J Assist Reprod Genet

DOI 10.1007/s10815-017-1047-7

REVIEW

Polycystic ovary syndrome throughout a woman’s life

José Bellver 1 & Luis Rodríguez-Tabernero 2 & Ana Robles 3 & Elkin Muñoz 4 &
Francisca Martínez 5 & José Landeras 6 & Juan García-Velasco 7 & Juan Fontes 8 &
Mónica Álvarez 9 & Claudio Álvarez 10 & Belén Acevedo 11 & Group of interest in
Reproductive Endocrinology (GIER) of the Spanish Fertility Society (SEF)

Received: 16 May 2017 / Accepted: 12 September 2017

# Springer Science+Business Media, LLC 2017

Abstract Polycystic ovary syndrome (PCOS) is the most com- phenotypes separately, as they may require different treatments
mon endocrine disorder among reproductive-aged women and and have different consequences. In this way, PCOS exhibits a
the main cause of infertility due to anovulation. However, this great metabolic complexity and its diagnosis needs to be revised
syndrome spans the lives of women affecting them from in- once again and adapted to recent data obtained by new technol-
utero life until death, leading to several health risks that can ogies. According to the current medical literature, lifestyle ther-
impair quality of life and increase morbidity and mortality rates. apy constitutes the first step in the management, especially
Fetal programming may represent the beginning of the condi- when excess body weight is associated. Pharmacotherapy is
tion characterized by hyperandrogenism and insulin resistance frequently used to treat the most predominant manifestations
which leads to a series of medical consequences in adolescence, in each age group, such as irregular menses and hirsutism in
adulthood, and old age. Menstrual and fertility problems evolve adolescence, fertility problems in adulthood, and metabolic
into metabolic complications as age advances. An early and problems and risk of cancer in old age. Close surveillance is
precise diagnosis is important for an adequate management of mandatory in each stage of life to avoid health risks which may
PCOS, especially at the extreme ends of the reproductive also affect the offspring, since fetal and post-natal complications
lifespan. However, many different phenotypes are included un- seem to be increased in PCOS women.
der the same condition, being important to look at these different
Keywords Polycystic ovary syndrome . Childhood .
Adolescence . Perimenopause . Fertility . Pregnancy
* José Bellver complications
jose.bellver@ivi.es

1
IVI-Valencia, University of Valencia, Valencia, Spain Introduction
2
Hospital Clínico Universitario, Valladolid, Spain
3
Hospital del Mar, Barcelona, Spain
Polycystic ovary syndrome (PCOS) is the most common endo-
4
crine disorder among reproductive-aged women (5–10%) and
IVI-Vigo, Vigo, Spain
the main cause of infertility due to anovulation [1]. PCOS af-
5
Salud de la Mujer, Hospital Universitario Dexeus, Barcelona, Spain fects women from in-utero life until death, leading to several
6
IVI-Murcia, Murcia, Spain health risks that can impair quality of life and increase morbid-
7
IVI-Madrid, Rey Juan Carlos University, Madrid, Spain ity and mortality rates. This condition really includes many
8
Hospital Virgen de las Nieves, Granada, Spain
different phenotypes which may require different treatments
9
and may have different consequences and exhibits a great met-
Hospital Materno Infantil, Las Palmas, Spain
abolic complexity, thus needing an urgent revision of its diag-
10
URE Centro Gutenberg, Málaga, Spain nosis. The aim of the present review is to describe the medical
11
Fundación Jiménez Díaz, Madrid, Spain consequences of the syndrome from the beginning of the repro-
ductive life to its end according to the current medical literature
(Fig. 1). New research may change future knowledge about the
 J Assist Reprod Genet

Weight excess
Visceral adiposity Obesity
Irregular menses Carbohidrate intolerance Type II diabetes
Dis- /anovulation Dyslipemia Dyslipemia
Acne /Seborrhoea Infertility Cardiovascular
Hyperandrogenism/Hirsutism Pregnancy complications disease/Arterial
Insulin resistance hypertension
Adipose tissue dysfunction Endometrialcancer
Excessive post - natalcatch -
upweight gain
Premature adrenarche
Premature pubarche
Premature menarche

Fetalprogramming
Fetal
IUGR
Born SGA

Fig. 1 Main clinical and metabolic manifestations of polycystic ovary Menstrual, hyperandrogenic, and reproductive manifestations change to
syndrome according to women’s stage of life. Clinical manifestations of metabolic alterations as age advances, thus affecting this syndrome from
PCOS appear in adolescence, but the disease seems to be originated in the the beginning of life to its end. IUGR: intrauterine growth retardation;
intra-uterine environment through developmental programming. SGA: small for gestational age

syndrome once its different phenotypes are analyzed as com- marker of PCOS, although a universally agreed cut-off has not
plete separate entities. been established [11, 12]. In any case, PCOS must always be
diagnosed after all other conditions that involve HA or OA have
been excluded [13].
Definition and epidemiology The described prevalence of PCOS in women of reproduc-
tive age in the general population varies by geographic region,
PCOS is a complex syndrome with diagnostic criteria that have ranging from 1 to 19% according to population samples ana-
been grouped in different, somewhat controversial, classifica- lyzed in the USA, Western Europe, the Middle East, East Asia,
tions [2–6] (Table 1). According to the features of the syndrome and Australia [14, 15]. The varying prevalence of PCOS may
considered, up to 16 phenotypes may exist with different meta- be due to genetic and environmental factors. A lower socio-
bolic and reproductive consequences. Some of these phenotypes economic development is also associated with poorer health
will be included in the criteria of the commented classifications which can lead to hormonal alterations and/or activate a genetic
(Table 2). The Rotterdam criteria are the most commonly used, predisposition for the development of the syndrome. Lack of
although they are now over 10 years old and not accepted by all adequate healthcare provision also results in lower rates of cor-
[7], with calls for them to be updated [8, 9]. The criteria used to rect diagnosis and appropriate treatments [14, 16].
define oligo-anovulation (OA) are insufficient, an adequate def-
inition of biological hyperandrogenism (HA) is yet to be
established, and the characterization of polycystic ovarian mor-
phology (PCOM) proposed in 2003 has become obsolete in the Pathophysiology
face of the latest generations of ultrasound machines [10]. In
addition, these diagnostic criteria are not valid for early and late PCOS is characterized by diverse clinical presentations, both
ages (i.e., for teenagers and aged women). High anti-Müllerian reproductive and metabolic, throughout a woman’s life. Its
hormone (AMH) serum concentrations have emerged as a useful pathophysiology is not yet clear, but the heterogeneity of its
J Assist Reprod Genet

