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Metabolic features of the reproductive phenotypes of polycystic ovary

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Human Reproduction Update, Vol.15, No.4 pp. 477– 488, 2009
Advanced Access publication on March 11, 2009 doi:10.1093/humupd/dmp008

Metabolic features of the reproductive

phenotypes of polycystic ovary
syndrome
Lisa Moran 1,3,† and Helena Teede 1,2,†
1
The Jean Hailes Foundation for Women’s Health Research Unit, Monash Institute of Health Services Research, Monash University, Locked
Bag 29, Clayton, VIC 3168, Australia 2Diabetes Unit, Southern Health, Clayton, VIC 3168, Australia
3
Correspondence address. Tel: þ61-3-9594-7592; Fax: þ61-3-9594-7550; E-mail: lisa.moran@med.monash.edu.au

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table of contents
...........................................................................................................................
† Overview
† Methods
Diagnostic features of PCOS
† Assessment of specific phenotypes for metabolic features
† Non-NIH PCOS: hyperandrogenic ovulatory PCOS (phenotype C)
Non-NIH PCOS: non-hyperandrogenic anovulatory PCOS (phenotype D)
† Discussion

background: Polycystic ovary syndrome (PCOS) is a common condition in women of reproductive age with well established metabolic
abnormalities. There are numerous diagnostic criteria generating several reproductive diagnostic phenotypes [National Institute of Health
(NIH) hyperandrogenic anovulatory PCOS and non-NIH PCOS including hyperandrogenic ovulatory or non-hyperandrogenic anovulatory
PCOS]. There is ongoing debate regarding the optimal diagnostic criteria for PCOS and on the metabolic implications of newer non-NIH
PCOS phenotypes.
methods: We reviewed the literature on the presence of risk factors for type 2 diabetes (DM2) and cardiovascular disease (CVD) across
the reproductive diagnostic phenotypes of PCOS with the aims of comparing the metabolic features of the NIH and non-NIH groups and
identifying potential high metabolic risk phenotypes of PCOS.
results: NIH PCOS patients present with greater obesity, abdominal obesity, insulin resistance (IR) and risk factors for DM2 and CVD
compared with non-NIH ovulatory and non-hyperandrogenic PCOS patients. Where differences in metabolic features exist between the
phenotypes, they are generally related to the degree of total and abdominal obesity. There is emerging evidence suggesting ovulatory
and non-hyperandrogenic PCOS have greater metabolic abnormalities than controls primarily linked to abdominal adiposity. There is cur-
rently no evidence that non-hyperandrogenic PCOS is associated with a less adverse metabolic profile than ovulatory PCOS.
conclusions: Current metabolic evidence appears to justify the inclusion of both non-NIH PCOS groups (ovulatory and non-
hyperandrogenic) as PCOS subgroups. NIH PCOS is associated with a more adverse metabolic profile including greater total and abdominal
obesity, IR and risk factors for CVD and DM2 than non-NIH phenotypes.

Key words: polycystic ovary syndrome / diagnostic criteria / insulin resistance / hyperandrogenism

et al., 2000; Azziz et al., 2004). It is associated with a range of reproduc-

Overview tive, obstetric, metabolic and psychological features. Reproductive and
Polycystic ovary syndrome (PCOS) is a common endocrine condition obstetric manifestations include hyperandrogenism, menstrual dysfunc-
in women of reproductive age with prevalence estimated at 4 –8% tion, infertility and pregnancy complications. These include early preg-
(Knochenhauer et al., 1998; Diamanti-Kandarakis et al., 1999; Asuncion nancy loss, gestational diabetes, pregnancy-induced hypertensive
†L.M. and H.T. both contributed to article conception, design, drafting, manuscript writing, critical revision and final approval of version to be published.

& The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
For Permissions, please email: journals.permissions@oxfordjournals.org
478 Moran and Teede

disorders and neonatal complications (Boomsma et al., 2006). Meta-
bolic complications include an elevated risk of impaired glucose toler-
ance (IGT), type 2 diabetes (DM2) (Legro et al., 1999), the metabolic
syndrome (Apridonidze et al., 2005), elevated cardiovascular risk
factors (Meyer et al., 2005a, b) and potential increased risk for cardio-
vascular disease (CVD) (Shaw et al., 2008). Women with PCOS also
have psychological features with increased depression, poor self-image
and reduced quality of life (Himelein and Thatcher, 2006). PCOS thus
constitutes a significant health and economic burden estimated at
over $4 billion in the USA with 30.1% of costs related to hormonal
treatment of menstrual dysfunction, 12.2% infertility care, 14.2% treat-
ment of hirsutism and 40.5% of DM2 (Azziz et al., 2005). An economic
evaluation of PCOS recently advocated screening, diagnosis and inter-
vention, justifiable by ameliorating or preventing serious sequelae. This
is in keeping with the International Diabetes Federation recommen-
dations to focus on early intervention and avoidance or delay or pro-
gression to DM2 (Alberti et al., 2007). However, before this is
In this setting, the aim of this study was to review the literature on
the metabolic implications (adiposity, abdominal adiposity and risk
factors for DM2 and CVD) across the reproductive diagnostic pheno-
types of PCOS. Specifically, we aimed to compare the metabolic fea-
tures of the NIH and non-NIH groups and identify potential high
metabolic risk phenotypes of PCOS to target future screening and
prevention of metabolic diseases. We reviewed the metabolic features
of PCOS with a particular focus on the differences between the repro-
ductive diagnostic phenotypes: namely, NIH versus non-NIH PCOS;
non-NIH PCOS versus non-PCOS controls and the different
non-NIH subgroups compared with each other (hyperandrogenic ovu-
latory PCOS and non-hyperandrogenic anovulatory PCOS). We also
examined whether differences in metabolic features between the
reproductive phenotypes were due to different anthropometrics
(total or abdominal adiposity) or differences in features such as IR
and hyperandrogenism that vary across the diagnostic groups.
To address these aims, the key clinical questions with regard to the

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advocated greater understanding of appropriate screening, long-term metabolic features of the PCOS reproductive phenotypes were shown
risks and effective interventions to minimize metabolic morbidity is in Fig. 1.
urgently needed in women with PCOS (Azziz et al., 2005).
Both the reproductive and metabolic features of PCOS are under-
pinned by insulin resistance (IR). This is a key factor in the aetiology of
PCOS, with insulin stimulating ovarian androgen production and
decreasing hepatic sex hormone-binding globulin (SHBG production)
and increasing total and free androgens (Diamanti-Kandarakis and
Papavassiliou, 2006). The majority of PCOS women have underlying
IR, and there is ongoing debate as to whether this IR is intrinsic to
PCOS, related to obesity alone or related to both factors. There is
additionally potentially an increased prevalence of obesity and abdomi-
nal obesity in PCOS (Escobar-Morreale and San Millan, 2007), which
worsens the IR-associated clinical features (Kiddy et al., 1990; Balen
et al., 1995). It is hypothesized that lean women with PCOS therefore
have PCOS-specific IR or intrinsic IR, which is augmented by the pre-
sence of obesity-specific IR (Teede et al., 2007).
