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Metformin and Other Insulin Sensitizers in Polycystic Ovary Syndrome Wendy Vitek, MD1
John Queenan, MD1
1 Division of Reproductive Endocrinology and Infertility, Department
of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, New York Semin Reprod Med 2014;32:323–330
Abstract
Keywords
► ► ► ►
PCOS insulin sensitizers treatment infertility
Kathleen Hoeger, MD1
Address for correspondence Bala Bhagavath, MD, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 668, Rochester, NY 14642 (e-mail: [email protected]).
Polycystic ovary syndrome (PCOS) is a complex disorder affecting a substantial group of women from adolescent to menopausal age groups. A substantial subgroup of these women exhibits increased insulin resistance. Insulin resistance is difficult to establish in clinical practice and many surrogate tests are available, although their value in the clinical setting is uncertain. The QUICKI method is an inexpensive and easy test to administer and is probably the best test to be used in PCOS patients, preferably in a clinical trial context. There is considerable evidence that insulin-sensitizing agents are not contributory to infertility management in the majority of women with PCOS. Currently, there is no evidence that cardiovascular morbidity is decreased by long-term use of insulin sensitizers in PCOS women.
Polycystic ovary syndrome (PCOS) was first described in 1935 by Stein and Leventhal.1 They described women with amenorrhea and severe hyperandrogenism who also had polycystic ovaries upon laparotomy. It has since been recognized that this description only includes the extreme end of the spectrum of presentations this disease entity encompasses. The precise definition of this syndrome currently eludes us and much controversy exists. Menstrual irregularity and hyperandrogenism are accepted widely to be part of the syndrome. The inclusion of polycystic-appearing ovaries on imaging as part of the diagnostic criteria has been strenuously debated. Five decades after its initial description, insulin resistance was recognized as another association in a subgroup of PCOS patients.2 However, insulin resistance is difficult to quantify and the gold standards for measurement are too cumbersome for routine clinical use. Insulin sensitizers are medications that can be used to overcome insulin resistance. Use of insulin sensitizers in patients with PCOS therefore requires one to overcome many contentious issues—the confidence in classifying a patient as having the syndrome, the clarity with which a diagnosis of insulin resistance can be made, and the strength of evidence in favor of using an insulin-sensitizing
Issue Theme Common Practices in Reproductive Endocrinology and Infertility Supported by Weak or No Evidence; Guest Editor, Orhan Bukulmez, MD
agent for treatment of this population of women. The purpose of this article is to examine and review the evidence for insulin resistance in PCOS patients, the evidence that insulin sensitizers are helpful in patients with insulin resistance, and evidence that insulin sensitizers are useful in the management of infertility in PCOS patients as well as in the long-term care of these women.
Measuring Insulin Resistance Insulin acts on many peripheral tissues to increase glucose utilization and acts on liver to prevent glucose production. Insulin resistance therefore decreases peripheral glucose utilization and fails to inhibit hepatic glucose production. Although the concept is clear, the measurement of insulin resistance is fraught with challenges. “Hyperinsulinemic Euglycemic Glucose Clamp (HEGC)” is widely accepted as the gold standard in measuring insulin resistance. Even this method is subject to producing variable results based on whether a steady-state blood glucose concentration was achieved, at what glucose level the clamp was applied, the population being studied, and the experience of the operator.
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
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Unfortunately, it requires an expensive research setting with an experienced operator to perform the testing reliably. There is no ideal alternative and the sheer number of alternative testing methods available attests to the various problems associated with them. Insulin suppression test, minimal model analysis of frequently sampled intravenous glucose tolerance test, oral glucose tolerance test, meal tolerance test, fasting glucose, fasting insulin, and the QUICKI, Matsuda, Stumvoll, and Avignon indices are just a few of the available alternative tests for insulin resistance. The advantages and disadvantages of each one are briefly summarized in ►Table 1. The aim of summarizing this information in the table is to provide a quick point of reference for the various tests available. A description of how these tests are performed is beyond the scope of this article. The best surrogate index for measuring insulin resistance is the QUICKI index. It involves nondynamic testing and is relatively inexpensive. It has the best correlation with the glucose clamp among all the surrogate tests. It is notable that many PCOS studies have used the fasting glucose/fasting insulin index, which is conceptually flawed and is best avoided.3 While insulin resistance is present in PCOS in the majority of cases, there is little evidence that clinical management is altered with the use of insulin sensitivity measures.
