(Circulation. 2001;103:1410.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Polycystic Ovary Syndrome Is Associated With Endothelial Dysfunction
From the Department of Medicine, Indiana University School of Medicine (G.P., H.O.S., A.H., J.C., G.H., M.K.S., A.D.B.), and the Richard L. Roudebush Veterans Affairs Medical Center (A.D.B.), Indianapolis, Ind.
Correspondence to Alain D. Baron, MD, Indiana University School of Medicine, 541 N Clinical Dr, CL 459, Indianapolis, IN 46202-5111. E-mail abaron{at}iupui.edu
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Abstract |
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Background—We recently reported endothelial dysfunction as a novel cardiovascular risk factor associated with insulin resistance/obesity. Here, we tested whether hyperandrogenic insulin-resistant women with polycystic ovary syndrome (PCOS) who are at increased risk of macrovascular disease display impaired endothelium-dependent vasodilation and whether endothelial function in PCOS is associated with particular metabolic and/or hormonal characteristics.
Methods and Results—We studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (MCh) and to euglycemic hyperinsulinemia in 12 obese women with PCOS and in 13 healthy age- and weight-matched control subjects (OBW). LBF increments in response to MCh were 50% lower in the PCOS group than in the OBW group (P<0.01). Euglycemic hyperinsulinemia increased LBF above baseline by 30% in the PCOS and 60% in OBW group (P<0.05 between groups). Across all subjects, the maximal LBF response to MCh exhibited a strong inverse correlation with free testosterone levels (r=-0.52, P<0.007). This relationship was stronger than with any other parameter, including insulin sensitivity.
Conclusions—PCOS is characterized by (1) endothelial dysfunction and (2) resistance to the vasodilating action of insulin. This endothelial dysfunction appears to be associated with both elevated androgen levels and insulin resistance. Given the central vasoprotective role of endothelium, these findings could explain, at least in part, the increased risk for macrovascular disease in women with PCOS.
Key Words: blood flow • insulin • glucose • nitric oxide • hormones
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Introduction |
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We recently reported that obese insulin-resistant subjects, as a group, are characterized by impaired insulin-mediated vasodilation,1 reduced vasodilation to the endothelium-dependent vasodilator methacholine chloride (MCh), and blunting of the effect of insulin to enhance endothelium-dependent vasodilation.2 The contribution of endothelial dysfunction to the increased risk of atherosclerosis and cardiovascular disease in insulin-resistant subjects has been discussed extensively.2 3 Interestingly, on closer analysis of our data,1 we observed that obese women (OBW), in contrast to obese men, display endothelial function (MCh-induced vasodilation) that is similar to that of lean men.4 These sex differences suggested that sex hormones could modulate endothelial function. This hypothesis is consistent with epidemiological and experimental reports describing a protective effect of female hormonal patterns on the macrovasculature. Cardiovascular events are less prevalent in premenopausal women and in women receiving estrogen replacement than in postmenopausal women or men.5 6 In particular, studies have shown that estrogen replacement therapy improves endothelium-dependent vasodilation,7 with favorable influences on insulin sensitivity and lipid profile.8 9 In contrast, androgens are generally considered to decrease glucose tolerance, induce insulin resistance, and increase cardiovascular risk in women10 as well as in men.11
Women with polycystic ovary syndrome (PCOS) represent an intriguing biological experiment of nature that illustrates hormonal effects on cardiovascular risk. These patients, characterized by elevated testosterone levels, hirsutism, and oligomenorrhea,12 are typically obese and insulin resistant and are suspected to be at increased risk for cardiovascular disease.13 14 15 Therefore, this premenopausal subject group presents an interesting and propitious constellation of clinical findings that allows one to evaluate whether a male hormonal pattern abrogates the protective sex effects on endothelial function in OBW.
Thus, the present study was designed to test the hypothesis that women with PCOS display endothelial dysfunction and if so, to determine whether this abnormality is related to elevated testosterone levels.
