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Departments of Obstetrics and Gynecology, Biochemistry, and Family Medicine, Research Center, St. François d’Assise Hospital, Laval University, Québec, Canada G1L 3L5; Department of Food and Nutrition Sciences, Laval University, Québec, Canada G1K 7P4; and Fred Hutchinson Cancer Research Center, Seattle, Washington 98109
Address all correspondence and requests for reprints to: Dr. Sylvie Dodin, Département d’Obstétrique-Gynécologie, Centre de Recherche, Hôpital St. François d’Assise (CHUQ), Université Laval, Québec, Canada G1L 3L5. E-mail: sylvie.dodin{at}ogy.ulaval.ca.
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Abstract |
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Introduction |
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Along with soy products, flaxseed is increasingly incorporated into the diet of menopausal women. Indeed, flaxseed is the richest food source of lignans, one of the three major classes of phytoestrogens (3). Lignans as isoflavones are nonsteroidal polyphenolic compounds structurally related to estrogens (4). They have been shown to bind to estrogen receptors and exert partial agonist or antagonist action depending on the target tissue (5, 6). Lignans are ingested as glycosides and converted into enterodiol and enterolactone by bacteria in the colon (3). They influence hepatic estrogen metabolism and increase the synthesis of SHBG, which is involved in the linking and availability of sex steroids (5).
Moreover, flaxseed contains high levels of 
-linolenic acid (LNA) and insoluble and soluble fibers. LNA makes up approximately 57% of all fatty acids in flaxseed oil (4). In several large clinical trials (7, 8), diets rich in LNA significantly reduced the incidence of nonfatal infarction and overall mortality in men. Flaxseed is also an important source of dietary fiber. Two thirds of flaxseed fiber is insoluble, preventing constipation by increasing fecal bulk and promoting gut motility, whereas the soluble fraction may reduce glycemia and lipidemia (9).
Despite its greatly increasing popularity, no large randomized clinical trial evaluating the effects of flaxseed on chronic consequences of estrogen deficiency in healthy menopausal women has been published. Lucas et al. (10) showed that flaxseed supplementation (40 g/d) for 3 months improves lipid profile, but does not exert beneficial effects on biomarkers of bone turnover in postmenopausal women compared with a wheat-based regimen. Data from our cross-over study (11) in hypercholesterolemic menopausal women indicated that after 2 months of treatment, flaxseed is as effective as 0.625 mg conjugated estrogens in relieving mild menopausal symptoms and in lowering glucose and insulin levels, but produces no significant change in lipid profile or in markers related to cardiovascular health. These studies provide some evidence that flaxseed supplementation might be worthwhile among menopausal women, but long-term follow-up would be necessary for verification of the efficacy of flaxseed on lipid and bone metabolism.
The purpose of this 1-yr, randomized, double-blind, wheat germ placebo-controlled trial was to evaluate the effect of a flaxseed dietary supplement on lipid profile, bone mineral density (BMD), symptoms, anthropometric measurement, and blood pressure changes in healthy French Canadian menopausal women.
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Subjects and Methods |
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Women were recruited at Centre Ménopause Québec, a multidisciplinary clinic located in Québec, Canada. French Canadian menopausal women were recruited from the general population through newspaper, radio, and television advertising; flyers posted in clinics; and clinicians. All participants were between 45 and 65 yr of age and had serum FSH concentrations of 40 mIU/ml or more. Eligible women had at least 6 months of amenorrhea in the year before entry into the study and a normal mammogram in the past 2 yr. Criteria for exclusion were early onset of menopause (i.e. defined as before 40 yr), personal history of neoplasm, osteoporosis, CVD, hepatic or renal disease, uncontrolled hyper- or hypothyroidism or diabetes, abnormal lipid profile [total cholesterol/high-density lipoprotein (HDL) cholesterol, 
4.5 mmol/liter; triglycerides, >3.5 mmol/liter], blood pressure greater than 140/90 mm Hg, malabsorption disease or gastrectomy, and use of medication that interferes with lipid or calcium metabolism. In addition, women were excluded before enrollment if they had regularly consumed soy or flaxseed products (more than once per week) in the last 3 months, had taken medication affecting lignan absorption (antibiotics or antiacids) or had received HRT in the last 6 months, drank more than 40 g alcohol/d, or had known flaxseed allergies.
