Objective
The purpose of this study was to determine the efficacy of 3 nonhormonal therapies for the improvement of menopause-related quality of life in women with vasomotor symptoms.
Study Design
We conducted a 12-week 3 × 2 randomized, controlled, factorial design trial. Peri- and postmenopausal women, 40-62 years old, were assigned randomly to yoga (n = 107), exercise (n = 106), or usual activity (n = 142) and also assigned randomly to a double-blind comparison of omega-3 (n = 177) or placebo (n = 178) capsules. We performed the following interventions: (1) weekly 90-minute yoga classes with daily at-home practice, (2) individualized facility-based aerobic exercise training 3 times/week, and (3) 0.615 g omega-3 supplement, 3 times/day. The outcomes were assessed with the following scores: Menopausal Quality of Life Questionnaire (MENQOL) total and domain (vasomotor symptoms, psychosocial, physical and sexual).
Results
Among 355 randomly assigned women who average age was 54.7 years, 338 women (95%) completed 12-week assessments. Mean baseline vasomotor symptoms frequency was 7.6/day, and the mean baseline total MENQOL score was 3.8 (range, 1–8 from better to worse) with no between-group differences. For yoga compared to usual activity, baseline to 12-week improvements were seen for MENQOL total –0.3 (95% confidence interval, –0.6 to 0; P = .02), vasomotor symptom domain ( P = .02), and sexuality domain ( P = .03) scores. For women who underwent exercise and omega-3 therapy compared with control subjects, improvements in baseline to 12-week total MENQOL scores were not observed. Exercise showed benefit in the MENQOL physical domain score at 12 weeks ( P = .02).
Conclusion
All women become menopausal, and many of them seek medical advice on ways to improve quality of life; little evidence-based information exists. We found that, among healthy sedentary menopausal women, yoga appears to improve menopausal quality of life; the clinical significance of our finding is uncertain because of the modest effect.
More than 38 million US women who are 45-64 years old (88%) experience daytime hot flashes or night sweats during the menopausal transition. Hot flashes and night sweats or vasomotor symptoms (VMS) are the cardinal symptoms of menopause. However, other menopausal symptoms, which often are affected adversely by VMS frequency and bother (such as sleep and mood disturbances, pain, difficulty concentrating, and diminished energy) can affect daily functioning in work and social, leisure and sexual activities. Medical resources that have been expended to alleviate these problems are substantial, and there is a compelling need for effective treatments to relieve menopausal symptoms in midlife women.
Among symptomatic peri- and postmenopausal women with VMS, hormone therapy has demonstrated an improvement in quality of life (QOL). Because of the risks associated with hormone therapy among postmenopausal women, alternative lower risk behavioral therapies have been proposed for the treatment of VMS. Studies regarding the benefit of behavioral interventions for improving menopause-related QOL are less robust but suggest that yoga and exercise may be beneficial. Findings across studies have been inconsistent, perhaps because of different measures and outcomes of interest. Yoga findings, in particular, are limited by a paucity of studies, small sample sizes, and lack of control groups.
Nonphytoestrogenic supplements are used widely by midlife women but have not been examined specifically for improved midlife QOL. Omega-3 supplements that contain polyunsaturated fatty acids are among the most widely consumed supplements for a variety of medical conditions. Studies suggest that omega-3s modulate serotonergic and dopaminergic neurotransmission and may alleviate VMS. Two small randomized trials have examined the efficacy of omega-3s in the treatment of VMS with conflicting results.
We conducted a factorial design randomized controlled trial to evaluate the efficacy of yoga, exercise, and omega-3s on VMS frequency and bother. We found no benefit from any of these interventions for VMS, but we found suggestive evidence that self-reported sleep quality and depressive symptoms improved slightly with exercise and yoga (findings previously reported, not adjusted for multiple comparisons). In this analysis, we report findings on the impact of yoga, exercise, and omega-3s on menopause-related QOL.
Materials and Methods
Study design
Details about the Menopause strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) Research Network, study design, and protocols have been published. Briefly, we performed a multisite, 3 by 2 factorial randomized controlled trial. Eligible women were assigned randomly to 12 weeks of yoga, exercise, or usual activity and simultaneously were assigned randomly to 1.8 g/day of omega-3 or placebo capsules. The study was approved by the institutional review boards of all clinical sites and the Data Coordinating Center; all participants provided written informed consent. The Data Coordinating Center performed centralized training and monitored maintenance of the standardized protocol, fidelity to the intervention, and participant adherence.