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Methods |
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Subjects
The characteristics of the study groups are shown in Table 1
. Twelve OBW with PCOS were recruited for the
study. PCOS was diagnosed by an elevation of free testosterone (FT)
levels, associated with hirsutism and amenorrhea or chronic
oligomenorrhea (<6 periods per
year).12 Nonovarian causes
of hyperandrogenism were not formally excluded. Obesity was defined as
body mass index (BMI)=30, and fat content was determined by dual-energy
x-ray absorptiometry (DXA; system software 1.2; Lunar DPX-L). The
weight limit for accurate determination of body composition with our
DXA equipment is 110 kg; therefore, in 1 PCOS subject weighing >110
kg, body fat content was measured by underwater weighing. Thirteen
normal OBW matched with PCOS for age, weight, and body fat served as
control subjects. They had regular menses every 27 to 31 days and no
hirsutism or abnormal FT levels.
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All study subjects except 1 were normotensive and euglycemic. One woman with PCOS exhibited impaired glucose tolerance and chronic hypertension. Because both of these disorders are associated with endothelial dysfunction,16 including this woman in the study group could have introduced a bias in detecting whether PCOS per se determines impairment of endothelial function. Our results were similar, however, with and without inclusion of this woman. Thus, we decided to include her in the study group. None of the women were taking medications known to affect carbohydrate or sex hormone metabolism. All studies were performed regardless of the phase of the menstrual cycle. Studies were approved by the Indiana University Human Subjects Institutional Review Board, and all volunteers gave informed consent.
Protocol
At 
7:00
AM, after an overnight
14-hour fast, a catheter was inserted into the antecubital vein for
infusions of substances. Subsequently, the right femoral artery and
vein were cannulated. A 6F sheath (Cordis Corp) was placed in the right
femoral vein to allow the insertion of a custom-designed 5F
double-lumen thermodilution catheter (Baxter Scientific, Edwards
Division) to measure leg blood flow (LBF) as previously
described.17 The right
femoral artery was cannulated with a 5.5F double-lumen catheter (Arrow
International) to allow simultaneous infusion of substances through the
proximal (most caudad) and invasive blood pressure monitoring through
the distal (most cephalad) port. Heart rate and mean arterial blood
pressure (MAP) were monitored continuously via precordial leads and a
pressure transducer connected to a vital signs monitor (VSM 1,
Physiocontrol).
Hemodynamic Measurements
LBF, MAP, and heart rate measurements were obtained
at baseline and during intrafemoral artery infusion of MCh at
sequential doses of 5, 10, and 15 µg/min. All hemodynamic
measurements were repeated after 200 minutes of euglycemic
hyperinsulinemia.
Whole-Body Glucose Disposal: Leg Glucose
Uptake
Whole-body glucose disposal was assessed with the
euglycemic hyperinsulinemic clamp technique as previously
described.1 Each clamp was
performed during a 4-hour square-wave infusion of insulin at a rate of
120 mU · m-2 ·
min-1.
Leg glucose uptake (LGU) was calculated as the product of
the blood arteriovenous glucose difference (AVG
) and LBF,
LGU=AVGxLBF. Plasma glucose was converted to blood glucose by the
following formula: blood glucose=plasma
glucosex(1-0.3xhematocrit).
Statistical Analysis
Results are shown as the mean±SEM. Leg vascular
resistance (LVR) was defined as LVR=MAP/LBF and is expressed in
arbitrary units (U). Changes in blood flow are expressed as percent
change (%) to adjust for the differences at baseline. GDR is
expressed as mg · kg lean body mass-1
· min-1. Two-way ANOVA was used to
compare the responses to the graded MCh infusions. One-tailed paired
and unpaired t tests were
performed as appropriate for comparisons within or between groups.
Simple linear regression and partial correlation analysis were
performed to assess the relationship between the maximal increase in
LBF in response to the intrafemoral artery infusions of MCh and the
hormonal and metabolic characteristics studied. Subsequently, variables
whose correlation with the maximum LBF response to the intrafemoral
artery infusions of MCh achieved near statistical significance
(P<0.1) were entered into a
stepwise regression model to assess the magnitude of their individual
effects on the maximum LBF response to the intrafemoral artery
infusions of MCh. Statistical significance was accepted at a level of
P<0.05.
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Results |
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Rates of Whole Body Glucose Uptake and LGU
As expected, glucose disposal rate (GDR) was lower in the PCOS subjects than in OBW (4.78±0.54 versus 7.62±0.48 mg · kg-1 · min-1, P<0.0006, respectively), despite the higher insulin levels (358±22 versus 294±19 µU/mL, P<0.05). This difference in insulin-stimulated glucose metabolism between groups was even more striking when GDR was normalized to lean mass (P<0.0005, Figure 1A
).
