Open Journal of Obstetrics and Gynecology, 2011, 1, 36-41
doi:10.4236/ojog.2011.12008 Published Online June 2011 (http://www.SciRP.org/journal/ojog/
OJOG
).
Published Online June 2011 in SciRes. http://www.scirp.org/journal/OJOG
Defining prediabetes in polycystic ovarian syndrome
Mark P. Trolice
College of Medicine, University of Central Florida, Orlando, USA.
Received 21 April 2011; revised 25 May 2011; accepted 3 June 2011.
ABSTRACT
Objective: The article will review the associations
between Prediabetes (PD) and Polycystic Ovarian
Syndrome (PCOS) and present factors that decrease
the progression of PD into type 2 diabetes mellitus
(T2DM).Metformin will also be examined for its role
in ovulation induction, pregnancy and ameliorating
the metabolic syndrome. Study Design: Medline
search. Methods of study: Keyword search: Predia-
betes (PD), Polycystic Ovarian Syndrome (PCOS),
Metformin, Glucose Tolerance Test (GTT), Type 2
Diabetes Mellitus. Results: As the most common en-
docrinopathy during the reproductive years, PCOS
has a genetic multifactorial inheritance and is associ-
ated with a high risk of insulin resistance. The use of
metformin has shown mixed results in this patient
population as a therapy to improve ovulation func-
tion and the metabolic syndrome and showed no de-
finitive reduction in the rate of miscarriage. PCOS
patients are significantly predisposed to PD and
T2DM. Conclusion: Lifestyle changes such as weight
loss and physical activity reduce the progression of
PD into T2DM in PCOS patients. The new AACE
and ADA guidelines establish simplified methods of
screening and treating PD. The role of metformin
remains undefined in the infertile PCOS patient.
Keywords: Polycystic Ovarian Syndrome; Prediabetes;
Impaired Glucose Tolerance; Impaired Fasting Glucose;
Type 2 Diabetes
1. INTRODUCTION
Polycystic Ovarian Syndrome (PCOS) is the most pre-
valent endocrinopathy during the reproductive years,
affecting 5% - 10% of women [1]. PCOS is classically
associated with ovulatory dysfunction and hyperandro-
genism. In 2003, an expert conference was organized in
Rotterdam in May of 2003, co-sponsored by the Euro-
pean Society for Human Reproduction and Embryology
(ESHRE) and the American Society for Reproductive
Medicine (ASRM) resulting in revised criteria for mak-
ing the diagnosis of PCOS using two of the following
three features: 1) oligo- or anovulation (i.e. cycle inter-
val >35 d or <8 cycles/yr); 2) clinical or biochemical
signs of hyperandrogenism (i.e., demonstrated by ele-
vated total or free testosterone, DHEAS, free androgen
index [2] or signs of hirsutism or acne; 3) ultrasound
evidence of polycystic ovaries (12 or more follicles in
each ovary (2 mm - 9 mm), and/or increased ovarian
volume (>10 mL)—all at the exclusion of other etiolo-
gies (hyperprolactinemia, thyroid dysfunction, androgen-
secreting tumors, non-classic adrenal hyperplasia) [3,4].
Despite its prevalence, PCOS remains an enigma result-
ing in significant patient frustration and physician con-
fusion for the most appropriate method of diagnosis and
management.
In addition to the reproductive health issues of ab-
normal uterine bleeding, anovulation, infertility, and
endometrial hyperplasia, PCOS patients are at higher
prevalence for the metabolic syndrome, namely ab-
dominal obesity, dyslipidemia, hypertension, and pre-
diabetes (PD). The National Cholesterol Education Pro-
gram Adult Treatment Panel (NCEPATP) defined the
metabolic syndrome as the presence of three of the five
following factors: waist circumference greater than 88
cm in females; fasting serum glucose 110 mg/dl or more;
fasting serum triglycerides greater than 150 mg/dl; se-
rum HDL-cholesterol less than 50 mg/dl; and blood
pressure greater than 130/85 mm Hg [5]. The metabolic
syndrome occurs at an increased overall prevalence rate
of 43% - 47% in women with PCOS [6]. One of met-
formin’s actions is 5-AMP-activated protein kinase
(AMPK) pathway. While obesity, type 2 diabetes melli-
tus (T2DM), and the metabolic syndrome are all disor-
ders of energy balance and AMPK appears to regulate
this system, perhaps the role of metformin in improving
the metabolic syndrome is through this mechanism [7].
To date, there is no definitive evidence demonstrating
the benefit of metformin in PCOS patients as a treatment
or prevention for metabolic. As a result, lifestyle modi-
fications remain the mainstay for patients with the me-
tabolic syndrome.