Table 1 Different classifications of diagnostic criteria for PCOS

NIH: National Institutes of Health. Rotterdam: ESHRE/ASRM-sponsored PCOS
consensus workshop group. AES: The Androgen Excess and PCOS Society

a
Two criteria required out of three
b
Hyperandrogenism and ovarian dysfunction (oligo-anovulation and/or polycystic ovarian morphology)
c
Exclusion of other androgen excess or related disorders: 21-hydroxylase-deficiency, non-classic adrenal hyperplasia, androgen-secreting neoplasm,
androgenic/anabolic drug use or abuse, Cushing’s syndrome, severe insulin resistance, thyroid dysfunction and hyperprolactinemia

characteristics suggests that genetic, metabolic, endocrine, en- the main candidate genes [18, 19]. Environmental conditions
vironmental, and lifestyle factors are important in its clinical may mimic hormonal actions and activate pre-existing predis-
manifestations [17] (Fig. 2). posing factors, triggering the characteristic endocrine alter-
There is evidence of a pattern of inheritance of PCOS that ations of PCOS. They can be classified as prenatal (epigenetic
is not yet well defined. Most authors define PCOS as a poly- fetal programming) or postnatal (diet, obesity, sedentary life-
genic pathology. Key genes encoding factors involved in the style, and environmental toxins). It has also been proposed
synthesis, transport and regulation of androgens, the metabo- that PCOS may present a pattern of non-genetic inheritance
lism of insulin, and folliculogenesis have been described as in populations with an unhealthy lifestyle such as those with a

Table 2 Potential phenotypes of polycystic ovary syndrome (adapted from Azziz et al., 2009; reference 5)

Phenotype Hyperandrogenemia Hirsutism Oligo- Polycystic NIH 1990 Rotterdam 2003 AE-PCOS 2006
anovulation ovaries criteria criteria criteria

A + + + + X X X
B + + + X X X
C + + + X X X
D + + X X X
E + + + X X X
F + + X X X
G + + + X X
H + + X X
I + + X X
J + + X
K + +
L +
M +
N +
O +
P
 J Assist Reprod Genet

Fig. 2 Pathophysiology of Environmental factors FETAL DEVELOPMENTAL PROGRAMMING Genetic predisposition

polycystic ovary syndrome. The - Prenatal: catabolic state, Placental disease - Familial aggregation
endocrine disruptors … - Polygenic pathology
interaction between a genetic - Postnatal: Obesity, diet …
Mother malnutrition
- Polymorphisms (genes)
predisposition and some prenatal Fetal hypoxia

and postnatal environmental

factors seems to be responsible IUGR SGA newborn Maternal hyperandrogenism
for the development of the Fetal excess of Glucocorticoids (PCOS)
syndrome. Oxidative stress, low-
grade chronic inflammation, and
insulin and lipid metabolism al- Oxidative stress
terations are present in the back- Pro-inflammatory factors

ground of the main clinical mani- Gene expression

festations of the syndrome which alterations
Telomere shortening
constitute their diagnostic criteria Epigenetic modifications
during women’s reproductive
age: hyperandrogenism, Compensatory Growth
anovulation and polycystic ovary
morphology. IUGR: intrauterine Insulin metabolism alteration Lipid metabolism alteration
- Glucose intolerance - Dyslipidemia
growth retardation; PCOS: poly- - Insulin resistance - Visceral obesity
cystic ovary syndrome; SGA: - Hyperinsulinemia - Adrenal hyperandrogenism
small for gestational age - Ovarian hyperandrogenism

H y p e r a n d r o g e ni s m Anovulation Polycystic ovaries

PCOS

diet high in saturated fat, sedentary lifestyle, and alcohol and manifestations of PCOS in adolescence [19]. HA in fetal life
tobacco consumption [20]. may also lead to epigenetic reprogramming of reproductive
Changes in gene expression produced by exposure to steroids fetal tissues, resulting in a PCOS phenotype in adulthood. A
(mainly glucocorticoids and/or androgens) during critical periods significant increase in peripheral serum androgen concentra-
of fetal development have been related to the different pheno- tions has been demonstrated in singleton 22–28-week preg-
types of PCOS described [20]. In the case of fetal hypoxia due to nancies of PCOS women versus non-PCOS pregnant women
maternal dietary restriction or placental insufficiency, catabolic of similar gestational age [23], thus being a possible source of
phenomena lead to intrauterine growth restriction (IUGR) and fetal androgenization. However, other potential sources
low birth weight (LBW). As a survival mechanism, energy ex- should be considered, since placental aromatase would protect
penditure is reduced by redistributing fetal blood flow to essential the fetus from high maternal androgen concentrations. It has
organs (heart, brain, and adrenal glands). This leads to an in- been suggested that maternal obesity, diabetes mellitus, insu-
creased production of glucocorticoids as a consequence of the lin resistance, and excessive weight gain during pregnancy are
hyperactivity of the hypothalamic-pituitary-adrenal axis, which predictors of large for gestational age (LGA) offspring.
may induce epigenetic modifications [21]. Studies with experi- Because these conditions may also be associated with HA,
mental animals have found that fetuses with IUGR caused by LGA babies might exhibit a higher risk for PCOS via devel-
placental insufficiency or maternal malnutrition were born small opmental programming by androgen excess, but this hypoth-
for gestational age (SGA) and that these animals showed a pre- esis remains to be confirmed through clinical studies [20].
disposition to develop pathologies in postnatal life after compen- The manifestation of PCOS may be complete in adoles-
satory growth during the first 2 years of life. Clinical data show cence, with the activation of the hypothalamic-pituitary-
that compensatory growth might also be associated with the de- ovarian axis [20], although many women show regular cycles
velopment of comorbidities in humans, including PCOS. Thus, in the beginning which continue on to become
children born with SGA would exhibit a clinical marker of de- oligomenorrheic. In puberty, there is a physiological increase
velopmental programming by glucocorticoids associated with in insulin levels, resulting in a reduction of SHBG levels and
the development of PCOS and its associated comorbidities [20]. an increase in free androgen concentrations, with the subse-
PCOS has been described as an ovarian disease character- quent stimulation of ovarian steroidogenesis. In women with
ized by excessive androgen production [18, 22]. Studies in PCOS, physiological hyperinsulinemia in adolescence may
rhesus monkeys and sheep have shown that exposure of fe- trigger HA and ovulatory dysfunction. Girls predisposed to
tuses to high levels of androgens during the intrauterine period insulin resistance and weight excess are at a higher risk of
can alter folliculogenesis and induce the onset of clinical early adrenarche and subsequent PCOS.
J Assist Reprod Genet

