Review
Metabolic risk in PCOS: phenotype and
adiposity impact
Lisa J. Moran1,2, Robert J. Norman1, and Helena J. Teede1,2,3
1
The Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5006,
Australia
2
Monash Centre for Health Research Implementation, School of Public Health and Preventive Medicine, Monash University,
Monash, VIC 3168, Australia
3
Diabetes and Vascular Medicine Unit, Monash Health, Monash, VIC 3168, Australia
Polycystic ovary syndrome (PCOS) is a common condi-
tion in reproductive-aged women, with reproductive,
cardiometabolic, and psychological features. The het-
erogeneity in insulin resistance, obesity, and cardiome-
tabolic features has led to controversy on the
independent contributions of PCOS status, diagnostic
criteria, phenotype, and adiposity. It now appears that
women with PCOS have an increased risk of insulin
resistance and cardiometabolic features, which is inde-
pendent of, but worsened by, adiposity and central
adiposity, and is unrelated to reproductive phenotype.
Obesity may be more prevalent in the more severe
phenotypes, which suggests either an exacerbation of
the reproductive features or a more likely diagnosis in
overweight women with PCOS. Therefore, all women
with PCOS should be targeted for prevention, screening,
and management of cardiometabolic features.
Overview of the health risks, aetiology, and diagnosis of
PCOS
PCOS is a common condition that affects 618% of women
[14] with serious health impacts [57] (Figure 1). The
reproductive features of PCOS are well recognised. PCOS
is the primary cause of female infertility and increases
pregnancy complications, gestational diabetes, and uterine
malignancy risk (Figure 2). PCOS also has a significant
cardiometabolic impact, including a quadrupling of the risk
of type 2 diabetes mellitus (T2DM), with younger onset and
increasing cardiovascular risk factors (Figures 1 and 2)
[8,9]. PCOS is 80% heritable, and its health burden extends
to the next generation, with significant adverse impacts on
the children of affected mothers [10]. Importantly, PCOS
identifies women from puberty with high reproductive and
cardiometabolic risks who appear prone to gain weight,
which further exacerbates their condition, highlighting
the need to target these women for prevention and manage-
ment (Figures 1 and 2).
While PCOS is common and the clinical features rea-
sonably well described, many controversies remain. The
Corresponding author: Moran, L.J. (lisa.moran@adelaide.edu.au).
Keywords: polycystic ovary syndrome; obesity; insulin resistance; cardiometabolic;
diagnostic criteria.
1043-2760/
2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2014.12.003
136 Trends in Endocrinology and Metabolism, March 2015, Vol. 26, No. 3
Rotterdam diagnosis (see Glossary) is now internationally
accepted and is based on diagnosing two of three clinical
features that include androgen excess, ovulatory dysfunc-
tion (oligoovulation and/or anovulation), and polycystic
ovarian morphology on ultrasound [11]. However, individ-
ual diagnostic features remain ill defined. Within the
diagnostic criteria, there are at least four subcategories
or phenotypes of PCOS, with a need for further under-
standing of the natural history of these phenotypes. Diag-
nostic features vary across the lifespan and across ethnic
groups [2,12,13], and are focussed on reproductive features
of PCOS, but do not capture cardiometabolic features. In
this context, controversies remain on individual diagnostic
features and on the name of the condition, which focusses
on ultrasound-based ovarian morphology, with a clear
need for ongoing research [1416].
Glossary
Biochemical androgen excess: when levels or estimates of circulating
endogenous androgens [e.g., testosterone (T), total, unbound, or free; free
androgen index, androstenedione (A4); dehydroepiandrosterone (DHEA); and
the DHEA metabolite DHEAS] are supranormal.
Clinical androgen excess: the most common endocrine disorder in women of
reproductive age. It is characterised by unwanted hair growth or hirsutism,
seborrhoea, and/or acne, and androgenic alopecia or male pattern balding, a
result of excess androgen.
Insulin resistance: the reduced ability of insulin to exert its physiological effect
at normal concentrations. It is defined as less than the 25th centile of lean
matched controls on euglycaemic hyperinsulinaemic clamp-derived glucose
infusion rate (WHO criteria).
