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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 11 5137-5144
Copyright © 2003 by The Endocrine Society

Minimal Response of Circulating Lipids in Women with Polycystic Ovary Syndrome to Improvement in Insulin Sensitivity with Troglitazone

Richard S. Legro, Ricardo Azziz, David Ehrmann, Anita Gmerek Fereshetian, Mary O’Keefe and Mahmoud N. Ghazzi for the PCOS/Troglitazone Study Group

Department of Obstetrics and Gynecology, Pennsylvania State University (R.S.L.), Hershey, Pennsylvania 17033; Department of Obstetrics and Gynecology, Cedars Sinai Hospital (R.A.), Los Angeles, California 90048; Department of Medicine, University of Chicago Medical Center (D.E.), Chicago, Illinois 60637; and Pfizer Pharmaceutical Research (A.G.F., M.O., M.N.G.), Ann Arbor, Michigan 48105

Address all correspondence and requests for reprints to: Richard S. Legro, M.D., C3608, Department of Obstetrics and Gynecology, H103, Pennsylvania State University College of Medicine, M. S. Hershey Medical Center, 500 University Drive, Hershey, Pennsylvania 17033. E-mail: rsl1{at}psu.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We hypothesized that the administration of troglitazone (TGZ), an insulin-sensitizing agent of the thiazolidinedione class, would improve dyslipidemia associated with insulin resistance in polycystic ovary syndrome (PCOS). Three hundred and ninety-eight women with PCOS in a multicenter, double-blind trial were randomly assigned to 44 wk of treatment with: placebo or troglitazone (150, 300, or 600 mg/d). We examined the responses of circulating lipid and lipoproteins [total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), and triglycerides (TTG)] by treatment arm, and the influence of glycemic parameters on baseline levels and response to treatment. There was a high prevalence of abnormal baseline lipid parameters, as defined by National Cholesterol Education Program guidelines [total cholesterol, >=200 mg/dl (35%); LDL-C, >=130 mg/dl (31%); HDL-C, <35 mg/dl (15%); TTG, >200 mg/dl (16%)]. Baseline models showed that parameters of insulin action had poor predictive power on lipid parameters. There was no significant response of any of the circulating lipids to treatment with either placebo or one of the troglitazone arms (after correction for multiple analyses). There were favorable, but nonsignificant, trends in HDL-C (increase) and LDL-C (decrease) and a trend toward decreased circulating TTG in the 300- and 600-mg TGZ dose treatment arms, both in an intention to treat analysis (n = 375) and in study completers (44 wk; n = 152). There also was a minimal treatment effect noted when only subjects with abnormal baseline levels were examined, and responders differed little from nonresponders in terms of indices of insulin action. There is a substantial prevalence of clinically recognized dyslipidemia in the population of women with unrecognized PCOS without type 2 diabetes. Treatment with an insulin-sensitizing agent may have minimal impact on circulating lipids. Further surveillance and treatment of abnormal lipid levels may be necessary in these women.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is a common and heterogeneous disorder characterized by unexplained androgen excess and oligoovulation. The fundamental pathophysiological defect in PCOS is unknown, but women with PCOS often demonstrate insulin resistance, which results in compensatory hyperinsulinemia (1, 2, 3). Hyperinsulinemia, in turn, leads to increased blood levels of androgens because of the effects of insulin to lower SHBG production (4) and increase ovarian androgen secretion (5, 6, 7). In addition to the association of hyperinsulinemia and insulin resistance with the reproductive disorders that characterize PCOS, a number of metabolic abnormalities have also been associated with insulin resistance. The insulin resistance syndrome has been characterized by glucose intolerance, hypertension, and dyslipidemia (8).

The focus of our study is circulating lipids. Insulin resistance per se has been associated with decreased high density lipoprotein cholesterol (HDL-C) levels and elevated triglyceride (TTG) levels (8), and this pattern of dyslipidemia has frequently been found in PCOS (9, 10, 11). Dyslipidemia is common in women with PCOS, although the extent and type of dyslipidemia have been variable (12). Low density lipoprotein cholesterol (LDL-C) elevations have been reported in several studies of women with PCOS (13, 14, 15, 16), a finding not usually noted in insulin-resistant states, suggesting a heterogeneous origin for the dyslipidemia in these women.

