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Sizing up insulin resistance—one treatment doesn’t fit all
Is PCOS a way station on the road to diabetes?
Treatment algorithm based on 4 degrees of insulin resistance
Admittedly, some evidence supports this approach. For example, a recent meta-analysis1 demonstrated that metformin improves ovulation and, in conjunction with clomiphene citrate, boosts pregnancy rates. That may be rationale enough to use the drug routinely for ovulatory-related infertility in women with PCOS.
But for the rest of our PCOS patients, measuring the degree of insulin resistance—by assessing the patient for metabolic syndrome and glucose intolerance—can yield a reasonably accurate view of long-term risk, as well as the optimal intervention for a given patient.
More good news: Effective treatment does exist, including lifestyle modification and pharmacologic therapy. And lest we assume drugs are the strongest medicine, consider this: Intensive lifestyle intervention reduces the risk of diabetes by as much as 58%—about twice the efficacy of medication.2
While many small reports implicate insulin resistance or hyperinsulinemia in a variety of reproductive disorders and even endometrial cancer, the quality and quantity of that evidence pale in comparison with data showing it can cause type 2 diabetes.3 Anything we can do to slow the progression is bound to benefit the patient and, in the long run, help prevent cardiovascular disease as well.
How to identify insulin resistance
The best way is to assess the patient for metabolic syndrome (TABLE) and then measure the 2-hour glucose level after a 75-g oral glucose load. The World Health Organization criterion for impaired glucose tolerance (IGT) after this test is a plasma glucose level of 140–199 mg/dL.4
TABLE
Is it metabolic syndrome or not?
| 3 or more risk factors make the diagnosis | |
|---|---|
| RISK FACTOR | CUTOFF |
| Abdominal obesity (waist circumference) | >88 cm (>35 in) |
| Triglycerides | 150 mg/dL |
| HDL cholesterol | |
| Blood pressure | 130/85 mm Hg |
| Fasting and/or 2-hour glucose from a 75-g oral glucose tolerance test | 110–126 mg/dL* and/or 2-hour glucose level of 140–199 mg/dL† |
| HDL = high-density lipoprotein | |
| *As recommended by the Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults | |
| †As recommended by ACOG and AACE | |
Limitations of other tests
The problem with traditional research tests such as euglycemic clamp studies and intravenous glucose/insulin tolerance tests is that they are invasive, labor intensive, time-consuming, and require a skilled team to perform—all of which translate into a poor clinical test. And among the limitations of the homeostatic models devised to replace them—which use fasting glucose and insulin levels as surrogate measures of these dynamic tests—is poor sensitivity in patients with IGT.
These models also have shifting cutoff levels in different studies in different populations.
Clinical parameters are more practical
Rather than rely on these traditional and homeostatic tests, some experts focus on validated clinical parameters. For example, the Third Report of the National Cholesterol Education Program Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP-III) defined metabolic syndrome using biometric and biochemical measures of centripetal obesity, hypertension, fasting hyperglycemia, and dyslipidemia (TABLE).5
Metabolic syndrome is closely related to insulin resistance syndrome, or syndrome X, which is characterized by dyslipidemia (depressed high-density lipoprotein [HDL] cholesterol and elevated triglycerides), hypertension, and glucose intolerance.6
Other groups such as ACOG7 and the American Association of Clinical Endocrinologists8 recommend adding a modified glucose tolerance test to the fasting blood tests used to identify metabolic syndrome.
Although a 2-hour glucose level after dynamic challenge does not test insulin sensitivity, it is more likely to identify a pathological relationship between insulin sensitivity and compensatory insulin secretion—one that is less detectable using fasting measures of glucose and insulin. One reason: In most women with IGT, fasting glucose levels are in the normal range. Thus, the fasting test alone would provide little discriminatory information.
Why glucose intolerance is important
Impaired glucose tolerance is a strong risk factor for diabetes, and recent studies show it is possible to delay progression to diabetes in women with IGT using lifestyle and, when appropriate, pharmacotherapy.2,9,10 IGT also identifies excess risk for mortality, especially in women.11 This is important because in obese women with PCOS, IGT approaches 40%.12-14 And the incidence of type 2 diabetes among women with PCOS is 11.9%, compared with only 1.4% in healthy controls.15
In type 2 diabetes, as well as polycystic ovary syndrome (PCOS), a main component is peripheral insulin resistance,20 although women with PCOS have somewhat better beta cell function than diabetic women, with initial hypersecretion and compensation. Over time, dysfunction develops, leading to inadequate insulin secretion, beta cell exhaustion, fasting hyperglycemia, and frank type 2 diabetes.
Just what is insulin resistance?
Insulin is the primary anabolic hormone in the body, acting in diverse ways in different tissues. Yet insulin resistance is usually defined as a single action: decreased insulin-mediated glucose uptake by peripheral tissues (largest utilizer: skeletal muscle).
Most research tests, such as euglycemic clamp studies, focus on glucose uptake—or its disappearance from the circulation—during dynamic challenge tests. The higher the glucose uptake, the greater the insulin sensitivity and the lower the eventual risk of developing diabetes.
Signs of insulin resistance in PCOS patients
In women with PCOS, the picture is complicated by selective tissue sensitivity to insulin and/or selective actions within tissues that are either sensitive (adrenal or ovary) or resistant (skeletal muscle) to insulin.21
Women with PCOS are profoundly resistant to insulin at the level of skeletal muscle, where 85% to 90% of insulin is utilized. This is comparable to the resistance in women with type 2 diabetes.22
In the target tissues of women with PCOS, compensatory hyperinsulinemia is thought to create aberrant states, suggesting that these tissues are differentially responsive to insulin’s action. For instance, hyperinsulinemia drives excess ovarian and adrenal androgen production, stimulates the proliferation of the piloseba-ceous unit (worsening acne and hirsutism), and suppresses hepatic sex hormone binding globulin production, thus increasing the bioavailable androgen load.