Menstrual dysfunction: a condition whereby menstrual cycles, or more
accurately vaginal bleeding episodes, come at intervals of more than 35 days,
or less than ten bleeds per year. Menstrual dysfunction may also be the result
of cycles of less than 25 days.
Polycystic ovaries: the presence of 25 or more follicles in each ovary in women
aged 1835 years and/or increased ovarian volume (10 ml), according to the
updated AE-PCOS task force recommendations [25]; formerly, >12 antral
follicles and/or increased ovarian volume (>10 ml) under the Rotterdam criteria
[11].
Reproductive phenotypes: PCOS comprises androgen excess and ovulatory
dysfunction with polycystic ovaries on ultrasound, androgen excess and
ovulatory dysfunction without polycystic ovaries on ultrasound, androgen
excess and polycystic ovaries on ultrasound without ovulatory dysfunction,
and ovulatory dysfunction and polycystic ovaries on ultrasound without
androgen excess.
Rotterdam diagnostic: criteria of PCOS refer to the diagnostic criteria
developed at a European Society of Human Reproduction and Embryology/
American Society for Reproductive Medicine consensus conference. These
diagnostic criteria are now internationally accepted and are based on
diagnosing two of three clinical features that include androgen excess,
ovulatory dysfunction (oligoovulation and/or anovulation), and polycystic
ovarian morphology on ultrasound.
 Review Trends in Endocrinology and Metabolism March 2015, Vol. 26, No. 3

patients originally described by the two gynaecologists

Genecs Life style who reported on wedge resection of the ovary [18]. The
introduction of ultrasound and ability to measure testoster-
one evolved our understanding, and resulted in widening of
Hormonal changes
the definition and changing the nomenclature. As men-
Obesity exacerbates hormonal changes tioned above, currently, the accepted diagnostic definition
of PCOS is the Rotterdam criteria, now supported by the
European Society of Human Reproduction and Embryology,
Androgens Insulin the American Society for Reproductive Medicine, the Na-
tional Institute of Health (NIH), and the Australian PCOS
Ovarian follicles Diabetes Alliance [5,11,19]. While the three diagnostic criteria of
anovulaon metabolic anovulatory menstrual cycles, changes in ovarian morphol-
oestrogen syndrome ogy, and androgen excess are accepted, individual compo-
nents, including androgen excess, ovulatory dysfunction,
Hirsusm Menstrual disturbances Cardiovascular and polycystic ovarian morphology, suffer from lack of
acne subferlity risk clarity [17].
While irregular, anovulatory periods have been cardinal
Psychosocial issues: body image, self esteem, depression, anxiety to the diagnosis, this is ill defined in clinical practice.
Regular menstrual periods do not ensure ovulation, while
TRENDS in Endocrinology & Metabolism irregular periods can be ovulatory [17]. Some use the
Figure 1. Polycystic ovary syndrome (PCOS) aetiology and clinical features. Insulin
definition of less than eight menstrual periods per year
resistance and hyperinsulinaemia have a key pathophysiological role in PCOS. [20], while others monitor cycles to check progesterone
Women with PCOS may have a form of intrinsic insulin resistance, which is indicating ovulation. Menstrual cycles are also irregular
worsened by obesity-associated insulin resistance. In addition to underlying
abnormalities in steroidogenesis or gonadotropin regulation, this insulin
in most young women during the first 2 years after men-
resistance can further worsen hyperandrogenism. The two key features of arche and ultrasound criteria are less helpful in young
hyperandrogenism and insulin resistance then contribute to the key clinical adolescents [17]. The PCOS guidelines note that the origi-
reproductive, metabolic, and psychological presentation of PCOS. Reproduced,
with permission, from [17]. nal NIH criteria, independent of ultrasound-defined poly-
cystic ovaries, should be applied in adolescents
[17]. Towards the end of reproductive life, menstrual cycles
become more regular, then ultimately become irregular
The aetiology of PCOS is both genetic and lifestyle and absent due to menopause, making it difficult to define
related, and promotes insulin resistance, hyperinsulinae- PCOS at this life stage [12,13].