Recently we reported that use of the insulin-sensitizing agent troglitazone (TGZ) in a randomized, double-blind, dose-ranging study resulted in a significant dose-response improvement in ovulation and circulating hyperandrogenemia (as determined by free testosterone levels) and, at the highest dose of troglitazone, a significant improvement in hirsutism (17). These changes were accompanied by significant improvements in basal and glucose-challenged circulating insulin levels. In other insulin-resistant populations, improvement in insulin sensitivity with troglitazone has resulted in improvement in dyslipidemia (18, 19, 20).

We theorized that if insulin resistance was central to the etiology of the dyslipidemia associated with the syndrome, then the dose-response improvement in insulin sensitivity would result in corresponding improvements in circulating lipid levels. This was a predetermined secondary parameter of the study. The primary efficacy parameters, as reported in our previous paper, were the incidence of ovulation and the change in unbound testosterone levels (17).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Of the 782 premenopausal women with suspected PCOS who were screened for this study, 410 patients qualified and were randomized to double-blind treatment in a multicenter trial. Of these we have baseline lipid levels after randomization for 398 subjects. Of these, 375 (91%) patients completed the study sufficiently to meet evaluability criteria (at least 1 follow-up lipid analysis at >=4 wk; see below). For the purposes of this study, PCOS was diagnosed by the presence of 1) chronic ovulatory dysfunction, defined as intermenstrual intervals of 45 d or longer or a total of fewer than 8 menses/yr; 2) hyperandrogenemia, defined as a serum level of free testosterone greater than the upper normal limit in the central laboratory used in this study (i.e. >=6.3 pg/ml); and 3) the exclusion of other disorders, such as nonclassic adrenal hyperplasia, as previously described (21). These diagnostic (i.e. inclusion) criteria for PCOS are consistent with the suggestions arising from a preliminary consensus conference sponsored by the NICHD, NIH, in April 1990 (22).

Other exclusionary criteria included unresolved medical conditions, hysterectomy and/or oophorectomy, type 1 or type 2 diabetes mellitus, significant cardiovascular disease, active cancer within the past 5 yr, and participation in another investigational study within the past 30 d. The use of medications known or suspected to affect reproductive or metabolic functions within 60 d of study entry was prohibited. This study was approved by and conducted according to the guidelines of the institutional review boards of each of the 30 participating centers. All subjects provided written informed consent.

Study protocol

After a 2-wk baseline evaluation, eligible patients were randomized in a double-blind fashion to one of the following treatment groups: placebo or TGZ [150 mg/d (TGZ-150), 300 mg/d (TGZ-300), or 600 mg/d (TGZ-600)]. Parke-Davis Pharmaceutical Research, Inc. (Detroit, MI; the sponsor of the study), provided the medication. Patients were asked to follow a weight maintenance diet throughout the study to minimize the effect of weight loss on the disease state.

Patients returned for assessment of circulating lipids 4 wk after the start of the double-blind, randomized phase and every 8 wk thereafter (wk 4–44). The assessment of serum lipids thus was performed at multiple time points (0, 4, 12, 20, 28, 36, and 44 wk) throughout the study (see Fig. 1Go). An oral glucose tolerance test (OGTT) was performed at wk 0 and 20 and at the completion of the study. For the OGTT, blood samples were obtained at -10, 0, 30, 60, 90, and 120 min after the oral ingestion of 75 g glucose.



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  		FIG. 1. Mean levels of circulating lipids, total cholesterol, HDL-C, and TTG and the number of women present in the study (see table) at varying time points in the study. To convert lipid values to Systeme International units (millimoles per liter), multiply the value (milligrams per deciliter) by 0.02586.