M. P. Trolice / Open Journal of Obstetrics and Gynecology 1 (2011) 36-41 37
While all medical issues should be addressed in PCOS
patients, particularly those trying to conceive, PD can be
elusive and requires vigilance with formal testing. Fur-
thermore, there is an indolent but clear progression of
PD to T2DM unless intervention is applied early. This
article will serve to elucidate the morbid association of
PCOS with PD by examining the insulin resistance con-
nection, and presenting new guidelines from the Ameri-
can Association of Clinical Endocrinologists and Amer-
ican Diabetes Association to simplify methods of diag-
nosing and treating PD as well as to decrease the pro-
gression into T2DM.
2. REPRODUCTIVE CONSEQUENCES
Approximately 40% of female infertility is attributed to
ovulation dysfunction of which PCOS is the prevailing
diagnosis. Multiple regimens (beyond the scope of this
article) have been presented for ovulation induction par-
ticularly in PCOS patients resistant to clomiphene citrate,
including the addition of metformin (see below), yet this
latter agent has not been shown to be as effective as
clomiphene. The second ESHRE/ASRM-Sponsored
PCOS Consensus Workshop Group in 2007 concluded
clomiphene citrate is the first line agent for ovulation
induction followed by gonadotropins or laparoscopy
ovarian diathermy [8]. The expert panel concluded met-
formin should be limited to PCOS patients with glucose
intolerance as current evidence does not support the rou-
tine use of metformin in ovulation induction. Metformin
appears to be superior to placebo regarding ovulation
induction for PCOS patients [9]. Controversy remains
when metformin is compared with clomiphene. A recent
meta analysis and clinical trial demonstrates improve-
ment in ovulation with metformin [10,11] contrary to a
Cochrane Review stating limited improvement of met-
formin vs. clomiphene [12] and an excellent randomized
control trial showing superiority of clomiphene over
metformin [13]. It is plausible the disparity in results
from these studies may be attributed to patient hetero-
geneity, i.e. BMI, genotype, androgen levels, ethnicity,
and racial differences [14].
Aromatase inhibitors such as letrozole and anastrozole
have been studied as alternatives to clomiphene. A recent
meta-analysis to compare clinical efficacy and safety
showed no difference between letrozole and cloimiphene
regarding miscarriage, pregnancy rates and multiple
pregnancy rates and concluded equal effectiveness of the
two drugs for ovulation induction in PCOS patients [15].
Anastrozole is inferior to clomiphene and should not be
used as a first line for ovulation induction [16]. Both
letrozole and anastrozole use for ovulation induction are
non-FDA approved applications. Furthermore, weight
loss has demonstrated the same efficacy in inducing
ovulation as metformin [17]. Though a patient should
strive for a BMI of less than 27 kg/m2, to improve ovu-
lation and pregnancy rates, a weight loss of only 2% to
5% may restore normal menstrual function [18-20].
PCOS is not only a common cause of infertility but
has been indicated as a risk factor for spontaneous abor-
tions (SAB), particularly among women treated with
assisted reproductive technology [21-23]. When con-
trolled for confounding effects of body mass index
(BMI), age and PCOS status, insulin resistance signifi-
cantly increases the risk for SAB [24] estimated to be in
the range from 39%-73%, far exceeding the general
population [25]. Recent studies have indicated that hy-
perinsulinemia, obesity, and hyperandrogenemia all may
be a source for the increased SAB rate due to adverse
affects on the function of the endometrium [26-28].
Though once thought to be a significant enhancement
to the treatment of SAB in PCOS patients, the role of
metformin is ambiguous. The first double blind placebo
controlled trial comparing metformin and clomiphene
citrate in non-obese PCOS patients, revealed metformin
was superior in terms of achieved pregnancies (15.1% vs
7.2%), lower abortion rate and increased live births [11].
However, a recent meta analysis failed to demonstrate
any benefit from metformin use before pregnancy on
preventing miscarriage in PCOS patients [29]. The
Cochrane Database concluded that current studies did
not support the reduction in miscarriage in PCOS pa-
tients undergoing IVF while on metformin [30].
3. THE INSULIN RESISTANCE
CONNECTION
PCOS is well supported to have a genetic multifactorial
inheritance. Insulin resistance (IR) is found in 65-70% of
PCOS patients when various diagnostic tools are utilized,
including the cumbersome hyperinsulinemic euglycemic
clamp study [31,32] While the exact etiology of IR re-
mains unclear, the prevailing theory is a post insulin
receptor defect affecting signal transduction resulting in
an increase in ovarian and adrenal androgens [33-36].
