- Email: [email protected]
Hormone replacement therapy use and menopausal symptoms among women participating in a behavioral lifestyle intervention
Preventive
Medicine 33, 108-114
doi:10.1006/pmed.2001.0858,
(2001)
available
online at http://www.idealibrary.com
on
IDEhl@
Hormone Replacement Therapy Use and Menopausal Symptoms among Women Participating in a Behavioral Lifestyle Intervention’ Miriam A. Boraz,*,2 Laurey R. Simkin-Silverman ,* Rena R. Wing,t Elaine N. Meilahn,” and Lewis H. Kuller” *Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and TDepartment of Psychiatry, Brown University, Providence, Rhode Island 02912
the perimenopause did not affect menopausal symp toms. G2001 American Health Foundation and Academic Press Key Words: hormone therapy; menopause; cardiovascular; lifestyle intervention.
The decision to take hormone replacement therapy (HRT) is a choice many women encounter when entering menopause. The purpose of this study was to examine the choice to take HRT while participating in a lifestyle intervention to reduce cardiovascular risk through the menopause. Methods. The Women’s Healthy Lifestyle Project is a randomized clinical trial designed to examine whether a behavioral lifestyle intervention can decrease the expected rise in cardiovascular risk through the menopause. Participants (N = 535) completed questionnaires and were interviewed regarding menopausal symptoms, menopausal status, hot flashes, and HRT use at baseline and 54 months. Results. The intervention was successful in preventing risk elevation through the 54-month visit. At the final visit, there was no difference between the intervention and control groups in the percentage who had become postmenopausal (32.9% vs 35.0%, respectively), there was no difference between control and intervention with HRT use, with 31.2% reporting use of HRT, and there was no difference between groups with menopausal symptoms. The women started HRT an average of 6 months after they missed a period. Baseline risk factors did not predict HRT use at the 54-month visit. Conclusions. A sizable number of women reported HRT use. The decision to use HRT was not influenced by the lifestyle intervention or their baseline cardiovascular risk, and these women started HRT very early in the peri- to postmenopause. Further, weight loss in Background.
INTRODUCTION
Women in their late forties and early fifties are faced with the question of whether to use hormone replacement therapy (HRT) to manage menopausal symptoms and manage disease risk. This paper addresses HRT patterns of use in women through the menopause. The decision to take HRT depends on careful consideration of both the long- and short-term effects of HRT. The short term benefit of HRT use is the attenuation of menopausal symptoms such as hot flashes, skin changes, and urogenital atrophy 111.HRT is currently considered one of the most effective treatments for relief of hot flashes and night sweats. Seventy-five percent of per-i-to postmenopausal women experience hot flashes. Interestingly, only 30% of women seek help for hot flashes 121,implying that many women experience hot flashes and cope with them nonmedically and suggesting a wide range in severity. Despite the short-term benefits of HRT for symptom reduction, many women choose not to take HRT (or take sporadically) because of the side effects. The possible adverse effects include irritability, depressed mood, fluid retention, and headaches, not unlike the premenstrual syndrome. These adverse effects may be due to cyclic progestin in some HRT regimens [31. HRT may have a protective effect in the prevention of cardiovascular disease (CVD) and osteoporosis. The benefits of HRT for CVD prevention recently have been questioned based on the results of the Heart EstrogenProgesterone Replacement Study (HERS). The exact mechanisms by which estrogens may modify CVD risk
1This research was supported by NIH Grant HL45167 to L.H.K. 2 To whom reprint requests should be addressed at Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA 15261. Fax: (412) 6242920. E-mail: [email protected]. 108
0091-7435/01 $35.00 Copyright 0 2001 by American Health Foundation and Academic Press Ail rights of reproduction in any form reserved.
HRT USE AND LIFESTYLE
are unclear, but widely subscribed theories include estrogen’s role in lipid and lipoprotein metabolism and the direct effect of estrogen on the arterial wall [41. However, estrogens taken orally are not the same as endogenous estrogens secreted premenopausally. Estrone levels, as opposed to estradiol levels, are significantly increased after taking HRT. Past studies suggest a decrease in CVD risk factors among women who are taking estrogen both alone or in combination with progestin; however, oral estrogen is a risk factor for venous thromboembolism among postmenopausal women. Current HRT users may have a greater cardioprotective effect as opposed to past users [51. Women who are taking HRT need to consider the possibility of very long term use, as there is no definitive length of time to achieve maximum protection. More recent studies are directly addressing CVD event risk as opposed to risk factor elevation. The HERS trial, the first clinical trial of the efficacy of HRT on secondary prevention of CVD events, has suggested an increased risk of CVD events, including stroke, during the first few years of HRT use 161. Many studies have found that HRT is a highly effective preventive measure for osteoporosis as well [7,8]. However, when HRT is discontinued, there is a significant decline in bone density, and any protection that was gained is lost [9]. Therefore, the decision to take HRT to prevent osteoporosis also implies long term use. Although long-term use of HRT may have protective effects in both CVD and osteoporosis, long-term use is not without risk. The evidence concerning the link between HRT use and the lifetime risk of breast cancer is inconsistent [IO], although current studies suggest that the risk of breast cancer increases with duration of use, and it diminishes when HRT is stopped [III. Women who are taking estrogen and progestin may be at higher risk compared with those taking estrogen alone. Further, due to the increased density in breast tissue in women taking HRT, breast cancer is more difficult to detect by mammography in these women, increasing the risk of interval breast cancer [121. An alternative to using HRT to improve CVD risk factors and attenuate menopausal symptoms is modifying aspects of one’s lifestyle that affect specific risk factors. For instance, caloric restriction and the adoption of a low-fat diet lead to weight loss, lower total cholesterol, low-density lipoprotein cholesterol (LDLc), and a reduction in systolic blood pressure @BP) [13,14]. Physical activity, independent of weight loss, has been shown to increase high-density lipoprotein cholesterol (HDLc) 1151. Further, physical activity has been associated with attenuation of bone loss in menopausal women [161. As for menopausal symptom reduction, soy protein has been associated with a decrease in vasomotor symptoms, due to soy’s phytoestrogen content [171. Women’s experience of menopause and CVD risk
109
INTERVENTION
is significantly varied, at least in part, due to their lifestyle. Weight reduction, however, may have unpropitious effects. Weight loss has been shown to accelerate bone loss in perimenopausal women 1161. With these factors in mind, women have choices as to how they can manage their disease risk and menopausal symptoms during the perimenopausal years. In this ancillary study of the Women’s Healthy Lifestyle Project (WHLP), we examined the patterns of HRT use in women who participated in a behavioral intervention to prevent the expected rise in CVD risk factors, specifically increased weight and LDLc, during the peri- to postmenopause. We hypothesize that menopausal women who are attempting to make health behavior changes may be less likely to opt for medication management, particularly given the controversy over the side effects of HRT. It is possible, however, that weight loss as a function of a change in lifestyle during the preto perimenopause may intensify menopausal symptoms due to the reduction in estrogen production and aromatization of androstenedione in the fat tissue [IS]. Therefore, the purpose of this study was to compare HRT use between intervention and control groups on completion of this 5-year randomized clinical trial. A secondary aim was to determine whether weight gain prevention in the lifestyle intervention group was associated with increased menopausal symptomatology. METHODS
Participants A sample of 535 healthy premenopausal women, aged 44-50 (mean = 47, SD = 1.9) participated in this randomized clinical trial. Institutional review board approval was received and all participants completed a written consent to participate. A detailed description of recruitment and eligibility criteria has been previously published [191. Inclusion criteria included LDLc between 2.1 and 4.1 mmoWL (80 and 160 mg/dL), body mass index (BMI) between 20 and 34 kg/m2, total cholesterol between 3.6 and 6.7 mmoYL (140 and 260 mg/dL), and not taking HRT at baseline. Participants were predominantly Caucasian (92%), married (74% 1, educated beyond high school (85%‘c), and employed for wages (86%) (Table 1). The mean baseline BMI was 25.1 kg/m2 (SD = 3.31, and the average weight was 67.3 kg (SD = 0.56). Baseline cholesterol was 4.9 mmo/L (SD = 0.621, LDLc was 3.0 mmol/L (SD = 0.331, HDLc was 1.5 mmol/L (SD = 0.33), and triglycerides were 0.9 mmoUL (SD = 0.46). Mean baseline SBP was 110.2 mm Hg (SD = 12.9) and diastolic blood pressure (DBP) was 68.2 mm Hg (SD = 8.2). The mean baseline physical activity was 1332.1 kcal/week (SD = 1241.31, with 26% expending less than 500 kcal/week. A substantial percentage of participants were physically active, with 47.7% of the participants reporting physical activity
110
BORAZ ET AL.