Insulin resistance is not always a disorder
Determining precisely who is insulin-resistant, and assigning clinical cutoffs, are complicated tasks. We lack standardized assays for insulin, and results vary from lab to lab. Normal insulin sensitivity varies widely and is influenced by age, gender, ethnicity, diet, and obesity. Simply put, not all people with impaired insulin sensitivity are necessarily suffering from a disorder. Pregnancy, a temporary condition of markedly diminished insulin sensitivity, is one example.
Thus, establishing limits for normal degrees of insulin sensitivity is arbitrary; often the bottom 10% to 25% of a population is labeled “insulin-resistant.”
Managing impaired glucose tolerance
Diet and exercise double risk reduction
In a recent trial by the Diabetes Prevention Program Research Group, which offers excellent guidelines for intervention,2 both metformin and lifestyle intervention reduced diabetes risk, although lifestyle was far more effective (58% reduction versus 29%).
That trial randomized 3,234 men and women with IGT to 3 treatments: conventional lifestyle recommendations, intensive and active lifestyle intervention, or insulin sensitization with metformin.
Intensive lifestyle intervention involved a case manager to ensure compliance with the study’s goals: at least a 7% loss in body weight maintained over the life of the study, and at least 150 minutes of exercise weekly. Exercise was key. Individuals who complied with intensive lifestyle intervention exercised an average of 6 hours weekly over the 4 years of the trial. The other groups exercised on average less than 2 hours weekly.
For metabolic abnormalities, start with lifestyle
With this information, it is possible to devise an algorithm for women with PCOS, depending on their degree of metabolic abnormality (FIGURE).
All individuals—even those taking medication—should be counseled about the importance of a healthy lifestyle, including staying physically active and quitting smoking. In addition:
- In women with metabolic syndrome, intensive lifestyle intervention is warranted, preferably supervised (ie, by a registered dietician and exercise trainer). This may involve out-of-pocket expense, but expert advice in these areas requires a professional. Obese, metabolically challenged women should also avoid overstrenuous exercise programs.
- Impaired glucose tolerance arouses further concern; insulin sensitization with metformin may be appropriate.
- If type 2 diabetes is diagnosed, repeat the blood tests to confirm the diagnosis and then evaluate the patient for sequelae and refer her for more intensive management.
If metabolic syndrome progresses, or if individual parameters change for the worse, additional therapy may be warranted, such as altering the dose or the choice of insulin sensitizer.
Guidelines into action
SUZANNE’S CASE
Suzanne is a 32-year-old mother of twins who presents with PCOS at a new-patient appointment, seeking advice about longterm care. She has a history of irregular menses; she conceived her twins on clomiphene 6 years ago, and now is being treated with an oral contraceptive (OC) containing 30 μg ethinyl estradiol, which she has taken for 4 years. She does not desire fertility.
Although Suzanne has a history of hirsutism, and occasionally plucks chest hair, she has been satisfied with her response to the OC. She has no other medical problems and does not smoke. Although she has a strong family history of type 2 diabetes, with both parents now on oral agents, there is no family history of premature heart disease.
She is 5 ft 9 inches tall and weighs 200 lb, with a body mass index of 29.5 kg/m2 (a BMI of 25 to 30 is overweight). Her blood pressure is 110 mm Hg systolic, 70 mm Hg diastolic, and her waist circumference is 90 cm. She has mild hirsutism. Other physical examination findings, including breast and pelvic examinations, are normal.
A fasting lipid profile reveals that Suzanne’s HDL cholesterol is 55 mg/dL, triglycerides are 175 mg/dL, and total and low-density lipoprotein (LDL) cholesterol are normal. A modified oral glucose tolerance test (OGTT) shows a fasting glucose level of 95 mg/dL and a 2-hour glucose level of 180 mg/dL, consistent with IGT.
Diagnostic phase. Polycystic ovary syndrome (PCOS) signs and symptoms are reported as such until you identify PCOS. For example, if the patient has excessive body hair, use hirsutism code ICD-9-CM 704.1; for obesity, code for unspecified obesity (278.00), morbid or severe obesity (278.01), or obesity of endocrine origin (259.9). If she has irregular menstrual periods, use the code for that condition (626.4).
Use the code for polycystic ovaries and PCOS (ICD-9-CM 256.4) once you have a diagnosis, during management, or when additional metabolic studies are done to rule out coexisting problems.
Link tests to suspected condition. A battery of laboratory tests will usually be part of diagnosis. Because many payers do not reimburse for routine screening tests, it is important to indicate that these tests are being performed to diagnose a suspected condition.
When screening women for metabolic syndrome and glucose intolerance, you may consider:
- Lipid panel (CPT 80061), linked to a diagnosis of obesity or a family history of cardiovascular disease (V17.4).
- Diabetes screening (CPT 82947 for fasting glucose plus 82950 for the 2-hour post glucose specimen) linked to a history of gestational diabetes (V13.29, other genital system and obstetric disorders) or family history of diabetes (V18.0), and possibly obesity.
After diagnosis, use E/M codes. Once you confirm PCOS and determine that management of affected systems is required, most follow-up care will be reported using evaluation and management (E/M) codes (99212–99215 for the established patient). Also use the E/M codes for initial physician encounters for diagnosis: consultation codes if another provider sends the patient to you for evaluation, or new/established patient codes if not.
Document counseling time. Some visits may entail counseling, so it is important to document counseling time (as well as total face-to-face time) with the patient. This allows you to select the E/M code based on total time, rather than on 2 of the 3 key components of history, examination, and/or medical decision-making.
The linking diagnosis during the management phase will be PCOS (256.4), along with any supporting diagnosis related to coexisting problems being managed at the time of the visit.
—Melanie Witt, RN, CPC, MA
Consider overall risk, modifiable factors
Besides the IGT, this patient has other risk factors for diabetes, including her BMI, strong family history, and several stigmata of metabolic syndrome, although she does not meet the ATP-III criteria for the syndrome. Nevertheless, the IGT merits attention.
While small case series suggest OCs can worsen glucose tolerance in women with PCOS, the overall evidence is conflicting. The Nurses Health Study16 found no association between type 2 diabetes and OC use.
One treatment option would be to discontinue the OC and see whether glucose tolerance normalizes, but Suzanne expresses a desire to continue the OC, given her overall satisfaction with its contraceptive benefit and control of hirsutism. Another factor to consider is the profound lifetime benefit OCs offer in protection against endometrial cancer.
