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Obstetrics & Gynecology 2000;96:359-365
© 2000 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Raloxifene and Estrogen Effects on Quality of Life in Healthy Postmenopausal Women: A Placebo-Controlled Randomized Trial

RONALD STRICKLER, MD, DALE W. STOVALL, MD, DIANE MERRITT, MD, WEI SHEN, PhD, MAYME WONG, PhD and SHERYL L. SILFEN, MD

From the Department of Obstetrics and Gynecology, Henry Ford Hospital, Detroit, Michigan; the Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia; Barnes Jewish Hospital, St. Louis, Missouri; and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.

Address reprint requests to: Sheryl L. Silfen, MD Lilly Research Laboratories Eli Lilly and Company Indianapolis, IN 46285


   Abstract
Top
Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To assess the effects of raloxifene, estrogen, and placebo on quality of life in healthy, asymptomatic, postmenopausal women.

Methods: In a multicenter, double-blind, 12-month study, 398 women were assigned randomly to one of four groups: raloxifene HCl, 60 (n = 97) or 150 mg/day (n = 100); conjugated equine estrogens, 0.625 mg/day (n = 96); or placebo (n = 105). The Women’s Health Questionnaire, a validated quality-of-life instrument for perimenopausal and postmenopausal women, was administered at baseline and 3-month intervals.

Results: Overall, quality of life from baseline to end point was preserved equally in all treatment groups. Six domains (depressed mood, somatic symptoms, memory/ concentration, sexual behavior, sleep problems, and perceived attractiveness) were unchanged in all groups. Three domains (menstrual symptoms, vasomotor symptoms, and anxiety/fears) were statistically significantly different among groups. Mean scores for menstrual symptoms significantly worsened and vasomotor symptoms significantly improved from baseline to end point in the estrogen group. Mean scores for vasomotor symptoms did not worsen at any point in the raloxifene 60 mg/day group. Mean anxiety/fears scores improved significantly during raloxifene 60 mg/day administration throughout treatment (P < .05), irrespective of previous hormone replacement therapy, baseline estradiol (E2) levels, or years postmenopause.

Conclusion: Most quality-of-life domains were not affected by treatment with estrogen or raloxifene. Estrogen provided relief from vasomotor symptoms but caused menstrual symptoms. Raloxifene 60 mg/day improved anxiety levels in postmenopausal women.

The physiologic changes that result from decreased estrogen production occur concurrently with physical aging and midlife psychosocial adaptations. Decreases in quality of life that may occur during menopause, including disturbed sleep patterns, increased anxiety or depression, short-term memory loss, and somatic symptoms, could be the result of any or all of these physiologic, psychologic, and social changes.1 On the basis of the assumption that the physiologic and psychologic symptoms at menopause result solely from estrogen deprivation, estrogen administration was expected to alleviate these symptoms and improve quality of life.2 Data from menopausal women with vasomotor symptoms3,4 and women who had just undergone surgical castration5 supported the initial impression that estrogen administration would improve vasomotor symptoms, mood, depression, anxiety, and memory. However, recent clinical trials that enrolled menopausal women not seeking relief of vasomotor symptoms defined a more narrow scope of estrogen benefits on quality-of-life–related outcomes.6,7 Furthermore, evidence suggests that the severity of menopausal symptoms and the frequency with which women seek medical treatment are highly conditioned by sociocultural factors.8,9

Raloxifene, a selective estrogen receptor modulator, acts as an estrogen agonist on bone and serum lipid metabolism and as an estrogen antagonist in the breast and uterus.10 In healthy postmenopausal women, raloxifene therapy prevents bone loss11 and decreases serum cholesterol levels.12 In postmenopausal women with osteoporosis, raloxifene therapy was associated with a decreased relative risk of incident vertebral fractures13 and breast cancer.14 Three reports address the effects of raloxifene on quality-of-life–related outcomes. In young healthy postmenopausal women, the incidence of hot flushes was higher in the raloxifene group compared with placebo.11,12 In a randomized, 1-year, double-blind, placebo-controlled study of postmenopausal women with osteoporosis, raloxifene treatment neither improved nor impaired cognitive function as measured by using the Memory Assessment Clinics battery or the Walter Reed Performance Assessment Battery.15 The same study also found that women in the raloxifene treatment group did not have significant changes in mood, as assessed by using the Geriatric Depression Scale, compared with the placebo group.