TABLE Baseline
Sociodemographic
1
Characteristics (N = 535)
Baseline characteristic Mean age at study entry Race (% white) Education % High school graduate % College (>O to 4 years) % Graduate school % Married 8 Employed for wages % Current smokers
of Study Participants
Control (n = 263)
Intervention (n = 2461
P value
46.8 92.4
46.9 91.9
.99 .66
16.7 51.4 31.5 75.3 86.3 9.9
13.8 45.2 40.6 74.0 86.6 8.5
.14 .86 .93 .65
participants were advised to seek medical advice from their physician regarding the participant’s choice to take HRT. The team never offered any recommendations regarding HRT use in these women. Measures of HRT use, menopausal status, and menopausal symptoms. The measures pertaining to this
Participants were randomized to either an assessment-only control group or a lifestyle intervention group. The lifestyle intervention was implemented throughout the 54-month trial. Participants in the control group were free to make lifestyle changes on their own, but they did not receive any instruction from the project staff. All participants completed clinic evaluations at baseline, 6 months, and yearly for the next 4 years.
study are as follows. At each clinic visit interviewers assessed menopausal status by asking participants to report the date of their last menstrual period. Premenopause was defined as missing fewer than three consecutive periods. Perimenopausal status was defined as missing between 3 and 11 menstrual periods. Postmenopausal status included women who missed 12 or more consecutive periods or had undergone hysterectomy with bilateral oophorectomy (n = 22). FSH levels were drawn on only a small sample of women when they had missed 3 or more consecutive periods, to examine the perimenopausal sex hormone levels. Therefore, it was not possible to use FSH levels to verify postmenopausal status. Further, the sizable number of women taking HRT made the results of FSH levels tenuous. Use and type of HRT were evaluated by self-report. Oral contraceptives were not classified as HRT for this study. Menopausal symptoms were evaluated by a symptom checklist of 29 items, addressing typical and frequent complaints of women during menopause 1231. Adequate sensitivity and validity of this measure have been demonstrated. Test-retest reliability was 0.79, and the measure significantly differentiated the menopausal group from the pre- and perimenopausal women in validity studies. Reports of hot flashes were collected both during the clinical interview and as an item on the Menopausal Symptom Checklist. Measures of CVD risk are listed elsewhere 1241.
Procedures
Statistical Analyses
levels greater than 1000 kcal/week. Participants reported consuming an average of 1457.6 Cal/day (SD = 566.11, with 32.5% of calories from fat and 11.6% of calories from saturated fat. This study presents data collected at baseline and at the final visit of the lifestyle intervention at 54 months. Ninety-five percent of the participants completed the 54-month visit (n = 509). Study Design
and Measures
The goal of main study was to test the efficacy of behaviorally reducing cardiovascular risk factors (i.e., weight and lipids) to protect against the expected rise through the menopause 114,19-211. The lifestyle intervention was a 5-year behavioral program that prescribed lowering dietary fat intake to 25% of total calories, saturated fat to 7%, and dietary cholesterol to 100 mg/day. Further, interventionists worked with participants to increase their physical activity expenditure to 1000 to 1500 kcal/week, as measured by the Paffenbarger Activity Questionnaire 1221.If a participant was physically active at this level upon study entry, efforts were made either to enhance the participant’s program or to aid in physical activity maintenance. All intervention participants received a moderate weight loss goal at baseline and a caloric reduced meal plan (1300 Cal/day), to buffer the expected weight gain through the menopause. The intervention team provided education about the menopause and HRT, but Lifestyle intervention.
A P value less than or equal to 0.05 was used to indicate statistical significance. Power calculations were completed, and the power to detect a 20% difference between treatment groups with HRT use is 0.616. Descriptive statistics were used to summarize demographic information and baseline risk factors. Differences between the intervention and control groups were determined with analysis of variance (ANOVA) for continuous variables, and x2 values were used for categorical variables. The association between menopausal symptoms and HRT use was analyzed by one-way ANOVA’s. Logistic regression with forward entry was used to examine predictors of HRT use in postmenopausal women. Data were analyzed using a Gateway E-4200 computer and SPSS Version 9.0 statistical package. RESULTS
Ninety-five percent (n = 509) of the participants attended the 54-month visit. At the end of the 5-year
HRT USE AND LIFESTYLE
study, there were significant differences between the intervention and control groups in weight and other CVD risk factors which are reported elsewhere 1241.In the intervention group, the attempt to prevent weight gain was highly successful 1241.At the 54-month visit, the intervention group lost 0.08 kg (0.18 lb) and the control group gained 2.36 kg (5.2 lb) (P < 0.01). The intervention group’s waist circumference decreased 2.9 cm, and the control group’s waist circumference decreased by 0.46 cm (P < 0.01) 1251.At the end of 54 months, the intervention group reported more physical activity than the control group (1510 kcal vs 1284 kcal, P = 0.04). Mean LDLc in the lifestyle intervention group increased 0.09 mmol& while the control group’s LDLc increased an average of 0.23 mmoUL, and triglyceride elevation was blunted in women in the intervention (P < 0.01). The individuals who were in the control group and not on HRT had an LDLc level that was approximately 0.36 mmol/L higher than that of the participants in the intervention group who were also taking HRT. HDLc increased for women on HRT in both the intervention and control groups 1251. There was no significant difference in menopausal status between the control and intervention groups. At the 54-month visit, 55.7% of the intervention group and 55.5% of the control group remained premenopausal. Perimenopausal women accounted for 9.5% of the control group and 11.4% of the intervention group, and 32.9% of the intervention group and 35.0% of the controls were postmenopausal (P = 0.75). There was no significant difference in HRT use between intervention and control groups at the 54-month assessment (32.2% vs 30.4%, respectively). One hundred fifty-nine women in the study reported hormone therapy use at the 54-month visit. Of these women, 20 reported estrogen-only therapy, 2 used progestin, 127 reported combination estrogen and progestin therapy, and 10 reported other types of hormone use. Of the postmenopausal women in the intervention group, 62.5% were on hormone therapy (n = 50); of the perimenopausal women, 21.4% were on hormone therapy; and 16.8% of the premenopausal women in the intervention group were taking HRT (Table 2). Similar findings are evident with the control group, with 56.5% of
TABLE 2 Percentage
on Hormone Therapy by Menopausal Months
Status at 54
% on HRT (n)
Premenopausal Perimenopausal Postmenopausal
Intervention
Control
P value
16.8 (23) 21.4 (5) 62.5 (50,
