Abstract
Objective
To determine the efficacy and tolerability of omega-3 fatty acids in reducing VMS frequency and bother in peri- and postmenopausal women.
Methods
Three-by-two factorial, randomized, controlled 12-week trial. Eligible women were randomized to double-blind comparison of omega-3s (n=177) or placebo (n=178) capsules, and simultaneously to yoga (n=107), aerobic exercise (n=106), or their usual physical activity (n=142). Participants received 12 weeks of omega-3 dosage at a dose of 1.8 grams daily. Each capsule contained ethyl eicosapentaenoic acid (EPA; 425 mg) and docosahexaenoic acid (DHA; 100 mg) and other omega-3s (90mg). Primary outcomes were VMS frequency and bother. Secondary outcomes included sleep quality (Pittsburg Sleep Quality Index), insomnia symptoms (Insomnia Severity Index), depressive symptoms (Physician's Health Questionnaire-8), and anxiety (Generalized Anxiety Disorder-7).
Results
The mean baseline frequency of VMS/day was 7.6 (95% confidence interval [CI] 7.0, 8.2). After 12 weeks, reduction in VMS frequency for omega-3 (−2.5, 95% CI −3.0, −1.9) did not differ significantly from that in placebo (−2.7, 95% CI −3.3, −2.2), with a relative difference of 0.3 fewer hot flashes per day (95% CI −0.5, 1.0, p=0.28). Changes in VMS bother at 12 weeks were also similar between groups, with no relative difference on a 4-point scale (95% CI −0.1, 0.2, p=0.36). Omega-3s compared with placebo showed no improvement in self-reported sleep or mood (p>0.09 for all comparisons).
Conclusion
Among healthy peri- and postmenopausal sedentary women, 12 weeks of omega-3 treatment compared with placebo did not improve VMS frequency, VMS bother, sleep, or mood compared to placebo.
Keywords: omega-3, fish oils, hot flashes, vasomotor symptoms, clinical trials network, menopause
INTRODUCTION
Vasomotor symptoms affect up to 80% of women during the menopausal transition, frequently last several years, and can be disruptive and compromise quality of life.1 Many women seek alternative treatments to hormonal agents or selective serotonergic reuptake inhibitors (SSRIs) to manage VMS in light of demonstrated risks of hormonal interventions1 and bothersome side effects of SSRIs.2 Women who experience an array of menopausal symptoms frequently turn to complementary and alternative therapies, particularly herbal supplements. A recent report from the National Center for Complementary and Alternative Medicine (NCCAM) indicated that over 40% of the adult population in the U.S. used at least one complementary or alternative medicine (CAM) treatment over the previous year, with women more likely than men to use CAM.3,4
Omega-3 supplements are polyunsaturated fatty acids (PUFAs) that include the longer chain ω-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as alpha-linolenic acid (ALA), and are among the most widely consumed supplements for a variety of medical conditions (including cardiovascular disease, rheumatoid arthritis, depression and other cognitive disorders).5 Human and animal studies of omega-3s suggest mechanisms of action that include modulation of serotonergic and dopaminergic neurotransmission.6-8
To date, two small randomized trials have examined the efficacy of omega-3s in the treatment of VMS.9,10 In an 8-week trial of an enriched EPA supplement containing 350 mg of EPA and 50 mg of DHA given 3 times daily vs. placebo among 91 emotionally distressed women with VMS, hot flash frequency and intensity improved significantly in the active treatment group relative to the placebo group.9 In a second trial (n=28) that included two studies, one of isoflavone vs. placebo and the other isoflavones+PUFA vs. placebo, results were inconclusive due to small number of participants investigated and a large number of women who failed to complete the study.10 Given small sample sizes, conflicting results, and the widespread use of this supplement for a spectrum of symptoms including VMS, there has been a need for a larger, more rigorously conducted trial to definitively delineate the role of omega-3s in the treatment of vasomotor symptoms.
In the current study, we report results of a randomized placebo controlled study testing the efficacy of omega-3s for the reduction in frequency and bother of VMS in peri- and postmenopausal women. We also examine the effect of omega-3s vs. placebo on other menopausal symptoms including self-reported measures of sleep, depressive, and anxiety symptoms, all of which commonly co-occur with VMS.
