Leah Whigham, PhD

 

Women with polycystic ovary syndrome (PCOS), compared with women without the condition, have a greater chance of developing metabolic syndrome (also known as syndrome X). Recent data have drawn attention to these long-term metabolic risks of PCOS. What is metabolic syndrome, and how can its first-line treatment, metformin, affect my patient’s symptoms of PCOS, including hyperandrogenism, anovulation, infertility, weight loss, and early pregnancy loss?

We address these questions in part 3 of this four-part series, which will continue to be posted on the OBG Management Web site. [Editor’s note: For readers’ ease of access, all installments of this series will, as they are published, be collected on a single Web page of links.]

Metabolic syndrome

What is metabolic syndrome and what are the criteria for diagnosis?

Metabolic syndrome is a cluster of risk factors for cardiovascular disease that, together, increase a woman’s likelihood of a heart attack or stroke (by fourfold compared with those free of the condition) and increase the chance of her developing diabetes mellitus (DM). According to the American Heart Association, between 20% and 25% of the US adult population (between 58 and 73 million men and women) has metabolic syndrome.¹

The diagnostic criteria for metabolic syndrome are presence of at least three of the following:

• abdominal obesity (excessive fat tissue in and around the abdomen)
• atherogenic dyslipidemia (blood fat disorders—including elevated triglyceride level, low high-density lipoprotein cholesterol [HDL-C] level, and elevated low-density cholesterol [LDL-C] level—that foster arterial plaque buildup)
• elevated blood pressure
• insulin resistance or glucose intolerance
• prothrombotic state (which is a high level of fibrinogen or plasminogen activator inhibitor–1 in the blood)
• proinflammatory state (which is elevated plasma C-reactive protein level).

Metformin

We know metformin is used to treat insulin resistance…but can it help hyperandrogenism, anovulation, infertility, weight loss, and early pregnancy loss?

Metformin, a biguanide antidiabetic drug, was first described in the scientific literature in 1957.² It was first marketed in France in 1979, but it did not receive approval by the US Food and Drug Administration (FDA) for DM until 1994. In contrast to sulfonylurea medications, which work rapidly to control elevated blood glucose levels by increasing pancreatic insulin production, metformin is an insulin-sensitizing agent—it improves peripheral insulin sensitivity and suppresses hepatic gluconeogenesis. Metformin is preferred for initial DM treatment because it does not induce hypoglycemia. Although metformin is not FDA-approved to treat PCOS, it is increasingly being used to treat the syndrome in patients with impaired glucose tolerance and those with no impaired glucose tolerance. More recent research has focused on metformin’s effect on other associated maladies of PCOS, including hirsutism, acne, weight loss, anovulation, pregnancy, and pregnancy loss.

Metformin and hirsutism

What is the status of metformin and the treatment of hirsutism?

PCOS and its associated hyperinsulinemic state causes excess ovarian androgen production and reduces hepatic sex hormone binding globulin (SHBG) production. As treatment with metformin results in lower circulating insulin, the net affect is reduced ovarian androgen production and less free testosterone. Thus, it is reasonable to think metformin would be effective in the treatment of hirsutism. However, conflicting results have been reported with respect to this issue.

While some study results suggest an improvement in patients’ hirsutism symptoms with metformin treatment, results of a recent meta-analysis of randomized controlled trials involving treatment with metformin for at least 6 months for hirsutism suggest that insulin sensitizers provide limited or no important benefit for women with hirsutism. Of 348 studies, 16 trials (22 comparisons) that were eligible for inclusion in the meta-analysis showed a small decrease in Ferriman-Gallwey scores in women treated with insulin sensitizers compared with women treated with placebo. There was no significant difference in hirsutism between women treated with insulin sensitizers and women treated with oral contraceptives; metformin was inferior to both spironolactone and flutamide. Further study into metformin’s role in treatment for hirsutism is warranted.³

Metformin and acne

What is the status of metformin and the treatment of acne?
The use of insulin-sensitizing agents, such as metformin, to treat acne also requires more research. The same mechanism of action that infers metformin’s use in hirsutism also applies to its use in acne treatment. In a Cochrane Review⁴ of randomized controlled trials comparing insulin-sensitizing agents to OCs (alone or in combination) for treating acne, limited data demonstrated no evidence of difference in effect between metformin and the OC. This analysis included six trials, four of which compared metformin with an OC (104 participants) and two of which compared an OC combined with metformin with an OC alone (70 participants).

 

Metformin and weight loss

What is the status of metformin and weight loss?
Weight loss leads to greater improvements in overall health, increased fecundity, and improved pregnancy outcome. In spite of the advantages, most patients with PCOS have difficulty losing weight and often regain lost weight over time. Many investigators have raised the question as to whether treatment with insulin-sensitizing drugs contributes to weight loss, compared with diet or a lifestyle modification program.

A systematic search of the literature for randomized controlled trials in women of reproductive age that assessed the effect of insulin-sensitizing drugs on weight loss compared with placebo and diet and/or a lifestyle modification program, revealed 14 trials in the literature, including two in women with PCOS.⁵ Treatment with metformin showed a statistically significant decrease in body mass index compared with placebo, with some indication of greater effect with high-dose metformin (>1,500 mg/day) and longer duration of therapy (>8 weeks).

Clearly, a structured lifestyle modification program to achieve weight loss should still be the first-line treatment in obese women with or without PCOS. Further adequately powered studies are necessary to confirm such findings.² As new weight loss drugs become available, they should also be considered for treatment of obesity in women with PCOS.

Metformin and anovulation

What is the status of metformin and the treatment of anovulation?
While metformin may offer limited assistance with weight loss, especially when combined with diet and lifestyle therapy, and weight loss generally improves ovulation in overweight women with PCOS, there is no evidence that metformin is a powerful ovulatory drug.⁶ However, results of a meta-analysis that included 17 studies totaling more than 1,600 women with PCOS, showed that metformin did improve ovulation, especially in non-clomiphene–resistant women.⁷ Metformin alone did not increase the odds of pregnancy, but in combination with clomiphene, pregnancy was increased. The combination of metformin and clomiphene was especially beneficial in clomiphene-resistant women.

It is important to note that, in women with PCOS, treatment with metformin alone, and in combination with clomiphene, helps to reduce the number of multiple pregnancies, compared with treatment with clomiphine alone.⁹

Metformin and early pregnancy loss

What is the status of metformin and the treatment of early pregnancy loss?
While there is mixed evidence as to metformin’s effect on early pregnancy loss, the strongest evidence to date does not indicate a beneficial effect. In a large, randomized, prospective study of 626 infertile women with PCOS, the rate of pregnancy loss was similar between the clomiphene only and clomiphene plus metformin groups, and there was a slight trend for an increase in pregnancy loss in the metformin alone group.⁹

In a comprehensive review of the literature, Mathur and colleagues concludes that, while some studies have found improvements or no difference in the rates of early pregnancy loss with metformin (alone or in combination with clomiphene), there are “no conclusive data to support a beneficial effect of metformin on pregnancy loss.”⁶

Metformin and pregnancy outcomes

What is the status of metformin and improving pregnancy outcomes?
In a meta-analysis of eight studies of women with PCOS or DM exposed to metformin during the first trimester of pregnancy with major fetal malformations as the primary outcome, the authors concluded there was no evidence of an increased risk with metformin.⁸

While it is logical to say that metformin could even be beneficial during pregnancy, given its effect of reducing the risk of developing gestational diabetes, there is inadequate evidence to support the use of metformin during pregnancy at this time.^6,8

In the next installment: The authors address several questions about current opinion and future considerations: “What is the current opinion concerning how important circulating LH/FSH ratios are to the diagnosis of PCOS?” “Are there any new tests on the horizon that will make the diagnosis of PCOS easier?” “My patient has excessive hair growth and acne and only wants cosmetic results. Other than traditional therapy with oral contraceptives, what medical treatment options does she have?” “We hear a lot about weight loss improving the clinical effects of PCOS. Are there any specific dietary approaches that are more successful than others in PCOS?”

We want to hear from you! Tell us what you think.

 

Women with polycystic ovary syndrome (PCOS), compared with women without the condition, have a greater chance of developing metabolic syndrome (also known as syndrome X). Recent data have drawn attention to these long-term metabolic risks of PCOS. What is metabolic syndrome, and how can its first-line treatment, metformin, affect my patient’s symptoms of PCOS, including hyperandrogenism, anovulation, infertility, weight loss, and early pregnancy loss?

We address these questions in part 3 of this four-part series, which will continue to be posted on the OBG Management Web site. [Editor’s note: For readers’ ease of access, all installments of this series will, as they are published, be collected on a single Web page of links.]

Metabolic syndrome

What is metabolic syndrome and what are the criteria for diagnosis?

Metabolic syndrome is a cluster of risk factors for cardiovascular disease that, together, increase a woman’s likelihood of a heart attack or stroke (by fourfold compared with those free of the condition) and increase the chance of her developing diabetes mellitus (DM). According to the American Heart Association, between 20% and 25% of the US adult population (between 58 and 73 million men and women) has metabolic syndrome.¹

The diagnostic criteria for metabolic syndrome are presence of at least three of the following:

• abdominal obesity (excessive fat tissue in and around the abdomen)
• atherogenic dyslipidemia (blood fat disorders—including elevated triglyceride level, low high-density lipoprotein cholesterol [HDL-C] level, and elevated low-density cholesterol [LDL-C] level—that foster arterial plaque buildup)
• elevated blood pressure
• insulin resistance or glucose intolerance
• prothrombotic state (which is a high level of fibrinogen or plasminogen activator inhibitor–1 in the blood)
• proinflammatory state (which is elevated plasma C-reactive protein level).

Metformin

We know metformin is used to treat insulin resistance…but can it help hyperandrogenism, anovulation, infertility, weight loss, and early pregnancy loss?

Metformin, a biguanide antidiabetic drug, was first described in the scientific literature in 1957.² It was first marketed in France in 1979, but it did not receive approval by the US Food and Drug Administration (FDA) for DM until 1994. In contrast to sulfonylurea medications, which work rapidly to control elevated blood glucose levels by increasing pancreatic insulin production, metformin is an insulin-sensitizing agent—it improves peripheral insulin sensitivity and suppresses hepatic gluconeogenesis. Metformin is preferred for initial DM treatment because it does not induce hypoglycemia. Although metformin is not FDA-approved to treat PCOS, it is increasingly being used to treat the syndrome in patients with impaired glucose tolerance and those with no impaired glucose tolerance. More recent research has focused on metformin’s effect on other associated maladies of PCOS, including hirsutism, acne, weight loss, anovulation, pregnancy, and pregnancy loss.

Metformin and hirsutism

What is the status of metformin and the treatment of hirsutism?

PCOS and its associated hyperinsulinemic state causes excess ovarian androgen production and reduces hepatic sex hormone binding globulin (SHBG) production. As treatment with metformin results in lower circulating insulin, the net affect is reduced ovarian androgen production and less free testosterone. Thus, it is reasonable to think metformin would be effective in the treatment of hirsutism. However, conflicting results have been reported with respect to this issue.

