Review

Polycystic ovary syndrome and insulin: our

understanding in the past, present and
future

Insulin resistance is prevalent in women with polycystic ovary syndrome (PCOS), Stéphanie B Mayer*,1, William
and plays a critical pathophysiologic role in both the metabolic and reproductive S Evans2 & John E Nestler1
complications of PCOS. This review focuses on the contribution of insulin resistance
1
Division of Endocrinology & Metabolism,
Virginia Commonwealth University,
to anovulation in PCOS and to the high risk for Type 2 diabetes, metabolic syndrome
Richmond, VA, USA
and early cardiovasular disease. Key points for clinicians emphasized by this review 2
Division of Endocrinology & Metabolism,
are the following: PCOS is a clinical diagnosis and alternative diagnoses must be University of Virginia, Charlottesville,
excluded; PCOS carries an inherent risk of insulin resistance and, hence, metabolic VA, USA
consequences for which women with PCOS should be screened regardless of BMI or *Author for correspondence:
Tel.: 804 828 9696
degree of obesity; and PCOS is associated with infertility and this should be discussed
Fax: 804 828 8389
early on in care of women diagnosed with PCOS, recognizing that there are several smayer@ mcvh-vcu.edu
possible strategies to address infertility in women with PCOS, each with its own risks
and benefits.

Keywords:  cardiovascular disease risk • infertility • insulin • insulin resistance

• metformin • PCOS

Evolution of a definition of ultrasound imaging to ovarian tissue; rec-

In 1935, Stein and Leventhal described the
association of oligo- or amenorrhea, hirsut-
ism and obesity with polycystic ovaries, label-
ing this the Stein–Leventhal syndrome [1] .
This syndrome was initially defined as
chronic anovulation associated with andro-
gen excess, phenotyped as women with hir-
sutism, seborrhea, acne and alopecia, and,
rarely, virilization. Presence of all phenotypic
features simultaneously was required to meet
the diagnosis of Stein–Leventhal syndrome,
and treatment consisted primarily of bilateral
ovarian wedge resection.
Subsequently it came to light that both
obese and lean women with certain – but
not necessarily all – of the above features
were presenting to clinicians, prompting a re-
evaluation of the syndrome and resulting in
a new syndrome called the polycystic ovary
syndrome (PCOS) with an expanded defi-
nition. Advances in technology over time,
including means of measuring serum gonad-
otropins and sex steroid levels; the application
ognition of the presence of insulin resistance
as a feature of this syndrome; recognition of
hereditary differences in degree of sensitiv-
ity to circulating androgens by target tissues;
and association and linkage analysis stud-
ies indicating that PCOS is a multifactorial
polygenic disorder, have further expanded
the definition. It became evident that women
with PCOS could be obese or thin, with a
range of androgen-related cosmetic issues.
The diagnosis of PCOS is ultimately a
clinical one, and no one specific test is diag-
nostic of the syndrome. The most commonly
cited definitions of PCOS are those drafted
at the NIH in 1990, commonly referred to
as the NIH Expert Conference, and the sub-
sequent statement issued from Rotterdam
in 2003. The NIH Expert Conference [2]
definition of PCOS requires that all of the
following criteria be met: clinical hyperan-
drogenism and/or biochemical hyperandro-
genemia; chronic oligo- or anovulation; and
part of
exclusion of other causes of androgen excess

