Obr1053 PDF

obesity reviews
doi: 10.1111/j.1467-789X.2012.01053.x
Obesity Comorbidity
The effect of obesity on polycystic ovary syndrome:

a systematic review and meta-analysis
S. S. Lim1,2, R. J. Norman,1 M. J. Davies1 and L. J. Moran1
The Robinson Institute, University of
Adelaide, Adelaide, South Australia, Australia;

2
Greater Green Triangle University
Department of Rural Health, Flinders

University and Deakin University,
Warrnambool, Victoria, Australia
Received 12 July 2012; revised 2 September

2012; accepted 13 September 2012
Address for correspondence: RJ Norman, The

Robinson Institute, University of Adelaide,
Adelaide, South Australia 5005, Australia.
E-mail: [email protected]
Summary
While many women with polycystic ovary syndrome (PCOS) are overweight,
obese or centrally obese, the effect of excess weight on the outcomes of PCOS is
inconsistent. The review aimed to assess the effects of overweight, obesity and
central obesity on the reproductive, metabolic and psychological features of
PCOS. MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled
Trials (CENTRAL) and PSYCINFO were searched for studies reporting outcomes
according to body mass index categories or body fat distribution. Data were
presented as mean difference or risk ratio (95% confidence interval). This review
included 30 eligible studies. Overweight or obese women with PCOS had
decreased sex hormone-binding globulin (SHBG), increased total testosterone,
free androgen index, hirsutism, fasting glucose, fasting insulin, homeostatic model
assessment-insulin resistance index and worsened lipid profile. Obesity significantly worsened all metabolic and reproductive outcomes measured except for
hirsutism when compared to normal weight women with PCOS. Overweight
women had no differences in total testosterone, hirsutism, total-cholesterol and
low-density lipoprotein-cholesterol compared to normal weight women and no
differences in SHBG and total testosterone compared to obese women. Central
obesity was associated with higher fasting insulin levels. These results suggest that
prevention and treatment of obesity is important for the management of PCOS.
Keywords: Central obesity, obesity, overweight, polycystic ovary syndrome.
obesity reviews (2013) 14, 95109
Introduction
The prevalence of obesity has increased worldwide in the
last few decades including Europe, United States and Australia (13). This had significant impact on the development of chronic diseases such as the metabolic syndrome,
coronary heart disease and type 2 diabetes. In addition,
obesity also has a significant impact on reproductive
health, as excess body weight is the main cause for ovulatory infertility (4). This is closely associated with polycystic ovary syndrome (PCOS), a common endocrine
disorder among reproductive-aged women associated
with anovulation, infertility and hyperandrogenism. It is
2012 The Authors

obesity reviews 2012 International Association for the Study of Obesity
estimated that 47% of reproductive-aged women have

PCOS according to the National Institutes of Health
(NIH) criteria of hyperandrogenism and anovulation
(59) or 1518% according to the European Society of
Human Reproductive and Embryology/American Society
for Reproductive Medicine (ESHRE/ASRM) criteria of
two of the three features of (i) anovulation; (ii) hyperandrogenism; and (iii) polycystic ovaries on ultrasound
(10,11). Women with PCOS have increased risk of metabolic syndrome (12), type 2 diabetes (1315), and cardiovascular diseases including coronary heart disease and
stroke (16,17). Many women with PCOS also suffer from
psychological comorbidities including anxiety, depression,
95
14, 95109, February 2013
obesity reviews
96 Obesity and central obesity in PCOS S. S. Lim et al.
low health-related quality of life, psychological distress

and body dissatisfaction (1821).
A large proportion of women with PCOS are overweight, obese or centrally obese. However, the exact prevalence is not known due to the lack of representative
population data. A US study reported that the prevalence
of obesity in women with PCOS has increased from 51%
in 19871990 to 74% in 20002002 (22). Conversely, a
study in Italy reported that only 14% of women with
PCOS were obese (23). Excess body weight worsens
certain features of PCOS including hyperandrogenism (24
27), menstrual disturbances (24,25,27), infertility (24,28),
insulin resistance (2931) and dyslipidaemia (29,30).
Obesity also further increases the risk of metabolic syndrome, impaired glucose tolerance (IGT) and type 2 diabetes in women with PCOS (13,14,32). However, several
studies suggest that obesity has little or no impact on the
symptoms or the development of PCOS (6,22). Furthermore, even studies reporting a negative impact of obesity
on the features of PCOS fail to report a consistent pattern
in their findings. While one study reported that obesity is
associated with biochemical hyperandrogenemia and not
hirsutism (25), another study found that both biochemical
hyperandrogenemia and hirsutism are affected (24). Similarly, studies have not been in consensus on whether excess
body mass index (BMI) would have a significant impact on
reproductive and metabolic features of PCOS such as sex
hormone-binding globulin (SHBG) levels, total testosterone levels, ovarian volume, infertility and dyslipidaemia
(24,25,27,29,30). Obesity may contribute to the psychological comorbidities of PCOS such as anxiety and depression, but this is not consistently reported (20,3336). It is
additionally unclear if being overweight would be as detrimental as being obese for women with PCOS. Studies in
the general population have shown that for many health
outcomes there is a critical threshold for BMI, beyond
which the risk of disease would greatly increase (3739).
The distribution of body fat may also contribute significantly to some features of PCOS. While women with
PCOS and upper body obesity appeared to have significantly higher fasting insulin levels (4042), its impact on
the other features of PCOS is unclear (4044).
Having excess body weight or a central distribution of
adiposity is likely to have an effect on at least some aspects
of PCOS. However, the effect of being overweight, obese or
centrally obese on the metabolic, reproductive and psychological features of PCOS is inconsistent from the existing
literature. It is also unclear if being overweight but not
obese would be deleterious to the health of women with
PCOS.
Accordingly, the objective of this study was to determine
the effects of overweight, obesity and central obesity on the
metabolic, reproductive and psychological features of
PCOS.
14, 95109, February 2013
Methods
Identification of studies and eligibility criteria
Relevant studies were identified from the following electronic databases using the subject headings as shown in
Supporting Information Table S1: MEDLINE, EMBASE,
CINAHL, PSYCINFO and the Cochrane Central Register of
Controlled Trials (CENTRAL). All articles published before
November 2010 were considered for eligibility. Only articles
published in the English language were included. The search
strategy shown in Supporting Information Table S1 was
constructed for MEDLINE. Equivalent subject headings
were used for the searches in other databases. All reviewers
were also asked to provide any potentially relevant studies
for consideration. All studies of women with PCOS were
considered for eligibility. We selected studies where the
metabolic, reproductive and psychological outcomes of
PCOS were compared between overweight or obese and
normal weight women and where participants were either
consecutively recruited or randomly sampled. We excluded
studies where body weight, BMI, waist circumference or
waisthip ratio was part of the selection criteria. For study
inclusion, PCOS was defined according to the NIH (5) or
ESHRE/ASRM (45) criteria. Overweight or obesity in adults
was defined by World Health Organization (WHO) (46)
(BMI 25 kg m-2 for overweight, BMI 30 kg m-2 for
obesity). In studies on Asian subjects, overweight was considered at BMI 23 and obesity at BMI 25 (46). For
adolescents, agegender specific percentile distributions for
BMI in the Centers for Disease Control and Prevention
growth charts were used to identify those who were overweight (85th95th percentile) or obese (>95th percentile)
(47). Central obesity was defined as waisthip ratio above
0.85 (48). Two reviewers (SL and LM) independently identified the articles that met the selection criteria of this review.
Discrepancies were resolved by consultation and arbitration
(SL, LM, RN and MD).
Data extraction
General characteristics of the study (author, year of publication, study location, study period, study design), characteristics of the study population (recruitment source,
sampling method, age, ethnicity, number of women with
and without PCOS, proportion of women who were lean,
overweight, obese or centrally obese), definition of PCOS,
pre-existing medication, physical activity and diet history,
definition of obesity or central obesity, measurement of
height, weight and waist circumference, and the outcomes
of PCOS by BMI (total-cholesterol, high-density lipoprotein [HDL]-cholesterol, low-density lipoprotein [LDL]cholesterol, triglycerides, fasting insulin, fasting glucose,
homeostatic model assessment-insulin resistance index
2012 The Authors
obesity reviews
[HOMA-IR], prevalence of impaired fasting glucose [IFG]

