Review

Metabolic syndrome and oocyte quality

Eden Cardozo, Mary Ellen Pavone and Jennifer E. Hirshfeld-Cytron
Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, 676 N St Clair Street Suite 1845
Chicago, IL 60611, Evanston, IL, USA

Metabolic syndrome affects one in four women in the

USA, and the incidence is rising every year. Metabolic
syndrome is strongly associated with development of
coronary artery disease and diabetes. Women of reproductive age are not spared from the complications of
metabolic syndrome, which overlaps with obesity and
polycystic ovary syndrome (PCOS), both of which are
linked to infertility and poor reproductive outcome.
Therefore, the relationship between the metabolic syndrome and reproductive dysfunction is an active area of
study. In this review, we discuss the animal and human
data available to determine if the abnormality is at the
level of the ovary and/or endometrium, and discuss the
underlying mechanisms causing the associated poor
reproductive outcomes.
Background
Metabolic syndrome is a growing health epidemic, currently affecting nearly 25% of all women in the USA [1]. The
syndrome is defined by both lipid and non-lipid criteria,
and identifies individuals at increased risk for coronary
heart disease and type 2 diabetes [24]. Its prevalence
increases with age, and there has been a significant increase in its incidence among women of reproductive age;
that is, those aged 2039 years [1,5,6]. Central obesity has
the strongest correlation with metabolic syndrome [7].
Metabolic syndrome is present in 28% of overweight and
50% of obese women [6]; furthermore, in women with
abdominal obesity (defined as a waist circumference
>89 cm), 43% develop metabolic syndrome within 5 years
[8]. In addition, insulin resistance is present in the vast
majority of cases [9] (Table 1). Thus, central obesity and
insulin resistance are thought to be the two major risk
factors for the development of metabolic syndrome [10,11],
and in this review, we focus on the effects of these metabolic disturbances on oocyte quality.
Many of the metabolic abnormalities of metabolic syndrome overlap with those of polycystic ovary syndrome
(PCOS), a common condition affecting 58% of women of
reproductive age in the USA [12,13]. PCOS is characterized by chronic lack of ovulation and presence of hyperandrogenism, with variable clinical features including
oligomenorrhea, infertility and hirsuitism (Table 2). Because women with PCOS have high rates of glucose intolerance and type 2 diabetes, in addition to several risk
factors for cardiovascular disease, it has been assumed
that many are also likely to meet the criteria for metabolic
syndrome. Additionally, it is believed that both PCOS and
metabolic syndrome might share the same pathogenesis,

namely, hyperinsulinemia and glucose intolerance [10]. A

link between these two conditions has been reported in
many studies [1416], with the presence of metabolic
syndrome ranging from 33% to 46% of women with a
diagnosis of PCOS. In fact, 33.4% of women with PCOS
in a study also had undiagnosed metabolic syndrome, with
obesity having an independent effect on the development of
metabolic syndrome [15]. Specifically, women in the highest quartile of body mass index (BMI) had a increase of
nearly 14-fold in the risk of having metabolic syndrome,
compared with women in the lowest quartile of BMI
(Table 3). Interestingly, none of the women with PCOS
who had a BMI of <27.0 kg/m2 met the criteria for metabolic syndrome [15].
Obesity on its own results in an increased risk of infertility, mostly because of ovulatory dysfunction, and is also
associated with negative reproductive outcomes (Table 4).
Specifically, the risk of anovulatory infertility increases
with increasing BMI. Women with a BMI of >30 have been
found to be nearly three times as likely to have anovulatory
Glossary
Anovulation: a condition in which ovulation does not take place. Sex steroids
are still produced, but not cyclically, resulting in unpredictable endometrial
bleeding of variable flow and duration.
First-cycle recipients: for each recipient of donor oocytes, data was collected
from their first IVF cycle in which they received a donor oocyte, but not
subsequent cycles if the first cycle failed.
Functional competence: often refers to oocyte quality and its ability to perform
its essential function for reproduction, namely, resumption of meiosis and
embryo development.
Hirsuitism: development of androgen-dependent terminal body hair in a
woman. Polycystic ovary syndrome (PCOS) is one of the most common
causes.
Hyperandrogenism: excessive production and/or secretion of androgens.
The major androgens in the serum of normal cycling women are dehydroepiandrosterone (DHEA), androstenedione (A), and testosterone (T). In PCOS,
hyperandrogenism presents clinically as hirsutism, acne, and male pattern
balding.
Inhibin B: a hormone produced in the gonads, pituitary gland, placenta and
other organs. FSH stimulates the secretion of inhibin from the granulosa cells
of the ovarian follicles in the ovaries. In turn, inhibin suppresses FSH. Inhibin B
reaches a peak in the early to mid-follicular phase, and a second peak at
ovulation.
Luteal pergnanediol glocuronide (Pdg): a hormone used to identify a functional
corpus luteum. A significant rise in urinary Pdg can be considered evidence of
luteal activity, which correlates with presumed ovulation.
Oligomenorrhea: menstrual bleeding that occurs at an interval > 35 days.
Pre-eclampsia: a syndrome defined by new onset of hypertension and
proteinuria after 20 weeks of gestation in a previously normotensive woman.
Pregnancy category C drug: animal reproduction studies have shown an
adverse effect of the drug on the fetus, and there are no adequate and wellcontrolled studies in humans, but potential benefits might warrant use of the
drug in pregnant women despite the potential risks.
Oocyte donation model: a model that uses oocytes of a donor (in this context
non-obese women) and donates them to recipients (in this context, women of
variable BMI), then examines the outcomes to distinguish the effect of
endometrial receptivity from oocyte quality.