While some study results suggest an improvement in patients’ hirsutism symptoms with metformin treatment, results of a recent meta-analysis of randomized controlled trials involving treatment with metformin for at least 6 months for hirsutism suggest that insulin sensitizers provide limited or no important benefit for women with hirsutism. Of 348 studies, 16 trials (22 comparisons) that were eligible for inclusion in the meta-analysis showed a small decrease in Ferriman-Gallwey scores in women treated with insulin sensitizers compared with women treated with placebo. There was no significant difference in hirsutism between women treated with insulin sensitizers and women treated with oral contraceptives; metformin was inferior to both spironolactone and flutamide. Further study into metformin’s role in treatment for hirsutism is warranted.³

Metformin and acne

What is the status of metformin and the treatment of acne?
The use of insulin-sensitizing agents, such as metformin, to treat acne also requires more research. The same mechanism of action that infers metformin’s use in hirsutism also applies to its use in acne treatment. In a Cochrane Review⁴ of randomized controlled trials comparing insulin-sensitizing agents to OCs (alone or in combination) for treating acne, limited data demonstrated no evidence of difference in effect between metformin and the OC. This analysis included six trials, four of which compared metformin with an OC (104 participants) and two of which compared an OC combined with metformin with an OC alone (70 participants).

 

Metformin and weight loss

What is the status of metformin and weight loss?
Weight loss leads to greater improvements in overall health, increased fecundity, and improved pregnancy outcome. In spite of the advantages, most patients with PCOS have difficulty losing weight and often regain lost weight over time. Many investigators have raised the question as to whether treatment with insulin-sensitizing drugs contributes to weight loss, compared with diet or a lifestyle modification program.

A systematic search of the literature for randomized controlled trials in women of reproductive age that assessed the effect of insulin-sensitizing drugs on weight loss compared with placebo and diet and/or a lifestyle modification program, revealed 14 trials in the literature, including two in women with PCOS.⁵ Treatment with metformin showed a statistically significant decrease in body mass index compared with placebo, with some indication of greater effect with high-dose metformin (>1,500 mg/day) and longer duration of therapy (>8 weeks).

Clearly, a structured lifestyle modification program to achieve weight loss should still be the first-line treatment in obese women with or without PCOS. Further adequately powered studies are necessary to confirm such findings.² As new weight loss drugs become available, they should also be considered for treatment of obesity in women with PCOS.

Metformin and anovulation

What is the status of metformin and the treatment of anovulation?
While metformin may offer limited assistance with weight loss, especially when combined with diet and lifestyle therapy, and weight loss generally improves ovulation in overweight women with PCOS, there is no evidence that metformin is a powerful ovulatory drug.⁶ However, results of a meta-analysis that included 17 studies totaling more than 1,600 women with PCOS, showed that metformin did improve ovulation, especially in non-clomiphene–resistant women.⁷ Metformin alone did not increase the odds of pregnancy, but in combination with clomiphene, pregnancy was increased. The combination of metformin and clomiphene was especially beneficial in clomiphene-resistant women.

It is important to note that, in women with PCOS, treatment with metformin alone, and in combination with clomiphene, helps to reduce the number of multiple pregnancies, compared with treatment with clomiphine alone.⁹

Metformin and early pregnancy loss

What is the status of metformin and the treatment of early pregnancy loss?
While there is mixed evidence as to metformin’s effect on early pregnancy loss, the strongest evidence to date does not indicate a beneficial effect. In a large, randomized, prospective study of 626 infertile women with PCOS, the rate of pregnancy loss was similar between the clomiphene only and clomiphene plus metformin groups, and there was a slight trend for an increase in pregnancy loss in the metformin alone group.⁹

In a comprehensive review of the literature, Mathur and colleagues concludes that, while some studies have found improvements or no difference in the rates of early pregnancy loss with metformin (alone or in combination with clomiphene), there are “no conclusive data to support a beneficial effect of metformin on pregnancy loss.”⁶

Metformin and pregnancy outcomes

What is the status of metformin and improving pregnancy outcomes?
In a meta-analysis of eight studies of women with PCOS or DM exposed to metformin during the first trimester of pregnancy with major fetal malformations as the primary outcome, the authors concluded there was no evidence of an increased risk with metformin.⁸

While it is logical to say that metformin could even be beneficial during pregnancy, given its effect of reducing the risk of developing gestational diabetes, there is inadequate evidence to support the use of metformin during pregnancy at this time.^6,8

In the next installment: The authors address several questions about current opinion and future considerations: “What is the current opinion concerning how important circulating LH/FSH ratios are to the diagnosis of PCOS?” “Are there any new tests on the horizon that will make the diagnosis of PCOS easier?” “My patient has excessive hair growth and acne and only wants cosmetic results. Other than traditional therapy with oral contraceptives, what medical treatment options does she have?” “We hear a lot about weight loss improving the clinical effects of PCOS. Are there any specific dietary approaches that are more successful than others in PCOS?”

We want to hear from you! Tell us what you think.

 

Women with polycystic ovary syndrome (PCOS), compared with women without the condition, have a greater chance of developing metabolic syndrome (also known as syndrome X). Recent data have drawn attention to these long-term metabolic risks of PCOS. What is metabolic syndrome, and how can its first-line treatment, metformin, affect my patient’s symptoms of PCOS, including hyperandrogenism, anovulation, infertility, weight loss, and early pregnancy loss?

We address these questions in part 3 of this four-part series, which will continue to be posted on the OBG Management Web site. [Editor’s note: For readers’ ease of access, all installments of this series will, as they are published, be collected on a single Web page of links.]

Metabolic syndrome

What is metabolic syndrome and what are the criteria for diagnosis?

Metabolic syndrome is a cluster of risk factors for cardiovascular disease that, together, increase a woman’s likelihood of a heart attack or stroke (by fourfold compared with those free of the condition) and increase the chance of her developing diabetes mellitus (DM). According to the American Heart Association, between 20% and 25% of the US adult population (between 58 and 73 million men and women) has metabolic syndrome.¹

The diagnostic criteria for metabolic syndrome are presence of at least three of the following:

• abdominal obesity (excessive fat tissue in and around the abdomen)
• atherogenic dyslipidemia (blood fat disorders—including elevated triglyceride level, low high-density lipoprotein cholesterol [HDL-C] level, and elevated low-density cholesterol [LDL-C] level—that foster arterial plaque buildup)
• elevated blood pressure
• insulin resistance or glucose intolerance
• prothrombotic state (which is a high level of fibrinogen or plasminogen activator inhibitor–1 in the blood)
• proinflammatory state (which is elevated plasma C-reactive protein level).

Metformin

We know metformin is used to treat insulin resistance…but can it help hyperandrogenism, anovulation, infertility, weight loss, and early pregnancy loss?

Metformin, a biguanide antidiabetic drug, was first described in the scientific literature in 1957.² It was first marketed in France in 1979, but it did not receive approval by the US Food and Drug Administration (FDA) for DM until 1994. In contrast to sulfonylurea medications, which work rapidly to control elevated blood glucose levels by increasing pancreatic insulin production, metformin is an insulin-sensitizing agent—it improves peripheral insulin sensitivity and suppresses hepatic gluconeogenesis. Metformin is preferred for initial DM treatment because it does not induce hypoglycemia. Although metformin is not FDA-approved to treat PCOS, it is increasingly being used to treat the syndrome in patients with impaired glucose tolerance and those with no impaired glucose tolerance. More recent research has focused on metformin’s effect on other associated maladies of PCOS, including hirsutism, acne, weight loss, anovulation, pregnancy, and pregnancy loss.

Metformin and hirsutism

What is the status of metformin and the treatment of hirsutism?

PCOS and its associated hyperinsulinemic state causes excess ovarian androgen production and reduces hepatic sex hormone binding globulin (SHBG) production. As treatment with metformin results in lower circulating insulin, the net affect is reduced ovarian androgen production and less free testosterone. Thus, it is reasonable to think metformin would be effective in the treatment of hirsutism. However, conflicting results have been reported with respect to this issue.

While some study results suggest an improvement in patients’ hirsutism symptoms with metformin treatment, results of a recent meta-analysis of randomized controlled trials involving treatment with metformin for at least 6 months for hirsutism suggest that insulin sensitizers provide limited or no important benefit for women with hirsutism. Of 348 studies, 16 trials (22 comparisons) that were eligible for inclusion in the meta-analysis showed a small decrease in Ferriman-Gallwey scores in women treated with insulin sensitizers compared with women treated with placebo. There was no significant difference in hirsutism between women treated with insulin sensitizers and women treated with oral contraceptives; metformin was inferior to both spironolactone and flutamide. Further study into metformin’s role in treatment for hirsutism is warranted.³

Metformin and acne

What is the status of metformin and the treatment of acne?
The use of insulin-sensitizing agents, such as metformin, to treat acne also requires more research. The same mechanism of action that infers metformin’s use in hirsutism also applies to its use in acne treatment. In a Cochrane Review⁴ of randomized controlled trials comparing insulin-sensitizing agents to OCs (alone or in combination) for treating acne, limited data demonstrated no evidence of difference in effect between metformin and the OC. This analysis included six trials, four of which compared metformin with an OC (104 participants) and two of which compared an OC combined with metformin with an OC alone (70 participants).

 

Metformin and weight loss

What is the status of metformin and weight loss?
Weight loss leads to greater improvements in overall health, increased fecundity, and improved pregnancy outcome. In spite of the advantages, most patients with PCOS have difficulty losing weight and often regain lost weight over time. Many investigators have raised the question as to whether treatment with insulin-sensitizing drugs contributes to weight loss, compared with diet or a lifestyle modification program.

A systematic search of the literature for randomized controlled trials in women of reproductive age that assessed the effect of insulin-sensitizing drugs on weight loss compared with placebo and diet and/or a lifestyle modification program, revealed 14 trials in the literature, including two in women with PCOS.⁵ Treatment with metformin showed a statistically significant decrease in body mass index compared with placebo, with some indication of greater effect with high-dose metformin (>1,500 mg/day) and longer duration of therapy (>8 weeks).

Clearly, a structured lifestyle modification program to achieve weight loss should still be the first-line treatment in obese women with or without PCOS. Further adequately powered studies are necessary to confirm such findings.² As new weight loss drugs become available, they should also be considered for treatment of obesity in women with PCOS.

Metformin and anovulation

What is the status of metformin and the treatment of anovulation?
While metformin may offer limited assistance with weight loss, especially when combined with diet and lifestyle therapy, and weight loss generally improves ovulation in overweight women with PCOS, there is no evidence that metformin is a powerful ovulatory drug.⁶ However, results of a meta-analysis that included 17 studies totaling more than 1,600 women with PCOS, showed that metformin did improve ovulation, especially in non-clomiphene–resistant women.⁷ Metformin alone did not increase the odds of pregnancy, but in combination with clomiphene, pregnancy was increased. The combination of metformin and clomiphene was especially beneficial in clomiphene-resistant women.