or IGT, prevalence of type 2 diabetes, SHBG, total testosterone, free androgen index [FAI], hirsutism, acne, irregular menses, psychological disturbances) were extracted
from all included studies. One reviewer extracted the data
from all articles while another independently extracted the
data from 10% of randomly selected studies. Inter-reviewer
agreement of 0.99 was reached. Discrepancies were
resolved by consensus.
Quality assessment
Quality of the included studies was assessed using criteria
based on the NewcastleOttawa scale for non-randomized
studies (49). Criteria assessed the selection of women with
PCOS, comparability of the normal weight, overweight,
obese or centrally obese groups, and the quality of outcome
measurement. One reviewer assessed all the articles
while another independently appraised 10% of randomly
selected studies. Inter-reviewer agreement of 0.78 was
reached, and discrepancies were resolved by consensus.
Outcomes of interest
The primary a priori end points were the metabolic, reproductive and psychological outcomes of overweight and
obese women combined compared to normal weight
women with PCOS. The secondary a priori end point was
the comparison of metabolic, reproductive and psychological outcomes in normal weight, overweight and obese
women with PCOS as separate subgroups (i.e. comparing
normal weight with overweight, normal weight with obese,
and overweight with obese women with PCOS), and in
PCOS women with or without central obesity.
Obesity and central obesity in PCOS S. S. Lim et al. 97
(The Nordic Cochrane Centre, The Cochrane Collaboration, 2011, Copenhagen, Denmark).
Results
Characteristics of included studies and quality
assessment
The search yielded 9,874 citations as shown in Fig. 1.
Based on our selection criteria, 1,485 studies were identified for further assessment in full text. Of these, 670 were
excluded due to insufficient data to determine the proportion of women who were overweight, obese or centrally
obese, 234 due to women with PCOS not being consecutively or randomly sampled, 188 due to PCOS diagnosis
not consistent with NIH or ESHRE/ASRM criteria, 178
due to definition of the overweight and obesity not consistent with WHO criteria, 91 due to patients recruited based
on BMI or body weight, 77 due to outcomes not presented
according to BMI categories, 7 due to non-English reports,
and 10 due to duplication of data. Finally, 30 studies were
included in this systematic review and meta-analysis.
Characteristics of the included studies are shown in
Table 1. Twenty studies compared the outcomes of overweight and obese women to normal weight women with
Records identified
through database
searching (n = 9870)
Additional records
identified by reviewers
(n = 4)
Records after duplicates removed (n = 7948)
Data analysis
Mean differences (MDs) and 95% confidence intervals
(CIs) were calculated for each continuous outcome for all
included studies. Risk ratio (RR) and 95% CI were calculated for each dichotomous outcome for all included
studies. Continuous data were combined using the inverse
variance model while dichotomous data were combined
using the MantelHaenszel model. Heterogeneity between
the studies was examined by c2 tests for significance
(P < 0.1 was considered statistically significant). Inconsistency between studies was quantified using I2 tests (I2 < 25%
was considered low heterogeneity, I2 > 50% was considered substantial heterogeneity). The fixed fixed-effects
model was used when there was no statistically significant
heterogeneity and the random-effects model was used when
significant statistical heterogeneity was present. Funnel
plots were used to assess publication bias. The data analyses were performed using Review Manager (RevMan) 5.1
2012 The Authors
Records excluded on
title/abstract (n = 6463)
Full-text articles assessed

for eligibility (n = 1485)
Full-text articles
excluded (n = 1455)
Studies included in the

meta-analysis (n = 30)
Figure 1 Flow chart for study inclusion.
14, 95109, February 2013
14, 95109, February 2013
2012 The Authors