A normal folliculogenesis depends on intra- and extra- mellitus by the age of 40 [28]. The phenotype with HA and IR
ovarian factors. An imbalance of these factors can alter follic- seems to carry a higher metabolic risk.
ular development and the production of mature oocytes,
compromising fertility in PCOS women. Extra-ovarian factors
include FSH deficit, hypersecretion of LH, HA of ovarian or Childhood and adolescence
adrenal origin, and hyperinsulinemia with insulin resistance
(IR). Intra-ovarian factors correspond to the family of growth LBW followed by excessive postnatal catch-up weight gain
factors, cytokines, and inhibins present in the follicular fluid may initiate a cascade of metabolic changes including in-
and whose concentrations correlate with plasma levels [24]. creased adipose body composition, IR, and a less favorable
The relationship between vitamin D deficiency and PCOS is adipokine profile as early as pre-school age. These events can
inconclusive. Existing data on vitamin D supplementation do lead to an increased risk of premature adrenarche, pubertal
not demonstrate a clear effect on metabolic and reproductive development and menarche (by nearly a year, compared to
parameters of PCOS [25]. non-LBW counterparts), and PCOS [29–31].
Regardless of weight or body mass index (BMI), 50–70% Premature pubarche (PP) is defined as the appearance of
of PCOS patients present with IR, which means that greater pubic hair before the age of 8 in girls and 9 in boys. PP in girls
amounts of insulin are required for normal function. This is may be a precedent of metabolic syndrome and clinical ovar-
reflected in an increase in insulin secretion by pancreatic β ian androgen excess in adolescence, particularly when it oc-
cells, leading to compensatory hyperinsulinemia and normal curs after LBW and excessive postnatal catch-up, and can
glycaemia. When the pancreatic response is inadequate, glu- moderately reduce final height. In girls with PP, early metfor-
cose intolerance and/or type 2 diabetes can develop [22]. The min therapy is initiated in pre-puberty, at a mean age of 8 years,
mechanisms leading to IR consist of a defective binding of and maintained throughout puberty (for 4 years). It normalizes
insulin to its receptor or to changes in insulin signal transduc- body composition and excessive visceral fat, delays menarche
tion. It is postulated that hyperinsulinemia contributes to HA by about 1 year, and increases adult stature [32, 33]. The
by stimulating ovarian androgen production and inhibiting benefits of early metformin therapy on body composition,
hepatic synthesis of SHBG, thus increasing levels of free tes- lipids, circulating insulin, and testosterone are maintained
tosterone. Insulin also increases adrenal androgens and stim- 2 years after the treatment has terminated. Other independent
ulates ovarian steroidogenesis mediated by LH through an prepubertal risk factors for the development of PCOS are obe-
action on thecal and granulosa cells [26]. sity and metabolic syndrome [34].
In addition, an imbalance between oxygen free radicals or While the diagnosis of PCOS in adulthood is based on the
reactive oxygen species (ROS) and antioxidant factors can presence of clinical or biochemical HA in combination with
lead to cell damage, a situation that can occur in the follicular ovarian dysfunction or PCOM—once other possible causes
fluid of women with PCOS which undermines oocyte matu- have been excluded—diagnosis during childhood and adoles-
ration and embryo quality. The inflammatory environment cence is more challenging, mainly because some features re-
caused by oxidative stress also promotes IR and contributes lated to PCOS are common in the transition from puberty to
to HA [24]. Alteration in cortisol metabolism can also cause adulthood (Tables 3 and 4). First, menstrual irregularities and
HA. In PCOS women, there is an elevated activity of 5α- anovulatory cycles are very common in the first 2 years after
reductase leading to increased inactivation of cortisol or im- menarche (25% in the first year, 35–40% up to the third and
paired 11β-hydroxysteroid dehydrogenase and thus impaired fourth year). Complete maturation of the hypothalamic-
regeneration of cortisol. Impaired activity of these enzymes pituitary-ovarian axis is usually achieved in the first 5 years
causes increased ACTH secretion with decreased negative after menarche. In the context of variations in the adolescent
feedback signaling thereby maintaining normal serum cortisol menstrual cycle, the persistence of oligomenorrhea (menstrual
with increased adrenal androgen. Thus, adrenal androgen ex- cycles > 35 days), secondary amenorrhea (absence of cycles
cess in PCOS is associated with increased inactivation of cor- for more than 3 months), or primary amenorrhea (absence of
tisol by 5β-reductase that may lower cortisol blood levels and menarche by age 15 years [35]) in girls with complete pubertal
stimulate ACTH-dependent steroidogenesis [27]. development and adult stature suggests an excess of andro-
A metabolic disorder has been widely documented in gens [36]. Prolonged adolescent oligomenorrhea at 14–
PCOS women. Vascular alterations such as endothelial dys- 19 years is reported to be predictive of persistent ovarian dys-
function, increased arterial stiffness, and intima-media thick- function later in life [37].
ness are more prevalent in these patients. Most women with Secondly, mild acne, hirsutism, and physiologic IR, as well
PCOS also exhibit some or most components of the metabolic as obesity, are frequently observed during puberty. A diagno-
syndrome, including obesity, hypertension, dyslipidemia, and sis of HA should be considered in adolescents with hirsutism
IR. Up to 30–40% of women with PCOS have impaired glu- (male-like hair growth), moderate to severe inflammatory ac-
cose tolerance and as many as 10% develop type 2 diabetes ne, and/or menstrual irregularities. Acne that is persistent and
 J Assist Reprod Genet

