Coronary Heart Disease Risk Profile of Women with PCOS:

Collision of Evidence and Assumptions

Evelyn Talbott, Dr.P.H.Kim Sutton-Tyrrell, Dr.P.H.

Lewis H. Kuller, M.D., Dr.P.H.Jeanne V. Zborowski, Ph.D.

Dept. of EpidemiologyGraduate School of Public Health

University of Pittsburgh

Learning Objective I

To review some of the designs employed in the To review some of the designs employed in the study of Cardiovascular Disease risk factors in study of Cardiovascular Disease risk factors in women with PCOSwomen with PCOS RetrospectiveRetrospective ProspectiveProspective Historical ProspectiveHistorical Prospective

Learning Objective II

To provide an overview of the controversy in To provide an overview of the controversy in the literature to date linking PCOS and the the literature to date linking PCOS and the risk of Heart Disease in women.risk of Heart Disease in women.

Learning Objective III

To more fully understand the metabolic To more fully understand the metabolic parameters of PCOS in women in relation to parameters of PCOS in women in relation to Cardiovascular Disease risk over time andCardiovascular Disease risk over time and

to discuss future research in this area.to discuss future research in this area.

Prevalence of Polycystic Ovary Syndrome (PCOS)

PCOS is a condition that affects 5-10% of PCOS is a condition that affects 5-10% of women in the US.women in the US.

It is a heterogeneous reproductive It is a heterogeneous reproductive endocrine disorder.endocrine disorder.

Characteristics of PCOS

Chronic anovulationChronic anovulation HyperandrogenemiaHyperandrogenemia Insulin ResistanceInsulin Resistance HyperinsulinemiaHyperinsulinemia ObesityObesity Impaired Glucose Tolerance (IGT)Impaired Glucose Tolerance (IGT) Central Adiposity Central Adiposity

Etiology of Polycystic Ovary Syndrome (PCOS)

Primary dysregulation of ovarian steroidogenesis (Ehrmann, Primary dysregulation of ovarian steroidogenesis (Ehrmann, 1995); insulin post-receptor binding defect (Dunaif, 1992)1995); insulin post-receptor binding defect (Dunaif, 1992)

Multiple arrested follicles are present with increased ovarian Multiple arrested follicles are present with increased ovarian stroma (pearl necklace effect)stroma (pearl necklace effect)

Results in hypertrophied ovarian theca cells, elevated Results in hypertrophied ovarian theca cells, elevated androgens, lack of a mid-cycle estradiol surge, and disrupted androgens, lack of a mid-cycle estradiol surge, and disrupted folliculogenesis (Barnes, 1997)folliculogenesis (Barnes, 1997)

Atretic Follicle

ThickenedCapsule

From: The Menstrual Cycle (1993), Ferin, Jewelewicz, and Warren

The Polycystic Ovary

EnlargedOvary with Abundant Stroma

Differing Criteria of PCOS

ULTRASOUND BIOCHEMICAL

CLINICAL

Review of the Evidence related to CHD Risk and PCOS

Women with PCOS may be at increased risk of Women with PCOS may be at increased risk of heart disease with increased prevalence of CHD heart disease with increased prevalence of CHD risk factors: (LDL, HDL, triglycerides, risk factors: (LDL, HDL, triglycerides, hypertension and diabetes.)hypertension and diabetes.)

However, the literature to date has been However, the literature to date has been inconsistent. inconsistent.

Studies to date have been observational, largely Studies to date have been observational, largely consisting of case-control and cross sectional consisting of case-control and cross sectional designs.designs.

