Risk of Cardiovascular Disease by Hysterectomy Status, With and Without Oophorectomy
http://www.100md.com
循环学杂志 2005年第3期
the MedStar Research Institute (B.V.H., M.R.), Washington, DC
University of Pittsburgh (L.K.), Pittsburgh, Pa
UCSD School of Medicine (R.L.), La Jolla, Calif
Brigham and Women’s Hospital (J.E.M.), Harvard Medical School, Boston, Mass
University of Wisconsin (C.A.), Madison, Wis
The Memorial Hospital of Rhode Island (A.A.), Pawtucket, RI
Fred Hutchinson Cancer Research Center (B.B.C.), Seattle, Wash
University of Medicine and Dentistry of New Jersey (N.L.), Newark, NJ
Northwestern University (L.V.H.), Chicago, Ill
Stanford School of Medicine (M.L.S.), Stanford, Calif
Buffalo General Hospital (M.T.), Buffalo, NY.
Abstract
Background— Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in women and may vary by hysterectomy (or oophorectomy) status. This study compared CVD risk factors and rates between postmenopausal women who had and had not undergone hysterectomy, with or without oophorectomy.
Methods and Results— This analysis was conducted on 89 914 women in the Women’s Health Initiative (WHI) Observational Study. Participants reported demographic characteristics, medical history, dietary habits, physical activity, medications, and previous hysterectomy (with or without oophorectomy). Baseline weight, height, waist circumference, and blood pressure were measured. CVD events were ascertained during 5.1 years of mean follow-up and adjudicated with standard criteria. Black, Hispanic, and American Indian women had higher rates of hysterectomy than white women (52.9%, 44.6%, and 49.2% versus 40.0%, respectively), and Asian/Pacific Islander women had lower rates (33.8%). Women with a hysterectomy (regardless of oophorectomy status) had an adverse risk profile at baseline compared with women with no hysterectomy, including a higher proportion of hypertension, diabetes, high cholesterol, obesity, and lower education, income, and physical activity (all P<0.01). Total mortality and fatal and nonfatal CVD were higher among women with a hysterectomy. Hysterectomy (regardless of oophorectomy status) was a significant predictor of CVD (HR: 1.26, P<0.001). After adjustment for demographic variables and CVD risk factors, the effect was reduced and nonsignificant.
Conclusions— Women with a hysterectomy had a worse risk profile and higher prevalence and incidence of CVD in this cohort. Multivariate models suggest that hysterectomy is not the major determinant of this outcome; rather, CVD risk may be due to the more adverse initial risk profile of women who had undergone hysterectomy.
Key Words: hysterectomy ; mortality ; cardiovascular disease ; risk factors
Introduction
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in women in the United States. Hysterectomy is the most common surgical procedure for US women,1 and in 1989 it was estimated that one third of US women would undergo hysterectomy by the age of 65 years.2 Recent US surveillance data suggest that significant differences exist between women who do and do not undergo hysterectomy. Some3–5 but not all6 reports suggest that hysterectomy rates are higher among racial/ethic minority women than among white women. In addition, having had a hysterectomy has been associated with lower educational attainment, lower than average income, increased parity, and other variations in socioeconomic and reproductive history7,8 that may influence CVD risk. Furthermore, the loss of endogenous estrogen and the other hormone mediators produced by the uterus and ovaries and possible changes in iron balance, especially if surgery was performed at ages significantly below that of natural menopause, may have an impact on cardiovascular function.9 It is therefore important to separately examine the influence of hysterectomy on CVD risk factors and CVD.
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Baseline data from the 2 Women’s Health Initiative (WHI) hormone trials showed greater CVD risk factors in women with a hysterectomy than in women with no hysterectomy,6 and CVD rates differed for the placebo group in the 2 trials.10,11 To the best of our knowledge, there have been no comparisons of CVD risk factors and outcomes in women with or without hysterectomy in a longitudinal cohort. We sought to examine the hypothesis that the prevalence of CVD risk factors and rates of CVD may vary in women by hysterectomy status.
The WHI Observational Study is composed of 93 676 women who, after baseline examination, have been under continued surveillance for CVD outcomes. These women represent a wide range of ethnicity, education, and socioeconomic status, and 41% have undergone hysterectomy. This data set provides an opportunity to examine whether hysterectomy independently increases risk for CVD in postmenopausal women. In this article, rates of CVD, total mortality, and the prevalence of CVD risk factors are compared in women who had and had not undergone hysterectomy/oophorectomy at the time of enrollment to explore the relationship of hysterectomy with or without oophorectomy to CVD risk factors and to CVD events.
Methods
Study Population
The WHI Observational Study includes 93 676 women who were invited to join 1 of 2 randomized, controlled clinical trials (a diet trial and a hormone trial) but who were either ineligible or were not interested after initiating screening and who were interested in contributing natural history data.12 Postmenopausal women ages 50 to 79 years were recruited at 40 clinical centers throughout the United States between September 1994 and December 1998. The only exclusions were the expectation of not residing in the area for 3 years, having a medical condition associated with a predicted survival of <3 years, and inability to provide informed consent. Postmenopausal status was defined as absence of menstrual bleeding for 1 year if under age 55 years and for 6 months if over age 55. The participants provided written informed consent in a form approved by the clinical centers’ institutional review boards before completing self-administered forms and undergoing an interview, physical examination, and blood sample collection at baseline. The present analysis is based on baseline and follow-up data for a subset of women in the WHI Observational Study (n=89 914) for whom ethnicity and previous hysterectomy and oophorectomy could be characterized as described below.
Measures
Participants provided data on a wide range of variables, including dietary habits, medical history, physical activity, medications and supplements, and socioeconomic status. Ethnicity was determined by self-report with the following categories: non-Hispanic white, African-American/black (non-Hispanic), Hispanic, Asian/Pacific Islander, American Indian/Alaska Native, or unknown (women who indicated "other" ethnicity or did not answer the question). In this analysis, participants in the "Unknown" ethnicity category were excluded. The proportion of caloric intake as fat and as saturated fat was determined by a food frequency questionnaire that was based on instruments used in the Women’s Health Trial studies,13,14 the Working Well Study,15 and the Women’s Health Trial Feasibility Study in Minority Populations.16 Physical activity was assessed by self-report of frequency and duration of 4 walking speeds and 3 other types of recreational activity (classified as strenuous, moderate, or light intensity). The analytic variable was calculated as episodes per week of moderate or strenuous physical activity of at least 20 minutes’ duration (includes walking fairly fast or very fast, moderate physical activity, and strenuous physical activity at metabolic equivalent 4.0). Education and income were ascertained by choice from a range of categories. Current use of postmenopausal hormone therapy was ascertained via an interview on current and past hormone use.
Hysterectomy status was determined by asking, "Did you ever have a hysterectomy; (This is an operation to take out your uterus or womb.)" Oophorectomy status was determined by asking, "Did you ever have an operation to have one or both of your ovaries taken out;" with response categories of "No," "Yes, one was taken out," "Yes, both were taken out," "Yes, part of an ovary was taken out," "Yes, unknown number taken out," and "Don’t know." Women indicating either of the latter 2 categories had their bilateral oophorectomy status set as "missing." All women with missing hysterectomy or bilateral oophorectomy status (n=2094) were excluded from this analysis, as were women who reported an intact uterus but a bilateral oophorectomy (n=360). Women retaining both, 1, or part of 1 ovary were assigned to the "ovarian preservation" category. Age at menarche and hysterectomy, parity, and age at first birth were ascertained via self-administered questionnaires. Early hysterectomy was defined as having the surgery before 40 years of age.
Baseline weight was determined on a calibrated balance beam scale, with the women wearing indoor clothing but no shoes. Height was determined with a calibrated, wall-mounted stadiometer. Waist circumference was measured at the end of normal expiration over nonbinding undergarments in a horizontal plane at the natural waist. Blood pressure was measured with standard protocols, including measurement of an arm circumference for cuff size and having the subject sit quietly for 5 minutes before the measurement. The average of 2 determinations, 30 seconds apart, was used. Hypertension was defined as a blood pressure of 140/90 mm Hg or more or self-report of the use of antihypertension medication.