Turkey
Brazil
Italy
Finland
Spain
Hong Kong
Italy
Italy
Italy
Germany
Germany
Germany
Greece
Spain
United States
and Italy
Sweden
Denmark
Germany
UK
Korea
United States
UK
Spain
Italy
India
Italy
Iran
Saudi Arabia
Germany
Turkey
Adali et al., 2010 (124)
Barcellos et al., 2007 (125)
Bernasconi et al., 1996 (44)
Buyalos et al., 1995 (77)
Castelo-Branco et al., 2010 (99)
Cheung et al., 2008 (126)
Ciampelli et al., 2000 (127)
Cupisti et al., 2007a (130)
Cupisti et al., 2007b (131)
Cupisti et al., 2008 (76)
Economou et al., 2009 (132)
Escobar-Morreale et al., 2006 (51)
Essah et al., 2008 (100)
Gennarelli et al., 1997 (133)
Glintborg et al., 2004 (52)
Hahn et al., 2007 (67)
Kiddy et al., 1990 (27)
Lee et al., 2009 (53)
Marcondes et al., 1995 (134)
Marsden et al., 2001 (66)
Martinez-Guisasola et al., 2001 (135)
Mozzanega et al., 2004 (136)
Mukherjee et al., 2009 (137)
Pasquali et al., 1993 (41)
Sharifi et al., 2010 (138)
Siddiqui et al., 2010 (140)
Spranger et al., 2004 (124)
Yildizhan et al., 2009 (141)
ESHRE/ASRM
NIH
ESHRE/ASRM
ESHRE/ASRM
ESHRE/ASRM
ESHRE/ASRM
ESHRE/ASRM
NIH
NIH
ESHRE/ASRM
ESHRE/ASRM
ESHRE/ASRM
NIH
NIH
ESHRE/ASRM
NIH
ESHRE/ASRM
NIH
NIH
ESHRE/ASRM
NIH
ESHRE/ASRM
ESHRE/ASRM
ESHRE/ASRM
ESHRE/ASRM
ESHRE/ASRM
NIH
ESHRE/ASRM
NIH
ESHRE/ASRM
PCOS definition
16; 7 lean, 9 owt/ob

225; 85 lean, 47 owt, 65 ob
295; 117 lean, 178 owt/ob
31.0 2.0
29.0 1.0
28.4 8.4
30.2 6.4
26.4 1.1
27.3 1.1
184; 74 lean, 110 owt/ob

76; 25 lean, 17 owt, 34 ob
28.2 7.0
28.0 6.9
25.0 4.9
26.0 6.0
194; 118 lean, 20 owt, 55 ob

5; 4 lean, 1 owt
20; 2 lean, 8 owt, 10 ob
167; 117 lean, 50 owt/ob
180; 75 lean, 105 owt/ob
100; 59 non-centrally ob, 41 centrally ob
103; 34 lean, 69 owt/ob
100; 43 lean, 57 owt/ob
22.0 4.4
27.5 4.1
24.2 5.1
30.0 1.4
29.4 2.3
24.8 5.3
20.8 5.9
24.8 5.6
35.9 5.0
28.9 0.6
25.5 3.9
26.7 3.6
263; 172 lean, 91 owt/ob
411; 140 lean, 75 owt, 196 ob
125; 43 lean, 82 owt/ob
26.0 5.0
29.0 5.0
NA
28.0 6.3
Median: 29 (2334, 25th

and 75th %ile)
24.0 1.0
27.4 1.2
Italy: 108; 34 lean, 41 owt, 33 ob;

United States: 106; 11 lean, 17 owt, 78 ob
108; 59 lean, 49 owt/ob
Italy: 24.7 5.2

United States: 29.9 7.5
16; 9 lean, 1 owt, 6 ob
31.4 5.8
32.6 6.7
Range: 1534
Range: 1933
112; 60 lean, 52 owt/ob; 20 non-centrally

ob, 32 centrally ob
Range: 1933
69; 18 lean, 19 owt, 32 ob
22.5 5.3
23.2 6.9
26.88 2.21
24.73 2.91
25.6 5.6
Participants (n)
Age (mean SD
or otherwise stated)
Testosterone, total-C, HOMA-IR, triglyceride, hirsutism
Testosterone
Hirsutism
Fasting glucose, total-C, HOMA-IR, triglyceride, fasting insulin, HDL-C
Fasting insulin, fasting glucose, testosterone, SHBG
Fasting glucose, testosterone, HOMA-IR, fasting insulin, 2-h glucose,

SHBG, FAI, free T
Fasting glucose, testosterone, fasting insulin, SHBG
Testosterone, fasting insulin, SHBG, free T
Hirsutism, testosterone
Hirsutism
IFG/IGT
SHBG, testosterone, free T
Hirsutism, SHBG, testosterone, HOMA-IR, FAI
Diabetes, IFG/IGT
Fasting glucose, testosterone, fasting insulin, SHBG, FAI
Triglyceride, HDL-C, total-C, LDL-C
Triglyceride, hirsutism, SHBG, HDL-C, fasting insulin, total-C,

testosterone, LDL-C, fasting glucose, free T
Fasting glucose, testosterone, total-C, HOMA-IR, triglyceride, fasting

insulin, SHBG, FAI
Fasting glucose, testosterone, total-C, HOMA-IR, triglyceride, 2-h

insulin, fasting insulin, 2-h glucose, HDL-C, LDL-C, SHBG, FAI
Testosterone, SHBG, hirsutism, FAI, free T
Testosterone, SHBG, free T
Testosterone, total-C, fasting insulin, triglyceride, SHBG, HDL-C,

fasting glucose, LDL-C
Testosterone, total-C, fasting insulin, triglyceride, SHBG, HDL-C,

fasting glucose, LDL-C
Testosterone
IFG/IGT
Triglyceride, HDL-C, HOMA-IR, LDL-C, total-C
Testosterone
SHBG, free T
Fasting insulin, testosterone, HOMA-IR, fasting glucose
Testosterone, hirsutism, total-C, HDL-C, LDL-C, triglyceride, HOMA-IR
Outcome measures
C, cholesterol; ESHRE/ASRM, European Society for Human Reproductive and Embryology/American Society for Reproductive Medicine; FAI, free androgen index; free T, free testosterone; HDL, high-density lipoprotein; HOMA-IR,
homeostatic model assessment-insulin resistance index; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LDL, low-density lipoprotein; NA, not applicable; NIH, National Institutes of Health; ob, obese; owt, overweight;
PCOS, polycystic ovary syndrome; SD, standard deviation; SHBG, sex hormone-binding globulin.
Country
Author (year)
Table 1 Summary of included studies
obesity reviews
obesity reviews
PCOS, eight studies compared the outcomes of obese,