METHODS
Study design
Details describing the MsFLASH Network, its protocols, and its overarching study procedures have been published elsewhere.11 This study was a multi-center, 3 by 2 factorial design, randomized, controlled trial of 12 weeks duration testing the efficacy of 1.8 g/day of omega-3 supplementation from fish oil or a matching placebo from olive oil for reducing the frequency and/or relieving the bother of vasomotor symptoms (VMS). Concurrent with randomization to omega-3s or placebo, participants were also cross-randomized to aerobic exercise, yoga, or their usual physical activity. Randomization was accomplished through a secure Web-based database, maintained by the MsFLASH DCC, utilizing a dynamic randomization algorithm to maintain comparability between study groups with respect to clinical site. Data collectors were blinded to randomization assignment. The current study reports the results of the omega-3 intervention; results for the exercise and yoga interventions are reported separately.
Within each behavioral intervention group (yoga, exercise, or regular physical activity), women were randomized to receive placebos pill or 1.8 g/day (3 pills/day, each containing 425 mg of EPA, 100 mg DHA and 90 mg of other omega-3s) of high-quality omega-3s. Women randomized to yoga attended a weekly class with a trained instructor and practiced at home on other days; those randomized to exercise attended supervised aerobic exercise sessions three times per week; women randomized to usual activity were asked to follow their usual physical activity routine and offered their choice of a 3-hour yoga workshop or a one-month gym membership at study end. Each woman participated for 15 weeks, including a 3-week eligibility run-in period, 12-week intervention period, and a final clinic visit during week 12.
The study was approved by the institutional review boards at each participating site and the Data Coordinating Center (DCC), and all participants provided written informed consent and authorization to use protected health information.
Study population
The trial was conducted at three MsFLASH network sites (Indianapolis, Seattle, and Oakland). Participants were recruited from February 2011 through January 2012, primarily by mass mailings to age-eligible women using purchased mailing lists and health-plan enrollment files. Eligible women were aged 40-62 years; in the menopause transition (amenorrhea ≥60 days in the past year) or postmenopausal (≥12 months since last menstrual period or bilateral oophorectomy) or had a hysterectomy with FSH >20 mIU/mL and estradiol of ≤50 pg/mL; and in general good health.
VMS enrollment criteria were: ≥14 hot flashes/night sweats per week recorded on daily VMS diaries for 3 weeks; VMS rated as bothersome or severe during at least 4 or more 12-hour (day/night) blocks of times per week; and the VMS frequency in week 3 did not decrease >50% from the mean weekly levels in weeks 1 and 2. Exclusion criteria included: BMI>37; use of hormones or hormonal contraceptives in the past 2 months; use of prescription or over-the-counter treatments for VMS in the past month; any unstable medical conditions; contraindications to exercise training (e.g., physical limitations), yoga, or omega-3 (allergy to soy or fish; current, regular use of anti-coagulants); current participation in regular exercise or yoga; current use of omega-3 supplements or frequent consumption of fish (4 or more servings a week); or a major depressive episode in the past three months.
Treatment
The omega-3 study supplement contained omega-3 (ω-3, n-3) fatty acids from fish oils (also described as polyunsaturated fatty acids (PUFAs), manufactured by Nordic Naturals, Watsonville, CA). Each gel capsule had a total omega-3 dosage of 615 mg, which included the two major omega-3 components of ethyl eicosapentaenoic acid (EPA; 425 mg) and docosahexaenoic acid (DHA; 100 mg) along with other assorted omega-3s (90mg). Vitamin E (15 IU), an antioxidant, was added to each gel capsule of active treatment and placebo in order to preserve freshness. Participants assigned to placebo took identical gel capsules containing olive oil. Gel capsules (placebo and omega-3) contained natural lemon oil and rosemary extract to enhance taste. Participants, study clinicians, and staff were blinded to study pill treatment assignment. Participants were instructed to take three capsules per day of omega-3s or placebo for 12 weeks.
Screening and baseline data collection
Women who were eligible after a telephone screen completed a two-week hot flash diary and a questionnaire. Women who continued to meet eligibility criteria came to a clinic visit during which additional information was collected, including vital signs, blood draw, and baseline questionnaire. Women were given an additional hot flash diary to be completed before the next clinic visit a week later, at which time final eligibility was assessed and randomization occurred.