Corresponding author: Hirshfeld-Cytron, J.E. (jhirshfeldcytron@gmail.com)

1043-2760/$ see front matter 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2010.12.002 Trends in Endocrinology and Metabolism, March 2011, Vol. 22, No. 3

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Trends in Endocrinology and Metabolism March 2011, Vol. 22, No. 3

Table 1. Definition of the metabolic syndrome [10,11]

Source
Measure

National Cholesterol Education Program/Adult Treatment Panel III

Presence of any three of the five clinical criteria

Clinical criteria

1.
2.
3.
4.
5.

Elevated waist circumference (central obesity)

Elevated triglycerides
Reduced HDL cholesterol
Elevated blood pressure
Elevated fasting glucose

International Diabetes Federation

Presence of central obesity
plus any two of the four clinical criteria
1. Elevated triglycerides
2. Reduced HDL cholesterol
3. Elevated blood pressure
4. Elevated fasting glucose

HDL, high-density lipoprotein.

Table 2. Criteria for defining PCOS [6769]

Source
Measure
Criteria

NIH (1990)
Two of two criteria
1. Chronic anovulation
2. Clinical and/or biochemical
signs of hyperandrogenism
and exclusion of other
etiologies

Rotterdam (2003)
Two of three criteria
1. Oligovulation or anovulation
2. Clinical and or biochemical
signs of hyperandrogenism
3. Polycystic ovaries and exclusion
of other etiologies

Androgen Excess and PCOS Society (2009)

Three of Three criteria
1. Hyperandrogenism (hirsutism and/or hyperandrogenemia)
2. Ovarian dysfunction (oligovulation or anovulation and/or
polycystic ovaries)
3. Exclusion of other androgen excess or related disorders

NIH, National Institutes for Health.

Table 3. World Health Organization BMI classification

Classification
Underweight
Normal
Overweight
Obese

BMI
<18.5
18.524.9
25.029.9
>30.0

BMI, body mass index.

infertility when compared with women with a BMI of <24

[17]. Obesity also negatively affects pregnancy; overweight
and obese women are at increased risk for miscarriage [18],
and compared with women of normal weight, obese women
are twice as likely to have a stillbirth [19]. Furthermore,
obese mothers are at increased risk of having pregnancies
complicated by congenital anomalies, neural tube defects
and spina bifida [20]. Some of the proposed mechanisms of
the negative effects of obesity on pregnancy outcomes
include hyperglycemia, nutritional deficiencies (reduced
folate levels), hypertension, decreased sensitivity of ultrasonography, and decreased ability to perceive a decrease in
fetal movement [19,20]. This remains a very active area of
investigation.
These negative reproductive outcomes associated with
obesity are known to be reversible. Weight loss has been
shown to improve both ovulation and pregnancy rates and
decrease miscarriage rates in both obese and PCOS women
[21,22]. Bariatric surgery has become increasingly common
among women of reproductive age, with more than 150,000
procedures performed in women aged 1845 years in the