At the first clinical visit, women were required to fast for 12 h before their appointment. The risks and benefits of the study were described in detail. According to a standard protocol, weight, height, waist circumference, and blood pressure were measured by the research nurses. Demographic characteristics, gynecological history, and smoking and alcohol consumption were self-reported by the women. Dietary intake of phytoestrogens (lignans and isoflavones) in the last month was evaluated using a food frequency questionnaire. A 3-d food diary, including 1 weekend day, was completed by each woman to evaluate individual energy and nutrient intakes. After the patient had been sitting for 5 min, a 20-ml sample of blood was taken to measure lipid profile and hormone levels (TSH and FSH). Clinical and gynecological exams, including a pap test and a transvaginal ultrasound, were performed.
If the woman was still eligible, the 3-d food diary was analyzed using the FUEL nutrition software program (Logiform International, Inc., Québec, Canada), based on data in the Canadian database. Daily dietary consumption was measured by means of the 3-d food diary to determine daily intake of energy, proteins, carbohydrates, lipids, and other nutrients. The emerging feeding habit profile was then used to incorporate seeds in a flexible, yet controlled, 7-d menu adapted for long-term nutritional studies. Each eligible woman met with a nutritionist for a second visit of approximately 60 min. The nutritionist provided a sample customized menu and the necessary explanations. One month after this second visit, the subject was asked to visit the center for the randomization visit.
All participants provided written informed consent, and the protocol was approved by the institutional review board of the St. François d’Assise Hospital.
Study design
The randomization schedule was prepared by the clinical unit of the research center of St. François d’Assise Hospital using computer-generated randomization in blocks of four to eight. Subjects, investigators, staff, and statisticians were blinded to dietary assignments for the duration of the study. Women were randomly assigned to consume 40 g flaxseed/d or placebo (wheat germ) for a period of 12 months. Women were to be seen in the clinical unit for a follow-up check at months 3, 6, 9, and 12. Immediately after randomization, subjects met with a nutritionist, who gave practical information about incorporating, instead of supplementing, flaxseed or wheat germ into their diets.
The flaxseed incorporation provided daily 21,071 µg total lignans, 180 calories, 16 g lipids (57% LNA), and 11 g total dietary fiber, whereas placebo (wheat germ) provided 196 µg total lignans, 144 calories, 4 g lipids (6.9% LNA), and 6 g total dietary fiber. Both flaxseed and wheat germ were given in two different ways. Half of the daily amount was given as two slices of bread, which replaced the usual bread in the diet, and the other 20 g was provided as ground grains to add to cereal, juice, or yogurt, depending of the food preferences of the women. To respect the short phytoestrogen half-life of the seeds and to promote compliance with the treatment, women were encouraged to divide the portions of seeds into at least two separate intakes. Using a recipe developed for our pilot study (12), a local baker prepared loaves of bread. Each week, the loaves of bread were delivered in sealed, opaque unmarked wrappers to the Department of Food and Nutrition Sciences at Laval University. The seeds were ground up and vacuum-packed in the same laboratory. The Department of Food and Nutrition Sciences was responsible for labeling the bags of bread and packages of seeds with the subject’s randomization number. Bread and packages of seeds were provided on a 3-month basis. The foods that both groups received was similar in appearance and packaging and was kept frozen until consumption to avoid essential fatty acid oxidation.
A short questionnaire was used at randomization to record social and demographic characteristics, regular physical exercise, calcium supplementation, use of tobacco, and alcohol consumption. Dietary intake of phytoestrogens during the previous month was measured using the food frequency questionnaire at randomization and at 6 and 12 months. A 3-d food diary, including 1 weekend day, was completed at randomization and at 6 and 12 months and was evaluated by a nutritionist as previously described. Women were asked to report any use of calcium supplements, antibiotics or other medications, tobacco, and consumption of alcohol at each visit. Anthropometric measurements were obtained as previously described at randomization and at each visit. Quality of life was also recorded at randomization and at each visit and evaluated by the MENQOL (Menopause-Specific Quality of Life) questionnaire (13). This questionnaire is a self-administered instrument composed of 30 questions with four domains (vasomotor, physical, psychosocial, and sexual) rated on 6-point scales, indicating the extent to which symptoms have been experienced in the last month. Each domain score ranges up to 8, and the smallest clinically important change was a difference of 1 point in each of the domains (13). Menopausal symptoms were assessed by the two individual items (hot flushes and night sweats) from the vasomotor domain as evaluated by the MENQOL questionnaire. To evaluate compliance, first morning urine collection was performed at randomization and at month 12 to measure urinary lignan levels. In addition, study participants recorded their daily intake of seeds on diary cards and were asked to return unused bread and packages of seeds at each visit.