It is important to note that, in women with PCOS, treatment with metformin alone, and in combination with clomiphene, helps to reduce the number of multiple pregnancies, compared with treatment with clomiphine alone.⁹

Metformin and early pregnancy loss

What is the status of metformin and the treatment of early pregnancy loss?
While there is mixed evidence as to metformin’s effect on early pregnancy loss, the strongest evidence to date does not indicate a beneficial effect. In a large, randomized, prospective study of 626 infertile women with PCOS, the rate of pregnancy loss was similar between the clomiphene only and clomiphene plus metformin groups, and there was a slight trend for an increase in pregnancy loss in the metformin alone group.⁹

In a comprehensive review of the literature, Mathur and colleagues concludes that, while some studies have found improvements or no difference in the rates of early pregnancy loss with metformin (alone or in combination with clomiphene), there are “no conclusive data to support a beneficial effect of metformin on pregnancy loss.”⁶

Metformin and pregnancy outcomes

What is the status of metformin and improving pregnancy outcomes?
In a meta-analysis of eight studies of women with PCOS or DM exposed to metformin during the first trimester of pregnancy with major fetal malformations as the primary outcome, the authors concluded there was no evidence of an increased risk with metformin.⁸

While it is logical to say that metformin could even be beneficial during pregnancy, given its effect of reducing the risk of developing gestational diabetes, there is inadequate evidence to support the use of metformin during pregnancy at this time.^6,8

In the next installment: The authors address several questions about current opinion and future considerations: “What is the current opinion concerning how important circulating LH/FSH ratios are to the diagnosis of PCOS?” “Are there any new tests on the horizon that will make the diagnosis of PCOS easier?” “My patient has excessive hair growth and acne and only wants cosmetic results. Other than traditional therapy with oral contraceptives, what medical treatment options does she have?” “We hear a lot about weight loss improving the clinical effects of PCOS. Are there any specific dietary approaches that are more successful than others in PCOS?”

We want to hear from you! Tell us what you think.

Polycystic ovary syndrome, or PCOS, is an enigmatic condition. It presents with varying levels of severity of those symptoms and conditions associated with it—clinical hyperandrogenism (hirsutism, acne, alopecia), obesity, and menstrual disturbance. Although its exact cause is unknown, at least half of all women with PCOS are overweight or obese. What does obesity and, more specifically, insulin resistance, contribute to the pathogenesis of PCOS, and why is it important to screen your patient with PCOS for insulin resistance?

In part 2 of this 4-part series, which will continue to be posted here on the OBG Management Web site, we address these questions. [Editor’s note: As they are published, future installments of this series will continue to be collected on a single Web page for ease of access.]

The roles of obesity and insulin resistance

Can you define obesity and explain how its associated insulin resistance comes into play in the pathology of PCOS?

Overweight: BMI ≥ 25 kg/m²

Obesity: BMI ≥ 30 kg/m²

Morbid obesity: BMI ≥ 40 kg/m²

PCOS is associated with truncal fat distribution, manifesting as an increased waist-to-hip ratio. According to the Centers for Disease Control and Prevention (CDC), more than one-third of the population was obese in 2009 and 2010.¹ Approximately 50% to 65% of women with PCOS are overweight or obese, and most of them have the truncal fat distribution phenotype. ²

Obesity is associated with an increase in insulin resistance (IR) and hyperinsulinemia. IR can be characterized as impaired action of insulin in the uptake and metabolism of glucose. Impaired insulin action leads to elevated insulin levels. Insulin synergizes with abnormally high secretion of luteinizing hormone (perhaps induced by hyperinsulinemia) to promote excess androgen production by intraovarian theca cells and an arrest of follicular development resulting in chronic anovulation.

In addition, hyperinsulinemia causes a decrease in hepatic sex hormone binding globulin, resulting in free circulating androgens and, thus, hirsutism and acne issues. While this picture tends to be more pronounced in women who have PCOS and are obese, it is important to realize that a nonobese patient with PCOS also may have IR, which suggests that insulin plays a major role in the pathogenesis of this disease.^3,4

Does hyperandrogenism cause the insulin resistance or does insulin resistance cause the hyperandrogenism?

Most of the evidence suggests that hyperinsulinemia causes hyperandrogenism and not the reverse. Weight loss and insulin sensitizers are associated with a reduction in androgens, particularly testosterone and androstenedione. Gonadotropin-releasing hormone–analogs, which reduce androgen secretion from the ovaries, do not result in a reduction in insulin.^3,4

Screening for insulin resistance: The rationale

How prevalent are insulin resistance, impaired glucose tolerance, and diabetes in PCOS, and what is the best way to screen for them?

The documented prevalence of IR and type 2 diabetes mellitus (DM) in women with PCOS suggests that impaired glucose tolerance (IGT) is present in 31% to 35% of women with PCOS^5,6—and DM, classified according to World Health Organization (WHO) criteria, is present in 7.5% to 10% of women with PCOS.

The prevalence of IR and DM are considerably lower in women without PCOS. According to the Third National Health and Nutrition Examination Survey, in US women of similar age, the prevalence of IR is 1.6%, and the prevalence of DM is 2.2%.⁷

2003 consensus: Screen for IGT in obese PCOS patients. In view of the high prevalence of IR and IGT, a 2003 PCOS consensus⁸ established that obese women with PCOS should be screened for insulin sensitivity and undergo screening for the metabolic syndrome, including glucose intolerance. For nonobese women, the consensus recommended screening only if additional risk factors are present.

Unfortunately, IGT also occurs independent of obesity. In lean women with PCOS, 5% may have IGT, while 2% are frankly diabetic. Moreover, the conversion from normal glucose tolerance to IGT in patients with PCOS can be as high as 16% per year,⁹ while the conversion rate from IGT to DM among women with PCOS has been reported to be as high as 2% per year.

2007 position statement: Screen for IGT in all PCOS patients. A position statement by the Androgen Excess–PCOS Society on glucose intolerance and PCOS recommends screening for IGT in all PCOS women, regardless of BMI, at least once every 2 years.¹⁰

Screening for insulin resistance: The methods

There are two ways to determine insulin sensitivity:

 

• direct infusion of IV glucose and/or insulin
• indirect assessment using surrogate markers (such as fasting glucose and insulin, or C-peptide, and oral glucose tolerance test [OGTT]).

Direct infusion of IV glucose or insulin reveals how insulin disposes of glucose from the blood stream; however, this method is expensive, time consuming, and potentially dangerous due to possible hypoglycemia. Indirect assessments are less complex to perform and correlate reasonably well with the results of the more invasive direct measures.

What are the current direct-infusion methods to measure insulin sensitivity?

Direct infusion of glucose and insulin

The hyperinsulinemic euglycemic clamp is the gold standard, but drawbacks relegate it to medical research only. This method measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. Numerous blood samplings (every 5 to 10 minutes) are taken to monitor serum glucose so that a steady “fasting” level can be maintained. The degree of insulin resistance is measured by the amount of glucose that is taken up by tissues during the procedure.^11-14

The “clamp” technique is the most scientifically sound method for measuring insulin sensitivity, and it’s the standard against which all other tests are usually compared. Because the clamp technique is expensive, time consuming (about 2 hours), and labor intensive, however, it is not practical and is rarely performed in clinical care. It is primarily used in medical research.

Frequently sampled IV glucose tolerance tests: “minimal model.” The frequently sampled IV glucose tolerance test estimates insulin sensitivity through a computer-based mathematical analysis of the glucose-insulin dynamics. Though this test still requires 11 to 34 blood samples over a 3-hour period, it is less labor intensive than the clamp technique. However, in contrast to the clamp, it does not distinguish between peripheral and hepatic glucose utilization.¹⁵

Direct infusion of insulin

Insulin sensitivity test. This test involves IV infusion of a set glucose load and a fixed-rate infusion of insulin over approximately 3 hours. The mean plasma glucose concentration over the last 30 minutes of the test reflects insulin sensitivity. Although lengthy, the insulin sensitivity test is less labor intensive and requires fewer blood samples than the clamp technique.¹⁶

Insulin tolerance test. This test is a simplified version of the insulin sensitivity test, as it measures the decline in serum glucose after an IV bolus of insulin is administered. Several insulin and glucose levels are sampled over the following 15 minutes. In contrast to the clamp and the minimal model, the insulin tolerance test primarily measures insulin-stimulated uptake of glucose into skeletal muscle, and insulin sensitivity values reflect the rate of decline of log transformed glucose values.¹⁷

Direct infusion of glucose

Continuous infusion of glucose with model assessment. This method utilizes a constant IV glucose infusion; samples for glucose and insulin are drawn at 50, 55, and 60 minutes. A mathematical model is then used to calculate insulin sensitivity. The results are correlated with clamp techniques; however, few laboratories have used this continuous-infusion method for insulin sensitivity testing in women with PCOS.¹⁸

Unfortunately, all of these methods require IV access and multiple venipunctures, making them relatively impractical for office assessment. To overcome these obstacles, alternative tests have been developed including fasting methods and the OGTT, the latter of which does not require IV access and does correlate reasonably well with dynamic clamp techniques.

What are the current indirect assessments to measure insulin sensitivity?

Fasting methods

Fasting insulin. The measurement of fasting serum insulin is simple and inexpensive. Generally, a fasting level of 30 μU/mL indicates greater insulin resistance in a diabetic individual than in a normoglycemic patient. However, fasting insulin levels may be in the “normal” range in up to 40% of PCOS patients who have impaired glucose tolerance diagnosed by the OGTT. It has been suggested by some investigators that a fasting insulin greater than 20 μU/mL in white women and greater than 23 μU/mL in Mexican-American women probably indicates insulin resistance in women with PCOS. Some have also advocated averaging two or three readings to account for day-to-day variability.^19-21

Fasting plasma glucose. This is a simple blood test taken after 8 hours of fasting. Fasting plasma glucose (FPG) levels are considered normal up to 100 mg/dL (or 5.5 mmol/L). Levels between 100 and 125 mg/dL (5.5 to 7.0 mmol/L) are considered impaired fasting glucose or prediabetes. These levels are considered to be risk factors for DM and its complications. DM is diagnosed when FPG levels are 126 mg/dL (7.0 mmol/L) or higher. A “normal” result on the FPG test is not always reliable. Repeat testing with the OGTT is recommended if risk factors are suggestive for the presence of DM or a prediabetic condition.

 

Glucose/insulin ratio

The glucose/insulin (G/I) ratio has become very popular since its first description in 1998 as an accurate index of insulin sensitivity in women with PCOS. The ratio of glucose to insulin is easy to calculate, with lower values depicting higher degrees of insulin resistance. A G/I ratio of less than 4.5 has been shown to be sensitive (95%) and specific (84%) for insulin resistance in women with PCOS, compared with a control group. The normal range for G/I ratios may vary in different ethnic groups and have not been fully validated in nonobese patients.^22-25

Homeostatic model assessment

First described in 1985, homeostatic model assessment (HOMA) has been used widely in clinical research to assess insulin sensitivity. Rather than using fasting insulin or a G/I ratio, the product of the fasting values of glucose (expressed as mg/dL) and insulin (expressed as μU/mL) is divided by a constant: I0 x G0 ÷ 405.

The constant 405 should be replaced by 22.5 if glucose is expressed in SI units (mmol/L). Unlike fasting insulin and the G/I ratio, the HOMA calculation compensates for fasting hyperglycemia. The HOMA value correlates well with clamp techniques and has been used frequently to assess changes in insulin sensitivity after treatment. HOMA also has been used to study insulin resistance among PCOS patients of differing ethnic origins.^12,24-26

Quantitative insulin sensitivity check index

Like HOMA, quantitative insulin sensitivity check index (QUICKI) can be applied to normoglycemic and hyperglycemic patients. It is derived by calculating the inverse of the sum of logarithmically expressed values of fasting glucose and insulin: 1 ÷ [log(I0) + log(G0)].