I recommend a structured lifestyle intervention and would refer her to an exercise physiologist and dietician, because I am concerned about her other risk factors for diabetes, including her weight and strong family history.
When to add metformin
This patient also may benefit from concomitant use of metformin. Although we lack evidence that the combination of intensive lifestyle intervention and metformin is superior to lifestyle intervention alone, there is suggestive evidence from a small pilot clinical trial in women with PCOS.17
In Suzanne’s case I would treat the IGT more aggressively, given her strong family history of diabetes and her overweight status, by recommending that she add metformin to her regimen.
Higher doses may be more effective. Although the Diabetes Prevention Program study recommends a metformin dose of 850 mg twice a day, I prefer 2,000 mg a day in 2 divided doses. A dose-ranging study for type 2 diabetes found this to be the most effective dose for improving glycemic parameters.18 I use a step-up regimen of 500-mg doses over 5 to 7 days until the 2,000-mg dose is attained, and will plateau the patient at a lower dosage if she does not tolerate the higher amount, most commonly due to gastrointestinal side effects.
Monitor at least annually
This patient warrants visits at least yearly to monitor her condition. The visits should include a lipid profile and, every few years, an OGTT. A glycosylated hemoglobin in lieu of the OGTT may be another option.
It also is prudent to monitor renal function at baseline and at least annually, given the renal clearance of metformin.
In addition, I would continue the OC, as there are no known interactions between OCs and metformin, and at least 1 randomized study19 suggests the combination of the 2 is metabolically superior to an OC alone.
Scant evidence suggests that metformin alone improves hirsutism or results in eumenorrhea, and there are no data on endometrial cancer protection.
Dr. Legro has received grant support from Pfizer and served as a consultant for Ortho-McNeil and Abbott Laboratories.
1. Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. 2003;327:951-953.
2. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
3. Gerich JE. The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev. 1998;19:491-503.
4. Modan M, Harris MI, Halkin H. Evaluation of WHO and NDDG criteria for impaired glucose tolerance. Results from two national samples. Diabetes. 1989;38:1630-1635.
5. Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
6. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607.
7. American College of Obstetricians and Gynecologists. Practice Bulletin #41: Polycystic Ovary Syndrome. Washington, DC: ACOG; December 2002. Obstet Gynecol. 2002;100:1389-1402.
8. Bloomgarden ZT. American Association of Clinical Endocrinologists (AACE) Consensus Conference on the Insulin Resistance Syndrome: 25-26 August 2002, Washington, DC. Diabetes Care. 2003;26:933-939.
9. Lindstrom J, Louheranta A, Mannelin M, et al. The Finnish Diabetes Prevention Study (DPS): lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care. 2003;26:3230-6.
10. Laaksonen DE, Niskanen L, Lakka HM, Lakka TA, Uusitupa M. Epidemiology and treatment of the metabolic syndrome. Ann Med. 2004;36:332-346.
11. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The Decode Study Group. European Diabetes Epidemiology Group. Diabetes epidemiology: collaborative analysis of diagnostic criteria in Europe. Lancet. 1999;354:617-621.
12. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84:165-169.
13. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22:141-146.
14. Ehrmann DA, Kasza K, Azziz R, Legro RS, Ghazzi MN. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab. 2004;90:66-71.
15. Talbott EO, Zborowski JV, Sutton-Tyrrell K, McHugh-Pemu KP, Guzick DS. Cardiovascular risk in women with polycystic ovary syndrome. Obstet Gynecol Clin North Am. 2001;28:111-133.
16. Chasen-Taber L, Willett WC, Stampfer MJ, et al. A prospective study of oral contraceptives and NIDDM among US women. Diabetes Care. 1997;20:330-335.
17. Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, Guzick DS. A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril. 2004;82:421-429.
18. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose–response trial. Am J Med. Dec. 1997;103:491-497.
19. Elter K, Imir G, Durmusoglu F. Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study. Hum Reprod. 2002;17:1729-1737.
20. Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993;42:1663-1672.
21. Poretsky L. On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev. 1991;12:3-13.
22. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165-1174.
Is PCOS a way station on the road to diabetes?
Treatment algorithm based on 4 degrees of insulin resistance
Admittedly, some evidence supports this approach. For example, a recent meta-analysis1 demonstrated that metformin improves ovulation and, in conjunction with clomiphene citrate, boosts pregnancy rates. That may be rationale enough to use the drug routinely for ovulatory-related infertility in women with PCOS.
But for the rest of our PCOS patients, measuring the degree of insulin resistance—by assessing the patient for metabolic syndrome and glucose intolerance—can yield a reasonably accurate view of long-term risk, as well as the optimal intervention for a given patient.
More good news: Effective treatment does exist, including lifestyle modification and pharmacologic therapy. And lest we assume drugs are the strongest medicine, consider this: Intensive lifestyle intervention reduces the risk of diabetes by as much as 58%—about twice the efficacy of medication.2
While many small reports implicate insulin resistance or hyperinsulinemia in a variety of reproductive disorders and even endometrial cancer, the quality and quantity of that evidence pale in comparison with data showing it can cause type 2 diabetes.3 Anything we can do to slow the progression is bound to benefit the patient and, in the long run, help prevent cardiovascular disease as well.
How to identify insulin resistance
The best way is to assess the patient for metabolic syndrome (TABLE) and then measure the 2-hour glucose level after a 75-g oral glucose load. The World Health Organization criterion for impaired glucose tolerance (IGT) after this test is a plasma glucose level of 140–199 mg/dL.4
TABLE
Is it metabolic syndrome or not?
| 3 or more risk factors make the diagnosis | |
|---|---|
| RISK FACTOR | CUTOFF |
| Abdominal obesity (waist circumference) | >88 cm (>35 in) |
| Triglycerides | 150 mg/dL |
| HDL cholesterol | |
| Blood pressure | 130/85 mm Hg |
| Fasting and/or 2-hour glucose from a 75-g oral glucose tolerance test | 110–126 mg/dL* and/or 2-hour glucose level of 140–199 mg/dL† |
| HDL = high-density lipoprotein | |
| *As recommended by the Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults | |
| †As recommended by ACOG and AACE | |
Limitations of other tests
The problem with traditional research tests such as euglycemic clamp studies and intravenous glucose/insulin tolerance tests is that they are invasive, labor intensive, time-consuming, and require a skilled team to perform—all of which translate into a poor clinical test. And among the limitations of the homeostatic models devised to replace them—which use fasting glucose and insulin levels as surrogate measures of these dynamic tests—is poor sensitivity in patients with IGT.