Insulin Resistance in Patients with Polycystic Ovary Syndrome The association between insulin resistance and PCOS was recognized when characterizing hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and hyperinsulinemia.2 Insulin resistance has been characterized in 60 to 70% of PCOS women and up to 95% of obese PCOS women.4,5 Studies using the Rotterdam criteria have confirmed that the phenotype with hyperandrogenism and anovulation has the highest incidence of insulin resistance compared with other phenotypes.6,7 There is some evidence that another phenotypic association between upper body (android) obesity and hyperandrogenism exists.8,9 It is interesting to note that upper body obesity (determined by wait/hip ratios) can be present in both obese and lean PCOS women. Subcutaneous adipocytes in these women (both lean and obese PCOS) have been noted to be larger than those from normal women and have defective insulin action.9 Insulin resistance is found only in a subset of women with PCOS. Insulin resistance, when present, has a modifying effect on PCOS.9 It is possible that the intrinsic defect in PCOS women may be a hypersensitivity of ovarian tissue to insulin action.10 Women with peripheral insulin resistance may develop PCOS as a result of the increased circulating insulin acting upon the normal insulin receptors in the ovary. It is possible that a defect in postreceptor insulin signal transduction is the underlying molecular basis for the insulin resistance.11 Insulin resistance has been noted to be familial and transcends gender. Men in a family with strong history of PCOS Seminars in Reproductive Medicine
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also have insulin resistance.12 These men develop premature balding and display hirsutism.13,14 Although familial tendency for developing PCOS has been recognized for many years, the exact genetic etiology remains elusive. Genome-wide association studies have been most promising and several candidate genes have emerged including DENND1A, THADA, FBN3, and SHBG genes.15–18 It is notable that none of these genes have a link to insulin pathway. Other metabolic associations have also been noted in women with PCOS. Impaired glucose tolerance, gestational diabetes, type 2 diabetes, and obesity are more prevalent in PCOS women. In summary, insulin resistance has been well characterized in women with PCOS. Although insulin resistance is clearly a contributing factor to the disease, further evidence is needed to implicate it as the underlying cause.
Insulin Sensitizers Treatment of diabetes involves multiple approaches. For the patient with type 1 diabetes mellitus who suffers from insulin deficiency, insulin supplementation with insulin or an analog is the key. However, for the patient with type 2 diabetes who can have insulin resistance, deficient insulin secretion, or a combination of both, various other treatment modalities are available. Insulin sensitivity can be improved by use of insulin sensitizers, insulin secretion can be augmented by use of secretagogues, carbohydrate digestion and absorption can be delayed by α-glucosidase inhibitors, and gastric emptying can be delayed by amylin analogs and decreasing glucose reabsorption in the kidney by inhibiting subtype 2 sodium– glucose transport protein.19 The defect in PCOS patients is thought to be an increase in insulin resistance as described earlier. Therefore, the only class of agents likely to lead to an improvement is insulinsensitizing agents. There are two groups or agents in this class —Biguanides and Peroxisome Proliferator Activator Receptor (PPAR) agonists. Metformin is the only agent in the class of Biguanides that is Food and Drug Administration (FDA) approved. There are four subclasses of agents in the PPAR agonist group—PPARα, PPARγ, PPARδ, and Dual/Pan PPAR agonists. PPARα agonists are primarily useful for treating lipid abnormalities and not useful to treat insulin resistance. PPARγ agonists improve insulin sensitivity and include thiazolidinediones. PPARδ agonists induce the body to prefer lipids as a fuel source as opposed to glucose. This paradoxically seems to improve metabolic syndrome. There are no pure PPARδ agonists in the market, but a dual PPAR agonist, Aleglitazar, is currently undergoing phase III trials. Currently, metformin, which is a biguanide, and thiazolidinediones (rosiglitazone and pioglitazone), which are PPARγ agonists, are the only insulin-sensitizing agents available for clinical use and have been studied. Berberine is an over-thecounter medication and is discussed later. In direct comparisons in randomized controlled trials, metformin and thiazolidinediones were both equally efficacious in lowering HbA1C levels. Metformin has a slightly better
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Table 1 Comparison of the assumptions, limitations and use of the different methods for measuring insulin resistance Method
Assumptions
Limitations
Use
HEGCa
1. Steady-state concentration of glucose achieved 2. Hepatic glucose production is completely suppressed 3. Glucose level at which the test is “clamped” is determined at a predetermined level 4. Glucose infusion rate at steady-state concentration is measured at a single insulin infusion rate
1. Expensive 2. Labor intensive 3. Operator dependent
1. Small study population of < 100
ISTb
1. Same as for HEGC 2. Steady infusions of somatostatin, insulin, and glucose achieve steadystate concentration of glucose and suppress hepatic glucose production
1. Expensive 2. Labor intensive (but less than HEGC) 3. In type 2 diabetes, glucosuria may occur and underestimation of insulin resistance may occur
1. Can be used in larger studies than HEGC, as it is less labor intensive
MMA of FSIVGTTc
1. Instantaneous distribution of infused glucose in a single compartment 2. Glucose is removed from the compartment at a steadily exponential rate 3. Glucose concentration in the compartment is the same at the beginning and the end 4. Insulin is assumed to be in a different compartment compared with glucose 5. Peripheral glucose disposal and suppression of hepatic glucose production are linked and proportional
1. Labor intensive (less than HEGC and IST) 2. Single compartment assumption results in overestimation of glucose and underestimation of insulin. Use of labeled glucose can overcome this limitation to some extent 3. Assumption that hepatic glucose suppression and glucose disposal are linked results in negative values for the calculated serum insulin values in a significant portion of subjects
