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ORIGINAL RESEARCH |
From the Départements d’Obstétrique-Gynécologie, de Biochimie, and des Sciences des Aliments et de Nutrition, Centre de Recherche, Hôpital St-François d’Assise (CHUQ), Université Laval, Québec, Canada.
Address reprint requests to: André Lemay, MD, PhD, Hôpital St-François d’Assise, Département d’Obstétrique-Gynécologie, 10 rue de I’Espinay, Québec, PQ GIL-3L5, Canada; E-mail: andre.lemay{at}ogy.ulaval.ca.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Twenty-five menopausal patients with total cholesterol greater than 6.2 mmol/L (240 mg/dL), a cholesterol/high-density lipoprotein-cholesterol ratio greater than 4.5 and triglycerides less than 3.5 mmol/L (310 mg/ dL) after a 4-month diet, were randomized to add 40 g/day of crushed flaxseed to their diet or to take daily 0.625 mg of conjugated equine estrogens alone (hysterectomy, n = 10) or combined with 100 mg of micronized progesterone (intact uterus, n = 15). After 2 months of treatment, both groups continued the diet alone during a 2-month washout period before crossing over to the alternate treatment for 2 more months.
RESULTS: Differences were found between hormone replacement therapy and flaxseed respectively for decrease of low-density lipoprotein cholesterol (3.8 ± 0.2 versus 4.4 ± 0.2 mmol/L) (148 ± 8 versus 170 ± 8 mg/dL) (P = .10), increase of high-density lipoprotein cholesterol (1.6 ± 0.04 versus 1.3 ± 0.03 mmol/L) (62 ± 1 versus 50 ± 1 mg/dL) (P = .001), and increase of apolipoprotein A-1 (1.71 ± 0.07 versus 1.42 ± 0.05 g/L) (P = .003). These changes were not related to modifications in diet, exercise, or anthropometric measurements evaluated in parallel. Both treatments produced similar decreases in menopausal symptoms and in glucose and insulin levels. Only hormone replacement therapy as compared with flaxseed induced an elevation of sex hormone binding globulin (P = .004), lowered fibrinogen (P = .08), and plasminogen activator inhibitor type 1 (P = .01).
CONCLUSION: Although 40 g of flaxseed is as effective as oral estrogen-progesterone to improve mild menopausal symptoms and to lower glucose and insulin levels, only hormone replacement therapy significantly improves cholesterol profile in hypercholesterolemic women and favorably modifies markers related to cardiovascular health.
A study made in the 1980s has reported that 10.8% of patients between 45 and 54 years use medicinal herbs to control symptoms.1 An updated report by this group and in the same population indicated a significant increase in the use of herbal medicine from 1990 to 1997 with a greater consumption by women (48.9%) than by men (37.8%).2 Although functional foods are widely used to control symptoms of menopause, little information is available regarding the clinical parameters of menopause to assess the efficacy and safety of these products.
Most of the data pertain to the evaluation of isoflavones. According to a consensus established by a panel of the North American Menopause Society and to other recent papers, there is some evidence supporting the efficacy of isoflavones in reducing the incidence and severity of hot flashes. However, many studies have found no differences between the isoflavone recipients and the controls.3,4 Initial studies have associated isoflavones with significant reductions in low-density lipoprotein (LDL) cholesterol and triglycerides as well as increases in high-density lipoprotein (HDL) cholesterol.5 Wide variations in the results have been observed from no effects to limited changes in lipid fractions depending on initial levels of cholesterol, use of soy extracts or protein, and duration of use.6–8
An alternate approach to soy protein intake is the supplementation of the diet with flaxseed, which is a rich source of lignans but also of 
-linolenic acid and soluble fiber mucilage. The literature on the effect of flaxseed is rather limited, although many women are more inclined to take flaxseed rather than soy derivatives as a source of phytoestrogens in our own population. Four studies have reported a decrease in LDL-cholesterol after the intake of ground flaxseed replacing bread and cereal in the diet in healthy women9 and hyperlipidemic men,10 or whole flaxseed included in bread and muffins in menopausal women,11 or a diet supplement of partially defatted flaxseed in small groups of hyperlipidemic men.12
Because women progressively intend to take phytoestrogens to minimize the symptoms of menopause and to reduce the risk of cardiovascular disease, there is a need to assess the effects of a dietary supplement of flaxseed as compared with a classic hormone replacement therapy (HRT) regimen on serum lipids in women presenting with elevated levels of cholesterol. We report the results of a direct comparison of the effects of crushed flaxseed added to the National Cholesterol Education Program step 1 diet versus the prescription of continuous conjugated equine estrogens alone or combined with micronized progesterone in a group of hypercholesterolemic menopausal women. The effects of interventions on clinical symptoms and on selected factors associated with cardiovascular disease were also looked at as secondary objectives.