Follow-up
Study staff blinded to treatment assignment contacted participants at week 2 to encourage compliance and evaluate pill tolerance. Six weeks and 12 weeks post-randomization participants completed additional 7-day VMS diaries. Other baseline measurements were repeated at the week 12 post-randomization clinic visit. Treatment adherence was assessed by counting the number of pills returned at the last visit. Participants received $50 after each of 3 clinic visits for their time and effort, for a possible total of $150.
Study outcomes
Primary outcomes
The primary outcomes were VMS frequency and bother based on daily diaries at baseline and Weeks 6 and 12 in which participants entered the number of VMS they had experienced upon awakening for nighttime symptoms and before going to sleep for daytime symptoms. They rated VMS bother for each day and night on a 1-4 scale (none, a little, moderately, and a lot).
Secondary outcomes
The secondary outcomes were each measured at baseline and 12 weeks, and were evaluated as continuous scores: subjective sleep quality (Pittsburgh Sleep Quality Index – PSQI),12 insomnia symptoms (Insomnia Severity Index – ISI),13 depressive symptoms (Physician's Health Questionnaire depression domains – PHQ-8),14 and anxiety (Generalized Anxiety Disorder questionnaire – GAD-7)15.
Adverse Events
Adverse events (AE) were assessed at each visit using a self-administered questionnaire listing common yoga, exercise, and omega-3 adverse events. Participants were instructed to call the study nurse to report any potential AEs during the study. Newly emergent adverse events were identified by comparing adverse event reports during treatment to each woman's baseline report.
Statistical analysis
A sample size of 176 participants in each of the omega-3 and placebo groups was planned to provide 90% power to detect a mean difference of 1.6 HF per day reduction between treatment groups (a 0.40 standard deviation (SD) units reduction in HF/day based on preliminary data). This calculation was based on a t-test with 2-sided significance level of 0.025 to account for two primary outcomes, and allowance for 10% loss to follow-up.
All analyses of treatment effect were based on the intention-to-treat principle where all randomized participants who provided diary data at any point in follow-up were included and analyzed by randomized treatment assignment, regardless of their adherence to treatment assignment. Baseline hot flash frequency was calculated as the mean of the daily (24 hour) totals reported in the first two screening weeks. Hot flash frequency at weeks 6 and 12 were calculated as the mean of the daily (24 hour) frequencies for the week prior. Hot flash bother scores were calculated in a similar way. A categorical variable to indicate clinical VMS improvement was defined as ≥50% decrease in VMS frequency at 12 weeks from baseline.
Treatment group contrasts were computed as Wald statistics from linear regression models summarizing the frequency or bother of VMS at weeks 6 and 12 as a function of randomization assignment, adjusting for clinical site, visit (week 6 or 12), behavioral intervention assignment, and the baseline value of the outcome measure. Because VMS frequency values were skewed to the right, the raw values were transformed via natural logarithm to meet model assumptions of a normally distributed outcome. Robust standard errors were calculated via generalized estimating equations to account for correlation between repeated measures from each participant.
Ten baseline variables were hypothesized a priori to modify hot flash frequency treatment response: smoking status, body mass index (BMI), menopausal status, depressive symptoms (PHQ-8), anxiety (GAD-7), insomnia symptoms (ISI), alcohol use, age, race, and baseline hot flash frequency. Tests for interaction between these variables and treatment assignment were performed within the linear regression model, with continuous variables analyzed as such for interaction tests. Secondary outcomes were also analyzed by linear regression to model changes in sleep and mood as a function of treatment assignment, following a similar approach to that used with primary outcomes.
Baseline characteristics were compared between treatment groups using t-tests for continuous variables and χ2 tests for categorical variables. Incidence of newly emergent adverse events was compared between treatment groups via Fisher exact test.
A 2-sided p-value <0.025 was considered statistically significant for the two primary outcomes. For the four outcomes examined as secondary analyses, a p-value <0.0125 was considered statistically significant. Analyses were conducted using SAS version 9.2 (SAS Institute Inc., Cary, NC).
RESULTS
Three hundred and fifty five women were randomly assigned to receive omega-3s (N=177) or placebo (N=178) (Figure 1). Follow-up data collection retention was high: 173 women in each of the omega-3 groups (98%) and the placebo groups (97%) provided diary data at week 6 and/or week 12.
Figure 1.