Many investigators believe that QUICKI is superior to HOMA as a way of determining insulin sensitivity, although the two values correlate well. As the SI decreases, QUICKI values decrease.²⁷

Oral glucose tolerance test

As OGTT does not require IV access, it is the current standard in practice for diagnosis of IGT and DM. It provides a better assessment of IGT and DM than fasting techniques because these patients may have normal fasting glucose values despite abnormal 2-hour fasting levels. The OGTT uses a 50-, 75-, or 100-g glucose load and measures glucose and insulin at various intervals over 1 to 3 hours. The WHO currently recommends a 75-g oral dose in all adults. A 50-g dose is used to screen for gestational diabetes over an hour, and the 100-g load over 3 hours if abnormal.²⁸ See TABLE for normal and abnormal values. Insulin sensitivity has been assessed by calculating insulin area under the curve (AUC insulin), AUC glucose/AUC insulin, and by an insulin sensitivity index (ISI) that applies only the glucose and insulin values from 0 and 120 minutes into a complex mathematical formula.^13,25,29-31

Criteria for diagnosis of diabetes

	Venous plasma glucose (mg/dL)
	Fasting Level*	2-hour postglucose load**
Normal/Low risk	≤99	≤139
Prediabetes/Increased risk	100–125	140–199
Diabetes	≥126	≥200
*Fasting is defined as no caloric intake for at least 8 h **OGTT using a glucose load or 75 g as described by the World Health Organization SOURCE: American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35 (suppl 1):s11–s63. doi:10.2337/dc12-s011.

Test for glycosylated hemoglobin

Tests for blood levels of glycosylated hemoglobin, also known as hemoglobin A_1c (HbA_1c) are not currently used for an initial diagnosis because normal HbA_1c levels do not necessarily rule out diabetes, but they are strongly associated with complications of diabetes. The test is not affected by food intake so it can be taken at any time. A normal HbA_1c level is below 7%.

We want to hear from you! Tell us what you think.

Polycystic ovary syndrome, or PCOS, is an enigmatic condition. It presents with varying levels of severity of those symptoms and conditions associated with it—clinical hyperandrogenism (hirsutism, acne, alopecia), obesity, and menstrual disturbance. Although its exact cause is unknown, at least half of all women with PCOS are overweight or obese. What does obesity and, more specifically, insulin resistance, contribute to the pathogenesis of PCOS, and why is it important to screen your patient with PCOS for insulin resistance?

In part 2 of this 4-part series, which will continue to be posted here on the OBG Management Web site, we address these questions. [Editor’s note: As they are published, future installments of this series will continue to be collected on a single Web page for ease of access.]

The roles of obesity and insulin resistance

Can you define obesity and explain how its associated insulin resistance comes into play in the pathology of PCOS?

Overweight: BMI ≥ 25 kg/m²

Obesity: BMI ≥ 30 kg/m²

Morbid obesity: BMI ≥ 40 kg/m²

PCOS is associated with truncal fat distribution, manifesting as an increased waist-to-hip ratio. According to the Centers for Disease Control and Prevention (CDC), more than one-third of the population was obese in 2009 and 2010.¹ Approximately 50% to 65% of women with PCOS are overweight or obese, and most of them have the truncal fat distribution phenotype. ²

Obesity is associated with an increase in insulin resistance (IR) and hyperinsulinemia. IR can be characterized as impaired action of insulin in the uptake and metabolism of glucose. Impaired insulin action leads to elevated insulin levels. Insulin synergizes with abnormally high secretion of luteinizing hormone (perhaps induced by hyperinsulinemia) to promote excess androgen production by intraovarian theca cells and an arrest of follicular development resulting in chronic anovulation.

In addition, hyperinsulinemia causes a decrease in hepatic sex hormone binding globulin, resulting in free circulating androgens and, thus, hirsutism and acne issues. While this picture tends to be more pronounced in women who have PCOS and are obese, it is important to realize that a nonobese patient with PCOS also may have IR, which suggests that insulin plays a major role in the pathogenesis of this disease.^3,4

Does hyperandrogenism cause the insulin resistance or does insulin resistance cause the hyperandrogenism?

Most of the evidence suggests that hyperinsulinemia causes hyperandrogenism and not the reverse. Weight loss and insulin sensitizers are associated with a reduction in androgens, particularly testosterone and androstenedione. Gonadotropin-releasing hormone–analogs, which reduce androgen secretion from the ovaries, do not result in a reduction in insulin.^3,4

Screening for insulin resistance: The rationale

How prevalent are insulin resistance, impaired glucose tolerance, and diabetes in PCOS, and what is the best way to screen for them?

The documented prevalence of IR and type 2 diabetes mellitus (DM) in women with PCOS suggests that impaired glucose tolerance (IGT) is present in 31% to 35% of women with PCOS^5,6—and DM, classified according to World Health Organization (WHO) criteria, is present in 7.5% to 10% of women with PCOS.

The prevalence of IR and DM are considerably lower in women without PCOS. According to the Third National Health and Nutrition Examination Survey, in US women of similar age, the prevalence of IR is 1.6%, and the prevalence of DM is 2.2%.⁷

2003 consensus: Screen for IGT in obese PCOS patients. In view of the high prevalence of IR and IGT, a 2003 PCOS consensus⁸ established that obese women with PCOS should be screened for insulin sensitivity and undergo screening for the metabolic syndrome, including glucose intolerance. For nonobese women, the consensus recommended screening only if additional risk factors are present.

Unfortunately, IGT also occurs independent of obesity. In lean women with PCOS, 5% may have IGT, while 2% are frankly diabetic. Moreover, the conversion from normal glucose tolerance to IGT in patients with PCOS can be as high as 16% per year,⁹ while the conversion rate from IGT to DM among women with PCOS has been reported to be as high as 2% per year.

2007 position statement: Screen for IGT in all PCOS patients. A position statement by the Androgen Excess–PCOS Society on glucose intolerance and PCOS recommends screening for IGT in all PCOS women, regardless of BMI, at least once every 2 years.¹⁰

Screening for insulin resistance: The methods

There are two ways to determine insulin sensitivity:

 

• direct infusion of IV glucose and/or insulin
• indirect assessment using surrogate markers (such as fasting glucose and insulin, or C-peptide, and oral glucose tolerance test [OGTT]).

Direct infusion of IV glucose or insulin reveals how insulin disposes of glucose from the blood stream; however, this method is expensive, time consuming, and potentially dangerous due to possible hypoglycemia. Indirect assessments are less complex to perform and correlate reasonably well with the results of the more invasive direct measures.

What are the current direct-infusion methods to measure insulin sensitivity?

Direct infusion of glucose and insulin

The hyperinsulinemic euglycemic clamp is the gold standard, but drawbacks relegate it to medical research only. This method measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. Numerous blood samplings (every 5 to 10 minutes) are taken to monitor serum glucose so that a steady “fasting” level can be maintained. The degree of insulin resistance is measured by the amount of glucose that is taken up by tissues during the procedure.^11-14

The “clamp” technique is the most scientifically sound method for measuring insulin sensitivity, and it’s the standard against which all other tests are usually compared. Because the clamp technique is expensive, time consuming (about 2 hours), and labor intensive, however, it is not practical and is rarely performed in clinical care. It is primarily used in medical research.

Frequently sampled IV glucose tolerance tests: “minimal model.” The frequently sampled IV glucose tolerance test estimates insulin sensitivity through a computer-based mathematical analysis of the glucose-insulin dynamics. Though this test still requires 11 to 34 blood samples over a 3-hour period, it is less labor intensive than the clamp technique. However, in contrast to the clamp, it does not distinguish between peripheral and hepatic glucose utilization.¹⁵

Direct infusion of insulin

Insulin sensitivity test. This test involves IV infusion of a set glucose load and a fixed-rate infusion of insulin over approximately 3 hours. The mean plasma glucose concentration over the last 30 minutes of the test reflects insulin sensitivity. Although lengthy, the insulin sensitivity test is less labor intensive and requires fewer blood samples than the clamp technique.¹⁶

Insulin tolerance test. This test is a simplified version of the insulin sensitivity test, as it measures the decline in serum glucose after an IV bolus of insulin is administered. Several insulin and glucose levels are sampled over the following 15 minutes. In contrast to the clamp and the minimal model, the insulin tolerance test primarily measures insulin-stimulated uptake of glucose into skeletal muscle, and insulin sensitivity values reflect the rate of decline of log transformed glucose values.¹⁷

Direct infusion of glucose

Continuous infusion of glucose with model assessment. This method utilizes a constant IV glucose infusion; samples for glucose and insulin are drawn at 50, 55, and 60 minutes. A mathematical model is then used to calculate insulin sensitivity. The results are correlated with clamp techniques; however, few laboratories have used this continuous-infusion method for insulin sensitivity testing in women with PCOS.¹⁸

Unfortunately, all of these methods require IV access and multiple venipunctures, making them relatively impractical for office assessment. To overcome these obstacles, alternative tests have been developed including fasting methods and the OGTT, the latter of which does not require IV access and does correlate reasonably well with dynamic clamp techniques.

What are the current indirect assessments to measure insulin sensitivity?

Fasting methods

Fasting insulin. The measurement of fasting serum insulin is simple and inexpensive. Generally, a fasting level of 30 μU/mL indicates greater insulin resistance in a diabetic individual than in a normoglycemic patient. However, fasting insulin levels may be in the “normal” range in up to 40% of PCOS patients who have impaired glucose tolerance diagnosed by the OGTT. It has been suggested by some investigators that a fasting insulin greater than 20 μU/mL in white women and greater than 23 μU/mL in Mexican-American women probably indicates insulin resistance in women with PCOS. Some have also advocated averaging two or three readings to account for day-to-day variability.^19-21

Fasting plasma glucose. This is a simple blood test taken after 8 hours of fasting. Fasting plasma glucose (FPG) levels are considered normal up to 100 mg/dL (or 5.5 mmol/L). Levels between 100 and 125 mg/dL (5.5 to 7.0 mmol/L) are considered impaired fasting glucose or prediabetes. These levels are considered to be risk factors for DM and its complications. DM is diagnosed when FPG levels are 126 mg/dL (7.0 mmol/L) or higher. A “normal” result on the FPG test is not always reliable. Repeat testing with the OGTT is recommended if risk factors are suggestive for the presence of DM or a prediabetic condition.

 

Glucose/insulin ratio

The glucose/insulin (G/I) ratio has become very popular since its first description in 1998 as an accurate index of insulin sensitivity in women with PCOS. The ratio of glucose to insulin is easy to calculate, with lower values depicting higher degrees of insulin resistance. A G/I ratio of less than 4.5 has been shown to be sensitive (95%) and specific (84%) for insulin resistance in women with PCOS, compared with a control group. The normal range for G/I ratios may vary in different ethnic groups and have not been fully validated in nonobese patients.^22-25

Homeostatic model assessment

First described in 1985, homeostatic model assessment (HOMA) has been used widely in clinical research to assess insulin sensitivity. Rather than using fasting insulin or a G/I ratio, the product of the fasting values of glucose (expressed as mg/dL) and insulin (expressed as μU/mL) is divided by a constant: I0 x G0 ÷ 405.

The constant 405 should be replaced by 22.5 if glucose is expressed in SI units (mmol/L). Unlike fasting insulin and the G/I ratio, the HOMA calculation compensates for fasting hyperglycemia. The HOMA value correlates well with clamp techniques and has been used frequently to assess changes in insulin sensitivity after treatment. HOMA also has been used to study insulin resistance among PCOS patients of differing ethnic origins.^12,24-26

Quantitative insulin sensitivity check index

Like HOMA, quantitative insulin sensitivity check index (QUICKI) can be applied to normoglycemic and hyperglycemic patients. It is derived by calculating the inverse of the sum of logarithmically expressed values of fasting glucose and insulin: 1 ÷ [log(I0) + log(G0)].