mia, and androgen excess (Figure 2) [17]. The hormonal Measurement of androgen excess has also proved chal-
features of the condition appear to be intrinsic to PCOS, lenging. The measurement of testosterone was previously
which are then further exacerbated by extrinsic obesity- primarily performed following solvent extraction and chro-
related changes, although the relative impact of intrinsic matography, with subsequent immunoassay. This provid-
and extrinsic abnormalities is controversial (Figure 2). ed excellent specificity and sensitivity. While this method
Here, we review the recent literature on the cardiometa- was ideal for research-based studies, it was not suitable
bolic features of PCOS across the different phenotypes and for population-based screening and diagnosis. Automated
explore the impact of adiposity. immunoassays for testosterone were introduced, yet have
poor specificity, low sensitivity, and poor correlation with
The diagnosis of PCOS equilibrium dialysis, considered to be the reference meth-
The definition and diagnosis of PCOS has evolved over time. od. Recently, mass spectrometry combined with liquid
The name PCOS was generated in the setting of the original chromatography has become more popular and more wide-
SteinLeventhal syndrome, which in turn reflected the ly available, but remains expensive, and is not yet suitable

Polycysc Irregular
Inherited risk and Pregnancy Uterine
ovary cycles and Inferlity
insulin resistance complicaons malignancy
syndrome hirsusm

Weight gain across the life span exacerbates reproducve and metabolic risks

Inherited risk and insulin Polycysc ovary Risk of prediabetes, gestaonal

resistance syndrome diabetes, type 2 diabetes and
cardiovascular risk factors

TRENDS in Endocrinology & Metabolism

Figure 2. Reproductive and metabolic features across the lifespan exacerbated by weight gain. Polycystic ovary syndrome (PCOS) is a condition with both genetic and
environmental contributors. It comprises an early stage in the reproductive life of women that can act as a target for positive life-style changes to prevent excess weight gain
and reduce infertility, pregnancy complications, and cardiometabolic risk. Adapted, with permission, from [17].

137
Review
for clinical use outside major centres and in many countries
where PCOS is common [21]. New generations of automat-
ed immunoassays have been proposed, and more rapid
liquid chromatography mass spectrometry methods have
become available [22,23]. However, an optimal, easily
applicable method remains uncertain [17]. It is noted that
a major endocrine journal has specified that manuscripts
reporting sex steroid assays as important endpoints must
use mass spectrometry-based assays [24] and more com-
prehensive data sets using this technology are required to
determine the appropriate cut-offs between PCOS and
normal women. The recent PCOS Guidelines noted that
there was no clear cut-off for discrimination between cases
and controls because this may vary depending on labora-
tory and populations used; therefore, levels of free testos-
terone elevated above the normal range for a given
laboratory are commonly used [17].
The issue of ultrasound detection of polycystic ovaries is
even more vexed. The original pelvic ultrasound with
transabdominal probes, part of the Rotterdam definition,
provided little resolution [25]. With the introduction of
vaginal imaging, greater image resolution and recent
advances in magnetic resonance imaging, diagnostic power
increased, but controversy remains about true discrimina-
tion between polycystic ovaries and normal ovaries, on
imaging. The problem is again highlighted in adolescence,
with most young women exhibiting polycystic ovary-like
morphology [26]. The original Rotterdam criteria com-
prised >12 antral follicles and/or increased ovarian volume
(10 ml) [11]. A recent statement by the Androgen Excess
and PCOS Society (AE-PCOS) highlighted these chal-
lenges and suggested refined criteria for polycystic ovary
diagnosis on ultrasound [14] comprising 25 or more follicles
in each ovary in women aged 1835 years and/or increased
ovarian volume (>10 ml) [25]. However, this recommenda-
tion has not received widespread recognition as yet.