At randomization and at each visit, fasting blood samples were collected and kept at –20 C for subsequent analysis. The components of the lipid profile were measured at randomization and at each visit thereafter at the Clinical Biochemistry Laboratory of St. François d’Assise Hospital. Cholesterol and triglyceride levels were measured on a Hitachi 917 chemistry analyzer using reagent from Roche (Laval, Canada). Low- density lipoprotein (LDL) cholesterol was calculated according to the Friedwald equation (14). HDL was obtained using the heparin-MgCl2 precipitation method from the fasting serum. Interassay variability was 2%, 3.5%, and 3.4% for total cholesterol, HDL cholesterol, and triglyceride concentrations, respectively.
BMD was measured at randomization and at months 6 and 12 using dual energy x-ray absorptiometry (DPX-L, Lunar Radiation Corp., Madison, WI; software version 3.2). These measurements were performed on lumbar vertebrae L2–L4 and femoral neck. The long-term reproducibility of the measures, evaluated on a daily basis, gave a coefficient of variation smaller than 1%.
Statistical analyses
Sample size was determined using the results observed in our pilot study (12). Based on the SD observed in the pilot study, a total of 160 women (80/arm) provided 80% power with an level of 5% (two-sided) to detect a difference equal to or larger than 2%, 3.6%, 8.4%, 4.7%, and 18.7% between the two arms in the relative change at month 12 from randomization in BMD, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides, respectively. A 25% loss to follow-up per year was anticipated, such that the sample size was initially increased to a total of 220 women (110/arm). A total of 199 women were randomized in the trial, with a 10% loss to follow-up at month 12, which yielded a sample size of 179 women to evaluate the primary objective.
SAS statistical software version 8 (SAS Institute, Cary, NC) was used for all statistical analyses. All statistical analyses concerning the efficacy of flaxseed intervention used the intention to treat principle. The primary outcome measures were lipid profile and BMD changes. Primary outcomes were derived by computing the difference between the observed value after 12 months of follow-up and the observed value at randomization. Unpaired t tests were used to compare the primary outcomes between the arms. There were no substantial changes in statistical significance or in the magnitude of effects after adjustment for age, weight, and body mass index (BMI) in all of the above analyses. A two-sided value of P 
0.05 was judged to be statistically significant.
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Results |
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). After 6 and 12 months, 19% and 10%, respectively, were lost to follow-up or missed their scheduled visits. The main reasons for dropping out of the study in flaxseed and wheat germ placebo arms were digestive problems (n = 15; 10 and five women, respectively), inability to respect the protocol’s requirements (n = 13; five and eight women, respectively), and difficulty with treatment intake (n = 6; five and one women, respectively). Twenty-three women who discontinued intervention had an end-point evaluation at month 12, and 16% (16 of 101) and 4% (four of 98) of women were lost to follow-up at month 12 in the flaxseed and wheat germ placebo arms, respectively. A total of 179 women (85 and 94 in the flaxseed and wheat germ placebo arms, respectively) had visits at baseline and month 12 and were available for the intention to treat analysis. Both arms were well balanced for baseline characteristics (Table 1). At baseline, serum lipid levels were within normal reference values and did not differ between the two arms. As assessed using the MENQOL questionnaire, women in both arms had a good quality of life and mild vasomotor symptoms. Only 10% of women had moderate to severe vasomotor symptoms.
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. Flaxseed significantly increased total lipid, polyunsaturated fatty acid (PUFA), and fiber daily intakes by 2.9%, 40.5%, and 22.2%, respectively, whereas wheat germ placebo incorporation changed these variables by –10.6%, 9.2%, and –6.8%, respectively.