10.2217/WHE.14.73 © 2015 Future Medicine Ltd Womens Health (2015) 11(2), 137–149 ISSN 1745-5057 137
Review  Mayer, Evans & Nestler
or oligoovulation, such as hyperprolactinemia, hypo-
or hyperthyroidism, congenital adrenal hyperplasia
and hypercortisolism. In contrast, the Rotterdam cri-
teria of 2003 [3] designates as PCOS, after exclusion
of differential for hyperandrogenism and oligoovula-
tion, whenever two out of the three following criteria
are met: first, chronic oligo- or anovulation; second,
clinical and/or biochemical hyperandrogenism; OR
third, anatomically polycystic ovaries on ultrasono-
graphic imaging. The Rotterdam definition is in effect
more inclusive. It includes all women who would be
diagnosed by the NIH criteria, but also adds two new
phenotypes: women who are ovulatory but have poly-
cystic ovaries and hyperandrogenism, and oligo- or
anovulatory women with polycystic ovaries but with-
out clinical or biochemical signs of hyperandrogenism.
This expansion of the definition and inclusion of two
new categories of women with PCOS have led to some
controversy as to the clinical implications of the syn-
drome [4] . Specifically, perhaps not all phenotypes carry
the same metabolic and vascular risk association. One
must also keep in mind that anovulation, of any cause,
may lead to polycystic ovaries on ultrasound evalua-
tion in 75% of those evaluated [5] , and that ∼23% of
normal volunteers without any menstrual disturbance
had polycystic ovaries on ultrasound, more commonly
in younger women [6] .
The Androgen Excess Society guidelines sought to
arbitrate the above controversy and proposed that the
definition of PCOS be similar to the Rotterdam cri-
teria, with the caveat that hyperandrogenism must be
present [7] , stating that PCOS is distinguished by the
presence of hyperandrogenism.
For the clinician evaluating an individual patient for
the diagnosis of PCOS, it is critical to start with a thor-
ough history and physical examination, and obtaining
serum total and free testosterone and DHEA-sulfate
levels to evaluate for hyperandrogenemia and screen for
androgen-secreting ovarian or adrenal tumors. Tests
to exclude other causes of oligoovulation or androgen
excess should also be obtained, such as serum prolac-
tin, 17α-hydroxyprogesterone (to exclude non-classical
congenital adrenal hyperplasia), thyroid-stimulating
hormone (TSH) and in cases where warranted by clin-
ical suspicion testing to exclude Cushing’s syndrome
(either a 24-h urine collection for creatinine and free
cortisol, or a 1 mg overnight dexamethasone suppres-
sion test). In cases of oligo/anovulation without clini-
cal or biochemical signs of hyperandrogenism, con-
sideration should be given to obtaining a pregnancy
test and serum estradiol, follicle-stimulating hormone
(FSH) and  luteinizing hormone (LH) to exclude pre-
mature ovarian failure or functional hypothalamic
amenorrhea.
138 Womens Health (2015) 11(2)
Metabolic consequences of PCOS
Insulin resistance in PCOS
One of the earliest reports linking insulin resistance
to PCOS was the 1921 treatise by Emile Achard and
Joseph Thiers on the diabetes of bearded women (i.e.,
diabète des femmes à barbe). Decades later, the obser-
vation in 1976 that young women who are hyperinsu-
linemic due to a genetic defect in the insulin receptor
are also virilized led to the concept that insulin may
play a critical role in PCOS [8,9] . Further study of PCOS
women demonstrated a positive correlation between
serum concentration of fasting serum insulin and of
testosterone and androstenedione [10] . It has since been
demonstrated in cultured human ovarian tissue that
insulin stimulates ovarian testosterone production by
theca cells from women with PCOS [11] , and in vivo
studies have demonstrated that suppression of insulin
release in women with PCOS reduces ovarian cyto-
chrome P450c17α activity [12] and circulating testoster-
one levels [13] . Further, IGF receptors have been discov-
ered in ovarian cells which also produce IGF-binding
proteins. IGF-1 and IGF-II, structurally related to
insulin, similarly participate in normal follicle develop-
ment [14,15] . These observations support the idea that
in women with PCOS hyperinsulinemia stimulates
ovarian androgen production and contributes to the
hyperandrogenemia. Figure 1 is a proposed schema in
which insulin resistance, in the setting of predisposing
genetic factors, is a critical driver of hyperandrogenism.
To this day, however, the directionality of events – that
is, whether hyperinsulinism causes hyperandrogenism,
vice versa, or both – remains to be fully elucidated.
Role of insulin resistance in androgen excess
in PCOS
Several lines of evidence support the idea that insu-
lin resistance and its compensatory hyperinsulinemia
are intrinsic to the PCOS state and play a key role in
producing the androgen excess of PCOS. First, women
with PCOS who have undergone either partial [16] or
total [17] oophorectomy, or have been treated with a
long-acting gonadotropin-releasing hormone agonist
to supress pituitary LH and FSH release [18,19] , still
remain insulin-resistant despite a hypoandrogenic
state. Also, girls who are pre-pubertal can have symp-
toms of hyperinsulinemia with acanthosis nigricans
years before elevations in serum androgens appear [20] ,
suggesting that the insulin resistance may precede the
hyperandrogenism of PCOS. Finally, normal men have
significantly higher androgen levels than women with
PCOS but do not demonstrate the insulin resistance or
hyperinsulinemia typical of PCOS [13] .
Sex hormone-binding globulin (SHBG) is the pri-
mary binding protein for testosterone, and it is the
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 Polycystic ovary syndrome & insulin: our understanding in the past, present & future  Review

Pituitary Decreased FSH/increased LH

Insulin resistance Increased circulating Genetically prone

insulin levels ovary

Insulin binds to
insulin receptors and
stimulates androgen
production
Liver

Reduced SHBG production Increased androgen levels

Figure 1. Insulin resistance in polycystic ovary syndrome, effects on ovarian androgen production.
FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; SHBG: Sex hormone binding globulin.