There remains considerable controversy on the optimal diagnostic
criteria for PCOS (Azziz, 2006; Franks, 2006). Although the National
Institute of Health (NIH) criteria (hyperandrogenism and anovulation)
were proposed in 1992 (Zawdaki and Dunaif, 1992), these have now
been expanded to include the non-NIH diagnostic criteria. In 2003,
European Society for Human Reproduction and Embryology/
American Society for Reproductive Medicine (ESHRE/ASRM) diag-
nostic criteria were formulated as two of the three criteria of hyper-
androgenism, polycystic ovaries on ultrasound (PCO) and irregular
anovulatory periods. This introduced two new PCOS phenotypes of
hyperandrogenic ovulatory women with PCO or non-hyperandrogenic
anovulatory women with PCO (2004). An amendment to these cri-
teria was proposed in 2006 by the Androgen Excess Society (AES)
to exclude the phenotype of PCO and irregular cycles without hyper-
androgenism (Azziz et al., 2006, 2009). The majority of literature to
date has focused on the NIH diagnosis of PCOS, and research on
the metabolic implications of non-NIH phenotypes is only just emer-
ging. To date, there is limited understanding of the relative prevalence
of risk factors for metabolic diseases (DM2 and CVD) across the
reproductive diagnostic phenotypes of PCOS. Clarification of this
Figure 1 Summary of relevant clinical questions with regard to the
will aid in determining whether to include non-NIH phenotypes as metabolic implications of the reproductive diagnostic phenotypes of
part of the complex condition of PCOS and in identifying if specific PCOS.
reproductive PCOS phenotypes have elevated metabolic risks.
Metabolic features of PCOS phenotypes
Methods
A review was conducted of the medical literature to identify studies eval-
uating the implications of reproductive diagnostic criteria or reproductive
phenotypes on the metabolic features of PCOS. Supplementary references
were obtained from initial citations. We searched the database MEDLINE.
Search terms as keywords in article text or as subject headings included
polycystic ovarian syndrome, polycystic ovary syndrome, polycystic
ovaries, PCOS or PCO, and diagnostic criteria, diagnosis, presentation
or phenotype with searches limited to females and humans. This search
resulted in 4512 papers. On screening for title or abstract, we selected
23 for our review that compared metabolic features of PCOS [impaired
fasting glucose (IFG), IGT, DM2, metabolic syndrome, IR, glucose toler-
ance, lipid levels, blood pressure and adipokines and family history of cor-
onary artery disease, CVD, DM2 or hypertension] between different
diagnostic phenotypes (NIH and non-NIH) of PCOS. In addition, we hand-
searched references of relevant reviews and systematic reviews and
included studies to locate other potentially eligible studies. The results
were presented as a comparison of (i) NIH PCOS with the non-NIH
PCOS diagnostic phenotypes (hyperandrogenic ovulatory PCOS or non-
hyperandrogenic anovulatory PCOS), (ii) non-NIH hyperandrogenic ovula-
tory PCOS or non-hyperandrogenic anovulatory PCOS with non-PCOS
controls and (iii) non-NIH hyperandrogenic ovulatory PCOS with non-
hyperandrogenic anovulatory PCOS (Fig. 1).
Diagnostic features of PCOS
PCOS is a heterogeneous condition, and diagnostic criteria are based on
reproductive features: anovulation or menstrual disturbance, polycystic
ovaries on ultrasound (PCO) and hyperandrogenism. Menstrual disturb-
ances comprise anovulation, amenorrhoea (lack of menstruation for .3
months) and oligomenorrhoea (irregular menstruation). A recent review
reported that 78.4% of PCOS patients present with oligomenorrhoea
and 18.1% present with eumenorrhoea, amenorrhoea and anovulation
(Goldzieher, 1981; Franks, 1989; Balen et al., 1995). PCO are defined
as the presence of 12 or more follicles measuring 2 – 9 mm in each
ovary and/or increased ovarian volume (.10 ml or cm3) (Balen et al.,
2003) and are present in up to 22% of women in the general population
(Farquhar et al., 1994) and 75% of women with PCOS (Azziz et al., 2006).
Assessment of clinical hyperandrogenism involves subjective clinical
scoring of degrees of hirsutism (excessive growth of terminal hair in
women in a male-like pattern) such as the Ferriman – Gallwey score or
later modifications (Ferriman and Gallwey, 1961; Hatch et al., 1981).
Other hyperandrogenic features include acne (Oberemok and Shalita,
2002; Witkowski and Parish, 2004), seborrhoea and androgenic alopecia.
The recommended assessment of biochemical hyperandrogenism is pri-
marily through measurement of the ovarian androgens testosterone as
total testosterone (free and bound to SHBG), free testosterone
Table I The different diagnostic criteria for PCOS
NIH criteria Consensus European Society for Human Reproduction and
Statement (Zawdaki and Dunaif, Embryology/American Society for Reproductive
1992) Medicine Consensus Statement (2004a, b)
.............................................................................................................................................................................................
Oligo-ovulation and clinical and/or Two out of three oligo- and/or anovulation or clinical
biochemical signs of hyperandrogenism and/or biochemical signs of hyperandrogenism or
and exclusion of other aetiologies* polycystic ovaries and exclusion of other aetiologies*
*Congenital adrenal hyperplasia, androgen-secreting tumours, Cushing’s syndrome, 21-hydroxylase-deficient non-classic adrenal hyperplasia, androgenic/anabolic drug use or abuse,
syndromes of severe IR, thyroid dysfunction, hyperprolactinaemia.
479
(measured by equilibrium dialysis) or calculated as a function of total tes-
tosterone and SHBG levels (free androgen index) or estimated from equi-
librium binding equations (Vermeulen et al., 1999). Although there is
considerable variation between hormone assays and a lack of accurate
ranges for well-defined non-PCOS populations (Hart et al., 2004), elev-
ated circulating androgens are nevertheless present in 60 – 80% of
women with PCOS (Azziz et al., 2006).
As a syndrome, PCOS is by definition a constellation of features with no
specific diagnostic test. There is considerable variability in the diagnosis of
biochemical or clinical hyperandrogenism, menstrual features (anovulation,
amenorrhoea or oligomenorrhoea) and PCO leading to great diversity in
the clinical presentation of PCOS (Geisthovel and Rabe, 2007). The limit-
ations and challenges with regard to the need for accurate and consistent
definition of each diagnostic parameter (Geisthovel and Rabe, 2007) have
been extensively discussed elsewhere. Indeed, the diagnostic criteria for
PCOS remain controversial with several proposed criteria still in use, as
detailed in Table I and below.