period 20032005 [23]. Although data are limited, initial

studies of reproductive outcomes after bariatric surgery
suggest improvement in fertility rates [24,25] and a decrease in obesity-associated pregnancy complications (including gestational diabetes and pre-eclampsia) [23,24].
Reproductive hormone levels (including luteal pergnanediol glocuronide and whole cycle luteinizing hormone)
show some improvement with weight loss at 612 months
after bariatric surgery, indicating a partial return of luteal
function, but hormone levels do not return to those seen in
women of normal weight [26].
Studies have also shown that obesity hinders assisted
reproductive techniques. Compared with women with a
BMI of <25, overweight and obese women have a lower
chance of pregnancy with in vitro fertilization [27]. When
undergoing assisted reproduction, overweight and obese
women require higher doses of gonadotropins [27], have
fewer oocytes retrieved, and have lower fertilization rates
[28,29]. A study evaluating the effect of BMI on fecundity
found that women with a normal BMI have a 60% higher
chance of achieving pregnancy compared with women
having a BMI of >35 [30]. Overweight and obese women
also have an increased miscarriage rate [27] and an overall
lower live birth rate after in vitro fertilization, compared
with women of normal weight [31].
Literature search
Given the known adverse reproductive outcomes associated with components of the metabolic syndrome, we were

Table 4. Implications of metabolic syndrome and PCOS on reproductive dysfunction [14,13,15,17,21,22,24,25,7073]

PCOS

Obesity

Prevalence
58% Women of
reproductive age

Effect on fertility
Anovulation

Metabolic syndrome
3075% obese, 3040%
impaired glucose
tolerance

25% of women
in the USA

Anovulation;
BMI >30 leads to
3  the risk of infertility
compared with BMI <24

Insulin resistance,
risk factor for diabetes
and CVD

ART, Assisted reproductive technology; CVD, cardiovascular disease.

104

Mechanism
1. ?Hyperinsulinemia
2. Hyperandrogenism
leading to amenorrhea/
infertility
1. ?Insulin resistance/insulin
excess
2. Hyperandrogenism lead
to amenorrhea/infertility

Potential therapy
1. Weight loss/exercise
2. Insulin sensitizers
3. ART
1. Weight loss/exercise
2. ? Bariatric surgery

Review
interested in exploring the effects of the metabolic syndrome specifically on the oocyte. We conducted a review on
PubMed from 19952010, using the following search terms
in various combinations: oocyte, oocyte quality, metabolic syndrome, obesity, overweight, body mass index,
BMI, diabetes, maternal, reproduction, reproductive
outcome, IVF, pregnancy, and PCOS. Abstracts were
evaluated to identify studies appropriate to the review.
Additional references were identified by manually searching the reference lists of studies identified by our original
search. Articles published before 1995 that provided essential background were not excluded.
Obesity and insulin resistance, two major components of
the metabolic syndrome, have been shown in both animal
and human data to have a negative effect on oocyte quality,
subsequent pregnancy rates and reproductive outcomes.
Given the limited number of data investigating the role of
metabolic syndrome itself on reproductive outcomes, and
the understanding that central obesity is strongly correlated with the metabolic syndrome, we will use the terms
obesity and metabolic syndrome interchangeably from
this point forward.
Animal studies
Effects of obesity on oocyte quality
Animal studies have demonstrated the negative effect
that both obesity and insulin resistance have on oocyte
quality. A recent study examined the relationship between
obesity, insulin resistance and oocyte quality in mice.
Female mice were fed a high-fat diet (HFD) for 16 weeks
to induce obesity and insulin resistance, and then caged
with a male mouse. Females were examined daily, and if a
postcoital vaginal plug was present, they were declared
pregnancy day 1, thus, blood and ovulated oocytes were
collected, and ovarian effects assessed and compared with
lean control animals [32]. Mice in the HFD group were less
likely to have ovulated; however, those in the subset of
HFD mice that did ovulate had an increased ovulation
rate. Ovulated and denuded oocytes of obese and control
mated females were then placed in in vitro media, and
assessed for fertilization and appropriate development of
the fertilized oocyte [32]. Fertilization rates were similar,
but the embryos of HFD mice had slower development at
all embryonic milestones assessed (48 cell stage, morula/
early blastocyst stage, hatching blastocyst stage) [32,33].
Blastocysts from HFD mice also had a higher ratio of
trophectoderm to inner cell mass (ICM) than did controls
[32].
A phenotype of this altered ratio has been shown to be
developmentally significant, as the sizes of pre-implantation lineages in rodent models exert long-term effects
throughout gestation, potentially because of aberrant allocations of stem cells required for normal growth [34]. More
specifically, a decrease in ICM has been linked to fetal
growth restriction and large placentas in a diabetes model,
and to abnormally large offspring in sheep and cattle
models [3537]. This study demonstrated that oocytes from
obese animals have inherent differences that affect in vitro
embryonic development, and that the effects of obesity and
insulin resistance on the oocyte occur even before fertilization. Interestingly, these effects maintain their influence