These models also have shifting cutoff levels in different studies in different populations.
Clinical parameters are more practical
Rather than rely on these traditional and homeostatic tests, some experts focus on validated clinical parameters. For example, the Third Report of the National Cholesterol Education Program Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP-III) defined metabolic syndrome using biometric and biochemical measures of centripetal obesity, hypertension, fasting hyperglycemia, and dyslipidemia (TABLE).5
Metabolic syndrome is closely related to insulin resistance syndrome, or syndrome X, which is characterized by dyslipidemia (depressed high-density lipoprotein [HDL] cholesterol and elevated triglycerides), hypertension, and glucose intolerance.6
Other groups such as ACOG7 and the American Association of Clinical Endocrinologists8 recommend adding a modified glucose tolerance test to the fasting blood tests used to identify metabolic syndrome.
Although a 2-hour glucose level after dynamic challenge does not test insulin sensitivity, it is more likely to identify a pathological relationship between insulin sensitivity and compensatory insulin secretion—one that is less detectable using fasting measures of glucose and insulin. One reason: In most women with IGT, fasting glucose levels are in the normal range. Thus, the fasting test alone would provide little discriminatory information.
Why glucose intolerance is important
Impaired glucose tolerance is a strong risk factor for diabetes, and recent studies show it is possible to delay progression to diabetes in women with IGT using lifestyle and, when appropriate, pharmacotherapy.2,9,10 IGT also identifies excess risk for mortality, especially in women.11 This is important because in obese women with PCOS, IGT approaches 40%.12-14 And the incidence of type 2 diabetes among women with PCOS is 11.9%, compared with only 1.4% in healthy controls.15
In type 2 diabetes, as well as polycystic ovary syndrome (PCOS), a main component is peripheral insulin resistance,20 although women with PCOS have somewhat better beta cell function than diabetic women, with initial hypersecretion and compensation. Over time, dysfunction develops, leading to inadequate insulin secretion, beta cell exhaustion, fasting hyperglycemia, and frank type 2 diabetes.
Just what is insulin resistance?
Insulin is the primary anabolic hormone in the body, acting in diverse ways in different tissues. Yet insulin resistance is usually defined as a single action: decreased insulin-mediated glucose uptake by peripheral tissues (largest utilizer: skeletal muscle).
Most research tests, such as euglycemic clamp studies, focus on glucose uptake—or its disappearance from the circulation—during dynamic challenge tests. The higher the glucose uptake, the greater the insulin sensitivity and the lower the eventual risk of developing diabetes.
Signs of insulin resistance in PCOS patients
In women with PCOS, the picture is complicated by selective tissue sensitivity to insulin and/or selective actions within tissues that are either sensitive (adrenal or ovary) or resistant (skeletal muscle) to insulin.21
Women with PCOS are profoundly resistant to insulin at the level of skeletal muscle, where 85% to 90% of insulin is utilized. This is comparable to the resistance in women with type 2 diabetes.22
In the target tissues of women with PCOS, compensatory hyperinsulinemia is thought to create aberrant states, suggesting that these tissues are differentially responsive to insulin’s action. For instance, hyperinsulinemia drives excess ovarian and adrenal androgen production, stimulates the proliferation of the piloseba-ceous unit (worsening acne and hirsutism), and suppresses hepatic sex hormone binding globulin production, thus increasing the bioavailable androgen load.
Insulin resistance is not always a disorder
Determining precisely who is insulin-resistant, and assigning clinical cutoffs, are complicated tasks. We lack standardized assays for insulin, and results vary from lab to lab. Normal insulin sensitivity varies widely and is influenced by age, gender, ethnicity, diet, and obesity. Simply put, not all people with impaired insulin sensitivity are necessarily suffering from a disorder. Pregnancy, a temporary condition of markedly diminished insulin sensitivity, is one example.
Thus, establishing limits for normal degrees of insulin sensitivity is arbitrary; often the bottom 10% to 25% of a population is labeled “insulin-resistant.”
Managing impaired glucose tolerance
Diet and exercise double risk reduction
In a recent trial by the Diabetes Prevention Program Research Group, which offers excellent guidelines for intervention,2 both metformin and lifestyle intervention reduced diabetes risk, although lifestyle was far more effective (58% reduction versus 29%).
That trial randomized 3,234 men and women with IGT to 3 treatments: conventional lifestyle recommendations, intensive and active lifestyle intervention, or insulin sensitization with metformin.
Intensive lifestyle intervention involved a case manager to ensure compliance with the study’s goals: at least a 7% loss in body weight maintained over the life of the study, and at least 150 minutes of exercise weekly. Exercise was key. Individuals who complied with intensive lifestyle intervention exercised an average of 6 hours weekly over the 4 years of the trial. The other groups exercised on average less than 2 hours weekly.
For metabolic abnormalities, start with lifestyle
With this information, it is possible to devise an algorithm for women with PCOS, depending on their degree of metabolic abnormality (FIGURE).
All individuals—even those taking medication—should be counseled about the importance of a healthy lifestyle, including staying physically active and quitting smoking. In addition:
- In women with metabolic syndrome, intensive lifestyle intervention is warranted, preferably supervised (ie, by a registered dietician and exercise trainer). This may involve out-of-pocket expense, but expert advice in these areas requires a professional. Obese, metabolically challenged women should also avoid overstrenuous exercise programs.
- Impaired glucose tolerance arouses further concern; insulin sensitization with metformin may be appropriate.
- If type 2 diabetes is diagnosed, repeat the blood tests to confirm the diagnosis and then evaluate the patient for sequelae and refer her for more intensive management.