Eligibility, screening, randomization, and blinding
Participants were recruited from February 2011 through January 2012 primarily by mass-mailing to women who were 40-62 years old with the use of purchased lists and health-plan enrollment files at 3 sites (Indianapolis, IN, Oakland, CA, and Seattle, WA). Eligible women were in the menopausal or postmenopausal transition. Screening was performed centrally with standardized inclusion, exclusion, and final eligibility criteria across sites.
Randomization was conducted in a secure central web-based database, with the use of a dynamic randomization algorithm to maintain comparability between study groups with respect to clinical site. An unequal allocation was used for the behavioral interventions (3:3:4; yoga:exercise:control), and equal allocation was used for omega-3 and placebo treatments, which were provided in masked identical capsules and containers.
Interventions
Yoga
The yoga intervention (studio and home practice) emphasized a practice of “cooling” breathing exercises, 11-13 poses (Asana Yoga: restorative, inverted, lateral bends or twists, forward bends, and counter-poses), which had been suggested previously for VMS relief, and guided meditation (Yoga Nidra). Instruction was provided during 12 weekly 90-minute classes. Daily home practice was expected for 20 minutes on days when class was not attended.
Exercise
The exercise intervention consisted of 12 weeks of 3 individual cardiovascular conditioning training sessions/week at local fitness facilities that were supervised by trained, certified exercise trainers. The targeted training heart rate was 50-60% of the heart rate reserve for the first month and 60-70% for the remainder of the intervention (approximately 125-145 beats/minute). Women exercised 40-60 minutes per session to achieve the energy expenditure goal of 16 kcal/kg (approximately 1000-1500 kcals/week).
Usual activity
Women in the usual activity group were instructed to follow their usual physical activity behavior and were asked not to begin yoga or a new exercise regimen.
Omega-3 and placebo capsules
To standardize the expectation of benefit, all women in both behavioral interventions and the usual activity group received either a placebo that contained olive oil or an active omega-3 capsule. The omega-3 supplement contained 425 mg ethyl eicosapentaenoic acid, 100 mg docosahexaenoic acid, and 90 mg of other omega-3s. All capsules (placebo and omega-3) contained natural lemon oil, rosemary extract, and vitamin E.
Follow-up and compensation
Participants were contacted by study staff members who were masked to pill randomization assignment to encourage pill compliance and to evaluate tolerance at 2 and 6 weeks. Participants were compensated $50 after each clinic visit for a possible total of $150.
Data collection
Outcomes (baseline to 12-week change): Menopausal Quality of Life Questionnaire, total and specific domain scores
The Menopausal Quality of Life Questionnaire (MENQOL; range, 1–8) is a 29-item assessment of menopause-related QOL. Scoring generates a total score and 4 domain scores (vasomotor, physical, psychosocial, sexual functioning); higher scores on all scales indicate poorer QOL. Women were asked whether an item was experienced in the past 4 weeks. Each item score includes nonendorsement “1” or endorsement “2” plus the bother score (0-6) for a maximum score of 8. The domain-specific score is the mean of the item scores within that domain. The total MENQOL score is the mean of the specific domain scores. Validity, internal consistency, reliability, and responsiveness to change are adequate to excellent.
Other measures (covariates)
Demographic factors were assessed by a baseline questionnaire. Weight and height were measured at baseline and body mass index (kilograms/square meter) calculated. Frequency and severity of VMS were recorded retrospectively on daily diaries that were completed in the morning for night sweats and in the evening for daytime hot flashes. Standardized and validated baseline questionnaires (covariates and possible effect modifiers) included insomnia severity (7-item Insomnia Severity Index), subjective sleep quality (Pittsburgh Sleep Quality Index), depressive symptoms (8-item scale from the Patient Health Questionnaire), and anxiety (7-item Generalized Anxiety Disorder scale).
Additional individual validated MENQOL measures included the Hot Flash–Related Daily Interference Scale (HFRDIS), Perceived Stress Scale, Pain Intensity, Interference with Enjoyment of Life, and Interference with General Activity scale (PEG), and Female Sexual Function Index (FSFI) ; the data were collected at baseline and 12 weeks.