Participant recruitment 1
1. Randomization occurred concurrently to Yoga (n=107), Exercise (n=106), or Usual Activity (n=142).
The only nominally significant differences between the omega-3 and placebo groups in baseline characteristics were for race (p <0.001) and baseline VMS bother score (p=0.019). A somewhat higher proportion of white women were randomized to the omega-3 group than the placebo group (Table 1). Overall, the mean age was 54.7 (SD 3.7); 64% were white, 26% were African-American, and 10% were of another race group. A small proportion of women (8%) had substantial depressive symptoms (PHQ-8 > 9), and a similar percentage of participants had high levels of anxiety symptoms (GAD-7); 33% of participants had moderate to severe insomnia (ISI) as defined by a baseline ISI >14.
Table 1.
Baseline demographic and clinical characteristics by Omega-3 arm
| Omega-3 (N =177) | Placebo (N =178) | |||
|---|---|---|---|---|
| N | % | N | % | |
| Age at screening (yrs), mean (SD) | 54.39 (3.55) | 54.98 (3.79) | ||
| < 50 | 10 | 5.6 | 9 | 5.1 |
| 50 - 54 | 87 | 49.2 | 75 | 42.1 |
| 55 - 59 | 63 | 35.6 | 67 | 37.6 |
| 60+ | 17 | 9.6 | 27 | 15.2 |
| Race | ||||
| White | 125 | 70.6 | 103 | 57.9 |
| African American | 45 | 25.4 | 48 | 27.0 |
| Other | 7 | 4.0 | 27 | 15.2 |
| Clinical Center | ||||
| Indianapolis | 58 | 32.8 | 60 | 33.7 |
| Oakland | 55 | 31.1 | 55 | 30.9 |
| Seattle | 64 | 36.2 | 63 | 35.4 |
| Education | ||||
| ≤ High school diploma/GED | 14 | 7.9 | 7 | 3.9 |
| School/training after high school | 49 | 27.7 | 63 | 35.4 |
| College graduate | 114 | 64.4 | 107 | 60.1 |
| Employment status | ||||
| Retired or no employment | 27 | 15.3 | 22 | 12.4 |
| Full-time | 107 | 60.5 | 108 | 60.7 |
| Part-time | 28 | 15.8 | 24 | 13.5 |
| Homemaker | 7 | 4.0 | 6 | 3.4 |
| Other | 8 | 4.5 | 17 | 9.6 |
| Marital Status | ||||
| Never married | 13 | 7.3 | 21 | 11.8 |
| Divorced | 36 | 20.3 | 40 | 22.5 |
| Widowed | 4 | 2.3 | 3 | 1.7 |
| Married/living with partner | 124 | 70.1 | 112 | 62.9 |
| Smoking | ||||
| Never | 112 | 63.3 | 120 | 67.4 |
| Past | 48 | 27.1 | 41 | 23.0 |
| Current | 16 | 9.0 | 16 | 9.0 |
| Alcohol use (drinks/week) | ||||
| 0 | 60 | 33.9 | 77 | 43.3 |
| 1-<7 | 78 | 44.1 | 78 | 43.8 |
| 7+ | 38 | 21.5 | 22 | 12.4 |
| BMI (m/kg2), mean (SD) | 26.81 (4.42) | 27.09 (4.33) | ||
| <25 | 63 | 35.6 | 60 | 33.7 |
| 25 – 29 | 72 | 40.7 | 72 | 40.4 |
| ≥ 30 | 42 | 23.7 | 46 | 25.8 |
| Menopause status | ||||
| Postmenopausal | 146 | 82.5 | 140 | 78.7 |
| Late transition | 28 | 15.8 | 34 | 19.1 |
| Early transition | 3 | 1.7 | 4 | 2.2 |
| Hysterectomy | 35 | 19.8 | 29 | 16.3 |
| Bilateral Oophorectomy | 18 | 10.2 | 14 | 7.9 |
| Self-reported health | ||||
| Excellent | 31 | 17.5 | 27 | 15.2 |
| Very Good | 78 | 44.1 | 84 | 47.2 |
| Good | 60 | 33.9 | 59 | 33.1 |
| Fair | 8 | 4.5 | 7 | 3.9 |
| Depression score, mean (SD) | 3.63 (3.48) | 4.37 (4.03) | ||
| No depression (0-4) | 118 | 66.7 | 107 | 60.1 |
| Mild depression (5-9) | 49 | 27.7 | 48 | 27.0 |
| Moderate+ depression (10+) | 10 | 5.6 | 19 | 10.7 |