unbound testosterone (also called free testosterone)
that acts on target tissues. Insulin is thought to increase
circulating levels of free testosterone by two specific
mechanisms: first, by stimulating ovarian biosynthesis
and secretion of testosterone, and, second, by directly
suppressing hepatic production of SHBG.
Regarding insulin’s stimulation of ovarian testos-
terone production, in vitro studies have demonstrated
greater stimulation of testosterone production by
human theca cells obtained from women with PCOS
compared with theca cells obtained from normal
women, and insulin has been shown to inhibit hepatic
production of SHBG both in vitro [21] and in vivo [22] .
In vivo studies in which hyperinsulinemia was induced
resulted in increases in circulating androgens in women
with PCOS but not in normal women, both indepen-
dently of gonadotropin release [23] , and independently
of BMI [24] . Conversely, administration of diazoxide
to inhibit insulin release in obese women with PCOS
resulted in a decrease in serum total and free testoster-
one levels with no change in gonadotropin level, sug-
gesting a direct effect of insulin to stimulate ovarian
testosterone production [13] . A similarly designed study
of administration of diazoxide to normal non-obese
women without PCOS found no effect of diazoxide
on circulating serum testosterone concentrations [25] ,
suggesting that women with PCOS have an inherent
susceptibility to the hyperandrogenic effects of insulin.
With regard to insulin’s suppression of hepatic pro-
duction of SHBG, in vitro insulin has been shown to
inhibit SHBG production by cultured HepG2 cells [21] ,
and, in vivo, administration of diazoxide to pharmaco-
logically castrated women with PCOS resulted in an
increase in levels of SHBG despite no change in sex
steroids [22] .
Finally, it is noteworthy that studies of women with
both Type 2 diabetes (DM2) [26,27] and Type 1 diabe-
tes, including lean patients, [28–31] , reported a higher
prevalence of PCOS in these women than in the gen-
eral population. This suggests that insulin resistance,
or more specifically hyperinsulinemia (whether endog-
enous or exogenous), is responsible for the ovarian
hyperandrogenism in these diabetic patients.
Prevalence of insulin resistance in women with
PCOS
Insulin resistance is observed independently of obesity
in women with PCOS, and it is critical for physicians