 
Data evaluability

Efficacy analyses for measures of circulating lipids and all secondary parameters were performed on the intent to treat (ITT) patient population. The ITT population was defined as any patient randomized to treatment with a baseline visit and at least one follow-up measurement (at 4 wk or later). Patients who withdrew or were withdrawn before completing the study were included in the ITT analysis using the last observation carried forward rule. As reported previously, the principal reasons for patients not completing at least 40 wk of the study were early termination of the study by the sponsor (range, 11.5–19.8%/treatment arm of number initially randomized) and lack of compliance (range, 5.0–13.6%) (17). The percentage of patients withdrawing from the study due to adverse events ranged from 4–7%; this was not different between treatment arms (17). The reason for early termination by the sponsor of this study was due to withdrawal of TGZ from the market in March 2000 (23). We also report on the subset of patients who completed at least 40 wk of the study, defined as study completers, to better illustrate the prolonged effects of treatment as well as to answer concerns about bias that noncompletion may have introduced into the results.

Statistical analysis

Primary treatment comparisons were those between each TGZ treatment arm and placebo. Baseline was defined as the measurement taken at wk 0. The change from baseline in each lipid parameter was calculated as the follow-up measurement minus baseline. Tests were two-sided and conducted at {alpha} = 0.05. In general, the method used for the analysis was analysis of covariance, with treatment and center in the model and baseline as the covariates for all parameters. Means were adjusted for center and baseline differences (see Tables 2Go and 3Go). All P values reported from the analyses of covariance and ANOVAs are from stepdown trend tests via contrast statements.


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  		TABLE 2. Adjusted mean change (milligrams per deciliter) at the end of the study in women with PCOS according to treatment arm for subjects with at least one follow-up level (ITT analysis)

 

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  		TABLE 3. Adjusted mean change (milligrams per deciliter) at the end of the study in women with PCOS according to treatment arm for study completers (>=40 wk)

 
We performed further post hoc analyses of these data, including analysis of the response for subjects with elevated levels of baseline circulating lipids by National Cholesterol Education Program (NCEP) criteria (see above) by treatment arm. Response was defined as a return to normal levels by NCEP criteria by the end of study measure. Nonresponse was defined as persistently elevated levels by NCEP criteria. We used {chi}2 tests to compare percent response by treatment arm and uncorrected t tests to compare baseline variables between responders and nonresponders.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline data

As previously reported (17), there were no significant differences in baseline features, including race, age, body mass index, waist/hip ratio, percent smoking, and number of self-reported menstrual cycles in the 12 months before the study. There were no differences between baseline lipid and lipoprotein levels according to treatment arm (Table 1Go). The mean values were all within normal levels as defined by the NCEP (24). We identified the prevalence of abnormalities according to the categorical NCEP criteria (borderline total cholesterol, 200–239 mg/dl; borderline LDL-C, 130–159 mg/dl; borderline TTG, 200–399 mg/dl; high total cholesterol >=240 mg/dl; abnormal HDL-C, < 35 mg/dl; high LDL-C >=160 mg/dl; high TTG >=400 mg/dl) (24). These prevalences are also found in Table 1Go both by treatment arm and as a cohort.


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  		TABLE 1. Baseline lipid values in women with PCOS according to treatment arm and as a cohort

