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 Epidemiology Graduate School of Public Health University of Pittsburgh Evelyn Talbott, Dr.P.H. Dept. of Epidemiology Graduate School of Public Health

Learning Objective I To review some of the designs employed in the study of Cardiovascular Disease risk factors in women with PCOS To review some of the designs employed in the study of Cardiovascular Disease risk factors in women with PCOS  Retrospective  Prospective  Historical Prospective

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

Learning Objective III To more fully understand the metabolic parameters of PCOS in women in relation to Cardiovascular Disease risk over time and To more fully understand the metabolic parameters of PCOS in women in relation to Cardiovascular 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 women in the US.  It is a heterogeneous reproductive endocrine disorder.

Characteristics of PCOS U Chronic anovulation U Hyperandrogenemia U Insulin Resistance U Hyperinsulinemia U Obesity U Impaired Glucose Tolerance (IGT) U Central Adiposity

Etiology of Polycystic Ovary Syndrome (PCOS) U Primary dysregulation of ovarian steroidogenesis (Ehrmann, 1995); insulin post-receptor binding defect (Dunaif, 1992) U Multiple arrested follicles are present with increased ovarian stroma (pearl necklace effect) U Results in hypertrophied ovarian theca cells, elevated androgens, lack of a mid-cycle estradiol surge, and disrupted folliculogenesis (Barnes, 1997)

Atretic Follicle Thickened Capsule From: The Menstrual Cycle (1993), Ferin, Jewelewicz, and Warren The Polycystic Ovary Enlarged Ovary 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 heart disease with increased prevalence of CHD risk factors: (LDL, HDL, triglycerides, hypertension and diabetes.)  However, the literature to date has been inconsistent.  Studies to date have been observational, largely consisting of case-control and cross sectional designs.

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PCOS and Cardiovascular Risk U PCOS is associated with an increased prevalence of cardiovascular disease risk factors (Wild, 1988; Talbott, 1995) U In both lean and obese PCOS cases exhibited > fasting insulin levels (Slowinska-Srzednicka, 1991) U PCOS women have evidence of metabolic derangements similar to the Metabolic Cardiovascular Syndrome (Syndrome X) [dyslipidemia (  LDLc,  HDLc,  triglycerides), hypertension, and Type II diabetes]

Literature continued Conversely, other investigators have noted little difference in LDLc levels in thin versus obese PCOS cases and controls (Norman l992, Conway, l995). Conversely, other investigators have noted little difference in LDLc levels in thin versus obese PCOS cases and controls (Norman l992, Conway, l995). Earlier studies had small sample sizes and did not control for potential confounders Earlier studies had small sample sizes and did not control for potential confounders

Summary of Studies Linking Adverse Lipid Profiles in Women with PCOS Click for larger picture

Hyperinsulinemia, Insulin Resistance, and Impaired Hemostatic Function U Hyperinsulinemia and insulin resistance, as observed in PCOS, have been associated with increased CVD risk (Haffner, 1992; Savage, 1996; Reaven, 1998) U Recent evidence suggests hyperinsulinemia in PCOS correlates with increased CVD risk independent of obesity (Mather, 2000) U Increased risk may be a direct effect of elevated insulin or an indirect effect, through the influence of insulin on other metabolic processes (e.g. thrombosis, fibrinolysis) U Whether this translates into a true “ increased risk” of CHD is not known

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

Types of Cohort Studies Click for larger picture

Pierpoint et al., J Clinical Epi, 51(7), 1998 Click for larger picture

Brief Literature Review In an earlier study of sudden cardiac death among women aged in Allegheny County (Talbott ’89), we noted an > rate of childlessness in ever married cases compared to controls (N=80 cases, 80 controls). In an earlier study of sudden cardiac death among women aged in Allegheny County (Talbott ’89), we noted an > rate of childlessness in ever married cases compared to controls (N=80 cases, 80 controls). Detailed reproductive histories,however, were not available. Detailed reproductive histories,however, were not available. The question of whether a reproductive endocrine abnormality such as PCOS was somehow linked to sudden cardiac death was intriguing. The question of whether a reproductive endocrine abnormality such as PCOS was somehow linked to sudden cardiac death was intriguing.

Risk of CHD in PCOS (Phase I l ) (Talbott, Guzick, Berga et. al.)  PCOS was a common enough diagnosis in medical practices that a large-scale study was possible.  The specific aim of our first study was to provide information on whether women with PCO have a greater incidence of known risk factors for CHD compared to age matched controls.

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

Recruitment continued  Review of records of Dr. David Archer ( ) /Drs. David Guzick and Sarah Berga (2800 records, 10% met PCOS criteria)  Definition of PCOS :chronic anovulation and 1) evidence of clinical (hirsutism) or biochemical (Total T > 2.0 nmol/L) hyperandrogenism or 2) LH:FSH > 2.0

Research Methodology Clinic Visit Clinic Visit  Questionnaire data: demographics, lifestyle assessment, medical, reproductive, and menstrual histories  Anthropometrics (height, weight, waist and hip circumferences)  Blood pressure assessment  Lipids ( total cholesterol, triglycerides, LDLc, HDLc)  Fasting glucose and insulin

Results  Hormone levels PCOS cases vs controls  Blood lipid and insulin levels cases vs controls  Anthropometrics  Decided to look at age relationships

Selected Demographic and Reproductive Factors in PCOS Cases and Controls VARIABLES Age BMI HDL T LDLc Insulin Triglycerides WHR CASES (n=244) CONTROLS (n=244) * * * * * * * p < 0.01 ** p < 0.05

CHD Risk Factors by Age in PCOS Click for larger picture

CHD Risk Factors by Age in PCOS (cont.) Click for larger picture

Age Relationships  Risk profile by 10 year age groups  LDL levels: Women with PCOS had sig > LDL levels at ages less than 35 years  Insulin was higher in each age group than controls  BP was significantly greater than controls in the 35 to 44 group only

Control for BMI PCOS cases <40 yrs. showed significantly higher LDL levels than controls and this appears to be independent of BMI PCOS cases <40 yrs. showed significantly higher LDL levels than controls and this appears to be independent of BMI simple regression line of risk factors by age for cases and controls. simple regression line of risk factors by age for cases and controls.

Predictors of CHD Risk Factors in PCOS 1Triglyceride levels were log transformed *p<.05

Summary Younger women less than 40 with PCOS exhibit adverse lipid profiles Younger women less than 40 with PCOS exhibit adverse lipid profiles Approximately 50% of PCOS are insulin resistant as demonstrated by a GIR <5 Approximately 50% of PCOS are insulin resistant as demonstrated by a GIR <5