Previously proposed criteria for PCOS diagnosis include
the luteinising hormone (LH):follicle-stimulating hormone
(FSH) ratio, insulin resistance or sensitivity, hirsutism or
acne, and the presence of obesity. With the exception of
cosmetic features, none are defining diagnostic features for
PCOS. The exception would be hirsutism, which occurs in
higher prevalence in some ethnic groups, and acne, which
appears to be more common in patients of East Asian origin
[27]. Different cut-off ranges for the Ferriman-Gallwey
(FG) score have also been proposed for these populations,
such as a modified FG of >6 for Korean [28] or 5 for
Southern Chinese populations [29] in comparison to the
standard cut-off of 8, It should also be noted that thyroid,
adrenal, and hypothalamic disorders need to be excluded to
confirm the diagnosis of PCOS [17].
Diagnostic phenotypes
With only two of three criteria required for diagnosis, a
range of reproductive subgroups or phenotypes emerged
[30]. These comprise androgen excess and ovulatory dys-
function with polycystic ovaries on ultrasound, androgen
excess and ovulatory dysfunction without polycystic ova-
ries on ultrasound, androgen excess and polycystic ovaries
on ultrasound without ovulatory dysfunction, and ovulato-
ry dysfunction and polycystic ovaries on ultrasound with-
138
Trends in Endocrinology and Metabolism March 2015, Vol. 26, No. 3
out androgen excess. The 2012 NIH PCOS workshop
recommended consistently adopting the Rotterdam defini-
tion of PCOS, and also recommended indicating the repro-
ductive phenotypes in all research and publications [5]
(Box 1). These range from more severe (androgen excess
and ovulatory dysfunction or all three criteria) to mild
(polycystic ovarian morphology and either ovulatory dis-
turbance or androgen excess only) based on the number of
the reproductive clinical features present. However, given
the challenges of individual diagnostic features, reproduc-
tive phenotypes may not represent distinct clinical enti-
ties, with potential for considerable overlap. Phenotypes
are further influenced by life stage, ethnicity, and body
weight [31], and may represent a spectrum of severity
that varies within an individual over time, as age and
weight change, and between individuals of different eth-
nicities. However, the natural history of PCOS is not well
studied and changes in the clinical features of PCOS over
time are yet to be conclusively determined. Characterisa-
tion of metabolic features across the phenotypes is even
less well studied, with most PCOS publications not report-
ing phenotypes [31], and no quality long-term natural
history studies addressing this issue.
Insulin resistance in PCOS
Insulin resistance appears to be a central aetiological
characteristic in most women with PCOS [17,27,32]. Insulin
resistance and compensatory hyperinsulinaemia increase
ovarian androgen production, and decrease hepatic sex-
hormone binding globulin (SHBG) production, resulting in
androgen excess [32]. The degree of androgen excess
increases with obesity and impacts the reproductive fea-
tures of PCOS, and the phenotypes. It may also influence
metabolic features, although this remains controversial.
Many studies focussing on androgen excess and metabolic
features primarily note an association with calculated
androgen inclusive of factors influenced by insulin resis-
tance (e.g., free androgen index is inclusive of SHBG, which
is a marker of insulin resistance in PCOS) [33]. Together,
both insulin resistance and androgen excess underpin the
features of PCOS. A full discussion of the mechanisms of
insulin resistance is beyond the scope of this paper and has
recently been reviewed elsewhere [32].
Box 1. NIH recommendations on PCOS phenotypes
A panel of invited experts participating in the Evidence-based
Methodology Workshop on Polycystic Ovary Syndrome, in 2012,
proposed the following [5]:
We recommend maintaining the broad, inclusionary diagnostic
criteria of Rotterdam (which includes the classic NIH and AE-PCOS
criteria) while specifically identifying the phenotype:
 Androgen Excess + Ovulatory Dysfunction*
 Androgen Excess + Polycystic Ovarian Morphology*
 Ovulatory Dysfunction + Polycystic Ovarian Morphology
 Androgen Excess + Ovulatory Dysfunction + Polycystic Ovarian
Morphology
The specific phenotypes should be reported explicitly in all
research studies and clinical care. This recommendation should be
disseminated to journal editors, funding sources, and professional
societies.
*Note that the first two phenotypes are described throughout this
paper as mild, while the latter two are described as more severe
reproductive phenotypes.