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Review  Mayer, Evans & Nestler
treating women with PCOS to bear in mind that
both obese and lean women with PCOS demonstrate
hyperinsulinemic insulin resistance, independently of
their adiposity [32,33] . In 1989, Dunaif et al. [34] , using
the hyperinsulinemic-euglycemic clamp technique to
measure whole-body insulin sensitivity, demonstrated
that both obese and lean women with PCOS were
significantly insulin-resistant compared with their
weight-matched normal controls, with lean women
with PCOS being as insulin-resistant as obese nor-
mal women, and obese normoglycemic women with
PCOS being as insulin-resistant as DM2 women. In
this study, PCOS status and obesity synergistically
reduced insulin sensitivity – that is, insulin sensitivity
was greatest in lean normal > lean PCOS = obese nor-
mal > and worst of all in obese PCOS women, so that
having both PCOS and obesity worsened insulin resis-
tance in a complementary fashion [34] . A take home
point is that insulin resistance is a frequent feature of
PCOS regardless of BMI.
Methodologies to test accurately for insulin resistance
remain technically challenging and are not used in clini-
cal practice. However, there are several clinical param-
eters that reflect underlying insulin resistance, including
obesity, increased waist-to-hip ratio, presence of acan-
thosis nigricans, low HDL-c level, elevated triglyceride
level, and reduced serum SHBG. One clinical conse-
quence of insulin resistance is impaired glucose toler-
ance (IGT) and, more severely, overt DM2. In two pro-
spective trials of women with PCOS conducted in the
USA [35,36] , there was a 31–35% prevalence of IGT and a
7.5–10.0% prevalence of DM2 in young to middle-aged
women with PCOS. In a prospective, controlled trial
over a 2–3-year follow-up, among women with PCOS
there was at baseline a 37% prevalence of IGT and 10%
prevalence of DM2, with a subsequent 16% conversion/
year from normal glucose tolerance (NGT) to IGT and
a 2% conversion/year from IGT to DM2. Consistent
with these observations, in the Nurses’ Health Study II
(NHSII) of 101,073 women followed for 8 years, the
conversion rate to DM2 was approximately twofold
higher in oligomenorrheic women, independent of
weight, than those with normal menses [37] .
Collectively, studies indicate that in the USA there
is a 10-fold increased prevalence of DM2 in young
women with PCOS, and that 30–50% of obese women
with PCOS develop IGT or DM2 by the age of 30 years
old (earlier than their peers without PCOS). Of note,
abnormalities of carbohydrate metabolism, resulting in
IGT or DM2, tend to cluster in first degree relatives
of women with PCOS [38,39] . Similar to patients with
DM2 without PCOS, in patients with PCOS a positive
first degree relative with DM2 correlates significantly
with the risk of having DM2 [40] . In short, women with
140 Womens Health (2015) 11(2)
PCOS have been found to be at substantially increased
risk of developing DM2 [35] .
Detection of glucose intolerance in women
with PCOS
Neither insulin resistance nor biochemical evidence
of glucose intolerance is necessary for the diagnosis of
PCOS. Moreover, many women with PCOS will have
demonstrable insulin resistance with no clinical evi-
dence of glucose intolerance. Nonetheless, given the evi-
dence above of a high prevalence of glucose intolerance
and DM2 in PCOS, it behooves clinicians to screen for
these disorders at the time of PCOS diagnosis. Expert
opinion would recommend screening all women with
PCOS for glucose intolerance at the time of diagnosis
using a 2-h 75-g oral glucose tolerance test (OGTT)
(regardless of BMI) and repeat screening at 2–5 year
intervals [41,42] . An OGTT is the recommended screen-
ing test for glucose intolerance, since, as noted below,
studies indicate that in women with PCOS the fasting
serum glucose and HbA1c levels may be in the nor-
mal range even when a woman with PCOS has IGT or
DM2 when assessed by an OGTT [43–45] .
In women with PCOS, the OGTT remains the gold
standard test for screening for glucose intolerance.
Legro et al. have demonstrated in both adult and ado-
lescent patients with PCOS that a fasting plasma glu-
cose fails to identify a substantial portion of women
who have IGT or DM2 by OGTT testing [46] . Simi-
larly, recent evaluations of HbA1c for diagnosis of glu-
cose intolerance in women with PCOS have proved
disappointing. A study of 252 Turkish women with
PCOS and 117 control women without PCOS [43]
compared HbA1c levels with OGTT results and
found that HgbA1c provided a less robust measure
of testing with a 52.4% sensitivity, 74.4% specificity,
67.1% positive and 60.9% negative predictive values.
Again, women who had IGT or DM2 by OGTT were
mis-identified as normal by HbA1c testing. Similarly,
a retrospective study of 208 premenopausal women
with PCOS [44] reported a poor sensitivity of 35% but
excellent specificity of 99% using HbA1c ≥ 6.5% for
the diagnosis of diabetes in women with PCOS, com-
pared with the diagnosis established by OGTT. The
authors concluded that the HbA1c is less reliable than
the OGTT to uncover glucose intolerance or diag-
nose diabetes in PCOS. In another study of 111 adult
women with PCOS who were prospectively screened
for DM2, IGT (pre-DM) and insulin resistance using
various diagnostic methods and OGTT as the gold
standard, screening with fasting plasma glucose failed
to identify 41% of IGT and 20% of DM2 subjects.
Further, OGTT and HbA1c had only fair agreement
(κ = 0.29) [45] .
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 Polycystic ovary syndrome & insulin: our understanding in the past, present & future  Review
Prevention of glucose intolerance in women
with PCOS
Treatment options for reducing the rate of conversion
to diabetes in women with PCOS focus on lifestyle
modification, including the use of low glycemic index
and low carbohydrate diets, and use of insulin sensitiz-
ing agents, specifically metformin. Use of thiazolidin-
ediones had previously shown promise in this regard,
but given recent concerns for risk for bladder cancer
with prolonged pioglitazone use, caution with rosigli-
tazone and cardiac concerns, removal of troglitazone in
the face of idiosyncratic hepatitis, and concern to bone
health and increased fracture risk in postmenopausal
women, this class of agents has fallen out of favor.
A recent systematic review [47] of six articles from five
studies, with 137 women included, found subtle differ-
ences between various dietary interventions in PCOS.
Greater weight loss was seen in monounsaturated fat-
enriched diets, and low-glycemic index diets seemed
to improve menstrual irregularity. Greater reductions
in insulin resistance were seen with both low-carbo-
hydrate and low-glycemic index diets. The authors
found an improved quality of life with the use of a low-
glycemic index diet and improved depression and self-
esteem with a high-protein diet. Conversely, an unde-
sirable increased in free androgen index resulted from
high-carbohydrate diets, perhaps due to comparatively
enhanced insulin release suppressing SHBG.
While several studies have demonstrated a reduc-
tion in progression to DM2 in non-PCOS individuals
treated with the drug metformin, the only such study
specifically in PCOS is a retrospective chart review of 50
women with PCOS, all of whom were started on met-
formin therapy at diagnosis, had OGTT testing at base-
line, did not have diabetes at baseline and had a mini-
mum of 1-year of follow-up with repeat OGTT testing.
The study found that, at baseline, 39 women (78%) had
NGT and 11 women (22%) had IGT. The women with
NGT were followed for an average of 43.3 months and
the women with IGT for 28.9 months. During these
periods, the annual conversion rate from NGT or IGT
to DM2 was 0% (none had developed diabetes), and
1.4% from NGT to IGT [48] . This rate of conversion
from NGT to IGT was ∼10-fold lower than the con-
version to IGT among women with PCOS with NGT
not treated with metformin reported in the prospective
studies mentioned above (16–19% NGT to IGT) [35,36] .
Cardiovascular disease in PCOS
Women with PCOS are often found to have an accumu-
lation of risk factors for cardiovascular disease (CVD)
including obesity, hypertension, low levels of HDL-
c, elevated triglyceride levels, increased plasminogen
activator inhibitor (PAI-1), increased endothelin-1, low
future science group
levels of adiponectin and increased C-reactive protein
levels. Anatomic and functional markers for CVD
are also increased in women with PCOS, including
increased carotid intima-medial thickness, coronary
artery calcium (CAC) scores and abnormal flow medi-
ated dilation, all suggesting an increased risk in women
with PCOS.
In terms of lipids, in premenopausal women with
PCOS, higher rates of dyslipidemia were found than
in controls [49] . A case–control study of 195 non-His-
panic white women with PCOS [50] found elevations
in LDL-c levels in women with PCOS, independent
of obesity [50] .
A prospective study followed 125 women with PCOS
and 142 controls over the course of 3 years with B-mode
ultrasonography of the carotid arteries to measure carotid