Diagnostic criteria for PCOS
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NIH diagnostic criteria
NIH diagnostic criteria have been used for the past 15 years based on bio-
chemical or clinical hyperandrogenism and anovulation (excluding other
secondary causes including thyroid dysfunction, non-congenital adrenal
hyperplasia or hyperprolactinaemia) (Zawdaki and Dunaif, 1992). Accord-
ing to these criteria, 4 – 8% of women in a general population have PCOS
(Knochenhauer et al., 1998; Diamanti-Kandarakis et al., 1999; Asuncion
et al., 2000; Azziz et al., 2004). The majority of research has used NIH cri-
teria for diagnosis of PCOS.
Non-NIH diagnostic criteria: ESHRE/ASRM and AES diagnostic criteria
In 2003, the ESHRE/ASRM (2004a, b) criteria were developed. These cri-
teria diagnosed PCOS based on two of the three criteria of hyperandro-
genism, irregular anovulatory periods and PCO, thus introducing two
additional phenotypic subsets (PCO and anovulation/menstrual dysfunc-
tion or hyperandrogenism) (2004). There is currently no data on the
prevalence of PCOS as defined by the ESHRE/ASRM criteria in the
general population, although these would be expected to include more
women than NIH criteria. There is some prevalence data in infertile or
anovulatory oligomenorrheic populations; Broekmans et al. (2006) esti-
mated ESHRE/ASRM diagnosed PCOS to account for 91% of World
Health Organisation II anovulatory infertility compared with 55% for NIH-
diagnosed PCOS. Belosi et al. (2006) found that the ESHRE/ASRM criteria
expanded the population of women diagnosed with PCOS by over 20%.
AES diagnostic criteria
In 2006, the AES published a position statement which suggested that andro-
gen excess is the key component of PCOS related to clinical presentation and
AES Position Statement (Azziz et al., 2006)
Hyperandrogenism (hirsutism and/or
hyperandrogeniaemia) and ovarian dysfunction
(oligo-anovulation and/or polycystic ovaries) and
exclusion of other androgen excess related disorders*
480
Table II Comparison of the different reproductive
diagnostic criteria for PCOS resulting in potentially
different phenotypes
Features Phenotypes
..............................................
A B C D E F
........................................................................................
Hyperandrogenism þ þ þ 2 þ 2
(biochemical or clinical)
Oligo- or anovulation þ þ 2 þ 2 2
Polycystic ovaries þ 2 þ þ 2 þ
p p
NIH criteria
p p p p
ESHRE/ASRM criteria
p p p the newer diagnostic phenotypes with milder reproductive features of
AES criteria
long-term morbidity. The AES suggested that the diagnostic criteria be modi-
fied to include only those with hyperandrogenism (biochemical or clinical)
and PCO and/or ovarian dysfunction (oligo-anovulation and/or polycystic
ovaries) (with the exclusion of other related disorders) (Azziz et al.,
2006). This definition excluded the phenotypic subset of PCO and ovarian
dysfunction but no hyperandrogenism (Table II).
Concerns with the current diagnostic criteria include the fact that the
ultrasound criteria are non-specific enough to be observed in other
common conditions, including functional hypothalamic anovulation sec-
ondary to situations such as stress, weight loss or exercise. As noted by
Dewailly et al. (2006), this may lead to artificial PCOS phenotypes being
created with medical and psychological implications. However, this classi-
fication (World Health Organisation Class I anovulation or hypogonado-
trophic hypogonadal ovulation) is not normogonadotrophic and
therefore not World Health Organisation Class II and should not be con-
sidered as PCOS. Where there is potentially uncertainty, it is important to
exclude World Health Organisation I or hypothalamic anovulation. This
can be excluded either with vaginal ultrasound for endometrial thickness
or progestin-induced withdrawal bleed to test for estrogen status.
Women with relatively mild endocrinological disturbances may also,
potentially, be inappropriately diagnosed with PCOS. For example, a
case of acne and PCO in the context of normal biochemical hyperandro-
genism and ovulation may still be theoretically defined as PCOS. However,
this is controversial and many would consider this group to not have
PCOS (Norman et al., 2007).
Hyperandrogenism itself, in the absence of ovulatory disturbances, may
also contribute to an adverse metabolic profile and IR. Emerging evidence
suggests that hyperandrogenism increases abdominal obesity, which in turn
increases IR (Escobar-Morreale and San Millan, 2007). Pre-adipocytes are
known to have androgen receptors, and adipose cell function is regulated
by androgens at a mechanistic level. Increased androgens have also been
shown to induce selective IR in cultured adipocytes (Corbould, 2007).
This is further supported by the effects of anti-androgens like spironolac-
tone, which appear to reduce IR in some (Ganie et al., 2004) but not all
studies (Sahin et al., 2004; Vrbikova et al., 2004; Gambineri et al.,
2006). Furthermore, the metabolic syndrome in women without PCOS
has been linked to increasing androgen status at menopause in the
setting of increased abdominal obesity (Janssen et al., 2008).
Implications of different diagnostic criteria
The development of the new ESHRE/ASRM and AES criteria has intro-
duced greater heterogeneity into PCOS from a reproductive and possibly
from a metabolic perspective.
Moran and Teede
For simplification, PCOS can be subdivided into four reproductive pheno-
types: NIH- diagnosed PCOS either with (phenotype A) or without PCO
(phenotype B); biochemical/clinical hyperandrogenism with PCO but no
oligo/anovulation (phenotype C), or no biochemical/clinical hyperandro-
genism with PCO and oligo/anovulation (phenotype D) (Fig. 1, Table II).
Although it has been suggested that these newer non-NIH phenotypes (C
G and D) generally demonstrate a milder reproductive presentation than NIH-
diagnosed PCOS (A and B) (Belosi et al., 2006), there is conflicting data on
2 the metabolic implications of the different phenotypes.
Reproductive severity reflected by the number of clinical features of
þ PCOS (menstrual irregularity, acne, hirsutism, elevated testosterone and
2 elevated luteinising hormone) is associated with metabolic severity with
increased body fat, waist-to-hip ratio (WHR) and IR (fasting insulin and
HOMA-IR) (Michelmore et al., 2001). Hence, with the introduction of
PCOS, there is the potential for the inclusion of women with milder meta-
bolic presentations and lower long-term reproductive and metabolic risks.
Furthermore, PCOS is associated with impaired psychosocial health
(Himelein and Thatcher, 2006), and the relative contribution of the differ-
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ent features of PCOS to this (metabolic, hirsutism, impaired reproductive
function, obesity) across the phenotypes is not clear. Thus, potentially the
overall severity of reproductive features may track with metabolic and
psychological features, rendering the phenotypes A and B more severe
than C and D.