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). Significant reductions in systolic and diastolic blood pressure from baseline were observed only in flaxseed arm [–3.8% (P = 0.004) and –5.3% (P = 0.0005), respectively], but no statistical difference was found between the two arms.
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. Differences in total (–0.20 ± 0.51 mmol/liter; P = 0.012) and HDL (–0.08 ± 0.24 mmol/liter; P = 0.031) cholesterol concentrations between flaxseed and wheat germ placebo arms were significant. The changes from baseline in serum total and HDL cholesterol levels corresponded to 0.1% and 2.6% decreases in the flaxseed arm and 3.2% and 2.1% elevations in the wheat germ placebo arm, respectively. There was a borderline significant decrease in serum LDL cholesterol level (–0.13 ± 0.48 mmol/liter; P = 0.086) with flaxseed compared with wheat germ placebo and no significant difference in serum triglyceride concentrations between the two arms.
Neither the flaxseed nor the wheat germ placebo treatments suppressed the progressive bone loss observed in menopausal women (Table 4). We observed no significant changes in lumbar (–0.01 ± 0.04 g/cm2; P = 0.093) or femoral neck (0.01 ± 0.04 g/cm2; P = 0.116) BMD between the two arms.
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). To assess changes in menopausal symptoms, only data from symptomatic women at baseline were considered in the two arms. Both seed incorporations reduced severity scores of hot flushes (–35% and –38%, respectively; P < 0.0001) and night sweats (–44% and –42%, respectively; P < 0.0001) from baseline, whereas differences were similar among the arms.
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Discussion |
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It is relevant to point out and discuss the utilization of wheat germ as a placebo to flaxseed. In fact, wheat germ did not have a neutral effect compared with flaxseed, because it, too, provided lignans, LNA, and dietary fiber. However, these grains contained 99% less lignans, 75% less fat, and 45% less fiber than flaxseed. The principal advantage in using wheat germ as placebo to the flaxseed intervention was that bread and ground seeds of both treatments were similar in appearance. This fact ensures the success of blinding and prevents bias. Interestingly, previous studies that investigated the effects of flaxseed on lipid profile or bone metabolism in menopausal women also used wheat as the placebo or control group (10, 15, 16). Consequently, the comparison of flaxseed to wheat germ is a reasonable one, and the relative lack of effect in the present study is important to present.
Based on the return of unused bread and packages of seeds at month 12, a very good compliance with the intervention was observed during the follow-up and did not differ across arms. This finding suggests that 40 g flaxseed/d could be incorporated into the usual diet of women with few or no side-effects. Overall, 90% of randomized women were retained in the study after 12 months. However, the loss to follow-up rate was differential between flaxseed and wheat germ placebo arms, and the main reason for dropping out and/or stopping the trial regimen was digestive problems (10 and five women, respectively). An explanation for this differential loss to follow-up may be that daily flaxseed consumption provides 2-fold more dietary fiber compared with wheat germ placebo, which may have contributed to the digestive symptoms observed mainly in the flaxseed arm.
Flaxseed incorporation into the daily diet provides 4- and 2-fold more total dietary lipids and dietary fibers, respectively, compared with wheat germ placebo. Therefore, it is not surprising that the flaxseed incorporation induced higher total lipid, PUFA, and fiber daily intakes than did wheat germ. However, at the end of the experimental period, no statistically significant difference in energy intake was observed between the two arms, although flaxseed contains 20% more calories than wheat germ. These results are in good agreement with our previous study (11), in which we observed that a consumption of 40 g flaxseed/d significantly increased the daily intakes of PUFA and fibers between the baseline and the end of the 2-month treatment period.
Although the difference in weight and BMI were statistically significant between flaxseed incorporation in the diet and wheat germ placebo, the smaller weight and BMI gains achieved after 1 yr of treatment with flaxseed were too small (0.8 kg and 0.3 kg/m2) to be clinically significant. Furthermore, there were no substantial changes in statistical significance or in the magnitude of effects after adjustment for weight and BMI in all analyses. Therefore, we can speculate that flaxseed failed to affect weight and BMI in normal weight women. This lack of effect was also observed in our previous cross-over study (11) and in the clinical trial by Lucas and colleagues (10).