overweight and normal weight women with PCOS, and
two studies compared women with PCOS with or without
central obesity (Table 1). All studies were conducted in
adults, with the exception of one study (50) that included
both adolescents and adults. Eleven studies used a diagnosis consistent with the NIH criteria while 19 used a diagnosis consistent with the ESHRE/ASRM criteria (Table 1).
Three studies were conducted in the Americas, 20 in
Europe, and 7 in Asia and Middle East. Of the studies that
reported reproductive and metabolic outcomes, all of them
reported the laboratory methods for hormonal, lipid or
glucose assessments. All studies used the FerrimanGallwey
method to assess hirsutism. Nine studies measured insulin
resistance using HOMA-IR while one study (51) used
HOMA-B and insulin sensitivity index instead. Only
studies reporting HOMA-IR were included in the metaanalyses. Twenty-five studies reported the use of medication that could affect the study outcomes (Supporting
Information Table S2). No studies reported acne, irregular
menses or psychological disturbances as outcomes
(Table 1). The date of publication for included studies
ranged from 1990 to 2010.
A summary of the methodological quality of the studies
is shown in Table 2. The assessment criteria were based on
the NewcastleOttawa scale for observational studies (49).
As determined by our inclusion criteria, all participants
were recruited either consecutively or randomly. Independent measurements of height and weight were reported in 15
studies. All cases and controls were recruited from the same
source. As consistent with our inclusion criteria, all studies
defined overweight or obesity according to the WHO criteria. None of the studies specifically controlled for age or
any other factors as part of the study design when comparing outcomes between the lean and obese groups. All
studies determined their reproductive and metabolic outcomes through independent assessments. The same method
of assessment was used between the comparative groups in
all studies. Eighteen studies reported that the non-response
rate for lean and overweight or obese groups was the same.
The funnel plot for studies on SHBG was largely symmetrical (Supporting Information Fig. S1). Funnel plot for
studies on total testosterone showed some asymmetry for
smaller studies (Supporting Information Fig. S2). The
number of studies for the other outcomes was too small for
the assessment of publication bias through funnel plots.
Overweight or obese women (BMI 25 or

BMI 23 for Asian population) compared
to normal weight women with polycystic
ovary syndrome
Being overweight or obese was associated with significantly
lower SHBG and HDL-cholesterol and significantly
2012 The Authors
Obesity and central obesity in PCOS S. S. Lim et al. 99
increased total testosterone, FAI, hirsutism scores, fasting

insulin, HOMA-IR, fasting glucose, glucose at 2 h during
the oral glucose tolerance test (OGTT), insulin at 2 h
during OGTT, total-cholesterol, LDL-cholesterol and
triglycerides in women with PCOS (Table 3). There was
no significant heterogeneity in studies reporting SHBG,
hirsutism, 2-h insulin and LDL-cholesterol. Significant
statistical heterogeneity was observed in studies reporting
total testosterone, FAI, fasting insulin, HOMA-IR, fasting
glucose, 2-h glucose, total-cholesterol, HDL-cholesterol
and triglycerides.
Overweight or obese women with PCOS had higher RR
of IFG/IGT and type 2 diabetes compared to those with
normal weight but this did not reach statistical significance
(Table 3). Significant heterogeneity was seen in the analysis
for IFG/IGT while only one study reported the prevalence
of type 2 diabetes (52).
Subgroup analyses
Overweight women (BMI 2529.9 or BMI 2324.9 for
Asian population) compared to normal weight women
with polycystic ovary syndrome
Overweight women with PCOS had lower SHBG and
HDL-cholesterol, and higher FAI, fasting insulin, HOMAIR, fasting glucose and triglyceride (Table 4). Being overweight had no significant effect of total testosterone,
hirsutism, total-cholesterol and LDL-cholesterol in women
with PCOS. No studies comparing overweight women
to normal weight women reported 2-h OGTT insulin
or glucose. Significant heterogeneity was seen in studies
reporting hirsutism, HOMA-IR, but not in studies reporting SHBG, total testosterone, fasting insulin, fasting
glucose and all lipid parameters.
According to the only study reporting the prevalence of
IFG/IGT of overweight and normal weight women with
PCOS (53), those who were overweight had higher RR for
IFG/IGT compared to those with normal weight (Table 4).
No study comparing overweight to normal weight women
with PCOS reported the prevalence of type 2 diabetes.
Obese women (BMI 30 or BMI 25 for Asian)
compared to normal weight women with polycystic
ovary syndrome
Obese women with PCOS had lower SHBG and HDLcholesterol, and higher total testosterone, FAI, fasting
insulin, HOMA-IR, fasting glucose, total-cholesterol, LDLcholesterol and triglyceride compared to normal weight
women (Table 4). Obesity had no significant effect on
hirsutism. No studies comparing obese to normal weight
women with PCOS reported 2-h OGTT insulin or glucose.
There was significant heterogeneity in the studies reporting
SHBG, hirsutism, fasting insulin, HOMA-IR, HDLcholesterol and triglyceride, but no heterogeneity was seen
14, 95109, February 2013
obesity reviews
Author (year)
Selection
Comparability
Exposure
Total
Adali et al., 2010 (124)

Barcellos et al., 2007 (125)
Bernasconi et al., 1996 (44)
Buyalos et al., 1995 (77)
Castelo-Branco et al., 2010 (99)
Cheung et al., 2008 (126)
Cupisti et al., 2007a (130)
Cupisti et al., 2007b (131)
Cupisti et al., 2008 (76)
Economou et al., 2009 (132)
Escobar-Morreale et al., 2006 (51)
Essah et al., 2008 (100)
Gennarelli et al., 1997 (133)
Glintborg et al., 2004 (52)
Hahn et al., 2007 (67)
Kiddy et al., 1990 (27)
Lee et al., 2009 (53)
Marcondes et al., 1995 (134)
Marsden et al., 2001 (66)
Martinez-Guisasola et al., 2001 (135)
Mozzanega et al., 2004 (136)
Mukherjee et al., 2009 (137)
Pasquali et al., 1993 (41)
Sharifi et al., 2010 (138)
Siddiqui et al., 2010 (139)
Spranger et al., 2004 (140)
Yildizhan et al., 2009 (141)
3
3
3
3
4
4
3
3
3
4
4
4
4
4
3
3
4
4
3
4
3
3
3
3
4
4
4
4
3
4
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3
3
2
3
2
2
3
3
3
3
3
2
3
3
2
3
2
2
2
2
2
2
3
3
3
3
3
3
2
3
6
6
5
6
6
6
6
6
6
7
7
6
7
7
5
6
6
6
5
6
5
5
6
6
7
7
7
7
5
7
Table 2 The quality assessment of included