Review
Insulin resistance can be assessed using a range of
methods based on fasting insulin and glucose, and oral
glucose tolerance testing (OGTT), including area under the
glucose and insulin curves [34]. These are all relatively
easily performed and calculated, but lack accuracy and are
inadequate for mechanistic or interventional research
[34]. The euglycaemic-hyperinsulinaemic clamp is consid-
ered the gold standard in measuring insulin sensitivity in
research, and can be used to define a specific cut-off for
insulin resistance with current WHO criteria and the
inclusion of a control group [27,34,35].
Insulin resistance related to obesity and phenotype
Traditionally, insulin resistance was attributed primarily
to obesity in PCOS. The concept of intrinsic insulin resis-
tance was previously controversial due to conflicting liter-
ature, small sample sizes, and inaccurate measurements
[36,37]. However, the presence of intrinsic insulin resis-
tance has been supported by mechanistic studies, includ-
ing evidence of insulin-signalling abnormalities or insulin
resistance through clamps with both unique PCOS- and
common body mass index (BMI)-related abnormalities
[27,3840]. A community-recruited study of PCOS and
controls, with both lean and overweight women, used
clamp studies and WHO criteria for insulin resistance
[27]. Insulin resistance was intrinsic to PCOS, indepen-
dent of adiposity, and was present in 85% of women with
PCOS, with 75% of lean women with PCOS and 95% of
overweight women with PCOS affected [27,41]. Further-
more, while BMI impacted adversely on insulin resistance
in both PCOS and controls, the adverse impact of obesity
was greater in PCOS. Overweight control women had
similar insulin resistance to lean women with PCOS,
suggesting that women with PCOS are effectively meta-
bolically equivalent to obese, non-PCOS women [27]. In
more recent literature, the issue of insulin resistance
across the phenotypes has been explored. Many studies
applying Rotterdam diagnostic criteria and inclusive of
milder phenotypes demonstrated the presence of intrinsic
insulin resistance. Furthermore, insulin resistance on
clamp studies remains higher than in controls in milder
reproductive phenotypes and, after correction for BMI,
appears similar to those with more severe phenotypes [27].
Adiposity in PCOS and impact on PCOS reproductive
phenotype
A recent systematic review and meta-analysis on prevalence
of overweight, obesity, or central obesity in women with
PCOS, compared with controls (106 studies), reported a
pooled prevalence of 61% (6100%) for overweight or obesi-
ty, 49% (12.5100%) for obesity and 54% (2085.5%) for
central obesity. On meta-analysis, women with PCOS had
an increased prevalence of overweight {relative risk (RR)
[95% confidence interval (CI): 1.95 (1.52, 2.50)], obesity
[2.77 (1.88, 4.10)] and central obesity [1.73 (1.31, 2.30)},
compared with controls [42]. However, few studies assessed
central obesity, and there were multiple sources of hetero-
geneity, including ethnicity, geographic location, recruit-
ment source, age, sample size, reporting of lifestyle (diet
or physical activity), or relevant medication use [42]. Most of
these studies recruited clinic referred populations and
Trends in Endocrinology and Metabolism March 2015, Vol. 26, No. 3
targeted women with higher BMI. This may have biased
results towards greater adiposity, and is consistent with
recent studies reporting higher adiposity in women with
PCOS recruited from clinics (endocrinology, reproductive, or
other) compared with women with PCOS recruited from the
general population [43].
In community-recruited studies, including a large Aus-
tralian community study (Australian Longitudinal Study
on Womens Health), women with PCOS also had higher
BMIs (24.490.07 versus 22.450.05 kg/m2, P<0.001),
than women not reporting PCOS [7]. However, this study
utilised self-reported PCOS diagnosis, which may have
been biased towards those with higher adiposity. Other
community-recruited and screened population studies in
Australia [1] and in Turkey [44] showed greater adiposity
in women with PCOS, compared with those without PCOS.
Conversely, in a generally lean Asian population, similar
adiposity was noted in women with PCOS compared with
non-PCOS women [43,45]. This suggests that, while PCOS
status is associated with elevated adiposity, it varies across
ethnicities. Further research in community-recruited and
screened populations is needed.