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PCOS and Cardiovascular Risk PCOS is associated with an increased prevalence of PCOS is associated with an increased prevalence of

cardiovascular disease risk factors (Wild, 1988; cardiovascular disease risk factors (Wild, 1988; Talbott, 1995)Talbott, 1995)

In both lean and obese PCOS cases exhibited > fasting In both lean and obese PCOS cases exhibited > fasting insulin levels (Slowinska-Srzednicka, 1991)insulin levels (Slowinska-Srzednicka, 1991)

PCOS women have evidence of metabolic PCOS women have evidence of metabolic derangements similar to the Metabolic Cardiovascular derangements similar to the Metabolic Cardiovascular Syndrome (Syndrome X) [dyslipidemia (Syndrome (Syndrome X) [dyslipidemia ( LDLc, LDLc, HDLc, HDLc, triglycerides), hypertension, and Type II triglycerides), hypertension, and Type II diabetes]diabetes]

Literature continued

Conversely, other investigators have noted Conversely, other investigators have noted little difference in LDLc levels in thin versus little difference in LDLc levels in thin versus obese PCOS cases and controls (Norman l992, obese PCOS cases and controls (Norman l992, Conway, l995).Conway, l995).

Earlier studies had small sample sizes and did Earlier studies had small sample sizes and did not control for potential confoundersnot control for potential confounders

Summary of Studies Linking Adverse Lipid Profiles in Women with PCOS

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Hyperinsulinemia, Insulin Resistance, and Impaired Hemostatic Function

Hyperinsulinemia and insulin resistance, as observed in PCOS, Hyperinsulinemia and insulin resistance, as observed in PCOS, have been associated with increased CVD risk (Haffner, 1992; have been associated with increased CVD risk (Haffner, 1992; Savage, 1996; Reaven, 1998)Savage, 1996; Reaven, 1998)

Recent evidence suggests hyperinsulinemia in PCOS correlates Recent evidence suggests hyperinsulinemia in PCOS correlates with increased CVD risk independent of obesity (Mather, 2000) with increased CVD risk independent of obesity (Mather, 2000)

Increased risk may be a direct effect of elevated insulin or an Increased risk may be a direct effect of elevated insulin or an indirect effect, through the influence of insulin on other indirect effect, through the influence of insulin on other metabolic processes (e.g. thrombosis, fibrinolysis) metabolic processes (e.g. thrombosis, fibrinolysis)

Whether this translates into a true “ increased risk” of CHD is Whether this translates into a true “ increased risk” of CHD is not knownnot known

CHD Mortality -Previous Literature

To date, one historical prospective study of To date, one historical prospective study of 768 PCOS women (McKeigue et al) 768 PCOS women (McKeigue et al) undergoing wedge resection in the l930-1979 undergoing wedge resection in the l930-1979 has been conducted. There was no increased has been conducted. There was no increased risk of cardiovascular disease noted in this risk of cardiovascular disease noted in this population.population.

Types of Cohort Studies

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Pierpoint et al., J Clinical Epi, 51(7), 1998

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Brief Literature Review

In an earlier study of sudden cardiac death among In an earlier study of sudden cardiac death among women aged 25-64 in Allegheny County (Talbott ’89), we women aged 25-64 in Allegheny County (Talbott ’89), we noted an > rate of childlessness in ever married cases noted an > rate of childlessness in ever married cases compared to controls (N=80 cases, 80 controls). compared to controls (N=80 cases, 80 controls).

Detailed reproductive histories,however, were not Detailed reproductive histories,however, were not available. available.

The question of whether a reproductive endocrine The question of whether a reproductive endocrine abnormality such as PCOS was somehow linked to abnormality such as PCOS was somehow linked to sudden cardiac death was intriguing.sudden cardiac death was intriguing.

Risk of CHD in PCOS (Phase I l992-94) (Talbott, Guzick, Berga et. al.)

PCOS was a common enough diagnosis in medical PCOS was a common enough diagnosis in medical practices that a large-scale study was possible.practices that a large-scale study was possible.

The specific aim of our first study was to provide The specific aim of our first study was to provide information on whether women with PCO have a information on whether women with PCO have a greater incidence of known risk factors for CHD greater incidence of known risk factors for CHD compared to age matched controls.compared to age matched controls.