studies
Selection
(1) Is the definition of overweight/obesity adequate? (a) yes, with independent validation*, (b) yes,
e.g. record linkage or based on self-reports, (c) no description.
(2) Representativeness of the cases: (a) consecutive or obviously representative series of cases*,
(b) potential for selection biases or not stated.
(3) Selection of normal weight controls: (a) same source as cases*, (b) hospital controls, (c) no
description.
(4) Definition of normal weight controls: (a) not overweight or obese by WHO criteria*, (b) no
description of source.
Comparability
(1) Comparability of cases and controls on basis of design or analysis: (a) study controls for age*,
(b) study controls for any additional factor*
Exposure
(1) Ascertainment of metabolic, reproductive and psychological outcomes: (a) secure record (e.g.
surgical records) or independently measured*, (b) structured interview blinded to case/control
status*, (c) interview not blinded to case/control status, (d) written self-report or medical record only,
(e) no description.
(2) Same method of ascertainment for cases and controls: (a) yes*, (b) no.
(3) Non-response rate: (a) same rate for both groups*, (b) non-respondents described, (c) rate
difference and no designation.
*=1 point awarded.
in studies reporting total testosterone, fasting glucose

levels, total-cholesterol and LDL-cholesterol.
Obesity was associated with significantly higher RR for
IFG/IGT (53) (Table 4). No study comparing obese and
normal weight women with PCOS reported the prevalence
of type 2 diabetes.
14, 95109, February 2013
Obese women (BMI 30 or BMI 25 for Asian)

compared to overweight (BMI 2529.9 or BMI 2324.9
for Asian) women with polycystic ovary syndrome
Obese women had higher FAI, hirsutism, fasting insulin,
HOMA-IR and fasting glucose compared to overweight
women with PCOS (Table 4). The SHBG and total testoster 2012 The Authors
obesity reviews
Obesity and central obesity in PCOS S. S. Lim et al.
101
Table 3 Results of meta-analyses for studies comparing overweight and obese (BMI 25) to normal weight (BMI < 25) women with PCOS
Analysis
Studies
Participants
Mean difference (95% CI), statistical model, P value
c2 (P value)
I2 (%)
SHBG (nmol L-1)

Testosterone (nmol L-1)
FAI
Hirsutism (FG score)
Fasting insulin (pmol L-1)
HOMA-IR
Fasting glucose (mmol L-1)
2-h glucose (mmol L-1)
2-h insulin (pmol L-1)
IFG/IGT, n
Diabetes, n
Total-C (mmol L-1)
LDL-C (mmol L-1)
HDL-C (mmol L-1)
Triglyceride (mmol L-1)
12
16
5
5
9
6
8
2
1
2
1
7
4
5
7
988
1,304
550
325
800
700
633
364
184
396
102
567
281
384
567
-22.57 (-25.39, -19.75), fixed, P < 0.001

0.30 (0.05, 0.55), random, P = 0.02
4.01 (2.28, 5.73), random, P < 0.001
0.89 (0.22, 1.55), fixed, P = 0.009
39.75 (29.95, 49.55), random, P < 0.001
1.58 (1.00, 2.16), random, P < 0.001
0.25 (0.13, 0.37), random, P < 0.001
0.95 (0.31, 1.59), random, P = 0.004
443.30 (303.89, 582.71), fixed, P < 0.001
RR: 3.28 (0.21, 50.33), random, P = 0.39
RR: 6.37 (0.38, 108.12), fixed, P = 0.20
0.35 (0.07, 0.64), random, P = 0.01
0.35 (0.23, 0.48), fixed, P < 0.001
-0.23 (-0.38, -0.07), random, P = 0.005
0.37 (0.23, 0.50), random, P < 0.001
11.89 (P = 0.37)
140.60 (P < 0.001)
11.97 (P = 0.02)
5.70 (P = 0.13)
20.40 (P = 0.09)
46.10 (P < 0.001)
12.89 (P = 0.07)
4.80 (P = 0.03)
NA
11.06 (P < 0.001)
NA
19.08 (P = 0.004)
5.53 (P = 0.14)
16.29 (P = 0.003)
35.72 (P < 0.001)
8
89
67
47
61
89
46
79
NA
91
NA
69
46
75
83
BMI, body mass index; C, cholesterol; CI, confidence interval; FAI, free androgen index; FG, FerrimanGallwey; HDL, high-density lipoprotein;
HOMA-IR, homeostatic model assessment-insulin resistance index; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LDL, low-density
lipoprotein; NA, not applicable; PCOS, polycystic ovary syndrome; RR, risk ratio; SHBG, sex hormone-binding globulin.
one and fasting lipids did not differ significantly between

obese and overweight women with PCOS. There was significant heterogeneity among studies reporting SHBG,
HOMA-IR, HDL-cholesterol and triglyceride, but not
among those reporting total testosterone, hirsutism,
fasting insulin, fasting glucose, total-cholesterol and
LDL-cholesterol.
The RR for IFG/IGT was not significantly higher among
the obese women compared to the overweight women with
PCOS (53) (Table 4). No study comparing obese and overweight women with PCOS reported the prevalence of type
2 diabetes.
Centrally obese women compared to non-centrally
obese women with polycystic ovary syndrome
Two studies (n = 121) reported the effect of central obesity
on SHBG (41,44). Central obesity had no significant effect
on SHBG in women with PCOS (MD 2.04 [-3.01, 7.09],
P = 0.43). There was no significant heterogeneity in this
analysis (I2 = 0%, c2 = 0.01, P = 0.94).
One study (41) reported the effect of central obesity on
total testosterone (n = 75), fasting insulin (n = 92) and
fasting glucose (n = 94). In this study, total testosterone
(MD 0.19 [-0.26, 0.65], P = 0.40) and fasting glucose (MD
-0.01 [-0.20, 0.18], P = 0.92) did not differ significantly
between those with and without central obesity. Central
obesity was associated with increased fasting insulin (MD
95.00 [54.81, 135.19], P < 0.001).
No study comparing women with and without central
obesity reported outcomes on FAI, hirsutism scores,
acne, irregular menses, HOMA-IR, OGTT glucose or
insulin, IGT/IFG, type 2 diabetes, total-cholesterol, LDLcholesterol, HDL-cholesterol, triglyceride or psychological
morbidities.
2012 The Authors
Discussion
Principal findings
We report here that being overweight or obese was associated with significantly worse reproductive and metabolic
features of PCOS. We additionally report that being obese
was significantly associated with worse metabolic and
reproductive outcomes measured, except for hirsutism,
when compared to normal weight women with PCOS.
In contrast, women who were overweight but not obese
only had no differences in total testosterone, hirsutism,
total-cholesterol and LDL-cholesterol compared to normal
weight women, and no differences in SHBG, total testosterone and fasting lipids compared to obese women. Central
obesity was associated with higher fasting insulin. There
were no data on psychological parameters and limited data
on prevalence of IFG, IGT and type 2 diabetes mellitus.
Interpretation of findings
Overweight and obesity on sex
hormone-binding globulin
BMI has previously shown to be negatively associated with
SHBG in women with and without PCOS (27,54,55) with
this relationship likely to be mediated by insulin. SHBG
and insulin were inversely related in women with and
without PCOS, as insulin inhibits hepatic SHBG production (56). Decreased SHBG contributes to hyperandrogenism by increasing bioavailable androgens delivered to
target organs (57,58) and is therefore a negative reproductive consequence of being overweight or obese. From the
current analysis, it is possible that the effect of adiposity on
SHBG predominantly occurs in overweight women with
14, 95109, February 2013
obesity reviews
Table 4 Results of meta-analyses for studies comparing obese (BMI 30), overweight (BMI 2529.9) and normal weight (BMI < 25) women with
PCOS
Analysis
Studies
Participants
Mean difference (95% CI), statistical model, P value
c2 (P value)
I2 (%)
1.19 (P = 0.28)
12.78 (P < 0.001)
3.75 (P = 0.05)
16
92
73
0.59 (P = 0.90)
5.27 (P = 0.15)
2.17 (P = 0.57)
0
43
0
SHBG (nmol L-1)
Owt vs. normal