Table 3 Clinical features of polycystic ovary syndrome in adolescent usefulness of AMH for diagnosing PCOS among adolescent
(14–21 years old) and advanced age (> 50 years old) women
girls are inconsistent [41].
Adolescence Advanced age There is no consensus about clinical criteria to define
PCOS in the adolescent population. The ESHRE/ASRM
Hyperandrogenism -Hirsutism - Hirsutism working group [42] and the Endocrine Society [43] have sug-
-Moderate to severe or - Less pronounced
persistent acne and poor phenotype
gested that, when adolescent PCOS is not clearly evident by
response to treatments. adult standards, the disorder should be considered if there
Oligo-anovulation -Persistence of - More regular have been increased serum androgen levels and/or progressive
(OA) oligomenorrhea menstrual cycles hirsutism in association with persistent oligomenorrhea for at
-Secondary amenorrhea after age of 40
-Primary amenorrhea in girls - 2-year delay of
least 2 years after menarche and/or primary amenorrhea by
with complete pubertal menopause age 16 years and/or ovarian volume > 10 cm3, after exclusion
development of secondary causes. More recently, international professional
Metabolic and -Fewer vasomotor societies of pediatric and adolescent medicine have defined
endocrine symptoms
disorders -Overweight or
that persistent elevation of total and/or free testosterone serum
obese levels is the most determinant biochemical test for confirming
-Insulin resistance HA in the adolescent population. Importantly, treatment may
-Metabolic be indicated even in the absence of a definitive diagnosis [36].
syndrome
The main objective of the treatment of PCOS in adolescent
girls should be to restore normal ovulation and menstrual cycle,
poorly responsive to topical dermatologic treatment also sug- to reduce/eliminate hirsutism and acne, to achieve weight loss in
gests HA. Due to variability in the results of testosterone as- overweight or obese individuals, and to treat hyperlipidemia and
says and limited data regarding normal developmental fluctu- hyperglycaemia. A healthy diet combined with exercise should
ations in testosterone levels during puberty, there is no clear be the priority in overweight/obese adolescents. Losing weight
testosterone cut-off level. In general, for an assay using an will help to prevent clinical manifestations of PCOS, improve
extraction step, total testosterone concentrations > 55 ng/dl self-esteem, and normalize menstrual periods [44].
are consistent with HA [38]. Hirsutism treatments may need to integrate pharmacologi-
Third, PCOM occurs in up to 25% of healthy adolescents, cal agents, cosmetic procedures, and psychological support
and ovarian volume is typically greater during puberty than in [45]. The cornerstone of treatment of hirsutism is the applica-
adulthood [39]. PCOM is highly prevalent in healthy non- tion of cosmetic measures. The most commonly used are
hyperandrogenic girls since multifollicular ovaries can be a shaving and waxing techniques. They are quite efficacious,
normal stage of development in adolescence and early adult- inexpensive, and safe. Other additional but more expensive
hood [40]. measures are topical agents that inhibit local hair growth
There is a consensus that an ovarian volume > 12.0 cm3 (eflornithine hydrochloride cream) and thermal destruction
(calculated by the formula for a prolate ellipsoid) should be of dermal papilla (laser therapy or electrolysis). When these
considered enlarged. Follicle counts should not be used to methods are not effective enough for the patient, the combi-
define PCOM in adolescents. Available data regarding the nation of both physical and hormonal therapies constitutes an
option [46]. Oral contraceptives with anti-androgenic
gestagen preparations (cyproterone and drospirenone) in-
Table 4 Diagnostic criteria of polycystic ovary syndrome in adolescent crease SHBG and reduce free testosterone serum index levels,
(14–21 years old) and advanced age (> 50 years old) women
hirsutism, and acne [47]. Other pharmacological therapies that
Adolescence Advanced age can be used in combination with androgen suppression are
flutamide 250 mg twice daily, spironolactone 100 mg daily,
Hyperandrogenism -Persistent elevation of -Well-documented
and finasteride 5 mg daily [45].
total testosterone serum long-term history of
levels hyperandrogenism Adolescents with classical PCOS have alterations in some
-Hirsutism surrogate markers of cardiovascular risk which can be ameliorat-
-Moderate to severe acne ed by metformin. Hyperandrogenic girls such as those with ad-
Oligo-anovulation -Persistent oligomenorrhea -Well-documented
olescent PCOS exhibit abnormal insulin responses to glucose
(OA) for at least 2 years after long-term history of
menarche oligomenorrhea loading, higher low-density lipoprotein cholesterol (LDLC) to
-Primary amenorrhea by high-density lipoprotein cholesterol (HDLC) ratios, and lowered
age 16 and complete SHBG levels. In addition, elevated levels of circulating insulin
pubertal development
coincide with a reciprocal decline of SHBG, thereby allowing for
Polycystic ovarian Ovarian volume > 12 cm3
morphology increased availability of free testosterone [48]. A combination of
low-dose flutamide and metformin normalizes HA, IR,
J Assist Reprod Genet

dyslipidemia, body adiposity, low-grade cardiovascular markers infertility, the main cause is androgen and LH hypersecretion,
of inflammation, and hirsutism/acne in addition to regularizing which lead to OA, irregular menses, and reduced
menstrual cycles [49]. Low-dose polytherapy [metformin fecundability. Irregular periods—oligo/amenorrhea—will be
(850 mg/day), flutamide (62.5 mg/day), pioglitazone (7.5 mg/ a first sign of ovarian dysfunction that can be easily detected
day), ethinylestradiol (20 μg/day) plus drospirenone (3 mg/day) in the first visit. Usually, these women will have a very high
21/28 days] for 24 months leads to improvements in endocrine- antral follicle count and AMH concentrations [53].
metabolic profile, total and visceral adiposity, and markers of
cardiovascular health [50]. Lifestyle therapy: bariatric surgery
Adolescent women with PCOS are also at an increased risk
for depression and anxiety disorders which can be prominent in The first line of treatment for ovulation induction in PCOS is
those faced with issues of self-presentation, and in women of all lifestyle intervention, especially in obese patients, which seeks
ages with respect to eating, overweight, and clinical manifesta- to improve body composition (BMI, body weight, and waist-
tions of androgen excess [51]. The overemphasizing for weight to-hip ratio), HA, and IR [54]. The objective should be a
loss in some psychological predisposed adolescents with PCOS reduction of at least 5 to 10% of the initial weight [55].
could contribute to the development of eating disorders, most Although controversial, better body-weight control has been
often anorexia and bulimia nervosa. Moreover, it has been hy- reported when metformin has been added to lifestyle modifi-
pothesized that PCOS may promote bulimic behavior since cation [56]. Lifestyle therapy consists of a hypocaloric diet
androgens have appetite-stimulating effects and could impair (1200–1400 kcal/day for 3 months [57] or a 500–1000 Kcal/
impulse control. Nevertheless, dieting and overall eating disor- day deficit [58]) in combination with physical exercise
der symptoms in PCOS adolescents have not been described (120 min of exercise per day, 3 to 5 days/week for 6 months)
significantly higher than in women with normal ovaries [52]. [59]. The patient’s capacity to adhere to diet and exercise
programs and to maintain an appropriate weight over time is
paramount [60]. In this context, psychological support is es-
Adulthood: fertility (Fig. 3) sential. Pharmacotherapy for weight reduction has not dem-
onstrated its effectiveness for fertility purposes. Bariatric sur-
Infertility and hirsutism are the two main clinical problems gery can be considered in women with BMI ≥ 40 kg/m2 or ≥
that bring a woman with PCOS to the clinic. Regarding 35 kg/m2 with associated comorbidities and who have failed