 
A multivariable linear regression model was fit to assess the predictive strength of various factors on circulating baseline lipid levels (n = 398). The predictive variables entered in the model were treatment group, age, body mass index, waist/hip ratios, fasting and 2-h glucose, fasting and 2-h insulin levels, and area under the curve (AUC) for glucose and insulin during the baseline OGTT. Only age was significantly associated with all lipid parameters. For every 1-yr increase in age, there was a 1.5 mg/dl increase [95% confidence interval (CI), 0.9–2.1 mg/dl; P = 0.0001] in total cholesterol, a 1.1 mg/dl increase (95% CI 0.5–1.6 mg/dl, P = 0.0001) in LDL-C, a 0.3 mg/dl increase (95% CI, 0.04–0.5 mg/dl; P = 0.016) in HDL-C, and a 1.7 mg/dl increase (95% CI, 0.4–3.1 mg/dl; P = 0.0001) in TTG. Body mass affected only HDL-C levels, and fat distribution impacted on both HDL-C and TTG levels. For every 1-U increase in body mass index, there was a 0.4 mg/dl decrease (95% CI, -0.2 to -0.5 mg/dl; P = 0.0001) in HDL-C. For every 0.1-U increase in the waist/hip ratio, there was a 2.2 mg/dl decrease in HDL-C levels (95% CI, -0.7 to -3.7 mg/dl; P = 0.001) and a 24.7 mg/dl increase (95% CI, 15.6–33.7 mg/dl; P = 0.001) in TTG levels. Glycemic parameters (AUC glucose or AUC insulin) were only correlated with cholesterol and its lipoprotein components. For every 1-U increase in AUC glucose, there was a 0.4 mg/dl increase (95% CI, 0.2–0.7 mg/dl; P = 0.002) in total cholesterol. For every 10-U increase in AUC insulin, there was a 0.5 mg/dl decrease (95% CI, -0.1 to -0.9 mg/dl; P = 0.02) in HDL-C and a 0.2 mg/dl increase in LDL-C (95% CI, 0.1–0.3 mg/dl; P = 0.0002). However, the low r2 of our models suggests that there are other factors that impact on these lipid levels (total cholesterol, 0.09; HDL-C, 0.17; LDL-C, 0.07; TTG, 0.08).

Response to treatment

All subjects. There was no significant response of any lipid parameter to treatment with either placebo or one of the TGZ arms (after correction for multiple analyses; Table 2Go). There were favorable, but nonsignificant, trends in HDL-C (increase) and LDL-C (decrease). There was a trend toward decreased circulating TTG in the 300- and 600-mg dose treatment arms (with a modestly significant P value in the 300-mg dose arm). Because the early termination by the sponsor of the study in addition to the other reasons for drop-outs from the study may have affected our results, we examined the effects of treatment in those who completed the study (defined as completing 40–44 wk; Table 3Go). There were no significant improvements at any of the doses. Further time of exposure to troglitazone appears to have minimal effects on circulating lipids based on the mean results reported from different time points in the study (Fig. 1Go), although we did not perform tests of significance at these earlier time points.

Baseline abnormal lipid levels. We then examined the response rate in those women who had elevated lipid parameters according to NCEP criteria at baseline (see cut-offs and percent increases/decreases from baseline lipid levels in Table 1Go) using all subjects who had a baseline level and at least one follow-up level. Response was defined as a return of abnormal baseline levels to the normal range as defined by the NCEP Criteria reported above. We did not examine HDL-C response rates for several reasons, including the low prevalence of abnormal baseline values due to NCEP criteria (<15%) and the corresponding small numbers in individual treatment arms. For the other parameters, total cholesterol, LDL-C, and TTG, the range of response was 25–53%, with no difference between TGZ treatment arms and placebo, without a clear dose-response effect (Table 4Go). The best response rate was in the circulating TTG levels in the highest TGZ treatment arm of 53%. There were, however, no significant differences in the response rate between the placebo arm and the treatment arm for any lipid parameter.


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  		TABLE 4. Response rate (percentage) of women with PCOS with abnormal baseline lipid levels by NCEP guidelines by treatment arm (based on ITT analysis)

 
We further examined responders and nonresponders within this group of abnormal baseline NCEP parameters (combining all treatment arms including placebo) for differences in baseline levels for a variety of biometric and biochemical parameters. These baseline parameters included age, body mass index, waist/hip ratio, and glucose and insulin levels (fasting, 2 h during OGTT, and AUC values) or hemoglobin A1c levels, and lipid levels (Table 5Go). There were no significant differences between mean values of responders and nonresponders for the biometric variables, and only AUC insulin was significantly elevated in total cholesterol nonresponders, a difference not noted in the LDL-C and TTG groups. There was a more consistent pattern among baseline lipids, with responders displaying lower mean baseline levels than nonresponders (Table 5Go).