1. Can be used in large population-based studies, as it is less labor intensive and has good correlation with HEGC
OGTT/MTTd
1. No assumptions—assesses body’s ability to dispose of glucose
1. Does not measure insulin resistance!
1. Many of the “surrogate indices using dynamic tests” use OGTT and MTT (see below)
Indirect sampling
Surrogate indices using steady-state conditions 1/Fasting insulin
1. No assumptions
1. Does not correlate with insulin resistance in individuals with impaired glucose tolerance or diabetes 2. Correlation between this ratio and insulin sensitivity is nonlinear
1. Useful in clinical practice, large clinical trials
Glucose/Insulin
1. Fasting glucose is normal in all individuals (in reality, it is increased in IGT and diabetes)
1. “Fasting glucose/Fasting insulin” correlates well with “1/Fasting insulin’ in subjects without any glucose intolerance. However, given the same fasting insulin levels, this ratio starts increasing and gives erroneous results in subjects with
1. This is a conceptually flawed index 2. Unfortunately, it is the most common index used in many PCOS studies
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Direct sampling
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Table 1 (Continued) Method
Assumptions
Limitations
Use
impaired glucose tolerance compared with normal individuals HOMA-IRe
1. The constant denominator of 22.5 assumes a fasting insulin of 5 μU/mL and fasting glucose of 4.5 mmol/L in a “normal” individual
1. Coefficient of variation varies considerably depending on the type of insulin assay used 2. Not useful in individuals with severely impaired glucose tolerance or diabetes
1. Large clinical trials and epidemiological studies
QUICKIf
1. Same as HEGC
1. None
1. Large epidemiologic studies and clinical trials 2. Most thoroughly validated surrogate index with best correlation with HEGC
1. Same as FSIVGTT and OGTT 2. Relatively more labor intensive and expensive compared with surrogate indices using steady-state conditions
1. Helpful in assessing insulin secretion as well as insulin resistance 2. Large clinical trials and epidemiological studies that require information about insulin secretion as well as resistance
Surrogate indices using dynamic tests Avignon index Belfiore index Gutt index Matsuda index Stumvoll index
1. Dynamic testing incorporates hepatic as well as peripheral insulin action
a
Hyperinsulinemic euglycemic glucose clamp. Insulin suppression test. c Minimal model analysis of frequently sampled intravenous glucose tolerance test. d Oral glucose tolerance test/meal tolerance test. e Homeostasis model assessment of insulin resistance. f Quantitative insulin sensitivity check index. b
profile for inducing weight loss, whereas a slight weight gain has been noted with thiazolidinediones. Metformin seems to be better at reducing low-density lipoprotein (LDL) levels and triglyceride levels. Neither has a favorable effect on elevating HDL levels. Metformin induces diarrhea significantly more often than the thiazolidinediones.20 Although the large, 4year ADOPT trial did not show any difference in congestive heart failure rates with thiazolidinediones, conflicting reports from other trials has led FDA to place a boxed warning for congestive heart failure.20,21 It is important to note that Rosiglitazone has been withdrawn from the market in many countries, although it is still available in the United States. Thiazolidinediones are roughly 10 times more expensive than metformin. Berberine is an isoquinoline alkaloid that has been used in traditional Chinese medicine for many centuries. It is an overthe-counter medication available in many countries including the United States. It has been shown to reduce fasting blood sugar levels and decrease insulin resistance in diabetic rat models by increasing insulin receptor expression.22,23 In addition, it has been shown to improve glucose transport by a mechanism independent of insulin.24 In human studies, Berberine was shown to be as effective as metformin in decreasing fasting blood sugar levels, improving insulin sensitivity, and decreasing HbA1C levels in newly diagnosed type Seminars in Reproductive Medicine
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2 diabetes patients as well as in poorly controlled type 2 diabetes patients.25
Insulin Sensitizers in Polycystic Ovary Syndrome Infertility By definition, anovulation is a key feature of PCOS. The only possible phenotype without anovulation is the hyperandrogenic patient with polycystic-appearing ovaries that is possible if the Rotterdam criteria are used. Because anovulation causes infertility, these patients often present with infertility as the sole complaint. Up to 30% of infertility may be due to PCOS.26 As mentioned earlier, a post-receptor insulin transduction defect is considered as one of the possible underlying causes for anovulation. Metformin therapy has been shown to decrease hyperinsulinemia and insulin resistance.27 Based on this, the practice of treating PCOS women with metformin as a single agent emerged in the 1990s.27 Most of the published studies are not randomized and meta-analysis of these data seemed to suggest that metformin was effective at inducing ovulation.28 Clomiphene citrate, a selective estrogen receptor modulator, has been a key agent used to induce ovulation for many
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decades. However, approximately one in four women are resistant to its ovulation inducing effects and an alternative approach is needed.29 Letrozole, an aromatase inhibitor, may overcome this resistance in up to 50% of these patients and addition of dexamethasone has been shown to be effective as an adjunct in some patients.29 However, the favorite adjunct agent was metformin, which was administered daily to patients resistant to clomiphene. In addition, some patients were prescribed metformin from the outset without any evidence for insulin or clomiphene resistance. The effectiveness of this strategy was not clear until a randomized controlled trial was published in 2007 by the Reproductive Medicine Network (RMN). The RMN network trial conducted in the United States recruited 626 obese PCOS women. The women were treated for six menstrual cycles. The women were divided into three groups for treatment—those who received metformin only, those who received clomiphene only, and the last group received metformin in addition to clomiphene. The use of metformin alone resulted in live-birth in 7.2% of the women as opposed to 22.5% in women taking clomiphene only and 26.8% in women taking both clomiphene