Statistical analyses
The intent-to-treat analysis included all randomly assigned participants with response data that were collected regardless of intervention adherence. Baseline characteristics were compared between treatment groups with t tests or χ 2 tests.
Primary analyses consisted of treatment group contrasts from linear regression models that summarized each outcome (total MENQOL and 4 domains) at 12 weeks as a function of treatment assignment; we adjusted each model for clinical center, concurrent intervention assignment, and baseline value of the outcome measure. Treatment group comparisons included yoga vs usual activity, exercise vs usual activity, and omega-3 vs placebo. Analyses that compared the treatment effects of yoga and exercise were adjusted for omega-3 assignment, and the omega-3 analyses were adjusted for the behavioral intervention assignment. Sensitivity analyses were conducted to determine whether the intervention effects differed among women who were adherent to the intervention.
Additional analyses assessed treatment group contrasts from linear regression models that summarized the HFRDIS (hot flash interference), Perceived Stress Scale (stress), PEG (pain), and FSFI (sexual function) scores at 12 weeks as a function of treatment assignment. Each model was adjusted for clinical center, concurrent intervention assignment, and baseline value of the outcome measure.
We hypothesized that the intervention effects on the total MENQOL might be modified by symptom thresholds that were measured at baseline: anxiety (Generalized Anxiety Disorder scale continuous), depressive symptoms (Patient Health Questionnaire, continuous), poor sleep quality (Pittsburgh Sleep Quality Index, >8), or moderate-to-severe insomnia (Insomnia Severity Index, >14). Tests of interaction between treatment assignment and each of these 4 variables were performed within the linear regression models with an estimate of mean 12-week MENQOL as a function of the treatment arm, the covariate of interest, and the interaction between treatment assignment and covariate; models were adjusted for clinical center, concurrent intervention assignment, and baseline outcome value. Nominal probability values were calculated for the 8 potential interactions that were examined. Thus, less than 1 probability value would be expected to be statistically significant at the .05 level by chance alone.
Reported probability values were based on the Wald statistic, with a 2-sided probability value ≤ .05 considered statistically significant. Analyses were conducted with SAS software (version 9.2; SAS Institute, Cary, NC).
Results
Sample sizes by intervention assignments, available MENQOL data for analyses, and study completion are shown in the Figure . Overall, 78% of the women met the yoga adherence threshold; 83% of the women met the threshold for adherence to exercise ; and 82% of women assigned randomly to omega-3 and 79% assigned randomly to placebo took at least 80% of dispensed pills.