Trends in Endocrinology and Metabolism March 2011, Vol. 22, No. 3

after the oocyte has been removed from the aberrant

maternal metabolic environment. [33].
The negative consequences of obesity on the oocyte were
further explored in a study comparing the pre-ovulatory
ovarian follicles of female mice that had HFD-induced
obesity with those of controls in the pre- and peri-conceptual periods. Ovaries were stained for follicular apoptosis
or dissected to evaluate oocyte size and meiotic maturation. Obese mice had significantly more apoptotic ovarian
follicles, and smaller and fewer mature oocytes, compared
with controls [38]. This finding is notable, as human studies indicate that oocytes retrieved from smaller follicles
have lower fertilization and cleavage rates [39]. In fact, a
recent study demonstrated that patients with PCOS [40],
particularly obese patients with PCOS, had smaller
oocytes than did lean patients with PCOS and control
women. Therefore, decreased oocytes size might be an
important marker of decreased oocyte quality.
Altered mitochondrial activity has been proposed as a
mechanism for compromised oocyte quality and poor reproductive outcomes in obese females [41]. It is known that
correct mitochondrial quality, quantity and distribution
plays a key role in the functional competence of oocytes,
as mitochondria are maternally inherited and do not begin
replicating until after implantation, therefore any mitochondrial deficiencies could negatively affect the ability of
the embryo to progress through the pre-implantation stages
[4245]. Indeed, the oocytes of obese mice have increased
inner mitochondrial membrane potential, uneven distribution of mitochrondria throughout the ooplasm, increased
generation of reactive oxygen species, and a more oxidized
redox state [41]. The increased oxidative stress in the
oocytes of obese mice results in upregulation of mitochondrial biogenesis and increased mitochondrial DNA
(mtDNA) copy number, but might also cause damage to
the mtDNA itself [41]. The oocytes of these mice demonstrated decreased ability to develop to the blastocyst stage
compared with those of non-obese mice, indicating the
importance of correct mitochondrial function for normal
embryonic development [41].
Insulin resistance and oocyte quality
To differentiate the effects on oocyte development of insulin resistance from those of obesity, obese and insulinresistant mice were treated before mating with one of
three insulin-sensitizing and plasma glucose-reducing
medications given once daily for 4 days: 5-aminoimidazole
4-carboxamide-riboside (AICAR), a glucose- and lipid-lowering AMP kinase activator; sodium salicylate, an ILL
inhibitor that reverses insulin resistance; or rosiglitazone,
a peroxisome proliferator-activated receptor gamma
(PPARg) transcription factor agonist. The effects of each
drug on ovulation and on early embryonic developmental
competence in vitro were compared to identify important
cellular pathways in the periconception ovarian response
to obesity or insulin resistance [32,33]. Treatment with
rosiglitazone reversed the poor oocyte quality caused by
diet-induced obesity, including normalizing early embryo
development rates and the trophectoderm:ICM ratio to
those of females on the control diet. Rosiglitazone concomitantly lowered blood glucose, insulin and triglyceride
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Review