Many investigators believe that QUICKI is superior to HOMA as a way of determining insulin sensitivity, although the two values correlate well. As the SI decreases, QUICKI values decrease.²⁷

Oral glucose tolerance test

As OGTT does not require IV access, it is the current standard in practice for diagnosis of IGT and DM. It provides a better assessment of IGT and DM than fasting techniques because these patients may have normal fasting glucose values despite abnormal 2-hour fasting levels. The OGTT uses a 50-, 75-, or 100-g glucose load and measures glucose and insulin at various intervals over 1 to 3 hours. The WHO currently recommends a 75-g oral dose in all adults. A 50-g dose is used to screen for gestational diabetes over an hour, and the 100-g load over 3 hours if abnormal.²⁸ See TABLE for normal and abnormal values. Insulin sensitivity has been assessed by calculating insulin area under the curve (AUC insulin), AUC glucose/AUC insulin, and by an insulin sensitivity index (ISI) that applies only the glucose and insulin values from 0 and 120 minutes into a complex mathematical formula.^13,25,29-31

Criteria for diagnosis of diabetes

	Venous plasma glucose (mg/dL)
	Fasting Level*	2-hour postglucose load**
Normal/Low risk	≤99	≤139
Prediabetes/Increased risk	100–125	140–199
Diabetes	≥126	≥200
*Fasting is defined as no caloric intake for at least 8 h **OGTT using a glucose load or 75 g as described by the World Health Organization SOURCE: American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35 (suppl 1):s11–s63. doi:10.2337/dc12-s011.

Test for glycosylated hemoglobin

Tests for blood levels of glycosylated hemoglobin, also known as hemoglobin A_1c (HbA_1c) are not currently used for an initial diagnosis because normal HbA_1c levels do not necessarily rule out diabetes, but they are strongly associated with complications of diabetes. The test is not affected by food intake so it can be taken at any time. A normal HbA_1c level is below 7%.

We want to hear from you! Tell us what you think.

Polycystic ovary syndrome, or PCOS, is an enigmatic condition. It presents with varying levels of severity of those symptoms and conditions associated with it—clinical hyperandrogenism (hirsutism, acne, alopecia), obesity, and menstrual disturbance. Although its exact cause is unknown, at least half of all women with PCOS are overweight or obese. What does obesity and, more specifically, insulin resistance, contribute to the pathogenesis of PCOS, and why is it important to screen your patient with PCOS for insulin resistance?

In part 2 of this 4-part series, which will continue to be posted here on the OBG Management Web site, we address these questions. [Editor’s note: As they are published, future installments of this series will continue to be collected on a single Web page for ease of access.]

The roles of obesity and insulin resistance

Can you define obesity and explain how its associated insulin resistance comes into play in the pathology of PCOS?

Overweight: BMI ≥ 25 kg/m²

Obesity: BMI ≥ 30 kg/m²

Morbid obesity: BMI ≥ 40 kg/m²

PCOS is associated with truncal fat distribution, manifesting as an increased waist-to-hip ratio. According to the Centers for Disease Control and Prevention (CDC), more than one-third of the population was obese in 2009 and 2010.¹ Approximately 50% to 65% of women with PCOS are overweight or obese, and most of them have the truncal fat distribution phenotype. ²

Obesity is associated with an increase in insulin resistance (IR) and hyperinsulinemia. IR can be characterized as impaired action of insulin in the uptake and metabolism of glucose. Impaired insulin action leads to elevated insulin levels. Insulin synergizes with abnormally high secretion of luteinizing hormone (perhaps induced by hyperinsulinemia) to promote excess androgen production by intraovarian theca cells and an arrest of follicular development resulting in chronic anovulation.

In addition, hyperinsulinemia causes a decrease in hepatic sex hormone binding globulin, resulting in free circulating androgens and, thus, hirsutism and acne issues. While this picture tends to be more pronounced in women who have PCOS and are obese, it is important to realize that a nonobese patient with PCOS also may have IR, which suggests that insulin plays a major role in the pathogenesis of this disease.^3,4

Does hyperandrogenism cause the insulin resistance or does insulin resistance cause the hyperandrogenism?

Most of the evidence suggests that hyperinsulinemia causes hyperandrogenism and not the reverse. Weight loss and insulin sensitizers are associated with a reduction in androgens, particularly testosterone and androstenedione. Gonadotropin-releasing hormone–analogs, which reduce androgen secretion from the ovaries, do not result in a reduction in insulin.^3,4

Screening for insulin resistance: The rationale

How prevalent are insulin resistance, impaired glucose tolerance, and diabetes in PCOS, and what is the best way to screen for them?

The documented prevalence of IR and type 2 diabetes mellitus (DM) in women with PCOS suggests that impaired glucose tolerance (IGT) is present in 31% to 35% of women with PCOS^5,6—and DM, classified according to World Health Organization (WHO) criteria, is present in 7.5% to 10% of women with PCOS.

The prevalence of IR and DM are considerably lower in women without PCOS. According to the Third National Health and Nutrition Examination Survey, in US women of similar age, the prevalence of IR is 1.6%, and the prevalence of DM is 2.2%.⁷

2003 consensus: Screen for IGT in obese PCOS patients. In view of the high prevalence of IR and IGT, a 2003 PCOS consensus⁸ established that obese women with PCOS should be screened for insulin sensitivity and undergo screening for the metabolic syndrome, including glucose intolerance. For nonobese women, the consensus recommended screening only if additional risk factors are present.

Unfortunately, IGT also occurs independent of obesity. In lean women with PCOS, 5% may have IGT, while 2% are frankly diabetic. Moreover, the conversion from normal glucose tolerance to IGT in patients with PCOS can be as high as 16% per year,⁹ while the conversion rate from IGT to DM among women with PCOS has been reported to be as high as 2% per year.

2007 position statement: Screen for IGT in all PCOS patients. A position statement by the Androgen Excess–PCOS Society on glucose intolerance and PCOS recommends screening for IGT in all PCOS women, regardless of BMI, at least once every 2 years.¹⁰

Screening for insulin resistance: The methods

There are two ways to determine insulin sensitivity:

 

• direct infusion of IV glucose and/or insulin
• indirect assessment using surrogate markers (such as fasting glucose and insulin, or C-peptide, and oral glucose tolerance test [OGTT]).

Direct infusion of IV glucose or insulin reveals how insulin disposes of glucose from the blood stream; however, this method is expensive, time consuming, and potentially dangerous due to possible hypoglycemia. Indirect assessments are less complex to perform and correlate reasonably well with the results of the more invasive direct measures.

What are the current direct-infusion methods to measure insulin sensitivity?

Direct infusion of glucose and insulin

The hyperinsulinemic euglycemic clamp is the gold standard, but drawbacks relegate it to medical research only. This method measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. Numerous blood samplings (every 5 to 10 minutes) are taken to monitor serum glucose so that a steady “fasting” level can be maintained. The degree of insulin resistance is measured by the amount of glucose that is taken up by tissues during the procedure.^11-14

The “clamp” technique is the most scientifically sound method for measuring insulin sensitivity, and it’s the standard against which all other tests are usually compared. Because the clamp technique is expensive, time consuming (about 2 hours), and labor intensive, however, it is not practical and is rarely performed in clinical care. It is primarily used in medical research.

Frequently sampled IV glucose tolerance tests: “minimal model.” The frequently sampled IV glucose tolerance test estimates insulin sensitivity through a computer-based mathematical analysis of the glucose-insulin dynamics. Though this test still requires 11 to 34 blood samples over a 3-hour period, it is less labor intensive than the clamp technique. However, in contrast to the clamp, it does not distinguish between peripheral and hepatic glucose utilization.¹⁵

Direct infusion of insulin

Insulin sensitivity test. This test involves IV infusion of a set glucose load and a fixed-rate infusion of insulin over approximately 3 hours. The mean plasma glucose concentration over the last 30 minutes of the test reflects insulin sensitivity. Although lengthy, the insulin sensitivity test is less labor intensive and requires fewer blood samples than the clamp technique.¹⁶

Insulin tolerance test. This test is a simplified version of the insulin sensitivity test, as it measures the decline in serum glucose after an IV bolus of insulin is administered. Several insulin and glucose levels are sampled over the following 15 minutes. In contrast to the clamp and the minimal model, the insulin tolerance test primarily measures insulin-stimulated uptake of glucose into skeletal muscle, and insulin sensitivity values reflect the rate of decline of log transformed glucose values.¹⁷

Direct infusion of glucose

Continuous infusion of glucose with model assessment. This method utilizes a constant IV glucose infusion; samples for glucose and insulin are drawn at 50, 55, and 60 minutes. A mathematical model is then used to calculate insulin sensitivity. The results are correlated with clamp techniques; however, few laboratories have used this continuous-infusion method for insulin sensitivity testing in women with PCOS.¹⁸

Unfortunately, all of these methods require IV access and multiple venipunctures, making them relatively impractical for office assessment. To overcome these obstacles, alternative tests have been developed including fasting methods and the OGTT, the latter of which does not require IV access and does correlate reasonably well with dynamic clamp techniques.

What are the current indirect assessments to measure insulin sensitivity?

Fasting methods

Fasting insulin. The measurement of fasting serum insulin is simple and inexpensive. Generally, a fasting level of 30 μU/mL indicates greater insulin resistance in a diabetic individual than in a normoglycemic patient. However, fasting insulin levels may be in the “normal” range in up to 40% of PCOS patients who have impaired glucose tolerance diagnosed by the OGTT. It has been suggested by some investigators that a fasting insulin greater than 20 μU/mL in white women and greater than 23 μU/mL in Mexican-American women probably indicates insulin resistance in women with PCOS. Some have also advocated averaging two or three readings to account for day-to-day variability.^19-21

Fasting plasma glucose. This is a simple blood test taken after 8 hours of fasting. Fasting plasma glucose (FPG) levels are considered normal up to 100 mg/dL (or 5.5 mmol/L). Levels between 100 and 125 mg/dL (5.5 to 7.0 mmol/L) are considered impaired fasting glucose or prediabetes. These levels are considered to be risk factors for DM and its complications. DM is diagnosed when FPG levels are 126 mg/dL (7.0 mmol/L) or higher. A “normal” result on the FPG test is not always reliable. Repeat testing with the OGTT is recommended if risk factors are suggestive for the presence of DM or a prediabetic condition.

 

Glucose/insulin ratio

The glucose/insulin (G/I) ratio has become very popular since its first description in 1998 as an accurate index of insulin sensitivity in women with PCOS. The ratio of glucose to insulin is easy to calculate, with lower values depicting higher degrees of insulin resistance. A G/I ratio of less than 4.5 has been shown to be sensitive (95%) and specific (84%) for insulin resistance in women with PCOS, compared with a control group. The normal range for G/I ratios may vary in different ethnic groups and have not been fully validated in nonobese patients.^22-25

Homeostatic model assessment

First described in 1985, homeostatic model assessment (HOMA) has been used widely in clinical research to assess insulin sensitivity. Rather than using fasting insulin or a G/I ratio, the product of the fasting values of glucose (expressed as mg/dL) and insulin (expressed as μU/mL) is divided by a constant: I0 x G0 ÷ 405.

