AS110 - Sex steroid hormones and risk of coronary heart disease: a nested case control study

Investigator Names and Contact Information

Kathryn Rexrode (krexrode@partners.org)

Introduction/Intent

Several lines of evidence suggest that sex steroid hormones may reduce risk of coronary heart disease (CHD) in women. In biologic studies, estrogen has diffuse protective effects on the cardiovascular system including favorable effects on lipid profiles, coagulation and fibrinolytic proteins, and antioxidant systems.[Mendelsohn, 1999 #130] CHD risk rapidly escalates as women pass through the menopause and endogenous estrogen levels fall,[Colditz, 1987 #178] while higher levels of endogenous estrogens have been associated with favorable lipid profiles.[Barrett‑Connor, 1995 #30;Svendsen, 1993 #41;Svendsen, 1993 #41;Kuller, 1990 #42;Haffner, 1995 #40] Additionally, exogenous hormones in the form of hormone replacement therapy have been associated with reduced risk of CHD in observational studies.[Grodstein, 1996 #91; Psaty, 1994 #92] High androgen levels in women appear to increase cardiovascular risk in women. Androgens are associated with adverse lipid profiles[Haffner, 1995 #40; Haffner, 1992 #106; Barrett‑Connor, 1996 #35; Wild, 1990 #43] and are directly related to diastolic and systolic blood pressure, increased risk of hypertension and abnormal glucose metabolism.[Phillips, 1997 #46; Mantzoros, 1995 #47; Haffner, 1995 #40;Barrett‑Connor, 1996 #35; Haffner, 1992 #106; Haffner, 1993 #108] While endogenous sex steroid hormone levels have been associated with risk of osteoporosis[Cummings, 1998 #51] and breast cancer,[Toniolo, 1995 #31; Dorgan, 1996 #32; Cauley, 1999 #96] only two small prospective studies [Barrett‑Connor, 1995 #29;Barrett‑Connor, 1995 #30;Lapidus, 1986 #52] have investigated the relationship of endogenous serum sex steroid hormones and risk of CHD in postmenopausal women. Reports thus far have been inconclusive, limited in size and conducted solely in Caucasian populations.

We propose to analyze the relationship of endogenous serum sex steroid levels (free and total testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin, free and total estradiol, and estrone sulfate) and risk of CHD among postmenopausal women in the Women’s Health Initiative Observational Study (WHI-OS) using a “nested” case-control design. The WHI-OS is an ethnically diverse, well-characterized cohort of postmenopausal women ages 50-79 years. In addition to investigating the relationship between androgens and estrogens and risk of CHD, we will evaluate the association between these hormones and biomarkers of thrombosis and inflammation, lipids, glucose and insulin, to determine the extent to which these factors might mediate or modify the relationship between endogenous hormones and risk of CHD. The extent to which obesity, fat distribution, ethnicity and behavioral factors may mediate or modify the relationship between sex steroid hormones and CHD will also be analyzed. Due to the supporting structure of the WHI and prior funding of other biomarkers (including lipids, glucose, insulin, and several thrombotic and inflammatory markers), this study will also be able to examine these questions in an extremely efficient and cost-effective manner.

Aims

A. To evaluate the relationship of endogenous sex steroid hormone levels and risk of CHD (myocardial infarction and coronary revascularization) in postmenopausal women.

1. Elevated free and total testosterone are associated with increased risk.

2. Elevated dehydroepiandrosterone sulfate (DHEAS) levels are associated with increased risk.

3. Low sex hormone binding globulin (SHBG) levels are associated with an increased risk of myocardial infarction in postmenopausal women.

4. Low free and total estradiol levels are associated with increased risk.

5. Low estrone sulfate levels are associated with increased risk.

6. A high testosterone/estrogen ratio is associated with increased risk.

B. To evaluate the correlation between endogenous sex steroid hormone levels and previously measured thrombotic and inflammatory markers of CHD in this cohort of postmenopausal women, specifically: tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), total plasma homocysteine, prothrombin fragment 1+2, D-dimer, C-reactive protein, and sICAM-1 and to examine whether these biomarkers might mediate the relationship between sex steroid hormones and CHD.

C. To examine the relationship between endogenous sex steroid hormone levels and previously measured lipoproteins, including total cholesterol, HDL, LDL, triglycerides and lipoprotein(a) and determine whether the effects of sex steroid hormones on CHD are independent of these factors.

D. To evaluate the correlation between endogenous sex steroid hormone levels and glucose metabolism, as measured by previously assayed fasting glucose and insulin levels, and to determine whether glucose metabolism mediates of modifies the effects of sex steroid hormones on CHD risk.

E. To evaluate the relationship between endogenous sex steroid hormones and anthropometric variables, including waist circumference, waist/hip ratio, (body mass index) BMI, and %body fat by DEXA, and to examine whether these factors mediate or modify the relationship between sex steroid hormones and CHD.

F. To evaluate the correlation between endogenous sex steroid hormone levels and ethnicity and various lifestyle, behavioral and health factors, such as smoking, alcohol consumption, physical activity, hysterectomy status and diet in postmenopausal women and to examine whether these factors modify the relationship between sex steroid hormones and risk of CHD.