Obesity and PCOS phenotypes
Obesity may also vary across the phenotypes. In a recent
review of 106 studies of adiposity in PCOS, 43 studies
included the more severe phenotypes, and 63 applied the
broader Rotterdam criteria [42]. On comparison of these
42 and 63 studies, the prevalence of overweight and obesity
(more severe 20100% versus Rotterdam 5.993.7%), obe-
sity (14.3100% versus 12.594.6%), and central obesity
(49.385.5% versus 20.066.5%), were heterogeneous, yet
appeared broadly similar. On a priori analysis, there were
no significant differences in adiposity in PCOS across the
more severe or milder reproductive phenotypes. The
caveats outlined above on this meta-analysis still apply
here, and none of the studies in the meta-analysis specifi-
cally compared mild to more severe reproductive pheno-
types in community-screened and recruited cohorts
[42]. However, in more recent literature where phenotypes
were specifically described and populations were commu-
nity recruited, greater adiposity was found in more severe
reproductive PCOS phenotypes. A recent Australian study
focussed on phenotype and noted that lean women had
milder reproductive phenotypes compared with those who
were overweight [27], and adiposity was higher in those
with more severe phenotypes [8]. These findings are con-
sistent with a Turkish community-recruited population [6],
where the more severe phenotypes were seen in 5% of lean
and 15% of overweight women, whereas the broader Rot-
terdam PCOS inclusive of milder phenotypes was noted in
19% lean and 30% of overweight women.
Overall, these data suggest that obesity is increased in
PCOS and population studies and, thus, that it exacerbates
the PCOS reproductive phenotype. This is consistent with
the data on insulin resistance and obesity in PCOS, indicat-
ing that both the reproductive and metabolic PCOS pheno-
types are exacerbated by obesity. This may have clinical
implications, because PCOS diagnosis is often delayed and
many women remain undiagnosed [46,47]. It may be that
lean or less severe PCOS phenotypes are less likely to be
139
Review
diagnosed, influencing data on PCOS, obesity, and pheno-
types. More research is needed using community-screened
populations focussing on phenotypes. It is likely that adi-
posity has a bidirectional relation in PCOS, with adiposity
being secondary to PCOS, and adiposity driving PCOS
reproductive and metabolic phenotypes and severity in
PCOS. However, this remains to be clarified [7]. Emerging
literature also suggests a role for adipose tissue dysfunction
in PCOS; however, this is beyond the scope of this review.
Cardiometabolic risks in PCOS related to obesity or
phenotypes
Systematic reviews and meta-analysis document worsened
risk factors for cardiovascular disease, including elevated
C-reactive protein (CRP) [48,49], carotid intima-media
thickness [50], plasminogen activator inhibitor-1 [49], ad-
vanced glycation end products [49], lipoprotein a [49], and
homocysteine [49,51]; altered oxidative stress markers,
including malondialdehyde, asymmetric dimethylargi-
nine, glutathione, and paraoxonase-1 [51]; and lower adi-
ponectin [52], impaired flow-mediated dilation [53], and
dyslipidaemia [47]. Systematic reviews and meta-analysis
have also reported increased gestational diabetes [54],
impaired glucose tolerance, T2DM, metabolic syndrome
[55], and increased coronary heart disease and stroke
[56], in women with PCOS compared with controls.
Risks related to obesity
The association of adiposity and central adiposity with
worsened T2DM and cardiometabolic risk is well recog-
nised in general populations, and has been previously
hypothesised as the primary driver of increased cardiome-
tabolic risk in PCOS. However, the literature increasingly
reports that these risks occur in PCOS independently of
adiposity, including studies using BMI-matched popula-
tions, or on meta-regression assessing the contribution of
BMI [48,5358]. In a recent systematic review and meta-
analysis, cardiometabolic profiles were compared across
BMI categories in women with PCOS [59]. Overweight or
obese women with PCOS had an adverse lipid profile
[lower high-density lipoprotein (HDL) cholesterol, elevated
total cholesterol, low-density lipoprotein (LDL) cholesterol
and triglycerides], and worsened glucose tolerance, com-
pared with lean women with PCOS. Women with PCOS
who were overweight but not obese still had adverse
HDL cholesterol, triglycerides, and fasting glucose, but
no differences in total cholesterol or LDL cholesterol,
compared with lean women with PCOS. However, the lipid
profiles in the obese and overweight groups were not
significantly different, indicating that it is difficult to
determine a threshold of excess adiposity where metabolic
abnormalities related to obesity occur [59], and more re-
search in this area is needed.