13.7 (20) 32.0 (8) 56.5 (52)
0.28 0.21 0.28
INTERVENTION
111
the postmenopausal women, 32.0% of the perimenopausal women, and 13.7% of the premenopausal women on hormone therapy. Differences in baseline demographics between HRT users and nonusers within treatment groups at 54 months were evaluated to examine potential associations with subsequent HRT use at 54 months. Intervention and control groups were analyzed separately to control for treatment effect. Within the control group, there were no baseline cardiovascular risk factors (LDLc, HDLc, DBP, SBP, or weight) that predicted 54month HRT use. In the intervention group, women who reported current HRT had a lower baseline waist-hip ratio than women who were not using HRT (0.78 cm vs 0.76 cm, P = 0.035). No other baseline risk factors were significant in predicting HRT use. To look at baseline predictors for women who would be more likely to be targeted for HRT use, a logistic regression analysis was completed to examine baseline predictors of 54-month HRT use in postmenopausal women. With baseline risk factors, WHR significantly predicted 54-month HRT use (R = 0.11, P = 0.023). No baseline menopausal symptoms predicted 54-month HRT use for the postmenopausal women. The length of time between missing a period, or the beginning of change from premenopausal to perimenopausal status, and commencement of HRT use was examined. One hundred eighty-nine women had reported at some point in the study that they had taken HRT (37.1%). Ninety-one of these women reported that they did not miss a period before commencing HRT and had continued bleeding while on HRT, which they reported as periods. Of these 91 women, 43% (n = 39) reported continued HRT use at 54 months. Forty-nine of the ninety-one women (53.8%) reported current periods at the 54-month visit. For the remaining 98 women, the average length of time between the last menstrual period and the commencement of HRT was 5.99 months (SD = 6.43). The range of time reported with starting HRT was 0 to 32.95 months. Thirty-three percent (n = 32) of these participants reported HRT initiation within 1 month of missing a period, and a total of 66% (n = 65) reported HRT initiation within 6 months of missing a period. At the visit these participants reported first HRT use, they were asked the reasons that they started HRT. Approximately 35% of the women reported they started HRT because of “menopause.“The next most frequently reported reason for starting HRT was hot flashes (13.9%). Nine participants (5%) reported they started HRT for chronic disease prevention, including heart disease and osteoporosis. Menopausal
Symptoms
The following analysis was taken from the report of hot flashes during the clinical interview. There were no
112
BORAZ ET AL.
significant differences in vasomotor symptoms between intervention and control groups at baseline or at 54 months. Vasomotor symptoms or hot flashes were reported in the clinical interview by 21.0% of the participants at baseline, increasing to 29.8% at 54 months. Of the participants who reported hot flashes at baseline, 50.5% were postmenopausal as of the 54-month visit, as opposed to 29.6% of the individuals who did not report hot flashes at baseline (P = O.OO)(Table3). Of the participants who were experiencing hot flashes at baseline (n = 1071, 44.3% (n = 47) reported HRT use at the 54-month visit, compared with 27.9% (n = 112) of the participants who did not report baseline hot flashes (n = 402, P = 0.00). At 54 months, 20% (n = 16) of the control group on HRT (n = 80) were still experiencing hot flashes while taking HRT. Similar findings were evident with the intervention group, with 19.7% (n = 15) of the intervention group taking HRT (n = 78) and reporting hot flashes. Among the control and intervention groups not on HRT at 54 months, 31.3% of the controls and 38.1% of the intervention group reported hot flashes. Total baseline scores on the self-administered Menopausal Symptom Checklist in both the intervention and control groups did not correlate with HRT use at the 54-month visit. Further, 54-month scores on the menopausal symptom checklist did not correlate with HRT use at 54 months. The individual items on the Menopausal Symptom Checklist were examined by 54-month HRT use for baseline and 54 months. For the intervention and control groups, fewer individuals taking HRT reported hot flashes on the Menopausal Symptom Checklist than individuals not on HRT (P = 0.00).
that is, they did not have a period for 12 consecutive months, and one-half of the participants remained premenopausal. There was no difference in both menopausal status and reported HRT use between intervention and controls. Managing cardiovascular risk with a behavioral intervention may not influence the decision to use HRT. A very small number of women stated that they were taking HRT for the management of disease risk. The behavioral intervention did not elicit more menopausal symptoms as suggested by the Menopausal Symptom Checklist. Although the women in the intervention group clearly lost more weight, they did not report more menopausal symptoms than the control group. Other studies have found that women who are thinner experience more menopausal symptoms 1211. Explanations given include increased estrogen production in fat cells which serve as a buffer for the estrogen depletion during the menopause 1211. Our findings imply that while a premenopausal lower weight may elicit the report of menopausal symptoms, weight loss during the perimenopause may have no effect. Of the participants who did not report hot flashes at the baseline visit, 28% were taking HRT at 54 months. Of the participants who reported hot flashes at baseline, nearly half were taking HRT at 54 months. This suggests that women who have hot flashes may choose HRT for relief, as they are a salient and often uncomfortable reality for many women through the menopause. It is possible that the individuals who are reporting hot flashes were, in fact, entering the perimenopause, and therefore more likely to be subsequently taking HRT. However, the number of menopausal symptoms women reported on the Menopausal Symptom Checklist was not associated with HRT use at baseline or at 54 months. It is possible that the number of symptoms is not the reason women take HRT, but either severity of symptoms or simply hot flashes may be the reason women start hormone therapy. For the women who had used HRT at any point in the study, the average length of time between missing a period and starting HRT was approximately 6 months. This is a short period between change in menopausal status and starting HRT, especially because their CVD risk is not driving their decision, nor is the number of
DISCUSSION
This study examined early HRT use and report of menopausal symptoms among healthy women who were participating in a 5-year randomized clinical trial, studying the efficacy of a behavioral lifestyle intervention to prevent cardiovascular risk elevation through the menopause. The intervention was highly successful in preventing the expected rise in cardiovascular risk (i.e., weight gain, LDLc, and decreasing physical activity) through a critical period in these women’s lives. At the end of the study, one-third became postmenopausal,
TABLE Report on Baseline Hot Flashes and Subsequent
3 54-Month
HRT Use by Menopausal
Status
‘+I (% on HRT) Baseline hot flashes Yes No P = 0.000.