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MATERIALS AND METHODS |
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). For the first 4 months, participants were instructed to follow a hypocholesterolemia diet and to avoid sources of phytoestrogens from food. At the end of the diet period, participants started with a 2-month period of flaxseed supplementation or with HRT. A period of 2 months free of treatment (washout) followed before crossing over to the other intervention for the final 2 months. Computer-generated blocks of six to ten were prepared for randomization, which was done by phone call to a secretary blinded to the study the morning of the first intervention. The study was conducted from May 1999 to April 2000.
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Of 67 screened women, 28 did not meet the selection criteria: 22 had a cholesterol/HDL-cholesterol ratio less than 4.5; three had a body mass index greater than 30, two smoked more than ten cigarettes per day, and one had a very high cholesterol. Among eight other women who did not enter the protocol, seven were not interested anymore in the study at the time of inclusion, and one requested immediate HRT because of severe hot flushes. Thirty-one women were included in the initial National Cholesterol Education Program step 1 diet. Six of these women dropped out before randomization: three did not comply with the protocol, one changed her mind about the eventuality of taking HRT, one had a personal reason, and one was excluded because of failure to obtain results of her mammogram. All 25 remaining subjects (n = 10, hysterectomy; n = 15, intact uterus) completed the study, 12 being initially randomized to HRT and 13 to flaxseed.
Total calories were evaluated to maintain a desirable weight aiming at the proportions recommended by the National Cholesterol Education Program step 1 diet for cases of moderate hypercholesterolemia: less than 10% saturated, 10% polyunsaturated, and 10–15% monounsaturated fatty acids, 50–60% carbohydrates, 10–20% proteins, and less than 300 mg/day cholesterol.13 This diet was explained in details and reinforced at regular visits with the dietician. Participants were given a food guide.
Forty grams of flaxseed (Flaxseed Canada, Winnipeg, Manitoba, Canada) providing 21 mg of total lignans, 16 g of fat (53% linolenic acid), and 11 g of fiber was given in the form of bread and grains.14 One half of the daily amount of flaxseed was given as two slices of bread, and the other 20 g as crushed grains. Loaves of bread containing 150 g of flaxseed were prepared in batches by a local baker. The ingredients involved in this special preparation were adjusted to compensate for the amount of lipids and fibers contained in the addition of flaxseed, which gave a somewhat different taste and consistency. Each loaf was cut into 15 slices giving 10 g of flaxseed per slice. Participants were required to consume two slices of bread each day providing 20 g of flaxseed as replacement of the bread they normally ate. The participants were also required to add 20 g of crushed flaxseed each day to cereal, fruit juice, yogurt, salads, soup, or main dish depending on their food preference. The flaxseed was crushed and vacuum-packed in the Department of Nutrition at Laval University. Four opaque packages each containing 150 g of crushed flaxseed were distributed each month of the flaxseed treatment period of the protocol. Participants were requested to keep the loaves of bread and the seeds in their freezer. Participants were also told to record the amount eaten and to return any unused quantities, which were then weighed in our laboratory.
Women with prior hysterectomy took 0.625 mg of oral conjugated equine estrogen (Premarin, Wyeth-Ayerst Canada, Montréal, Québec, Canada). Those with an intact uterus also took daily 100 mg of micronized progesterone (Prometrium, Schering Canada Inc., Montréal, Québec, Canada) in combination with conjugated equine estrogen. Hormones were taken daily continuously during the 2-month treatment period.