There were no significant differences between the randomized treatment groups in baseline characteristics ( Table 1 ), with the exception of age (exercise group older than usual activity group) and ethnicity (omega-3 group more likely to be white than the placebo group).
| Baseline Characteristic | Total participant, n | Behavioral intervention, % | Omega-3, % | |||
|---|---|---|---|---|---|---|
| Yoga (n = 107) | Exercise (n = 106) | Usual activity (n = 142) | Active (n = 177) | Placebo (n = 178) | ||
| Age at screening, y a | 355 | 54.3 ± 3.9 | 55.8 ± 3.6 | 54.2 ± 3.5 | 54.4 ± 3.6 | 55.0 ± 3.8 |
| <50 | 19 | 6.5 | 1.9 | 7.0 | 5.6 | 5.1 |
| 50-54 | 162 | 46.7 | 40.6 | 48.6 | 49.2 | 42.1 |
| 55-59 | 130 | 36.4 | 37.7 | 35.9 | 35.6 | 37.6 |
| ≥60 | 44 | 10.3 | 19.8 | 8.5 | 9.6 | 15.2 |
| Race | ||||||
| White | 228 | 63.6 | 66.0 | 63.4 | 70.6 | 57.9 |
| African American | 93 | 23.4 | 25.5 | 28.9 | 25.4 | 27.0 |
| Other b | 34 | 13.1 | 8.5 | 7.7 | 4.0 | 15.2 |
| College graduate | 221 | 64.5 | 54.7 | 66.2 | 64.4 | 60.1 |
| Employment status | ||||||
| Retired or no employment | 49 | 13.1 | 16.0 | 12.7 | 15.3 | 12.4 |
| Full/part-time | 267 | 72.0 | 77.4 | 76.1 | 76.3 | 74.2 |
| Other | 38 | 14.0 | 6.6 | 11.3 | 8.5 | 12.9 |
| Married/living with partner | 236 | 68.2 | 62.3 | 68.3 | 70.1 | 62.9 |
| Current smoker | 32 | 7.5 | 7.5 | 11.3 | 9.0 | 9.0 |
| ≥7 alcohol drinks/wk | 60 | 13.1 | 17.9 | 19.0 | 21.5 | 12.4 |
| Body mass index, m/kg 2 a | 27.1 ± 4.6 | 26.8 ± 3.9 | 26.9 ± 4.6 | 26.8 ± 4.4 | 27.1 ± 4.3 | |
| ≥30 | 88 | 27.1 | 23.6 | 23.9 | 23.7 | 25.8 |
| Menopause status | ||||||
| Postmenopausal | 286 | 74.8 | 84.9 | 81.7 | 82.5 | 78.7 |
| Perimenopausal | 69 | 25.2 | 15.1 | 18.3 | 17.5 | 21.3 |
| Hot flashes/ day at screening a | 7.4 ± 3.8 | 7.3 ± 3.3 | 8.0 ± 4.1 | 7.7 ± 3.9 | 7.6 ± 3.8 | |
| ≥9 | 114 | 29.9 | 30.2 | 35.2 | 33.9 | 30.3 |
| Hysterectomy | 64 | 15.9 | 23.6 | 15.5 | 19.8 | 16.3 |
| Bilateral oophorectomy | 32 | 7.5 | 10.4 | 9.2 | 10.2 | 7.9 |
| Self-reported health | ||||||
| Excellent/very good | 220 | 58.9 | 59.4 | 66.2 | 61.6 | 62.3 |
| Good | 119 | 36.4 | 37.7 | 28.2 | 33.9 | 33.1 |
| Fair | 15 | 4.7 | 1.9 | 5.6 | 4.5 | 3.9 |
b 18% Hispanic, 23% American Indian, 35% Asian/Pacific Islander, and 24% other groups (with <5 individuals).
Additional factors that might affect menopause-related QOL were compared at baseline ( Table 2 ). There were no differences among groups, with the exception that women who were assigned randomly to exercise had a higher mean PEG score than did the women in the usual activity group and that women who were assigned randomly to receive omega-3s had a lower mean FSFI score than did the women in the placebo group. Overall, 35% of the women had mild/moderate depressive symptoms; 27% of them had mild/moderate anxiety, and 40% of them had poor sleep quality. Mean hot flash interference score was 32.4 (HFRDIS; range, 0–100). Stress levels were relatively low, with an overall mean Perceived Stress Scale score of 13.8 ± 7.0 (SD) that was similar to the standard norm of 13.7 ± 6.6. The mean PEG score was low at 1.1 ± 1.8. Sexual function was relatively poor with a mean FSFI score of 18.4 ± 10.5.