The objective of our prospective study was to evaluate the effects of raloxifene compared with estrogen or placebo on quality of life in healthy postmenopausal women at baseline and 3-month intervals. The Women’s Health Questionnaire, which was specifically developed to subjectively measure physical and emotional well-being in perimenopausal and postmenopausal women,16 has been validated and administered in studies of hormone replacement therapy.17


   Materials and Methods
Top
Abstract
 Materials and Methods
Results
 Discussion
 References
 
This 12-month, phase 3, double-masked, parallel study was conducted at 32 study sites, grouped for analysis according to geographic regions in the United States. Participants were assigned randomly in blocks of four to one of four therapy groups: raloxifene HCl, 60 or 150 mg/day; encapsulated conjugated equine estrogens, 0.625 mg/day; or placebo. Inclusion criteria were age 47 to 60 years, 2 to 8 years after final menstrual period, serum estradiol (E2) level less than 73 pmol/L (less than 20 pg/mL), and lumbar spine bone mineral density two standard deviations (SD) above to 2.5 SD below the mean peak lumbar spine bone mineral density of premenopausal women. Exclusion criteria were intolerable menopausal symptoms requiring therapy; uterine bleeding of unknown cause; body mass index less than 18 kg/m2 or greater than 31 kg/m2, history of deep venous thromboembolic disease; use of corticosteroids, estrogen, or progestin within 6 months before beginning the study; and chronic illness. Investigators obtained ethical review board approval, and women signed an informed-consent document before entering the study. The objective of this study, with respect to uterine response, has been reported previously.18

To maintain masking, placebo was provided both as tablets identical in appearance to raloxifene and capsules identical in appearance to estrogen (double-dummy packaging). Women took one tablet and one capsule of masked study medication. The study medication and placebo, packaged in kits numbered according to a random-number table, were assigned sequentially to each woman at randomization, beginning with the lowest number available. In addition to study medication, all women received calcium, 520 mg/day.

The Women’s Health Questionnaire, a validated instrument that subjectively assesses quality of life in perimenopausal and postmenopausal women,16 was administered at baseline and at 3-month intervals. The 36 questions (Table 1Go) cover nine predetermined domains: depressed mood, somatic symptoms, memory/ concentration, vasomotor symptoms, anxiety/fears, sexual behavior, sleep problems, menstrual symptoms, and perceived attractiveness. Women had the option of omitting the questions on sexuality. Each participant was asked to respond with one of four possible answers, "yes, definitely," "yes, sometimes," "no, not much," and "no, not at all," based on her current feelings. For directional consistency in the calculations, each response was assigned to a 4-point scale, with 4 considered the best condition and 1 the worst. As each domain is reported, an increased mean score indicates an improvement in symptoms and a decreased mean score indicates a worsening of symptoms. Although the Women’s Health Questionnaire was developed as a binary outcome measure, the original 4-point categoric patient score and overall scores are considered more informative for directional evaluations.19,20 If any unexpected overall changes were noted in any domain, additional analyses were performed to examine these changes in subpopulations of women. The women were categorized by using clinically relevant variables, including baseline domain scores, baseline E2 levels, previous HRT use, and years postmenopause.