and metformin.30 The difference between clomiphene alone and the combined metformin/clomiphene group was not statistically significant. A recent randomized controlled trial from Finland recruited 320 PCOS patients (obese and lean) and used metformin only for 3 months followed by clomiphene or gonadotropins as dictated by clinical need. The cumulative live-birth rate was shown to be higher in the metformin group compared with the placebo group (41.9 vs. 28.8%). When a subgroup analysis was performed, the difference was significant in the obese PCOS patients and not in the thin PCOS patients (49 vs. 31.4%).31 A Cochrane review was published soon after the publication of the Finnish study. Unfortunately, the Finnish study was not included in the Cochrane analysis that reviewed 44 studies. The majority of the studies included in that analysis were on metformin and its effect on fertility. A total of 3,495 women from 38 trials were included in the analysis comparing metformin with placebo or clomiphene. The conclusion of the analysis was that metformin does not improve live-birth rates either as a single agent or in combination with clomiphene.32 However, improved clinical pregnancy rate was noted in the metformin and clomiphene group versus clomiphene-only group. The remaining trials included in the Cochrane analysis studied Rosiglitazone, Pioglitazone, or Dchiro-Inositol and did not show any advantages to improving live-birth rate in PCOS patients. Currently, a multicenter randomized trial comparing letrozole with and without the addition of Berberine is being conducted in China.33 The use of insulin sensitizers in PCOS patients undergoing gonadotropin therapy for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment cycles has been studied extensively. A recent meta-analysis of 10 randomized controlled trials concluded that metformin use does not increase live-birth rates in these patients.34 However, subgroup analysis revealed certain potential advantages. Use of metformin decreased miscarriage rates and this decrease was
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more marked with longer pretreatment use, higher dosage, and delaying the discontinuation of metformin. Another surprising finding was the 70% decrease in the incidence of OHSS in women taking metformin. One randomized trial comparing Berberine with metformin and placebo has been published.35 One hundred and fifty women with PCOS undergoing IVF/ICSI treatment cycles were pretreated for 3 months with Berberine, metformin, or placebo. The live-birth rates were 48.6% in the Berberine group, 36.8% in the metformin group, and 20.6% in the placebo group. The OHSS rate was 5.4, 5.3, and 17.6%, respectively, in these groups. Further randomized trials are needed to confirm that Berberine can be advantageous in PCOS patients undergoing IVF/ICSI treatment cycles. In summary, the strength of evidence from multiple trials seems to indicate no improvement in live-birth by addition of insulin sensitizers for ovulation induction cycles or for IVF/ ICSI cycles. There may be an advantage to using metformin in patients at risk for OHSS. Berberine is recently being studied for use in infertility patients and more evidence from randomized trials is needed.
Nonfertility-Related Long-Term Care Women with PCOS are at risk for menstrual irregularity, endometrial cancer, impaired glucose tolerance, type 2 diabetes, cardiovascular risk factors, anxiety, depression, poor self-perception, and reduced health-related quality of life.36–39 Metformin was inferior to oral contraceptive pills in regularizing the menstrual cycle in women with PCOS based on meta-analysis of six randomized trials.40 There is no evidence for reduction in uterine cancer risk using oral contraceptive pills or insulin sensitizers. Although much concern has been expressed about the higher prevalence of cardiovascular risk factors in women with PCOS, very little evidence exists for higher morbidity and mortality related to cardiovascular events in these women.40–43 It is possible that as women age, those without PCOS develop the cardiovascular risk factors and catch up with the risks faced by PCOS women.42,44 As a result, we currently do not have any evidence in favor of long-term use of insulin-sensitizing agents to improve cardiovascular morbidity and mortality in these women. The use of insulin-sensitizing agents in PCOS women should be guided by the guidelines for the treatment of impaired glucose tolerance or type 2 diabetes in women without PCOS.19,45 There is currently no evidence that use of insulin-sensitizing agents decreases the incidence of endometrial cancer or psychological disorders. Adolescents are a special group in which the diagnosis of PCOS can be challenging.46 Use of metformin in this group can restore regular menstrual cycles and decreases hirsutism.43 These results, however, are not consistently seen across randomized trials.47 One recent trial in a group of Catalan adolescents with a history of precocious puberty combined pioglitazone, flutamide, and metformin (PioFluMet) and administered to adolescent thin PCOS girls with hyperandrogenism and menstrual irregularity and compared it with oral contraceptive pills. The effect on the regularization of menses Seminars in Reproductive Medicine
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was similar. However, the PioFluMet-treated girls were more likely to have regular menses and had lower insulin levels.48 Racial and ethnic differences in the incidence of PCOS have been noted.49 However, no specific ethnic difference in response to insulin-sensitizing agents has been noted. In summary, there is currently no evidence to support the use of insulin-sensitizing agents to counter possible longterm morbidity and mortality associated with metabolic disturbances noted in women with PCOS. More trials are needed in adolescent girls to establish a role for insulin sensitizers.
13 Ferriman D, Purdie AW. The inheritance of polycystic ovarian
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Conclusion Insulin resistance is present in a subgroup of patients with PCOS. QUICKI is the best surrogate method to evaluate insulin resistance in PCOS patients, although its clinical value is uncertain. Routine use of insulin sensitizers in patients undergoing ovulation induction with oral agents or with gonadotropins for IVF does not increase the live-birth rates. A subgroup of patients may benefit from decreased incidence of OHSS. The value of insulin sensitizers in decreasing longterm cardiovascular morbidity remains to be established.
