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The Dietary Clinical Trials of the Women’s Health Initiative: Part 2

J. Kell Williams, MD; H. James Brownlee, MD

In the March issue of The Female Patient (2010;35[3]:32-34), we looked at nonhormone clinical trials of the Women’s Health Initiative focusing on the results of low-fat diet modification and of calcium plus vitamin D supplementation. Here we will report on a number of other associations prospectively observed.

The portion of the controversial Women’s Health Initiative (WHI) given the least attention comprises the almost 160,000 women in the ongoing prospective observational study.1 When fully analyzed, this cohort may be the largest of its kind and could provide a wealth of clinical information. The areas of interest are incredibly diverse and at this point appear to be quite random. Thus far, a number of epidemiologic reports have been published, many with unexpected results.

Kabat et al looked at the relationship between body mass index (BMI), waist circumference, and the incidence of lung cancer.2 There had been 1,365 incident cases at the time of the report. Of all the possible variables, 2 comparisons were found to have a difference reaching statistical significance. BMI by quartile was inversely associated with lung cancer in current smokers (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.22-0.72); ie, the greater the BMI, the less the risk for lung cancer. In contrast, in current smokers, waist circumference by quartile increased risk (HR, 1.56; CI, 0.98-2.31). In never smokers, height showed borderline positive association with lung cancer.

In a related study, Kabat and colleagues reported on the relationship between dietary carbohydrates and 1,476 cases of colorectal cancer.3 Factors examined were total carbohydrates, sugars, fiber, glycemic index, glycemic load, BMI, and physical activity. They found no relationship between dietary carbohydrates and colorectal carcinogenesis.

Thompson et al investigated antioxidant and vitamin A intake and the risk for ovarian cancer.4 In the 451 incident cases, covariates included vitamins C, A, and E, selenium, and carotenoids. They found no association between antioxidants, vitamin A, and ovarian cancer. Another study examined vitamin A and retinol intakes and the risk for fractures.5 The adjusted covariates were age, BMI, vitamins K and D, calcium, caffeine, alcohol, smoking, hormone use, and geographic region. They found no association between vitamin A and retinol intake and risk for fractures, except with high vitamin A and low vitamin D intake.

Observational data reaffirmed epidemiologic risk factors for fractures.6 Included were clinical risk factors of age, ethnicity, diabetes, and corticosteroid use, family history of fracture in parent after age 54, health factors such as weight, height, physical activity, and smoking, and biomarkers such as low vitamin D, low testosterone, high cystatin C, and high sex hormone binding globulin. In a separate analysis, 7 biomarkers for hemorrhagic stroke risk were found: C-reactive protein, tissue plasminogen activator, interleukin 5, D-dimer, neopterin, leukocyte count, and homocysteine.7 C-reactive protein emerged as the only independent single predictor of ischemic stroke.

Lederle et al reported on the 184 incident abdominal aortic aneurysm events.8 Increased risk was related to age, height, smoking, hypertension, coronary artery disease, and a variety of cholesterol-lowering treatments. Decreased risk was found in women taking postmenopausal hormone therapy and, interestingly, in those with diabetes.

Another epidemiologic consideration was dose-response relationships between the cumulative number of months women lactated and postmenopausal risk factors for cardiovascular disease.9 A dose-response relationship was seen in women who reported a lifetime history of longer than 12 months of lactation. They were less likely to have hypertension (odds ratio [OR], 0.88; P<.001), diabetes (OR, 0.80; P<.001), or hyperlipidemia (OR, 0.81; P<.001). Over the 8-year study period, women with a single live birth who breastfed for 7 to 12 months were significantly less likely to develop cardiovascular disease (HR, 0.72; CI, 0.53-0.97) than were women who never breastfed.

A straightforward report examined the incidence of fractures, breast cancer, and cardiovascular events in a subgroup of 83,724 women ages 70 to 79 with an average 7.7 years of follow-up.10 Contrary to public opinion, the rate of osteoporotic fracture was more than invasive breast cancer and cardiovascular events combined—except in black women, where the order was cardiovascular events, followed by fracture, then breast cancer.

Duffy and colleagues reported on the relationship of alcohol intake and risk for breast cancer and whether folate might modify this relationship.11 There were 1,783 breast cancer cases in 88,530 postmenopausal women over 5 years. Alcohol was associated with a small but significant increased risk for breast cancer (relative risk [RR], 1.005; CI, 1.001-1.009) that was directly related to dose. They found no significant interaction between alcohol and folate on breast cancer risk but admitted difficulty in calculating alcohol and folate intake in this observational study design.

Also investigated were the racial differences in cancer survivors’ quality of life (QoL).12 Of the 5,021 breast cancer survivors, African American women had small but clinically meaningful decrements in QoL scores compared with white survivors. Confounding the conclusion was that African American women had higher grade tumors and higher cancer mortality.

Depression and cancer screening were the focus of another study.13 Depressive symptoms were assessed using the 6-item Center for Epidemiologic Studies Depression scale at baseline (15.8%) and 3 years (6.9%). The overall average screening rate was 71% for breast cancer and 53% for colorectal cancer. Not surprisingly, depressive symptoms lowered the breast cancer screening rate by 1.5%. However, depression had no effect on the colorectal screening rate.