| Baseline characteristic | Total participant, n | Behavioral intervention | Omega-3 | |||
|---|---|---|---|---|---|---|
| Yoga (n = 107) | Exercise (n = 106) | Usual activity (n = 142) | Active (n = 177) | Placebo (n = 178) | ||
| Depression score a,b | 4.0 ± 3.6 | 4.0 ± 4.2 | 4.1 ± 3.6 | 3.6 ± 3.5 | 4.4 ± 4.0 | |
| Mild+ depression: ≥5, % | 126 | 38.3 | 34.0 | 34.5 | 33.3 | 37.6 |
| Anxiety score a,c | 3.2 ± 3.8 | 3.4 ± 4.1 | 3.0 ± 3.0 | 2.9 ± 3.4 | 3.5 ± 3.8 | |
| Mild+ anxiety: ≥5, % | 95 | 27.1 | 27.4 | 26.1 | 24.3 | 29.2 |
| Insomnia Severity Index score a,d | 11.8 ± 5.4 | 11.5 ± 5.9 | 12.2 ± 5.2 | 11.8 ± 5.2 | 12.0 ± 5.7 | |
| Moderate+ insomnia: >14, % | 264 | 32.7 | 31.1 | 33.8 | 32.2 | 33.1 |
| Pittsburgh Sleep Quality Index score a,e | 7.7 ± 3.4 | 7.8 ± 3.4 | 8.4 ± 3.3 | 7.9 ± 3.3 | 8.2 ± 3.4 | |
| Poor sleep quality: >8, % | 294 | 34.6 | 40.6 | 43.7 | 35.6 | 44.4 |
| Hot Flash–Related Daily Interference Scale a,f | 336 | 31.7 ± 21.3 | 31.8 ± 22.5 | 33.6 ± 21.4 | 32.4 ± 20.0 | 32.5 ± 23.2 |
| Perceived Stress Score a,g | 347 | 13.5 ± 7.0 | 14.1 ± 7.3 | 13.6 ± 6.9 | 13.5 ± 7.1 | 14.0 ± 6.9 |
| Pain Intensity, Interference with Enjoyment of Life, and Interference with General Activity scale score a,h | 353 | 1.2 ± 2.0 | 0.8 ± 1.1 | 1.3 ± 2.0 | 1.0 ± 1.7 | 1.3 ± 1.8 |
| Female Sexual Function Index score a,i | 290 | 18.5 ± 10.5 | 16.8 ± 10.6 | 19.6 ± 10.4 | 20.0 ± 10.3 | 16.8 ± 10.6 |
| Treadmill test duration, min a | 355 | 10.4 ± 3.1 | 9.6 ± 2.9 | 10.3 ± 2.9 | 10.3 ± 2.9 | 9.9 ± 3.1 |
b Patient Health Questionaire-8 (range, 0–20)
c Generalized Anxiety Disorder-7 (range, 0–17)
The mean total MENQOL score was 3.8 (range, 1–8) at baseline, with no between-group differences at baseline ( Tables 3 and 4 ). The yoga intervention resulted in significantly greater improvement in MENQOL scores at 12 weeks, compared with the usual activity group in adjusted linear regression models ( P = .02), but there were no group differences between exercise and usual activity or omega-3 and placebo. The mean difference in change from baseline to 12 weeks in the total MENQOL score for the yoga intervention, compared with the usual activity group, was –0.3 (95% CI, –0.6 to 0). Statistically significant differences in MENQOL domain scores that favored the yoga intervention group were observed for the vasomotor (–0.3; 95% CI, –0.8 to 0.2; P = .02) and sexual domains (–0.5; 95% CI, –1.0 to 0; P = .03). For exercise and omega-3 groups, evaluation of the 4 MENQOL domains showed only a statistically significant treatment group difference that favored the exercise group for the physical domain (–0.2; 95% CI, –0.5 to 0; P = .02), and no domain scores varied between the omega-3 and placebo groups.
| MENQOL score a | Intervention arm | Difference | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Yoga | Exercise | Usual activity | Yoga vs usual activity | Exercise vs usual activity | ||||||
| n | Mean (95% CI) | n | Mean (95% CI) | n | Mean (95% CI) | Mean (95% CI) | P value b | Mean (95% CI) | P value b | |