| Anxiety score, mean (SD) | 2.89 (3.43) | 3.46 (3.77) | ||
| No anxiety (0-4) | 134 | 75.7 | 126 | 70.8 |
| Mild anxiety (5-9) | 33 | 18.6 | 34 | 19.1 |
| Moderate+ anxiety (10+) | 10 | 5.6 | 18 | 10.1 |
| PSQI, mean (SD) | 7.87 (3.29) | 8.16 (3.37) | ||
| Good sleep quality | 23 | 13.0 | 27 | 15.2 |
| Poor sleep quality | 149 | 84.2 | 145 | 81.5 |
| ISI, mean (SD) | 11.76 (5.16) | 12.03 (5.69) | ||
| No clinically significant insomnia (≤7) | 42 | 23.7 | 44 | 24.7 |
| Subthreshold insomnia (8-14) | 75 | 42.4 | 73 | 41.0 |
| Clinical insomnia (moderate, 15-21) | 52 | 29.4 | 50 | 28.1 |
| Clinical insomnia (severe, 22+) | 5 | 2.8 | 9 | 5.1 |
Hot flash frequency and bother
The mean baseline hot flash frequency was 7.6, with 95% confidence interval (CI) 7.0-8.2, per day. As seen in Figure 2, omega-3s did not significantly reduce hot flash frequency compared to placebo (p=0.28, Table 2). In the omega-3 group, mean hot flash frequency at week 12 decreased to 5.2 (95% CI 3.0-1.9) VMS/day corresponding to a 32% decrease or a mean of 2.5 fewer VMS/day compared to baseline. The placebo group decreased to 4.9 (95% CI 3.3-2.2) VMS/day at week 12, a 36% decrease or a mean of 2.7 fewer VMS per day. Similarly, there was no difference in VMS bother reduction between the two groups (p=0.36). The incidence of clinical improvement in VMS at week 12 (≥50% decrease from baseline in VMS frequency) also did not differ between the omega-3 and placebo groups, 34% and 38%, respectively (p=0.43).
Figure 2.
Hot flash frequency over time by omega-3 assignment 1
1. Mean difference in number of hot flashes/day from baseline to week 12; Baseline = 0.1 (−0.7,0.9); Week 6-baseline = 0.2 (−0.5, 0.9); Week 12-baseline =0.3 (−0.5, 1.0)
Table 2.
Change in primary and secondary outcomes by Omega-3 arm
| Primary Outcomes | N | Omega-3 Mean (95% CI) | N | Placebo Mean (95% CI) | Difference Mean (95% CI) | p-valuea |
|---|---|---|---|---|---|---|
| Hot flashes / dayc | 0.283 | |||||
| Baseline | 177 | 7.7 (7.1, 8.2) | 178 | 7.6 (7.0, 8.1) | 0.1 (−0.7, 0.9) | |
| Week 6 – baseline | 168 | −2.0 (−2.5, −1.5) | 170 | −2.2 (−2.7, −1.7) | 0.2 (−0.5, 0.9) | |
| Week 12 – baseline | 169 | −2.5 (−3.0, −1.9) | 169 | −2.7 (−3.3, −2.2) | 0.3 (−0.5, 1.0) | |
| Bother (1-4) | 0.359 | |||||
| Baseline | 177 | 3.0 (2.9, 3.1) | 178 | 2.9 (2.8, 3.0) | 0.1 (0.0, 0.2) | |
| Week 6 – baseline | 167 | −0.4 (−0.5, −0.3) | 168 | −0.4 (−0.5, −0.3) | 0.0 (−0.1, 0.1) | |
| Week 12 – baseline | 168 | −0.5 (−0.6, −0.4) | 165 | −0.5 (−0.6, −0.4) | 0.0 (−0.1, 0.2) | |
| Secondary Outcomes | N | Omega-3 Mean (95% CI) | N | Placebo Mean (95% CI) | Difference Mean (95% CI) | p-valueb |
|---|---|---|---|---|---|---|
| ISI Sleep | 0.729 | |||||
| Baseline | 174 | 11.8 (11.0,12.5) | 176 | 12.0 (11.2, 12.9) | −0.3 (−1.4, 0.9) | |
| Week 12 – baseline | 164 | −3.8 (−4.5, −3.2) | 164 | −3.7 (−4.5, −2.9) | −0.2 (−1.2, 0.8) | |
| PSQI Sleep | 0.093 | |||||
| Baseline | 172 | 7.9 (7.4, 8.4) | 172 | 8.2 (7.7, 8.7) | −0.3 (−1.0, 0.4) | |
| Week 12 – baseline | 162 | −2.1 (−2.6, −1.7) | 162 | −1.7 (−2.2, −1.3) | −0.4 (−1.0, 0.2) | |