The relative prevalence of the PCOS subgroups are also difficult to
determine from the current literature (Supplementary Appendix I) with
bias introduced by the variable recruitment strategies from endocrinology
or fertility clinics rather than the general population. Depending on the
population recruited from, up to 18% of women with PCOS by ESHRE/
ASRM criteria can have non-hyperandrogenic PCOS (D) and up to 25%
of women can have ovulatory PCOS (C). This indicates an increasing
number of women with PCOS who may experience different reproductive
and metabolic risks, when compared with those who have NIH PCOS
with potential implications for research, screening and clinical practice.
Assessment of specific
phenotypes for metabolic
features
Within these four main phenotypes of PCOS (Fig. 1), it is clinically rel-
evant to understand how the metabolic features track with the repro-
ductive phenotypes in order to provide insights into how to target
metabolic screening and prevention strategies. There are currently
few studies that specifically compare the different reproductive diag-
nostic phenotypes or presentations of PCOS and their metabolic
implications.
NIH PCOS: phenotypes A and B
IR is a key pathophysiological feature of PCOS and a significant contri-
butor to both reproductive and metabolic complications. The link
between IR, IGT, DM2 and CVD in the general population is well
established (Haffner et al., 1990; Lundgren et al., 1990; Lillioja et al.,
1993; Folsom et al., 1997; Ruige et al., 1998; Lehto et al., 2000;
Rutter et al., 2005), suggesting women with PCOS and IR have an
elevated risk of these metabolic conditions. Consistent with the
increased IR, women with PCOS display an increased prevalence of
IGT and DM2. A recent study reported a 5-fold risk of developing
DM2 over a period of 8 years in women with PCOS, compared
Metabolic features of PCOS phenotypes
with the risk calculated using age- and weight-matched controls
(Boudreaux et al., 2006). There is also emerging evidence that women
with PCOS have a greater chance of developing gestational diabetes, with
a recent meta-analysis reporting an OR of 2.94 (Boomsma et al., 2006).
There is currently no good data to establish whether clinical cardio-
vascular events are increased in PCOS and there are limited long-term
studies appropriately addressing this question (Pierpoint et al., 1998;
Wild et al., 2000; Shaw et al., 2008). However, women with PCOS
have an increased prevalence of traditional (hyperlipidaemia) and
novel (increased homocysteine, inflammation, oxidative stress and leu-
kocyte counts and impaired fibrinolysis and metabolic syndrome) risk
factors for CVD mostly compared with weight-matched controls.
They also display increased clinical and subclinical markers of premature
atherosclerosis [endothelial dysfunction, impaired pulse wave velocity
(PWV)]; increased carotid intima-media wall thickness (IMT); presence
of carotid plaque and increased coronary artery calcification, as demon-
strated by our group and others (Apridonidze et al., 2005; Meyer et al.,
2005a, b; Bhattacharya, 2008; Cussons et al., 2008). PCOS is thus
defined as a population with a high risk of developing IGT and DM2
and a potentially high risk for CVD. These elevated risks occur indepen-
dent of obesity and are worsened by the presence of obesity (Legro
et al., 1999, 2001; Boudreaux et al., 2006; Ehrmann et al., 2006).
However, the majority of the aforementioned literature on the meta-
bolic implications of PCOS was conducted prior to the introduction of
the newer non-NIH diagnostic phenotypes. As such, it is not yet
known whether these recognized metabolic implications of PCOS are
applicable to all the reproductive diagnostic phenotypes of PCOS.
NIH PCOS with or without PCO: phenotypes
A and B
The majority of women with NIH PCOS also have PCO (phenotype A).
Of those that do not, the few studies specifically comparing NIH PCOS
with or without PCO (phenotype A versus B) have generally shown
similar glucose tolerance, IR [fasting or oral glucose tolerance test
(OGTT) insulin or insulin sensitivity index] or lipid profiles (Loucks
et al., 2000; Legro et al., 2005; Dewailly et al., 2006; Hahn et al., 2006;
Welt et al., 2006b; Diamanti-Kandarakis and Panidis, 2007; Hsu et al.,
2007; Shroff et al., 2007). Conversely, in one study increased IR
[assessed by insulin tolerance test (ITT)] was reported for PCOS with
PCO (phenotype A) compared with PCOS without PCO (phenotype
B) (Najmabadi et al., 1997). In addition, higher low-density lipoprotein
cholesterol (LDL-C), total cholesterol, family history of DM2 (Shi
et al., 2008) and triglycerides (Chae et al., 2008) were reported for
women with NIH PCOS without PCO, when compared with NIH
PCOS with PCO despite similar weight, BMI, waist or hip circumference.
Overall, the evidence suggests a similar risk of metabolic disease for the
two phenotypes of NIH PCOS.
Non-NIH PCOS: phenotypes C and D
The metabolic literature examining the newer phenotypes of PCOS intro-
duced by the ESHRE/ASRM is contradictory. There is emerging evidence
that these phenotypes have a less adverse metabolic profile than NIH
PCOS. A number of studies have demonstrated elevated BMI, WHR,
waist circumference (Belosi et al., 2006; Hsu et al., 2007; Pehlivanov
and Orbetzova, 2007), fasting insulin, homeostasis assessment of IR
(HOMA-IR), metabolic syndrome prevalence (Pehlivanov and
481
Orbetzova, 2007) and IR on euglycaemic hyperinsulinaemic clamp
(Belosi et al., 2006) for NIH PCOS when compared with ovulatory
PCOS or non-hyperandrogenic PCOS. Where NIH and non-NIH
PCOS women were of similar BMI (Cenk Sayin et al., 2003; Diamanti-
Kandarakis and Panidis, 2007) and WHR (Diamanti-Kandarakis and
Panidis, 2007), similar metabolic features such as surrogate markers of
IR were generally reported (Cenk Sayin et al., 2003; Diamanti-Kandarakis
and Panidis, 2007), although one study reported a less adverse lipid profile
for non-NIH PCOS (Cenk Sayin et al., 2003). Differences in total and
abdominal adiposity between NIH PCOS and non-NIH PCOS may there-
fore account for differences in IR and metabolic risk. However, these
studies did not assess metabolic and anthropometric comparisons
within the non-NIH diagnostic phenotypes to determine the relative
degree of metabolic impairment for phenotypes C and D (Fig. 1).