levels [32]. This indicates that oocytes are affected by
insulin sensitivity, and that treatment of obese/insulinresistant females with an insulin sensitizer before conception can significantly improve embryonic developmental
competence [33]. Neither AICAR nor sodium salicylate had
any effect on the aforementioned parameters (other than
lowering the level of circulating insulin). Because rosiglitazone was the only insulin sensitizer that effectively
improved oocyte quality and increased embryonic developmental competence, it is likely that its target, the transcription factor PPARg, plays an important role in the
effect of metabolism on oocyte quality [32,33].
PPARg is thought to influence ovarian function both
directly, and through its influence on other tissues including adipose tissue and immune cells, which in turn affect
lipid uptake and transport, glucose metabolism, insulin
sensitivity and regulation of inflammatory mediators,
which (as will be discussed in this review), all have an
effect on the oocyte [46]. It remains unclear whether rosiglitazone exerts its effect on oocytes via improvements to
systemic metabolic parameters (such as insulin sensitivity), by direct action on PPARg-regulated gene expression
in ovarian cells, or a combination of both [32]. More research is needed to understand the mechanism of action of
this drug. Of note, rosiglitazone is a pregnancy category C
drug (not tested for use during pregnancy); however, studies in mouse models report no adverse embryonic or fetal
outcome when administered during pregnancy [47]. Therefore, rosiglitazone has the potential to be a useful intervention to improve reproductive outcomes in pregnant
women with metabolic syndrome, but more research is
needed to confirm its safety in pregnancy.
Effect of obesity on fetal and neonatal development
The effects of obesity and insulin resistance persist beyond
the pre- and peri-conception period, effecting embryonic
development and reproductive outcomes, and the growth
and development of offspring. Embryos recovered from
obese mice had decreased embryonic insulin-like growth
factor I receptor (IGF-IR) expression at the blastocyst stage,
an indicator of insulin resistance in the embryo [38]. Obese
mice also demonstrated increased placental IGF-2R mRNA,
a maternal gene known to influence placental and fetal size
[38]. Increased expression of placental Igf2r is known to
decrease embryonic growth and birth weight [48]. Indeed,
these obese mice produced smaller fetuses and smaller pups
[38]. Furthermore, after 13 weeks, the pups delivered from
obese mice (despite being fed the same diet as controls) were
larger, and showed evidence of glucose intolerance, increased cholesterol and higher body fat percentage, suggestive of the early development of metabolic syndrome [38],
providing additional evidence that exposure to the altered
maternal metabolic environment translates to health consequences for the offspring. The negative influence of the
altered maternal metabolic environment probably exerts its
effect even before the embryo develops. Evidence shows that
exposure of the oocyte and subsequent embryo to a diabetic
environment has a negative effect on the fetus, even when
the fetus is removed from the diabetic environment as early
as the one-cell zygote stage [49]. For example, zygotes from a
diabetic mouse model transferred at the one-cell stage to a
106