If metabolic syndrome progresses, or if individual parameters change for the worse, additional therapy may be warranted, such as altering the dose or the choice of insulin sensitizer.
Guidelines into action
SUZANNE’S CASE
Suzanne is a 32-year-old mother of twins who presents with PCOS at a new-patient appointment, seeking advice about longterm care. She has a history of irregular menses; she conceived her twins on clomiphene 6 years ago, and now is being treated with an oral contraceptive (OC) containing 30 μg ethinyl estradiol, which she has taken for 4 years. She does not desire fertility.
Although Suzanne has a history of hirsutism, and occasionally plucks chest hair, she has been satisfied with her response to the OC. She has no other medical problems and does not smoke. Although she has a strong family history of type 2 diabetes, with both parents now on oral agents, there is no family history of premature heart disease.
She is 5 ft 9 inches tall and weighs 200 lb, with a body mass index of 29.5 kg/m2 (a BMI of 25 to 30 is overweight). Her blood pressure is 110 mm Hg systolic, 70 mm Hg diastolic, and her waist circumference is 90 cm. She has mild hirsutism. Other physical examination findings, including breast and pelvic examinations, are normal.
A fasting lipid profile reveals that Suzanne’s HDL cholesterol is 55 mg/dL, triglycerides are 175 mg/dL, and total and low-density lipoprotein (LDL) cholesterol are normal. A modified oral glucose tolerance test (OGTT) shows a fasting glucose level of 95 mg/dL and a 2-hour glucose level of 180 mg/dL, consistent with IGT.
Diagnostic phase. Polycystic ovary syndrome (PCOS) signs and symptoms are reported as such until you identify PCOS. For example, if the patient has excessive body hair, use hirsutism code ICD-9-CM 704.1; for obesity, code for unspecified obesity (278.00), morbid or severe obesity (278.01), or obesity of endocrine origin (259.9). If she has irregular menstrual periods, use the code for that condition (626.4).
Use the code for polycystic ovaries and PCOS (ICD-9-CM 256.4) once you have a diagnosis, during management, or when additional metabolic studies are done to rule out coexisting problems.
Link tests to suspected condition. A battery of laboratory tests will usually be part of diagnosis. Because many payers do not reimburse for routine screening tests, it is important to indicate that these tests are being performed to diagnose a suspected condition.
When screening women for metabolic syndrome and glucose intolerance, you may consider:
- Lipid panel (CPT 80061), linked to a diagnosis of obesity or a family history of cardiovascular disease (V17.4).
- Diabetes screening (CPT 82947 for fasting glucose plus 82950 for the 2-hour post glucose specimen) linked to a history of gestational diabetes (V13.29, other genital system and obstetric disorders) or family history of diabetes (V18.0), and possibly obesity.
After diagnosis, use E/M codes. Once you confirm PCOS and determine that management of affected systems is required, most follow-up care will be reported using evaluation and management (E/M) codes (99212–99215 for the established patient). Also use the E/M codes for initial physician encounters for diagnosis: consultation codes if another provider sends the patient to you for evaluation, or new/established patient codes if not.
Document counseling time. Some visits may entail counseling, so it is important to document counseling time (as well as total face-to-face time) with the patient. This allows you to select the E/M code based on total time, rather than on 2 of the 3 key components of history, examination, and/or medical decision-making.
The linking diagnosis during the management phase will be PCOS (256.4), along with any supporting diagnosis related to coexisting problems being managed at the time of the visit.
—Melanie Witt, RN, CPC, MA
Consider overall risk, modifiable factors
Besides the IGT, this patient has other risk factors for diabetes, including her BMI, strong family history, and several stigmata of metabolic syndrome, although she does not meet the ATP-III criteria for the syndrome. Nevertheless, the IGT merits attention.
While small case series suggest OCs can worsen glucose tolerance in women with PCOS, the overall evidence is conflicting. The Nurses Health Study16 found no association between type 2 diabetes and OC use.
One treatment option would be to discontinue the OC and see whether glucose tolerance normalizes, but Suzanne expresses a desire to continue the OC, given her overall satisfaction with its contraceptive benefit and control of hirsutism. Another factor to consider is the profound lifetime benefit OCs offer in protection against endometrial cancer.
I recommend a structured lifestyle intervention and would refer her to an exercise physiologist and dietician, because I am concerned about her other risk factors for diabetes, including her weight and strong family history.
When to add metformin
This patient also may benefit from concomitant use of metformin. Although we lack evidence that the combination of intensive lifestyle intervention and metformin is superior to lifestyle intervention alone, there is suggestive evidence from a small pilot clinical trial in women with PCOS.17
In Suzanne’s case I would treat the IGT more aggressively, given her strong family history of diabetes and her overweight status, by recommending that she add metformin to her regimen.
Higher doses may be more effective. Although the Diabetes Prevention Program study recommends a metformin dose of 850 mg twice a day, I prefer 2,000 mg a day in 2 divided doses. A dose-ranging study for type 2 diabetes found this to be the most effective dose for improving glycemic parameters.18 I use a step-up regimen of 500-mg doses over 5 to 7 days until the 2,000-mg dose is attained, and will plateau the patient at a lower dosage if she does not tolerate the higher amount, most commonly due to gastrointestinal side effects.
Monitor at least annually
This patient warrants visits at least yearly to monitor her condition. The visits should include a lipid profile and, every few years, an OGTT. A glycosylated hemoglobin in lieu of the OGTT may be another option.
It also is prudent to monitor renal function at baseline and at least annually, given the renal clearance of metformin.
In addition, I would continue the OC, as there are no known interactions between OCs and metformin, and at least 1 randomized study19 suggests the combination of the 2 is metabolically superior to an OC alone.
Scant evidence suggests that metformin alone improves hirsutism or results in eumenorrhea, and there are no data on endometrial cancer protection.
Dr. Legro has received grant support from Pfizer and served as a consultant for Ortho-McNeil and Abbott Laboratories.
Is PCOS a way station on the road to diabetes?
Treatment algorithm based on 4 degrees of insulin resistance
Admittedly, some evidence supports this approach. For example, a recent meta-analysis1 demonstrated that metformin improves ovulation and, in conjunction with clomiphene citrate, boosts pregnancy rates. That may be rationale enough to use the drug routinely for ovulatory-related infertility in women with PCOS.