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To further evaluate the ability of insulin to stimulate LBF
and muscle glucose uptake, we analyzed LGU in both groups studied. As
illustrated
(Figure 1B
), under basal conditions LGU was similar in OBW
and PCOS women (P=NS) as a
result of similar LBF and AVG (0.28±0.02 versus 0.31±0.04 L/min,
P=NS, and 2.1±0.3 versus
1.7±0.3 mg/dL, P=NS,
respectively). Conversely, during steady-state euglycemic
hyperinsulinemia, LGU in PCOS was nearly 40% lower than in OBW
(P<0.01). The differences in
LGU between the 2 groups reflect their differences in LBF and AVG,
for which PCOS displayed both smaller increments in muscle glucose
extraction, as indicated by their lower AVG (21.4±1.8 versus
14.9±2.4 mg/dL, P<0.03 versus
OBW), and somewhat reduced rates of insulin-mediated LBF (0.43±0.04
versus 0.37±0.03 L/min, P=0.10
versus OBW).
Lipids
Lipid patterns of PCOS and OBW are shown in
Table 1. PCOS had lower HDL-cholesterol levels and nearly
40% higher triglyceride levels with respect to OBW
(P<0.01). No differences were
seen between the 2 groups with regard to the other
lipids.
Hemodynamic Data
MAP was somewhat higher in PCOS, but this difference
did not reach statistical significance
(Table 1). MAP did not change in response to euglycemic
hyperinsulinemia in the PCOS group. In OBW, conversely, MAP displayed
an 7% decrease from basal values
(P<0.003). In response to the
intrafemoral artery infusion of MCh, MAP was unchanged under either
basal or hyperinsulinemic conditions in both
groups.
Vascular Reactivity
Basal LBF was 0.28±0.02 and 0.31±0.04 L/min in OBW
and PCOS, respectively (P=NS).
Euglycemic hyperinsulinemia induced a 58.6±15.5% increase in LBF in
insulin-sensitive OBW
(P<0.003), whereas in
insulin-resistant PCOS, the increment in LBF was only 29.5±14.8%
(P=NS). LBF showed a
significant dose-dependent increase
(P<0.01) in response to graded
intrafemoral artery infusions of MCh in both groups. Compared with OBW,
LBF increments in response to the intrafemoral artery infusion of MCh
were on average 50% lower
(Figure 2A) in the PCOS group
(P<0.01). The diminished
response to the intrafemoral artery infusion of MCh suggests that
endothelium-dependent vasodilation is impaired in women with PCOS.
During steady-state euglycemic hyperinsulinemia, the LBF rise above
baseline was 50% lower in PCOS than in OBW
(P<0.05)
(Figure 3A). Thus, the blunted effect of insulin to induce
vasodilation in PCOS suggests that these women display resistance to
the vascular action of insulin.
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Basal LVR was similar in the OBW and PCOS groups (354±23
versus 354±31 U, respectively,
P=NS). Conversely, during
euglycemic hyperinsulinemia, LVR was significantly lower in OBW than in
PCOS (224±18 versus 279±27 U,
P<0.05). The percent decrease
in LVR below baseline in response to euglycemic hyperinsulinemia was
also more marked in OBW than in PCOS
(P<0.03,
Figure 3B). In response to the intrafemoral artery infusions
of MCh, LVR decreased in a dose-dependent manner in both groups, and
changes in LVR mirrored the changes in LBF. Changes in LVR were
significantly more pronounced in OBW than in PCOS women
(P<0.01,
Figure 2B).
Correlational Analyses
The results of the regression analysis
(Table 2) suggest that levels of FT and total testosterone
are directly associated with the magnitude of impairment of
endothelium-dependent vasodilation. A strong negative association was
also found between the degree of obesity (as gauged by BMI) and the
maximal increase in LBF in response to MCh. GDR (insulin sensitivity)
and the maximum LBF response to MCh were directly associated; however,
this relation did not quite achieve statistical significance
(P=0.062). Because FT, BMI, and
GDR were interrelated, we performed stepwise regression analysis to
evaluate their independent contribution to predict the
endothelium-dependent vasodilation. Stepwise regression analysis
(Table 3) revealed that FT accounted for 27% of the
variance of the maximum LBF response to MCh under basal conditions
(Figure 4), whereas BMI contributed an additional 18%. GDR
did not contribute to the regression
model.