Trends in Endocrinology and Metabolism March 2011, Vol. 22, No. 3

non-diabetic gestational carrier showed higher rates of

growth retardation and congenital malformations, including neural tube defects [49]. This highlights the long-lasting
consequences of an abnormal metabolic environment on the
progeny of obese animals.
Human studies
Effect of obesity on oocyte quality
Human studies have further demonstrated the effect of
obesity and insulin resistance on oocyte quality. Obesity
has been associated with lower levels of anti-mullerian
hormone (AMH), a hormone secreted by granulosa cells of
the ovary, which can indicate decreased ovarian reserve or
available secondary follicles in obese women [50]. AMH
levels have been found to increase as a reflection of PCOS
severity; however, among women with PCOS, obese women still have lower levels of AMH compared with non-obese
women [51]. Obese women also have lower levels of LH
than do women of normal weight, and an independent
positive association between LH and AMH levels has been
demonstrated, which might explain the lower levels of
AMH in obese women [51]. Higher BMI is also associated
in pre-menopausal women with lower inhibin B levels,
another indirect marker of ovarian function [52]. Furthermore, women with BMI >25 have lower excretion of gonadotropins and luteal phase progesterone metabolites,
implying that obesity has a negative effect on corpus
luteum function [53]. Thus, follicular dysfunction exists
in obese women, even in those not ovulating.
In cases of assisted reproduction, implantation and pregnancy rates are lower in overweight subjects versus those of
normal weight [27,30,54]. The oocyte donation model has
been used to distinguish whether oocyte/embryo quality or
uterine receptivity is the cause of decreased implantation
rates. A retrospective study analyzed 97 first-cycle recipients of oocyte donation under conditions of controlled hormonal stimulation and embryo quality, and found no
relationship between recipient BMI and implantation rates
[55]. This implies that the oocyte or embryo, not uterine
receptivity, is the cause of decreased pregnancy rates in
obese women. However, this was a small study and might
not have been sufficiently powered to detect a small effect of
obesity on uterine receptivity [55]. Further evidence that
BMI does not negatively affect endometrial receptivity came
from another retrospective study of 536 first-cycle recipients
of donor oocytes, and concluded that BMI does not adversely
affect rates of implantation, ongoing pregnancy or spontaneous abortion in recipients of donor oocytes [56]. A case
control study that analyzed 134 embryo transfers in which
one donor was matched with two recipients, and discordant
outcomes (only one ongoing pregnancy) among recipient
pairs were assessed, found that BMI was not a predictor
of success [57], further supporting the hypothesis that BMI
does not affect uterine receptivity, and that poor-quality
oocytes and resulting embryos are probably the cause of poor
reproductive outcomes in overweight women undergoing
fertility treatment.
Mechanisms of decreased oocyte quality
Studies directly studying oocyte quality have suggested
that an altered maternal metabolic environment results in

Review
an abnormal follicular fluid microenvironment, and subsequently poor oocyte and embryo quality. A study exploring
differences in the pre-ovulatory follicular environment of
obese women, by analyzing aspirated follicular fluid at
oocyte retrieval, found that women with higher BMI had
increased levels of insulin, lactate, triglycerides and
C-reactive protein (CRP) in the follicular fluid, and had
decreased levels of steroid hormone-binding globulin [58],
indicating that the maternal metabolic environment has a
direct effect on the ovarian follicular microenvironment.
The increased level of CRP in the follicular fluid of obese
women is of particular concern, because it might indicate
inflammation and increased oxidative stress, which has
been associated with decreased developmental potential in
the oocyte [58,59]. The increased oxidative stress might be
a potential additional mechanism by which obesity affects
oocyte quality.
A retrospective analysis of the in vitro fertilization (IVF)
cycles of women with polycystic ovaries noted that, compared with controls or women with polycystic ovaries
without insulin resistance or obesity, women with insulin
resistance, obesity and polycystic ovaries, had decreased
oocyte quality, as evidenced by lower fertilization rates and
failure of implantation in both self and recipient uteri;
however, successful pregnancy often occurred on the first
attempt with a donor oocyte. The ability of the donor oocyte
to improve pregnancy success suggests that poor oocyte
and embryo quality, rather than the endometrium, was the
causative factor. [60]. Alternatively, a retrospective analysis of the effect of BMI on 426 IVF/ intracytoplasmic sperm
injection (ICSI) cycles determined that BMI has no effect
on oocyte quality, but negatively affects embryo development in young women [61]. To address these disparate
findings on the effect of BMI on IVF outcome, a recent
retrospective analysis examined oocyte quality by light
microscopy. By defining good quality as the ability to
resume meioisis (metaphase I and II oocyte) and poor
quality as the remainder (germinal vesicle stage, atretic
and degenerated oocytes), this study found a significant
difference in the rate of good-quality oocytes retrieved
depending on BMI classification, with the highest percentage of good-quality oocytes obtained from the normal
weight group compared with the overweight (BMI 25)
or underweight (BMI <20) groups [62]. A recent retrospective analysis of women with PCOS undergoing IVF/ICSI
found that both obesity and PCOS independently resulted
in smaller oocyte size compared with the control group [40],
which is consistent with data from insulin-resistant and
obese mouse models. However, little is known about the
effect of oocyte size on developmental competence and
pregnancy outcomes, and thus this is an important area
for future research. Overall, these studies suggest that
insulin resistance and obesity do have a direct negative
effect on oocyte quality, but more studies are needed to
clarify the exact mechanism of decreased oocyte quality.
Obesity negatively affects endometrial receptivity
As mentioned, it is possible that obesity results in poor
endometrial receptivity, which might also contribute to
the poor reproductive outcomes seen in obese women.
The oocyte donation model has been used to evaluate the