Ob vs. normal
Ob vs. owt
2
2
2
252
395
317
-13.09 (-19.88, -6.30), fixed, P < 0.001

-21.83 (-40.84, -2.82), random, P = 0.02
-7.51 (-18.95, 3.94), random, P = 0.20
Testosterone (nmol L-1)
Owt vs. normal

Ob vs. normal
Ob vs. owt
4
4
4
299
457
386
0.05 (-0.17, 0.26), fixed, P = 0.66

0.18 (0.00, 0.35), fixed, P = 0.04
0.12 (-0.09, 0.33), fixed, P = 0.26
FAI
Owt vs. normal

Ob vs. normal
Ob vs. owt
1
1
1
210
336
266
2.30 (0.90, 3.70), fixed, P = 0.001

5.90 (4.63, 7.17), fixed, P < 0.001
3.60 (1.95, 5.25), fixed, P < 0.001
NA
NA
NA
NA
NA
NA
Hirsutism (FG score)
Owt vs. normal

Ob vs. normal
Ob vs. owt
3
3
3
262
407
335
-1.78 (-6.22, 2.66), random, P = 0.43

0.54 (-4.02, 5.11), random, P = 0.82
2.17 (0.55, 3.78), fixed, P = 0.009
9.93 (P = 0.007)
11.14 (P=0.004)
0.24 (P = 0.89)
80
82
0
Fasting insulin (pmol L-1)
Owt vs. normal

Ob vs. normal
Ob vs. owt
2
2
2
79
109
102
36.37 (12.74, 59.99), fixed, P = 0.003

123.13 (60.28, 185.97), random, P < 0.001
72.17 (41.30, 103.04), fixed, P < 0.001
2.43 (P = 0.12)
4.51 (P = 0.03)
0.25 (P = 0.62)
59
78
0
HOMA-IR
Owt vs. normal

Ob vs. normal
Ob vs. owt
3
3
3
379
536
429
1.00 (0.40, 1.60), random, P = 0.001

3.75 (1.69, 5.81), random, P < 0.001
2.41 (0.89, 3.93), random, P = 0.002
7.69 (P = 0.02)
66.34 (P < 0.001)
23.95 (P < 0.001)
74
97
92
Fasting glucose (mmol L-1)
Owt vs. normal

Ob vs. normal
Ob vs. owt
2
2
2
79
109
102
0.33 (0.15, 0.52), fixed, P < 0.001

0.59 (0.42, 0.77), fixed, P < 0.001
0.26 (0.05, 0.46), fixed, P = 0.01
0.26 (P = 0.61)
0.01 (P = 0.91)
0.32 (P = 0.57)
0
0
0
IFG/IGT (n)
Owt vs. normal

Ob vs. normal
Ob vs. owt
1
1
1
139
174
75
RR: 5.10 (1.91, 13.62), fixed, P = 0.001

RR: 6.18 (2.78, 13.75), fixed, P < 0.001
RR: 1.21 (0.57, 2.58), fixed, P = 0.62
Total-C (mmol L-1)
Owt vs. normal

Ob vs. normal
Ob vs. owt
3
4
3
145
365
220
0.06 (-0.29, 0.40), fixed, P = 0.74

0.62 (0.44, 0.80), fixed, P < 0.001
0.31 (-0.04, 0.65), fixed, P = 0.08
2.70 (P = 0.26)
5.46 (P = 0.14)
1.13 (P = 0.57)
26
45
0
LDL-C (mmol L-1)
Owt vs. normal

Ob vs. normal
Ob vs. owt
3
4
3
145
365
220
0.10 (-0.17, 0.38), fixed, P = 0.47

0.53 (0.36, 0.70), fixed, P < 0.001
0.24 (-0.04, 0.52), fixed, P = 0.09
2.77 (P = 0.25)
3.40 (P = 0.33)
2.76 (P = 0.25)
28
12
28
HDL-C (mmol L-1)
Owt vs. normal

Ob vs. normal
Ob vs. owt
4
4
4
277
365
332
-0.08 (-0.14, -0.01), fixed, P = 0.03

-0.29 (-0.49, -0.08), random, P = 0.005
-0.21 (-0.44, 0.01), random, P = 0.06
5.72 (P = 0.13)
23.45 (P < 0.001)
34.68 (P < 0.001)
48
87
91
Triglyceride (mmol L-1)
Owt vs. normal

Ob vs. normal
Ob vs. owt
4
4
4
277
365
332
0.13 (0.01, 0.25), fixed, P = 0.03

0.57 (0.25, 0.89), random, P < 0.001
0.44 (-0.12, 0.99), random, P = 0.12
5.70 (P = 0.13)
19.29 (P < 0.001)
37.31 (P < 0.001)
47
84
92
NA
NA
NA
NA
NA
NA
BMI, body mass index; C, cholesterol; CI, confidence interval; FAI, free androgen index; FG, FerrimanGallwey; HDL, high-density lipoprotein;
HOMA-IR, homeostatic model assessment-insulin resistance index; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LDL, low-density
lipoprotein; NA, not applicable; ob, obese; owt, overweight; PCOS, polycystic ovary syndrome; RR, risk ratio; SHBG, sex hormone-binding globulin.
the effect plateauing in obesity. Alternatively, the regulation