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Metformin and Other Insulin Sensitizers in PCOS
Metformin and Other Insulin Sensitizers in Polycystic Ovary Syndrome Wendy Vitek, MD1
John Queenan, MD1
1 Division of Reproductive Endocrinology and Infertility, Department
of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, New York Semin Reprod Med 2014;32:323–330
Abstract
Keywords
► ► ► ►
PCOS insulin sensitizers treatment infertility
Kathleen Hoeger, MD1
Address for correspondence Bala Bhagavath, MD, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 668, Rochester, NY 14642 (e-mail: [email protected]).
Polycystic ovary syndrome (PCOS) is a complex disorder affecting a substantial group of women from adolescent to menopausal age groups. A substantial subgroup of these women exhibits increased insulin resistance. Insulin resistance is difficult to establish in clinical practice and many surrogate tests are available, although their value in the clinical setting is uncertain. The QUICKI method is an inexpensive and easy test to administer and is probably the best test to be used in PCOS patients, preferably in a clinical trial context. There is considerable evidence that insulin-sensitizing agents are not contributory to infertility management in the majority of women with PCOS. Currently, there is no evidence that cardiovascular morbidity is decreased by long-term use of insulin sensitizers in PCOS women.
Polycystic ovary syndrome (PCOS) was first described in 1935 by Stein and Leventhal.1 They described women with amenorrhea and severe hyperandrogenism who also had polycystic ovaries upon laparotomy. It has since been recognized that this description only includes the extreme end of the spectrum of presentations this disease entity encompasses. The precise definition of this syndrome currently eludes us and much controversy exists. Menstrual irregularity and hyperandrogenism are accepted widely to be part of the syndrome. The inclusion of polycystic-appearing ovaries on imaging as part of the diagnostic criteria has been strenuously debated. Five decades after its initial description, insulin resistance was recognized as another association in a subgroup of PCOS patients.2 However, insulin resistance is difficult to quantify and the gold standards for measurement are too cumbersome for routine clinical use. Insulin sensitizers are medications that can be used to overcome insulin resistance. Use of insulin sensitizers in patients with PCOS therefore requires one to overcome many contentious issues—the confidence in classifying a patient as having the syndrome, the clarity with which a diagnosis of insulin resistance can be made, and the strength of evidence in favor of using an insulin-sensitizing
Issue Theme Common Practices in Reproductive Endocrinology and Infertility Supported by Weak or No Evidence; Guest Editor, Orhan Bukulmez, MD
agent for treatment of this population of women. The purpose of this article is to examine and review the evidence for insulin resistance in PCOS patients, the evidence that insulin sensitizers are helpful in patients with insulin resistance, and evidence that insulin sensitizers are useful in the management of infertility in PCOS patients as well as in the long-term care of these women.
Measuring Insulin Resistance Insulin acts on many peripheral tissues to increase glucose utilization and acts on liver to prevent glucose production. Insulin resistance therefore decreases peripheral glucose utilization and fails to inhibit hepatic glucose production. Although the concept is clear, the measurement of insulin resistance is fraught with challenges. “Hyperinsulinemic Euglycemic Glucose Clamp (HEGC)” is widely accepted as the gold standard in measuring insulin resistance. Even this method is subject to producing variable results based on whether a steady-state blood glucose concentration was achieved, at what glucose level the clamp was applied, the population being studied, and the experience of the operator.
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1375186. ISSN 1526-8004.
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Bala Bhagavath, MD1
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Unfortunately, it requires an expensive research setting with an experienced operator to perform the testing reliably. There is no ideal alternative and the sheer number of alternative testing methods available attests to the various problems associated with them. Insulin suppression test, minimal model analysis of frequently sampled intravenous glucose tolerance test, oral glucose tolerance test, meal tolerance test, fasting glucose, fasting insulin, and the QUICKI, Matsuda, Stumvoll, and Avignon indices are just a few of the available alternative tests for insulin resistance. The advantages and disadvantages of each one are briefly summarized in ►Table 1. The aim of summarizing this information in the table is to provide a quick point of reference for the various tests available. A description of how these tests are performed is beyond the scope of this article. The best surrogate index for measuring insulin resistance is the QUICKI index. It involves nondynamic testing and is relatively inexpensive. It has the best correlation with the glucose clamp among all the surrogate tests. It is notable that many PCOS studies have used the fasting glucose/fasting insulin index, which is conceptually flawed and is best avoided.3 While insulin resistance is present in PCOS in the majority of cases, there is little evidence that clinical management is altered with the use of insulin sensitivity measures.