Methods

Using both historical and current records Using both historical and current records from the Reproductive Endocrine Clinic at from the Reproductive Endocrine Clinic at Magee Women’s our goal was to identify 300 Magee Women’s our goal was to identify 300 women with PCO and match them with 300 women with PCO and match them with 300 neighborhood controls.neighborhood controls.

Recruitment continued

Review of records of Dr. David Archer Review of records of Dr. David Archer (1972-1986) /Drs. David Guzick and Sarah (1972-1986) /Drs. David Guzick and Sarah Berga (2800 records, 10% met PCOS Berga (2800 records, 10% met PCOS criteria)criteria)

Definition of PCOSDefinition of PCOS :chronic anovulation :chronic anovulation and 1) evidence of clinical (and 1) evidence of clinical (hirsutism) hirsutism) or or biochemicalbiochemical (Total T > 2.0 nmol/L) (Total T > 2.0 nmol/L) hyperandrogenism or 2) LH:FSH > 2.0hyperandrogenism or 2) LH:FSH > 2.0

Research Methodology

Clinic VisitClinic Visit Questionnaire dataQuestionnaire data: demographics, lifestyle : demographics, lifestyle

assessment, medical, reproductive, and menstrual assessment, medical, reproductive, and menstrual historieshistories

AnthropometricsAnthropometrics (height, weight, waist and hip (height, weight, waist and hip circumferences)circumferences)

Blood pressure assessmentBlood pressure assessment Lipids ( total cholesterol, triglycerides, LDLc, HDLc)Lipids ( total cholesterol, triglycerides, LDLc, HDLc)

Fasting glucose and insulinFasting glucose and insulin

Results

Hormone levels PCOS cases vs controlsHormone levels PCOS cases vs controls Blood lipid and insulin levels cases vs Blood lipid and insulin levels cases vs

controlscontrols AnthropometricsAnthropometrics Decided to look at age relationshipsDecided to look at age relationships

Selected Demographic and Reproductive Factors in PCOS Cases and Controls

VARIABLES

Age

BMI

HDLT

LDLc

Insulin

Triglycerides

WHR

CASES (n=244)

35.3 +7.4

29.9 +7.95

51.2 +14.74

119.9 +31.8

23.3 +17.8

123.6 +88.7

0.83 +0.13

CONTROLS (n=244)

36.7 +7.7

26.6 +6.77*

56.1 +14.43*

112.0 +32.6*

13.6 +8.7*

87.3 +63.1*

0.76 +0.07*

* p < 0.01** p < 0.05

CHD Risk Factors by Age in PCOS

Table 3. DISTRIBUTION OF CHD RISK FACTORS IN PCOS CASES AND CONTROLS BY AGE- 19-34 years

19-24

25-34

Cases N=24

Controls

N=21

Cases N=87

Controls

N=73 Body Mass Index

27.1 (6.4)

25.7 (7.5)

28.7 (7.1)

25.9 (6.5)*

Waist/Hip Ratio

.76 (.06)

.73 (.06)

.82 (.10)

.77 (.07)

Total Cholesterol HDLT (mg/dL) Calc LDL (mg/dL)

186.5 (29.1) 58.5 (16.6) 111.1 (31.4)

163.2 (37.9)* 55.0 (13.9) 91.1 (39.2)

192.6 (36.8) 50.1 (14.5) 120.1 (37.0)

181.1 (38.2) 54.9 (13.8)* 110.1 (33.3)*

Triglycerides (mg/dL) *

Median

83.5 (36.1)

82.5

85.5 (69.3)

73.0

114.3 (81.0)

97.0

77.4 (42.9)

62.5 ** Insulin (μU/L)

22.0 (14.5)

16.8 (12.3)

21.9 (21.8)

13.2 (10.1)**

Systolic (BP) (mm Hg)

108.9 (9.2)

106.7 (10.2)

109.9 (11.3)

107.6 (9.9)

Diastolic BP (mm Hg)

70.6 (7.9)

67.6 (5.9)

71.0 (9.0)

69.8 (7.3)

*p<.05 **p<.01

Adapted from the Journal of Clinical Epidemiology vol 51, No 5, 1998, Pages 415-422.