Fig. 3 Fertility approach of

polycystic ovary syndrome. The FERTILITY APPROACH
first-line therapeutic approach in
obese infertile women with PCOS
consists of lifestyle therapy.
When it fails or weight excess is Lifestyle therapy
not present, pharmacotherapy is First line Aim: Reduction of at least 5-10% of initial weight
advised. In patients with impaired
glucose tolerance or type 2 dia-
betes, metformin can be adminis-
Patients with PCOS and impaired
tered. In the remaining cases,
glucose tolerance or type 2
clomiphene citrate is the first
diabetes that do not respond to
choice for ovulation induction
lifestyle therapy
and letrozole the second option,
although some recent studies
suggest letrozole as the first phar- Clomiphene Citrate (CC)
Metformin
macological option. Laparoscopic
ovarian drilling can be considered
in selected cases with caution. No response
Gonadotropins are recommended
when no success is achieved with
the drugs previously commented Letrozole (also suggested Consider ovarian
for ovulation induction or when
Second line
as first line option) drilling
there is an indication for IVF.
BMI: body mass index; CC: clo-
miphene citrate; PCOS: polycys-
tic ovary syndrome Third line Gonadotropins

IVF
 J Assist Reprod Genet

to lose enough weight with other treatments in ≥ 6 months. It of embryo implantation. In addition, the cervical mucus char-
shows several benefits, including the improvement or resolu- acteristics can also change making sperm penetration more
tion of type 2 diabetes mellitus [61], IR, and fertility problems difficult [71]. The starting dose of CC is 50 mg/day for 5 days
[62]. However, surgery is a risky option with important asso- from the second to fifth day of the cycle. This dose should be
ciated complications before and during pregnancy [63]. increased if there is no response after two cycles, as only two-
Moreover, it is not a quick approach to achieve pregnancy, thirds of patients respond to 50 mg/day in the first cycle [64].
since it should be avoided for at least 12 to 18 months after With this 5-day course of treatment, the ovulation rate can
surgery to reduce fetal complications [64]. Therefore, bariatric reach 46%, rising to 85% if the dose is increased to more than
surgery should be considered the last therapeutic option in 150 mg/day [72]. According to ESHRE/ASRM consensus,
obese women with fertility problems. the maximal dose should not exceed 150 mg/day, as there is
no clear evidence of efficacy at higher doses [73]. The multi-
Anti-androgen therapy ple pregnancy rate per conception cycle is around 8% after CC
[74]. This rate is lower than the obtained with gonadotropin
When considering anti-androgen therapy in adult women, there but higher than with letrozole (0.46, 0.23 to 0.92) and metfor-
are several pragmatic approaches to be discussed with the pa- min (0.22, 0.05 to 0.92) [75]. The advantages of CC are its low
tient: (a) minimizing circulating androgens with either oral con- cost and its oral administration. Approximately 15% of wom-
traceptive pill and/or insulin sensitizing agents, (b) peripheral en with PCOS do not respond to the maximum dose of CC
blockage of androgen receptor with spironolactone, flutamide, and are considered resistant to this medication [76].
ciproterone acetate, or finasteride, or (c) inhibiting facial or
other body parts hair growth by eflornithine hydrochloride [65]. Letrozole

Metformin This aromatase inhibitor is administered to women with PCOS

as an alternative in order to avoid the anti-estrogenic effect of
Metformin is an insulin-sensitizing agent which acts by reduc- CC on the endometrium. Furthermore, it preserves ovarian pi-
ing gluconeogenesis and lipogenesis and by enhancing glu- tuitary feedback, has a lower risk of multiple follicle develop-
cose uptake in the liver, skeletal muscle, adipose tissue, and ment than CC [77], and reduces the peripheral conversion of
ovaries. In PCOS women, metformin inhibits ovarian andro- androgens to estrogens in ovarian granulosa cells by blocking
gen production by approximately 20 to 25%, decreases serum aromatase [78]. The recommended dose is 5 or 7.5 mg/day for 5
LH, and increases SHBG [66]. Metformin may also improve to 10 days starting 3–7 days after menses [79]. A potential risk
ovulatory function. A meta-analysis of PCOS patients re- of teratogenic effects of letrozole was suggested in a prelimi-
vealed an increase in pregnancy rates but not in live birth rates nary report [80], but subsequent studies have discarded them
among those receiving metformin [67]. A systematic review [78]. Letrozole has been suggested as a second-line pharmaco-
and meta-analysis of patients with PCOS undergoing IVF or logical therapy in women resistant to CC, and as a first-line
ICSI treatment did not show significant differences in terms of therapy for ovulation induction in women with PCOS and a
pregnancy and live birth outcomes between patients receiving BMI greater than 30 kg/m2 given the higher live birth rate in
metformin and those given a placebo [68]. Therefore, metfor- comparison to that achieved with CC []. However, the PPCOS
min is not recommended as a first-line agent for ovulatory trial (pregnancy in PCOS patients) [74] evaluated in a double-
infertility, but it is advised in women with PCOS and impaired blind, multicenter trial the efficacy of letrozole vs CC not only
glucose tolerance or type 2 diabetes that do not respond to in determining ovulation but also pregnancy in a very large
lifestyle modifications [69]. sample size (1500 patients). This trial showed that PCOS wom-
en who received letrozole had more cumulative live births than
Clomiphene citrate those who received CC (27.5 vs 19.1%, p = 0.007, RR 1.44,
95% CI 1.10–1.87) for all BMIs, with no differences among
Clomiphene citrate (CC) is considered the first-line treatment miscarriage or twinning rates. This data is encouraging enough
for ovulation induction in women with PCOS [43]. This drug to consider letrozole a first-line drug in PCOS women when
is an estrogen receptor modulator with a controversial mech- considering ovulation induction.
anism of action. When administered in the first days of the
follicular phase, it competes with estrogens for their receptors Gonadotropin therapy
in the hypothalamus and pituitary, blocking the negative feed-
back mechanism. Subsequently, endogenous gonadotropins Gonadotropins (FSH or HMG) constitute the third line of phar-
are released and the dominant follicle is selected [70]. macological treatment in PCOS women in whom CC and
Endometrial proliferation may be inappropriate due to the letrozole have not been effective. Low doses are recommended
anti-estrogenic effect of CC, which can decrease the chance to achieve monofollicular growth (37.5 to 75 IU/day or every
J Assist Reprod Genet