Clinical symptoms, side effects, other medications, weight, blood pressure, diary record, and compliance were evaluated at each visit at the clinic at the end of months 2, 4, 5, 6, 7, 8, 9, and 10 (Figure 1
). The presence and severity of menopausal symptoms were assessed using the Kupperman index, which represents the sum of the numeric conversion of the 11 most common menopausal complaints to a figure based on severity (from 0 = absent to 3 = most severe).15 At each visit, a blood sample was drawn in a vacutainer tube for lipid analysis, the patient having fasted for 12 h and being in a sitting position. Blood samples were also drawn in glass tubes with gel separator for glucose, insulin, sex hormone binding globulin, and in siliconized glass tubes containing 3.2% sodium citrate for hemostatic factors at the end of the initial diet phase and at the end of each treatment period. The participants met with the dietician at baseline and at months 2, 4, 6, 8, and 10. Physical activity was assessed at the same visits, and waist and hip girth were measured at baseline and at the end of each treatment period.
At baseline, the eating habits of each patient were evaluated by a 3-day food diary record including a weekend day. Compliance to the diet was assessed by repeated 3-day food diaries at the scheduled visits, by revision of flaxseed diary, and by estimation of leftover bread and seeds. Detailed analyses of food intake were then performed using a computer program calculating proportions of carbohydrates, proteins, types of lipids, small nutrients, and alcohol based on nutrient values of Canadian common foods.16
Physical activity was evaluated by a validated questionnaire and scored by asking the patient at scheduled visits: how many times did you practice a physical activity for 20–30 minutes or more in the last 3 months? The following scores were given: 1 for no activity or baseline daily activity, 2 for less than once per month, 3 for once per month, 4 for two to three times per month, 5 for one to two times per week, and 6 for three times or more per week.17
For lipid analysis, serum samples were centrifuged, separated in aliquots, and kept at -20C in a freezer without vacuum. Samples were assayed in batches. Cholesterol, HDL-cholesterol, and triglyceride concentrations were measured by enzymatic colorimetric reactions on a chemistry analyzer Hitachi 917 using reagents from Roche Diagnostics, Laval, Québec, Canada. LDL-cholesterol was calculated according to Friedewald equation.18 Within run coefficients of variation were 0.8%, 1.3%, and 1.5% for cholesterol, HDL-cholesterol, and triglycerides, respectively. The corresponding day-today coefficients of variation were 1.7%, 2.6%, and 1.8%. Serum control materials were from Baxter (Baxter Health Care Corp.; Pointe-Claire, Québec, Canada). Results were expressed in nmol/L (x 0.02586 = mg/dL) for cholesterol and (x 0.01127 = mg/dL) for triglycerides. Serum apolipoprotein A-1 and apolipoprotein B-100 were measured with commercial reagents (apolipoprotein A-1, code OUED15; apolipoprotein B-100, code OSAN15; Dade-Behring, Mississauga, Canada) on BN-100 Nephelometer (Dade-Behring, Marburg, Germany). Total imprecision was 5% for apolipoprotein A-1 and 6% for apolipoprotein B-100.
Follicle-stimulating hormone and thyroid-stimulating hormone were measured by electrochemoluminescence immunoassay on a Elecsys 2010 immunoassay analyzer using commercial kits (Roche Diagnostics, Laval, Québec, Canada) having intra-assay and interassay coefficients of variations less than 2% and less than 5%, respectively, for both assays. In our laboratory, the established reference ranges are 0.3–5.0 mU/L for thyroid-stimulating hormone and 20–120 IU/L for follicle-stimulating hormone in menopausal women. Insulin was determined by a completely homologous radioimmuno-assay kit using an antibody not reacting with proinsulin (less than 0.2%) (Linco Research, Inc., St-Charles, MO.). The coefficients of variation within and between runs were less than 4.4% and less than 6.0%, respectively. The normal range of values for adults is 30– 90 pmol/L. Sex hormone binding globulin concentrations were measured by an immunoradiometric method using monoclonal antibodies (Diagnostic Products Corp., InterMedico, Markham, Ontario, Canada). The intra-assay and inter-assay coefficients of variation were less than 5.5% and less than 8.5%, respectively. The reference interval was 16–120 nmol/L in normal women.