Although fasting blood samples were collected from the entire cohort, laboratory measures have been performed only on a subsample (1% in the Observational Study), stratified by age and ethnicity. Thus, elevated cholesterol was estimated as those women who reported that a doctor told them they had high cholesterol that required the use of pills. Diabetes was determined by the participant’s self-report of a doctor’s diagnosis of diabetes or high blood sugar when not pregnant.
Outcome Ascertainment
Detailed definitions of outcomes and methods for ascertaining, documenting, and classifying outcomes have been published.17 In brief, women were contacted twice each year to determine whether they had been hospitalized or had undergone a procedure suggestive of a CVD end point. Medical records for all positive responses were reviewed and abstracted. Adjudication of the key cardiovascular outcomes requiring hospitalization was performed centrally by WHI physician adjudicators. Summary measures of total CVD included a broader list of events that were adjudicated by either the central or local physician adjudicators. A definition of the key outcome is summarized below.
Cardiovascular Disease
Coronary heart disease was defined as acute myocardial infarction (MI) that required overnight hospitalization or as coronary death. Stroke diagnosis was based on the rapid onset of a neurological deficit that lasted >24 hours and required hospitalization and was supported by imaging studies when available. Coronary revascularization procedures were validated by medical record review. The incident CVD outcome for the present analysis encompasses coronary death, MI, stroke, and coronary revascularization procedures.
Statistical Methods
Hysterectomy status was divided into 3 groups: no hysterectomy and no bilateral oophorectomy, hysterectomy only (with ovarian preservation), and hysterectomy plus bilateral oophorectomy. The relationship between ethnicity and hysterectomy status was examined by first looking at the percentage of participants who had a hysterectomy, followed by the percentage of women who also had a bilateral oophorectomy for each ethnic group (Table 1). A Bonferroni adjustment for the 10 possible ethnic comparisons was used to compare percentages between ethnic groups.
Descriptive statistics, such as frequencies, percentages, and means, were used to describe the study population and to explore the relationship between descriptive variables and the 3 groups of women by hysterectomy/oophorectomy status (Table 2). Comparisons for continuous variables were made with ANOVA models with the covariate of interest as a response variable and hysterectomy/oophorectomy status as an explanatory variable. For categorical variables, comparisons were measured with a 2 test. Probability values are presented that compare the 3 hysterectomy status groups and all those with hysterectomy to those without.
Frequencies and annual percentages were computed to examine the relationship between various incident CVD outcomes and the 3 groups of women by hysterectomy status (Table 3). Percentages were calculated as the total number of events divided by the total follow-up time (measured in participant years). Follow-up here is the time from enrollment to the event, or if no event, to the date of the last follow-up contact. Probability values to compare the relationship between the occurrence of the individual CVD outcomes and hysterectomy status were computed from a Cox proportional hazards model, with hysterectomy status (done separately with and without an extra level for oophorectomy status) modeled as a predictor of each individual event. Participants who reported baseline CVD, angina, or congestive heart failure were excluded both from this annualized percentage analysis and all modeling.
Variables significant at the 0.05 level in the descriptive analyses were fitted in 3 separate Cox proportional hazards models, with incident CVD as the response variable. Each hysterectomy status group was analyzed in a separate model in an attempt to ascertain which variables were predictors of incident CVD.
Finally, 1 main Cox proportional hazards model was run that combined all 3 hysterectomy status groups and each of the significant predictors of incident CVD from the 3 individual models, thus forming a combined final model. This model was initially run with hysterectomy status as the only covariate and then rerun multiple times with the addition of demographics, body measures, and baseline conditions. The no hysterectomy/no bilateral oophorectomy group served as the reference level for hysterectomy status. Interactions between hysterectomy status and ethnicity were considered in this final modeling phase; however, none of the combinations of ethnicity and hysterectomy status interactions proved to be significant at the 0.05 level in any of the successive models. Therefore, these interactions were removed from the final results. Hazard ratios, 95% confidence limits, and probability values are presented for all proportional hazards models (Table 4). All analyses were performed with SAS System for Windows, version 9.0.
Results
Of the 92 368 women of known ethnicity enrolled in the WHI Observational Study, 2454 had missing or equivocal data on hysterectomy or oophorectomy status and were eliminated from the analysis. Of those 89 914 who remained, 41% had undergone a hysterectomy; of those with a hysterectomy, approximately half had undergone bilateral oophorectomy (Table 1). Women with a hysterectomy who reported partial oophorectomy (5142 women) were included in the hysterectomy-alone category. Black, Hispanic, and American Indian women were more likely to have undergone hysterectomy, whereas Asian/Pacific Islander women were less likely to have undergone hysterectomy than were white women. Among black and Hispanic women, hysterectomy was less likely to involve an oophorectomy than it was in white women (Table 1), whereas in Asian/Pacific Islander women, hysterectomies were more likely to involve oophorectomy. In black, Hispanic, and American Indian women, the age distribution at the time of hysterectomy was younger than in white or Asian/Pacific Islander women, with more of those women having a hysterectomy before 40 years of age (Table 1).
Women who had undergone hysterectomy differed from those who had not in many CVD risk factors at initial screening (Table 2 ). They were more obese and had greater waist circumferences. They were more likely to be hypertensive, a greater proportion reported high cholesterol that required medication, and white blood cell count was higher. A greater proportion of these women were taking postmenopausal hormone therapy in the form of unopposed estrogen; of women who had not undergone hysterectomy, the majority of hormone users were taking combination hormone therapy, whereas only 1265 (6.8%) were taking estrogen alone (data not shown). The women who had undergone hysterectomy participated in fewer episodes of exercise per week and had slightly higher percentages of caloric intake from saturated fat. They had relatively lower incomes, had attained lower levels of education, and had greater parity. Ages at menarche and first birth were younger. In addition, they had more self-reported CVD at baseline by all indicators, including prior MIs, coronary revascularization procedures, stroke, and congestive heart failure. They also reported more angina and peripheral arterial disease at baseline and had a greater family history of early myocardial infarction. Women who had undergone hysterectomy had a higher percentage of diabetes at baseline. In general, those with oophorectomy were slightly worse off on measured health characteristics than those who retained their ovaries.
After a mean 5.1-year follow-up, total CVD (fatal plus nonfatal) was significantly higher in those women who had undergone hysterectomy (Table 3). A significantly greater proportion of women with hysterectomy had an incident nonfatal cardiovascular event, including MI, revascularization procedure, stroke, angina, and reported congestive heart failure. CVD deaths tended to be higher in women with a hysterectomy, reaching significance when the 3 groups were compared.
When women with hysterectomy were compared with those without hysterectomy, risk factors for CVD were relatively similar in multivariate models, with incident CVD as a dependent variable run separately for women with a uterus, without a uterus but with ovaries, and again for those women with both a hysterectomy and bilateral oophorectomy. The following baseline variables were significant as independent predictors of CVD in all groups: age, hypertension, smoking, high cholesterol, diabetes, white blood cell count, and family history of early myocardial infarction. Weekly number of episodes of physical activity was inversely related to CVD in all groups. Parity and marital status were marginally significant in at least 1 of the models (data not shown).