other day). In the low-dose step-up regimen, the dose is in- rates. A recent review showed that gonadotropins are the most
creased after 14 days if there is no response. Currently, an effective treatment in patients resistant to CC [89]. In a study
ultra-low increment of FSH (8.3–12.5 IU) is possible with the of 945 treatment cycles in which a low-dose regimen of 50 IU
newly available pen devices [82]. As the required starting dose of rFSH was applied, 61.3% monofollicular development was
of gonadotropin is not easy to determine, a careful monitoring achieved with 14.4% PR per cycle and 53.1% cumulative PR
of follicular development is essential, and patients should be after six treatment cycles [83]. Compared to timed intercourse
made aware of cancelation rates of hCG administration in the (TI), IUI does not increase PRs in couples with PCOS and
first attempts of ovarian stimulation. A cohort study of 343 normal semen undergoing ovulation induction. In a recent
PCOS patients receiving a starting dose of 50 IU FSHr/day study, PR was similar in the TI group (17.5%) vs IUI group
presented a cancelation rate of 13.5% owing to hyperresponse, (16.6%) [90]. In the absence of other fertility problems that
defined as the presence of more than three follicles ≥ 16 mm require IVF, ovulation induction for TI or IUI seems to be the
[83]. A Cochrane review about the use of gonadotropins for indicated first step of fertility treatment in PCOS women.
ovulation induction in women with PCOS highlighted similar
live birth rates and OHSS incidence with the use of urinary- IVF outcome
derived gonadotropins, recombinant FSH, or HMG/HP-HMG
[84]. Prescription of gonadotropins requires consideration re- Whether oocyte quality is affected in PCOS patients remains an
garding the cost, the intensive monitoring required, and the open question. Some studies have shown lower fertilization
potential risks of multiple pregnancy and OHSS. rates in conventional IVF in PCOS patients compared to con-
In IVF, gonadotropins should be administered in a GnRH trols, but similar pregnancy, miscarriage, and live birth rates
antagonist protocol, since different meta-analyses and ran- [91]. Other authors have described a poor oocyte quality, lead-
domized controlled trials have shown similar outcome param- ing to lower fertilization, embryo cleavage and implantation
eters but lower OHSS rates than in classic long agonist proto- rates, and higher miscarriage rates [92]. Although an associa-
cols in PCOS women [85]. tion between poor oocyte and embryo quality and increased
aneuploidy and miscarriage rates has been described [93, 94],
Laparoscopic ovarian drilling recent data show that PCOS patients present similar percent-
ages of euploid embryos than controls, and even a higher ab-
A review about the role of laparoscopic ovarian drilling solute numbers of euploid embryos due to the higher oocyte
(LOD) in PCOS women drew attention to its benefits in pa- yield after controlled ovarian hyperstimulation [95]. Alterations
tients with CC resistance, BMI < 30 kg/m2 and preoperative in the intrafollicular microenviroment or in intra-ovarian factors
LH above 10 IU/L. In addition, the authors described that the belonging to growth factor families have been also suggested to
performance of 5 to 10 perforations on the surface of each affect the oocyte competence and maturation [96, 97].
ovary using monopolar energy was the preferred surgical tech- According to the current evidence, despite a higher cancel-
nique [86]. LOD may be considered in infertile PCOS women ation rate is observed in PCOS women [91], biochemical
resistant to CC or letrozole, especially if laparoscopy is indi- pregnancy, implantation, clinical pregnancy, ongoing preg-
cated by another reason such as tubal patency assessment or nancy, live birth, and cumulative live birth rates are compara-
salpingectomy. A prospective RCT analyzed the effect of uni- ble to those of non-PCOS women [98, 99]. However, repro-
lateral and bilateral LOD in PCOS women; 87 PCOS patients ductive outcome in PCOS may be influenced by BMI [100];
with ovulation induction failure were randomly allocated to in fact, a different endometrial gene expression during the
either unilateral or bilateral LOD by electrocautery. Ovulation, window of implantation has been described in obese patients,
pregnancy, and miscarriage rates were similar in both groups, particularly in those with PCOS [101].
but unilateral LOD was less time-consuming and probably
associated with fewer complications than bilateral drilling Ovarian stimulation risks
[87]. In the long term, not only adhesions may be generated
by the healing process after LOD, but also a compromised Multiple pregnancy and OHSS are serious risks in patients
ovarian function and even induced iatrogenic premature ovar- undergoing ART. Multiple pregnancy can be prevented by
ian failure if the procedure is too aggressive [88]. Therefore, it careful monitoring of the number of follicles larger than
is a treatment option that should be selected with caution. 12 mm during ovulation induction. Recent data suggests that
cancelation of cycles should be considered when estradiol
Ovulation induction and intrauterine insemination (IUI) levels are > 1200 pg/mL or there is an excessive number (≥
outcome 5) of developing follicles [102]. When more than 3 follicles >
14 mm are observed, cancelation should be seriously consid-
Few studies have analyzed the outcome of ovulation induction ered. In IVF, the multiple pregnancy rate can be decreased by
or IUI in PCOS patients in terms of pregnancy or live birth a strict policy of elective single embryo transfer [103].
 J Assist Reprod Genet