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Discussion |
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The results of this study reveal the following new findings: (1) compared with age- and weight-matched control subjects, women with PCOS exhibit an
50% reduction in endothelium-dependent
vasodilation; (2) the physiological ability of insulin to cause
endothelium-dependent vasodilation is markedly impaired in PCOS; and
(3) endothelial function is inversely and strongly related to FT
levels. Endothelium-dependent vasodilation was examined after an overnight fast (basal insulin levels) by measuring the LBF response to graded intrafemoral artery infusions of MCh. MCh-induced vasodilation is a well-established method to assess endothelial relaxing function and is considered to largely reflect NO production/release.18 Therefore, the data suggest that diminished vasodilatory response to MCh in women with PCOS is due, at least in part, to impaired production/release of NO.
Hyperinsulinemia caused LBF to rise above baseline by
30% in PCOS and by 60% in OBW subjects
(P<0.05). These findings
indicate that women with PCOS display resistance to the vasodilatory
action of insulin.
In keeping with other reports, women with PCOS exhibited a
remarkable defect in insulin-stimulated glucose uptake, with 38%
lower whole-body GDRs.19 As
stated in the Methods section, control subjects were not studied at a
consistent phase of the menstrual cycle, whereas women with PCOS were
studied mostly in anovulatory status. If endothelial function and
insulin sensitivity vary during the menstrual
cycle,20 21 this
could confound our results. When we analyzed the data from OBW
according to the phase of the menstrual cycle, however, we found that
endothelial function, as expressed by the maximal LBF response to MCh
and steady-state GDRs of 7 women who were in the follicular phase, was
similar to that of the 6 women studied during the luteal phase
(232±41% versus 234±44%,
P=NS, and 15.1±1 versus
15.3±1.5 mg · kg lean body mass-1 ·
min-1,
P=NS, respectively). Therefore,
it is not likely that the differences observed in endothelial function
and insulin sensitivity between OBW and PCOS were greatly influenced by
differences in menstrual cycle phase.
It is interesting to note that GDRs were directly related to
the magnitude of the action of insulin to vasodilate
(r=0.421,
P<0.04). These data are
consistent with our previously published reports in non-PCOS subjects
supporting a strong association (metabolic coupling) between the
vascular action of insulin and its overall effect on glucose
metabolism.22 Reduced
insulin-mediated glucose disposal exhibited by PCOS was reflected at
the level of skeletal muscle. Indeed, whereas LGU was similar in the 2
groups under basal conditions, during hyperinsulinemia, LGU in PCOS was
40% lower than in OBW. This reduction of insulin-stimulated
skeletal muscle glucose uptake was mostly due to reductions in glucose
extraction (reflected by reduced AVG) and to a lesser degree to
reduced rates of glucose and/or insulin delivery (reflected by lower
rates of LBF). Given the previously reported relationship between
endothelial dysfunction and insulin resistance, it follows logically
that the marked insulin resistance displayed by women with PCOS could
account in large part for the endothelial dysfunction. It is important
to consider, however, that insulin resistance is not the only
characteristic of PCOS, which may have a detrimental effect on
endothelial function.
Androgens,23
dyslipidemia,24
obesity,2 25 and
hypertension26 all may
affect endothelial function. Therefore, we analyzed all the variables
to assess which of these play a major determinant role in the
endothelial dysfunction displayed by women with PCOS.
As in our previous study,2 we observed a strong negative correlation between BMI and the peak vasodilation in response to MCh. BMI, together with FT, was shown to be a powerful predictor of endothelial function, being able to explain 18% and 27%, respectively, of the variance in maximal endothelium-dependent vasodilation. Thus, obesity appears to have a significant modulating effect on endothelial function in women, independent of their hormonal status. In addition, given a certain degree of adiposity, hyperandrogenism appears to have an additive negative effect on endothelial function.