A series of models was constructed to explore the relation among hysterectomy/oophorectomy and CVD (Table 4). In univariate analyses, hysterectomy alone, hysterectomy with oophorectomy, and the combined group were significant predictors of CVD (hazard ratios 1.23, 1.28, and 1.26, respectively, P<0.001). The addition of demographic variables, such as age, ethnicity, family history, income, and education, to the models reduced the hazard ratios to 1.14, 1.19, and 1.16, respectively (P=0.021, P=0.002, and P<0.001). Further addition of physiological measures (body mass index and white blood cell count), physical activity, and dietary saturated fat reduced the hysterectomy-only hazard ratio to 1.11, 1.16, and 1.14, with probability values of 0.064, 0.009, and 0.006, respectively. The further addition of baseline medical data (hypertension, diabetes, high cholesterol, smoking, peripheral arterial disease, and deep venous thrombosis histories) had little effect on the hazard ratio, with hysterectomy only and hysterectomy plus oophorectomy both being nonsignificant and the combined group all being of borderline significance (respectively, 1.10, 1.11, and 1.10; P=0.118, 0.086, and 0.042). Addition of reproductive variables, such as postmenopausal hormone therapy, parity, and age at menarche or first birth, to the model did not substantially alter the conclusions. A similar series of models was constructed with "hard" coronary heart disease outcomes (MI or coronary death, n=859). Hazard ratios for hysterectomy and hysterectomy plus oophorectomy, either univariate (0.99 and 1.11) or adjusted (0.94 and 1.04), were not significant at the P=0.05 level. There were no significant ethnicity-hysterectomy/oophorectomy interactions.
Discussion
These data represent the largest analysis of incident CVD and its determinants by hysterectomy status in postmenopausal women to date. This cohort of women from the Observational Study of the WHI is not a population-based sample, but the cohort is geographically diverse and includes a wide range of ethnicity and socioeconomic status. Compared with National Health and Nutrition Examination Survey (NHANES) data, average body mass index was similar to other women in this age range, and ethnic distribution of the sample was similar to that of other US women in this age distribution. In general, however, the women in this cohort were healthier at baseline than women of this age in the general population, as indicated by lower baseline prevalence of hypertension,18 diabetes,19 CVD,20 high cholesterol that required medication (pills),21 and smoking22,23 compared with NHANES III or the National Health Interview Survey. Household income and level of education also were higher,22 and fewer women reported no leisure-time physical activity.24 That these women were at relatively low risk and had relatively healthier medical histories is not surprising given the voluntary recruitment strategy. On the other hand, the differences in most of these variables were not large.
The percentage of women who had a hysterectomy (average 41%) is higher than that reported in the general US population. This relatively higher overall hysterectomy rate might be related to the fact that some of these women were originally recruited as part of an effort to recruit for the WHI hormone trials, to which women with a hysterectomy might have been more attracted. In this sample, the hysterectomy rates were significantly higher in black and Hispanic women and lower in Asian/Pacific Islander women. Ethnic differences in hysterectomy rates have been reported in some3,4,6 but not all5 previous studies. As with other studies, we found that minority women underwent hysterectomy at an early age but (except for Asian/Pacific Islander women) were less likely to have their ovaries removed.4 Any ethnic differences must be interpreted with caution, because the smaller number of women in the minority groups makes it less likely that they are representative of the ethnic group as a whole.
The present data show that women with a hysterectomy had more obesity and diabetes and a worse CVD baseline risk factor profile than women without a hysterectomy in almost all respects. They had higher rates of hypertension and hypercholesterolemia, less physical activity, and higher saturated fat intake. In general, the adverse risk factor profile was present in women with a hysterectomy with or without oophorectomy, although risk factor profiles generally were worse in women who had also undergone oophorectomy. Although some of the differences in risk factors are small, several (hypertension, diabetes) were of clinical significance and taken together are predictive of increased CVD risk. The women who had undergone hysterectomy had lower average family incomes and less education. This is consistent with previous studies showing that hysterectomies are performed more commonly in women with low socioeconomic status.4 This increased rate may be explained by the higher rates of obesity and diabetes, which are associated with greater incidence of fibroids and abnormal menstrual bleeding, both of which are indicators for hysterectomy. The low socioeconomic status with lower access to health care also may explain the poorer CVD risk factor status; studies have shown that rates of hypertension and hyperlipidemia are higher in individuals with lower income and education.24
Higher rates of CVD by all measures were seen both at baseline and during surveillance in women with a history of hysterectomy, with or without oophorectomy. These women were more likely at baseline to report a history of MI, strokes, revascularization procedures such as CABG and PTCA, and other manifestations of CVD, such as angina, congestive heart failure, and peripheral arterial disease. Annual unadjusted incidence rates for total CVD were almost 25% higher in women who had undergone hysterectomy. The majority of events were MIs and revascularization procedures, but the differential also appeared to be present in incidence rates of total CVD, angina, and congestive heart failure. Total mortality was higher in women who had undergone hysterectomy, and women who had undergone hysterectomy plus oophorectomy had higher rates of CVD mortality.
Hysterectomy alone, hysterectomy with oophorectomy, or any hysterectomy were significant univariate predictors of CVD, with hazard ratios of 1.23, 1.28, and 1.26, respectively. In the multivariate models, adjustment for demographics, ethnicity, education, and income reduced the hazard ratios, although they remained statistically significant. On further adjustment for risk factors, such as body habitus, blood pressure, physical activity, and dietary habits, the hazard ratios were further reduced and were of borderline significance. Inclusion of the other medical variables associated with hysterectomy, such as baseline hypertension, diabetes, high cholesterol, and peripheral arterial disease, further reduced the hazard ratios for CVD, and most were no longer significant.
In considering the sequential models, the data suggest that hysterectomy status was not independently associated with risk of CVD; rather, the adverse outcome is due to the adverse risk factor profile of women who undergo hysterectomy. It could be argued that removal of reproductive organs, especially the ovaries, is associated with a multitude of hormone changes that have been reported to influence CVD risk, and we do not know the risk factor status of these women before hysterectomy or the reason for the surgery. However, the present data do support the hypothesis that women who undergo hysterectomy in the United States tend to have lower income and education levels, more obesity and diabetes, and more adverse CVD risk factors and therefore greater CVD.
Some limitations of the study include that this is not a population-based sample of women, although the participants represent a wide range of ethnicity, education, socioeconomic status, and geographic distribution. In addition, hysterectomy and oophorectomy status, as well as other reproductive factors, were all obtained from self-report and not confirmed by medical record review. On the other hand, other studies have reported reasonable validity for self-report of hysterectomy.25,26 Any inaccuracy in reporting could have obscured differences between the hysterectomy-alone and hysterectomy- plus-oophorectomy groups.
Much attention in the United States is being placed on preventing CVD in postmenopausal women, and aggressive control of risk factors is warranted in all postmenopausal women. The present data suggest that healthcare providers should be aware that women who have undergone hysterectomy are more likely to have multiple CVD risk factors and therefore to be at increased risk of CVD.
Appendix
List of WHI Investigators
Program Office (National Heart, Lung, and Blood Institute, Bethesda, Md)
Barbara Alving, Jacques Rossouw, Linda Pottern, Shari Ludlam, Joan McGowan.
Clinical Coordinating Centers
Fred Hutchinson Cancer Research Center, Seattle, Wash: Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth Patterson, Anne McTiernan, Barbara Cochrane, Julie Hunt, Lesley Tinker, Charles Kooperberg, Martin McIntosh, C. Y. Wang, Chu Chen, Deborah Bowen, Alan Kristal, Janet Stanford, Nicole Urban, Noel Weiss, Emily White. Wake Forest University School of Medicine, Winston-Salem, NC: Sally Shumaker, Pentti Rautaharju, Ronald Prineas, Michelle Naughton. Medical Research Labs, Highland Heights, Ky: Evan Stein, Peter Laskarzewski. University of California at San Francisco, San Francisco, Calif: Steven Cummings, Michael Nevitt, Maurice Dockrell. University of Minnesota, Minneapolis, Minn: Lisa Harnack. McKesson BioServices, Rockville, Md: Frank Cammarata, Steve Lindenfelser. University of Washington, Seattle, Wash: Bruce Psaty, Susan Heckbert.