OHSS is one of the most serious, and potentially lethal, risk of pre-eclampsia was detected only in a subgroup of
complications of ovarian stimulation. Induction of final oo- hyperandrogenic PCOS women [117]. A more recent retro-
cyte maturation with a bolus of gonadotropin-releasing hor- spective cohort analysis detected a fourfold increase in the risk
mone (GnRH) agonist, rather than the standard criterion hCG, of hypertensive disorders during pregnancy in women with
in patients undergoing ovarian stimulation with a GnRH an- PCOS after adjusting for age, parity, BMI, and time to con-
tagonist protocol significantly reduces the risk of OHSS by ception in singleton pregnancies [113].
inducing a quick and reversible luteolysis [104], although lu-
teal phase becomes defective. This is not a problem in cases of Gestational diabetes mellitus
freeze-all policy, but in a fresh embryo transfer luteal support
needs to be much more intensive than the conventional sup- Gestational diabetes is the most frequent pregnancy compli-
port. Main approaches have been either low dose hCG added cation described in PCOS women, with a two- to threefold
to oral estradiol and vaginal progesterone or high doses of risk in comparison to non-PCOS women, even after adjusting
estradiol combined with i.m. progesterone [105]. Antagonist data for confounders [109–111, 113, 116, 118]. Metformin
protocols are strongly recommended in these cases, since they therapy does not seem to reduce its incidence, according to a
reduce OHSS incidence by 50% and allow GnRH agonist recent randomized controlled trial in which this drug was
triggering [106]. compared with a placebo [119]. A recent meta-analysis of five
studies including 502 PCOS patients administered metformin
throughout pregnancy and 427 controls administered the drug
Adulthood: pregnancy only to achieve conception did not highlight differences in the
risk of gestational diabetes mellitus or pre-eclampsia between
Women with PCOS exhibit a significantly increased risk of the two groups [120].
obstetric and neonatal complications compared to controls,
regardless of the definition of PCOS applied [107], and even
when BMI and other confounders, such as age, parity, time to Fetal/neonatal complications
conception or number of fetuses, have been taken into account
[108–113]. HA, obesity, low-grade chronic inflammation, Miscarriage
dyslipemia, IR and other metabolic disturbances may play a
role in this increased risk and probably also in the reported Currently, there is no clear evidence regarding an increased
higher risk of metabolic and reproductive abnormalities in the risk of miscarriage in PCOS women compared with fertile
offspring [108, 112–114]. Moreover, factors related to infer- controls or non-PCOS infertile women undergoing IVF [91,
tility, including prolonged time to pregnancy, fertility drugs 112]. Some authors suggested that the hypersecretion of LH,
and assisted conception treatments, and a higher rate of mul- HA, and hyperinsulinemia present in PCOS women were
tiple pregnancies, also constitute risk factors for complications interlinked and together might result in disordered ovarian
during pregnancy [108]. All these elements may act directly and endometrial function related to an increased risk of early
and/or through a defective trophoblast invasion and placenta- pregnancy loss [121] However, miscarriage seems to be
tion to induce fetal-maternal complications, although an alter- strongly influenced by BMI, but not by PCOS itself [122].
ation in placental gene expression has been also suggested as a In addition, in early miscarriages, a lower aneuploidy rate
mechanism [115]. has been described in PCOS women than in non-PCOS wom-
en, even when adjusting for maternal age [123].
Maternal complications
Preterm delivery
Pregnancy-induced hypertension (PIH) and pre-eclampsia
Although a recent meta-analysis did not show a higher risk of
The risk of PIH and pre-eclampsia has been reported to be preterm delivery in PCOS women [111], two previous meta-
three to four times higher in PCOS women, but most of the analyses [109, 110] and two cohort studies [116, 117] de-
reports in question have been retrospective studies or meta- scribed a twofold increase in the said risk. In the cohort study
analyses without an adequate sub-analysis of confounders published by Naver et al. [117], the risk was confined to
[109–111]. A population-cohort study by Roos et al. [116] hyperandrogenic women with PCOS. In a recent retrospective
found a significantly increased incidence of pre-eclampsia in cohort study, the increased risk of preterm delivery up until
3787 women with PCOS compared to 1,191,336 women 37 weeks was eliminated after adjusting for PIH [113]. In twin
without PCOS after adjusting for BMI and use of ART (OR pregnancies, the presence of maternal PCOS has been associ-
1.45, 95%CI 1.24–1.69). Another two more recent studies ated with an increased risk of preterm delivery (RR 1.18 CI
have shown similar results [114, 117], but in one the increased 1.03–1.37) and very premature delivery (< 32 weeks) [124].
J Assist Reprod Genet