Non-NIH PCOS:
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hyperandrogenic ovulatory
PCOS (phenotype C)
Non-NIH PCOS (hyperandrogenic ovulatory
PCOS) compared with NIH PCOS
A number of studies have compared NIH PCOS with non-NIH hyper-
androgenic ovulatory PCOS (Fig. 1). The majority of studies report less
adverse metabolic profiles for ovulatory PCOS. Elevated BMI (Carmina
et al., 2005, 2006a, b; Welt et al., 2006b; Barber et al., 2007) and waist
or hip circumference (Welt et al., 2006b; Barber et al., 2007) were
observed for NIH PCOS compared with hyperandrogenic ovulatory
PCOS in association with significantly increased IR [fasting insulin,
HOMA-IR or quantitative insulin sensitivity check index (QUICKI)]
(Carmina et al., 2005; Welt et al., 2006b; Barber et al., 2007) and meta-
bolic syndrome prevalence (Welt et al., 2006b; Barber et al., 2007) and
worsened cardiovascular risk factors (elevated triglycerides, hsCRP and
homocysteine and lower HDL-C) (Carmina et al., 2005).
Not all metabolic parameters differed between phenotypes and no
differences in DM2, IFG, glycosylated haemoglobin A1c (HBA1c) and
fasting glucose were observed between ovulatory and NIH PCOS
(Welt et al., 2006b). Furthermore, on adjustment for age and BMI,
no differences in lipids, systolic blood pressure (SBP) and diastolic
blood pressure (DBP) (Welt et al., 2006b) or HDL-C and triglycerides
(Barber et al., 2007) were observed between subjects. This indicates a
contribution of elevated adiposity to the worsened metabolic risk
factors present in classic NIH PCOS. Age differences also existed
across the PCOS subsets. This could account for differences in meta-
bolic parameters between groups, although specific statistical details
were not provided (Barber et al., 2007).
However, in these studies due to the lack of weight matching, it is
not possible to determine whether the worsened cardiometabolic
profile in NIH compared with non-NIH ovulatory PCOS is due to
differences in adiposity or other factors. It is possible that weight
may be the modulating factor that primarily worsens IR and reproduc-
tive and metabolic function in PCOS (Carmina et al., 2005). In support
of this, a small number of studies comparing weight-matched NIH
PCOS and non-NIH hyperandrogenic ovulatory PCOS reported simi-
larities in the groups including: similar fasting glucose (Diamanti-
Kandarakis and Panidis, 2007), IR [fasting insulin (Carmina and
482
Lobo, 1999; Diamanti-Kandarakis and Panidis, 2007; Shroff et al.,
2007; Kauffman et al., 2008), OGTT insulin and minimal model
insulin (Kauffman et al., 2008)], QUICKI, glucose-to-insulin ratio (G/
I) and HOMA-IR) (Shroff et al., 2007), lipid profile (Shroff et al.,
2007; Kauffman et al., 2008) IFG, DM2, metabolic syndrome, family
history of coronary artery disease and DM2 (Shroff et al., 2007).
In contrast to this, NIH PCOS (phenotypes A/B) had significantly
higher IR [ITT (Robinson et al., 1993), fasting insulin (Sharp et al.,
1991; Carmina et al., 2003) and QUICKI (Carmina et al., 2003)]
than ovulatory PCOS (phenotype C) despite similar age and weight
(Sharp et al., 1991; Robinson et al., 1993; Carmina et al., 2003).
Abdominal obesity was not measured in these studies which could
account for the worsened metabolic risk reported in NIH PCOS.
This is supported by the finding that waist circumference is one of
the most sensitive markers of the metabolic syndrome in women
with NIH PCOS (Ehrmann et al., 2006). In support of this, similar
waist circumferences for NIH compared with age- and BMI-matched
ovulatory PCOS were observed in association with similar fasting
insulin (Dewailly et al., 2006). Furthermore, when comparing BMI-
matched anovulatory and ovulatory PCOS, ovulatory PCOS had
lower abdominal fat [by dual X-ray absorptiometry (DEXA)] with
lower IR (QUICKI, fasting insulin), hsCRP and higher adiponectin
(Carmina et al., 2008). Thus, even when total adiposity is constant,
differences in metabolic features between PCOS phenotypes may
be due to differences in abdominal or visceral fat.
Conversely, Norman et al. (1995a) reported higher post-OGTT and
fasting insulin and OGTT glucose for NIH compared with ovulatory
PCOS despite weight and WHR matching, although no differences in
total cholesterol, triglycerides and HDL-C between the subsets were
observed and the relative age of the different subsets was not stated.
Hence, some research suggests reduced IR in ovulatory PCOS is largely
a function of reduced adiposity. Others report higher IR in the NIH phe-
notypes to be either an inherent feature or related to increased abdominal
fat. The lack of measurement or use of a more imprecise measure of adi-
posity distribution [waist circumference or WHR (Norman et al., 1995a;
Dewailly et al., 2006) versus DEXA (Carmina et al., 2008)] in the majority
of studies limits conclusions in this area.
Summary of findings for Question 1
Do hyperandrogenic ovulatory women with PCOS (phenotype C) present
with similar metabolic risk to NIH PCO (phenotype A/B)?
Non-NIH (hyperandrogenic ovulatory) PCOS (phenotype C) generally
have lower body weight and BMI and better metabolic profiles compared
with NIH PCOS (phenotypes A/B). Non-NIH (hyperandrogenic
ovulatory) PCOS and weight-matched NIH PCOS appear to present with
similar metabolic risk profiles, particularly where abdominal fat is similar
between subjects.
Non-NIH PCOS (hyperandrogenic ovulatory
PCOS) phenotype C compared with
non-PCOS controls
Further assessment of the metabolic risk associated with ovulatory
PCOS can be demonstrated by a comparison of risk factors for DM2
and CVD with controls (Fig. 1). Where BMI is higher in ovulatory
PCOS, there is an increased prevalence of metabolic syndrome but no
Moran and Teede
differences in IFG, DM2, fasting glucose, lipid profile or family history
of coronary artery disease or DM2 (Shroff et al., 2007). Similarly,
where abdominal adiposity (waist circumference or WHR) was elevated
for ovulatory PCOS compared with age- and weight-matched controls,
greater IR (fasting insulin, G/I or QUICKI) (Carmina and Lobo, 2001;
Carmina et al., 2003, 2005; Dewailly et al., 2006) and lipid profile
(increased hsCRP, total cholesterol and LDL-C or decreased HDL-C)
were observed (Carmina and Lobo, 2001; Carmina et al., 2005).