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  		TABLE 5. Comparison of mean baseline variables in women with PCOS with abnormal baseline variables who responded with conversion to normal lipid levels for that variable by the end of the study (combined treatment groups) or did not convert to normal (nonresponder)

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our study demonstrates that improving insulin sensitivity in women with PCOS has a minimal effect on circulating lipid levels. Further, the etiology of dyslipidemia in this population appears to be minimally influenced by the improvement in parameters of glycemic action noted (17). This suggests that although there are multiple benefits to improving insulin sensitivity in women with PCOS, such as increased ovulatory frequency, decreased circulating bioavailable androgens, and improved hirsutism (17), there may not be global improvement in all metabolic abnormalities associated with the syndrome. Other, as of yet unrecognized factors, may be important to the development of other stigmata of PCOS. Thus, dyslipidemia in PCOS, much like PCOS, is a heterogeneous disorder.

The strength of our study is that the results were obtained from a well designed, multicenter trial in a large representative sample of the U.S. population of women with PCOS. In fact, in terms of sample size, this trial is the largest to date of lipid levels in women with PCOS and of treatment-related effects of an insulin-sensitizing agent. There are multiple caveats, however, to our findings. Changes in lipids were a secondary outcome of the trial, and the trial was not powered to detect small improvements in circulating lipids. Thus, given the minimal effects on circulating lipids detected, our study is underpowered and suffers from a potential type II error. Thus, an adequately powered trial may have found a significant beneficial lipid effect. The results of this trial may help to guide future trials in which this is an outcome of interest. In fact, such a trial may involve thousands of women with PCOS depending on the lipid parameter chosen. For instance, the large variability seen in serum TTG among the subjects of this trial would significantly elevate the sample size required to detect clinically important differences in TTG. This large variation in TTG at baseline has been noted in other large studies of circulating lipids in women with PCOS (11, 15, 16), and does not appear to be related to treatment compliance or the dropout experienced in our population. There are a number of confounding factors known to affect circulating lipid and lipoprotein levels, including exercise, smoking, alcohol use, and differences in diet and ethnicity (25, 26, 27, 28), that we did not address. There was also a nonsignificant trend toward weight gain by treatment dose during the study, which may have mitigated the effects on lipids (17).

The study was stopped prematurely, and only a minority of the subjects (40%) completed the full 44-wk trial. If the full cohort had continued the trial, there may have been further, and potentially significant, changes in circulating lipids. Thus, bias due to the overall low completion rate may have affected the results. We, however, believe that the low completion rate had little impact on the results of this study. First, the primary reason for the low completion rate was termination by the sponsor and not adverse events or failure to comply with treatment or protocol. Second, we noted no difference in mean lipids over the course of the study, documented with measures at 4- to 8-wk intervals. Third, we noted no differences when we performed an ITT analysis of efficacy in all subjects with at least 1 follow-up lipid level compared with the analysis that examined study completers only. Finally, if we only consider the completers only, this group of 152 women who completed 44 wk of treatment with an insulin-sensitizing agent still represents the largest such study to date in women with PCOS.

Our criteria for the diagnosis of PCOS, unexplained hyperandrogenic chronic anovulation, may have identified a heterogeneous population, of which only a fraction were significantly insulin resistant and/or suffering from dyslipidemia. PCOS and the insulin resistance syndrome overlap, but are not identical (29). Selection bias, based on our diagnostic criteria and exclusion criteria, may have removed subjects from the study who were most likely to benefit from the improvement of insulin sensitivity. This is supported by the normal mean baseline lipid levels as well as a predominance of normal levels (>50%) for any single lipid parameter based on NCEP criteria. Subjects with type 2 diabetes were excluded from the study, and they appear to benefit the most from thiazolidinediones, with treatment-related elevations in HDL-C and lowering of TTG (20). Similarly in our study, despite the small sample size, the highest response rate of an abnormal baseline level was with circulating TTG at the highest TGZ dose (we did not examine the HDL-C response).