Premenopausal 39.6 (21.4) 59.7 (14.2)
Perimenopausal 9.4 (40.0) 10.0 (22.5)
Postmenopausal 50.9 (55) 30.3 (56.6)
Total 100.0 (44.3) 100.0 (27.9)
HRT USE AND LIFES’IYLE
INTERVENTION
113
menopausal symptoms. This finding may also be an are necessary to determine which women will receive the most benefit from taking HRT, relative to their indicator of prescription patterns of physicians. There were virtually no baseline predictors of HRT likelihood of developing CVD. use at the 54-month visit in the control group. In the ACKNOWLEDGMENTS intervention group, HRT users had a lower waist-hip ratio at baseline than nonusers. This appears to be an The authors thank the participants of WHLP for their dedication. artifact, as any risk factor that would explain lower The WHLP investigators, intervention, and clinic staff (listed in alwaist-hip ratio (dietary intake, weight, physical activ- phabetical order) are: Michelle Berry, Alhaji Buhari, Michele Burity) was not a predictor. This suggests that the decision nette, Jane Cauley, David Chernew, D. J. Conner-Beatty, Debbi Cusick, Aileen Faulkner, Shannon Fitzgerald, Rich Foran, Sara Friel, to take HRT for these women was not based on elevated Ed Gregg, Donna Hansen, Beth Hauth, Diane Ives, Jan Kielty, Mary CVD risk factors, and perhaps that physicians are not Lou Klem, Andrea Kriska, Jean Lennon, Eileen McMahon, Araxi examining disease risk before prescribing HRT. The Macaulay, Mehran Massoudi, Nancy Mazzei, Marguerite Meyer, N. lack of difference in HRT use between the intervention Carole Milas, Joann Naujelus, Pam Carter-Nolan, Mary Parker, Anand control groups suggests that the interventionists nette Rexroad, Loran Salamone, Danit Shahar, Siao Mei Shick, Maria Smith, Pam Vincent, Michelle Volansky, Charlene Walter, Marie Wilkdid not introduce bias toward or against HRT use even erson and Randi Wolf for their contributions to the study. though participants would often approach interventionists to ask advice regarding their decision to comREFERENCES mence HRT. The initial hypothesis that women in an intense inI. Jacobs S, Hillard TC. Hormone replacement therapy in the aged: a state of the art review. Drugs Aging 1996;8:193-213. tervention including weight loss and dietary modificaBelchez P. Hormone treatment of postmenopausal women. N Engl 2. tion would become more symptomatic during the periJ Med 1994;330:1062-71. to- postmenopause and more likely to use HRT was not 3. Bjarnason K, Cerin A, Lindgren R, Weber T. Adverse endometrial supported by the results of the clinical trial. A second effects during long cycle hormone replacement therapy. Maturiinteresting and important observation was that CVD tas 1999;32:161-70. risk factor levels at baseline were not a primary deter4. Samsioe G. The menopause revisited. Int J Gynecol Obstet minant of HRT use. The results were consistent with 1995;51:1-13. findings for the Healthy Women Study [21]. Physicians’ 5. Kuller LH. Hormone replacement therapy and coronary heart recommendations for long-term HRT use among peridisease: a new debate. Med Clin North Am 2000;84:181-98. to early postmenopausal women are likely based on 6. Simon JA, Hsia J, Cauley J, Richards C, Harris F, Fong J, BarrettConner E, Hulley SB. Hormone therapy and risk of stroke. Circufactors other than health status. It is possible that many lation, in press. of the women could maintain a lower cardiovascular Riggs BL, Melton LJ. Involutional osteoporosis. N Engl J Med 7. risk by nonpharmacological behavioral lifestyle modifi1986;314:1676-86. cation during the pre- to postmenopause. 8. Cummings SR, Black DM, & Rubin SM. Lifetime risks of hip, This sample is primarily Caucasian and college eduColles’, or vertebral fracture and coronary heart disease among cated. These data should also be viewed within the white postmenopausal women. Arch Intern Med 1989;149: context that all of these women enrolled in a clinical 2445-8. trial and agreed, prior to randomization to participate 9. Melton LJ. How many women have osteoporosis now? J Bone Min Res 1995;10:175-7. in an intensive behavioral intervention. Further, clinical trials in heterogeneous populations should evaluate 10. Grady D, Rubin SM, Pettiti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern the potential of behavioral methods alone and in combiMed 1992;117:1016-36. nation with HRT to modify risk factors and disease Beral V, Banks E, Reeves G, Appleby P. Use of HRT and the 11. during the peri- to postmenopause. Another important subsequent risk of cancer. J Epidemiol Biostat 1999;4:191-210. limitation to the study is the manner in which menopause was defined. FSH levels were not taken on the 12. Beral V, Banks E, Reeves G, Wallis M. Hormone replacement therapy and high incidence of breast cancer between mammoparticipants in a systematic manner, so that menopause graphic screens. Lancet 1997;349:1103-94. could be as clearly classified. 13. Kuller LH. Eating fat or being fat and risk of cardiovascular In summary, these women participating in a behavdisease and cancer among women. Ann Epidemiol1994;4:119-27. ioral intervention to prevent CVD risk elevation 14. Simkin-Silverman LR, Wing RR, Boraz MA, Meilahn EN, Kuller LH. Maintenance of cardiovascular risk factor changes among through the menopause started hormone therapy very middle-aged women in a lifestyle intervention trial Women’s early in the perimenopause, they did not have greater Health Res Gender, Behav Policy 1998;4:255-71. baseline heart disease risk than the individuals who 15. Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects were not taking HRT, and they did not report more on plasma lipoproteins of a prudent weight-reducing diet; with menopausal symptoms than individuals who were not or without exercise, in overweight men and women. N Engl J taking hormone therapy. More research is indicated in Med 1991;325:461-6. examining the reasons these women were taking HRT 16. Salamone LM, Black D, Simkin-Silverman LR, Palermo L, et al. The effect of a behavioral intervention on bone mineral density and prescribing practices of physicians. Clinical trials
114
BORAZ ET AL. Weight gain at the 1991;151:97-102.
in health pre- and perimenopausal women: a randomized clinical trial. J Bone Miner Res 1996;11(S1):65.
17. Brzezinski
A, Adlercreutz H, Shaoul R, Shmueli R, Reosler A, Schenker JG. Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause J North Am Menopause sot 1997;4:89-94.
18. Kuller LH, Matthews KA, Meilahn EN. Estrogens and women’s health: interrelation of coronary heart disease, breast and osteoporosis. J Steroid Biochem Mol Biol, in press.
cancer,
19. Simkin-Silverman
LR, Wing RR, Hansen DH, Klem ML, Pasagian-Macauley A, Meilahn EN, Kuller LH. Prevention of cardiovascular risk factor elevations in healthy premenopausal women. Prev Med 1995;24:509-17.
20. Wing RR, Matthews KA, Kuller LH, Meilahn EN, Plantinga PL.
time
of menopause.
Arch
Intern
Med
21. Matthews ISA, Meilahn EN, Kuller LH, Kelsey SF, Cagguila AW, Wing RR. Menopause and risk factors for coronary heart disease. N Engl J Med 1989;321:641-6. 22. Paffenbarger RS, Wing AL, Hyde RT. Physical activity as an index of heart attack risk in college alumni. Am J Epidemiol 1978;108:161-75. 23. Neugarten BL, Kraines RI. “Menopausal symptoms” in women of various ages. Psychosom Med 1964;27:266-73. 24’
Kuller LH, Simkin-Silverman LR, Wing RR, Meilahn EN, Ives DG. The women’s healthy lifestyle project WHLP), a randomized clinical trial: results at 54 months. Circulation 2000; in press.
25. Simkin-Silverman LR, Kuller LH, Boraz MA, Wing RR. A randomized clinical trial of weight gain prevention in 535 healthy women during menopause. Circulation 2000;100:1238.