Up to 65% - 70% of PCOS women are obese and of-
ten have insulin resistance placing them at risk for overt
diabetes [37]. The impact of PCOS on impaired glucose
uptake is dramatically shown by lean PCOS demon-
strating the same degree of insulin resistance as ovula-
tory obese women [37]. To further illustrate this point,
PCOS patients are more insulin resistant than age- and
BMI-matched non-PCOS controls, irrespective of BMI
[8]. The relationship of insulin resistance and PCOS
underscores the need for performing a 2hr GTT in all
PCOS patients since a fasting glucose alone will has a
false negative rate of up to 30% in diagnosing PD [38].
Hyperinsulinemia acts synergistically with increased
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M. P. Trolice / Open Journal of Obstetrics and Gynecology 1 (2011) 36-41 38
OJOG
LH to induce elevated free IGF-1 (insulin-like growth
factor) with resultant hyperandrogenemia and ovulatory
dysfunction [39]. PCOS also increases the risk for the
development of gestational diabetes in 20% - 40% of
cases [40]. Several studies have demonstrated the use of
metformin in PCOS pregnant patients reduced the risk of
gestational diabetes compared to controls [41].
4. TREATMENT OPTIONS
Metformin is an oral biguanide insulin-sensitizing agent,
commonly used to maintain blood glucose control in
diabetes by augmenting the effects of insulin on glucose
uptake without concurrent hyperinsulinemia. Initial en-
thusiasm for the application of metformin in PCOS pa-
tients has waned as the available evidence is inconsistent
regarding its beneficence particularly in those trying to
conceive and in adolescence [42]. Though its effective-
ness may be independent of dosage, metformin may be
of benefit in the following groups: 1) clomiphene resis-
tance; 2) normal BMI; 3) PD; and 4) possibly during IVF.
Furthermore, ongoing debate carries over to whether
metformin reduces miscarriage (as reviewed earlier) and
gestational diabetes, both of which are significantly
higher risks in PCOS patients [43]. Metformin is a
“Class B” drug that has not been shown to increase the
incidence of congenital abnormalities [44].
Thiazolidinediones (TZD) are another category of
drugs to treat insulin resistance and improve insulin sensi-
tivity and reducing hyperinsulinemia by different mecha-
nisms than metformin, particularly by binding to the
PPAR-gamma receptor. Regarding infertility, new TZDs
such as rosiglitazone (pregnancy category C) may be
more effective than metformin in inducing ovulation [45].
5. PREVENTING PROGRESSION TO
DIABETES
By GTT, approximately 30% - 40% of PCOS women
have PD, and 12.6% present with T2DM [46-48]. Signs
and risk factors in PCOS women for developing PD &
T2DM include elevated BMI, acanthosis nigricans ( a
brown velvety verrucous discoloration in the intertrigi-
nous skin area), and a history of gestational diabetes.
The Center for Disease Control estimates there are 57
million persons in the United States with PD [49]. PD is
a significant risk factor for the development of T2DM,
macrovascular disease and microvascular disease [50].
The complications resulting from the disease are a sig-
nificant cause of morbidity and mortality and are associ-
ated with the damage or failure of various organs such as
the eyes, the kidney and the nerves. The progression of
PD to T2DM may be retarded by maintaining blood
sugar control through lifestyle changes and/or compli-
ance with diabetic medications thereby allowing pancre-
atic beta cells to maintain functionality.
Since 2003, the American Diabetes Association (ADA)
Expert Committee recommended the use of fasting
blood glucose levels and/or a 2 hr GTT to diagnose PD
(see Tabl e 1). HbA1C had been suggested as a diagnos-
tic test but studies had shown weak correlation between
A1C and fasting blood glucose and an even weaker cor-
relation between A1C and 2 hour glucose among non-
diabetic patients [50]. The ADA has recently revised
their clinical practice recommendations for diabetes di-
agnosis by using Glycosylated Hemoglobin (HgA1C)
[51]. A measure of average blood glucose for the pre-
ceding three months, HbA1C has now been advocated to
diagnosis PD (5.7% - 6.4%) and T2DM (greater than
6.5%). The new application of HbA1c results from im-
proved standardization of assays among different labo-
ratories. The American Association of Clinical Endocri-
nologists (AACE) and the American College of Endo-
crinology (ACE) recommend HgA1C range of 5.5% -
6/4% only as a screen for PD to facilitate formal testing
and not for diagnosing type 1 diabetes.
A Department of Health and Human Services sup-
ported research showed most people with PD will likely
develop diabetes within a decade unless they make
modest changes in their diet and level of physical activ-
ity to reduce their risk and avoid the debilitating disease
[52]. Lifestyle change has consistently demonstrated
benefit in prevention or delaying progression to T2DM,
delaying onset by 11.1 years. In addition it reduces the
incidence of diabetic complication including blindness
by 3%, limb amputation by 35%, Stroke by 9% and co-
ronary heart disease by 8%. The Diabetes Prevention
Program (DPP) study demonstrated a 58% reduction in
Table 1. Defining PD.