Insulin Resistance in Patients with Polycystic Ovary Syndrome The association between insulin resistance and PCOS was recognized when characterizing hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and hyperinsulinemia.2 Insulin resistance has been characterized in 60 to 70% of PCOS women and up to 95% of obese PCOS women.4,5 Studies using the Rotterdam criteria have confirmed that the phenotype with hyperandrogenism and anovulation has the highest incidence of insulin resistance compared with other phenotypes.6,7 There is some evidence that another phenotypic association between upper body (android) obesity and hyperandrogenism exists.8,9 It is interesting to note that upper body obesity (determined by wait/hip ratios) can be present in both obese and lean PCOS women. Subcutaneous adipocytes in these women (both lean and obese PCOS) have been noted to be larger than those from normal women and have defective insulin action.9 Insulin resistance is found only in a subset of women with PCOS. Insulin resistance, when present, has a modifying effect on PCOS.9 It is possible that the intrinsic defect in PCOS women may be a hypersensitivity of ovarian tissue to insulin action.10 Women with peripheral insulin resistance may develop PCOS as a result of the increased circulating insulin acting upon the normal insulin receptors in the ovary. It is possible that a defect in postreceptor insulin signal transduction is the underlying molecular basis for the insulin resistance.11 Insulin resistance has been noted to be familial and transcends gender. Men in a family with strong history of PCOS Seminars in Reproductive Medicine
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also have insulin resistance.12 These men develop premature balding and display hirsutism.13,14 Although familial tendency for developing PCOS has been recognized for many years, the exact genetic etiology remains elusive. Genome-wide association studies have been most promising and several candidate genes have emerged including DENND1A, THADA, FBN3, and SHBG genes.15–18 It is notable that none of these genes have a link to insulin pathway. Other metabolic associations have also been noted in women with PCOS. Impaired glucose tolerance, gestational diabetes, type 2 diabetes, and obesity are more prevalent in PCOS women. In summary, insulin resistance has been well characterized in women with PCOS. Although insulin resistance is clearly a contributing factor to the disease, further evidence is needed to implicate it as the underlying cause.
Insulin Sensitizers Treatment of diabetes involves multiple approaches. For the patient with type 1 diabetes mellitus who suffers from insulin deficiency, insulin supplementation with insulin or an analog is the key. However, for the patient with type 2 diabetes who can have insulin resistance, deficient insulin secretion, or a combination of both, various other treatment modalities are available. Insulin sensitivity can be improved by use of insulin sensitizers, insulin secretion can be augmented by use of secretagogues, carbohydrate digestion and absorption can be delayed by α-glucosidase inhibitors, and gastric emptying can be delayed by amylin analogs and decreasing glucose reabsorption in the kidney by inhibiting subtype 2 sodium– glucose transport protein.19 The defect in PCOS patients is thought to be an increase in insulin resistance as described earlier. Therefore, the only class of agents likely to lead to an improvement is insulinsensitizing agents. There are two groups or agents in this class —Biguanides and Peroxisome Proliferator Activator Receptor (PPAR) agonists. Metformin is the only agent in the class of Biguanides that is Food and Drug Administration (FDA) approved. There are four subclasses of agents in the PPAR agonist group—PPARα, PPARγ, PPARδ, and Dual/Pan PPAR agonists. PPARα agonists are primarily useful for treating lipid abnormalities and not useful to treat insulin resistance. PPARγ agonists improve insulin sensitivity and include thiazolidinediones. PPARδ agonists induce the body to prefer lipids as a fuel source as opposed to glucose. This paradoxically seems to improve metabolic syndrome. There are no pure PPARδ agonists in the market, but a dual PPAR agonist, Aleglitazar, is currently undergoing phase III trials. Currently, metformin, which is a biguanide, and thiazolidinediones (rosiglitazone and pioglitazone), which are PPARγ agonists, are the only insulin-sensitizing agents available for clinical use and have been studied. Berberine is an over-thecounter medication and is discussed later. In direct comparisons in randomized controlled trials, metformin and thiazolidinediones were both equally efficacious in lowering HbA1C levels. Metformin has a slightly better
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Table 1 Comparison of the assumptions, limitations and use of the different methods for measuring insulin resistance Method
Assumptions
Limitations
Use
HEGCa
1. Steady-state concentration of glucose achieved 2. Hepatic glucose production is completely suppressed 3. Glucose level at which the test is “clamped” is determined at a predetermined level 4. Glucose infusion rate at steady-state concentration is measured at a single insulin infusion rate
1. Expensive 2. Labor intensive 3. Operator dependent
1. Small study population of < 100
ISTb
1. Same as for HEGC 2. Steady infusions of somatostatin, insulin, and glucose achieve steadystate concentration of glucose and suppress hepatic glucose production
1. Expensive 2. Labor intensive (but less than HEGC) 3. In type 2 diabetes, glucosuria may occur and underestimation of insulin resistance may occur
1. Can be used in larger studies than HEGC, as it is less labor intensive
MMA of FSIVGTTc
1. Instantaneous distribution of infused glucose in a single compartment 2. Glucose is removed from the compartment at a steadily exponential rate 3. Glucose concentration in the compartment is the same at the beginning and the end 4. Insulin is assumed to be in a different compartment compared with glucose 5. Peripheral glucose disposal and suppression of hepatic glucose production are linked and proportional
1. Labor intensive (less than HEGC and IST) 2. Single compartment assumption results in overestimation of glucose and underestimation of insulin. Use of labeled glucose can overcome this limitation to some extent 3. Assumption that hepatic glucose suppression and glucose disposal are linked results in negative values for the calculated serum insulin values in a significant portion of subjects