| Total | .02 | .32 | ||||||||
| Baseline | 95 | 3.8 (3.6–4.0) | 93 | 3.8 (3.5–4.1) | 129 | 3.8 (3.6–4.0) | 0 (–0.3 to 0.3) | 0 (–0.3 to 0.3) | ||
| Week 12-baseline | 85 | –0.9 (–1.2 to –0.7) | 79 | –0.8 (–1.0 to –0.6) | 117 | –0.6 (–0.8 to –0.5) | –0.3 (–0.6 to 0) | –0.1 (–0.4 to 0.1) | ||
| DOMAINS | ||||||||||
| Vasomotor | .02 | .52 | ||||||||
| Baseline | 104 | 5.3 (5.0–5.6) | 105 | 5.3 (5.0–5.6) | 141 | 5.6 (5.4–5.8) | –0.3 (–0.7 to 0) | –0.3 (–0.7 to 0.1) | ||
| Week 12-baseline | 97 | –1.5 (–1.9 to –1.2) | 99 | –1.2 (–1.5 to –0.9) | 133 | –1.2 (–1.5 to –0.9) | –0.3 (–0.8 to 0.2) | 0 (–0.4 to 0.5) | ||
| Psychosocial | .78 | .57 | ||||||||
| Baseline | 105 | 3.3 (3.0–3.6) | 106 | 3.3 (3.0–3.6) | 140 | 3.3 (3.1–3.5) | 0 (–0.4 to 0.3) | 0 (–0.4 to 0.4) | ||
| Week 12-baseline | 98 | –0.6 (–0.8 to –0.4) | 98 | –0.6 (–0.9 to –0.4) | 130 | –0.6 (–0.7 to –0.4) | 0 (–0.3 to 0.3) | –0.1 (–0.4 to 0.2) | ||
| Physical | .13 | .02 | ||||||||
| Baseline | 98 | 3.2 (2.9–3.5) | 100 | 3.2 (2.9–3.4) | 137 | 3.3 (3.1–3.5) | –0.1 (–0.4 to 0.3) | –0.1 (–0.4 to 0.2) | ||
| Week 12-baseline | 90 | –0.6 (–0.8 to –0.4) | 91 | –0.7 (–0.9 to –0.5) | 129 | –0.5 (–0.6 to –0.3) | –0.1 (–0.4 to 0.1) | –0.2 (–0.5 to 0) | ||
| Sexual | .03 | .41 | ||||||||
| Baseline | 102 | 3.2 (2.7–3.6) | 100 | 3.4 (2.9–3.9) | 137 | 3.3 (2.9–3.7) | –0.1 (–0.7 to 0.5) | 0.1 (–0.5 to 0.8) | ||
| Week 12-baseline | 95 | –0.9 (–1.3 to –0.5) | 88 | –0.6 (–0.9 to –0.3) | 127 | –0.4 (–0.7 to –0.1) | –0.5 (–1.0 to 0) | –0.2 (–0.6 to 0.2) | ||
a MENQOL total score range, 1–8; domain scores range, 1–8
b P values from contrasts comparing active vs control in a linear model of outcome as a function of the intervention arm and adjusted for clinical center, baseline outcome value, and concurrent interventions.
| MENQOL score a | Intervention arm | |||||
|---|---|---|---|---|---|---|
| Omega-3 | Placebo | Difference | ||||
| n | Mean (95% CI) | n | Mean (95% CI) | Mean (95% CI) | P value b | |
| Total | .12 | |||||
| Baseline | 156 | 3.8 (3.6–3.9) | 161 | 3.9 (3.7–4.0) | –0.1 (–0.3 to 0.2) | |
| Week 12-baseline | 139 | –0.7 (–0.8 to –0.5) | 142 | –0.9 (–1.0 to –0.7) | 0.2 (–0.1 to 0.4) | |
| DOMAINS | ||||||
| Vasomotor | .06 | |||||
| Baseline | 173 | 5.5 (5.3–5.7) | 177 | 5.3 (5.1–5.6) | 0.2 (–0.1 to 0.5) | |
| Week 12-baseline | 164 | –1.2 (–1.5 to –1.0) | 165 | –1.4 (–1.7 to –1.1) | 0.2 (–0.2 to 0.6) | |
| Psychosocial | .29 | |||||
| Baseline | 175 | 3.2 (3.0–3.4) | 176 | 3.3 (3.2–3.6) | –0.2 (–0.5 to 0.1) | |
| Week 12-baseline | 163 | –0.5 (–0.7 to –0.3) | 163 | –0.7 (–0.8 to –0.5) | 0.2 (–0.1 to 0.4) | |
| Physical | .91 | |||||
| Baseline | 167 | 3.2 (3.0–3.4) | 168 | 3.2 (3.0–3.4) | 0 (–0.3 to 0.3) | |
| Week 12-baseline | 156 | –0.6 (–0.8 to –0.4) | 154 | –0.5 (–0.7 to –0.4) | 0 (–0.3 to 0.2) | |
| Sexual | .31 | |||||
| Baseline | 167 | 3.1 (2.8–3.5) | 172 | 3.4 (3.0–3.8) | –0.3 (–0.8 to 0.3) | |
| Week 12-baseline | 154 | –0.5 (–0.7 to –0.2) | 156 | –0.7 (–1.0 to –0.4) | 0.3 (–0.1 to 0.6) | |
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