Coagulation/Fibrinolytic Factors in PCOS

Table 4: Differences in Coagulation/Fibrinolytic Factors in PCOS Cases vs. Controls

(Adjusted for Age and Body Mass Index) Coagulation Factor

PCOS Cases N= 50

Controls N = 56

P value

PAI-1 ng/ml 27.6 18.8 .026 TPA ng/ml 11.0 9.9 .127 Factor VII % 128.0 132.0 .648 D-Dimer ng/ml 99.7 106.3 .715 Fragment 1.2 nM 1.16 1.23 .575 CRP g/ml 2.14 2.45 .414

The Alternative Hypothesis:

Conversely, PCOS women may be protected from Conversely, PCOS women may be protected from later life onset of CHD by the altered hormonal later life onset of CHD by the altered hormonal profile that includes increased estrone from profile that includes increased estrone from peripheral conversion of androgen in adipose and peripheral conversion of androgen in adipose and other tissueother tissue

This profile could be responsible for the This profile could be responsible for the inconsistencies observed between investigations of inconsistencies observed between investigations of risk factors in PCOS and the McKeigue risk factors in PCOS and the McKeigue retrospective follow-up of mortalityretrospective follow-up of mortality

Carotid IMT in PCOSTable 6: Carotid IMT results for PCOS cases and controls

Cases Controls IMT (mm) *

N Mean ±SE Age-BMI

Adj. Mean (CI)

N Mean ± SE Age-BMI

Adj Mean (CI)

p-value*

Total 125 .70 ± .01 .70 (.68-.73) 142 .68 ± .01 .67 (.65-69) .299

30-44 yr 78 .65 ± .01 .65 (.62-.69) 82 .66 ± .01 .64 (.61.67) .565

45+ yr 47 .78 ± .03 .77 (.74-.81) 60 .70 ± .01 .71(.68-.75) .005

*statistical test performed on transformed variable Reprinted with Permission pending from Arteriosclerosis, Thrombosis, and Vascular Biology 2000, 20:2414-2421.

Click for larger picture

Hemodynamic Measures in PCOSTable 7: Hemodynamic Measurements in PCOS Cases and Controls

Caucasian Only, 30+ Years of Age TOTAL N=95 N=116 Cases Controls Age 42.6 (6.0) 43.7 (6.2) Baseline Blood Pressure: Systolic mmHg 118.9 (16.7) 115.8 (16.6) Diastolic mmHg 75.7 (11.3) 73.4 (9.7) Pulse Pressure Values 43.2 (14.4) 42.4 (14.3) Baseline Lumen Diameter (mm) 3.09 (.50)** 2.88 (.37) Lumen Diameter at 30 seconds 3.21 (.53)** 3.00 (.38) Lumen Diameter at 60 seconds 3.23 (.50)** 3.01 (.39) Lumen Diameter at 90 seconds 3.19 (.47)** 2.99 (.39) Lumen Diameter at 12 0 seconds 3.20 (.50)** 2.98 (.39) Lumen Diameter at 150 seconds 3.19 (.51)** 2.97 (.38) Lumen Diameter 180 seconds 3.14 (.47)** 2.95 (.38) Lumen Diameter Peak 3.29 (.52) 3.08 (.39) FMD (% increase in Lumen Diameter from Baseline)

7.33 (5.71) 7.15 (4.17)

FMD=Flow mediated Vasodilation **p<.01

Click for larger picture

Correlation of Various Subclinical CHD Measures

Table 8. Correlations of IMT, Carotid Plaque, and Endothelial Function Measures in PCOS Cases and Controls

Cases Controls FMD LD baseline FMD LD baseline IMT .003 .142 -.012 -.161* Carotid Plaque (y/n) .038 .031 -.105 -.028

*borderline significant 0.05<p<.10

Click for larger picture

Interaction of PCOS and Age in IMT

0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.85

30-39 40-44 45-49 >=50

Age Groups (years)