An intriguing study by Liao et al used the WHI database to attempt to relate ambient particulate air pollution and ventricular ectopy to elucidate the environmental epidemiology of arrhythmogenesis.14 They matched the home addresses of 57,422 WHI participants to EPA estimates of daily mean concentrations of pollution at each geocoded address. The researchers found that only in current smokers were pollution scores significantly associated with these arrhythmias.

Equally intriguing are 2 recent analyses of WHI participants. The first evaluates women who reported physical and/or verbal abuse over the prior year.15 They had significantly higher mortality risk than women who did not report abuse (HR, 1.54; CI, 1.09-2.18), after adjusting for demographic and health-related factors. The second looked at factors of optimism and cynical hostility.16 Optimists (vs pessimists) had lower risks for coronary heart disease (CHD) (HR, 0.91; CI, 0.83-0.99), CHD-related mortality (HR, 0.70; CI, 0.55-0.90), cancer-related mortality (HR, 0.56; CI, 0.35-0.88), and total mortality (HR, 0.86; CI, 0.79-0.93). The most (vs least) cynical, hostile women had higher risks for cancer-related mortality (HR, 1.23; CI, 1.09-1.40) and total mortality (HR, 1.16; CI, 1.07-1.27).

As critical as the medical community has been with regard to the WHI hormone trials, a wealth of random epidemiologic information is currently being gathered from the large prospective cohort in the WHI observational study. Whether the results will justify the cost is yet to be seen.

The authors report no actual or potential conflicts of interest in relation to this article.

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J. Kell Williams, MD, is Professor and Director, Division of Gynecology, Department of Obstetrics and Gynecology, and H. James Brownlee, MD, is Professor and Chairman, Department of Family Medicine, both at the University of South Florida College of Medicine, Tampa.

References

1. Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials. 1998;19(1):61-109.
2. Kabat GC, Kim M, Hunt JR, Chlebowski RT, Rohan TE. Body mass index and waist circumference in relation to lung cancer risk in the Women’s Health Initiative. Am J Epidemiol. 2008;168(2):158-169.
3. Kabat GC, Shikany JM, Beresford SA, et al. Dietary carbohydrate, glycemic index, and glycemic load in relation to colorectal cancer risk in the Women’s Health Initiative. Cancer Causes Control. 2008;19(10):1291-1298.
4. Thomson CA, Neuhouser ML, Shikany JM, et al. The role of antioxidants and vitamin A in ovarian cancer: results from the Women’s Health Initiative. Nutr Cancer. 2008; 60(6):710-719.
5. Caire-Juvera G, Ritenbaugh C, Wactawski-Wende J, Snetselaar LG, Chen Z. Vitamin A and retinol intakes and the risk of fractures among participants of the Women’s Health Initiative Observational Study. Am J Clin Nutr. 2009;89(1):323-330.
6. Jackson RD, Donepudi S, Mysiw WJ. Epidemiology of fracture risk in the Women’s Health Initiative. Curr Osteoporos Rep. 2008;6(4):155-161.
7. Kaplan RC, McGinn AP, Baird AE, et al. Inflammation and hemostasis biomarkers for predicting stroke in postmenopausal women: the Women’s Health Initiative Observational Study. J Stroke Cerebrovasc Dis. 2008;17(6): 344-355.
8. Lederle FA, Larson JC, Margolis KL, et al. Abdominal aortic aneurysm events in the Women’s Health Initiative: cohort study. BMJ. 2008;337:a1724.
9. Schwarz EB, Ray RM, Stuebe AM, et al. Duration of lactation and risk factors for maternal cardiovascular disease. Obstet Gynecol. 2009;113(5):974-982.
10. Cauley JA, Wampler NS, Barnhart JM, et al. Incidence of fractures compared to cardiovascular disease and breast cancer: the Women’s Health Initiative Observational Study. Osteoporosis Int. 2008;19(12):1717-1723.
11. Duffy CM, Assaf A, Cyr M, et al. Alcohol and folate intake and breast cancer risk in the WHI Observational Study. Breast Cancer Res Treat. 2009;116(3):551-562.
12. Paskett ED, Alfano CM, Davidson MA, et al. Breast cancer survivors’ health-related quality of life: racial differences and comparisons with noncancer controls. Cancer. 2008;113(11):3222-3230.
13. Aggarwal A, Freund K, Sato A, et al. Are depressive symptoms associated with cancer screening and cancer stage at diagnosis among postmenopausal women? The Women’s Health Initiative observational cohort. J Womens Health (Larchmt). 2008;17(8):1353-1361.
14. Liao D, Whitsel EA, Duan Y, et al. Ambient particulate air pollution and ectopy—the environmental epidemiology of arrhythmogenesis in Women’s Health Initiative Study, 1999-2004. J Toxicol Environ Health A. 2009;72(1):30-38.
15. Baker MW, LaCroix AZ, Wu C, Cochrane BB, Wallace R, Woods NF. Mortality risk associated with physical and verbal abuse in women aged 50 to 79. J Am Geriatr Soc. 2009;57(10): 1799-1809.
16. Tindle HA, Chang YF, Kuller LH, et al. Optimism, cynical hostility, and incident coronary heart disease and mortality in the Women’s Health Initiative. Circulation. 2009; 120(8):656-662.

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