But for the rest of our PCOS patients, measuring the degree of insulin resistance—by assessing the patient for metabolic syndrome and glucose intolerance—can yield a reasonably accurate view of long-term risk, as well as the optimal intervention for a given patient.
More good news: Effective treatment does exist, including lifestyle modification and pharmacologic therapy. And lest we assume drugs are the strongest medicine, consider this: Intensive lifestyle intervention reduces the risk of diabetes by as much as 58%—about twice the efficacy of medication.2
While many small reports implicate insulin resistance or hyperinsulinemia in a variety of reproductive disorders and even endometrial cancer, the quality and quantity of that evidence pale in comparison with data showing it can cause type 2 diabetes.3 Anything we can do to slow the progression is bound to benefit the patient and, in the long run, help prevent cardiovascular disease as well.
How to identify insulin resistance
The best way is to assess the patient for metabolic syndrome (TABLE) and then measure the 2-hour glucose level after a 75-g oral glucose load. The World Health Organization criterion for impaired glucose tolerance (IGT) after this test is a plasma glucose level of 140–199 mg/dL.4
TABLE
Is it metabolic syndrome or not?
| 3 or more risk factors make the diagnosis | |
|---|---|
| RISK FACTOR | CUTOFF |
| Abdominal obesity (waist circumference) | >88 cm (>35 in) |
| Triglycerides | 150 mg/dL |
| HDL cholesterol | |
| Blood pressure | 130/85 mm Hg |
| Fasting and/or 2-hour glucose from a 75-g oral glucose tolerance test | 110–126 mg/dL* and/or 2-hour glucose level of 140–199 mg/dL† |
| HDL = high-density lipoprotein | |
| *As recommended by the Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults | |
| †As recommended by ACOG and AACE | |
Limitations of other tests
The problem with traditional research tests such as euglycemic clamp studies and intravenous glucose/insulin tolerance tests is that they are invasive, labor intensive, time-consuming, and require a skilled team to perform—all of which translate into a poor clinical test. And among the limitations of the homeostatic models devised to replace them—which use fasting glucose and insulin levels as surrogate measures of these dynamic tests—is poor sensitivity in patients with IGT.
These models also have shifting cutoff levels in different studies in different populations.
Clinical parameters are more practical
Rather than rely on these traditional and homeostatic tests, some experts focus on validated clinical parameters. For example, the Third Report of the National Cholesterol Education Program Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP-III) defined metabolic syndrome using biometric and biochemical measures of centripetal obesity, hypertension, fasting hyperglycemia, and dyslipidemia (TABLE).5
Metabolic syndrome is closely related to insulin resistance syndrome, or syndrome X, which is characterized by dyslipidemia (depressed high-density lipoprotein [HDL] cholesterol and elevated triglycerides), hypertension, and glucose intolerance.6
Other groups such as ACOG7 and the American Association of Clinical Endocrinologists8 recommend adding a modified glucose tolerance test to the fasting blood tests used to identify metabolic syndrome.
Although a 2-hour glucose level after dynamic challenge does not test insulin sensitivity, it is more likely to identify a pathological relationship between insulin sensitivity and compensatory insulin secretion—one that is less detectable using fasting measures of glucose and insulin. One reason: In most women with IGT, fasting glucose levels are in the normal range. Thus, the fasting test alone would provide little discriminatory information.
Why glucose intolerance is important
Impaired glucose tolerance is a strong risk factor for diabetes, and recent studies show it is possible to delay progression to diabetes in women with IGT using lifestyle and, when appropriate, pharmacotherapy.2,9,10 IGT also identifies excess risk for mortality, especially in women.11 This is important because in obese women with PCOS, IGT approaches 40%.12-14 And the incidence of type 2 diabetes among women with PCOS is 11.9%, compared with only 1.4% in healthy controls.15
In type 2 diabetes, as well as polycystic ovary syndrome (PCOS), a main component is peripheral insulin resistance,20 although women with PCOS have somewhat better beta cell function than diabetic women, with initial hypersecretion and compensation. Over time, dysfunction develops, leading to inadequate insulin secretion, beta cell exhaustion, fasting hyperglycemia, and frank type 2 diabetes.
Just what is insulin resistance?
Insulin is the primary anabolic hormone in the body, acting in diverse ways in different tissues. Yet insulin resistance is usually defined as a single action: decreased insulin-mediated glucose uptake by peripheral tissues (largest utilizer: skeletal muscle).
Most research tests, such as euglycemic clamp studies, focus on glucose uptake—or its disappearance from the circulation—during dynamic challenge tests. The higher the glucose uptake, the greater the insulin sensitivity and the lower the eventual risk of developing diabetes.
Signs of insulin resistance in PCOS patients
In women with PCOS, the picture is complicated by selective tissue sensitivity to insulin and/or selective actions within tissues that are either sensitive (adrenal or ovary) or resistant (skeletal muscle) to insulin.21
Women with PCOS are profoundly resistant to insulin at the level of skeletal muscle, where 85% to 90% of insulin is utilized. This is comparable to the resistance in women with type 2 diabetes.22
In the target tissues of women with PCOS, compensatory hyperinsulinemia is thought to create aberrant states, suggesting that these tissues are differentially responsive to insulin’s action. For instance, hyperinsulinemia drives excess ovarian and adrenal androgen production, stimulates the proliferation of the piloseba-ceous unit (worsening acne and hirsutism), and suppresses hepatic sex hormone binding globulin production, thus increasing the bioavailable androgen load.
Insulin resistance is not always a disorder
Determining precisely who is insulin-resistant, and assigning clinical cutoffs, are complicated tasks. We lack standardized assays for insulin, and results vary from lab to lab. Normal insulin sensitivity varies widely and is influenced by age, gender, ethnicity, diet, and obesity. Simply put, not all people with impaired insulin sensitivity are necessarily suffering from a disorder. Pregnancy, a temporary condition of markedly diminished insulin sensitivity, is one example.