By design, women with PCOS exhibited total testosterone and FT levels 2- and 4-fold higher, respectively, than those observed in OBW women. Perhaps the most intriguing finding in our study is the strong negative correlations between both total testosterone and FT and the peak vasodilation induced by MCh across all subjects, suggesting that increased androgen levels may impair endothelial function. As stated above, elevated FT levels were part of the selection criteria for PCOS. Therefore, to exclude the possibility that the correlation between FT and peak vasodilation induced by MCh could be influenced by other factors associated with PCOS, we performed a further analysis adjusting the relation for the variables that differed significantly between groups (eg, GDR, fasting insulin, HDL, triglyceride). This analysis revealed that the correlation remained significant (r=-0.41, P<0.05). We did not measure serum sex hormone–binding globulin levels. Given that insulin resistance leads to a decrease in serum sex hormone–binding globulin, resulting in elevated FT levels,27 28 this could possibly strengthen the negative relation between FT and endothelial function.
Consistent with our results, Herman et al23 reported that androgen deprivation in men is associated with enhanced endothelium-dependent vasodilatation. Conversely, it has also been shown that estrogen supplementation failed to improve endothelium-dependent vasodilation in men but did so in women.29 30 Therefore, it seems plausible that a deleterious effect of androgens rather than simply beneficial effects of estrogens may contribute to the observed sex difference in the risk of macrovascular disease in healthy subjects. In women with PCOS, androgen levels appear to be major contributors to endothelial dysfunction and, as such, a major potential mechanism of macrovascular disease in these patients.
In keeping with other reports, total and LDL cholesterol levels in PCOS subjects were similar to those observed in weight-matched control women.31 Moreover, there was no relationship between these lipids and FT or with steady-state GDRs (insulin sensitivity). Therefore, it is highly unlikely that these lipid parameters could account for the differences in endothelial function observed between our study groups. Women with PCOS had lower HDL cholesterol and higher triglyceride levels than control women. As in our previous reports,2 these lipids did not correlate with the peak endothelium-dependent vasodilation induced by MCh, although one cannot completely exclude an indirect contribution. Free fatty acid levels were similar in control and PCOS subjects and thus also cannot account for the difference in endothelium-dependent vasodilation observed between groups. In keeping with most studies, we found that resting blood pressure was not significantly higher in women with PCOS than in weight- and age-matched control subjects.32 Moreover, blood pressure did not correlate with the maximum response to intrafemoral artery infusions of MCh. Thus, it is not likely that the large difference in endothelial function observed between the study groups is related to the modest differences in blood pressure levels.
In conclusion, this study provides the first evidence that PCOS is characterized by endothelial dysfunction. This endothelial dysfunction appears to be most strongly associated with both elevated androgen levels and obesity/insulin resistance. Given the central vasoprotective role of the endothelium, these findings could explain, at least in part, the suspected increased risk for macrovascular disease in women with PCOS. Although the mechanism by which male hormone pattern/insulin resistance determines endothelial dysfunction remains to be defined, the data support the hypothesis that clinical strategies aimed at reducing both androgens and insulin resistance33 34 would have the most beneficial cardioprotective effects in women with PCOS.
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Acknowledgments |
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This work was supported by grants DK-42469, MO1-RR750-19, and DK-20452 from the National Institutes of Health and a Veterans Affairs Merit Review Award. Dr Giancarlo Paradisi was the recipient of a grant from the A. Griffini Foundation of Varese, Italy.
Received April 30, 1999; revision received November 17, 2000; accepted November 18, 2000.