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CHD Risk Factors by Age in PCOS (cont.)

Table 3. DISTRIBUTION OF CHD RISK FACTORS IN PCOS CASES AND CONTROLS BY AGE- 35+ years

35-44

45+

Cases N=106

Controls N=105

Cases N=27

Controls

N=45 Body Mass Index

31.3 (7.8)

26.9 (6.9)**

30.8 (10.3)

27.1 (6.3)

Waist/Hip Ratio

0.8 (.01)

0.8 (.08)

.89 (0.3)

.76 (0.1)*

Total Cholesterol HDLT (mg/dL) Calc LDL (mg/dL)

200.3 (30.6) 49.9 (14.3) 123.1 (29.0)

185.0 (33.5)** 54.7 (12.7)** 112.2 (30.9)**

198.4 (33.8) 54.1 (13.9) 117.0 (27.6)

203.3 (32.3) 62.4 (17.2)* 121.5 (29.3)

Triglycerides (mg/dL) *

Median

132.3 (90.8)

109.5

86.5 (50.3) *

73.0 **

149.4 (117.2)

111.0

93.5 (91.4)

67.0 * Insulin (μU/L)

24.4 (19.7)

15.2 (11.6)

22.0 (17.0)

12.6 (6.8)**

Systolic (BP) (mm Hg)

116.4 (15.3)

110.6 (13.4)**

119.7 (21.2)

115.5 (15.8)

Diastolic BP (mm Hg)

75.0 (11.2)

70.7 (8.5)**

72.7 (13.1)

73.2 (8.9)

*p<.05 **p<.01

Adapted from the Journal of Clinical Epidemiology vol 51, No 5, 1998, Pages 415-422.

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Age Relationships

Risk profile by 10 year age groupsRisk profile by 10 year age groups LDL levels: Women with PCOS had sig > LDL levels: Women with PCOS had sig >

LDL levels at ages less than 35 yearsLDL levels at ages less than 35 years Insulin was higher in each age group than Insulin was higher in each age group than

controlscontrols BP was significantly greater than controls in BP was significantly greater than controls in

the 35 to 44 group onlythe 35 to 44 group only

Control for BMI

PCOS cases <40 yrs. showed significantly PCOS cases <40 yrs. showed significantly higher LDL levels than controls and this higher LDL levels than controls and this appears to be independent of BMIappears to be independent of BMI

simple regression line of risk factors by age for simple regression line of risk factors by age for cases and controls.cases and controls.

Predictors of CHD Risk Factors in PCOSTable 2. Estimated Parameters from Multiple Linear Regression: Predictors of

CHD Risk Factors

Independent

Variable

HDLT

HDL2

CHOL

LDL

SBP

DBP

Trig1

PCOS2

Age Hormone Status

Insulin BMI

Smoking

-2.512

-.025 .050

-.159* -.437* -.474

-2.158*

.031 1.029 -.054* -.238* -.523

9.121*

.857* -3.687

.094 .653*

-1.833

6.980*

.539* -2.82

-.02 .761*

-1.867

.763

.394* -1.041 .143* .799*

1.650*

.520

.174* -.468 .103* .514* .952*

.197* .011* -.046 .010* .016* .037

1 Triglyceride levels were log transformed

*p<.05

Summary

Younger women less than 40 with PCOS Younger women less than 40 with PCOS exhibit adverse lipid profilesexhibit adverse lipid profiles

Approximately 50% of PCOS are insulin Approximately 50% of PCOS are insulin resistant as demonstrated by a GIR <5resistant as demonstrated by a GIR <5