However, our findings are not unprecedented. In another insulin-resistant, nondiabetic female population (those with a history of gestational diabetes), there was also no change in the lipid profile with TGZ treatment (30). Other insulin-sensitizing agents, such as metformin, have displayed only modest improvements in dyslipidemia (31) or, more commonly, no effect in women with PCOS (32, 33, 34) despite improvements in insulin sensitivity (32, 34). Therefore, in terms of dyslipidemia, a more severely affected population may receive a greater benefit from improvements in insulin sensitivity.

This does not appear to be the case with other outcomes of interest in the study where responders tended to have a milder phenotype. For instance, those most likely to respond to TGZ with increased ovulatory frequency were thinner and had lower baseline insulin levels (17). Similarly, in this present study responders were likely to have more normal baseline lipid levels than nonresponders.

The argument that we did not detect a significant benefit because the majority were normal at baseline did not hold for other metabolic parameters, which were largely normal at baseline. For instance, fasting glucose and hemoglobin A1c levels responded with a dose-response decrease to TGZ (17), although these changes were arguably closer to the mechanism of TGZ action in improving the PCOS phenotype (i.e. improving insulin sensitivity).

The minimal response to this action is predicted by our model of predictive factors on baseline lipid values. We examined a number of parameters associated with insulin sensitivity and found that they had a poor predictive value for determining the baseline circulating lipid levels. Hyperinsulinemia was only nominally associated with circulating levels of HDL-C and LDL-C, with no association with TTG. Although hyperinsulinemia secondary to insulin resistance has been significantly associated with lipid and lipoprotein abnormalities in women with PCOS in a number of studies (9, 10, 35), others have also found only minimal effects on circulating lipid levels (11, 16, 36, 37). When we examined baseline parameters of end of study responders (based on reversion to normal NCEP lipid levels), we found minimal effects of baseline fasting or stimulated glucose or insulin levels for the lipid parameters we examined, including TTG, which had the highest percent response. Although we note that such post hoc analyses of secondary data in subgroups should be viewed cautiously. The net effect of these data, however, suggests that the etiology of dyslipidemia in PCOS is both complex and heterogeneous, and it is simplistic to view hyperinsulinemia as the culprit (at least as detected by our conventional measures).

Our study holds important consideration for the clinical management of women with PCOS. The high percentage of baseline abnormal NCEP lipid levels in women with PCOS is comparable to that in another recent study (16). There is a substantial prevalence of clinically unrecognized dyslipidemia in the population of women with PCOS who do not have type 2 diabetes. Therefore, screening with a fasting lipid profile is indicated and is a high yield test for detecting clinically important abnormalities. Treatment with an insulin-sensitizing agent in women with PCOS may have minimal impact on lipids as a cardiovascular risk factor. Therefore, it should not be assumed that this treatment alone suffices to treat dyslipidemia in women with PCOS, and further surveillance and treatment of abnormal lipid levels may be necessary.


   Footnotes
 
This work was supported by a grant from Parke-Davis Pharmaceutical Research, Inc.

* In addition to the authors the following investigators participated in the PCOS/Troglitazone Study Group: Stephen Aronoff (Dallas, TX), Richard Bernstein (Greenbrae, CA), Donald Bodenner (Rochester, NY), Susan Braithwaite (Chicago, IL), Joshua Cohen (Washington, D.C.), David DePaolo (Boulder, CO), Daniel Einhorn (San Diego, CA), Jennifer Hone (Arvada, CO), Anne Kenshole (Toronto, Canada), Charles Kilo (St. Louis, MO), Siri Linda Kjos (Los Angeles, CA), Mary Korytkowski (Pittsburgh, PA), Diane Koster (Albuquerque, NM), Rebecca Lau (Indianapolis, IN), Rogerio Lobo (New York, NY), Jean Lucas (Atlanta, GA), Kathryn Martin (Boston, MA), William Meyer (Chapel Hill, NC), Sumer Pek (Ann Arbor, MI), Samantha Pfeifer (Philadelphia, PA), Robert Rebar (Cincinnati, OH), Geoffrey Redmond (Cleveland, OH), Roger Rittmaster (Halifax, Canada), Peter Ross (Fairfax, VA), Sherwyn Schwartz (San Antonio, TX), Robert Wild (Oklahoma City, OK), and Samuel Yen (La Jolla, CA).