Clinical Centers
Albert Einstein College of Medicine, Bronx, NY: Sylvia Wassertheil-Smoller, William Frishman, Judith Wylie-Rosett, David Barad, Ruth Freeman. Baylor College of Medicine, Houston, Tex: Jennifer Hays, Ronald Young, Jill Anderson, Sandy Lithgow, Paul Bray. Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass: JoAnn Manson, Julie Buring, J. Michael Gaziano, Kathryn Rexrode, Claudia Chae. Brown University, Providence, RI: Annlouise R. Assaf, Carol Wheeler, Charles Eaton, Michelle Cyr. Emory University, Atlanta, Ga: Lawrence Phillips, Margaret Pedersen, Ora Strickland, Margaret Huber, Vivian Porter. Fred Hutchinson Cancer Research Center, Seattle, Wash: Shirley A.A. Beresford, Vicky M. Taylor, Nancy F. Woods, Maureen Henderson, Mark Kestin. George Washington University, Washington, DC: Judith Hsia, Nancy Gaba, Joao Ascensao. Harbor-UCLA Research and Education Institute, Torrance, Calif: Rowan Chlebowski, Robert Detrano, Anita Nelson, James Heiner, John Marshall. Kaiser Permanente Center for Health Research, Portland, Ore: Cheryl Ritenbaugh, Barbara Valanis, Patricia Elmer, Victor Stevens, Njeri Karanja. Kaiser Permanente Division of Research, Oakland, Calif: Bette Caan, Stephen Sidney, Geri Bailey Jane Hirata. Medical College of Wisconsin, Milwaukee, Wis: Jane Morley Kotchen, Vanessa Barnabei, Theodore A. Kotchen, Mary Ann C. Gilligan, Joan Neuner. MedStar Research Institute/Howard University, Washington, DC: Barbara V. Howard, Lucile Adams-Campbell, Maureen Passaro, Monique Rainford, Tanya Agurs-Collins. Northwestern University, Chicago/Evanston, Ill: Linda Van Horn, Philip Greenland, Janardan Khandekar, Kiang Liu, Carol Rosenberg. Rush-Presbyterian St. Luke’s Medical Center, Chicago, Ill: Henry Black, Lynda Powell, Ellen Mason. Stanford Center for Research in Disease Prevention, Stanford University, Stanford, Calif: Marcia L. Stefanick, Mark A. Hlatky, Bertha Chen, Randall S. Stafford, Linda C. Giudice. State University of New York at Stony Brook, Stony Brook, NY: Dorothy Lane, Iris Granek, William Lawson, Gabriel San Roman, Catherine Messina. The Ohio State University, Columbus, Ohio: Rebecca Jackson, Randall Harris, Electra Paskett, W. Jerry Mysiw, Michael Blumenfeld. University of Alabama at Birmingham, Birmingham, Ala: Cora E. Lewis, Albert Oberman, James M. Shikany, Monika Safford, Brian K. Britt. University of Arizona, Tucson/Phoenix, Ariz: Tamsen Bassford, John Mattox, Marcia Ko, Timothy Lohman. University at Buffalo, Buffalo, NY: Jean Wactawski-Wende, Maurizio Trevisan, Ellen Smit, Susan Graham, June Chang. University of California at Davis, Sacramento, Calif: John Robbins, S. Yasmeen, Karen Lindfors, Judith Stern. University of California at Irvine, Orange, Calif: Allan Hubbell, Gail Frank, Nathan Wong, Nancy Greep, Bradley Monk. University of California at Los Angeles, Los Angeles, Calif: Howard Judd, David Heber, Robert Elashoff. University of California at San Diego, La Jolla/Chula Vista, Calif: Robert D. Langer, Michael H. Criqui, Gregory T. Talavera, Cedric F. Garland, R. Elaine Hanson. University of Cincinnati, Cincinnati, Ohio: Margery Gass, Suzanne Wernke, Nelson Watts. University of Florida, Gainesville/Jacksonville, Fla: Marian Limacher, Michael Perri, Andrew Kaunitz, R. Stan Williams, Yvonne Brinson. University of Hawaii, Honolulu, Hawaii: David Curb, Helen Petrovitch, Beatriz Rodriguez, Kamal Masaki, Santosh Sharma. University of Iowa, Iowa City/Davenport, Iowa: Robert Wallace, James Torner, Susan Johnson, Linda Snetselaar, Bradley VanVoorhis. University of Massachusetts/Fallon Clinic, Worcester, Mass: Judith Ockene, Milagros Rosal, Ira Ockene, Robert Yood, Patricia Aronson. University of Medicine and Dentistry of New Jersey, Newark, NJ: Norman Lasser, Bali Singh, Vera Lasser, John Kostis. University of Miami, Miami, Fla: Mary Jo O’Sullivan, Linda Parker, R. Estape, Diann Fernandez. University of Minnesota, Minneapolis, Minn: Karen L, Margolis, Richard H. Grimm, Donald B. Hunninghake, June LaValleur, Sarah Kempainen. University of Nevada, Reno, Nev: Robert Brunner, William Graettinger, Vicki Oujevolk. University of North Carolina, Chapel Hill, NC: Gerardo Heiss, Pamela Haines, David Ontjes, Carla Sueta, Ellen Wells. University of Pittsburgh, Pittsburgh, Pa: Lewis Kuller, Jane Cauley, N. Carole Milas. University of Tennessee, Memphis, Tenn: Karen C. Johnson, Suzanne Satterfield, Raymond W. Ke, Jere Vile, Fran Tylavsky. University of Texas Health Science Center, San Antonio, Tex: Robert Brzyski, Robert Schenken, Jose Trabal, Mercedes Rodriguez-Sifuentes, Charles Mouton. University of Wisconsin, Madison, Wis: Gloria Sarto, Douglas Laube, Patrick McBride, Julie Mares-Perlman, Barbara Loevinger. Wake Forest University School of Medicine, Winston-Salem, NC: Denise Bonds, Greg Burke, Robin Crouse, Lynne Parsons, Mara Vitolins. Wayne State University School of Medicine/Hutzel Hospital, Detroit, Mich: Susan Hendrix, Michael Simon, Gene McNeeley, Pamela Gordon, Paul Makela.
Former WHI Investigators
Catherine Allen (University of Wisconsin, Madison, Wis); Sandy Dougherty (University of Nevada, Reno, Nev); and Richard Carleton (Brown University, Providence, RI), all deceased.
Acknowledgments
The WHI program is funded by the National Heart, Lung, and Blood Institute, US Department of Health and Human Services. See Appendix for list of investigators.
Footnotes
Deceased.
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Henderson MM, Kushi LH, Thompson DJ, Gorbach SL, Clifford CK, Insull W Jr, Moskowitz M, Thompson RS. Feasibility of a randomized trial of a low-fat diet for the prevention of breast cancer: dietary compliance in the Women’s Health Trial vanguard study. Prev Med. 1990; 19: 115–133.
White E, Shattuck AL, Kristal AR, Urban N, Prentice RL, Henderson MM, Insull W Jr, Moskowitz M, Goldman S, Woods MN. Maintenance of a low-fat diet: follow-up of the Women’s Health Trial. Cancer Epidemiol Biomarkers Prev. 1992; 1: 315–323.
Kristal A, Patterson RE, Glanz K, Heimendinger J, Hebert JR, Feng Z, Probart C. Psychosocial correlates of healthful diets and intention to improve diet: baseline results from the Working Well Study. Prev Med. 1995; 24: 221–228.
Kristal AR, Feng Z, Coates RJ, Oberman A, George V. Associations of race/ethnicity, education, and dietary intervention with the validity and reliability of a food frequency questionnaire: the Women’s Health Trial feasibility study in minority populations. Am J Epidemiol. 1997; 146: 856–869.
Curb JD, McTiernan A, Heckbert SR, Kooperberg C, Stanford J, Nevitt M, Johnson KC, Proulx-Burns L, Pastore L, Criqui M, Daugherty S; WHI Morbidity and Mortality Committee. Outcomes ascertainment and adjudication methods in the Women’s Health Initiative. Ann Epidemiol. 2003: 13: S122–S128.
Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan MJ, Labarthe D. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension. 1995; 25: 305–313.
Kenny SJ, Aubert RE, Geiss LS. Prevalence and incidence of non-insulin-dependent diabetes. In: National Diabetes Data Group, ed. Diabetes in America. Bethesda, Md: NIDDKD; 1995:47–68. NIH publication No. 95-1468.
Department of Health and Human Services, National Center for Health Statistics (NCHS). NHANES III (National Health and Nutrition Examination Survey, 1988–1994), CD-ROM (PB97–502959INC). Springfield, Va: National Technical Information Service; 1997.
Sempos CT, Cleeman JI, Carroll MD, Johnson CL, Bachorik PS, Gordon DJ, Burt VL, Briefel RR, Brown CD, Lippel K. Prevalence of high blood cholesterol among US adults: an update based on guidelines from the Second Report of the National Cholesterol Education Program Adult Treatment Panel. JAMA. 1993; 269: 3009–3014.
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National Center for Health Statistics. Health United States, 1994. Hyattsville, Md: Public Health Service; 1995.
Brunner E, Shipley MJ, Blane D, Smith GD, Smith GD, Marmot MG. When does cardiovascular risk start; Past and present socioeconomic circumstances and risk factors in adulthood. J Epidemiol Commun Health. 1999; 53: 757–764.
Colditz GA, Stampfer MJ, Willett WC, Stason WB, Rosner B, Hennekens CH, Speizer FE. Reproducibility and validity of self-reported menopausal status in a prospective cohort study. Am J Epidemiol. 1987; 126: 319–325.
Brett KM, Madans JH. Hysterectomy use: the correspondence between self-reports and hospital records. Am J Public Health. 1994; 84: 1653–1655.(Barbara V. Howard, PhD; L)
University of Pittsburgh (L.K.), Pittsburgh, Pa
UCSD School of Medicine (R.L.), La Jolla, Calif
Brigham and Women’s Hospital (J.E.M.), Harvard Medical School, Boston, Mass
University of Wisconsin (C.A.), Madison, Wis
The Memorial Hospital of Rhode Island (A.A.), Pawtucket, RI
Fred Hutchinson Cancer Research Center (B.B.C.), Seattle, Wash
University of Medicine and Dentistry of New Jersey (N.L.), Newark, NJ
Northwestern University (L.V.H.), Chicago, Ill
Stanford School of Medicine (M.L.S.), Stanford, Calif
Buffalo General Hospital (M.T.), Buffalo, NY.
Abstract
Background— Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in women and may vary by hysterectomy (or oophorectomy) status. This study compared CVD risk factors and rates between postmenopausal women who had and had not undergone hysterectomy, with or without oophorectomy.
Methods and Results— This analysis was conducted on 89 914 women in the Women’s Health Initiative (WHI) Observational Study. Participants reported demographic characteristics, medical history, dietary habits, physical activity, medications, and previous hysterectomy (with or without oophorectomy). Baseline weight, height, waist circumference, and blood pressure were measured. CVD events were ascertained during 5.1 years of mean follow-up and adjudicated with standard criteria. Black, Hispanic, and American Indian women had higher rates of hysterectomy than white women (52.9%, 44.6%, and 49.2% versus 40.0%, respectively), and Asian/Pacific Islander women had lower rates (33.8%). Women with a hysterectomy (regardless of oophorectomy status) had an adverse risk profile at baseline compared with women with no hysterectomy, including a higher proportion of hypertension, diabetes, high cholesterol, obesity, and lower education, income, and physical activity (all P<0.01). Total mortality and fatal and nonfatal CVD were higher among women with a hysterectomy. Hysterectomy (regardless of oophorectomy status) was a significant predictor of CVD (HR: 1.26, P<0.001). After adjustment for demographic variables and CVD risk factors, the effect was reduced and nonsignificant.
Conclusions— Women with a hysterectomy had a worse risk profile and higher prevalence and incidence of CVD in this cohort. Multivariate models suggest that hysterectomy is not the major determinant of this outcome; rather, CVD risk may be due to the more adverse initial risk profile of women who had undergone hysterectomy.
Key Words: hysterectomy ; mortality ; cardiovascular disease ; risk factors
Introduction
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in women in the United States. Hysterectomy is the most common surgical procedure for US women,1 and in 1989 it was estimated that one third of US women would undergo hysterectomy by the age of 65 years.2 Recent US surveillance data suggest that significant differences exist between women who do and do not undergo hysterectomy. Some3–5 but not all6 reports suggest that hysterectomy rates are higher among racial/ethic minority women than among white women. In addition, having had a hysterectomy has been associated with lower educational attainment, lower than average income, increased parity, and other variations in socioeconomic and reproductive history7,8 that may influence CVD risk. Furthermore, the loss of endogenous estrogen and the other hormone mediators produced by the uterus and ovaries and possible changes in iron balance, especially if surgery was performed at ages significantly below that of natural menopause, may have an impact on cardiovascular function.9 It is therefore important to separately examine the influence of hysterectomy on CVD risk factors and CVD.
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Baseline data from the 2 Women’s Health Initiative (WHI) hormone trials showed greater CVD risk factors in women with a hysterectomy than in women with no hysterectomy,6 and CVD rates differed for the placebo group in the 2 trials.10,11 To the best of our knowledge, there have been no comparisons of CVD risk factors and outcomes in women with or without hysterectomy in a longitudinal cohort. We sought to examine the hypothesis that the prevalence of CVD risk factors and rates of CVD may vary in women by hysterectomy status.
The WHI Observational Study is composed of 93 676 women who, after baseline examination, have been under continued surveillance for CVD outcomes. These women represent a wide range of ethnicity, education, and socioeconomic status, and 41% have undergone hysterectomy. This data set provides an opportunity to examine whether hysterectomy independently increases risk for CVD in postmenopausal women. In this article, rates of CVD, total mortality, and the prevalence of CVD risk factors are compared in women who had and had not undergone hysterectomy/oophorectomy at the time of enrollment to explore the relationship of hysterectomy with or without oophorectomy to CVD risk factors and to CVD events.
Methods
Study Population
The WHI Observational Study includes 93 676 women who were invited to join 1 of 2 randomized, controlled clinical trials (a diet trial and a hormone trial) but who were either ineligible or were not interested after initiating screening and who were interested in contributing natural history data.12 Postmenopausal women ages 50 to 79 years were recruited at 40 clinical centers throughout the United States between September 1994 and December 1998. The only exclusions were the expectation of not residing in the area for 3 years, having a medical condition associated with a predicted survival of <3 years, and inability to provide informed consent. Postmenopausal status was defined as absence of menstrual bleeding for 1 year if under age 55 years and for 6 months if over age 55. The participants provided written informed consent in a form approved by the clinical centers’ institutional review boards before completing self-administered forms and undergoing an interview, physical examination, and blood sample collection at baseline. The present analysis is based on baseline and follow-up data for a subset of women in the WHI Observational Study (n=89 914) for whom ethnicity and previous hysterectomy and oophorectomy could be characterized as described below.
Measures
Participants provided data on a wide range of variables, including dietary habits, medical history, physical activity, medications and supplements, and socioeconomic status. Ethnicity was determined by self-report with the following categories: non-Hispanic white, African-American/black (non-Hispanic), Hispanic, Asian/Pacific Islander, American Indian/Alaska Native, or unknown (women who indicated "other" ethnicity or did not answer the question). In this analysis, participants in the "Unknown" ethnicity category were excluded. The proportion of caloric intake as fat and as saturated fat was determined by a food frequency questionnaire that was based on instruments used in the Women’s Health Trial studies,13,14 the Working Well Study,15 and the Women’s Health Trial Feasibility Study in Minority Populations.16 Physical activity was assessed by self-report of frequency and duration of 4 walking speeds and 3 other types of recreational activity (classified as strenuous, moderate, or light intensity). The analytic variable was calculated as episodes per week of moderate or strenuous physical activity of at least 20 minutes’ duration (includes walking fairly fast or very fast, moderate physical activity, and strenuous physical activity at metabolic equivalent 4.0). Education and income were ascertained by choice from a range of categories. Current use of postmenopausal hormone therapy was ascertained via an interview on current and past hormone use.