IMT

(m

m)

Figure 1: Interaction between PCOS and age in the determination of IMT

(Cases = solid, Controls = hatched) (PCOS X age interaction p =.031)

Reprinted with Permission from Arteriosclerosis, Thrombosis, and Vascular Biology, 2000;20:2414-2421

Click for larger picture

Lancet 1997; 350 (suppl I):15Click for larger picture

Lancet 1997;350:21 Click for larger picture

Introduction Polycystic Ovary Syndrome (PCOS) is associated Polycystic Ovary Syndrome (PCOS) is associated

with an increased prevalence of cardiovascular with an increased prevalence of cardiovascular disease risk factors (Wild, !988; Slowinska-disease risk factors (Wild, !988; Slowinska-Srezednicka, 1991; Talbott and Guzick, 1995)Srezednicka, 1991; Talbott and Guzick, 1995)

PCOS women have evidence of metabolic PCOS women have evidence of metabolic derangements similar to Syndrome X (derangements similar to Syndrome X (LDLc, LDLc, HDLc, HDLc, triglycerides, triglycerides, insulin, insulin, central central adiposity, hypertension, and Type II diabetes)adiposity, hypertension, and Type II diabetes)

Introduction (cont.)

Since LDLc is an important determinant Since LDLc is an important determinant of atherosclerosis in women, the of atherosclerosis in women, the increased LDLc levels seen in younger increased LDLc levels seen in younger PCOS suggests that these women may be PCOS suggests that these women may be at increased risk for subclinical and at increased risk for subclinical and clinical atherosclerosis at an earlier age clinical atherosclerosis at an earlier age than the general female population.than the general female population.

Characteristics of PCOS

Chronic AnovulationChronic Anovulation Hyperandrogenism Hyperandrogenism

(Elevated (Elevated Testosterone)Testosterone)

HirsutismHirsutism

ObesityObesity Insulin ResistanceInsulin Resistance InfertilityInfertility

Affects 5 to 10 percent of US Women, and the condition is marked by:

Research Questions Do women with PCOS have evidence of Do women with PCOS have evidence of

subclinical atherosclerosis as demonstrated by subclinical atherosclerosis as demonstrated by an increase in carotid intima-media thickness?an increase in carotid intima-media thickness?

If so, can the increase in carotid intima-media If so, can the increase in carotid intima-media thickness be linked to the various thickness be linked to the various cardiovascular risk factors seen in PCOS cardiovascular risk factors seen in PCOS women?women?

Current Study Population

Women participating in Phase II of the Women participating in Phase II of the Cardiovascular Health and Risk Measurement Cardiovascular Health and Risk Measurement Study (CHARM, 1997-98)Study (CHARM, 1997-98)

Cases and controls represent the initial 1/3 of the Cases and controls represent the initial 1/3 of the women recruited for Phase II participation (46 women recruited for Phase II participation (46 Cases with PCOS and 59 Controls)Cases with PCOS and 59 Controls)

PCOS is defined as chronic anovulation with PCOS is defined as chronic anovulation with clinical or biochemical evidence of clinical or biochemical evidence of hyperandrogenism without other identified hyperandrogenism without other identified causescauses

Selected Clinical and Lifestyle Factors in PCOS Cases and Controls- Preliminary Data

Age (Current) 42 8 43 7BMI 26.7 6.8 32.5 9.8**Diastolic Blood Pressure (mmHg)

70.2 8.6 74.4 12.2*

Currently Smoking 13 (28.3%) 8 (13.6%)

Hormone Use 1 (2.2%) 15 (25.4%)**

VARIABLES

(1993-94 Data)

CASES

(n=46)CONTROLS

(n=59)

* p .05** p .001

Selected Lipid and Hormone Levels in PCOS Cases and Controls- Preliminary Data

HDLc (mg/dL) 51.8 14.7 58.7 12.9*LDLc (mg/dL) 122.6 31.6 111.5 28.7Triglycerides (mg/dL) 114.0 73.3 78.5 34.1*