| Depression (PSQ-8) | 0.097 | |||||
| Baseline | 177 | 3.6 (3.1, 4.1) | 174 | 4.4 (3.8, 5.0) | −0.7 (−1.5, 0.1) | |
| Week 12 – baseline | 168 | 0.0 (−0.5, 0.6) | 161 | −0.8 (−1.4, −0.3) | 0.8 (0.1, 1.6) | |
| Anxiety (GAD-7) | 0.191 | |||||
| Baseline | 177 | 2.9 (2.4, 3.4) | 178 | 3.5 (2.9, 4.0) | −0.6 (−1.3, 0.2) | |
| Week 12 – baseline | 169 | −0.2 (−0.7, 0.3) | 168 | −0.9 (−1.4, −0.3) | 0.7 (−0.1, 1.4) | |
p-values from contrasts comparing omega-3 vs. placebo in a repeated measures linear model of outcome as a function of intervention arm and adjusted for clinical center, visit (week 6 or 12), active intervention assignment (exercise, yoga, usual activity), and baseline outcome value. A p-value < 0.025 was considered statistically significant to account for the 2 primary outcome comparisons of interest.
p-values from contrasts comparing omega-3 vs. placebo in a linear model of outcome as a function of intervention arm and adjusted for clinical center, active intervention assignment (exercise, yoga, usual activity), and baseline outcome value. A p-value < 0.0125 was considered statistically significant to account for the 4 secondary outcome comparisons of interest.
hot flash frequency values were log transformed for modeling
The lack of an effect of omega-3s on hot flash frequency was consistent across strata of baseline characteristics. There was no evidence of an interaction between treatment assignment and any of the baseline factors specified for testing (Table, Supplemental Digital Content, http://links.lww.com/MENO/A59).
Secondary outcomes
Compared with placebo, the omega-3 intervention did not significantly improve any secondary measure of sleep or mood, including sleep quality, insomnia symptoms, depressive symptoms, or anxiety (Table 2). The mean ISI reduction for the omega-3 group was 3.8 and 3.7 for the placebo (p=0.73). The mean PSQI reduction was 2.1 in the omega-3 group and 1.7 in the placebo group (p=0.09). There was no PHQ-8 change in the omega-3 group and a negligible change (−0.8) in the placebo group (p=0.10). The mean reduction for the GAD-7 score was 0.2 for the omega-3 group and 0.9 for the placebo group (p=0.19).
Adherence
Over the entire treatment period, 80% of participants (285/355) adhered to omega-3 or placebo pills defined as taking at least 80% of dispensed pills, with no significant difference in adherence between intervention groups (omega-3 82%, placebo 79%, p=0.44).
Adverse events
Newly-emergent AEs were reported by 39.0% of participants in the omega-3 group and 36.9% in the placebo group (p=0.82, Table 3), with no statistically significant differences between treatment groups in the incidence of individual symptoms; in particular, there was no difference in GI adverse events. All newly emergent symptoms were reported by fewer than 10% of participants in the omega-3 group. There were no serious AEs that required medical intervention or study withdrawal due to the study treatment. Tolerability of study treatment was very high: only 1 participant stopped treatment due to a protocol mandated reason (omega-3).
Table 3.