Abbreviations: AUC, Area under the curve; CI, confidence interval; HDL-C, high density lipoprotein cholesterol; ITT, intent to treat; LDL-C, low density lipoprotein cholesterol; NCEP, National Cholesterol Education Program; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; TGZ, troglitazone; TTG, triglycerides.

Received January 9, 2003.

Accepted July 19, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Dunaif A 1997 Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 18:774–800[Abstract/Free Full Text]
  2. Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA 1992 Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 167:1807–1812[Medline]
  3. Dunaif A, Segal KR, Futterweit W, Dobrjansky A 1989 Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38:1165–1174[Abstract]
  4. Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, Clore JN, Blackard WG 1991 A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 72:83–89[Abstract]
  5. Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Ryan KJ 1986 Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 62:904–910[Abstract]
  6. Willis D, Franks S 1995 Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the type-I insulin-like growth factor receptor. J Clin Endocrinol Metab 80:3788–3790[Abstract]
  7. Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N, Medina F 1998 Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 83:2001–2005[Abstract/Free Full Text]
  8. Reaven GM 1988 Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37:1595–1607[Abstract]
  9. Wild RA, Painter PC, Coulson PB, Carruth KB, Ranney GB 1985 Lipoprotein lipid concentrations and cardiovascular risk in women with polycystic ovary syndrome. J Clin Endocrinol Metab 61:946–951[Abstract]
  10. Conway GS, Agrawal R, Betteridge DJ, Jacobs HS 1992 Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol (Oxf) 37:119–125[Medline]
  11. Talbott E, Guzick D, Clerici A, Berga S, Detre K, Weimer K, Kuller L 1995 Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterio Thromb Vasc Biol 15:821–826[Abstract/Free Full Text]
  12. Legro RS 2003 Polycystic ovary syndrome and cardioivascular disease: a premature association? Endocr Rev 24:302–312[Abstract/Free Full Text]
  13. von Eckardstein S, von Eckardstein A, Bender HG, Schulte H, Assmann G 1996 Elevated low-density lipoprotein-cholesterol in women with polycystic ovary syndrome. Gynecol Endocrinol 10:311–318[Medline]
  14. Talbott E, Clerici A, Berga SL, Kuller L, Guzick D, Detre K, Daniels T, Engberg RA 1998 Adverse lipid and coronary heart disease risk profiles in young women with polycystic ovary syndrome: results of a case-control study. J Clin Epidemiol 51:415–422[CrossRef][Medline]
  15. Mather KJ, Kwan F, Corenblum B 2000 Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity. Fertil Steril 73:150–156[CrossRef][Medline]
  16. Legro RS, Kunselman AR, Dunaif A 2001 Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med 111:607–613[CrossRef][Medline]
  17. Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, O’Keefe M, Ghazzi MN, PCOS/Troglitazone Study Group 2001 Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 86:1626–1632[Abstract/Free Full Text]
  18. Antonucci T, Whitcomb R, McLain R, Lockwood D, Norris RM 1997 Impaired glucose tolerance is normalized by treatment with the thiazolidinedione troglitazone. Diabetes Care 20:188–193[Abstract]
  19. Tack CJ, Smits P, Demacker PN, Stalenhoef AF 1998 Troglitazone decreases the proportion of small, dense LDL and increases the resistance of LDL to oxidation in obese subjects. Diabetes Care 21:796–799[Abstract]
  20. Ghazzi MN, Perez JE, Antonucci TK, Driscoll JH, Huang SM, Faja BW, Whitcomb RW 1997 Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group. Diabetes 46:433–439[Abstract]