Small-for-gestational-age (SGA) neonates age (Tables 3 and 4). As women grow older, there is a signif-
icant decrease in androgenic production, but not as much as in
One meta-analysis did not detect a higher risk of SGA infants non-PCOS women [127]. This is why the classical phenotype
in women with PCOS [109], but a more recent one found a is tempered, with more regular cycles after the age of 40.
twofold increased risk [110]. Similarly, two recent case- There is also an attenuated decrease in AMH and ovarian
control studies have reported opposite results; a similar risk volume, with a normal postponement of the menopause of
of SGA in PCOS women and controls was observed in one 2 years [128]. Postmenopausal women with PCOS report hir-
[117], while a twofold increased risk was found in non-obese sutism more frequently, but exhibit fewer climacteric symp-
infertile women with PCOS who underwent ART compared toms than controls [129].
with control patients with tubal infertility factor in the other During this period, metabolic and endocrine disorders take
[125]. Palomba et al. [114] also detected a significantly higher preference over the gynecological problems. Around 40 to
incidence of SGA in a recent prospective controlled clinical 85% of women with PCOS are overweight or obese compared
study in which 150 pregnant PCOS women were compared with age-matched controls. IR is more prevalent among both
with 150 age- and BMI-matched healthy pregnant controls. lean and obese women with PCOS (30 and 70%, respectively)
compared with age- and weight-matched controls [130], with
Large-for-gestational-age (LGA) neonates and macrosomia PCOS subjects running an increased risk of developing type 2
diabetes. Metabolic syndrome is also more predominant in
One population-based study revealed a higher risk of LGA PCOS women in this age group. In fact, these women show
neonates in women with PCOS compared to controls with elevated total cholesterol, triglycerides, insulin secretion, lipid
tubal factor (OR 1.39, 95% CI 1.19–1.62) [133]. However, accumulation product, and blood pressure. At perimenopausal
two meta-analyses failed to detect differences regarding period (41–55 years old), these parameters are not different
LGA infants [110] or macrosomia [109] in women with between controls and PCOS women. HOMA-β is lower at
PCOS versus those without. Obesity is an evident confounder, late reproductive and perimenopausal periods compared to
since a difference in the incidence of LGA has not been de- the early reproductive age within the PCOS group.
scribed between non-obese controls and non-obese women Therefore, no further deterioration of metabolic parameters
with PCOS [125]. However, a prospective controlled clinical seems to occur during perimenopause [131, 132].
study by Palomba et al. [114] detected a significantly higher The higher rate of obesity, IR, impaired glucose intolerance
incidence of LGA in 150 pregnant PCOS women compared to (or type 2 diabetes), and dyslipidemia may lead to the devel-
150 age- and BMI-matched healthy pregnant controls, and a opment of coronary heart disease (CHD) [133]. However,
recent retrospective cohort study reported a significantly in- uncertainty exists as to whether PCOS status per se increases
creased risk of LGA infants after adjusting for BMI and ges- cardiovascular mortality [42]. Non-alcoholic fatty liver dis-
tational diabetes mellitus status in singleton pregnancies ease (NAFLD) is also more prevalent in older PCOS patients
[113]. In the Palomba et al.’s paper [114], both LGA and [134], as well as mood (depression and anxiety) [135] and
SGA babies were more prevalent in PCOS women. The in- eating (binge eating and bulimia nervosa) disorders, even with
creased risk of gestational diabetes in PCOS pregnant women respect to women with the same BMI. Sleeping apnea is also
may be related to the higher incidence of LGA babies, and the frequent due to obesity, androgen excess, and IR. Women with
poorer trophoblastic invasion/ placentation described in some PCOS also present risk factors for endometrial cancer (oligo-
PCOS women to the increased risk of SGA babies. ovulation, excess weight, and hyperinsulinemia). In fact, those
under 54 years of age present an increased risk of endometrial
Other complications cancer, but not of breast or ovarian cancer [136].
Once a diagnosis of PCOS is confirmed, a cardio-
In women with PCOS, a higher risk of admission to the NICU metabolic risk assessment including estimation of blood pres-
and a low Apgar score at 5 min have been observed in neo- sure and BMI, fasting lipid profile and 2-h glucose tolerance
nates, as well as higher perinatal mortality [109, 111, 116], test (OGTT) is recommended. Patients with normal glucose
although not all the literature supports a risk of adverse fetal tolerance should be re-screened at least once every 2 years, or
or neonatal outcomes, or a risk of cesarean section or operative more frequently if additional risk factors are detected. In the
vaginal delivery [113, 124, 126]. event of impaired glucose tolerance, an assessment of type 2
diabetes should be performed [137]. Women with PCOS
should be informed about the signs and side effects of sleeping
Perimenopause and elderly women apnea and excessive daytime sleepiness. Therapy in these
women should generally aim to manage hidden metabolic
Diagnosis of PCOS in the perimenopause can be difficult, abnormalities, reduce risk factors for developing type 2 dia-
since the clinical and biochemical manifestations change with betes and cardiovascular disease, and prevent endometrial
 J Assist Reprod Genet

hyperplasia and carcinoma. Available data suggest that life- 5. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and
PCOS Society criteria for the polycystic ovary syndrome: the
style (diet, exercise, and behavioral interventions) can im-
complete task force report. Fertil Steril. 2009;91:456–88.
prove metabolic risk factors and should constitute the first line 6. National Institutes of Health. Evidence-based methodology work-
of intervention for most women [54]. shop on polycystic ovary syndrome. December 3–5, 2012.
Executive summary. Available at https/prevention.nih.gov/docs/
programs/pcos/FinalReport.pdf. Accesed March 1, 2017.
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extreme ends of the reproductive lifespan. However, many of polycystic ovary syndrome: the ovarian follicle number and
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ly, as they may require different treatments and have different 12. Dewailly D, Gronier H, Poncelet E, et al. Diagnosis of polycystic
consequences. In this way, PCOS exhibits a great metabolic ovary syndrome (PCOS): revisiting the threshold values of follicle
complexity and its diagnosis should be revised once again count on ultrasound and of the serum AMH level for the definition
according to recent data obtained by new technologies. of polycystic ovaries. Hum Reprod. 2011;26:3123–9.
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Lifestyle therapy tends to be the first step in PCOS manage-
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Pharmacotherapy is frequently used to manage the most pre- 14. Stein S, Jennifer L, Sites CK, Yang D. Environmental determi-
dominant manifestations in each age group, such as irregular nants of polycystic ovary syndrome. Fertil Steril. 2016;106:16–24.
menses and hirsutism in adolescence, fertility problems in 15. Yildiz BO, Bozdag G, Yapici Z, Esinler I, Yarali H. Prevalence,
phenotype and cardiometabolic risk of polycystic ovary syndrome
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ferent phenotypes of the syndrome are analyzed as complete 16. Sirmans SM, Parish RC, Blake S, Wang X. Epidemiology and
separate entities. comorbidities of polycystic ovary syndrome in an indigent popu-
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17. Rutkowska AZ, Diamanti-Kandarakis E. Polycystic ovary syn-
Funding This research received no specific grant from any funding
drome and environmental toxins. Fertil Steril. 2016;106:948–58.
agency in the public, commercial, or not-for-profit sectors.
18. Franks S, Mc Carthy M, Hardy K. Development of polycystic
ovary syndrome: involvement of genetic and environmental fac-
Compliance with ethical standards tors. Int J Androl. 2006;29:278–85.
19. De Leo V, Musacchio MC, Cappelli V, Massaro MG, Morgante G,
Conflict of interests The authors declare that they have no conflict of Petraglia F. Genetic, hormonal and metabolic aspects of PCOS: an
interest. update. Reprod Biol Endocrinol. 2016;14:38.
20. De Melo AS, Dias SV, De Carvalho R, et al. Pathogenesis of
polycystic ovary syndrome: multifactorial assessment from the
foetal stage to menopause. Reproduction. 2015;150:11–24.
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