Where controls and hyperandrogenic ovulatory women with PCOS
were closely age- and weight-matched, no differences in lipids, fasting
or post-OGTT insulin and glucose or minimal model glucose testing
were observed (Kauffman et al., 2008). In another study, higher OGTT
glucose and fasting insulin (Robinson et al., 1993) but equivalent fasting
insulin and glucose (Robinson et al., 1993; Diamanti-Kandarakis and
Panidis, 2007) and surrogate markers of IR (OGTT insulin and ITT)
(Robinson et al., 1993) were observed for ovulatory PCOS compared
with weight-matched controls. The controls were older, potentially con-
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founding the results (Robinson et al., 1993; Diamanti-Kandarakis and
Panidis, 2007). Furthermore, as abdominal obesity was not measured, it
is not possible to rule out different visceral obesity between PCOS and
controls. Where abdominal adiposity (WHR or waist circumference)
was similar between BMI-matched hyperandrogenic ovulatory PCOS
and controls, similar IR (fasting insulin or HOMA-IR) (Norman et al.,
1995a; Welt et al., 2006b; Carmina et al., 2008), OGTT insulin
(Norman et al., 1995a), QUICKI (Carmina et al., 2008), OGTT glucose
(Norman et al., 1995a), adiponectin (Carmina et al., 2008), SBP, DBP,
lipid profile and prevalence of the metabolic syndrome, IFG and DM2
(Welt et al., 2006a) are also seen, although in one study controls demon-
strated a lower BMI and higher HDL-C and apolipoprotein A1 (Norman
et al., 1995a). The literature generally supports similar metabolic profiles
for hyperandrogenic ovulatory PCOS and controls where adiposity or
abdominal adiposity are matched.
Summary of findings for Question 2
Do hyperandrogenic ovulatory women with PCOS (phenotype C) present
with elevated metabolic risk compared with controls?
There is some evidence that ovulatory PCOS are more adversely
metabolically affected than controls, but this is not universally observed and
appears to be strongly related to the presence of adiposity and specifically
abdominal adiposity.
Non-NIH PCOS: non-hyperandrogenic
anovulatory PCOS (phenotype D)
The most controversial newer non-NIH PCOS subgroup has been
non-hyperandrogenic anovulatory PCOS (phenotype D), which was
included in the ESHRE/ASRM diagnostic criteria and excluded from
the AES diagnostic criteria in the AES position statement (Azziz
et al., 2006).
Non-NIH PCOS (non-hyperandrogenic
anovulatory PCOS) phenotype D compared
with NIH PCOS
There are limited studies examining non-hyperandrogenic women with
PCOS (Fig. 1). The majority of these show reduced weight, BMI or
Metabolic features of PCOS phenotypes
prevalence of obesity (Broekmans et al., 2006; Welt et al., 2006b; Barber
et al., 2007; Shroff et al., 2007) and reduced WHR and waist circumfer-
ence (Welt et al., 2006b; Barber et al., 2007) for non-hyperandrogenic
compared with NIH PCOS (Broekmans et al., 2006; Welt et al.,
2006b; Barber et al., 2007; Shroff et al., 2007). Of these studies, two
reported lower blood glucose (Broekmans et al., 2006) and less IR (G/
I , 0.25 mmol/mU) (Barber et al., 2007) for non-hyperandrogenic com-
pared to NIH PCOS. This again suggests that where metabolic differences
occur between phenotypic subsets, they may be accounted for by adi-
posity. When obese subsets were compared, the prevalence of IR
remained lower in phenotype D PCOS (Broekmans et al., 2006) and
differences in IR between the PCOS subsets remained on adjustment
for age and BMI (Barber et al., 2007) suggesting less metabolic impairment
for non-hyperandrogenic PCOS independent of adiposity. Conversely, an
increase in the prevalence of the metabolic syndrome but no differences
in IR (Welt et al., 2006b; Shroff et al., 2007), IFG, DM2, fasting glucose,
total cholesterol, LDL-C, family history of coronary artery disease or
DM2 (Shroff et al., 2007) was reported for non-hyperandrogenic PCOS
compared with NIH PCOS. However, only fasting measures of IR were
assessed (fasting insulin, HOMA-IR, QUICKI or G/I), which are less
optimal in PCOS than post-OGTT measures (Ciampelli et al., 2005).
The literature, although limited, suggests that non-hyperandrogenic ano-
vulatory women with PCOS have a more favourable metabolic profile
compared with NIH PCOS, an observation again potentially related to
greater adiposity and abdominal adiposity in NIH PCOS.
Reduced adiposity and abdominal adiposity contributes to a more
favourable metabolic profile in non-hyperandrogenic anovulatory
PCOS. This is confirmed by reports that BMI- or WHR-matched non-
hyperandrogenic anovulatory PCOS and NIH PCOS (Norman et al.,
1995a; Diamanti-Kandarakis and Panidis, 2007; Kauffman et al., 2008)
generally have similar lipid profiles (Kauffman et al., 2008), fasting and
OGTT glucose (Norman et al., 1995a; Kauffman et al., 2008) and IR
(fasting insulin, OGTT insulin or QUICKI) (Norman et al., 1995a;
Diamanti-Kandarakis and Panidis, 2007; Kauffman et al., 2008),
although in one study elevated triglycerides were reported for the non-
hyperandrogenic PCOS and it was not always possible to determine if
the groups were age-matched (Norman et al., 1995a). However, con-
clusions from this literature are limited as sample size for the non-
hyperandrogenic PCOS phenotype was often very small (Norman
et al., 1995a). Kauffman et al. (2008) also excluded women with DM2
and very obese women, potentially removing a subgroup with greater
metabolic abnormalities that may have differed between the PCOS
phenotypic subsets. Furthermore, when non-hyperandrogenic PCOS
present with lower waist circumference or WHR, despite being weight-
matched with NIH PCOS, they also display reduced fasting (Dewailly
et al., 2006; Chae et al., 2008) or OGTT insulin (Chae et al., 2008).
Overall, this supports the strong role of abdominal adiposity in the
pathogenesis of IR in PCOS.
Summary of findings for Question 3
Do non-hyperandrogenic anovulatory women with PCOS (phenotype D)
present with similar metabolic risk to NIH PCOS (phenotype A/B)?
Non-hyperandrogenic PCOS (phenotype D) generally present with lower
BMI and less adverse metabolic profiles compared with NIH PCOS
(phenotype A/B). Non-hyperandrogenic PCOS and NIH PCOS matched for
total and abdominal obesity generally present with similar metabolic profiles.
483
Non-NIH PCOS (non-hyperandrogenic
anovulatory PCOS) compared with
non-PCOS controls
Some evidence exists to suggest that non-hyperandrogenic anovulatory
PCOS have an adverse metabolic profile compared with controls
(Fig. 1). Where non-hyperandrogenic anovulatory PCOS displayed elev-
ated BMI compared with controls, increased triglycerides, fasting and
OGTT insulin, OGTT glucose, lower HDL-C and apolipoprotein A1
are reported (Norman et al., 1995a). Other research has also shown
elevated WHR for non-hyperandrogenic women with PCOS compared
with BMI-matched controls (Dewailly et al., 2006), suggesting increased
abdominal fat independent of total adiposity, although this was not
associated with elevated fasting insulin and no other measures of IR
or metabolic parameters were made. Moreover, when non-
hyperandrogenic PCOS displayed similar age, weight, BMI, waist circum-
ference, metabolic syndrome, IFG and DM2, fasting glucose, SPB, DBP
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and lipids to controls, they still demonstrated elevated insulin and
HOMA-IR (Welt et al., 2006b), suggesting some metabolic impairment
independent of total or abdominal fat.