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D. Romualdi, B. Costantini, L. Selvaggi, M. Giuliani, F. Cristello, F. Macri, A. Bompiani, A. Lanzone, and M. Guido Metformin improves endothelial function in normoinsulinemic PCOS patients: a new prospective Hum. Reprod., September 1, 2008; 23(9): 2127 - 2133. [Abstract] [Full Text] [PDF]
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 J. R. Meendering, B. N. Torgrimson, N. P. Miller, P. F. Kaplan, and C. T. Minson Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1630 - H1637. [Abstract] [Full Text] [PDF]
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 J. E. Nestler Metformin for the Treatment of the Polycystic Ovary Syndrome N. Engl. J. Med., January 3, 2008; 358(1): 47 - 54. [Full Text] [PDF]
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D. Heutling, H. Schulz, I. Nickel, J. Kleinstein, P. Kaltwasser, S. Westphal, F. Mittermayer, M. Wolzt, K. Krzyzanowska, H. Randeva, et al. Asymmetrical Dimethylarginine, Inflammatory and Metabolic Parameters in Women with Polycystic Ovary Syndrome before and after Metformin Treatment J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 82 - 90. [Abstract] [Full Text] [PDF]
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T. Cascella, S. Palomba, I. De Sio, F. Manguso, F. Giallauria, B. De Simone, D. Tafuri, G. Lombardi, A. Colao, and F. Orio Visceral fat is associated with cardiovascular risk in women with polycystic ovary syndrome Hum. Reprod., January 1, 2008; 23(1): 153 - 159. [Abstract] [Full Text] [PDF]
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R. Shroff, A. Kerchner, M. Maifeld, E. J. R. Van Beek, D. Jagasia, and A. Dokras Young Obese Women with Polycystic Ovary Syndrome Have Evidence of Early Coronary Atherosclerosis J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4609 - 4614. [Abstract] [Full Text] [PDF]
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 R. Muniyappa, M. Montagnani, K. K. Koh, and M. J. Quon Cardiovascular Actions of Insulin Endocr. Rev., August 1, 2007; 28(5): 463 - 491. [Abstract] [Full Text] [PDF]
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M. Luque-Ramirez, F. Alvarez-Blasco, C. Mendieta-Azcona, J. I. Botella-Carretero, and H. F. Escobar-Morreale Obesity Is the Major Determinant of the Abnormalities in Blood Pressure Found in Young Women with the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2141 - 2148. [Abstract] [Full Text] [PDF]
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 M.-J. Chen, W.-S. Yang, J.-H. Yang, C.-L. Chen, H.-N. Ho, and Y.-S. Yang Relationship Between Androgen Levels and Blood Pressure in Young Women With Polycystic Ovary Syndrome Hypertension, June 1, 2007; 49(6): 1442 - 1447. [Abstract] [Full Text] [PDF]
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J. A. Beckman, A. B. Goldfine, A. Dunaif, M. Gerhard-Herman, and M. A. Creager Endothelial Function Varies According to Insulin Resistance Disease Type Diabetes Care, May 1, 2007; 30(5): 1226 - 1232. [Abstract] [Full Text] [PDF]
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 R. S. Legro A 27-Year-Old Woman With a Diagnosis of Polycystic Ovary Syndrome JAMA, February 7, 2007; 297(5): 509 - 519. [Abstract] [Full Text] [PDF]
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A Dagre, J Lekakis, C Mihas, A Protogerou, L Thalassinou, D Tryfonopoulos, G Douridas, C Papamichael, and M Alevizaki Association of dehydroepiandrosterone-sulfate with endothelial function in young women with polycystic ovary syndrome. Eur. J. Endocrinol., June 1, 2006; 154(6): 883 - 890. [Abstract] [Full Text] [PDF]
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E. Diamanti-Kandarakis, T. Paterakis, K. Alexandraki, C. Piperi, A. Aessopos, I. Katsikis, N. Katsilambros, G. Kreatsas, and D. Panidis Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin Hum. Reprod., June 1, 2006; 21(6): 1426 - 1431. [Abstract] [Full Text] [PDF]
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G. Paradisi, A. Biaggi, R. Savone, F. Ianniello, C. Tomei, L. Caforio, and A. Caruso Cardiovascular Risk Factors in Healthy Women with Previous Gestational Hypertension J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1233 - 1238. [Abstract] [Full Text] [PDF]
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S. Topcu, M. Caliskan, E. E. Ozcimen, D. Tok, A. Uckuyu, D. Erdogan, H. Gullu, A. Yildirir, H. Zeyneloglu, and H. Muderrisoglu Do young women with polycystic ovary syndrome show early evidence of preclinical coronary artery disease? Hum. Reprod., April 1, 2006; 21(4): 930 - 935. [Abstract] [Full Text] [PDF]