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  		Table 1. The Women’s Health Questionnaire
 
Sample-size calculations were based on the expected difference in incidence of endometrial hyperplasia between the therapy groups. Women’s Health Questionnaire data analyses were considered exploratory in nature and therefore were not adjusted for multiple comparisons. This study had greater than 70% power to detect an overall treatment difference of 0.2 and greater than 80% power to detect a pairwise difference of 0.2. All statistical analyses were performed by using an intent-to-treat approach on data from women who had at least one follow-up visit after randomization. Missing values were replaced with values from a previous postrandomization visit (last observation carried forward). Women were included in the change-from-baseline analysis only if they had both a baseline and postbaseline Women’s Health Questionnaire assessment. For each of the nine domains, differences in changes among the therapy groups were assessed for each visit by using an analysis of variance model with fixed effects of therapy and geographic region. Pairwise comparisons between therapy groups were performed only if overall treatment effects were observed. Paired t-tests were used to analyze changes over time within each therapy group for each of the nine domains. Comparisons were tested at the .05 two-sided {alpha} level of significance.


   Results
Top
Abstract
 Materials and Methods
 Results
Discussion
 References
 
A total of 398 women were enrolled. The mean age of the participants was 54.7 years, and the mean number of years since their final menstrual period was 4.5. Therapy groups did not differ in baseline demographic characteristics (Table 2Go). Paired baseline and postbaseline assessments of the Women’s Health Questionnaire were obtained from 373 women. Mean baseline scores for all domains ranged from 2.78 to 3.59, and the overall baseline score was 3.23, consistent with an asymptomatic population. Therapy groups did not differ in mean values of any domain at baseline (Table 3Go).


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  		Table 2. Summary of Baseline Demographic Characteristics*
 

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  		Table 3. Women’s Health Questionnaire: Pooled Baseline Scores
 
The calculated overall quality-of-life score, which included all nine Women’s Health Questionnaire domains, did not change significantly from baseline to end point in any treatment group (Table 4Go). The changes in mean scores for six domains (depressed mood, somatic symptoms, memory/concentration, sexual behavior, sleep problems, and perceived attractiveness) did not differ significantly among therapy groups from baseline to end point. At 12 months, the mean score for sleep problems significantly improved from baseline only in the estrogen group (P < .05). The mean scores for the other five domains did not significantly differ from baseline to the 12-month end point in any group.


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  		Table 4. Women’s Health Questionnaire Scores: Changes from Baseline to 12-Month End Point*
 
The mean scores for three domains (menstrual symptoms, vasomotor symptoms, and anxiety/fears) differed significantly among therapy groups (P < .05, Table 4Go). Compared with baseline, mean scores for menstrual symptoms were worse at 3, 9, and 12 months in the estrogen group and at 6, 9 and 12 months in the raloxifene 150 mg/day group (P < .05). Menstrual symptom scores differed significantly between the placebo and raloxifene 150 mg/day groups at 6 months. These changes in menstrual symptom scores in the estrogen group also differed significantly from the placebo group at 3, 6, and 12 months (P < .05) and from the raloxifene 60 mg/day group at 3 months (P < .001). The mean scores for menstrual symptoms did not significantly change in the placebo or raloxifene 60 mg/day groups at any time. Vasomotor symptom scores improved significantly from baseline in the estrogen group and differed significantly from scores in the other groups at all times (P < .001 for all comparisons). Mean scores for vasomotor symptoms did not change significantly in either raloxifene group at any time.

The scores for anxiety/fears differed significantly among therapy groups (Table 4Go). In the raloxifene 60 mg/day group, mean scores for anxiety/fears improved significantly from baseline at all times (Figure 1Go) and were greater than the scores in the placebo and estrogen groups at 3 and 12 months (P < .05 for both groups). The mean scores for the anxiety/fears domain were examined further by dividing the study population according to clinically relevant parameters: baseline scores, baseline E2 levels, previous HRT use, and years after menopause (Table 5Go). In women who had baseline anxiety scores below the median (more anxious), both estrogen and raloxifene 60 mg/day significantly improved the anxiety/fears score. In women who had baseline anxiety scores at or above the median (less anxious), the mean anxiety/fears score at end point was significantly worse than baseline score only in the estrogen group. No change occurred in the placebo group. Raloxifene 60 mg/day significantly improved mean anxiety/fears scores from baseline, irrespective of previous HRT use, baseline E2 levels, or years postmenopause (Table 5Go). Raloxifene 150 mg/day significantly improved the mean anxiety/fears scores in women who had never used HRT.