Hysterectomy status was determined by asking, "Did you ever have a hysterectomy; (This is an operation to take out your uterus or womb.)" Oophorectomy status was determined by asking, "Did you ever have an operation to have one or both of your ovaries taken out;" with response categories of "No," "Yes, one was taken out," "Yes, both were taken out," "Yes, part of an ovary was taken out," "Yes, unknown number taken out," and "Don’t know." Women indicating either of the latter 2 categories had their bilateral oophorectomy status set as "missing." All women with missing hysterectomy or bilateral oophorectomy status (n=2094) were excluded from this analysis, as were women who reported an intact uterus but a bilateral oophorectomy (n=360). Women retaining both, 1, or part of 1 ovary were assigned to the "ovarian preservation" category. Age at menarche and hysterectomy, parity, and age at first birth were ascertained via self-administered questionnaires. Early hysterectomy was defined as having the surgery before 40 years of age.
Baseline weight was determined on a calibrated balance beam scale, with the women wearing indoor clothing but no shoes. Height was determined with a calibrated, wall-mounted stadiometer. Waist circumference was measured at the end of normal expiration over nonbinding undergarments in a horizontal plane at the natural waist. Blood pressure was measured with standard protocols, including measurement of an arm circumference for cuff size and having the subject sit quietly for 5 minutes before the measurement. The average of 2 determinations, 30 seconds apart, was used. Hypertension was defined as a blood pressure of 140/90 mm Hg or more or self-report of the use of antihypertension medication.
Although fasting blood samples were collected from the entire cohort, laboratory measures have been performed only on a subsample (1% in the Observational Study), stratified by age and ethnicity. Thus, elevated cholesterol was estimated as those women who reported that a doctor told them they had high cholesterol that required the use of pills. Diabetes was determined by the participant’s self-report of a doctor’s diagnosis of diabetes or high blood sugar when not pregnant.
Outcome Ascertainment
Detailed definitions of outcomes and methods for ascertaining, documenting, and classifying outcomes have been published.17 In brief, women were contacted twice each year to determine whether they had been hospitalized or had undergone a procedure suggestive of a CVD end point. Medical records for all positive responses were reviewed and abstracted. Adjudication of the key cardiovascular outcomes requiring hospitalization was performed centrally by WHI physician adjudicators. Summary measures of total CVD included a broader list of events that were adjudicated by either the central or local physician adjudicators. A definition of the key outcome is summarized below.
Cardiovascular Disease
Coronary heart disease was defined as acute myocardial infarction (MI) that required overnight hospitalization or as coronary death. Stroke diagnosis was based on the rapid onset of a neurological deficit that lasted >24 hours and required hospitalization and was supported by imaging studies when available. Coronary revascularization procedures were validated by medical record review. The incident CVD outcome for the present analysis encompasses coronary death, MI, stroke, and coronary revascularization procedures.
Statistical Methods
Hysterectomy status was divided into 3 groups: no hysterectomy and no bilateral oophorectomy, hysterectomy only (with ovarian preservation), and hysterectomy plus bilateral oophorectomy. The relationship between ethnicity and hysterectomy status was examined by first looking at the percentage of participants who had a hysterectomy, followed by the percentage of women who also had a bilateral oophorectomy for each ethnic group (Table 1). A Bonferroni adjustment for the 10 possible ethnic comparisons was used to compare percentages between ethnic groups.
Descriptive statistics, such as frequencies, percentages, and means, were used to describe the study population and to explore the relationship between descriptive variables and the 3 groups of women by hysterectomy/oophorectomy status (Table 2). Comparisons for continuous variables were made with ANOVA models with the covariate of interest as a response variable and hysterectomy/oophorectomy status as an explanatory variable. For categorical variables, comparisons were measured with a 2 test. Probability values are presented that compare the 3 hysterectomy status groups and all those with hysterectomy to those without.
Frequencies and annual percentages were computed to examine the relationship between various incident CVD outcomes and the 3 groups of women by hysterectomy status (Table 3). Percentages were calculated as the total number of events divided by the total follow-up time (measured in participant years). Follow-up here is the time from enrollment to the event, or if no event, to the date of the last follow-up contact. Probability values to compare the relationship between the occurrence of the individual CVD outcomes and hysterectomy status were computed from a Cox proportional hazards model, with hysterectomy status (done separately with and without an extra level for oophorectomy status) modeled as a predictor of each individual event. Participants who reported baseline CVD, angina, or congestive heart failure were excluded both from this annualized percentage analysis and all modeling.
Variables significant at the 0.05 level in the descriptive analyses were fitted in 3 separate Cox proportional hazards models, with incident CVD as the response variable. Each hysterectomy status group was analyzed in a separate model in an attempt to ascertain which variables were predictors of incident CVD.
Finally, 1 main Cox proportional hazards model was run that combined all 3 hysterectomy status groups and each of the significant predictors of incident CVD from the 3 individual models, thus forming a combined final model. This model was initially run with hysterectomy status as the only covariate and then rerun multiple times with the addition of demographics, body measures, and baseline conditions. The no hysterectomy/no bilateral oophorectomy group served as the reference level for hysterectomy status. Interactions between hysterectomy status and ethnicity were considered in this final modeling phase; however, none of the combinations of ethnicity and hysterectomy status interactions proved to be significant at the 0.05 level in any of the successive models. Therefore, these interactions were removed from the final results. Hazard ratios, 95% confidence limits, and probability values are presented for all proportional hazards models (Table 4). All analyses were performed with SAS System for Windows, version 9.0.
Results
Of the 92 368 women of known ethnicity enrolled in the WHI Observational Study, 2454 had missing or equivocal data on hysterectomy or oophorectomy status and were eliminated from the analysis. Of those 89 914 who remained, 41% had undergone a hysterectomy; of those with a hysterectomy, approximately half had undergone bilateral oophorectomy (Table 1). Women with a hysterectomy who reported partial oophorectomy (5142 women) were included in the hysterectomy-alone category. Black, Hispanic, and American Indian women were more likely to have undergone hysterectomy, whereas Asian/Pacific Islander women were less likely to have undergone hysterectomy than were white women. Among black and Hispanic women, hysterectomy was less likely to involve an oophorectomy than it was in white women (Table 1), whereas in Asian/Pacific Islander women, hysterectomies were more likely to involve oophorectomy. In black, Hispanic, and American Indian women, the age distribution at the time of hysterectomy was younger than in white or Asian/Pacific Islander women, with more of those women having a hysterectomy before 40 years of age (Table 1).
Women who had undergone hysterectomy differed from those who had not in many CVD risk factors at initial screening (Table 2 ). They were more obese and had greater waist circumferences. They were more likely to be hypertensive, a greater proportion reported high cholesterol that required medication, and white blood cell count was higher. A greater proportion of these women were taking postmenopausal hormone therapy in the form of unopposed estrogen; of women who had not undergone hysterectomy, the majority of hormone users were taking combination hormone therapy, whereas only 1265 (6.8%) were taking estrogen alone (data not shown). The women who had undergone hysterectomy participated in fewer episodes of exercise per week and had slightly higher percentages of caloric intake from saturated fat. They had relatively lower incomes, had attained lower levels of education, and had greater parity. Ages at menarche and first birth were younger. In addition, they had more self-reported CVD at baseline by all indicators, including prior MIs, coronary revascularization procedures, stroke, and congestive heart failure. They also reported more angina and peripheral arterial disease at baseline and had a greater family history of early myocardial infarction. Women who had undergone hysterectomy had a higher percentage of diabetes at baseline. In general, those with oophorectomy were slightly worse off on measured health characteristics than those who retained their ovaries.
