Steroids 77 (2012) 295299

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Steroids
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Review

Dyslipidemia in PCOS
Robert A. Wild
Oklahoma University Health Sciences Center, Oklahoma City, OK, United States

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

Article history: Life-long apolipoprotein lipid metabolic dysfunction in women with PCOS exaggerates the risk for cardio-
Received 13 October 2011 vascular disease (CVD) with aging. The dysfunction has involved insulin resistance (IR), which occurs in
Accepted 22 November 2011 most women with PCOS. Women with PCOS have androgen excess, IR, variable amounts of estrogen
Available online 14 December 2011
exposure, and many environmental factors, all of which can inuence lipid metabolism. On average,
women with PCOS were higher triglyceride [26.39 95% CI (17.24, 35.54)], lower HDL-cholesterol [6.41
Keywords: 95% CI (3.69, 9.14)], and higher non HDL cholesterol levels [18.82 95% CI (15.53, 22.11)] than their
Dyslipidemia
non-PCOS counterparts. They have higher ApoCIII/ApoCII ratios and higher ApoCI even if they are not
PCOS
Apolipoprotein
obese. ApoC1 elevation in women with PCOS needs to be further evaluated as a marker of dysfunction
Lipid metabolism and potential CVD risk. ApoB measurements track with non-HDL cholesterol as a surrogate for increased
atherogenic circulating small LDL particles. Elevated triglycerides and waist circumference predict CVD
risk and women with PCOS often have these phenotypes. Diet and exercise interventions followed by
selective lipid lowering medications are encouraged to normalize the dyslipidemia.
2012 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
2. Dyslipidemia of PCOS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
3. Apolipoprotein metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
4. Apolipoprotein lipids in PCOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
4.1. Androgens, hepatic lipase, and small LDL particles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
5. Epidemiological implications of dyslipidemia in PCOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
6. Implications for treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

1. Introduction given the importance of dyslipidemia as the major proximate cause

Life-long metabolic dysfunction in women with PCOS exagger-
ates the risk for cardiovascular disease (CVD) with aging. The met-
abolic dysfunction historically and physiologically has involved
insulin resistance, which occurs in most women with PCOS [1]. It
appears to be independent and additive to insulin resistance occur-
ring in obese individuals who do not have PCOS [2]. Dyslipidemia
in PCOS is associated with prevalent insulin resistance, although
not all women with PCOS have IR. Dyslipidemia in PCOS is multi-
factorial. Factors contributing to the dyslipidemia of PCOS has been
the research focus of our group for many years [3]. Understanding
reasons for the dyslipidemia has the potential for reducing CVD,
E-mail address: Robert-Wild@ouhsc.eduoma
of atherogenesis and given our ability to prevent or reverse athero-
sclerotic changes and consequently vascular disease. From a lipid
metabolism perspective, understanding PCOS is intriguing because
the PCOS phenotype is a fascinating biological experiment in nat-
ure. Women with PCOS have androgen excess, IR, variable amounts
of estrogen exposure, and many environmental factors, all of which
can inuence lipid metabolism.
A woman who has PCOS, as any woman, can harbor a rare ge-
netic lipid disorder, such as heterozygous familial dyslipidemia.
Aging, obesity, lifestyle (i.e., physical inactivity, diets high in sat-
urated fat and sugar and low in ber, smoking, illicit drug use)
and medication use can also inuence lipid metabolism in women
with PCOS. Teasing out what is unique to PCOS can be challeng-
ing. Understanding the nuances of dyslipidemia of PCOS in human
populations is especially important, particularly because we still

0039-128X/$ - see front matter 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2011.12.002
296 R.A. Wild / Steroids 77 (2012) 295299

Fig. 1. Triglycerides in PCOS women vs. non PCOS women NIH.