Fasting* Glucose 2hr 75gm GTT1 Hemoglobin A1C2 Classic symptoms of
hyperglycemia or h y pe r g l yc emic crisis
Euglycemia < 100 mg/dL < 140 mg/dL 4% - 6%
PD ( IFG/IGT) 100 mg/dL - 126 mg/dL 140 - 199 mg/dL 5.7% - 6.4%3
T2DM ≥ 126 mg/dL > 199 mg/dL ≥6.5%4 random plasma glucose ≥200 mg/dl
* fasting = no caloric intake for at least 8 h; 12003 ADA guidelines; 22010 ADA guidelines; 3AACE/ACE supports HgA1C range 5.5%-6.4%; 4AACE/ACE
considers HgA1C an optional criteria, not primary

M. P. Trolice / Open Journal of Obstetrics and Gynecology 1 (2011) 36-41 39
progression from PD to T2DM with intense lifestyle
changes [52]. In the study, these changes included a
weight loss of 7% and at least 150 minutes of physical
activity per week. The DPP study also demonstrated
metformin 850 mg twice daily in PD patients reduced
the progression to T2DM by 31%. The DPP study did
not evaluate the effect of combination of lifestyle modi-
fications and pharmacotherapy but computer modeling
has determined no additional benefit with combination
of lifestyle modification and metformin [50].
6. GUIDELINES
The American Association of Clinical Endocrinologist
(AACE) released a consensus statement in July of 2008
establishing two goals for the treatment of pre-diabetes:
1) Aggressive lifestyle management. The ADA further
recommends lifestyle modifications to include a sus-
tained weight loss goal of 5% - 10% combined with
moderate to intense physical activity of 30 - 60 minutes
daily, at least 150 minutes weekly [53].
2) Avoid cardiovascular complications associated with
elevated glucose levels with pharmacotherapy in PD
refractory to lifestyle modification.
All patients 45 years or older and overweight should
be screened for PD [54]. The ADA recommendations to
screen for PD are shown in Table 2. The Food and Drug
Administration (FDA) has yet to approve pharmaco-
therapy as a treatment for PD. Therefore, any physician
considering starting a patient on medications for this
condition must consider the available evidence and a
risk-benefit analysis. Metformin and acarbose have
strong evidence for reduction in progression of PD to
T2DM. Both drugs are relatively safe and may be ac-
ceptable pharmacotherapy for prevention [55].
Recommendations for monitoring patients with PD
Table 2. Screen for PD/T2DM in all patients >45 yrs or in
patients <45 years and overweight (BMI ≥ 25 kg/m2 with any
of the following risk factors.*
Hypertension (≥140/90mm Hg)
First degree relative with T2DM
A history of gestational diabetes or delivered an infant weighing >9
lbs.
PCOS
HgA1C ≥5.7% or PD
High blood triglycerides (>250 mg/dl) and/or low HDL cholesterol
(<35mg/dl)
Other clinical conditions associated with insulin resistance (e.g.,
severe obesity, acanthosis nigricans)
History of Cardiovascular disease
Native American, African American, Hispanic American, Asian
American and Pacific Islander
*if normal results, re-screen every three years.
Table 3. Monitoring patients with PD.
Semi-annual Annual
Fasting glucose
Hb A1C
Fasting lipids
Urine for microalbumin
2 hr - GTT1
12003 ADA guidelines
are shown in Ta b le 3 . Patients at highest risk should
be followed more carefully. These patients include those
with greater than one risk factor: impaired glucose tol-
erance, impaired fasting glucose level, or the metabolic
syndrome. Patients with PD should also have the same
target blood pressure less than130/80 mmHg and target
LDL less than 100 mg/dL as those with diabetes. If the
results of monitoring reveal worsening hyperglycemia or
CV parameters, intensified lifestyle and pharmacother-
apy must be considered.
The CDC estimates $107 billion of the health budget
is used each year to care for patients with diabetes
[49,56]. Identifying and treating patients with PD poten-
tially has several benefits: the onset of type 2 diabetes
and its subsequent complications can be prevented or
delayed decreasing morbidity and mortality; and billions
of dollars can ultimately be saved in health care expen-
diture.
7. CONCLUSIONS
Prediabetes (PD) is ubiquitous with the potential for
severe morbidity and mortality. Given the association
with the metabolic syndrome, all PCOS patients should
be screened for PD by either a 2hr GTT or HgA1C be-
cause a fasting glucose alone will miss up to 30%. Be-
havioral modification for weight loss including aggres-
sive lifestyle management may avoid cardiovascular
complications. Furthermore, while metformin appears to
reduce the progression of PD to Diabetes (T2DM), the
role of metformin remains undefined in the infertile
PCOS patient.
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