1. Can be used in large population-based studies, as it is less labor intensive and has good correlation with HEGC
OGTT/MTTd
1. No assumptions—assesses body’s ability to dispose of glucose
1. Does not measure insulin resistance!
1. Many of the “surrogate indices using dynamic tests” use OGTT and MTT (see below)
Indirect sampling
Surrogate indices using steady-state conditions 1/Fasting insulin
1. No assumptions
1. Does not correlate with insulin resistance in individuals with impaired glucose tolerance or diabetes 2. Correlation between this ratio and insulin sensitivity is nonlinear
1. Useful in clinical practice, large clinical trials
Glucose/Insulin
1. Fasting glucose is normal in all individuals (in reality, it is increased in IGT and diabetes)
1. “Fasting glucose/Fasting insulin” correlates well with “1/Fasting insulin’ in subjects without any glucose intolerance. However, given the same fasting insulin levels, this ratio starts increasing and gives erroneous results in subjects with
1. This is a conceptually flawed index 2. Unfortunately, it is the most common index used in many PCOS studies
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Direct sampling
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Table 1 (Continued) Method
Assumptions
Limitations
Use
impaired glucose tolerance compared with normal individuals HOMA-IRe
1. The constant denominator of 22.5 assumes a fasting insulin of 5 μU/mL and fasting glucose of 4.5 mmol/L in a “normal” individual
1. Coefficient of variation varies considerably depending on the type of insulin assay used 2. Not useful in individuals with severely impaired glucose tolerance or diabetes
1. Large clinical trials and epidemiological studies
QUICKIf
1. Same as HEGC
1. None
1. Large epidemiologic studies and clinical trials 2. Most thoroughly validated surrogate index with best correlation with HEGC
1. Same as FSIVGTT and OGTT 2. Relatively more labor intensive and expensive compared with surrogate indices using steady-state conditions
1. Helpful in assessing insulin secretion as well as insulin resistance 2. Large clinical trials and epidemiological studies that require information about insulin secretion as well as resistance
Surrogate indices using dynamic tests Avignon index Belfiore index Gutt index Matsuda index Stumvoll index
1. Dynamic testing incorporates hepatic as well as peripheral insulin action
a
Hyperinsulinemic euglycemic glucose clamp. Insulin suppression test. c Minimal model analysis of frequently sampled intravenous glucose tolerance test. d Oral glucose tolerance test/meal tolerance test. e Homeostasis model assessment of insulin resistance. f Quantitative insulin sensitivity check index. b
profile for inducing weight loss, whereas a slight weight gain has been noted with thiazolidinediones. Metformin seems to be better at reducing low-density lipoprotein (LDL) levels and triglyceride levels. Neither has a favorable effect on elevating HDL levels. Metformin induces diarrhea significantly more often than the thiazolidinediones.20 Although the large, 4year ADOPT trial did not show any difference in congestive heart failure rates with thiazolidinediones, conflicting reports from other trials has led FDA to place a boxed warning for congestive heart failure.20,21 It is important to note that Rosiglitazone has been withdrawn from the market in many countries, although it is still available in the United States. Thiazolidinediones are roughly 10 times more expensive than metformin. Berberine is an isoquinoline alkaloid that has been used in traditional Chinese medicine for many centuries. It is an overthe-counter medication available in many countries including the United States. It has been shown to reduce fasting blood sugar levels and decrease insulin resistance in diabetic rat models by increasing insulin receptor expression.22,23 In addition, it has been shown to improve glucose transport by a mechanism independent of insulin.24 In human studies, Berberine was shown to be as effective as metformin in decreasing fasting blood sugar levels, improving insulin sensitivity, and decreasing HbA1C levels in newly diagnosed type Seminars in Reproductive Medicine
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2 diabetes patients as well as in poorly controlled type 2 diabetes patients.25
Insulin Sensitizers in Polycystic Ovary Syndrome Infertility By definition, anovulation is a key feature of PCOS. The only possible phenotype without anovulation is the hyperandrogenic patient with polycystic-appearing ovaries that is possible if the Rotterdam criteria are used. Because anovulation causes infertility, these patients often present with infertility as the sole complaint. Up to 30% of infertility may be due to PCOS.26 As mentioned earlier, a post-receptor insulin transduction defect is considered as one of the possible underlying causes for anovulation. Metformin therapy has been shown to decrease hyperinsulinemia and insulin resistance.27 Based on this, the practice of treating PCOS women with metformin as a single agent emerged in the 1990s.27 Most of the published studies are not randomized and meta-analysis of these data seemed to suggest that metformin was effective at inducing ovulation.28 Clomiphene citrate, a selective estrogen receptor modulator, has been a key agent used to induce ovulation for many
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decades. However, approximately one in four women are resistant to its ovulation inducing effects and an alternative approach is needed.29 Letrozole, an aromatase inhibitor, may overcome this resistance in up to 50% of these patients and addition of dexamethasone has been shown to be effective as an adjunct in some patients.29 However, the favorite adjunct agent was metformin, which was administered daily to patients resistant to clomiphene. In addition, some patients were prescribed metformin from the outset without any evidence for insulin or clomiphene resistance. The effectiveness of this strategy was not clear until a randomized controlled trial was published in 2007 by the Reproductive Medicine Network (RMN). The RMN network trial conducted in the United States recruited 626 obese PCOS women. The women were treated for six menstrual cycles. The women were divided into three groups for treatment—those who received metformin only, those who received clomiphene only, and the last group received metformin in addition to clomiphene. The use of metformin alone resulted in live-birth in 7.2% of the women as opposed to 22.5% in women taking clomiphene only and 26.8% in women taking both clomiphene and metformin.30 The difference between clomiphene alone and the combined metformin/clomiphene