Trends in Endocrinology and Metabolism March 2011, Vol. 22, No. 3

effect of obesity on the endometrium, independent of its

effect on oocyte quality. A retrospective study using this
model assessed the risk of BMI on spontaneous abortion in
712 oocyte donor cycles (oocyte donors were 25.8  4.2 years
of age, with normal BMI, and no phenotypic or ultrasonographic evidence of PCOS) [63]. A significant increase in
spontaneous abortion rate was seen in the obese (BMI >30)
group compared with the normal and overweight groups,
but not in the overweight group compared with the normal
weight group [63]. The finding that BMI >30 is a negative
predictor of pregnancy after oocyte donation has been supported by a subsequent study [64]; however, these data
might have been influenced by the exclusive use of transfer
of freezethawed embryos. A subsequent study examined
2656 first ovum donation cycles with good-quality embryos
from healthy young women (26  4.3 years old) with normal
BMI, recording IVF/ICSI outcome based on BMI. This study
found that as BMI increased, there was a significant decrease in implantation rate and ongoing pregnancy rate [65].
Each of these studies implies that obesity has a negative
effect on the endometrium, and independent of its effect on
oocyte quality, this might play a role in the reproductive
outcomes of obese patients.
Further supporting the evidence that poor endometrial
receptivity contributes to inferior reproductive outcomes in
obese women, a subsequent retrospective study of 6500
IVF/ICSI cycles divided into groups based on BMI found no
difference in fertilization rate, day of embryo transfer,
number of transferred or cryopreserved embryos, percentage of blastocyst transfers, or embryo quality (number of
blastomeres and embryo fragmentation) on days 2 or 3, but
did find a significant progressive reduction in pregnancy
and live birth rates with each unit increase in BMI [66].
This suggests that there is no effect of BMI on oocyte and
embryo quality, and that the endometrium might play a
larger role than previously thought in the impaired IVF
outcomes of obese women [66]. However, the study methods have been criticized [56] for not restricting data to only
first cycles [63,64,66] and allowing recipients to be counted
in the data for multiple cycles, thus certain patients with
other risk factors for failed cycles might be over-represented in the dataset. More research is needed to clarify
the effect of obesity on the endometrium, and the role this
plays in conjunction with or as an alternative to poor oocyte
quality as the cause of decreased reproductive function in
obese women.
Conclusions
Metabolic syndrome has a major adverse effect on reproductive outcome, and this review emphasizes that the
negative effects of obesity and insulin resistance on fertility, pregnancy, and the health of offspring begin with its
effect on the quality of the pre-conception oocyte and
subsequent embryo. Furthermore, this review emphasizes
the need for further research in the field to understand the
exact mechanism of impaired oocyte quality, and to clarify
the existence and effect of obesity-associated decreased
endometrial receptivity. Although this review makes it
clear that an altered maternal metabolic environment is
directly associated with decreased function of oocytes and
endometrium and associated poor reproductive outcomes,
107

Review
the evidence also clearly demonstrates the benefit of
weight loss in improving reproductive parameters and
reproductive outcome. Given the constantly increasing
prevalence of obesity among women of reproductive age,
it is essential that women be counseled on the reproductive
risks of obesity and insulin resistance, and the proven
benefits of lifestyle modification. At present, no published
studies have addressed if and how well women are being
counseled, and what women understand about the effects
of obesity on reproductive outcomes. This is an important
area of intervention for public health. An altered metabolic
environment negatively affects reproductive outcomes before conception even occurs, therefore it is essential that
intervention occurs in the pre-conception period. As the
obesity epidemic imprints its deleterious effects onto subsequent generations, a nationwide effort to curtail this
growing problem needs to be a primary focus of our healthcare system.
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