In terms of IGT and T2DM, a recent systematic review
confirmed increased risk in PCOS compared with control
women [55]. T2DM risk was increased fourfold [odds ratio
(OR) (95% CI): 4/43 (4.06, 4.82)] and this finding was sus-
tained in the meta-analysis of studies correcting for BMI
(OR 4.00, 95% CI 1.97, 8.10) [55]. This was confirmed in a
recent large-scale community-based cohort study in
9145 women, aged 30.51.5 years, where T2DM was
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Trends in Endocrinology and Metabolism March 2015, Vol. 26, No. 3
increased ninefold (OR 8.8, 95% CI 3.9,20.1). Furthermore,
in PCOS cases, the risk of T2DM was independent of
BMI, whereas in controls, T2DM risk was dependent on
BMI [60]. Subsequent confirmatory prospective studies
have reported significantly higher age-standardised
T2DM over 10 years for women with PCOS, compared with
general population data (39.3% versus 5.8%). The likelihood
of developing T2DM was related to factors including base-
line BMI and fasting and OGTT glucose, and SHBG levels
at follow-up [61]. A second cohort study with 18-year follow-
up similarly reported higher odds of incident diabetes
(23.1% versus 13.1%) and dyslipidaemia (41.9% versus
27.7%), which was present even in normal-weight women
with PCOS [62]. This highlights the need to recognise that
women with PCOS have increased cardiometabolic risk
independent of obesity. There is a clear need to screen,
prevent, and manage these complications in PCOS.
Risks related to phenotype
There is emerging literature examining cardiometabolic
profiles across the different PCOS phenotypes. A system-
atic review reported that more severe reproductive
phenotypes have more severe dyslipidaemia associated
with insulin resistance, metabolic syndrome, and elevated
CRP, compared with the broader Rotterdam criteria.
However, differences were generally related to adiposity
[31]. Recent publications confirm that, for the more severe
reproductive phenotypes, cardiometabolic profiles are
worse than the milder phenotypes. However, this seems
largely related to elevated total or abdominal adiposity
[6367]. Likewise, similar cardiometabolic profiles are
present where the phenotypes have similar total or abdom-
inal adiposity, or where differences are corrected for adi-
posity [68,69]. Limited research on milder reproductive
phenotypes suggests adverse cardiometabolic features,
compared with controls [31]. These facts together suggest
that metabolic phenotype parallels reproductive pheno-
type, with differences across the metabolic phenotypes
again exacerbated by adiposity.
In the case of lipid abnormalities, similar findings are
noted. In a systematic review, women with more severe
reproductive phenotypes had greater differences in LDL
cholesterol (15 mg/dl, 95% CI 1316 versus 8 mg/dl, 95% CI
512) and non-HDL cholesterol (21 mg/dL, 95% CI 1625
versus 17 mg/dL, 95% CI 1322) compared with controls,
than women with both severe and milder reproductive
PCOS phenotypes compared with controls [58]. Subtle
differences in lipid profiles were observed in PCOS across
the severity of menstrual disturbance despite similar
BMIs, with the more severe menstrual disturbances asso-
ciated with more adverse lipid profiles [70]. In a systematic
review, women with more severe reproductive PCOS phe-
notypes had greater differences in LDL cholesterol and
nonLDL cholesterol compared with controls, than women
with milder PCOS phenotypes compared with controls.
However, nine out of 18 of the studies assessing more
severe phenotypes were BMI matched, compared with
ten out of 12 of the studies assessing milder PCOS phe-
notypes, suggesting that BMI impacted on these observa-
tions [58]. Overall, lipid abnormalities appear present
across the reproductive PCOS phenotypes.