Participants reporting newly-emergent adverse events during treatment by Omega-3 arm
| Omega-3 | Placebo | ||||||
|---|---|---|---|---|---|---|---|
| Symptom | n | Na | % | n | N1 | % | p-valueb |
| Burping / belching | 9 | 162 | 5.6 | 12 | 156 | 7.7 | 0.50 |
| Bad breath or aftertaste | 5 | 162 | 3.1 | 4 | 160 | 2.5 | 1.00 |
| Heartburn | 9 | 158 | 5.7 | 8 | 150 | 5.3 | 1.00 |
| Nausea | 10 | 168 | 6.0 | 6 | 164 | 3.7 | 0.44 |
| Vomiting | 1 | 168 | 0.6 | 1 | 168 | 0.6 | 1.00 |
| Diarrhea | 14 | 161 | 8.7 | 9 | 164 | 5.5 | 0.29 |
| Constipation | 6 | 160 | 3.8 | 6 | 156 | 3.9 | 1.00 |
| Mild flu-like symptoms | 8 | 159 | 5.0 | 9 | 162 | 5.6 | 1.00 |
| Dizziness or fainting | 1 | 164 | 0.6 | 4 | 166 | 2.4 | 0.37 |
| Heart palpitations | 0 | 162 | 0.0 | 7 | 158 | 4.2 | 0.02 |
| Skin rash | 6 | 159 | 3.8 | 6 | 163 | 3.7 | 1.00 |
| Muscle aches / strains | 12 | 154 | 7.8 | 17 | 144 | 11.8 | 0.33 |
| Strength / sensations of arms / legs change | 6 | 167 | 3.6 | 5 | 158 | 3.2 | 1.00 |
| Back pain | 14 | 152 | 9.2 | 11 | 154 | 7.1 | 0.54 |
| Bruising or bleeding | 2 | 168 | 1.2 | 3 | 164 | 1.8 | 0.68 |
| Other symptoms | 8 | 140 | 5.7 | 4 | 132 | 3.0 | 0.38 |
| Any New Symptom | 65 | 169 | 38.5 | 62 | 168 | 36.9 | 0.82 |
Participants not reporting the given symptom at baseline
2-sided p-value from a Fisher's Exact test
Fewer women in the omega-3 group reported being satisfied with their hot flash relief (38%) compared to women in the placebo group (49%, p=0.04). There was no difference in the proportion of women who wanted to continue their study pills between the omega-3 group (42%) and the placebo group (44%, p=0.61).
DISCUSSION
In this large multi-center, 3 by 2 factorial design, randomized controlled trial of three low-risk interventions (omega-3 supplementation, exercise, and yoga), omega-3 supplementation did not reduce VMS frequency or bother as compared to placebo in healthy peri- and postmenopausal women. While there are at least some data to support the salutary effects of omega-3 supplementation with respect to some health outcomes in other populations (including cardiovascular disease, rheumatoid arthritis, depression, and other cognitive disorders),16,17 data with respect to efficacy of this treatment for VMS in menopausal women have been incomplete and inconsistent.5
Despite the absence of conclusive data supporting efficacy of omega-3 supplementation for the treatment of VMS, the use of this particular supplement is frequent among midlife women experiencing VMS.9 Our results are consistent in theme to those noted in the Herbal Alternative for Menopause (HALT)16 trial, where testing of a widely used herbal intervention to treat vasomotor symptoms failed to demonstrate efficacy when studied under strict conditions. As in the current study, that investigation underscored the public health need for the careful study of agents whose efficacy is often assumed versus confirmed by systematic examination.
A previous randomized controlled study of omega-3 supplementation conducted in 91 women supported efficacy of this treatment for management of VMS.9 However, in contrast to the current study, participants were selected based on the presence of emotional distress (defined as a score of 72 or more on the Psychological Well-Being Scale) with improvement in the emotional domain constituting the primary outcome. Our study population differed from that previous study in that psychological distress, as measured by depressive and anxiety symptoms, in our participants was low. The population differences between studies raise questions of whether response to omega-3 supplementation with respect to VMS is mediated by other factors, including those associated with emotional well-being, or was a chance finding.
Omega-3 fatty acids have been studied as a treatment for major depressive disorder and in several18-20 but not all studies21,22 omega-3 fatty acids have been demonstrated to be more efficacious than placebo when added to the treatment regimen. The association between depressed mood and VMS has been described in several reports,23-25 including new onset major depressive episode.25,26 Whether results of the current study would have been different in a population of women with a greater degree of depressive or anxiety symptoms is unknown and warrants further study.
Study strengths include the large sample size, the inclusion of peri- and postmenopausal women, excellent adherence to therapy, a double-blinded, prospective assessment of VMS, and high compliance with follow-up data collection requirements. However, the trial has limitations. Although recruitment to all women in the sampling frame was community-based (i.e., recipients were not selected on any basis other than age and geography), participants may have self-selected to be highly motivated to seek treatment. Furthermore, the dose of omega-3s that was used may have been too low or may not have contained the optimal quantities of each constituent to see the full effect, although previous studies that demonstrated a decrease in VMS used a similar or a lower dose of omega-3s.9,10
CONCLUSION
In conclusion, in this randomized, double-blind, placebo-controlled trial, we found that omega-3 supplementation had no effect on VMS frequency or bother. Midlife women experience a wide array of menopausal symptoms which can impact quality of life. Investigators examining the potential efficacy of a wide spectrum of pharmacologic and non-pharmacologic treatments to manage these bothersome symptoms must identify therapies which are not only acceptable to women but which also afford clear evidence of efficacy.