of SHBG may occur independent of insulin (59) with
dietary influences such as monosaccharide-induced lipogenesis also attenuating SHBG levels (60). It is unclear if
the apparent uncoupling between BMI and SHBG with
increasing adiposity reflects the influence of these other
factors, or that a saturation effect accounts for the attenuation of SHBG by obesity.
Overweight and obesity on hyperandrogenemia
In agreement with previous findings (27,29), we report here
that overweight and obese women had higher total testo-
14, 95109, February 2013
sterone compared to normal weight women. This is likely

to be due to the effects of obesity-induced hyperinsulinaemia stimulating ovarian (58) and adrenal (61,62) androgen
production, increasing the sensitivity of the pituitary to
the effect of gonadotrophin-releasing hormone (63), and
enhancing the ovarian response to gonadotrophins (64).
Adipose tissue is also an important storage and metabolic
site for steroid hormones including androgens (65). A positive relationship between BMI and biochemical hyperandrogenism was confirmed here with FAI increasing from
normal weight, overweight to obese groups. Conversely,
the relationship between BMI and hirsutism did not appear
2012 The Authors
obesity reviews
to be linear. Two (51,66) out of the three studies in this

review (67) reported a J-shape relationship in which overweight women had the lowest hirsutism scores compared to
the lean or obese women. Obesity increases both oestrogen
and androgen production (58) and, in overweight women,
the effect of hyperestrogenism may counteract the effect of
hyperandrogenism such that at a clinical level less hirsutism
is observed.
Overweight and obese and insulin and
insulin resistance
Insulin resistance is a common condition in PCOS and
present in 1424% according to ESHRE/ASRM criteria or
2043% with NIH criteria (11,45,68). We report here a
dose-dependent relationship between adiposity and surrogate measures of insulin resistance consistent with previous
findings (69,70). Insulin resistance may be prevalent in
PCOS due to intrinsic defects in insulin signalling or receptor activity (71,72), decreased insulin clearance due to the
inhibitory effect of high testosterone levels (73), excess
adiposity (29,7477), and elevated adipose tissue free fatty
acid or cytokine production such as tumour necrosis factoralpha and interleukin-6 (7881). Thus, in addition to
defects intrinsic to PCOS, those with excess adiposity experience further impairment to the secretion, metabolism and
action of insulin. This is consistent with women with PCOS
being more insulin resistant than weight-matched women
without PCOS and obesity worsening insulin resistance in
PCOS (8284).
Overweight and obese on impaired fasting
glucose/impaired glucose tolerance, type 2 diabetes
We have previously reported an increased prevalence of
IGT and type 2 diabetes in women with PCOS compared to
women without PCOS (1315), which is further increased
in the presence of overweight or obesity (14,85). This is
likely related to the association between obesity and insulin
resistance with insulin resistance being an important predictor of IGT and type 2 diabetes in the general population
(86,87) and specifically in populations at high risk of type
2 diabetes (88,89). It is unclear if being obese as compared
to being overweight would further increase the risk for
IFG/IGT and type 2 diabetes for women with PCOS. We
report here an increased risk for IFG/IGT in overweight
women compared to normal weight women but no differences between overweight and obese women. This result,
from a single study (53) in a specific population (young
Korean women), requires confirmation in future research.
Overweight and obese and dyslipidaemia
A previous meta-analysis reported a more atherogenic lipid
profile in women with PCOS compared to women without
PCOS (90). We extend this literature to report that being
overweight or obese further worsens the fasting lipid
2012 The Authors
103
profile, as an important risk marker for cardiovascular

disease (91), in women with PCOS. This is consistent with
previous cross-sectional studies demonstrating that PCOS
and obesity exert synergistic effect on exacerbating fasting
lipids (29,30,9294) and epidemiological studies reporting
dyslipidaemia worsens steadily from a BMI of 20 onwards
(95). In contrast, total-cholesterol and LDL-cholesterol
were not increased in overweight women compared to
normal weight women with PCOS. The lipid pattern in
overweight women with PCOS in this review likely reflects
the influence of insulin resistance, which has previously
been shown to be associated with increased triglyceride and
decreased HDL-cholesterol (29,30,9698). In contrast to
previous studies (95), being obese did not consistently
result in significantly worse fasting lipid levels compared to
being overweight. Most of the studies included in the
current analysis on lipid levels were from the Mediterranean region (51,99,100), thus diet and ethnicity may have
influenced our results.
Polycystic ovary syndrome and psychological health
Women with PCOS experience high levels of psychological
morbidities including anxiety, depression and body dissatisfaction (20,34). Obesity appears to be a contributing
factor but not the sole cause for these conditions (34,35).
The association between depression and obesity may be
related to body image with this being strongly associated
with depression in women with PCOS (33). Despite the
significance of psychological impact resulting from PCOS
and the potential role of obesity in mediating these effects,
relatively few studies have been conducted in this area. No
studies included in this review reported psychological outcomes, which is an important clinical and research gap.
Central obesity and polycystic ovary syndrome
Women with PCOS have a greater tendency to accumulate
fat in the upper body when compared to controls matched
for weight or BMI (101106), although this is not consistently reported (107,108). Consistent with our current findings, central or visceral obesity is associated with elevated
fasting and glucose-stimulated insulin levels (40,41) and
greater insulin resistance in PCOS (43,102,106,109) likely
mediated by free fatty acids and the paracrine actions of
the visceral depot (7881). No studies used more precise
methods of measuring central obesity, such as dual X-ray
absorptiometry, computed tomography or magnetic resonance imaging. We did not confirm previous findings of
relationships between central obesity and SHBG (109), as
measured by computed tomography scan, which may
reflect the use of the less-sensitive measure of waisthip
ratio in the current analysis (41,44). We confirm previous
findings of no relationship between central obesity and
fasting glucose or total testosterone (40,109). While central
adiposity has been previously, although not consistently
14, 95109, February 2013
obesity reviews
(104), associated with increased FAI (102) and free testosterone (105) and dyslipidaemia (40,109,110), we are
unable to confirm these findings because there are no
available data for these outcomes. While there are many
mechanisms by which central adiposity could lead to hyperinsulinaemia and hyperandrogenism, high levels of insulin
and androgens could in turn promote central body fat
distribution (111,112). We also reported a lack of data for
all other outcomes, indicating the literature is limited with
regard to the effect of central obesity on reproductive,
metabolic and psychological outcomes in PCOS.
Strengths and weaknesses