intima-media wall thickness and plaque [51] . In those
women aged 45 years or older, there was significantly
more carotid mean intimal medial thickness in PCOS
cases than in the control women, and this remained
significant after adjusting for age and BMI [51] . In a
study of 36 women with PCOS and 71 age- and BMI-
matched control women aged 30–45 years (excluding
those with diabetes and known coronary heart disease),
evaluated by electron beam computed tomography
to noninvasively measure CAC, 39% of women with
PCOS compared with 21% of controls had CAC, and
when compared with community dwelling women the
prevalence was more startling still (9.9%; odds ratio,
5.9) [52] . An association was found between extent of
coronary artery disease (CAD) on coronary angiogra-
phy and presence of polycystic ovaries on ultrasound
in 143 women ≤60 years old referred for assessment of
chest pain or valvular disease in New Zealand in 1997,
so that women with polycystic ovaries (42%) had more
extensive coronary artery disease than women with nor-
mal ovaries (number of segments with >50% stenosis,
1.7 compared with 0.82). On logistic regression analysis
of this data, the extent of coronary artery disease and
family history of heart disease predicted the presence of
polycystic ovaries [53] .
Most notably, in a study, 30 young (mean age
22 years old) and lean (mean BMI 22 kg/m2) women
with PCOS, without any prior known cardiovascular
disease (CVD), were compared with 30 healthy age-
and BMI-matched control women with flow-mediated
dilation of the brachial artery and by Doppler ultra-
sound of the carotid arteries for intima-media thick-
ness [54] . Compared with the normal control women,
these young and lean women with PCOS were found
to have impaired flow-mediated dilation, accompanied
by an increased serum endothelin-1 level, and increased
intima-media thickness of the carotid arteries. Hence,
at an early age, these lean women with PCOS were
www.futuremedicine.com 141
Review  Mayer, Evans & Nestler
already exhibiting anatomic and functional cardiac
abnormalities placing them at risk for premature CVD.
Given the high prevalence of cardiovascular risk
factors, it would not be surprising that women with
PCOS would also have a higher prevalence of the
metabolic syndrome (MBS). As background, the MBS
in women is defined as having three out of five of the
following criteria: waist circumference >35 inches
(88 cm); triglyceride ≥150 mg/dl; HDL-c <50 mg/dl;
blood pressure ≥130/85 mmHg; fasting plasma glu-
cose ≥110 mg/dl. While MBS confers a two- to three-
fold higher risk for a cardiovascular event, the risk in
women with MBS may be greater than that of men
with MBS. Seven studies within a larger meta-analysis
found that the risk of CV events and death is 30%
higher in women than men meeting NCEP 2001
ATP III criteria for metabolic syndrome [55] .
In a retrospective chart review of 106 women
with PCOS, the prevalence of metabolic syndrome
was 43%, nearly two- to threefold higher than that
reported for age-matched women in the general popu-
lation from NHANES III data, even when matched
by BMI [56] . In this study, >90% of PCOS women had
at least one of the five cardiovascular risk factors that
comprise the MBS, and the most prevalent risk factor
among the women was a low HDL-c. The higher prev-
alence of the MBS in women with PCOS is not con-
fined to the USA, but has been confirmed in multiple
studies conducted worldwide [57–59] .
Studies of cardiac outcomes in PCOS are limited
in number, but overall support an increased risk of
cardiovascular events. In the Nurses Health Study
(NHS), which followed 82,439 women for 14 years,
in women with very irregular periods the risk ratio for
coronary heart disease was 1.5 and the risk ratio for
fatal myocardial infarction (MI) was increased two-
fold [60] . Further epidemiological evidence of increased
cardiovascular events in postmenopausal women with
a history of PCOS (defined by irregular menses and
elevated androgen measurements) was found in a sub-
set of the NIH’s National Heart, Lung, and Blood
Institute (NHLBI) sponsored prospective Women’s
Ischemia Syndrome Evaluation (WISE) study. The
cumulative 5-year cardiovascular event rate was 21.1%
for women with clinical features of PCOS (n = 104)
versus 11.3% for women without clinical features of
PCOS (n = 286) [61] .
Counter to these data is a retrospective review of
death certificates in the UK from women with PCOS
not showing a statistically significant increase in MI
compared with the general population. However, this
study was powered to detect a threefold increase in risk
and only 786/1028 charts were analyzed, and while
the standardized mortality ratio for ischemic heart
142 Womens Health (2015) 11(2)
disease was 1.4 for PCOS, this did not meet statistical
significance [62] .
Conversely and consistent with the results of the
NHS and WISE studies, in a 20-year retrospective
study of 2301 women with PCOS totalling >12,000
person-years, Mani et al. found that the prevalence of
MI in the age group 45–54 was 1.9%, age 55–64 was
6.0% and >65 years 27.3%. Prevalence of angina age
45–54 was 2.6%, age 55–64 was 6.0% and > 65 years
was 27.3%. Age-group-specific odds ratios for the
prevalence of MI and angina compared with the local
female population ranged between 2.6 and 12.9. The
highest odds ratio was for MI in the group of women
with PCOS >65 years old [63] .
When considered collectively, the majority of data
support the idea that women with PCOS, indepen-
dently of adiposity, are at increased risk for atheroscle-
rosis, and should be screened and targeted for primary
prevention of CVD.
This is in line with guideline recommendations of
the Androgen Excess and PCOS society [64] .
Reproductive consequences in PCOS
Prevalence
PCOS affects 5–10% of women of childbearing age
in the USA (3–5 million women), and is currently the
leading cause of anovulatory infertility [65,66] . Anovu-
lation presents clinically as irregular menstrual cycles
(either amenorrhea or oligomenorrhea) and infertility.
Seventy-five percent of women with PCOS have infer-
tility due to anovulation. In addition, early (first tri-
mester) miscarriages are threefold the rates of women
without PCOS [67] .
Weight loss of 5–10% can restore ovarian function
and ovulation in approximately 50% of patients with
PCOS and is thus an important pillar of fertility care
in women with this disorder. It seems likely that this
phenomenon is mediated via improved insulin sensitiv-
ity. However, sustained weight loss can be difficult to
achieve which in turn results in the need for additional
therapeutic strategies in many cases.
First-line medical strategies
The two most commonly used medical therapies to
treat infertility in women with PCOS are clomiphene
citrate and metformin. Clomiphene citrate acts as an
anti-estrogen which displaces endogenous estrogen
from the hypothalamic estrogen receptor and thus
removes negative feedback by endogenous estro-
gens. Clomiphene acts as an indirect stimulator of
FSH secretion. It restores ovulation in nearly 80% of
women and results in an approximate 50% conception
rate usually within three cycles of use. The primary
adverse effect of clomiphene citrate is the increased rate
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 Polycystic ovary syndrome & insulin: our understanding in the past, present & future  Review
of multiple gestations. Metformin is thought to treat
infertility by improving insulin sensitivity. In a trial
of 16 obese women with PCOS treated with metfor-
min for 6 months and evaluated by the euglycemic-
hyperinsulinemic clamp technique, glucose utilization
and insulin action improved and was accompanied
by significant increases in the levels of sex hormone-
binding globulin and decreases in free testosterone
and androstenedione levels [68] . Among these women,
44% resumed normal cycles and two cases of sponta-
neous pregnancy occurred during treatment. Current
expert theory proposes that reducing levels of circulat-
ing insulin will decrease intra-ovarian concentrations
of androgens and normalize gonadotropin secretory
dynamics.
One study followed 61 obese women with PCOS,
randomized to either metformin or placebo, for spon-
taneous ovulation over 35 days, and then administer-
ing clomiphene for 5 days to those women who did
not ovulate (21 in metformin arm and 25 in placebo
arm), while continuing either metformin or placebo,
and then monitoring serum progesterone levels. The
authors found that the women randomized to metfor-
min receiving clomiphene had a significant reduction
in mean AUC of insulin after oral glucose administra-
tion, whereas those on placebo did not, and 19 of 21
women on metformin + clomiphene ovulated (90%)
versus 2 of 25 on placebo + clomiphene ovulated
(8%)  [69] . In another study of non-obese women with
PCOS with normal OGTT, the rate of ovulation after
initiation of metformin therapy demonstrated a graded
increase over a 6 month time course with peak ovula-
tion rate at months 5 and 6 of therapy [70] . In a head
to head randomized controlled trial (RCT) of clomi-
phene citrate to metformin in non-obese anovulatory
women with PCOS [71] , 6 months of administration
