Defining prediabetes in polycystic ovarian syndrome

doi:10.4236/ojog.2011.12008

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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.

Email: [email protected]

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

M. P. Trolice / Open Journal of Obstetrics and Gynecology 1 (2011) 36-41

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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