Thus, establishing limits for normal degrees of insulin sensitivity is arbitrary; often the bottom 10% to 25% of a population is labeled “insulin-resistant.”
Managing impaired glucose tolerance
Diet and exercise double risk reduction
In a recent trial by the Diabetes Prevention Program Research Group, which offers excellent guidelines for intervention,2 both metformin and lifestyle intervention reduced diabetes risk, although lifestyle was far more effective (58% reduction versus 29%).
That trial randomized 3,234 men and women with IGT to 3 treatments: conventional lifestyle recommendations, intensive and active lifestyle intervention, or insulin sensitization with metformin.
Intensive lifestyle intervention involved a case manager to ensure compliance with the study’s goals: at least a 7% loss in body weight maintained over the life of the study, and at least 150 minutes of exercise weekly. Exercise was key. Individuals who complied with intensive lifestyle intervention exercised an average of 6 hours weekly over the 4 years of the trial. The other groups exercised on average less than 2 hours weekly.
For metabolic abnormalities, start with lifestyle
With this information, it is possible to devise an algorithm for women with PCOS, depending on their degree of metabolic abnormality (FIGURE).
All individuals—even those taking medication—should be counseled about the importance of a healthy lifestyle, including staying physically active and quitting smoking. In addition:
- In women with metabolic syndrome, intensive lifestyle intervention is warranted, preferably supervised (ie, by a registered dietician and exercise trainer). This may involve out-of-pocket expense, but expert advice in these areas requires a professional. Obese, metabolically challenged women should also avoid overstrenuous exercise programs.
- Impaired glucose tolerance arouses further concern; insulin sensitization with metformin may be appropriate.
- If type 2 diabetes is diagnosed, repeat the blood tests to confirm the diagnosis and then evaluate the patient for sequelae and refer her for more intensive management.
If metabolic syndrome progresses, or if individual parameters change for the worse, additional therapy may be warranted, such as altering the dose or the choice of insulin sensitizer.
Guidelines into action
SUZANNE’S CASE
Suzanne is a 32-year-old mother of twins who presents with PCOS at a new-patient appointment, seeking advice about longterm care. She has a history of irregular menses; she conceived her twins on clomiphene 6 years ago, and now is being treated with an oral contraceptive (OC) containing 30 μg ethinyl estradiol, which she has taken for 4 years. She does not desire fertility.
Although Suzanne has a history of hirsutism, and occasionally plucks chest hair, she has been satisfied with her response to the OC. She has no other medical problems and does not smoke. Although she has a strong family history of type 2 diabetes, with both parents now on oral agents, there is no family history of premature heart disease.
She is 5 ft 9 inches tall and weighs 200 lb, with a body mass index of 29.5 kg/m2 (a BMI of 25 to 30 is overweight). Her blood pressure is 110 mm Hg systolic, 70 mm Hg diastolic, and her waist circumference is 90 cm. She has mild hirsutism. Other physical examination findings, including breast and pelvic examinations, are normal.
A fasting lipid profile reveals that Suzanne’s HDL cholesterol is 55 mg/dL, triglycerides are 175 mg/dL, and total and low-density lipoprotein (LDL) cholesterol are normal. A modified oral glucose tolerance test (OGTT) shows a fasting glucose level of 95 mg/dL and a 2-hour glucose level of 180 mg/dL, consistent with IGT.
Diagnostic phase. Polycystic ovary syndrome (PCOS) signs and symptoms are reported as such until you identify PCOS. For example, if the patient has excessive body hair, use hirsutism code ICD-9-CM 704.1; for obesity, code for unspecified obesity (278.00), morbid or severe obesity (278.01), or obesity of endocrine origin (259.9). If she has irregular menstrual periods, use the code for that condition (626.4).
Use the code for polycystic ovaries and PCOS (ICD-9-CM 256.4) once you have a diagnosis, during management, or when additional metabolic studies are done to rule out coexisting problems.
Link tests to suspected condition. A battery of laboratory tests will usually be part of diagnosis. Because many payers do not reimburse for routine screening tests, it is important to indicate that these tests are being performed to diagnose a suspected condition.
When screening women for metabolic syndrome and glucose intolerance, you may consider:
- Lipid panel (CPT 80061), linked to a diagnosis of obesity or a family history of cardiovascular disease (V17.4).
- Diabetes screening (CPT 82947 for fasting glucose plus 82950 for the 2-hour post glucose specimen) linked to a history of gestational diabetes (V13.29, other genital system and obstetric disorders) or family history of diabetes (V18.0), and possibly obesity.
After diagnosis, use E/M codes. Once you confirm PCOS and determine that management of affected systems is required, most follow-up care will be reported using evaluation and management (E/M) codes (99212–99215 for the established patient). Also use the E/M codes for initial physician encounters for diagnosis: consultation codes if another provider sends the patient to you for evaluation, or new/established patient codes if not.
Document counseling time. Some visits may entail counseling, so it is important to document counseling time (as well as total face-to-face time) with the patient. This allows you to select the E/M code based on total time, rather than on 2 of the 3 key components of history, examination, and/or medical decision-making.
The linking diagnosis during the management phase will be PCOS (256.4), along with any supporting diagnosis related to coexisting problems being managed at the time of the visit.
—Melanie Witt, RN, CPC, MA
Consider overall risk, modifiable factors
Besides the IGT, this patient has other risk factors for diabetes, including her BMI, strong family history, and several stigmata of metabolic syndrome, although she does not meet the ATP-III criteria for the syndrome. Nevertheless, the IGT merits attention.
While small case series suggest OCs can worsen glucose tolerance in women with PCOS, the overall evidence is conflicting. The Nurses Health Study16 found no association between type 2 diabetes and OC use.
One treatment option would be to discontinue the OC and see whether glucose tolerance normalizes, but Suzanne expresses a desire to continue the OC, given her overall satisfaction with its contraceptive benefit and control of hirsutism. Another factor to consider is the profound lifetime benefit OCs offer in protection against endometrial cancer.
I recommend a structured lifestyle intervention and would refer her to an exercise physiologist and dietician, because I am concerned about her other risk factors for diabetes, including her weight and strong family history.