group was not statistically significant. A recent randomized controlled trial from Finland recruited 320 PCOS patients (obese and lean) and used metformin only for 3 months followed by clomiphene or gonadotropins as dictated by clinical need. The cumulative live-birth rate was shown to be higher in the metformin group compared with the placebo group (41.9 vs. 28.8%). When a subgroup analysis was performed, the difference was significant in the obese PCOS patients and not in the thin PCOS patients (49 vs. 31.4%).31 A Cochrane review was published soon after the publication of the Finnish study. Unfortunately, the Finnish study was not included in the Cochrane analysis that reviewed 44 studies. The majority of the studies included in that analysis were on metformin and its effect on fertility. A total of 3,495 women from 38 trials were included in the analysis comparing metformin with placebo or clomiphene. The conclusion of the analysis was that metformin does not improve live-birth rates either as a single agent or in combination with clomiphene.32 However, improved clinical pregnancy rate was noted in the metformin and clomiphene group versus clomiphene-only group. The remaining trials included in the Cochrane analysis studied Rosiglitazone, Pioglitazone, or Dchiro-Inositol and did not show any advantages to improving live-birth rate in PCOS patients. Currently, a multicenter randomized trial comparing letrozole with and without the addition of Berberine is being conducted in China.33 The use of insulin sensitizers in PCOS patients undergoing gonadotropin therapy for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment cycles has been studied extensively. A recent meta-analysis of 10 randomized controlled trials concluded that metformin use does not increase live-birth rates in these patients.34 However, subgroup analysis revealed certain potential advantages. Use of metformin decreased miscarriage rates and this decrease was
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more marked with longer pretreatment use, higher dosage, and delaying the discontinuation of metformin. Another surprising finding was the 70% decrease in the incidence of OHSS in women taking metformin. One randomized trial comparing Berberine with metformin and placebo has been published.35 One hundred and fifty women with PCOS undergoing IVF/ICSI treatment cycles were pretreated for 3 months with Berberine, metformin, or placebo. The live-birth rates were 48.6% in the Berberine group, 36.8% in the metformin group, and 20.6% in the placebo group. The OHSS rate was 5.4, 5.3, and 17.6%, respectively, in these groups. Further randomized trials are needed to confirm that Berberine can be advantageous in PCOS patients undergoing IVF/ICSI treatment cycles. In summary, the strength of evidence from multiple trials seems to indicate no improvement in live-birth by addition of insulin sensitizers for ovulation induction cycles or for IVF/ ICSI cycles. There may be an advantage to using metformin in patients at risk for OHSS. Berberine is recently being studied for use in infertility patients and more evidence from randomized trials is needed.
Nonfertility-Related Long-Term Care Women with PCOS are at risk for menstrual irregularity, endometrial cancer, impaired glucose tolerance, type 2 diabetes, cardiovascular risk factors, anxiety, depression, poor self-perception, and reduced health-related quality of life.36–39 Metformin was inferior to oral contraceptive pills in regularizing the menstrual cycle in women with PCOS based on meta-analysis of six randomized trials.40 There is no evidence for reduction in uterine cancer risk using oral contraceptive pills or insulin sensitizers. Although much concern has been expressed about the higher prevalence of cardiovascular risk factors in women with PCOS, very little evidence exists for higher morbidity and mortality related to cardiovascular events in these women.40–43 It is possible that as women age, those without PCOS develop the cardiovascular risk factors and catch up with the risks faced by PCOS women.42,44 As a result, we currently do not have any evidence in favor of long-term use of insulin-sensitizing agents to improve cardiovascular morbidity and mortality in these women. The use of insulin-sensitizing agents in PCOS women should be guided by the guidelines for the treatment of impaired glucose tolerance or type 2 diabetes in women without PCOS.19,45 There is currently no evidence that use of insulin-sensitizing agents decreases the incidence of endometrial cancer or psychological disorders. Adolescents are a special group in which the diagnosis of PCOS can be challenging.46 Use of metformin in this group can restore regular menstrual cycles and decreases hirsutism.43 These results, however, are not consistently seen across randomized trials.47 One recent trial in a group of Catalan adolescents with a history of precocious puberty combined pioglitazone, flutamide, and metformin (PioFluMet) and administered to adolescent thin PCOS girls with hyperandrogenism and menstrual irregularity and compared it with oral contraceptive pills. The effect on the regularization of menses Seminars in Reproductive Medicine
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was similar. However, the PioFluMet-treated girls were more likely to have regular menses and had lower insulin levels.48 Racial and ethnic differences in the incidence of PCOS have been noted.49 However, no specific ethnic difference in response to insulin-sensitizing agents has been noted. In summary, there is currently no evidence to support the use of insulin-sensitizing agents to counter possible longterm morbidity and mortality associated with metabolic disturbances noted in women with PCOS. More trials are needed in adolescent girls to establish a role for insulin sensitizers.
13 Ferriman D, Purdie AW. The inheritance of polycystic ovarian
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Conclusion Insulin resistance is present in a subgroup of patients with PCOS. QUICKI is the best surrogate method to evaluate insulin resistance in PCOS patients, although its clinical value is uncertain. Routine use of insulin sensitizers in patients undergoing ovulation induction with oral agents or with gonadotropins for IVF does not increase the live-birth rates. A subgroup of patients may benefit from decreased incidence of OHSS. The value of insulin sensitizers in decreasing longterm cardiovascular morbidity remains to be established.
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Vol. 32
No. 4/2014
329
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Metformin and Other Insulin Sensitizers in PCOS