Medicine 33, 108-114
doi:10.1006/pmed.2001.0858,
(2001)
available
online at http://www.idealibrary.com
on
IDEhl@
Hormone Replacement Therapy Use and Menopausal Symptoms among Women Participating in a Behavioral Lifestyle Intervention’ Miriam A. Boraz,*,2 Laurey R. Simkin-Silverman ,* Rena R. Wing,t Elaine N. Meilahn,” and Lewis H. Kuller” *Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and TDepartment of Psychiatry, Brown University, Providence, Rhode Island 02912
the perimenopause did not affect menopausal symp toms. G2001 American Health Foundation and Academic Press Key Words: hormone therapy; menopause; cardiovascular; lifestyle intervention.
The decision to take hormone replacement therapy (HRT) is a choice many women encounter when entering menopause. The purpose of this study was to examine the choice to take HRT while participating in a lifestyle intervention to reduce cardiovascular risk through the menopause. Methods. The Women’s Healthy Lifestyle Project is a randomized clinical trial designed to examine whether a behavioral lifestyle intervention can decrease the expected rise in cardiovascular risk through the menopause. Participants (N = 535) completed questionnaires and were interviewed regarding menopausal symptoms, menopausal status, hot flashes, and HRT use at baseline and 54 months. Results. The intervention was successful in preventing risk elevation through the 54-month visit. At the final visit, there was no difference between the intervention and control groups in the percentage who had become postmenopausal (32.9% vs 35.0%, respectively), there was no difference between control and intervention with HRT use, with 31.2% reporting use of HRT, and there was no difference between groups with menopausal symptoms. The women started HRT an average of 6 months after they missed a period. Baseline risk factors did not predict HRT use at the 54-month visit. Conclusions. A sizable number of women reported HRT use. The decision to use HRT was not influenced by the lifestyle intervention or their baseline cardiovascular risk, and these women started HRT very early in the peri- to postmenopause. Further, weight loss in Background.
INTRODUCTION
Women in their late forties and early fifties are faced with the question of whether to use hormone replacement therapy (HRT) to manage menopausal symptoms and manage disease risk. This paper addresses HRT patterns of use in women through the menopause. The decision to take HRT depends on careful consideration of both the long- and short-term effects of HRT. The short term benefit of HRT use is the attenuation of menopausal symptoms such as hot flashes, skin changes, and urogenital atrophy 111.HRT is currently considered one of the most effective treatments for relief of hot flashes and night sweats. Seventy-five percent of per-i-to postmenopausal women experience hot flashes. Interestingly, only 30% of women seek help for hot flashes 121,implying that many women experience hot flashes and cope with them nonmedically and suggesting a wide range in severity. Despite the short-term benefits of HRT for symptom reduction, many women choose not to take HRT (or take sporadically) because of the side effects. The possible adverse effects include irritability, depressed mood, fluid retention, and headaches, not unlike the premenstrual syndrome. These adverse effects may be due to cyclic progestin in some HRT regimens [31. HRT may have a protective effect in the prevention of cardiovascular disease (CVD) and osteoporosis. The benefits of HRT for CVD prevention recently have been questioned based on the results of the Heart EstrogenProgesterone Replacement Study (HERS). The exact mechanisms by which estrogens may modify CVD risk
1This research was supported by NIH Grant HL45167 to L.H.K. 2 To whom reprint requests should be addressed at Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA 15261. Fax: (412) 6242920. E-mail: [email protected]. 108
0091-7435/01 $35.00 Copyright 0 2001 by American Health Foundation and Academic Press Ail rights of reproduction in any form reserved.
HRT USE AND LIFESTYLE
are unclear, but widely subscribed theories include estrogen’s role in lipid and lipoprotein metabolism and the direct effect of estrogen on the arterial wall [41. However, estrogens taken orally are not the same as endogenous estrogens secreted premenopausally. Estrone levels, as opposed to estradiol levels, are significantly increased after taking HRT. Past studies suggest a decrease in CVD risk factors among women who are taking estrogen both alone or in combination with progestin; however, oral estrogen is a risk factor for venous thromboembolism among postmenopausal women. Current HRT users may have a greater cardioprotective effect as opposed to past users [51. Women who are taking HRT need to consider the possibility of very long term use, as there is no definitive length of time to achieve maximum protection. More recent studies are directly addressing CVD event risk as opposed to risk factor elevation. The HERS trial, the first clinical trial of the efficacy of HRT on secondary prevention of CVD events, has suggested an increased risk of CVD events, including stroke, during the first few years of HRT use 161. Many studies have found that HRT is a highly effective preventive measure for osteoporosis as well [7,8]. However, when HRT is discontinued, there is a significant decline in bone density, and any protection that was gained is lost [9]. Therefore, the decision to take HRT to prevent osteoporosis also implies long term use. Although long-term use of HRT may have protective effects in both CVD and osteoporosis, long-term use is not without risk. The evidence concerning the link between HRT use and the lifetime risk of breast cancer is inconsistent [IO], although current studies suggest that the risk of breast cancer increases with duration of use, and it diminishes when HRT is stopped [III. Women who are taking estrogen and progestin may be at higher risk compared with those taking estrogen alone. Further, due to the increased density in breast tissue in women taking HRT, breast cancer is more difficult to detect by mammography in these women, increasing the risk of interval breast cancer [121. An alternative to using HRT to improve CVD risk factors and attenuate menopausal symptoms is modifying aspects of one’s lifestyle that affect specific risk factors. For instance, caloric restriction and the adoption of a low-fat diet lead to weight loss, lower total cholesterol, low-density lipoprotein cholesterol (LDLc), and a reduction in systolic blood pressure @BP) [13,14]. Physical activity, independent of weight loss, has been shown to increase high-density lipoprotein cholesterol (HDLc) 1151. Further, physical activity has been associated with attenuation of bone loss in menopausal women [161. As for menopausal symptom reduction, soy protein has been associated with a decrease in vasomotor symptoms, due to soy’s phytoestrogen content [171. Women’s experience of menopause and CVD risk
109
INTERVENTION
is significantly varied, at least in part, due to their lifestyle. Weight reduction, however, may have unpropitious effects. Weight loss has been shown to accelerate bone loss in perimenopausal women 1161. With these factors in mind, women have choices as to how they can manage their disease risk and menopausal symptoms during the perimenopausal years. In this ancillary study of the Women’s Healthy Lifestyle Project (WHLP), we examined the patterns of HRT use in women who participated in a behavioral intervention to prevent the expected rise in CVD risk factors, specifically increased weight and LDLc, during the peri- to postmenopause. We hypothesize that menopausal women who are attempting to make health behavior changes may be less likely to opt for medication management, particularly given the controversy over the side effects of HRT. It is possible, however, that weight loss as a function of a change in lifestyle during the preto perimenopause may intensify menopausal symptoms due to the reduction in estrogen production and aromatization of androstenedione in the fat tissue [IS]. Therefore, the purpose of this study was to compare HRT use between intervention and control groups on completion of this 5-year randomized clinical trial. A secondary aim was to determine whether weight gain prevention in the lifestyle intervention group was associated with increased menopausal symptomatology. METHODS
Participants A sample of 535 healthy premenopausal women, aged 44-50 (mean = 47, SD = 1.9) participated in this randomized clinical trial. Institutional review board approval was received and all participants completed a written consent to participate. A detailed description of recruitment and eligibility criteria has been previously published [191. Inclusion criteria included LDLc between 2.1 and 4.1 mmoWL (80 and 160 mg/dL), body mass index (BMI) between 20 and 34 kg/m2, total cholesterol between 3.6 and 6.7 mmoYL (140 and 260 mg/dL), and not taking HRT at baseline. Participants were predominantly Caucasian (92%), married (74% 1, educated beyond high school (85%‘c), and employed for wages (86%) (Table 1). The mean baseline BMI was 25.1 kg/m2 (SD = 3.31, and the average weight was 67.3 kg (SD = 0.56). Baseline cholesterol was 4.9 mmo/L (SD = 0.621, LDLc was 3.0 mmol/L (SD = 0.331, HDLc was 1.5 mmol/L (SD = 0.33), and triglycerides were 0.9 mmoUL (SD = 0.46). Mean baseline SBP was 110.2 mm Hg (SD = 12.9) and diastolic blood pressure (DBP) was 68.2 mm Hg (SD = 8.2). The mean baseline physical activity was 1332.1 kcal/week (SD = 1241.31, with 26% expending less than 500 kcal/week. A substantial percentage of participants were physically active, with 47.7% of the participants reporting physical activity
110
BORAZ ET AL.
