction and subfertil-
ity.
The main consequence of severe ovulatory dysfunction in
women without gestational desire is an increased risk of devel-
oping hyperplasia and/or endometrial cancer, a risk present in
women who experience fewer than four menstrual cycles per
year.29 Annual monitoring for patients with mild to moderate men-
strual dysfunction is sufficient, while those with severe menstrual
dysfunction need pharmacological intervention.1
If patients do not have immediate gestational desires, using
combined OC is recommended in sexually active women without
contraindication or rejection of this treatment, especially if they
present with clinical hyperandrogenism and experience psycho-
emotional impact. In those patients without androgen excess and
who do not want treatment with OC there are other alternatives
such as the cyclical use of progestogens to induce menses by depri-
vation, progestogens for continuous use or intrauterine devices,
preferably levonorgestrel-releasing agents.1,8
In those women who do have gestational desires and excess
weight, the first measures are to reduce excess weight. Another
initial measure is to carry out a fertility study on the patient’s part-
ner using a seminogram, and if it is pathological, refer the couple
directly to a specialised fertility clinic to begin assisted reproduc-
tion techniques.1
In the event that there is only one female component that is
the cause of infertility, and if the ovulatory dysfunction is mild, ini-
tiating a careful assessment of the patient’s ovulation rhythm by
determining the basal temperature or biochemical data in urine,
and scheduling coitus for the most fertile days is advisable before
starting any pharmacological intervention, since it is possible that
pregnancy can be achieved with this simple method, avoiding
unnecessary tests and treatments.1
In the event that ovulation is not predictable, or if it is absent,
inducing ovulation through the use of clomiphene citrate, letrozole,
or exogenous gonadotrophins is recommened.30 Both clomiphene
citrate and exogenous gonadotrophins have the associated risk of
multiple gestation. Exogenous gonadotrophins, on the other hand,
can cause ovarian hyperstimulation syndrome, so their use requires
monitoring and strict follow-up in a specialised consultation.30 The
risk of this serious complication could be reduced with the use of
metformin, which can also be used as a second line of treatment,
although it is less effective in achieving births.30
Obesity and metabolic complications
First-line treatment in all patients with PCOS should be
hygienic-dietary recommendations aimed at reducing excess
weight or maintaining normal weight,24–26 in order to improve the
distribution of body fat, androgen excess and insulin resistance.1
Unfortunately, the maintenance of lifestyle changes is rarely
effective in the long term,1 especially in those patients with
moderate-severe obesity.
In women with BMI of >35 kg/m2 , reducing induced weight after
metabolic surgery significantly improves reproductive parameters
(menstrual dysfunction, ovulatory dysfunction, fertility), followed
by a marked decrease in circulating levels of androgens, an increase
in insulin sensitivity, the resolution of metabolic alterations and
ovulatory dysfunction.31 Obesity surgery is an option for this sub-
group of patients if they do not lose weight through conventional
measures, provided that future pregnancies are delayed until after
456 A.E. Ortiz-Flores et al. / Med Clin (Barc). 2019;152(11):450–457
the period of abrupt weight loss immediately after surgery, in
order to avoid intrauterine growth restriction due to nutritional
deficiencies.31 Currently, indications for bariatric surgery are the
same as those that apply to the general population.32
Although certain anti-obesity drugs have been used in patients
with PCOS, increasing weight loss when associated with changes
in lifestyle, their cost and the need for long-term administration
mean they are not generally recommended.1
In regard to the use of metformin in adult women with PCOS,
currently available evidence only allows it to be recommended in
those with documented alteration of glucose metabolism, or in
conjunction with OC in women at high risk of developing these
alterations.24,33 Its use during pregnancy is not indicated, since it
has not been shown to increase the rate of live newborns, and even
in the most recent studies it is associated with an increase in the
weight of offspring during their childhood.34 However, in patients
with DM it is the drug of choice for first-line treatment. Pioglita-
zone, on the other hand, has only been shown to be useful alone or in
combination with metformin, in cases of severe insulin resistance
associated with phenocopies of monogenic origin of the disease.33
Evidence in favour of other insulin sensitisers, such as resvera-
trol, berberine or inositol, is very limited,1 as is the use of drugs that
act on the incretin system, although GLP-1 receptor agonists are an
attractive alternative for patients with type 2 DM and obesity.
Regarding the treatment of dyslipidaemia, and despite the fact
that statins decrease testosterone levels in women with PCOS,24 the
use of hypolipidemic drugs has the same indications as in the gen-
eral population. Treatment with combined OC may slightly increase
blood pressure figures, which should be considered if this occurs.35
The combination of a drug such as spironolactone, which blocks the
mineralocorticoid receptor, and also blocks androgen receptors, is
particularly effective in hypertensive women with PCOS and could
counteract the adverse effects of OC on blood pressure.28
Conclusions
PCOS is the most frequent endocrine disorder in premenopausal
women. Its aetiopathogenesis is complex and associated with a sig-
nificant environmental, genetic and epigenetic influence. Diagnosis
is based on the confirmation of the presence of clinical and/or bio-
chemical hyperandrogenism, ovulatory dysfunction and/or POM,
discarding other causes that could justify the symptoms of andro-
gen excess and oligo-anovulation. Treatment must be chronic and
personalised, adapted to the needs of each patient throughout their
life, and aimed at improving the symptoms of androgen excess and
ovulatory dysfunction, and to prevent, or even treat, early associ-
ated metabolic complications.
Funding
This work has been possible with the funding provided by
the Carlos III Health Institute, Health Research Fund (PI01501686,
PIE1600050, PI1801122). Both CIBERDEM and IRYCIS are initia-
tives of the Carlos III Health Institute. Co-funded by the European
Regional Development Fund (ERDF).
Conflict of interest
The authors declare no conflict of interest.
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