The strengths of this study include the performing of subgroup analyses to assess the effect of body fat distribution
and degree of adiposity, the inclusion of moderate- to highquality studies, and the likely minimal effect of publication
bias on SHBG and testosterone. However, because of the
wide range of sample size (n = 16 to 411) and the minimal
number of studies for some reported outcomes, it was not
possible to assess publication bias for all other outcomes.
These small sample sizes also limited our ability to observe
relationships in subgroup analysis. Despite these limitations, we reported significant differences on the effect of
overweight compared to obesity on a number of the comorbidities of PCOS. Significant statistical heterogeneity was
found in half of the analyses, which may reflect clinical
heterogeneity related to variability in PCOS diagnostic
criteria, country setting, ethnicity, or diet and physical
activity. This indicates that caution should be applied in
extrapolating these results for wider applications. While we
aimed to minimize selection bias by including only studies
that recruited their participants in a consecutive or random
manner, all trials in this review recruited participants from
hospitals or clinics instead of general community which
may represent a population with more a severe manifestation of PCOS. None of the studies controlled for potential
confounders such as age, ethnicity or the use of medications
when comparing the various BMI groups. We also note that
as this is a cross-sectional investigation, the directionality
of event could not be determined.
Clinical implications, research implications and

future directions
Excess adiposity is associated with significantly worse
reproductive, metabolic and psychological features of
PCOS. However, the exact BMI cut-off that corresponds to
the increased risk for each outcome is unclear. For the
general population, the risk for coronary heart disease
increased at BMI > 22 kg m-2 (95). It is unclear if the cutoff would be similar or lower in PCOS. Being overweight
but not obese is also associated with adverse metabolic and
14, 95109, February 2013
reproductive outcomes in women with PCOS, although

being obese appears to further worsen most of these outcomes. This highlights the importance of screening, detection, and management of both overweight and obesity in
the treatment of PCOS. Lifestyle modification is recommended as a key initial treatment strategy in overweight
and obese women with PCOS (113,114) and improves
SHBG, hyperandrogenism, weight, waist circumference,
insulin resistance and psychological function (114121).
Lifestyle interventions are also effective in preventing the
development of chronic diseases such as type 2 diabetes in
the general population (122). Given the contribution of
obesity to the presentation of PCOS, future work should
also focus on the comparative efficacy of pharmacological,
surgical and lifestyle management of overweight and
obesity. Prevention of weight gain is also an important
aspect of obesity management, as weight gain is an important risk factor for various metabolic diseases (37) and
young women of reproductive age are a high-risk group for
weight gain (123). While the specific risk for longitudinal
weight gain and the effect of weight gain on features of
PCOS are not clear, this highlights the importance of prevention in addition to the treatment of overweight and
obesity for women with PCOS.
This review highlights the need for studies examining the
effect of overweight, obesity and central obesity on the
psychological health of women with PCOS, and the effect
of central obesity on the comorbidities in PCOS. We found
that the relationship between BMI and certain health outcomes including SHBG and hirsutism may be non-linear.
This warrants further examination for a range of outcomes
and BMIs. The identification of a BMI threshold for each
health outcome could aid the identification of target groups
for the appropriate interventions. It may be that even those
within the normal weight range may be at risk of some
diseases and should be targeted for disease prevention. The
effect of overweight, obesity and central obesity should also
be explored longitudinally to determine the causal role of
obesity in the development of these reproductive, metabolic
and psychological outcomes.
Conclusion
This systematic review reports an evaluation of the metabolic and reproductive effects of overweight, obesity and
central obesity in women with PCOS. We reported that
being overweight adversely affects many aspects of PCOS,
while being obese further worsens these outcomes. Further
studies are required to describe the effect of central obesity
on various outcomes of PCOS, and the effect of excess
weight on the psychological health of women with PCOS.
Research on the risks of metabolic, reproductive and psychological morbidities of PCOS across a wide range of
BMIs in women with PCOS is needed to identify the highest
2012 The Authors
obesity reviews
risk groups to target strategies for the prevention and treatment of adiposity-associated morbidities.
Conflict of Interest Statement

None.
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Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Figure S1. Funnel plot for studies on SHBG.
Figure S2. Funnel plot for studies on testosterone.
Table S1. MeSH terms.
Table S2. Description of included studies.
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obesity reviews

The effect of obesity on polycystic ovary syndrome:

The Robinson Institute, University of

Adelaide, Adelaide, South Australia, Australia;

Greater Green Triangle University

Department of Rural Health, Flinders

Received 12 July 2012; revised 2 September

Address for correspondence: RJ Norman, The

2012 The Authors

estimated that 47% of reproductive-aged women have

96 Obesity and central obesity in PCOS S. S. Lim et al.

low health-related quality of life, psychological distress

14, 95109, February 2013

[HOMA-IR], prevalence of impaired fasting glucose [IFG]

Obesity and central obesity in PCOS S. S. Lim et al. 97

Records after duplicates removed (n = 7948)

Full-text articles assessed

Studies included in the

Figure 1 Flow chart for study inclusion.

14, 95109, February 2013

14, 95109, February 2013

2012 The Authors

Adali et al., 2010 (124)

Barcellos et al., 2007 (125)

Bernasconi et al., 1996 (44)

Buyalos et al., 1995 (77)

Castelo-Branco et al., 2010 (99)

Cheung et al., 2008 (126)

Ciampelli et al., 2000 (127)

Ciampelli et al., 2001 (128)

Ciampelli et al., 2002 (129)

Cupisti et al., 2007a (130)

Cupisti et al., 2007b (131)

Cupisti et al., 2008 (76)

Economou et al., 2009 (132)

Escobar-Morreale et al., 2006 (51)

Essah et al., 2008 (100)

Gennarelli et al., 1997 (133)

Glintborg et al., 2004 (52)

Hahn et al., 2007 (67)

Kiddy et al., 1990 (27)

Lee et al., 2009 (53)

Marcondes et al., 1995 (134)

Marsden et al., 2001 (66)

Martinez-Guisasola et al., 2001 (135)

Mozzanega et al., 2004 (136)

Mukherjee et al., 2009 (137)

Pasquali et al., 1993 (41)

Sharifi et al., 2010 (138)

Siddiqui et al., 2010 (140)

Spranger et al., 2004 (124)

Yildizhan et al., 2009 (141)

16; 7 lean, 9 owt/ob

184; 74 lean, 110 owt/ob

194; 118 lean, 20 owt, 55 ob

263; 172 lean, 91 owt/ob

411; 140 lean, 75 owt, 196 ob

125; 43 lean, 82 owt/ob

18; 10 lean, 8 owt/ob