After a mean 5.1-year follow-up, total CVD (fatal plus nonfatal) was significantly higher in those women who had undergone hysterectomy (Table 3). A significantly greater proportion of women with hysterectomy had an incident nonfatal cardiovascular event, including MI, revascularization procedure, stroke, angina, and reported congestive heart failure. CVD deaths tended to be higher in women with a hysterectomy, reaching significance when the 3 groups were compared.
When women with hysterectomy were compared with those without hysterectomy, risk factors for CVD were relatively similar in multivariate models, with incident CVD as a dependent variable run separately for women with a uterus, without a uterus but with ovaries, and again for those women with both a hysterectomy and bilateral oophorectomy. The following baseline variables were significant as independent predictors of CVD in all groups: age, hypertension, smoking, high cholesterol, diabetes, white blood cell count, and family history of early myocardial infarction. Weekly number of episodes of physical activity was inversely related to CVD in all groups. Parity and marital status were marginally significant in at least 1 of the models (data not shown).
A series of models was constructed to explore the relation among hysterectomy/oophorectomy and CVD (Table 4). In univariate analyses, hysterectomy alone, hysterectomy with oophorectomy, and the combined group were significant predictors of CVD (hazard ratios 1.23, 1.28, and 1.26, respectively, P<0.001). The addition of demographic variables, such as age, ethnicity, family history, income, and education, to the models reduced the hazard ratios to 1.14, 1.19, and 1.16, respectively (P=0.021, P=0.002, and P<0.001). Further addition of physiological measures (body mass index and white blood cell count), physical activity, and dietary saturated fat reduced the hysterectomy-only hazard ratio to 1.11, 1.16, and 1.14, with probability values of 0.064, 0.009, and 0.006, respectively. The further addition of baseline medical data (hypertension, diabetes, high cholesterol, smoking, peripheral arterial disease, and deep venous thrombosis histories) had little effect on the hazard ratio, with hysterectomy only and hysterectomy plus oophorectomy both being nonsignificant and the combined group all being of borderline significance (respectively, 1.10, 1.11, and 1.10; P=0.118, 0.086, and 0.042). Addition of reproductive variables, such as postmenopausal hormone therapy, parity, and age at menarche or first birth, to the model did not substantially alter the conclusions. A similar series of models was constructed with "hard" coronary heart disease outcomes (MI or coronary death, n=859). Hazard ratios for hysterectomy and hysterectomy plus oophorectomy, either univariate (0.99 and 1.11) or adjusted (0.94 and 1.04), were not significant at the P=0.05 level. There were no significant ethnicity-hysterectomy/oophorectomy interactions.
Discussion
These data represent the largest analysis of incident CVD and its determinants by hysterectomy status in postmenopausal women to date. This cohort of women from the Observational Study of the WHI is not a population-based sample, but the cohort is geographically diverse and includes a wide range of ethnicity and socioeconomic status. Compared with National Health and Nutrition Examination Survey (NHANES) data, average body mass index was similar to other women in this age range, and ethnic distribution of the sample was similar to that of other US women in this age distribution. In general, however, the women in this cohort were healthier at baseline than women of this age in the general population, as indicated by lower baseline prevalence of hypertension,18 diabetes,19 CVD,20 high cholesterol that required medication (pills),21 and smoking22,23 compared with NHANES III or the National Health Interview Survey. Household income and level of education also were higher,22 and fewer women reported no leisure-time physical activity.24 That these women were at relatively low risk and had relatively healthier medical histories is not surprising given the voluntary recruitment strategy. On the other hand, the differences in most of these variables were not large.
The percentage of women who had a hysterectomy (average 41%) is higher than that reported in the general US population. This relatively higher overall hysterectomy rate might be related to the fact that some of these women were originally recruited as part of an effort to recruit for the WHI hormone trials, to which women with a hysterectomy might have been more attracted. In this sample, the hysterectomy rates were significantly higher in black and Hispanic women and lower in Asian/Pacific Islander women. Ethnic differences in hysterectomy rates have been reported in some3,4,6 but not all5 previous studies. As with other studies, we found that minority women underwent hysterectomy at an early age but (except for Asian/Pacific Islander women) were less likely to have their ovaries removed.4 Any ethnic differences must be interpreted with caution, because the smaller number of women in the minority groups makes it less likely that they are representative of the ethnic group as a whole.
The present data show that women with a hysterectomy had more obesity and diabetes and a worse CVD baseline risk factor profile than women without a hysterectomy in almost all respects. They had higher rates of hypertension and hypercholesterolemia, less physical activity, and higher saturated fat intake. In general, the adverse risk factor profile was present in women with a hysterectomy with or without oophorectomy, although risk factor profiles generally were worse in women who had also undergone oophorectomy. Although some of the differences in risk factors are small, several (hypertension, diabetes) were of clinical significance and taken together are predictive of increased CVD risk. The women who had undergone hysterectomy had lower average family incomes and less education. This is consistent with previous studies showing that hysterectomies are performed more commonly in women with low socioeconomic status.4 This increased rate may be explained by the higher rates of obesity and diabetes, which are associated with greater incidence of fibroids and abnormal menstrual bleeding, both of which are indicators for hysterectomy. The low socioeconomic status with lower access to health care also may explain the poorer CVD risk factor status; studies have shown that rates of hypertension and hyperlipidemia are higher in individuals with lower income and education.24
Higher rates of CVD by all measures were seen both at baseline and during surveillance in women with a history of hysterectomy, with or without oophorectomy. These women were more likely at baseline to report a history of MI, strokes, revascularization procedures such as CABG and PTCA, and other manifestations of CVD, such as angina, congestive heart failure, and peripheral arterial disease. Annual unadjusted incidence rates for total CVD were almost 25% higher in women who had undergone hysterectomy. The majority of events were MIs and revascularization procedures, but the differential also appeared to be present in incidence rates of total CVD, angina, and congestive heart failure. Total mortality was higher in women who had undergone hysterectomy, and women who had undergone hysterectomy plus oophorectomy had higher rates of CVD mortality.
Hysterectomy alone, hysterectomy with oophorectomy, or any hysterectomy were significant univariate predictors of CVD, with hazard ratios of 1.23, 1.28, and 1.26, respectively. In the multivariate models, adjustment for demographics, ethnicity, education, and income reduced the hazard ratios, although they remained statistically significant. On further adjustment for risk factors, such as body habitus, blood pressure, physical activity, and dietary habits, the hazard ratios were further reduced and were of borderline significance. Inclusion of the other medical variables associated with hysterectomy, such as baseline hypertension, diabetes, high cholesterol, and peripheral arterial disease, further reduced the hazard ratios for CVD, and most were no longer significant.
In considering the sequential models, the data suggest that hysterectomy status was not independently associated with risk of CVD; rather, the adverse outcome is due to the adverse risk factor profile of women who undergo hysterectomy. It could be argued that removal of reproductive organs, especially the ovaries, is associated with a multitude of hormone changes that have been reported to influence CVD risk, and we do not know the risk factor status of these women before hysterectomy or the reason for the surgery. However, the present data do support the hypothesis that women who undergo hysterectomy in the United States tend to have lower income and education levels, more obesity and diabetes, and more adverse CVD risk factors and therefore greater CVD.
Some limitations of the study include that this is not a population-based sample of women, although the participants represent a wide range of ethnicity, education, socioeconomic status, and geographic distribution. In addition, hysterectomy and oophorectomy status, as well as other reproductive factors, were all obtained from self-report and not confirmed by medical record review. On the other hand, other studies have reported reasonable validity for self-report of hysterectomy.25,26 Any inaccuracy in reporting could have obscured differences between the hysterectomy-alone and hysterectomy- plus-oophorectomy groups.
Much attention in the United States is being placed on preventing CVD in postmenopausal women, and aggressive control of risk factors is warranted in all postmenopausal women. The present data suggest that healthcare providers should be aware that women who have undergone hysterectomy are more likely to have multiple CVD risk factors and therefore to be at increased risk of CVD.