The constant 405 should be replaced by 22.5 if glucose is expressed in SI units (mmol/L). Unlike fasting insulin and the G/I ratio, the HOMA calculation compensates for fasting hyperglycemia. The HOMA value correlates well with clamp techniques and has been used frequently to assess changes in insulin sensitivity after treatment. HOMA also has been used to study insulin resistance among PCOS patients of differing ethnic origins.^12,24-26

Quantitative insulin sensitivity check index

Like HOMA, quantitative insulin sensitivity check index (QUICKI) can be applied to normoglycemic and hyperglycemic patients. It is derived by calculating the inverse of the sum of logarithmically expressed values of fasting glucose and insulin: 1 ÷ [log(I0) + log(G0)].

Many investigators believe that QUICKI is superior to HOMA as a way of determining insulin sensitivity, although the two values correlate well. As the SI decreases, QUICKI values decrease.²⁷

Oral glucose tolerance test

As OGTT does not require IV access, it is the current standard in practice for diagnosis of IGT and DM. It provides a better assessment of IGT and DM than fasting techniques because these patients may have normal fasting glucose values despite abnormal 2-hour fasting levels. The OGTT uses a 50-, 75-, or 100-g glucose load and measures glucose and insulin at various intervals over 1 to 3 hours. The WHO currently recommends a 75-g oral dose in all adults. A 50-g dose is used to screen for gestational diabetes over an hour, and the 100-g load over 3 hours if abnormal.²⁸ See TABLE for normal and abnormal values. Insulin sensitivity has been assessed by calculating insulin area under the curve (AUC insulin), AUC glucose/AUC insulin, and by an insulin sensitivity index (ISI) that applies only the glucose and insulin values from 0 and 120 minutes into a complex mathematical formula.^13,25,29-31

Criteria for diagnosis of diabetes

	Venous plasma glucose (mg/dL)
	Fasting Level*	2-hour postglucose load**
Normal/Low risk	≤99	≤139
Prediabetes/Increased risk	100–125	140–199
Diabetes	≥126	≥200
*Fasting is defined as no caloric intake for at least 8 h **OGTT using a glucose load or 75 g as described by the World Health Organization SOURCE: American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35 (suppl 1):s11–s63. doi:10.2337/dc12-s011.

Test for glycosylated hemoglobin

Tests for blood levels of glycosylated hemoglobin, also known as hemoglobin A_1c (HbA_1c) are not currently used for an initial diagnosis because normal HbA_1c levels do not necessarily rule out diabetes, but they are strongly associated with complications of diabetes. The test is not affected by food intake so it can be taken at any time. A normal HbA_1c level is below 7%.

We want to hear from you! Tell us what you think.

Polycystic ovary syndrome, or PCOS, is a condition characterized by hyperandrogenism and chronic anovulation—the most common endocrinopathy in women of reproductive age, affecting at least 1 in every 15. Associated metabolic and health complications are significant and serious, and include obesity, insulin resistance, dyslipidemia, pancreatic ß-cell dysfunction, type-2 diabetes, cardiovascular disease, endometrial cancer, sleep apnea, inflammation, and infertility. To the frustration of the medical community and patients, the exact cause (or causes) of PCOS remains largely unknown; making the diagnosis means, essentially, excluding disorders that mimic PCOS—including congenital adrenal hyperplasia, hyperprolactinemia, and thyroid disease. PCOS is an enigma, in that it is a heterogeneous disorder, with the severity of clinical hyperandrogenism (hirsutism, acne, alopecia), obesity, and menstrual disturbance being considerably variable.

Furthermore, as many as 40% of women who have PCOS do not express classic signs of hyperandrogenism, making the diagnosis exceedingly challenging, particularly in the case of a patient of the lean (i.e., physical appearance) phenotype.

The picture is further confused. The appearance of polycystic-appearing ovaries (multiple tiny cysts) on ultrasonography (US) is noted in as many as 20% of women who have polycystic ovaries without evidence of androgen excess. The significance of this as an isolated finding on imaging in an otherwise normal woman is unclear. Some experts have described the presence of this finding as, again, signaling a cryptic or unexpressed form of PCOS or a prelude to the manifestation of signs of PCOS later.

The four parts of this article that will be posted here on the OBG Management Web site over coming months address questions that are often asked by clinicians about this challenging clinical entity. [Editor’s note: Those four installments will, as they are published, be collected on a single Web page for ease of access.]

Historical perspective

I’m confused. Going back to medical school, we were always taught that PCOS was an anatomic abnormality in which the ovary 1) produced excess androgens and 2) had a thickened covering, thus preventing ovulation. Today, PCOS has evolved into a seemingly complex entity. How did that transformation happen?

In its original description in the medical literature in the 1800s, PCOS was called cystic oophoritis.^1,2 However, it wasn’t until the early 1930s that Stein and Leventhal first diagnosed what was initially coined Stein-Leventhal syndrome, reporting their findings in 1935.³ Later, the condition was referred to as polycystic ovarian disease.

In 1945, Stein published a follow-up report in which he added excessive male-pattern hair growth and obesity to the list of described symptoms. Although other associated symptoms have been noted in women who have the syndrome, the four principal ones established by Stein and Leventhal between 1935 and 1945 are irregular menstruation, infertility, obesity, and hirsutism.

Evolution as a disorder. PCOS was, initially, thought to be an anatomic disorder that specifically involved the ovaries and their thickened capsules. By the 1960s, with the advent of the radioimmunoassay, researchers could measure hormone levels in women who had the disorder. Studies confirmed that PCOS was associated with 1) increased androgen production from the ovaries and 2) abnormal gonadotropin secretion. Specifically, luteinizing hormone (LH) stimulated excess ovarian androgen production. From a historical perspective, then, the view of PCOS changed from anatomic disorder to, primarily, an endocrine disorder.

By the 1980s, clinical observations suggested a strong relationship between hyperinsulinemia and hyperandrogenism. The constellation of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) was then called HAIR-AN syndrome. Dunaif described how insulin, acting through ovarian insulin growth-factor receptors as mediators in ovarian dysfunction, led to hyperandrogenism.⁴ Two mechanisms appeared to account for HAIR-AN syndrome:

• hyperinsulinemia induced by insulin resistance causes hyperandrogenism
• hyperandrogenism causes insulin resistance and hyperinsulinemia (acanthosis nigricans is considered to be an epiphenomenon caused by hyperinsulinemia).

In the late 1980s, Reaven theorized that central obesity (male-type, or apple-shaped, obesity), diabetes, and hypertension have a common cause in insulin resistance (IR) and impaired glucose tolerance (IGT).⁵ This constellation of symptoms, at first called syndrome X, is known today as metabolic syndrome and is an object of extensive scientific inquiry—especially because the combination of findings strongly predisposes an affected person to cardiovascular disease.

By 2000, PCOS was viewed more as a metabolic disorder, with an array of cardiac and metabolic risk factors (insulin resistance and glucose intolerance; hypertension; dyslipidemia; and dysfibrinolysis) that have been linked to a number of health disorders, including type-2 diabetes and atherosclerotic cardiovascular and cerebrovascular disease. Today, diagnostic criteria for metabolic syndrome are at least three of these five findings:

 

• waist circumference, more than 35 inches
• triglycerides level, at least 50 mg/dL
• high-density lipoprotein-C level, greater than 50 mg/dL
• systolic BP, 130 mm Hg or higher, and diastolic BP, 85 mm Hg or higher
• fasting glucose level (after an oral glucose tolerance test) between 110 and 126 mg/dL or a 2-hour postprandial glucose level between 140 and 199 mg/dL, or both.

Prevalence

How prevalent is PCOS? Does prevalence vary if one considers clinical criteria, or biochemical criteria, or ultrasonographic criteria?

Data are scarce, making the prevalence of PCOS difficult to estimate—in part, because PCOS is a heterogeneous condition that can manifest with variable clinical evidence:

• hyperandrogenism—as either hirsutism, acne, or alopecia, or a combination of these signs
• menstrual or ovulatory dysfunction, or both
• overweight or obesity
• infertility
• insulin resistance and other metabolic abnormalities
• polycystic ovaries

Now that accepted diagnostic criteria for PCOS are in place, the prevalence rate of the syndrome will be easier to establish. In the discussion that follows, we attempt to establish estimates of prevalence based on histopathology, signs of clinical hyperandrogenism, and the US appearance of polycystic ovaries.

When PCOS is defined histopathologically (i.e., by the presence of polycystic ovaries at the time of oophorectomy or wedge resection), 1.4% to 3.5% of unselected women⁶ and 0.6% to 4.3% of infertile women⁷ have this syndrome.

When clinical criteria are used, prevalence varies with the clinical complaint. Hirsutism is usually a mark of increased ovarian or adrenal androgen production. Studies—including one in which more than 1,000 women were evaluated using the 1990 National Institutes of Health (NIH) criteria (see the next section)—suggest that, in fact, more than 75% of hirsute women have PCOS.^8,9

In the absence of frank hirsutism, when only unwanted facial hair is present, approximately 50% of these women meet the definition for having PCOS.¹⁰

Among women whose only complaint is acne, prevalence has been reported in as many as one-third (range, 19% to 37%, although diagnostic criteria for PCOS were not well defined in these three studies).^11-13

Last, in women who had any manifestation of clinical hyperandrogenism by the 2003 Rotterdam criteria (hirsutism, acne, or alopecia, or a combination; again, see the next section), PCOS was diagnosed in 72%.¹⁴

When PCOS is defined by a finding of polycystic ovaries on US, prevalence varies by study settings. Polycystic ovaries are seen in 92% of women who have idiopathic hirsutism¹⁵; in 87% of women who have oligomenorrhea¹⁵; in 21% to 23% of randomly selected women^14,16; and in 23% of women who described themselves as “normal” and reported having a “regular” menstrual cycle.¹⁷ However, up to 25% of women with polycystic appearing ovaries may be entirely asymptomatic.¹⁸

In contrast, not all women who have an excess of androgens have polycystic-appearing ovaries^19-21; this situation has been observed in 20% to 30% of young, healthy women.⁹

When biochemical parameters are used as diagnostic criteria, the prevalence of PCOS varies from 2.5% to 7.5%.²² In an unselected, minimally-biased population of women, overall prevalence of PCOS appears to be approximately 4.6%, although it could be as low as 3.5% and as high as 11.2%.²³

All these observations, findings, and criteria considered, it is generally accepted that PCOS is one of the most common reproductive endocrine disorders of women.

What are the diagnostic criteria for PCOS?

The diagnosis of PCOS is confusing; consensus statements seem to change over time. Can you clarify the confusion over definitions?

Since the original description in 1945 of the diagnostic criteria of PCOS—irregular menstruation, infertility, obesity, hirsutism—it’s become clear that this disorder is a heterogeneous condition. Some patients display classic symptoms; many have a mild variant.

NIH seeks clarity. To further understand and study PCOS, it was essential to standardize the definition to facilitate collaborative clinical trials. In 1990, an NIH-sponsored consensus workshop attempted to standardize the criteria for making a diagnosis of PCOS.²⁴ This included a combination of:

• chronic anovulation
• clinical (hirsutism) or biochemical (or both) signs of hyperandrogenism
• exclusion of other causes (including thyroid dysfunction, hyperprolactinemia, and adult-onset congenital adrenal hyperplasia).

A diagnosis of PCOS did not, however, require that the ovaries have polycystic characteristics on US imaging. In contrast, the European definition of PCOS was a syndrome that included polycystic ovaries on US in conjunction with clinical or biochemical hyperandrogenism; oligomenorrhea or amenorrhea; and obesity.