do not have a perfect animal model to study dyslipidemia in
PCOS.
2. Dyslipidemia of PCOS
In non-diabetic non-hypertensive women with PCOS, even in
their early 20s, carefully matched by age to normal women, we
found that circulating triglyceride levels were twice as high,
HDL-cholesterol levels was approximately 60% lower and impor-
tantly non HDL-cholesterol levels were twice as high in PCOS wo-
men compared to normal women [3]. This same pattern of
dyslipidemia has since been found throughout the world. A recent
meta-analyses of published studies was conducted, comparing
clearly diagnosed women with PCOS (either Rotterdam or NIH cri-
teria) with age-matched and carefully examined normal women
[4]. On average, women with PCOS were found to have 26 mg/dL
higher triglyceride [26.39 95% CI (17.24, 35.54)], lower HDL-
cholesterol [6.41 95% CI (3.69, 9.14)], and higher non HDL choles-
terol levels [18.82 95% CI (15.53, 22.11)] than their non-PCOS
counterparts (Figs. 14 see below). This same meta-analysis dem-
onstrated that women with PCOS have higher LDL-concentrations
even in studies employing BMI matching [8.32 95% CI (5.82,
10.81)]. Higher LDL cholesterol levels are found with PCOS, even
when PCOS women are neither overweight nor obese, [9.20 95%
CI (4.68, 13.72)].
Our original ndings were highly controversial because any
investigators believed that this dyslipidemia pattern represented
differences in body weight between PCOS women and controls.
Nevertheless, in weight-matched studies we found elevated circu-
lating triglyceride and non-HDL cholesterol concentrations in

Fig. 2. Triglycerides in PCOS women vs. non PCOS women Rotterdam.

 R.A. Wild / Steroids 77 (2012) 295299 297

Fig. 3. Non HDL cholesterol in PCOS women vs. non PCOS women NIH.

women with PCOS [5]. Both of these indicators of atherogenic tri-
glyceride metabolism correlated with weight in controls but not in
women with PCOS. In our studies, SHBG correlated with HDL cho-
lesterol after adjusting for documented androgen excess in women
with PCOS.
Conrmed in our recent 2011 meta-analysis, in weight-
matched studies, women with PCOS have lower HDL cholesterol,
and higher non-HDL cholesterol, LDL-cholesterol concentrations
as well as higher triglycerides levels than age-matched non PCOS
women. This pattern of dyslipidemia is worse in women with PCOS
who are also obese. Our original studies evaluated women who ful-
lled the NIH denition of PCOS, the severe PCOS phenotype.
Importantly the 2011 meta-analysis found that in studies using
the NIH denition, triglycerides were about 30 mg/dL higher vs.
controls, while in studies using the less severe PCOS phenotypes
by Rotterdam criteria, triglycerides were on average 17.7 mg/dL
(95% CI (8.10, 27.29) higher than controls. Non HDL cholesterol dif-
ferences by NIH criteria were 22 mg/dL higher and those studies
that evaluated PCOS women using Rotterdam criteria averaged
about 14 mg/dL [13.47 95% CI (8.89, 18.05)] higher.
While this dyslipidemia pattern of PCOS is now understood; the
question remains as to what factors contribute to the dyslipidemia
of PCOS. Is it related to hormonal changes that coexist in women
with PCOS? Insulin, estrogens and androgens are each well known
to alter lipoprotein lipid metabolism. In our original cross-sectional
report of lipoprotein lipid prole differences between normal and
PCOS women, ratios of abnormal to normal lipids were similar in
magnitude to differences in serum androgen levels between the
age-matched groups [3], suggesting androgen excess as a contrib-
uting factor. To better understand the inuences of steroidogenic
abnormalities and/or associated insulin resistance in PCOS, we
used GnRHa to remove hyperandrogenism and estrogen excess in
a cohort of Caucasian women with PCOS (n = 30) who participated
in a pre-on study as their own controls. During intervention by
intramuscular GnRHa for 3 months, circulating androgen and
estrogen levels were reduced, conrming ovarian suppression. Tri-
glyceride levels at 3 months follow-up were minimally changed
with androgen and estrogen reduction (mean concentrations went
from 123 to 115.1 mg/dL), as were non-HDL cholesterol levels
(150 mg/dL compared to 147 mg/dL). We also found that apolipo-