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  		Figure 1. Changes in Women’s Health Questionnaire scores (mean ± standard error) for the anxiety/fears domain were significantly increased in the raloxifene 60 mg/day group at all points, whereas the scores in the other groups were unchanged.

 

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  		Table 5. Women’s Health Questionnaire Scores for the Anxiety/Fears Domain: Subgroup Analyses of the Changes from Baseline to 12-Month End Point*
 
The proportion of women who had improvement in mean anxiety/fears scores differed significantly among therapy groups (overall P = .02). A higher proportion of women treated with either raloxifene dose showed improved anxiety scores. In the raloxifene 60 mg/day group, 48% of women had an improved anxiety score and 38% had no change. In the raloxifene 150 mg/day group, 52% of women had an improved anxiety score and 25% had no change. The proportion of women who had an improvement or no change in anxiety score was approximately 33% in both the estrogen and placebo groups.


   Discussion
Top
Abstract
 Materials and Methods
 Results
 Discussion
References
 
The 60-mg/day dose of raloxifene, approved for treatment and prevention of osteoporosis, was found to preserve overall quality-of-life as measured by using the Women’s Health Questionnaire. Domains for depression, somatic symptoms, memory/concentration, sexual behavior, sleep problems and perceived attractiveness were unchanged from baseline in all treatment groups. Self-reported cognitive function scores in the raloxifene groups were consistent with those in a previous raloxifene study that objectively measured cognitive function by using two batteries specific for cognition.15 Our findings in the menstrual and vasomotor symptom domains of the Women’s Health Questionnaire are consistent with the occurrence of self-reported adverse events.18 In addition, our study prospectively reports on vasomotor symptoms during raloxifene therapy. Scores were unchanged in both the 60-mg and the 150-mg groups. Previous raloxifene studies have reported spontaneous complaints of hot flushes.11,12

Raloxifene 60 mg/day was found to improve anxiety scores compared with baseline and with the other treatment groups. The degree of improvement was not significant with the higher raloxifene dose, possibly due to the sample size. Several explanations for the lack of dose response are possible, including a different symptom profile with the higher raloxifene dose, sensitivity of the Women’s Health Questionnaire, and physiologic or cellular mechanisms that are not yet understood. The improvement in anxiety scores with raloxifene 60 mg/day occurred regardless of previous use of HRT, baseline E2 level, or years postmenopause. Women who were more anxious at baseline had significantly improved anxiety scores when treated with raloxifene 60 mg/day or conjugated equine estrogens. In contrast, women who were less anxious at baseline had significantly worsened anxiety scores with conjugated equine estrogens.

In observational studies, women who were anxious and had poor stress-coping skills were more likely to seek HRT.9,21,22 Women who use estrogen were more likely to use concomitant anxiolytic agents.23 In the large randomized, double-masked, placebo-controlled Postmenopausal Estrogen/Progestin Interventions trial, only women who adhered to therapy with unopposed conjugated equine estrogens had a reduction in anxiety.6 In the same study, no effect on anxiety was noted with unopposed conjugated equine estrogens in the intention-to-treat population or in women treated with estrogen combined with progestin. The effects of raloxifene 60 mg/day differ from those of oral conjugated equine estrogens in that raloxifene improved anxiety scores regardless of baseline anxiety. Because raloxifene does not require progestin coadministration, attenuation of the potential benefits of estrogen6 by the adverse psychologic effects caused by progestin can be avoided.24 No conclusions can be drawn from our data about raloxifene compared with estrogen plus progestin, but there is no evidence to suggest that adding progestin to estrogen would improve quality-of-life outcomes.