Review
Table 1. International screening guidelines for cardiometabolic risk in PCOSa
Cardiometabolic feature Testing
IGT OGTT
T2DM OGTT
Obesity BMI, waist circumference
Dyslipidaemia Fasting lipid profile
Hypertension Blood pressure
a
Adapted from [17,72].
In terms of risk of IGT and T2DM across the PCOS
phenotypes, literature is limited. A systematic review
reported no differences in T2DM prevalence between the
milder reproductive phenotypes and the more severe phe-
notypes [31], and similar Finnish Diabetes Risk Scores for
women with severe PCOS and milder PCOS were reported,
despite elevated adiposity in the more severe cases
[71]. Both cardiometabolic risk factors and clinical diabetes
are prevalent in PCOS across the reproductive phenotypes.
Cardiometabolic screening
Insulin resistance is intrinsic to PCOS and occurs inde-
pendent of adiposity and reproductive PCOS phenotypes,
alongside cardiometabolic risk and T2DM. Current inter-
national cardiometabolic screening guidelines (Table 1)
vary, with some recommending screening for all women
with PCOS and others only for those with greater adiposity
[17,72]. However, it is clear that PCOS status confers
increased insulin resistance, cardiometabolic, and T2DM
risk. While adiposity may exacerbate both the reproductive
phenotype and the metabolic features, screening, preven-
tion, and management of cardiometabolic risk in all women
with PCOS appears warranted.
Concluding remarks and future perspectives
PCOS is a heterogeneous condition across diagnostic
reproductive and cardiometabolic features. Sources of
Box 2. Outstanding questions
 How can we best standardise the measurement of each of the
specific diagnostic criteria of PCOS?
 How do we achieve clarity on the impact of adiposity on
reproductive phenotypes in PCOS?
 How do we achieve clarity on the reproductive phenotypes, their
natural history, and how they relate to metabolic PCOS features
across the lifespan?
 How should excess adiposity clinically impact on screening and
metabolic risk management in PCOS?
 What is the efficacy and role of lifestyle and/or pharmacological
treatment in PCOS across the phenotypes and range of adiposity
in PCOS?
 How can we move forward with understanding the uncertain
aetiology of PCOS?
Trends in Endocrinology and Metabolism March 2015, Vol. 26, No. 3
Population Frequency Risk factors
All women 25 years Age, ethnicity, parental T2DM
All women 25 years history, high blood glucose history,
smoking, antihypertensive
medications, physical inactivity, and
waist circumference
All women Every visit N/A
All women Every 2 years Cardiometabolic risk factors: obesity,
or annually if smoking, dyslipidaemia, hypertension,
abnormal IGT, physical inactivity or high risk
for metabolic syndrome and/or T2DM
All women Annually if lean N/A
or each visit if
abnormal or
overweight and/or
obese
this heterogeneity, including the impact of adiposity and
reproductive phenotype, have been explored recently.
Literature now supports that insulin resistance and car-
diometabolic health are adversely affected in PCOS, inde-
pendent of excess adiposity. Concomitant adiposity further
exacerbates reproductive and cardiometabolic features.
Broadening of PCOS diagnostic criteria to include milder
reproductive phenotypes may also increase cardiometa-
bolic phenotypes, potentially impacting on screening and
management practices. Community-recruited population
studies suggest that metabolic features worsen across the
reproductive phenotypes, potentially linked to adiposity.
However, data remain heterogeneous in PCOS with con-
tributors including age, ethnicity, medication, concomitant
diseases, family history, reproductive life stage, smoking
status, or clinical features (Box 2). The quality of literature
also differs across recruitment sources, analytical techni-
ques used, selection of controls, and study size. These
factors all warrant consideration in the design and assess-
ment of future research. In the interim, we conclude that
all women with PCOS should be screened and treated for
metabolic and reproductive disease regardless of their
adiposity status or reproductive phenotype.
Acknowledgements
The authors acknowledge funding from NHMRC (program and project
grant) and the National Heart Foundation. H.J.T. is supported by an
NHMRC Practitioner Fellowship, and L.J.M. is supported by a
SACVRDP Fellowship; a program collaboratively funded by the NHF,
the South Australian Department of Health, and the South Australian
Health and Medical Research Institute.
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