We observed significant beneficial reductions in systolic (–5.0 mm Hg) and diastolic (–4.1 mm Hg) blood pressure from baseline only in the flaxseed arm, suggesting that flaxseed could have a beneficial effect on the incidence of CVD. However, this beneficial effect appears to be weak, because there was no significant difference between the two arms at the end of the experimental period. The effect, therefore, must be interpreted with caution. Our findings are consistent with the clinical trial by Jenkins and colleagues (15) in which partially defatted flaxseed supplementation (50 g/d for 3 wk) had no significant effect on blood pressure compared with wheat bran in 29 hyperlipidemic normotensive subjects. We hypothesize that this weak effect on blood pressure was attributable to our healthy normotensive female population, among whom only small changes in blood pressure were to be expected. Nevertheless, it will be helpful in additional studies to specifically investigate a hypertensive female population to elucidate the significance of the effect of flaxseed on blood pressure.
In the present study flaxseed caused a reduction in total and HDL cholesterol concentrations and a borderline significant reduction in LDL cholesterol concentrations. These results confirm those of Lucas and colleagues (10), who observed that flaxseed supplementation (40 g/d for 3 months) significantly lowered serum total cholesterol concentrations, whereas the placebo regimen had no such effect in postmenopausal women. Lucas and colleagues (10) also reported that HDL cholesterol levels were somewhat (P = 0.09) lowered, and apolipoprotein A-1 concentrations were significantly reduced by flaxseed consumption, but were not affected by the placebo regimen. Their results suggest that flaxseed incorporation into the diet can decrease HDL cholesterol levels by reducing HDL particle levels.
The hypocholesterolemic effect of flaxseed first appears to be due to its high PUFA content compared with wheat germ. Flaxseed is naturally low in saturated fatty acids and provides a high content of PUFA, resulting in a high polyunsaturated to saturated (P/S) fatty acid ratio (P/S = 8.1) compared with wheat germ (P/S = 3.4). PUFA are fatty acids well known to promote decreases in serum total and HDL cholesterol (17). In contrast, Prasad and colleagues (18) observed that ingestion of 7.5 g flaxseed/d, in which the LNA content had been reduced to 2%, significantly reduced cholesterol levels by 14% in rabbits. A randomized cross-over trial (15) also showed that ingestion of 50 g partially defatted flaxseed/d (<10% fat by weight) for 3 wk reduced serum total and LDL cholesterol concentrations and apolipoprotein A-1 levels in hyperlipidemic subjects (22 men and seven postmenopausal women). Therefore, other factors inherent to flaxseed, such as its higher content in lignans and fibers compared with wheat germ, could also have contributed to its hypocholesterolemic effect in the present study. In this regard, investigative work on several mechanisms of action involved in the hypocholesterolemic effect of phytoestrogens has been described, including increased bile acid secretion, enhanced thyroid function, and modified hepatic metabolism (19). A meta-analysis also noted that dietary fibers decrease total and LDL cholesterol levels and have a small borderline significant HDL-lowering effect (20). The hypocholesterolemic effect of dietary fibers could result from an increase in bile acid excretion and a decrease in the gastrointestinal absorption of dietary cholesterol (21). Consequently, the lowering effect of flaxseed on serum total and HDL cholesterol could be attributed to its high LNA, lignan, and fiber contents.
In the present study, although our total cholesterol changes reached statistical significance, the magnitude of the reduction achieved (–5.3%) may to be too modest to be of clinical significance. According to Law and colleagues (22), this reduction is associated with a small 14.3% decrease in the risk of ischemic heart disease. Furthermore, based on the evidence that HDL cholesterol concentrations are inversely related to the incidence of CVD (23), the 5.4% reduction in the HDL cholesterol levels observed in the present study may attenuate the CVD risk reduction.