International consensus sought. To foster agreement across borders, a joint workshop of the European Society of Human Reproduction and Embryology and the American Society for Reproductive Endocrinology workshop was held in Rotterdam in 2003,^25,26 resulting in an updated definition of PCOS. Ovarian morphology of multifollicular-appearing ovaries on US was recognized as an important component of the diagnosis; women who had clinical or biochemical hyperandrogenism in the face of a normal menstrual cycle could, therefore, have PCOS.

 

Workshop participants also agreed that a PCOS diagnosis required two of three criteria:

• oligo-ovulation or anovulation
• clinical or biochemical signs (or both) of hyperandrogenism
• polycystic ovaries on ultrasonography.

In addition, participants agreed that the exclusion of other causes of these findings—such as congenital adrenal hyperplasia, androgen-secreting tumors, Cushing’s syndrome, thyroid dysfunction, and an elevated prolactin level—was still critical to the diagnosis. (Note: We’ll discuss details of the diagnostic work-up for PCOS in a subsequent part of this article.)

The 2003 consensus meeting further described, in detail, US criteria by which to make a diagnosis of PCOS:

• at least 12 follicles in each ovary that are each 2 to 9 mm in diameter or
• ovarian volume greater than 10 mL.

These criteria do not apply to patients who are being treated with an oral contraceptive because their ovarian volume often appears smaller. In addition, having one ovary only that fits this definition was, and remains, sufficient to meet the US definition of PCOS. A so-called asymptomatic polycystic ovary—that is, positive US imaging in a woman who has regular cycles and a normal endocrine profile—should not be considered PCOS.

We want to hear from you! Tell us what you think.

Polycystic ovary syndrome, or PCOS, is a condition characterized by hyperandrogenism and chronic anovulation—the most common endocrinopathy in women of reproductive age, affecting at least 1 in every 15. Associated metabolic and health complications are significant and serious, and include obesity, insulin resistance, dyslipidemia, pancreatic ß-cell dysfunction, type-2 diabetes, cardiovascular disease, endometrial cancer, sleep apnea, inflammation, and infertility. To the frustration of the medical community and patients, the exact cause (or causes) of PCOS remains largely unknown; making the diagnosis means, essentially, excluding disorders that mimic PCOS—including congenital adrenal hyperplasia, hyperprolactinemia, and thyroid disease. PCOS is an enigma, in that it is a heterogeneous disorder, with the severity of clinical hyperandrogenism (hirsutism, acne, alopecia), obesity, and menstrual disturbance being considerably variable.

Furthermore, as many as 40% of women who have PCOS do not express classic signs of hyperandrogenism, making the diagnosis exceedingly challenging, particularly in the case of a patient of the lean (i.e., physical appearance) phenotype.

The picture is further confused. The appearance of polycystic-appearing ovaries (multiple tiny cysts) on ultrasonography (US) is noted in as many as 20% of women who have polycystic ovaries without evidence of androgen excess. The significance of this as an isolated finding on imaging in an otherwise normal woman is unclear. Some experts have described the presence of this finding as, again, signaling a cryptic or unexpressed form of PCOS or a prelude to the manifestation of signs of PCOS later.

The four parts of this article that will be posted here on the OBG Management Web site over coming months address questions that are often asked by clinicians about this challenging clinical entity. [Editor’s note: Those four installments will, as they are published, be collected on a single Web page for ease of access.]

Historical perspective

I’m confused. Going back to medical school, we were always taught that PCOS was an anatomic abnormality in which the ovary 1) produced excess androgens and 2) had a thickened covering, thus preventing ovulation. Today, PCOS has evolved into a seemingly complex entity. How did that transformation happen?

In its original description in the medical literature in the 1800s, PCOS was called cystic oophoritis.^1,2 However, it wasn’t until the early 1930s that Stein and Leventhal first diagnosed what was initially coined Stein-Leventhal syndrome, reporting their findings in 1935.³ Later, the condition was referred to as polycystic ovarian disease.

In 1945, Stein published a follow-up report in which he added excessive male-pattern hair growth and obesity to the list of described symptoms. Although other associated symptoms have been noted in women who have the syndrome, the four principal ones established by Stein and Leventhal between 1935 and 1945 are irregular menstruation, infertility, obesity, and hirsutism.

Evolution as a disorder. PCOS was, initially, thought to be an anatomic disorder that specifically involved the ovaries and their thickened capsules. By the 1960s, with the advent of the radioimmunoassay, researchers could measure hormone levels in women who had the disorder. Studies confirmed that PCOS was associated with 1) increased androgen production from the ovaries and 2) abnormal gonadotropin secretion. Specifically, luteinizing hormone (LH) stimulated excess ovarian androgen production. From a historical perspective, then, the view of PCOS changed from anatomic disorder to, primarily, an endocrine disorder.

By the 1980s, clinical observations suggested a strong relationship between hyperinsulinemia and hyperandrogenism. The constellation of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) was then called HAIR-AN syndrome. Dunaif described how insulin, acting through ovarian insulin growth-factor receptors as mediators in ovarian dysfunction, led to hyperandrogenism.⁴ Two mechanisms appeared to account for HAIR-AN syndrome:

• hyperinsulinemia induced by insulin resistance causes hyperandrogenism
• hyperandrogenism causes insulin resistance and hyperinsulinemia (acanthosis nigricans is considered to be an epiphenomenon caused by hyperinsulinemia).

In the late 1980s, Reaven theorized that central obesity (male-type, or apple-shaped, obesity), diabetes, and hypertension have a common cause in insulin resistance (IR) and impaired glucose tolerance (IGT).⁵ This constellation of symptoms, at first called syndrome X, is known today as metabolic syndrome and is an object of extensive scientific inquiry—especially because the combination of findings strongly predisposes an affected person to cardiovascular disease.

By 2000, PCOS was viewed more as a metabolic disorder, with an array of cardiac and metabolic risk factors (insulin resistance and glucose intolerance; hypertension; dyslipidemia; and dysfibrinolysis) that have been linked to a number of health disorders, including type-2 diabetes and atherosclerotic cardiovascular and cerebrovascular disease. Today, diagnostic criteria for metabolic syndrome are at least three of these five findings:

 

• waist circumference, more than 35 inches
• triglycerides level, at least 50 mg/dL
• high-density lipoprotein-C level, greater than 50 mg/dL
• systolic BP, 130 mm Hg or higher, and diastolic BP, 85 mm Hg or higher
• fasting glucose level (after an oral glucose tolerance test) between 110 and 126 mg/dL or a 2-hour postprandial glucose level between 140 and 199 mg/dL, or both.

Prevalence

How prevalent is PCOS? Does prevalence vary if one considers clinical criteria, or biochemical criteria, or ultrasonographic criteria?

Data are scarce, making the prevalence of PCOS difficult to estimate—in part, because PCOS is a heterogeneous condition that can manifest with variable clinical evidence:

• hyperandrogenism—as either hirsutism, acne, or alopecia, or a combination of these signs
• menstrual or ovulatory dysfunction, or both
• overweight or obesity
• infertility
• insulin resistance and other metabolic abnormalities
• polycystic ovaries

Now that accepted diagnostic criteria for PCOS are in place, the prevalence rate of the syndrome will be easier to establish. In the discussion that follows, we attempt to establish estimates of prevalence based on histopathology, signs of clinical hyperandrogenism, and the US appearance of polycystic ovaries.

When PCOS is defined histopathologically (i.e., by the presence of polycystic ovaries at the time of oophorectomy or wedge resection), 1.4% to 3.5% of unselected women⁶ and 0.6% to 4.3% of infertile women⁷ have this syndrome.

When clinical criteria are used, prevalence varies with the clinical complaint. Hirsutism is usually a mark of increased ovarian or adrenal androgen production. Studies—including one in which more than 1,000 women were evaluated using the 1990 National Institutes of Health (NIH) criteria (see the next section)—suggest that, in fact, more than 75% of hirsute women have PCOS.^8,9

In the absence of frank hirsutism, when only unwanted facial hair is present, approximately 50% of these women meet the definition for having PCOS.¹⁰

Among women whose only complaint is acne, prevalence has been reported in as many as one-third (range, 19% to 37%, although diagnostic criteria for PCOS were not well defined in these three studies).^11-13

Last, in women who had any manifestation of clinical hyperandrogenism by the 2003 Rotterdam criteria (hirsutism, acne, or alopecia, or a combination; again, see the next section), PCOS was diagnosed in 72%.¹⁴

When PCOS is defined by a finding of polycystic ovaries on US, prevalence varies by study settings. Polycystic ovaries are seen in 92% of women who have idiopathic hirsutism¹⁵; in 87% of women who have oligomenorrhea¹⁵; in 21% to 23% of randomly selected women^14,16; and in 23% of women who described themselves as “normal” and reported having a “regular” menstrual cycle.¹⁷ However, up to 25% of women with polycystic appearing ovaries may be entirely asymptomatic.¹⁸

In contrast, not all women who have an excess of androgens have polycystic-appearing ovaries^19-21; this situation has been observed in 20% to 30% of young, healthy women.⁹

When biochemical parameters are used as diagnostic criteria, the prevalence of PCOS varies from 2.5% to 7.5%.²² In an unselected, minimally-biased population of women, overall prevalence of PCOS appears to be approximately 4.6%, although it could be as low as 3.5% and as high as 11.2%.²³

All these observations, findings, and criteria considered, it is generally accepted that PCOS is one of the most common reproductive endocrine disorders of women.

What are the diagnostic criteria for PCOS?

The diagnosis of PCOS is confusing; consensus statements seem to change over time. Can you clarify the confusion over definitions?

Since the original description in 1945 of the diagnostic criteria of PCOS—irregular menstruation, infertility, obesity, hirsutism—it’s become clear that this disorder is a heterogeneous condition. Some patients display classic symptoms; many have a mild variant.

NIH seeks clarity. To further understand and study PCOS, it was essential to standardize the definition to facilitate collaborative clinical trials. In 1990, an NIH-sponsored consensus workshop attempted to standardize the criteria for making a diagnosis of PCOS.²⁴ This included a combination of:

• chronic anovulation
• clinical (hirsutism) or biochemical (or both) signs of hyperandrogenism
• exclusion of other causes (including thyroid dysfunction, hyperprolactinemia, and adult-onset congenital adrenal hyperplasia).

A diagnosis of PCOS did not, however, require that the ovaries have polycystic characteristics on US imaging. In contrast, the European definition of PCOS was a syndrome that included polycystic ovaries on US in conjunction with clinical or biochemical hyperandrogenism; oligomenorrhea or amenorrhea; and obesity.

International consensus sought. To foster agreement across borders, a joint workshop of the European Society of Human Reproduction and Embryology and the American Society for Reproductive Endocrinology workshop was held in Rotterdam in 2003,^25,26 resulting in an updated definition of PCOS. Ovarian morphology of multifollicular-appearing ovaries on US was recognized as an important component of the diagnosis; women who had clinical or biochemical hyperandrogenism in the face of a normal menstrual cycle could, therefore, have PCOS.

 

Workshop participants also agreed that a PCOS diagnosis required two of three criteria:

• oligo-ovulation or anovulation
• clinical or biochemical signs (or both) of hyperandrogenism
• polycystic ovaries on ultrasonography.