of metformin was more effective than six cycles of clo-
miphene citrate based on a non-statistically different
ovulation rate between the two treatment groups (62.9
vs 67.0%), but with a significantly higher pregnancy
rate in the metformin group (15.1 vs 7.2%), a lower
rate of abortion with metformin therapy over 6 months
(9.7 vs 37.5%), as well as a positive trend for live-birth
rate favoring metformin therapy (83.9 vs 56.3%). The
cumulative pregnancy rate was significantly higher
in the metformin group than the clomiphene citrate
group (68.9 vs 34.0%). Ovulation rates were higher
initially with clomiphene citrate use in the first cycle
but steadily rose with longer duration of metformin
use over the course of 6 months to surpass rates with
clomiphene citrate by month 6 (month 1: metformin
42% vs clomiphene 83%; in month 6: metformin
86% versus clomiphene 48%) [71] . In 2012, a system-
atic review and meta-analysis of four RCTs compar-
future science group
ing metformin with clomiphene citrate in women with
PCOS and BMI <32 kg/m2 found no statistically sig-
nificant difference for any outcome (ovulation, preg-
nancy, live birth, miscarriage and multiple pregnancy
rates) between these two treatment modalities [72] . The
authors did caution that there were conflicting findings
and heterogeneity across the RCTs.
A meta-analysis of 13 RCTs including 428 women
with PCOS found a 46% rate of ovulation in those
PCOS women assigned to metformin monotherapy
versus 24% in those receiving placebo [73] . Another
such meta-analysis found that metformin was 50%
better than placebo for ovulation induction in infer-
tile PCOS patients, but was not of confirmed ben-
efit versus placebo for achievement of pregnancy [74] .
A subsequent meta-analysis in 2008 of 17 studies in
1639 women compared metformin versus placebo, and
metformin + clomiphene versus clomiphene alone [75] .
In the 10 trials comparing metformin monotherapy
to placebo, metformin improved the odds of ovula-
tion. There was a 1.56-fold increase in clinical preg-
nancy rate, but this was not statistically significant [75] .
Metformin combined with clomiphene increased the
likelihood of ovulation (and pregnancy), compared
with clomiphene therapy alone [75] . A Cochrane meta-
analysis of metformin monotherapy in PCOS found
an improved ovulation rate in 16 RCTs with 1208
subjects. There was also an improved rate for clinical
pregnancy with metformin use in eight RCTs in 707
subjects. In combination with clomiphene, metformin
improved clinical pregnancy rates but this combina-
tion did not lead to improved live-birth rates. Met-
formin was also associated with a significantly higher
incidence of gastrointestinal disturbances than placebo
but no serious adverse effects were reported [76] .
In 2007 the Pregnancy in Polycystic Ovary Syn-
drome study (PPCOS) randomized 626 infertile
women with PCOS to clomiphene citrate plus pla-
cebo, extended-release metformin plus placebo, or a
combination of metformin and clomiphene for up to
6 months. Adding metformin to clomiphene citrate
increased the ovulation rate by 20%. In this study, the
live-birth rate was 22.5% in the clomiphene group,
7.2% in the metformin group and 26.8% in the com-
bination-therapy group, but the difference in live-birth
rates between the clomiphene group and combination-
therapy group did not attain statistical significance.
Notably, multiparity was 6.0% in the clomiphene
group, 0% in the metformin group and 3.1% in the
combination-therapy group [77] .
Because of the lack of a statistically significant dif-
ference in live-birth rates between clomiphene alone
and clomiphene in combination with metformin in
this study, the use of metformin for fertility induction
www.futuremedicine.com 143
Review  Mayer, Evans & Nestler
has somewhat fallen out of favor and does not figure
in the Endocrine Society’s guidelines on PCOS [42] .
However, it should be noted that in the PPCOS study
patients were not allowed a run-in time of metformin
therapy which may well have affected results. Since
its publication – and not included in the Endocrine
Society guideline – a 2012 study of 320 anovulatory
women with PCOS randomized to metformin versus
placebo found a 45% increase in live-birth rate after
metformin use compared with placebo. Metformin
significantly improved both pregnancy and live-birth
rates over placebo (pregnancy rate: 53.6 vs 40.4%; live-
birth rate: 41.9 vs 28.8%) [78] . Perhaps this discrepancy
is due to methodological differences in study protocols
by which the PPCOS study allowed insufficient time
for sufficient improvement in insulin sensitivity with
metformin therapy.
There are data suggesting that metformin use in
PCOS may reduce the rate of early pregnancy loss.
In a retrospective study of PCOS women treated for
infertility in one clinic, rates of early pregnancy loss
were lower (8.8%; 6 of 68 pregnancies) in the group
treated with meformin, as compared with 41.9% (13 of
31 pregnancies) in the control group [79] . Subsequently
in a prospective study of 208 pregnant women (98
women with PCOS treated with metformin through-
out pregnancy and 110 normal pregnant controls), there
was a reduction in miscarriage rate (9.1 vs 20%), ges-
tational diabetes (0 vs 13%) and gestational hyperten-
sion (0 vs 11%) and a non-significant decrease in pre-
eclampsia (0 vs 3%), in women with PCOS treated with
metformin preconception to 37 weeks gestation [80] .
Safety of metformin in pregnancy & lactation
Metformin is considered a Class B drug in pregnancy,
meaning that metformin is not teratogenic when used
in animal models of pregnancy. When compared
with insulin for treatment of gestational diabetes
(GDM), in 751 women with GDM randomized at
20–33 weeks gestation to either open-label metfor-
min (supplemental insulin if required) or insulin,
metformin was found to be safe. No serious adverse
events were associated with metformin use [81] . In a
prospective study of 126 live births (122 pregnancies)
to 109 women with PCOS who conceived while on
metformin and continued metformin through preg-
nancy, it was determined that metformin use reduced
the prevalence of gestational diabetes, was not found
to be teratogenic, and did not adversely affect birth
length and weight, growth or motor-social devel-
opment in the first 18 months of these babies’ lives
compared with controls [82] . An RCT of 257 pregnant
women with PCOS randomized to metformin ver-
sus placebo from first trimester to delivery found no
144 Womens Health (2015) 11(2)
difference in pregnancy complications between arms
in preeclampsia prevalence, GDM, or preterm deliv-
ery, or in a composite of those outcomes. Women in
the metformin group gained less weight during preg-
nancy than those on placebo. There was no difference
in fetal weight [83] .
A prospective pharmacokinetic study of metformin
concentrations in breast milk samples in six women
found that the relative infant dose was <0.5% of the
mother’s weight adjusted dose, and the authors con-
cluded that infant exposure to metformin through
breast milk is low [84] . Similarly, another study in seven
breastfeeding women taking metformin, concentra-
tions of metformin were measured by high performance
liquid chromatography and found that the mean rela-
tive infant dose was 0.28% (0.16–0.4%). Metformin
was found in undetectable to very low plasma concen-
trations in the infants. No health concerns were noted
in the infants evaluated [85] .
In follow-up questionnaires regarding breast size
increment and breastfeeding patterns, 1-year post-
partum, from participants of a completed RCT [83]
in which 240 participants with PCOS were random-
ized to treatment with metformin or placebo from
the first trimester to delivery, no difference was found
between the two groups. It was concluded that met-
formin had no impact on breastfeeding based on the
186 responders [86] .
In conclusion, it is likely that metformin use in
pregnancy and lactation is safe.
Individualized care
On an individual basis, the clinician must ultimately
tailor fertility treatment to the patient’s particular
timeline. The onset of action of metformin will be
slower than clomiphene citrate. It is critical to discuss
with patients that clomiphene is a fertility drug that
acts directly to induce ovulation with a rapid onset of
action and that it is associated with significant multi-
parity [87] . In contrast, metformin affects metabolism
to indirectly induce ovulation with a slow onset of
action. It results in a more physiologic ovulation and
release of a single egg at a time. An individual patient’s
favored timeline will help to direct therapy.
Alternative strategies
Letrozole is an aromatase inhibitor which induces
ovulation without anti-estrogenic effects that can
be seen with clomiphene. In clomiphene-resistant
women with PCOS unable to achieve fertility, alter-
native strategies of adding metformin to clomiphene,
versus using letrozole with and without additional
metformin, versus bilateral ovarian drilling can be
considered. In one RCT of 146 women with PCOS
future science group
 Polycystic ovary syndrome & insulin: our understanding in the past, present & future  Review