When to add metformin
This patient also may benefit from concomitant use of metformin. Although we lack evidence that the combination of intensive lifestyle intervention and metformin is superior to lifestyle intervention alone, there is suggestive evidence from a small pilot clinical trial in women with PCOS.17
In Suzanne’s case I would treat the IGT more aggressively, given her strong family history of diabetes and her overweight status, by recommending that she add metformin to her regimen.
Higher doses may be more effective. Although the Diabetes Prevention Program study recommends a metformin dose of 850 mg twice a day, I prefer 2,000 mg a day in 2 divided doses. A dose-ranging study for type 2 diabetes found this to be the most effective dose for improving glycemic parameters.18 I use a step-up regimen of 500-mg doses over 5 to 7 days until the 2,000-mg dose is attained, and will plateau the patient at a lower dosage if she does not tolerate the higher amount, most commonly due to gastrointestinal side effects.
Monitor at least annually
This patient warrants visits at least yearly to monitor her condition. The visits should include a lipid profile and, every few years, an OGTT. A glycosylated hemoglobin in lieu of the OGTT may be another option.
It also is prudent to monitor renal function at baseline and at least annually, given the renal clearance of metformin.
In addition, I would continue the OC, as there are no known interactions between OCs and metformin, and at least 1 randomized study19 suggests the combination of the 2 is metabolically superior to an OC alone.
Scant evidence suggests that metformin alone improves hirsutism or results in eumenorrhea, and there are no data on endometrial cancer protection.
Dr. Legro has received grant support from Pfizer and served as a consultant for Ortho-McNeil and Abbott Laboratories.
1. Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. 2003;327:951-953.
2. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
3. Gerich JE. The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev. 1998;19:491-503.
4. Modan M, Harris MI, Halkin H. Evaluation of WHO and NDDG criteria for impaired glucose tolerance. Results from two national samples. Diabetes. 1989;38:1630-1635.
5. Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
6. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607.
7. American College of Obstetricians and Gynecologists. Practice Bulletin #41: Polycystic Ovary Syndrome. Washington, DC: ACOG; December 2002. Obstet Gynecol. 2002;100:1389-1402.
8. Bloomgarden ZT. American Association of Clinical Endocrinologists (AACE) Consensus Conference on the Insulin Resistance Syndrome: 25-26 August 2002, Washington, DC. Diabetes Care. 2003;26:933-939.
9. Lindstrom J, Louheranta A, Mannelin M, et al. The Finnish Diabetes Prevention Study (DPS): lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care. 2003;26:3230-6.
10. Laaksonen DE, Niskanen L, Lakka HM, Lakka TA, Uusitupa M. Epidemiology and treatment of the metabolic syndrome. Ann Med. 2004;36:332-346.
11. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The Decode Study Group. European Diabetes Epidemiology Group. Diabetes epidemiology: collaborative analysis of diagnostic criteria in Europe. Lancet. 1999;354:617-621.
12. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84:165-169.
13. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22:141-146.
14. Ehrmann DA, Kasza K, Azziz R, Legro RS, Ghazzi MN. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab. 2004;90:66-71.
15. Talbott EO, Zborowski JV, Sutton-Tyrrell K, McHugh-Pemu KP, Guzick DS. Cardiovascular risk in women with polycystic ovary syndrome. Obstet Gynecol Clin North Am. 2001;28:111-133.
16. Chasen-Taber L, Willett WC, Stampfer MJ, et al. A prospective study of oral contraceptives and NIDDM among US women. Diabetes Care. 1997;20:330-335.
17. Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, Guzick DS. A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril. 2004;82:421-429.
18. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose–response trial. Am J Med. Dec. 1997;103:491-497.
19. Elter K, Imir G, Durmusoglu F. Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study. Hum Reprod. 2002;17:1729-1737.
20. Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993;42:1663-1672.
21. Poretsky L. On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev. 1991;12:3-13.
22. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165-1174.
1. Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. 2003;327:951-953.
2. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
3. Gerich JE. The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev. 1998;19:491-503.
4. Modan M, Harris MI, Halkin H. Evaluation of WHO and NDDG criteria for impaired glucose tolerance. Results from two national samples. Diabetes. 1989;38:1630-1635.
5. Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
6. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607.
7. American College of Obstetricians and Gynecologists. Practice Bulletin #41: Polycystic Ovary Syndrome. Washington, DC: ACOG; December 2002. Obstet Gynecol. 2002;100:1389-1402.
8. Bloomgarden ZT. American Association of Clinical Endocrinologists (AACE) Consensus Conference on the Insulin Resistance Syndrome: 25-26 August 2002, Washington, DC. Diabetes Care. 2003;26:933-939.
9. Lindstrom J, Louheranta A, Mannelin M, et al. The Finnish Diabetes Prevention Study (DPS): lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care. 2003;26:3230-6.
10. Laaksonen DE, Niskanen L, Lakka HM, Lakka TA, Uusitupa M. Epidemiology and treatment of the metabolic syndrome. Ann Med. 2004;36:332-346.
11. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The Decode Study Group. European Diabetes Epidemiology Group. Diabetes epidemiology: collaborative analysis of diagnostic criteria in Europe. Lancet. 1999;354:617-621.
12. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84:165-169.
13. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22:141-146.
14. Ehrmann DA, Kasza K, Azziz R, Legro RS, Ghazzi MN. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab. 2004;90:66-71.
15. Talbott EO, Zborowski JV, Sutton-Tyrrell K, McHugh-Pemu KP, Guzick DS. Cardiovascular risk in women with polycystic ovary syndrome. Obstet Gynecol Clin North Am. 2001;28:111-133.
16. Chasen-Taber L, Willett WC, Stampfer MJ, et al. A prospective study of oral contraceptives and NIDDM among US women. Diabetes Care. 1997;20:330-335.
17. Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, Guzick DS. A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril. 2004;82:421-429.
18. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose–response trial. Am J Med. Dec. 1997;103:491-497.
19. Elter K, Imir G, Durmusoglu F. Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study. Hum Reprod. 2002;17:1729-1737.
20. Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993;42:1663-1672.
21. Poretsky L. On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev. 1991;12:3-13.
22. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165-1174.