In addition, participants agreed that the exclusion of other causes of these findings—such as congenital adrenal hyperplasia, androgen-secreting tumors, Cushing’s syndrome, thyroid dysfunction, and an elevated prolactin level—was still critical to the diagnosis. (Note: We’ll discuss details of the diagnostic work-up for PCOS in a subsequent part of this article.)

The 2003 consensus meeting further described, in detail, US criteria by which to make a diagnosis of PCOS:

• at least 12 follicles in each ovary that are each 2 to 9 mm in diameter or
• ovarian volume greater than 10 mL.

These criteria do not apply to patients who are being treated with an oral contraceptive because their ovarian volume often appears smaller. In addition, having one ovary only that fits this definition was, and remains, sufficient to meet the US definition of PCOS. A so-called asymptomatic polycystic ovary—that is, positive US imaging in a woman who has regular cycles and a normal endocrine profile—should not be considered PCOS.

We want to hear from you! Tell us what you think.

Polycystic ovary syndrome, or PCOS, is a condition characterized by hyperandrogenism and chronic anovulation—the most common endocrinopathy in women of reproductive age, affecting at least 1 in every 15. Associated metabolic and health complications are significant and serious, and include obesity, insulin resistance, dyslipidemia, pancreatic ß-cell dysfunction, type-2 diabetes, cardiovascular disease, endometrial cancer, sleep apnea, inflammation, and infertility. To the frustration of the medical community and patients, the exact cause (or causes) of PCOS remains largely unknown; making the diagnosis means, essentially, excluding disorders that mimic PCOS—including congenital adrenal hyperplasia, hyperprolactinemia, and thyroid disease. PCOS is an enigma, in that it is a heterogeneous disorder, with the severity of clinical hyperandrogenism (hirsutism, acne, alopecia), obesity, and menstrual disturbance being considerably variable.

Furthermore, as many as 40% of women who have PCOS do not express classic signs of hyperandrogenism, making the diagnosis exceedingly challenging, particularly in the case of a patient of the lean (i.e., physical appearance) phenotype.

The picture is further confused. The appearance of polycystic-appearing ovaries (multiple tiny cysts) on ultrasonography (US) is noted in as many as 20% of women who have polycystic ovaries without evidence of androgen excess. The significance of this as an isolated finding on imaging in an otherwise normal woman is unclear. Some experts have described the presence of this finding as, again, signaling a cryptic or unexpressed form of PCOS or a prelude to the manifestation of signs of PCOS later.

The four parts of this article that will be posted here on the OBG Management Web site over coming months address questions that are often asked by clinicians about this challenging clinical entity. [Editor’s note: Those four installments will, as they are published, be collected on a single Web page for ease of access.]

Historical perspective

I’m confused. Going back to medical school, we were always taught that PCOS was an anatomic abnormality in which the ovary 1) produced excess androgens and 2) had a thickened covering, thus preventing ovulation. Today, PCOS has evolved into a seemingly complex entity. How did that transformation happen?

In its original description in the medical literature in the 1800s, PCOS was called cystic oophoritis.^1,2 However, it wasn’t until the early 1930s that Stein and Leventhal first diagnosed what was initially coined Stein-Leventhal syndrome, reporting their findings in 1935.³ Later, the condition was referred to as polycystic ovarian disease.

In 1945, Stein published a follow-up report in which he added excessive male-pattern hair growth and obesity to the list of described symptoms. Although other associated symptoms have been noted in women who have the syndrome, the four principal ones established by Stein and Leventhal between 1935 and 1945 are irregular menstruation, infertility, obesity, and hirsutism.

Evolution as a disorder. PCOS was, initially, thought to be an anatomic disorder that specifically involved the ovaries and their thickened capsules. By the 1960s, with the advent of the radioimmunoassay, researchers could measure hormone levels in women who had the disorder. Studies confirmed that PCOS was associated with 1) increased androgen production from the ovaries and 2) abnormal gonadotropin secretion. Specifically, luteinizing hormone (LH) stimulated excess ovarian androgen production. From a historical perspective, then, the view of PCOS changed from anatomic disorder to, primarily, an endocrine disorder.

By the 1980s, clinical observations suggested a strong relationship between hyperinsulinemia and hyperandrogenism. The constellation of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) was then called HAIR-AN syndrome. Dunaif described how insulin, acting through ovarian insulin growth-factor receptors as mediators in ovarian dysfunction, led to hyperandrogenism.⁴ Two mechanisms appeared to account for HAIR-AN syndrome:

• hyperinsulinemia induced by insulin resistance causes hyperandrogenism
• hyperandrogenism causes insulin resistance and hyperinsulinemia (acanthosis nigricans is considered to be an epiphenomenon caused by hyperinsulinemia).

In the late 1980s, Reaven theorized that central obesity (male-type, or apple-shaped, obesity), diabetes, and hypertension have a common cause in insulin resistance (IR) and impaired glucose tolerance (IGT).⁵ This constellation of symptoms, at first called syndrome X, is known today as metabolic syndrome and is an object of extensive scientific inquiry—especially because the combination of findings strongly predisposes an affected person to cardiovascular disease.

By 2000, PCOS was viewed more as a metabolic disorder, with an array of cardiac and metabolic risk factors (insulin resistance and glucose intolerance; hypertension; dyslipidemia; and dysfibrinolysis) that have been linked to a number of health disorders, including type-2 diabetes and atherosclerotic cardiovascular and cerebrovascular disease. Today, diagnostic criteria for metabolic syndrome are at least three of these five findings:

 

• waist circumference, more than 35 inches
• triglycerides level, at least 50 mg/dL
• high-density lipoprotein-C level, greater than 50 mg/dL
• systolic BP, 130 mm Hg or higher, and diastolic BP, 85 mm Hg or higher
• fasting glucose level (after an oral glucose tolerance test) between 110 and 126 mg/dL or a 2-hour postprandial glucose level between 140 and 199 mg/dL, or both.

Prevalence

How prevalent is PCOS? Does prevalence vary if one considers clinical criteria, or biochemical criteria, or ultrasonographic criteria?

Data are scarce, making the prevalence of PCOS difficult to estimate—in part, because PCOS is a heterogeneous condition that can manifest with variable clinical evidence:

• hyperandrogenism—as either hirsutism, acne, or alopecia, or a combination of these signs
• menstrual or ovulatory dysfunction, or both
• overweight or obesity
• infertility
• insulin resistance and other metabolic abnormalities
• polycystic ovaries

Now that accepted diagnostic criteria for PCOS are in place, the prevalence rate of the syndrome will be easier to establish. In the discussion that follows, we attempt to establish estimates of prevalence based on histopathology, signs of clinical hyperandrogenism, and the US appearance of polycystic ovaries.

When PCOS is defined histopathologically (i.e., by the presence of polycystic ovaries at the time of oophorectomy or wedge resection), 1.4% to 3.5% of unselected women⁶ and 0.6% to 4.3% of infertile women⁷ have this syndrome.

When clinical criteria are used, prevalence varies with the clinical complaint. Hirsutism is usually a mark of increased ovarian or adrenal androgen production. Studies—including one in which more than 1,000 women were evaluated using the 1990 National Institutes of Health (NIH) criteria (see the next section)—suggest that, in fact, more than 75% of hirsute women have PCOS.^8,9

In the absence of frank hirsutism, when only unwanted facial hair is present, approximately 50% of these women meet the definition for having PCOS.¹⁰

Among women whose only complaint is acne, prevalence has been reported in as many as one-third (range, 19% to 37%, although diagnostic criteria for PCOS were not well defined in these three studies).^11-13

Last, in women who had any manifestation of clinical hyperandrogenism by the 2003 Rotterdam criteria (hirsutism, acne, or alopecia, or a combination; again, see the next section), PCOS was diagnosed in 72%.¹⁴

When PCOS is defined by a finding of polycystic ovaries on US, prevalence varies by study settings. Polycystic ovaries are seen in 92% of women who have idiopathic hirsutism¹⁵; in 87% of women who have oligomenorrhea¹⁵; in 21% to 23% of randomly selected women^14,16; and in 23% of women who described themselves as “normal” and reported having a “regular” menstrual cycle.¹⁷ However, up to 25% of women with polycystic appearing ovaries may be entirely asymptomatic.¹⁸

In contrast, not all women who have an excess of androgens have polycystic-appearing ovaries^19-21; this situation has been observed in 20% to 30% of young, healthy women.⁹

When biochemical parameters are used as diagnostic criteria, the prevalence of PCOS varies from 2.5% to 7.5%.²² In an unselected, minimally-biased population of women, overall prevalence of PCOS appears to be approximately 4.6%, although it could be as low as 3.5% and as high as 11.2%.²³

All these observations, findings, and criteria considered, it is generally accepted that PCOS is one of the most common reproductive endocrine disorders of women.

What are the diagnostic criteria for PCOS?

The diagnosis of PCOS is confusing; consensus statements seem to change over time. Can you clarify the confusion over definitions?

Since the original description in 1945 of the diagnostic criteria of PCOS—irregular menstruation, infertility, obesity, hirsutism—it’s become clear that this disorder is a heterogeneous condition. Some patients display classic symptoms; many have a mild variant.

NIH seeks clarity. To further understand and study PCOS, it was essential to standardize the definition to facilitate collaborative clinical trials. In 1990, an NIH-sponsored consensus workshop attempted to standardize the criteria for making a diagnosis of PCOS.²⁴ This included a combination of:

• chronic anovulation
• clinical (hirsutism) or biochemical (or both) signs of hyperandrogenism
• exclusion of other causes (including thyroid dysfunction, hyperprolactinemia, and adult-onset congenital adrenal hyperplasia).

A diagnosis of PCOS did not, however, require that the ovaries have polycystic characteristics on US imaging. In contrast, the European definition of PCOS was a syndrome that included polycystic ovaries on US in conjunction with clinical or biochemical hyperandrogenism; oligomenorrhea or amenorrhea; and obesity.

International consensus sought. To foster agreement across borders, a joint workshop of the European Society of Human Reproduction and Embryology and the American Society for Reproductive Endocrinology workshop was held in Rotterdam in 2003,^25,26 resulting in an updated definition of PCOS. Ovarian morphology of multifollicular-appearing ovaries on US was recognized as an important component of the diagnosis; women who had clinical or biochemical hyperandrogenism in the face of a normal menstrual cycle could, therefore, have PCOS.

 

Workshop participants also agreed that a PCOS diagnosis required two of three criteria:

• oligo-ovulation or anovulation
• clinical or biochemical signs (or both) of hyperandrogenism
• polycystic ovaries on ultrasonography.

In addition, participants agreed that the exclusion of other causes of these findings—such as congenital adrenal hyperplasia, androgen-secreting tumors, Cushing’s syndrome, thyroid dysfunction, and an elevated prolactin level—was still critical to the diagnosis. (Note: We’ll discuss details of the diagnostic work-up for PCOS in a subsequent part of this article.)

The 2003 consensus meeting further described, in detail, US criteria by which to make a diagnosis of PCOS:

• at least 12 follicles in each ovary that are each 2 to 9 mm in diameter or
• ovarian volume greater than 10 mL.

These criteria do not apply to patients who are being treated with an oral contraceptive because their ovarian volume often appears smaller. In addition, having one ovary only that fits this definition was, and remains, sufficient to meet the US definition of PCOS. A so-called asymptomatic polycystic ovary—that is, positive US imaging in a woman who has regular cycles and a normal endocrine profile—should not be considered PCOS.

We want to hear from you! Tell us what you think.