TABLE Baseline
Sociodemographic
1
Characteristics (N = 535)
Baseline characteristic Mean age at study entry Race (% white) Education % High school graduate % College (>O to 4 years) % Graduate school % Married 8 Employed for wages % Current smokers
of Study Participants
Control (n = 263)
Intervention (n = 2461
P value
46.8 92.4
46.9 91.9
.99 .66
16.7 51.4 31.5 75.3 86.3 9.9
13.8 45.2 40.6 74.0 86.6 8.5
.14 .86 .93 .65
participants were advised to seek medical advice from their physician regarding the participant’s choice to take HRT. The team never offered any recommendations regarding HRT use in these women. Measures of HRT use, menopausal status, and menopausal symptoms. The measures pertaining to this
Participants were randomized to either an assessment-only control group or a lifestyle intervention group. The lifestyle intervention was implemented throughout the 54-month trial. Participants in the control group were free to make lifestyle changes on their own, but they did not receive any instruction from the project staff. All participants completed clinic evaluations at baseline, 6 months, and yearly for the next 4 years.
study are as follows. At each clinic visit interviewers assessed menopausal status by asking participants to report the date of their last menstrual period. Premenopause was defined as missing fewer than three consecutive periods. Perimenopausal status was defined as missing between 3 and 11 menstrual periods. Postmenopausal status included women who missed 12 or more consecutive periods or had undergone hysterectomy with bilateral oophorectomy (n = 22). FSH levels were drawn on only a small sample of women when they had missed 3 or more consecutive periods, to examine the perimenopausal sex hormone levels. Therefore, it was not possible to use FSH levels to verify postmenopausal status. Further, the sizable number of women taking HRT made the results of FSH levels tenuous. Use and type of HRT were evaluated by self-report. Oral contraceptives were not classified as HRT for this study. Menopausal symptoms were evaluated by a symptom checklist of 29 items, addressing typical and frequent complaints of women during menopause 1231. Adequate sensitivity and validity of this measure have been demonstrated. Test-retest reliability was 0.79, and the measure significantly differentiated the menopausal group from the pre- and perimenopausal women in validity studies. Reports of hot flashes were collected both during the clinical interview and as an item on the Menopausal Symptom Checklist. Measures of CVD risk are listed elsewhere 1241.
Procedures
Statistical Analyses
levels greater than 1000 kcal/week. Participants reported consuming an average of 1457.6 Cal/day (SD = 566.11, with 32.5% of calories from fat and 11.6% of calories from saturated fat. This study presents data collected at baseline and at the final visit of the lifestyle intervention at 54 months. Ninety-five percent of the participants completed the 54-month visit (n = 509). Study Design
and Measures
The goal of main study was to test the efficacy of behaviorally reducing cardiovascular risk factors (i.e., weight and lipids) to protect against the expected rise through the menopause 114,19-211. The lifestyle intervention was a 5-year behavioral program that prescribed lowering dietary fat intake to 25% of total calories, saturated fat to 7%, and dietary cholesterol to 100 mg/day. Further, interventionists worked with participants to increase their physical activity expenditure to 1000 to 1500 kcal/week, as measured by the Paffenbarger Activity Questionnaire 1221.If a participant was physically active at this level upon study entry, efforts were made either to enhance the participant’s program or to aid in physical activity maintenance. All intervention participants received a moderate weight loss goal at baseline and a caloric reduced meal plan (1300 Cal/day), to buffer the expected weight gain through the menopause. The intervention team provided education about the menopause and HRT, but Lifestyle intervention.
A P value less than or equal to 0.05 was used to indicate statistical significance. Power calculations were completed, and the power to detect a 20% difference between treatment groups with HRT use is 0.616. Descriptive statistics were used to summarize demographic information and baseline risk factors. Differences between the intervention and control groups were determined with analysis of variance (ANOVA) for continuous variables, and x2 values were used for categorical variables. The association between menopausal symptoms and HRT use was analyzed by one-way ANOVA’s. Logistic regression with forward entry was used to examine predictors of HRT use in postmenopausal women. Data were analyzed using a Gateway E-4200 computer and SPSS Version 9.0 statistical package. RESULTS
Ninety-five percent (n = 509) of the participants attended the 54-month visit. At the end of the 5-year
HRT USE AND LIFESTYLE
study, there were significant differences between the intervention and control groups in weight and other CVD risk factors which are reported elsewhere 1241.In the intervention group, the attempt to prevent weight gain was highly successful 1241.At the 54-month visit, the intervention group lost 0.08 kg (0.18 lb) and the control group gained 2.36 kg (5.2 lb) (P < 0.01). The intervention group’s waist circumference decreased 2.9 cm, and the control group’s waist circumference decreased by 0.46 cm (P < 0.01) 1251.At the end of 54 months, the intervention group reported more physical activity than the control group (1510 kcal vs 1284 kcal, P = 0.04). Mean LDLc in the lifestyle intervention group increased 0.09 mmol& while the control group’s LDLc increased an average of 0.23 mmoUL, and triglyceride elevation was blunted in women in the intervention (P < 0.01). The individuals who were in the control group and not on HRT had an LDLc level that was approximately 0.36 mmol/L higher than that of the participants in the intervention group who were also taking HRT. HDLc increased for women on HRT in both the intervention and control groups 1251. There was no significant difference in menopausal status between the control and intervention groups. At the 54-month visit, 55.7% of the intervention group and 55.5% of the control group remained premenopausal. Perimenopausal women accounted for 9.5% of the control group and 11.4% of the intervention group, and 32.9% of the intervention group and 35.0% of the controls were postmenopausal (P = 0.75). There was no significant difference in HRT use between intervention and control groups at the 54-month assessment (32.2% vs 30.4%, respectively). One hundred fifty-nine women in the study reported hormone therapy use at the 54-month visit. Of these women, 20 reported estrogen-only therapy, 2 used progestin, 127 reported combination estrogen and progestin therapy, and 10 reported other types of hormone use. Of the postmenopausal women in the intervention group, 62.5% were on hormone therapy (n = 50); of the perimenopausal women, 21.4% were on hormone therapy; and 16.8% of the premenopausal women in the intervention group were taking HRT (Table 2). Similar findings are evident with the control group, with 56.5% of
TABLE 2 Percentage
on Hormone Therapy by Menopausal Months
Status at 54
% on HRT (n)
Premenopausal Perimenopausal Postmenopausal
Intervention
Control
P value
16.8 (23) 21.4 (5) 62.5 (50,