  21. Azziz R, Hincapie LA, Knochenhauer ES, Dewailly D, Fox L, Boots LR 1999 Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study. Fertil Steril 72:915–925[CrossRef][Medline]
  22. Zawadski JK, Dunaif A 1992 Diagnostic criteria for polycystic ovary syndrome; towards a rational approach. In: Dunaif A, Givens JR, Haseltine F, Merriam GM, eds. Polycystic ovary syndrome. Boston: Blackwell Scientific; 377–384
  23. Azziz R, Ehrmann DA, Legro RS, Fereshetian AG, O’Keefe M, Ghazzi MN 2001 Authors’ response: troglizone use in polycystic ovary syndrome. J Clin Endocrinol Metab 86:5090–5091[Free Full Text]
  24. Anonymous 1993 Summary of the second report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). JAMA 269:3015–3023[CrossRef][Medline]
  25. Clevidence BA, Reichman ME, Judd JT, Muesing RA, Schatzkin A, Schaefer EJ, Li Z, Jenner J, Brown CC, Sunkin M 1995 Effects of alcohol consumption on lipoproteins of premenopausal women. A controlled diet study. Arterio Thromb Vasc Biol 15:179–184[Abstract/Free Full Text]
  26. Wei M, Mitchell BD, Haffner SM, Stern MP 1996 Effects of cigarette smoking, diabetes, high cholesterol, and hypertension on all-cause mortality and cardiovascular disease mortality in Mexican Americans. The San Antonio Heart Study. Am J Epidemiol 144:1058–1065[Abstract/Free Full Text]
  27. Mitchell BD, Stern MP, Haffner SM, Hazuda HP, Patterson JK 1990 Risk factors for cardiovascular mortality in Mexican Americans and Non-hispanic Whites. San Antonio Heart Study. Am J Epidemiol 131:423–433[Abstract/Free Full Text]
  28. Turley ML, Skeaff CM, Mann JI, Cox B 1998 The effect of a low-fat, high-carbohydrate diet on serum high density lipoprotein cholesterol and triglyceride. Eur J Clin Nutr 52:728–732[CrossRef][Medline]
  29. Korhonen S, Hippelainen M, Niskanen L, Vanhala M, Saarikoski S 2001 Relationship of the metabolic syndrome and obesity to polycystic ovary syndrome: a controlled, population-based study. Am J Obstet Gynecol 184:289–296[CrossRef][Medline]
  30. Berkowitz K, Peters R, Kjos SL, Goico J, Marroquin A, Dunn ME, Xiang A, Azen S, Buchanan TA 1996 Effect of troglitazone on insulin sensitivity and pancreatic ß-cell function in women at high risk for NIDDM. Diabetes 45:1572–1579[Abstract]
  31. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, Zanolin E, Muggeo M 2000 Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 85:139–146[Abstract/Free Full Text]
  32. Velazquez EM, Mendoza SG, Wang P, Glueck CJ 1997 Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 46:454–457[CrossRef][Medline]
  33. Acbay O, Gundogdu S 1996 Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril 65:946–949[Medline]
  34. Morin-Papunen LC, Koivunen RM, Ruokonen A, Martikainen HK 1998 Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril 69:691–696[CrossRef][Medline]
  35. Slowinska-Srzednicka J, Zgliczynski S, Wierzbicki M, Srzednicki M, Zgliczynski W, Soszynski P, Chotkowska E, Sadowski Z 1991 The role of hyperinsulinemia in the development of lipid disturbances in nonobese and obese women with the polycystic ovary syndrome. J Endocrinol Invest 14:569–575[Medline]
  36. Robinson S, Henderson AD, Gelding SV, Kiddy D, Niththyananthan R, Richmond W, Johnston DG, Franks S 1996 Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries. Clin Endocrinol (Oxf) 44:277–284[CrossRef][Medline]
  37. Legro RS, Blanche P, Krauss RM, Lobo RA 1999 Alterations in low-density lipoprotein and high-density lipoprotein subclasses among Hispanic women with polycystic ovary syndrome: influence of insulin and genetic factors. Fertil Steril 72:990–995[CrossRef][Medline]



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