Conversely, a comparison of non-hyperandrogenic women with
PCOS and controls with similar BMI (Shroff et al., 2007; Kauffman
et al., 2008) and waist circumference (Barber et al., 2007) showed
no differences in IR (fasting insulin, QUICKI, G/I or HOMA-IR)
(Barber et al., 2007; Kauffman et al., 2008), lipid profile (Barber
et al., 2007; Shroff et al., 2007; Kauffman et al., 2008), prevalence
of IFG, DM2 (Shroff et al., 2007) or the metabolic syndrome
(Barber et al., 2007; Shroff et al., 2007) and family history of coronary
artery disease and DM2 (Shroff et al., 2007). However, in two of these
studies, controls were older, which could worsen their metabolic
profile independent of their non-PCOS status (Barber et al., 2007;
Shroff et al., 2007) and abdominal fat distribution was not measured
in one study (Shroff et al., 2007). Chae et al. (2008) reported that
despite lower waist circumference for non-hyperandrogenic PCOS
versus BMI-matched controls, PCOS women displayed elevated SBP,
DBP, triglycerides, HOMA-IR, fasting insulin but similar total choles-
terol and HDL-C. However, this study comprises a different ethnic
subgroup (Korean) and there is emerging evidence that ethnicity pro-
foundly affects metabolic parameters in PCOS (Norman et al., 1995b;
Kauffman et al., 2002; Wijeyaratne et al., 2002, 2004; Al-Fozan et al.,
2005; Carmina et al., 2006a, b; Ehrmann et al., 2006; Kauffman et al.,
2006; Essah et al., 2008).
The evidence for worsened risk factors for DM2 and CVD in non-
hyperandrogenic PCOS compared with controls is therefore limited.
Limited data report that IR, independent of adiposity or abdominal
adiposity, may exist in the absence of hyperandrogenism in PCOS
with this IR potentially contributing to the reproductive features of
PCOS. Additionally, despite this subgroup of PCOS being less hyper-
androgenic than the other diagnostic phenotypes, they can still present
with either similar (Norman et al., 1995a; Barber et al., 2007; Chae
et al., 2008; Kauffman et al., 2008) or higher androgens (Dewailly
et al., 2006; Welt et al., 2006b; Hsu et al., 2007) than controls that
could independently impact on IR, reproductive and metabolic par-
ameters. One possibility is that the severity of hyperandrogenism
varies in women with PCOS, and while hyperandrogenism drives
PCOS in the majority of phenotypes (A, B and C), in women with a
mild abnormality in androgens (phenotype D or non-hyperandrogenic
484 Moran and Teede

PCOS), a greater contribution of inherent or environmentally Limitations of the existing literature

induced abdominal-obesity-related IR may be required to induce
reproductive and ovarian dysfunction (Escobar-Morreale and San
Millan, 2007).
Summary of findings for Question 4
Do non-hyperandrogenic anovulatory women with PCOS (phenotype D)
present with elevated metabolic risk compared with controls?
There is currently little evidence to indicate non-hyperandrogenic women
with PCOS matched for abdominal obesity have a more adverse metabolic
profile than controls.
Hyperandrogenic ovulatory PCOS
phenotype C compared with non-NIH PCOS
(non-hyperandrogenic anovulatory PCOS)
The studies discussed above include a wide range of ethnic groups
(Caucasian of American, Australian, European or the UK origin,
Mexican American, African American, Asian, Non-Mexican American
Hispanic, Asian, Arab/Mediterranean, Afro-Caribbean of UK origin,
Chinese, the Netherlands and Icelandic (Supplementary Appendix
I)]. Overall the literature suggests that different ethnicities of PCOS
present with differences in metabolic features, adiposity, abdominal
adiposity, hyperandrogenism, hirsutism, adrenal hormones, lipid
profile, homocysteine or IR (Norman et al., 1995b; Kauffman et al.,
2002, 2006; Wijeyaratne et al., 2002, 2004; Al-Fozan et al., 2005;
Carmina et al., 2006a, b; Ehrmann et al., 2006; Essah et al., 2008),
although this is not universally observed (Welt et al., 2006a).
Further variability in metabolic risk factors in PCOS may relate to
the number of clinical features and the majority of studies do not cat-
egorize PCOS populations based on number or severity of features.
For example, those with biochemical and clinical hyperandrogenism

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phenotype D and oligo-ovulation were the most severely metabolically affected
and subjects with clinical hyperandrogenism only had lower prevalence
There are even fewer studies comparing the non-NIH phenotypes of
of IR (Yildiz and Gedik, 2001; Chang et al., 2005; Diamanti-Kandarakis
hyperandrogenic ovulatory PCOS (phenotype C) and non-
and Panidis, 2007), although this is not reported by all investigators
hyperandrogenic anovulatory PCOS (phenotype D) and the literature
(Hassa et al., 2006). Control subjects in these studies were also vari-
is very conflicting (Fig. 1). No differences in family histories of coronary
ably defined. A number were precisely defined as regular ovulatory
artery disease, DM2, prevalence of IFG and DM2 (Shroff et al., 2007),
menses with no clinical or biochemical hyperandrogenism; some
IR [G/I, QUICKI, HOMA-IR (Shroff et al., 2007), fasting insulin (Shroff
only specified non-hirsute and did not assess biochemical hyperandro-
et al., 2007; Kauffman et al., 2008) or OGTT insulin (Kauffman et al.,
genism and not all assessed the presence of PCO in control subjects.