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S. Eisenhardt, N. Schwarzmann, V. Henschel, A. Germeyer, M. von Wolff, A. Hamann, and T. Strowitzki Early Effects of Metformin in Women with Polycystic Ovary Syndrome: A Prospective Randomized, Double-Blind, Placebo-Controlled Trial J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 946 - 952. [Abstract] [Full Text] [PDF]
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 B. Barutcuoglu, A. E. Bozdemir, D. Dereli, Z. Parildar, M. I. Mutaf, D. Ozmen, and O. Bayindir Increased Serum Neopterin Levels in Women with Polycystic Ovary Syndrome Ann. Clin. Lab. Sci., January 1, 2006; 36(3): 267 - 272. [Abstract] [Full Text] [PDF]
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F. Orio Jr., S. Palomba, T. Cascella, B. De Simone, F. Manguso, S. Savastano, T. Russo, A. Tolino, F. Zullo, G. Lombardi, et al. Improvement in Endothelial Structure and Function after Metformin Treatment in Young Normal-Weight Women with Polycystic Ovary Syndrome: Results of a 6-Month Study J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6072 - 6076. [Abstract] [Full Text] [PDF]
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K. Lakhani, A. Leonard, A.M. Seifalian, and P. Hardiman Microvascular dysfunction in women with polycystic ovary syndrome Hum. Reprod., November 1, 2005; 20(11): 3219 - 3224. [Abstract] [Full Text] [PDF]
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C. Meyer, B. P. McGrath, and H. J. Teede Overweight Women with Polycystic Ovary Syndrome Have Evidence of Subclinical Cardiovascular Disease J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5711 - 5716. [Abstract] [Full Text] [PDF]
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M. Kravariti, K. K. Naka, S. N. Kalantaridou, N. Kazakos, C. S. Katsouras, A. Makrigiannakis, E. A. Paraskevaidis, G. P. Chrousos, A. Tsatsoulis, and L. K. Michalis Predictors of Endothelial Dysfunction in Young Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5088 - 5095. [Abstract] [Full Text] [PDF]
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C. Meyer, B. P. McGrath, J. Cameron, D. Kotsopoulos, and H. J. Teede Vascular Dysfunction and Metabolic Parameters in Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4630 - 4635. [Abstract] [Full Text] [PDF]
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E Diamanti-Kandarakis, K Alexandraki, A Protogerou, C Piperi, C Papamichael, A Aessopos, J Lekakis, and M Mavrikakis Metformin administration improves endothelial function in women with polycystic ovary syndrome Eur. J. Endocrinol., May 1, 2005; 152(5): 749 - 756. [Abstract] [Full Text] [PDF]
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A. Vryonidou, A. Papatheodorou, A. Tavridou, T. Terzi, V. Loi, I.-A. Vatalas, N. Batakis, C. Phenekos, and A. Dionyssiou-Asteriou Association of Hyperandrogenemic and Metabolic Phenotype with Carotid Intima-Media Thickness in Young Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2740 - 2746. [Abstract] [Full Text] [PDF]
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 J. Vrbikova and D. Cibula Combined oral contraceptives in the treatment of polycystic ovary syndrome Hum. Reprod. Update, May 1, 2005; 11(3): 277 - 291. [Abstract] [Full Text] [PDF]
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D. A. Ehrmann Polycystic Ovary Syndrome N. Engl. J. Med., March 24, 2005; 352(12): 1223 - 1236. [Full Text] [PDF]
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A. Rickenlund, M. J. Eriksson, K. Schenck-Gustafsson, and A. L. Hirschberg Amenorrhea in Female Athletes Is Associated with Endothelial Dysfunction and Unfavorable Lipid Profile J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1354 - 1359. [Abstract] [Full Text] [PDF]
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C. Ortega-Gonzalez, S. Luna, L. Hernandez, G. Crespo, P. Aguayo, G. Arteaga-Troncoso, and A. Parra Responses of Serum Androgen and Insulin Resistance to Metformin and Pioglitazone in Obese, Insulin-Resistant Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1360 - 1365. [Abstract] [Full Text] [PDF]
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 A S T Bickerton, N Clark, D Meeking, K M Shaw, M Crook, P Lumb, C Turner, and M H Cummings Cardiovascular risk in women with polycystic ovarian syndrome (PCOS) J. Clin. Pathol., February 1, 2005; 58(2): 151 - 154. [Abstract] [Full Text] [PDF]
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E. O. Talbott, J. V. Zborowski, J. R. Rager, M. Y. Boudreaux, D. A. Edmundowicz, and D. S. Guzick Evidence for an Association between Metabolic Cardiovascular Syndrome and Coronary and Aortic Calcification among Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5454 - 5461. [Abstract] [Full Text] [PDF]
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F. Orio Jr., S. Palomba, T. Cascella, B. De Simone, S. Di Biase, T. Russo, D. Labella, F. Zullo, G. Lombardi, and A. Colao Early Impairment of Endothelial Structure and Function in Young Normal-Weight Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4588 - 4593. [Abstract] [Full Text] [PDF]