13.7 (20) 32.0 (8) 56.5 (52)
0.28 0.21 0.28
INTERVENTION
111
the postmenopausal women, 32.0% of the perimenopausal women, and 13.7% of the premenopausal women on hormone therapy. Differences in baseline demographics between HRT users and nonusers within treatment groups at 54 months were evaluated to examine potential associations with subsequent HRT use at 54 months. Intervention and control groups were analyzed separately to control for treatment effect. Within the control group, there were no baseline cardiovascular risk factors (LDLc, HDLc, DBP, SBP, or weight) that predicted 54month HRT use. In the intervention group, women who reported current HRT had a lower baseline waist-hip ratio than women who were not using HRT (0.78 cm vs 0.76 cm, P = 0.035). No other baseline risk factors were significant in predicting HRT use. To look at baseline predictors for women who would be more likely to be targeted for HRT use, a logistic regression analysis was completed to examine baseline predictors of 54-month HRT use in postmenopausal women. With baseline risk factors, WHR significantly predicted 54-month HRT use (R = 0.11, P = 0.023). No baseline menopausal symptoms predicted 54-month HRT use for the postmenopausal women. The length of time between missing a period, or the beginning of change from premenopausal to perimenopausal status, and commencement of HRT use was examined. One hundred eighty-nine women had reported at some point in the study that they had taken HRT (37.1%). Ninety-one of these women reported that they did not miss a period before commencing HRT and had continued bleeding while on HRT, which they reported as periods. Of these 91 women, 43% (n = 39) reported continued HRT use at 54 months. Forty-nine of the ninety-one women (53.8%) reported current periods at the 54-month visit. For the remaining 98 women, the average length of time between the last menstrual period and the commencement of HRT was 5.99 months (SD = 6.43). The range of time reported with starting HRT was 0 to 32.95 months. Thirty-three percent (n = 32) of these participants reported HRT initiation within 1 month of missing a period, and a total of 66% (n = 65) reported HRT initiation within 6 months of missing a period. At the visit these participants reported first HRT use, they were asked the reasons that they started HRT. Approximately 35% of the women reported they started HRT because of “menopause.“The next most frequently reported reason for starting HRT was hot flashes (13.9%). Nine participants (5%) reported they started HRT for chronic disease prevention, including heart disease and osteoporosis. Menopausal
Symptoms
The following analysis was taken from the report of hot flashes during the clinical interview. There were no
112
BORAZ ET AL.
significant differences in vasomotor symptoms between intervention and control groups at baseline or at 54 months. Vasomotor symptoms or hot flashes were reported in the clinical interview by 21.0% of the participants at baseline, increasing to 29.8% at 54 months. Of the participants who reported hot flashes at baseline, 50.5% were postmenopausal as of the 54-month visit, as opposed to 29.6% of the individuals who did not report hot flashes at baseline (P = O.OO)(Table3). Of the participants who were experiencing hot flashes at baseline (n = 1071, 44.3% (n = 47) reported HRT use at the 54-month visit, compared with 27.9% (n = 112) of the participants who did not report baseline hot flashes (n = 402, P = 0.00). At 54 months, 20% (n = 16) of the control group on HRT (n = 80) were still experiencing hot flashes while taking HRT. Similar findings were evident with the intervention group, with 19.7% (n = 15) of the intervention group taking HRT (n = 78) and reporting hot flashes. Among the control and intervention groups not on HRT at 54 months, 31.3% of the controls and 38.1% of the intervention group reported hot flashes. Total baseline scores on the self-administered Menopausal Symptom Checklist in both the intervention and control groups did not correlate with HRT use at the 54-month visit. Further, 54-month scores on the menopausal symptom checklist did not correlate with HRT use at 54 months. The individual items on the Menopausal Symptom Checklist were examined by 54-month HRT use for baseline and 54 months. For the intervention and control groups, fewer individuals taking HRT reported hot flashes on the Menopausal Symptom Checklist than individuals not on HRT (P = 0.00).
that is, they did not have a period for 12 consecutive months, and one-half of the participants remained premenopausal. There was no difference in both menopausal status and reported HRT use between intervention and controls. Managing cardiovascular risk with a behavioral intervention may not influence the decision to use HRT. A very small number of women stated that they were taking HRT for the management of disease risk. The behavioral intervention did not elicit more menopausal symptoms as suggested by the Menopausal Symptom Checklist. Although the women in the intervention group clearly lost more weight, they did not report more menopausal symptoms than the control group. Other studies have found that women who are thinner experience more menopausal symptoms 1211. Explanations given include increased estrogen production in fat cells which serve as a buffer for the estrogen depletion during the menopause 1211. Our findings imply that while a premenopausal lower weight may elicit the report of menopausal symptoms, weight loss during the perimenopause may have no effect. Of the participants who did not report hot flashes at the baseline visit, 28% were taking HRT at 54 months. Of the participants who reported hot flashes at baseline, nearly half were taking HRT at 54 months. This suggests that women who have hot flashes may choose HRT for relief, as they are a salient and often uncomfortable reality for many women through the menopause. It is possible that the individuals who are reporting hot flashes were, in fact, entering the perimenopause, and therefore more likely to be subsequently taking HRT. However, the number of menopausal symptoms women reported on the Menopausal Symptom Checklist was not associated with HRT use at baseline or at 54 months. It is possible that the number of symptoms is not the reason women take HRT, but either severity of symptoms or simply hot flashes may be the reason women start hormone therapy. For the women who had used HRT at any point in the study, the average length of time between missing a period and starting HRT was approximately 6 months. This is a short period between change in menopausal status and starting HRT, especially because their CVD risk is not driving their decision, nor is the number of
DISCUSSION
This study examined early HRT use and report of menopausal symptoms among healthy women who were participating in a 5-year randomized clinical trial, studying the efficacy of a behavioral lifestyle intervention to prevent cardiovascular risk elevation through the menopause. The intervention was highly successful in preventing the expected rise in cardiovascular risk (i.e., weight gain, LDLc, and decreasing physical activity) through a critical period in these women’s lives. At the end of the study, one-third became postmenopausal,
TABLE Report on Baseline Hot Flashes and Subsequent
3 54-Month
HRT Use by Menopausal
Status
‘+I (% on HRT) Baseline hot flashes Yes No P = 0.000.