Fig. 4. Non HDL cholesterol in PCOS women vs. non PCOS women Rotterdam.
298 R.A. Wild / Steroids 77 (2012) 295299
protein CIII was unchanged from pre to post GnRHa [5] supporting
the hypothesis that altered glucoseinsulin homeostasis is a stron-
ger contributor to the dyslipidemia pattern of PCOS than either
hyperandrogenism or chronic estrogen exposure present in oli-
goovulating women with PCOS.
Regarding PCOS-related abnormalities of apolipoprotein metab-
olism, PCOS women have higher ApoCIII levels compared to non
PCOS controls [6], along with elevated ratios of ApoCIII/ApoCII.
Moreover, Huang et al. found higher Apo-CI concentrations in nor-
mal-weight normo-glycemic PCOS women compared to normal
women [7], suggesting that this apolipoprotein might be a marker
of disturbed metabolism in non obese PCOS women and a predictor
of cardiovascular risk with age in such individuals.
3. Apolipoprotein metabolism
All of us have particles circulating with varying degrees of ath-
erogenic and anti-atherogenic potential. Our bodies have evolved
to normally clear most harmful lipid particles through the liver
and gut, just as we absorb needed lipoproteins for normal mem-
brane functioning, normal steroidogenesis, and other important
physiological needs. When too many particles circulate, by way
of a density gradient mechanism, they are able to enter vessel
walls, initiate an inammatory process that, depending upon
defensive mechanisms, can promote atherogenesis and ultimately
vascular dysfunction. Apolipoproteins on the surface of circulating
particles act like postal codes to help direct particle metabolism
into clearing and/or more reductive atherogenic pathways. Of the
most well-known atherogenic and therefore CVD risk indicators,
ApoA I/ApoB measurement is perhaps the best studied worldwide
[8]. The ApoA family of particles is important in helping with re-
verse cholesterol transport and clearing mechanisms. ApoCIII and
Apo V block ApoB and CII and E transport. ApoB is measured as a
more stable indicator of atherogenic risk than non HDL cholesterol.
ApoB clinically tracks very well with the number of circulating
small LDL cholesterol particles that are highly atherogenic
[911]. Unfortunately ApoB measurement is not as widely avail-
able as is non-HDL cholesterol, which can be easily determined
from a standard lipid prole. Total cholesterol/HDL-cholesterol or
LDL-cholesterol/HDL-cholesterol ratios are actually ApoB/ApoA
surrogates. ApoB is important for particle stability and is a ligand
for the LDL receptor. ApoE can delay VLDL lipolysis. It is also a li-
gand for VLDL and intermediate density (IDL) receptor related pro-
tein. The ratio of ApoCII/CIII determines the activity of lipoprotein
lipase, which is important for metabolizing VLDL as the major
component of triglyceride metabolism. Too much ApoCIII blocks
ApoB and CII and E. The consequences are more circulating highly
atherogenic small LDL-particles. This is the dyslipidemia pattern of
PCOS.
LDL cholesterol measurement sums the measurement of all cir-
culating LDL particles. The total number of circulating atherogenic
small LDL particles seems to be a better predictor of atherogenicity
than is LDL cholesterol measurement per se. For practical purposes,
circulating small LDL particles track with CVD risk in agreement
with ApoB measurements.
4. Apolipoprotein lipids in PCOS
Understanding ApoCIII metabolism is helpful to understanding
the pathophysiology of dyslipidemia of PCOS. PPAR alpha, gamma
Rev-erba, insulin and FXR are all important to the synthesis of
ApoCIII in the liver. Ginsberg and Brown [12] have recently reem-
phasized that in states of IR, elevated glucose leads to increased
synthesis of ApoC-III. In PCOS, with central obesity more free fatty
acids ow into the portal vein and more glucose is available,
causing altered apolipoprotein lipid metabolism. The ratio of ApoC-
III/CII is increased and triglycerides carried in VLDL are broken
down into more atherogenic small LDL particles, which circulate
and enter the arterial wall to initiate inammation. With elevated
triglycerides, as found in PCOS women, VLDL lipolysis is slowed,
causing greater residence time for ApoB, remnant particles, LD par-
ticles and small LDL-particles. ApoCI, recently shown to be elevated
in normal-weight PCOS women, blocks lipoprotein lipase, choles-
terol ester transferase, lecithin cholesterol acyltransferase, VLDL
receptors and LDL receptors in the liver. All of these events lead
to more exposure of the blood vessel wall to entry of atherogenic
particles with the potential for setting inammation and athero-
genesis. The elevated ApoCI levels in normal-weight, glucose toler-
ant PCOS women reported by Huang et al. [7] need to be
conrmed, as do ApoCI and other apolipoprotein particles as mea-
sures of increased risk for atherogenesis and CVD.
4.1. Androgens, hepatic lipase, and small LDL particles