who did not conceive with clomiphene, there was no
significant difference in ovulation (p = 0.24), preg-
nancy rate (p = 0.32) or abortion rate (p = 0.51) com-
paring those randomized to letrozole plus metformin
versus bilateral ovarian drilling [88] . An RCT of letro-
zole compared with combined metformin and clomi-
phene citrate, in 250 women with PCOS who did not
conceive on clomiphene alone, found no statistically
significant difference either in ovulation frequency or
in pregnancy rates (14.7 vs 14.4%) between these two
arms [89] . Finally, a head to head combined metformin-
letrozole versus metformin-clomiphene citrate trial in
59 women with PCOS who were clomiphene-resistant
found no statistical difference in pregnancy rate in
the metformin-letrozole group (10 patients, 34.5%)
versus the metformin-clomiphene group (5 patients,
16.67%); however, there were more full term preg-
nancies with metformin-letrozole (10 patients, 34.5%
vs 3 patients, 10%) [90] . The authors note that in this
last study metformin was allowed a 6–8 week run-in
period prior to additional agent use. As noted pre-
viously the pathophysiology of metformin affecting
insulin resistance can take time.
Conclusion & future perspective
In summary, insulin resistance plays a critical role in
both metabolism and reproduction of women with
PCOS. Insulin resistance unifies the defects seen in
PCOS of both increased risk for metabolic syndrome
and anovulation and reproductive concerns. Future
directions of research to tackle unresolved issues in
PCOS care and understanding of underlying patho-
physiologic mechanism may include pharmacoge-
netic evaluation of responders versus non-responders
to metformin, the role of free fatty acid stimula-
tion of androgens and the role that insulin plays,
and whether there are ethnic/genetic differences in
PCOS presentations. The molecular defect funda-
mentally underlying insulin resistance in PCOS has
been hinted at by findings of post-receptor defects
leading to abnormal patterns of phosphorylation of
specific residues of the insulin receptor. The latter
remains to be fully elucidated.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial in-
volvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or
materials discussed in the manuscript. This includes employ-
ment, consultancies, honoraria, stock ownership or options,
expert testimony, grants or patents received or pending, or
royalties.
No writing assistance was utilized in the production of this
manuscript.