The specific effects of phytoestrogen diet on bone metabolism in menopausal women remain controversial. A number of short-term interventions reported beneficial (24) or no (25, 26) effects of phytoestrogen supplementation on markers of bone turnover. Contradictory findings have also been obtained for studies on BMD (25, 27, 28). In contrast, only three studies evaluated flaxseed effects on bone metabolism in menopausal women. One randomized, double-blind, cross-over study (29) reported that postmenopausal women consuming 38 g flaxseed/d for 6 wk showed a significant decrease in serum tartrate-resistant acid phosphatase activity, a marker of bone resorption, compared with the sunflower seed arm. In contrast, the two other randomized, double-blind studies reported that flaxseed supplementation [40 g/daily for 3 months (10) or 25 g/daily for 4 months (16)] failed to induce amelioration of serum and urinary biomarkers of bone metabolism compared with placebo in postmenopausal women. In our study there were no statistically significant differences in BMD between the two arms. One explanation was the good health of our female population at baseline, determined by our exclusion criteria and by the fact that our population represented mainly menopausal women with an interest in their health and diet. Eligible women included in the trial did not have history of osteoporosis and had normal baseline bone status. Because the main action of estrogens is to prevent bone loss, we can speculate that this good bone status may have contributed to reducing the possibility of a significant effect of flaxseed on BMD. The lack of effect of flaxseed could be explained by the fact that BMD changes slowly over time, and a longer follow-up would be necessary for assessing the slight effect of flaxseed on bone metabolism.
To our knowledge, our study is the first randomized, double-blind, placebo-controlled trial that compared the impact of flaxseed to that of wheat germ placebo on menopausal symptoms and quality of life. The incorporation of either seed in the diet reduced severity scores of symptoms and improved quality of life in women, and no statistical difference was found between the two arms. These results are consistent with those of randomized, placebo-controlled trials that showed that isoflavone and placebo treatments led to a reduction in the Kupperman index (30) and in the daily number of hot flushes (31) in postmenopausal women, but that these reductions did not differ between the two arms. To assess the clinical significance of the reductions in symptoms and improvement in quality of life, we have determined the effect size, defined as the average differences between the effects of flaxseed and wheat germ placebo divided by the SD of the wheat germ placebo differences (32). All reductions are below the threshold for a smallest effect (generally considered 0.2) (33), suggesting no evidence of a beneficial clinical effect of the two interventions. The relatively mild severity of symptoms of our menopausal women at baseline could have reduced the possibility of detecting a strong effect of flaxseed consumption on the intensity and frequency of symptoms. In fact, one limitation of our clinical trial was that women who have moderate to severe vasomotor symptoms at baseline and who believed they needed medication to relieve the symptoms were unlikely to agree to participate in a 1-yr clinical trial and are not willing to be randomized to flaxseed or wheat germ placebo. Therefore, our results are not applicable to women who experienced moderate to severe vasomotor symptoms.
Our results indicate that flaxseed incorporation into the diet can modify cholesterolemia, but has no effect on BMD and menopausal symptoms in healthy French Canadian menopausal women. The failure to improve lipid profile, BMD, and symptoms with flaxseed was quite likely due to a ceiling effect, meaning that it was almost impossible to observe a distinct effect of flaxseed due to the good baseline characteristics of participants with normal lipid profiles and mild menopausal symptoms. Nevertheless, the beneficial effect on the lipid profile combined with the mild decreases in body weight, BMI, and blood pressure can contribute to a reduction in the incidence of lipid abnormalities and CVD. Additional research is needed to determine the effect of flaxseed and, more specifically, the effects of its major components on nontraditional markers of lipoprotein metabolism, hemostasis and inflammation.
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Acknowledgments |
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Footnotes |
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First Published Online December 21, 2004
Abbreviations: BMD, Bone mineral density; BMI, body mass index; CVD, cardiovascular disease; HDL, high-density lipoprotein; HRT, hormone replacement therapy; LDL, low-density lipoprotein; LNA, -linolenic acid; P/S, polyunsaturated to saturated; PUFA, polyunsaturated fatty acid.
Received June 16, 2004.
Accepted December 13, 2004.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-linolenic acid flaxseed (Linum usitatissimum): some nutritional properties in humans. Br J Nutr 69:443–453[CrossRef][Medline]
-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 343:1454–1459[CrossRef][Medline]
-linolenic acid. Atherosclerosis 136:367–375[CrossRef][Medline]
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