Insulin resistance, androgens and estrogens inuence hepatic
lipase activity, which is important in reductive metabolism of
intermediate density lipoproteins to small dense LDL particles.
Pirwany et al. found greater hepatic lipase activity in PCOS women
compared to controls [13]. They reported that in their PCOS
women, matched to non-PCOS women by BMI, the free androgen
index and waist measurements were each associated with small
LDL particle elevation when triglycerides were elevated. Berneis
and colleagues [14] have measured small LDL in PCOS women
and have found higher prevalence of circulating LDL-II, and IV
subclasses (smaller LDL). Rizzo and colleagues [15] have found that
47% of their Mediterranean women with PCOS have high small
dense LDL. Valkenburg and colleagues have found that women
with PCOS have higher ApoB concentrations and worse ApoA/ApoB
ratios [16].
An important challenge is to understand how much of the
altered lipid metabolism of the PCOS phenotype is because of IR
and how much is because of their disturbed androgen and/or estro-
gen metabolism. How much is linked to processes that eventuate
in what we now diagnose as the metabolic syndrome (MetS)? With
MetS, alterations in glucose and lipid production are intertwined.
Women with PCOS are at high risk for glucose intolerance or overt
Type2 Diabetes Mellitus, with such glucose intolerance intricately
connected to dyslipidemia. Because of the prevalence of MetS in
women with PCOS, sorting out how much dyslipidemia is innate
and how much is because of accompanying processes that lead
to MetS is challenging. Metabolic syndrome with attendant dysli-
pidemia is very prevalent in women with PCOS. Bhattacharya
[17] have reported a high prevalence of MetS in adolescent girls
with PCOS, an alarming concern given obesity as a risk for chronic
associated diseases, particularly early CVD with aging.
5. Epidemiological implications of dyslipidemia in PCOS
Studies tracking women with PCOS longitudinally of duration to
assess long term outcomes have not been performed. This is the
reason there is some degree of uncertainty regarding precision
for estimates of increased CVD risk with PCOS. Surrogate outcomes,
i.e., carotid intima changes are increased in PCOS [18]. Tracking of
dyslipidemic phenotypic changes common to dyslipidemic
changes with PCOS has been studied however. In 1992 William
Castelli reported that risk for CVD became increased in women
as opposed to men in the Framingham Offspring Heart Study when
triglyceride concentrations were above 150 mg/dL, the value now
considered to be upper normal for women. Tanko et al. reported
that an enlarged waist combined with elevated triglycerides is a
 R.A. Wild / Steroids 77 (2012) 295299
very strong risk factor predicting cardiovascular events over
10 years of follow up [19]. In the Womens Health Study, the rela-
tive risk of CVD events was highest in women in the highest quar-
tile of circulating LDL-particles [20]. In the AMORIS study, which
examined the relationship between apolipoproteins and lipids
and myocardial infarction in 76,831 women followed for 66
68 months, in multivariate analysis adjusted for age, total choles-
terol and triglyceride levels, apolipoprotein B was a stronger pre-
dictor of risk than was LDL cholesterol [21]. All of these
dyslipidemic risk indicators are reected in the dyslipidemia of
PCOS.
6. Implications for treatment
Lifestyle modication, including diet and exercise, is the main-
stay of therapy and the rst line therapy for anyone diagnosed with
a signicant dyslipidemia. Many women with PCOS are inactive
and this may be affected by concomitant depression and/or preva-
lent anxiety. Diets considered heart healthy are recommended.
Adequate fruits, vegetables, polyunsaturated fats and ber are
the main components of heart healthy dietary interventions. Exer-
cise is tailored and specic for age group and living circumstance.
Many patients with PCOS have developed a metabolic syndrome at
an early age. Practical targets for therapy include keeping LDL cho-
lesterol and ApoB levels below atherogenic thresholds (ApoB lev-
els < 80 mg/dL) and keeping blood pressure under systolic
130 mg/dL and/or diastolic blood pressure < 85 mg Hg, unless the
patient is already diabetic (<130/80). Triglycerides should be kept
under 150 mg/dL. LDL-cholesterol is the primary target (reected
in ApoB) and non-HDL cholesterol is a secondary target. Medica-
tion is used when diet and exercise are not enough. Statins are
the rst line therapy to keep LDL-cholesterol at threshold (unless
at risk of pregnancy) and secondary medications include Niacin, Fi-
brates, and bile Sequestrants depending upon the lipid pattern. A
useful guide for intervention is provided in the androgen excess
statement regarding PCOS and CVD risk [22].
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