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F. Orio Jr., S. Palomba, L. Spinelli, T. Cascella, L. Tauchmanova, F. Zullo, G. Lombardi, and A. Colao The Cardiovascular Risk of Young Women with Polycystic Ovary Syndrome: An Observational, Analytical, Prospective Case-Control Study J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3696 - 3701. [Abstract] [Full Text] [PDF]
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G. Paradisi, F. Cucinelli, M. C. Mele, A. Barini, A. Lanzone, and A. Caruso Endothelial function in post-menopausal women: effect of folic acid supplementation Hum. Reprod., April 1, 2004; 19(4): 1031 - 1035. [Abstract] [Full Text] [PDF]
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 M. T. Sheehan Polycystic Ovarian Syndrome: Diagnosis and Management Clin. Med. Res., February 1, 2004; 2(1): 13 - 27. [Abstract] [Full Text] [PDF]
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R. J. Gonzales, D. N. Krause, and S. P. Duckles Testosterone suppresses endothelium-dependent dilation of rat middle cerebral arteries Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H552 - H560. [Abstract] [Full Text] [PDF]
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The Rotterdam ESHRE/ASRM-sponsored PCOS consensus Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) Hum. Reprod., January 1, 2004; 19(1): 41 - 47. [Abstract] [Full Text] [PDF]
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R. S. Legro Polycystic Ovary Syndrome and Cardiovascular Disease: A Premature Association? Endocr. Rev., June 1, 2003; 24(3): 302 - 312. [Abstract] [Full Text] [PDF]
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E. Diamanti-Kandarakis, J.-P. Baillargeon, M. J. Iuorno, D. J. Jakubowicz, and J. E. Nestler A Modern Medical Quandary: Polycystic Ovary Syndrome, Insulin Resistance, and Oral Contraceptive Pills J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 1927 - 1932. [Full Text] [PDF]
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M. Schachter, A. Raziel, S. Friedler, D. Strassburger, O. Bern, and R. Ron-El Insulin resistance in patients with polycystic ovary syndrome is associated with elevated plasma homocysteine Hum. Reprod., April 1, 2003; 18(4): 721 - 727. [Abstract] [Full Text] [PDF]
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O. Baltatu, C. Cayla, R. Iliescu, D. Andreev, and M. Bader Abolition of End-Organ Damage by Antiandrogen Treatment in Female Hypertensive Transgenic Rats Hypertension, March 1, 2003; 41(3): 830 - 833. [Abstract] [Full Text] [PDF]
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G. Paradisi, H. O. Steinberg, M. K. Shepard, G. Hook, and A. D. Baron Troglitazone Therapy Improves Endothelial Function to Near Normal Levels in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 576 - 580. [Abstract] [Full Text] [PDF]
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L. A. Stadtmauer, B. C. Wong, and S. Oehninger Should patients with polycystic ovary syndrome be treated with metformin?: Benefits of insulin sensitizing drugs in polycystic ovary syndrome--beyond ovulation induction Hum. Reprod., December 1, 2002; 17(12): 3016 - 3026. [Abstract] [Full Text] [PDF]
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J. E. Nestler Should patients with polycystic ovarian syndrome be treated with metformin?: An enthusiastic endorsement Hum. Reprod., August 1, 2002; 17(8): 1950 - 1953. [Abstract] [Full Text] [PDF]
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C. J. G. Kelly, H. Lyall, J. R. Petrie, G. W. Gould, J. M. C. Connell, A. Rumley, G. D. O. Lowe, and N. Sattar A Specific Elevation in Tissue Plasminogen Activator Antigen in Women with Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3287 - 3290. [Abstract] [Full Text] [PDF]
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G. Paradisi, A. Biaggi, S. Ferrazzani, S. De Carolis, and A. Caruso Abnormal Carbohydrate Metabolism During Pregnancy : Association with endothelial dysfunction Diabetes Care, March 1, 2002; 25(3): 560 - 564. [Abstract] [Full Text] [PDF]
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 M. A. Sader and D. S. Celermajer Endothelial function, vascular reactivity and gender differences in the cardiovascular system Cardiovasc Res, February 15, 2002; 53(3): 597 - 604. [Full Text] [PDF]
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C. J. G. Kelly, A. Speirs, G. W. Gould, J. R. Petrie, H. Lyall, and J. M. C. Connell Altered Vascular Function in Young Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 742 - 746. [Abstract] [Full Text] [PDF]
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