Appendix
List of WHI Investigators
Program Office (National Heart, Lung, and Blood Institute, Bethesda, Md)
Barbara Alving, Jacques Rossouw, Linda Pottern, Shari Ludlam, Joan McGowan.
Clinical Coordinating Centers
Fred Hutchinson Cancer Research Center, Seattle, Wash: Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth Patterson, Anne McTiernan, Barbara Cochrane, Julie Hunt, Lesley Tinker, Charles Kooperberg, Martin McIntosh, C. Y. Wang, Chu Chen, Deborah Bowen, Alan Kristal, Janet Stanford, Nicole Urban, Noel Weiss, Emily White. Wake Forest University School of Medicine, Winston-Salem, NC: Sally Shumaker, Pentti Rautaharju, Ronald Prineas, Michelle Naughton. Medical Research Labs, Highland Heights, Ky: Evan Stein, Peter Laskarzewski. University of California at San Francisco, San Francisco, Calif: Steven Cummings, Michael Nevitt, Maurice Dockrell. University of Minnesota, Minneapolis, Minn: Lisa Harnack. McKesson BioServices, Rockville, Md: Frank Cammarata, Steve Lindenfelser. University of Washington, Seattle, Wash: Bruce Psaty, Susan Heckbert.
Clinical Centers
Albert Einstein College of Medicine, Bronx, NY: Sylvia Wassertheil-Smoller, William Frishman, Judith Wylie-Rosett, David Barad, Ruth Freeman. Baylor College of Medicine, Houston, Tex: Jennifer Hays, Ronald Young, Jill Anderson, Sandy Lithgow, Paul Bray. Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass: JoAnn Manson, Julie Buring, J. Michael Gaziano, Kathryn Rexrode, Claudia Chae. Brown University, Providence, RI: Annlouise R. Assaf, Carol Wheeler, Charles Eaton, Michelle Cyr. Emory University, Atlanta, Ga: Lawrence Phillips, Margaret Pedersen, Ora Strickland, Margaret Huber, Vivian Porter. Fred Hutchinson Cancer Research Center, Seattle, Wash: Shirley A.A. Beresford, Vicky M. Taylor, Nancy F. Woods, Maureen Henderson, Mark Kestin. George Washington University, Washington, DC: Judith Hsia, Nancy Gaba, Joao Ascensao. Harbor-UCLA Research and Education Institute, Torrance, Calif: Rowan Chlebowski, Robert Detrano, Anita Nelson, James Heiner, John Marshall. Kaiser Permanente Center for Health Research, Portland, Ore: Cheryl Ritenbaugh, Barbara Valanis, Patricia Elmer, Victor Stevens, Njeri Karanja. Kaiser Permanente Division of Research, Oakland, Calif: Bette Caan, Stephen Sidney, Geri Bailey Jane Hirata. Medical College of Wisconsin, Milwaukee, Wis: Jane Morley Kotchen, Vanessa Barnabei, Theodore A. Kotchen, Mary Ann C. Gilligan, Joan Neuner. MedStar Research Institute/Howard University, Washington, DC: Barbara V. Howard, Lucile Adams-Campbell, Maureen Passaro, Monique Rainford, Tanya Agurs-Collins. Northwestern University, Chicago/Evanston, Ill: Linda Van Horn, Philip Greenland, Janardan Khandekar, Kiang Liu, Carol Rosenberg. Rush-Presbyterian St. Luke’s Medical Center, Chicago, Ill: Henry Black, Lynda Powell, Ellen Mason. Stanford Center for Research in Disease Prevention, Stanford University, Stanford, Calif: Marcia L. Stefanick, Mark A. Hlatky, Bertha Chen, Randall S. Stafford, Linda C. Giudice. State University of New York at Stony Brook, Stony Brook, NY: Dorothy Lane, Iris Granek, William Lawson, Gabriel San Roman, Catherine Messina. The Ohio State University, Columbus, Ohio: Rebecca Jackson, Randall Harris, Electra Paskett, W. Jerry Mysiw, Michael Blumenfeld. University of Alabama at Birmingham, Birmingham, Ala: Cora E. Lewis, Albert Oberman, James M. Shikany, Monika Safford, Brian K. Britt. University of Arizona, Tucson/Phoenix, Ariz: Tamsen Bassford, John Mattox, Marcia Ko, Timothy Lohman. University at Buffalo, Buffalo, NY: Jean Wactawski-Wende, Maurizio Trevisan, Ellen Smit, Susan Graham, June Chang. University of California at Davis, Sacramento, Calif: John Robbins, S. Yasmeen, Karen Lindfors, Judith Stern. University of California at Irvine, Orange, Calif: Allan Hubbell, Gail Frank, Nathan Wong, Nancy Greep, Bradley Monk. University of California at Los Angeles, Los Angeles, Calif: Howard Judd, David Heber, Robert Elashoff. University of California at San Diego, La Jolla/Chula Vista, Calif: Robert D. Langer, Michael H. Criqui, Gregory T. Talavera, Cedric F. Garland, R. Elaine Hanson. University of Cincinnati, Cincinnati, Ohio: Margery Gass, Suzanne Wernke, Nelson Watts. University of Florida, Gainesville/Jacksonville, Fla: Marian Limacher, Michael Perri, Andrew Kaunitz, R. Stan Williams, Yvonne Brinson. University of Hawaii, Honolulu, Hawaii: David Curb, Helen Petrovitch, Beatriz Rodriguez, Kamal Masaki, Santosh Sharma. University of Iowa, Iowa City/Davenport, Iowa: Robert Wallace, James Torner, Susan Johnson, Linda Snetselaar, Bradley VanVoorhis. University of Massachusetts/Fallon Clinic, Worcester, Mass: Judith Ockene, Milagros Rosal, Ira Ockene, Robert Yood, Patricia Aronson. University of Medicine and Dentistry of New Jersey, Newark, NJ: Norman Lasser, Bali Singh, Vera Lasser, John Kostis. University of Miami, Miami, Fla: Mary Jo O’Sullivan, Linda Parker, R. Estape, Diann Fernandez. University of Minnesota, Minneapolis, Minn: Karen L, Margolis, Richard H. Grimm, Donald B. Hunninghake, June LaValleur, Sarah Kempainen. University of Nevada, Reno, Nev: Robert Brunner, William Graettinger, Vicki Oujevolk. University of North Carolina, Chapel Hill, NC: Gerardo Heiss, Pamela Haines, David Ontjes, Carla Sueta, Ellen Wells. University of Pittsburgh, Pittsburgh, Pa: Lewis Kuller, Jane Cauley, N. Carole Milas. University of Tennessee, Memphis, Tenn: Karen C. Johnson, Suzanne Satterfield, Raymond W. Ke, Jere Vile, Fran Tylavsky. University of Texas Health Science Center, San Antonio, Tex: Robert Brzyski, Robert Schenken, Jose Trabal, Mercedes Rodriguez-Sifuentes, Charles Mouton. University of Wisconsin, Madison, Wis: Gloria Sarto, Douglas Laube, Patrick McBride, Julie Mares-Perlman, Barbara Loevinger. Wake Forest University School of Medicine, Winston-Salem, NC: Denise Bonds, Greg Burke, Robin Crouse, Lynne Parsons, Mara Vitolins. Wayne State University School of Medicine/Hutzel Hospital, Detroit, Mich: Susan Hendrix, Michael Simon, Gene McNeeley, Pamela Gordon, Paul Makela.
Former WHI Investigators
Catherine Allen (University of Wisconsin, Madison, Wis); Sandy Dougherty (University of Nevada, Reno, Nev); and Richard Carleton (Brown University, Providence, RI), all deceased.
Acknowledgments
The WHI program is funded by the National Heart, Lung, and Blood Institute, US Department of Health and Human Services. See Appendix for list of investigators.
Footnotes
Deceased.
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