Premenopausal 39.6 (21.4) 59.7 (14.2)
Perimenopausal 9.4 (40.0) 10.0 (22.5)
Postmenopausal 50.9 (55) 30.3 (56.6)
Total 100.0 (44.3) 100.0 (27.9)
HRT USE AND LIFES’IYLE
INTERVENTION
113
menopausal symptoms. This finding may also be an are necessary to determine which women will receive the most benefit from taking HRT, relative to their indicator of prescription patterns of physicians. There were virtually no baseline predictors of HRT likelihood of developing CVD. use at the 54-month visit in the control group. In the ACKNOWLEDGMENTS intervention group, HRT users had a lower waist-hip ratio at baseline than nonusers. This appears to be an The authors thank the participants of WHLP for their dedication. artifact, as any risk factor that would explain lower The WHLP investigators, intervention, and clinic staff (listed in alwaist-hip ratio (dietary intake, weight, physical activ- phabetical order) are: Michelle Berry, Alhaji Buhari, Michele Burity) was not a predictor. This suggests that the decision nette, Jane Cauley, David Chernew, D. J. Conner-Beatty, Debbi Cusick, Aileen Faulkner, Shannon Fitzgerald, Rich Foran, Sara Friel, to take HRT for these women was not based on elevated Ed Gregg, Donna Hansen, Beth Hauth, Diane Ives, Jan Kielty, Mary CVD risk factors, and perhaps that physicians are not Lou Klem, Andrea Kriska, Jean Lennon, Eileen McMahon, Araxi examining disease risk before prescribing HRT. The Macaulay, Mehran Massoudi, Nancy Mazzei, Marguerite Meyer, N. lack of difference in HRT use between the intervention Carole Milas, Joann Naujelus, Pam Carter-Nolan, Mary Parker, Anand control groups suggests that the interventionists nette Rexroad, Loran Salamone, Danit Shahar, Siao Mei Shick, Maria Smith, Pam Vincent, Michelle Volansky, Charlene Walter, Marie Wilkdid not introduce bias toward or against HRT use even erson and Randi Wolf for their contributions to the study. though participants would often approach interventionists to ask advice regarding their decision to comREFERENCES mence HRT. The initial hypothesis that women in an intense inI. Jacobs S, Hillard TC. Hormone replacement therapy in the aged: a state of the art review. Drugs Aging 1996;8:193-213. tervention including weight loss and dietary modificaBelchez P. Hormone treatment of postmenopausal women. N Engl 2. tion would become more symptomatic during the periJ Med 1994;330:1062-71. to- postmenopause and more likely to use HRT was not 3. Bjarnason K, Cerin A, Lindgren R, Weber T. Adverse endometrial supported by the results of the clinical trial. A second effects during long cycle hormone replacement therapy. Maturiinteresting and important observation was that CVD tas 1999;32:161-70. risk factor levels at baseline were not a primary deter4. Samsioe G. The menopause revisited. Int J Gynecol Obstet minant of HRT use. The results were consistent with 1995;51:1-13. findings for the Healthy Women Study [21]. Physicians’ 5. Kuller LH. Hormone replacement therapy and coronary heart recommendations for long-term HRT use among peridisease: a new debate. Med Clin North Am 2000;84:181-98. to early postmenopausal women are likely based on 6. Simon JA, Hsia J, Cauley J, Richards C, Harris F, Fong J, BarrettConner E, Hulley SB. Hormone therapy and risk of stroke. Circufactors other than health status. It is possible that many lation, in press. of the women could maintain a lower cardiovascular Riggs BL, Melton LJ. Involutional osteoporosis. N Engl J Med 7. risk by nonpharmacological behavioral lifestyle modifi1986;314:1676-86. cation during the pre- to postmenopause. 8. Cummings SR, Black DM, & Rubin SM. Lifetime risks of hip, This sample is primarily Caucasian and college eduColles’, or vertebral fracture and coronary heart disease among cated. These data should also be viewed within the white postmenopausal women. Arch Intern Med 1989;149: context that all of these women enrolled in a clinical 2445-8. trial and agreed, prior to randomization to participate 9. Melton LJ. How many women have osteoporosis now? J Bone Min Res 1995;10:175-7. in an intensive behavioral intervention. Further, clinical trials in heterogeneous populations should evaluate 10. Grady D, Rubin SM, Pettiti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern the potential of behavioral methods alone and in combiMed 1992;117:1016-36. nation with HRT to modify risk factors and disease Beral V, Banks E, Reeves G, Appleby P. Use of HRT and the 11. during the peri- to postmenopause. Another important subsequent risk of cancer. J Epidemiol Biostat 1999;4:191-210. limitation to the study is the manner in which menopause was defined. FSH levels were not taken on the 12. Beral V, Banks E, Reeves G, Wallis M. Hormone replacement therapy and high incidence of breast cancer between mammoparticipants in a systematic manner, so that menopause graphic screens. Lancet 1997;349:1103-94. could be as clearly classified. 13. Kuller LH. Eating fat or being fat and risk of cardiovascular In summary, these women participating in a behavdisease and cancer among women. Ann Epidemiol1994;4:119-27. ioral intervention to prevent CVD risk elevation 14. Simkin-Silverman LR, Wing RR, Boraz MA, Meilahn EN, Kuller LH. Maintenance of cardiovascular risk factor changes among through the menopause started hormone therapy very middle-aged women in a lifestyle intervention trial Women’s early in the perimenopause, they did not have greater Health Res Gender, Behav Policy 1998;4:255-71. baseline heart disease risk than the individuals who 15. Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects were not taking HRT, and they did not report more on plasma lipoproteins of a prudent weight-reducing diet; with menopausal symptoms than individuals who were not or without exercise, in overweight men and women. N Engl J taking hormone therapy. More research is indicated in Med 1991;325:461-6. examining the reasons these women were taking HRT 16. Salamone LM, Black D, Simkin-Silverman LR, Palermo L, et al. The effect of a behavioral intervention on bone mineral density and prescribing practices of physicians. Clinical trials
114
BORAZ ET AL. Weight gain at the 1991;151:97-102.
in health pre- and perimenopausal women: a randomized clinical trial. J Bone Miner Res 1996;11(S1):65.
17. Brzezinski
A, Adlercreutz H, Shaoul R, Shmueli R, Reosler A, Schenker JG. Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause J North Am Menopause sot 1997;4:89-94.
18. Kuller LH, Matthews KA, Meilahn EN. Estrogens and women’s health: interrelation of coronary heart disease, breast and osteoporosis. J Steroid Biochem Mol Biol, in press.
cancer,
19. Simkin-Silverman
LR, Wing RR, Hansen DH, Klem ML, Pasagian-Macauley A, Meilahn EN, Kuller LH. Prevention of cardiovascular risk factor elevations in healthy premenopausal women. Prev Med 1995;24:509-17.
20. Wing RR, Matthews KA, Kuller LH, Meilahn EN, Plantinga PL.
time
of menopause.
Arch
Intern
Med
21. Matthews ISA, Meilahn EN, Kuller LH, Kelsey SF, Cagguila AW, Wing RR. Menopause and risk factors for coronary heart disease. N Engl J Med 1989;321:641-6. 22. Paffenbarger RS, Wing AL, Hyde RT. Physical activity as an index of heart attack risk in college alumni. Am J Epidemiol 1978;108:161-75. 23. Neugarten BL, Kraines RI. “Menopausal symptoms” in women of various ages. Psychosom Med 1964;27:266-73. 24’
Kuller LH, Simkin-Silverman LR, Wing RR, Meilahn EN, Ives DG. The women’s healthy lifestyle project WHLP), a randomized clinical trial: results at 54 months. Circulation 2000; in press.
25. Simkin-Silverman LR, Kuller LH, Boraz MA, Wing RR. A randomized clinical trial of weight gain prevention in 535 healthy women during menopause. Circulation 2000;100:1238.