In our study of asymptomatic postmenopausal women, six of the nine Women’s Health Questionnaire domains did not statistically differ among therapy groups, indicating a stable quality of life regardless of treatment. Large population-based surveys report that most women going through menopause have neutral or positive views on this transition, contrary to the common medical impression of a deterioration in quality of life.1,25,26 Studies that show an improvement in quality of life with estrogen administration, including those that used the Women’s Health Questionnaire, were confounded by enrolling women who had moderate-to-severe vasomotor symptoms.17,19,27 In those studies, relief from vasomotor symptoms obtained with estrogen could have positively influenced other quality-of-life domains, such as cognitive function. The benefit of estrogen on cognitive function among cohorts of women not seeking relief from vasomotor symptoms is challenged by a growing body of evidence.23,28 Randomized trials6,29 and a meta-analysis that stratified results on the basis of the presence or absence of menopausal symptoms30 also raise questions about the universal benefit of estrogen.

Our results suggest that asymptomatic postmenopausal women should expect to maintain a stable quality of life irrespective of therapy with raloxifene, unopposed conjugated equine estrogens, or no treatment. Women specifically seeking relief from vasomotor symptoms, who are usually treated with estrogen, were not included in this study. Therefore, our results should be applied only to women seeking therapy for prevention or treatment of osteoporosis.

Finally, we detected some differences in quality of life among the raloxifene, conjugated equine estrogens, and placebo groups. Although conjugated equine estrogens administration improved vasomotor symptoms scores, it worsened menstrual symptom scores. Neither vasomotor nor menstrual symptom scores were affected by raloxifene administration. Raloxifene 60 mg/day significantly improved anxiety scores. Further research is needed to determine whether this improvement in anxiety could enhance continuance of therapy in asymptomatic women taking raloxifene for treatment or prevention of osteoporosis.


   Footnotes
 
Financial disclosure

This research was supported by Eli Lilly and Company, maker of raloxifene. Doctors Shen, Wong, and Silfen are employees of and hold stock in Eli Lilly and Company. Doctors Strickler, Stovall, and Merritt have received honoraria for their services to Eli Lilly and Company.

PII S0029-7844(00)00937-6

Received November 29, 1999. Received in revised form March 14, 2000. Accepted March 24, 2000.


   References
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2. Ravnikar VA. Compliance with hormone replacement therapy: Are women receiving the full impact of hormone replacement therapy preventative health benefits? Women’s Health Issues 1992;2:75–82.

3. Cagnacci A, Volpe A, Arangino S, Malmusi S, Draetta FP, Matteo ML, et al. Depression and anxiety in climacteric women: Role of hormone replacement therapy. Menopause 1997;4:206–11.

4. Hilditch JR, Lewis J, Ross AH, Peter A, van Maris B, Franssen E, et al. A comparison of the effects of oral conjugated equine estrogen and transdermal estradiol-17 beta combined with an oral progestin on quality of life in postmenopausal women. Maturitas 1996;24: 177–84.[Medline]

5. Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 1992; 17:485–95.[Medline]

6. Greendale GA, Reboussin BA, Hogan P, Barnabei VM, Shumaker S, Johnson S, et al. Symptom relief and side effects of postmenopausal hormones: Results from the Postmenopausal Estrogen/ Progestin Interventions Trial. Obstet Gynecol 1998;92:982–8.[Abstract]

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12. Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998;279:1445–51.[Abstract/Free Full Text]

13. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial. JAMA 1999;282:637–45.[Abstract/Free Full Text]

14. Cummings S, Eckert S, Krueger K, Grady D, Powles T, Cauley J, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999;281:2189–97.[Abstract/Free Full Text]

15. Nickelsen T, Lufkin EG, Riggs BL, Cox DA, Crook TH III. Raloxifene hydrochloride, a selective estrogen receptor modulator: Safety assessment of effects on cognitive function and mood in postmenopausal women. Psychoneuroendocrinology 1999;24:115–28.[Medline]

16. Hunter M. The Women’s Health Questionnaire: A measure of mid-aged women’s perceptions of their emotional and physical health. Psychology and Health 1992;7:45–54.

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