Supplementary Material
ACKNOWLEDGEMENTS
The MsFLASH research network was established under an NIH cooperative agreement to conduct studies of the efficacy of treatments for the management of menopausal VMS. The studies are sponsored by the National Institute of Aging (NIA), in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), the National Center for Complementary and Alternative Medicine (NCCAM), and the Office of Research on Women's Health (ORWH).
The network sites that participated in this study were: Seattle, WA (Group Health Research Institute and University of Washington: Principal Investigators Katherine M. Newton, PhD and Susan D. Reed, MD, MPH); Indianapolis, IN (Indiana University; Principal Investigator: Janet S. Carpenter, PhD, RN, FAAN); and Oakland, CA (Kaiser Permanente Division of Research; Principal Investigators: Barbara Sternfeld, PhD and Bette Caan, PhD). The Data Coordinating Center of the network is based at the Fred Hutchinson Cancer Research Center; Principal Investigators: Andrea LaCroix, PhD and Garnet Anderson, PhD. The chairperson is Kris E. Ensrud, MD, University of Minnesota.
Other investigators of the MsFLASH Network that contributed to this study include Lee Cohen, MD and Hadine Joffe, MD, MSc, Massachusetts General Hospital; Ellen W. Freeman, PhD, University of Pennsylvania; and Sheryl Sherman, PhD: National Institute on Aging/US National Institutes of Health, Bethesda, MD.
Funding/Support:
This study was funded by the National Institutes of Health as a cooperative agreement issued by the National Institute on Aging (NIA), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Center for Complementary and Alternative Medicine (NCCAM), the Office of Research on Women's Health (ORWH) and grants U01 AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699, U01AG032700 from the NIA. At Indiana University, the project was funded in part with support from the Indiana Clinical and Translational Sciences Institute, grant UL1RR02571 from the NIH, National Center for Research Resources, Clinical and Translational Sciences Award. The omega-3 study supplement (ω-3, n-3, or polyunsaturated fatty acids) was manufactured as EPA and donated, with matching placebo, by Nordic Naturals, Watsonville, CA.
Role of the Sponsor:
NIH staff critically reviewed the study protocol and drafts of the manuscript prior to journal submission. Nordic Naturals had no role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, or in the preparation of the manuscript.
Disclaimer:
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Source of Funding:
Dr. Cohen has received research support from: Astra-Zeneca Pharmaceuticals; Bristol-Myers Squibb; Cephalon, Inc.; National Institute on Aging; Ortho-McNeil Janssen; Sunovion Pharmaceuticals, Inc. Dr. Cohen has done advisory/consulting for; Noven Pharmaceuticals. Dr. Joffe received grant support from Cephalon/Teva, is on the advisory board for Noven, and has done consulting for Sunovion. Dr. Ensrud is a consultant on a Data Monitoring Committee for Merck, Sharp & Dohme. Dr. M. Freeman received research funding from: Glaxosmith Kline and Forest, Lilly. She has done consulting for PamLab, is on the advisory board for Takeda/Lundbeck and Otsuka, and she received a stipend for medical editing for DSM nutritionals. Dr. Learman is a consultant on a Data Monitoring Committee for Ariosa Diagnostics. Dr. Newton received research support from Otsuka Pharmaceutical Co., Ltd., and Integrated Diagnostics Inc. Dr. E. Freeman received research support from Forest Laboratories, Inc.and Bionovo, Inc.
Footnotes
Conflicts of Interests
All other authors have no direct conflicts of interest or financial disclosures relevant to this manuscript.
Presentations & Meetings: Parts of this manuscript were presented at the annual meeting of the North American Menopause Society (NAMS) meeting, Oct. 7, 2012, Orlando, FL.
AUTHOR CONTRIBUTIONS:
Dr. Katherine A. Guthrie had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors made substantial contributions to the study and this manuscript. None were compensated for the manuscript preparation.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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