2008)] or lipid profile (Kauffman et al., 2008) were reported for
Although not uniformly observed (Michelmore et al., 2001; Legro
heavier (Shroff et al., 2007) or weight-matched (Kauffman et al.,
et al., 2005), women with PCO only may have adverse reproductive
2008) groups. The lack of measurement of abdominal adiposity in
and metabolic parameters reported in association with increased
these studies limits the conclusions that can be drawn. However, in
obesity (Clayton et al., 1992), androgens (Kousta et al., 1999;
another study, the strong effect of abdominal obesity on IR and meta-
Adams et al., 2004), risk factors for CVD including reduced arterial
bolic profiles in the PCOS phenotypes was confirmed by lower waist
compliance (Lakhani et al., 2002) and surrogate markers of IR
circumferences and fasting insulin levels for non-hyperandrogenic
(Adams et al., 2004), potentially influencing the metabolic status of
women with PCOS compared with age- and BMI-matched ovulatory
the control subjects. Furthermore, despite the recognition of IR as a
PCOS (Dewailly et al., 2006). When adiposity and abdominal adiposity
contributor to the metabolic presentation of PCOS, there is a
(WHR or waist circumference) were matched, one study reported
lack of consensus on the agreed defined biochemical cut off, the
similar SBP, DBP, HBA1c, metabolic syndrome, IFG, DM2, fasting
appropriate method to use its measurement and longitudinal
insulin, HOMA-IR and lipid profile (Welt et al., 2006b). An earlier
studies to validate surrogate measures (Ciampelli et al., 2005). The
study with a very small number of non-hyperandrogenic PCOS (n ¼
measurement of IR remains a useful research tool in women with
6) reported elevated triglycerides, fasting insulin and OGTT glucose
PCOS but is not currently recommended for routine clinical practice
and insulin (Norman et al., 1995a) for non-hyperandrogenic PCOS
(Samaras et al., 2006). The impact of ethnicity, more precisely
compared with ovulatory PCOS. This indicates higher rather than
defined PCOS and control populations as well as the use of
lower metabolic risk factors in non-hyperandrogenic ovulatory
more accurate methodologies to examine androgen status, IR
PCOS. From this limited literature, non-hyperandrogenic anovulatory
and abdominal fat distribution are needed to clarify the metabolic
PCOS do not display improved metabolic risk factors compared
implications of PCOS.
with hyperandrogenic ovulatory PCOS. There is thus currently
limited evidence to support the exclusion of non-hyperandrogenic
PCOS as a phenotype of PCOS based on metabolic presentation. Discussion
Summary of findings for Question 5 There is an increasing body of literature devoted to examining the
metabolic implications of the reproductive diagnostic phenotypes of
Do hyperandrogenic ovulatory women with PCOS (non-NIH phenotype PCOS. The evidence currently suggests that those with NIH PCOS,
C) present with similar metabolic risk to non-hyperandrogenic anovulatory
who are hyperandrogenic and generally IR, have the most severe
women with PCOS (non-NIH phenotype D)?
metabolic features. The adverse metabolic profile is related to
There is currently little evidence to indicate non-hyperandrogenic women
with PCOS have a less adverse metabolic profile than ovulatory PCOS.
obesity and abdominal obesity, which appears to be more marked
in NIH PCOS than in other non-NIH phenotypes. Hyperandrogenism
Metabolic features of PCOS phenotypes
and IR have both been implicated in adverse metabolic profiles and are
both likely to underpin the metabolic phenotypes of women with
PCOS, either directly or through an increased predilection for
abdominal obesity. The newer reproductive phenotypes (ovulatory
PCOS and non-hyperandrogenic PCOS) have milder metabolic phe-
notypes than NIH PCOS and again these are strongly related to
abdominal adiposity. While the ovulatory subgroup is more hyperan-
drogenic, evidence suggests the non-hyperandrogenic group has
similar IR than ovulatory PCOS. In the setting of either hyperandro-
genism or IR, metabolic abnormalities are observed. This review pro-
vides insights into the pathophysiology of metabolic abnormalities in
PCOS. It is possible that intrinsic PCOS-related abnormalities in
insulin signalling and/or a predisposition to visceral weight gain may
be greater in the NIH phenotypes contributing to their more severe
reproductive and metabolic presentation. Accumulation of obesity
and abdominal or visceral obesity then further exacerbates the meta-
bolic abnormalities seen in PCOS.
There is ongoing controversy over the diagnostic criteria for PCOS.
The inclusion of ovulatory PCOS, and even more so of non-
hyperandrogenic PCOS, has received criticism (Azziz et al., 2006).
From a metabolic perspective, although the literature is limited, it
appears that both of the newer PCOS phenotypes (ovulatory and
non hyperandrogenic) demonstrate a less adverse reproductive and
metabolic profile, compared with NIH PCOS. However, when weight-
matched the metabolic profile of the newer phenotypes is similar to
the profile seen in NIH phenotypes. The newer phenotypes also
appear to have a more adverse metabolic profile than controls, but
this is not universally observed and is strongly related to adiposity
and abdominal adiposity. Finally, non-hyperandrogenic women
appear to have a similar metabolic profile to ovulatory PCOS with
limited evidence even suggesting they present with more severe IR
and dyslipidaemia. Therefore, we propose that the metabolic litera-
ture in PCOS supports the inclusion of both the newer phenotypes
of PCOS based on the ESHRE/ASRM Rotterdam diagnostic criteria
and suggests these phenotypes are a more mild form of PCOS.
The limitations of the literature on metabolic features of PCOS are
not insignificant. Ethnic diversity, recruitment sources of participants,
consistency in the use of end-points and inconsistently defined con-
trols are but a few of the concerns. Current research has also primarily
focused on metabolic syndrome features or on surrogate markers of
DM2 and CVD. No studies have adequately examined the natural
history of metabolic disease in PCOS across the different diagnostic
phenotypes of women, especially in the newer phenotypes. The
majority of research has additionally studied risk factors for metabolic
disease and only a few papers examined clinical disease outcomes (e.g.
DM2, coronary artery disease, subclinical or clinical atherosclerosis)
(Welt et al., 2006b; Barber et al., 2007; Pehlivanov and Orbetzova,
2007; Shroff et al., 2007; Chae et al., 2008). Robust, well designed
studies with well-defined controls and longitudinal follow-up to
capture clinical outcomes are needed to resolve many of the outstand-
ing questions on the metabolic phenotype of PCOS. Furthermore, the
majority of the literature reports elevated risk factors for DM2 and
CVD in family members of women with PCOS (Yilmaz et al., 2005;
Sam et al., 2006; Baillargeon and Carpentier, 2007; Crisosto et al.,
2007; Unluhizarci et al., 2007), but this is poorly examined across
the diagnostic phenotypes of PCOS (Shi et al., 2008; Shroff et al.,
2007; Chae et al., 2008).
485
In conclusion, abdominal obesity appears to be the primary deter-
minant of metabolic abnormalities in PCOS. IR and hyperandrogenism
may also, either directly or indirectly, influence metabolic abnormal-
ities and potentially contribute to abdominal obesity. However,
more research is needed to provide a greater understanding of the
interaction between hyperandrogenism, IR and abdominal adiposity
in PCOS. The optimal screening and treatment for each PCOS pheno-
type and their relatives also needs to be better understood. Overall,
there remain considerable gaps in the literature which require
further research. Ultimately, classification of the metabolic compli-
cations for each phenotype will provide an evidence base for screening
of metabolic risk upon diagnosis of PCOS and may guide optimal
treatment to prevent metabolic complications of PCOS. Insights in
these areas across the phenotypes will also assist in understanding
the underlying pathophysiology of metabolic features of this condition.
Supplementary data
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Supplementary data are available at http://humupd.oxfordjournals.
org/.
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Submitted on August 8, 2008; resubmitted on January 29, 2009; accepted on
February 3, 2009