HDL2 (mg/dL) 7.9 5.5 12.4 7.6**Insulin (U/L) 25.8 19.5 13.8 9.6**FSH (IU/L) 6.3 7.6 13.5 24.9*Total Testosterone(ng/dL)

2.6 1.2 1.0 0.5**

VARIABLES

(1993-4 Data)CASES

(n=46)CONTROLS

(n=59)

* p .05** p .001

Differences in CAI in PCOS Cases vs. Controls by Age

0.75 *

0,7 0.69

0,66

0.79 **

0,71

0,580,6

0,620,640,660,68

0,70,720,740,760,78

0,8C

AI

(mm

)

All < 40 years >= 40 years

PCOS Controls* p = 0.004

** p = 0.021

Analysis of CAI Predictors in PCOS Cases and Controls

Employed a multiple linear regression model with Employed a multiple linear regression model with forced entry of predictorsforced entry of predictors

Dependent variable: CAIDependent variable: CAI Independent variables in the fixed model included: Independent variables in the fixed model included:

age, BMI, DBP, smoking and hormone useage, BMI, DBP, smoking and hormone use Lipids and insulin were added separately to the fixed Lipids and insulin were added separately to the fixed

model to determine the change in Rmodel to determine the change in R22

PCOS status was added to the final model to evaluate PCOS status was added to the final model to evaluate attenuation of the relationships by case statusattenuation of the relationships by case status

Regression - Fixed Model

Age .000 .406 .000BMI .004

DBP .042Hormone .517Smoking .350

PredictorsP-value

of PredictorsModel

Adjusted R2

ModelSignificance

Forced entry of CVD risk factors:

Dependent variable = CAI

Regression - Lipids and Insulin

CHOL .138 .414 .000TRIG .403 .404 .000HDL .377 .405 .000LDL .095 .418 .000Insulin .689 .408 .000

PredictorsP-value

of PredictorsModel

Adjusted R2

ModelSignificance

Individual entry of lipids and insulin to CVD fixed model:

Dependent Variable = CAI

Regression - PCOS Status

Age .000 .437 .000BMI .024DBP .065Hormone .883Smoking .349LDL .155PCOS .043

Predictors P-valueof Predictors

ModelAdjusted R2

ModelSignificance

Entry of PCOS status to CVD fixed model including LDL:

Dependent variable = CAI

Conclusions PCOS women demonstrate increased carotid PCOS women demonstrate increased carotid

intima-media thickness compared to age matched intima-media thickness compared to age matched controls at a relatively young age (< 40 years).controls at a relatively young age (< 40 years).

However, the most striking evidence of However, the most striking evidence of subclinical atherosclerosis in PCOS appears in subclinical atherosclerosis in PCOS appears in the the 40 year age group. 40 year age group.

Conclusions (cont.)

Age, BMI, and diastolic blood pressure are Age, BMI, and diastolic blood pressure are significant predictors of CAI in womensignificant predictors of CAI in women

Atherosclerotic potential in the younger PCOS Atherosclerotic potential in the younger PCOS women is mediated by in part by higher LDLc women is mediated by in part by higher LDLc levels and increased BMI.levels and increased BMI.

Implications

Since abnormal LDLc levels and increased Since abnormal LDLc levels and increased BMI appear to contribute to subclinical BMI appear to contribute to subclinical atherosclerosis in PCOS, interventions atherosclerosis in PCOS, interventions directed at decreasing LDLc and directed at decreasing LDLc and controlling weight in younger PCOS women controlling weight in younger PCOS women may improve the later-life cardiovascular may improve the later-life cardiovascular risk profile in this high risk population.risk profile in this high risk population.

Evelyn O. TalbottA544 Crabtree HallPittsburg, PA(412) 624-3074