Executive summary
Evolution of a definition
• Polycystic ovary syndrome (PCOS) is a clinical diagnosis.
• PCOS can be present at any BMI, that is, in both thin and obese women.
• When considering the diagnosis of PCOS, obtain tests to assess androgen status and exclude the following
conditions: hyperprolactinemia, thyroid dysfunction, non-classical congenital adrenal hyperplasia and
Cushing’s syndrome if clinically indicated.
Cardiovascular disease in polycystic ovary syndrome
• It is reasonable to consider all women with PCOS at risk of insulin resistance.
• Clinical markers of insulin resistance in PCOS include obesity, increased waist-to-hip ratio, presence of
acanthosis nigricans, low HDL-C, high triglycerides and low sex hormone-binding globulin.
• Screening for women with PCOS should include a measure of adiposity (BMI, waist circumference), serial
blood pressure measurements, serum lipid panel and evaluation for glucose intolerance using an oral glucose
tolerance test. A fasting plasma glucose and HbA1c are not satisfactory screening tests for glucose intolerance
in PCOS.
• Consideration of dietary and lifestyle intervention and/or initiation of an insulin sensitizer (metformin) at the
time of diagnosis of PCOS for primary prevention of DM2 and cardiovascular disease are recommended.
Reproductive consequence in polycystic ovary syndrome
• The clinician must:
–– Assess the individual woman’s sense of readiness or imperative for pregnancy at the time of presentation
and diagnosis, or shortly thereafter.
–– Recognize that:
• Metformin may take a longer time to increase ovulation rates but may do so in a more physiologic
fashion with less multiparity and less hyperstimulation syndrome
• Clomiphene citrate may achieve swifter onset of increased ovulation in a pharmacologic fashion which
may be more commonly associated with multiparity.
• Alternative strategies for infertility are actively being explored.

future science group www.futuremedicine.com 145

Review  Mayer, Evans & Nestler
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