Fibrinogen was measured fresh after centrifugation, whereas the other hemostatic factors were assayed on thawed plasma kept frozen at -20C. The determination of coagulation factors consisted in the measurement of clotting time in the presence of cephaline and activator for factor VIII and of thrombin for fibrinogen according to reagents supplied by Diagnostica Stago (catalogue no. 00725 and 00674, Asnièresur-Seine, France). These two assays were performed on a STA Compact analyzer (Abbott Laboratories, Mississauga, Ontario, Canada). For factor VIII, the intra-assay and interassay coefficient of variations of the activated partial thromboplastin time were less than 1% and less than 1.5%, respectively. The normal plasma range of factor VIII in the adult population was between 60% and 150%. For fibrinogen, the intra-assay and interassay coefficients of variation were less than 4%. Thrombin antithrombin III complex was quantified by a sandwich enzyme immunoassay using the kit enzygnost thrombin antithrombin micro of Dade Behring (Mississauga, Ontario, Canada) using a Coda analyzer (BioRad, Mississauga, Ontario, Canada). According to this technique, the reference range was 1.0–4.1 µg/L for adults with 4–6% and 6–9% for intra-assay and interassay coefficients of variation, respectively. Plasminogen activator inhibitor type 1 was assayed with the spectrolyse tissue plasminogen activator/plasminogen activator inhibitor activity kit of Organon Teknika Inc (Scarborough, Ontario, Canada) using an incubator and microplaque reader from the same company. This technique is based on the inhibition of tissue plasminogen activator; plasma from healthy individuals rapidly inhibits 1.8 ± 1.8 IU/mL of tissue plasminogen activator for a normal range of 0–6 IU/mL.
All statistical analysis were done with SAS statistical software (SAS Institute Inc., Cary, NC). A cross-over analysis was done as described by Armitage and Hills.19 Parameters to be evaluated were compared between the two groups by Student t test at baseline, at end of initial pretreatment diet (month 4), and at end of the washout period (month 8) and found not to be statistically different, allowing pooling of the crossed treatments. Paired t test was then used for within-treatment comparisons of differences between beginning and end of each intervention phase and between treatments. Comparisons were done by Student t test using the Bonferroni correction for multiple comparisons. A difference was considered to be statistically significant when P value was < .05. Mean ± standard deviation was used in the table for baseline and end of the diet characteristics, whereas mean ± standard error of the mean was used in result tables. A prestudy power calculation estimated that 30 women would be needed to obtain a 10% reduction (P < .05) of LDL-cholesterol at a power of 80% after HRT. Considering the result obtained, there was enough power with the 25 subjects who completed the study to achieve significant (P < .05) and highly significant (P < .01) differences after HRT not only for LDL-cholesterol but also for HDL-cholesterol, apolipoprotein, glucose, fibrinogen, and plasminogen activator inhibitor type 1 at a power of at least 80%.
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RESULTS |
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, the 25 participants to this study are representative of women early after confirmed menopause with mild menopausal symptoms and typical anthropomorphic characteristics, eating a rather equilibrated diet and exercising moderately. According to the selection criteria, they smoked less than ten cigarettes per day and consumed less than 40 g (1 imperial ounce) of alcohol per day. They also ate less than 300 mg of cholesterol per day (data not shown). Physical examination was normal including blood pressure, breast, and gynecologic examinations. The anthropometric measurements, physical activity, laboratory data, and Kupperman index also evaluated at the end of the initial pretreatment diet period were not statistically different from those reported at baseline (Table 1).
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Both HRT and flaxseed were effective in causing significant score reductions of -3.6 ± 1.0 (-32.7%, P < .01) and of -3.2 ± 0.8 (-24.2%, P < .001) of the Kupperman index in each group, respectively. No statistical difference in the Kupperman index was found between the two interventions.
The serum lipid levels at baseline and at the end of each intervention are presented in Table 2. There were no significant changes in lipid profile at the end of the diet period. Flaxseed did not cause apparent changes in any of the lipid parameters, whereas HRT decreased LDL-cholesterol and increased HDL-cholesterol and apolipoprotein A-1, resulting in an overall decrease of the cholesterol/HDL-cholesterol ratio. Significant differences of lipid levels in response to flaxseed versus oral HRT treatment were obtained for HDL-cholesterol, cholesterol/HDL-cholesterol ratio, and apolipoprotein A-1. No differences in the serum lipids were found between women taking conjugated equine estrogens alone and those receiving combined conjugated equine estrogens and micronized progesterone (data not shown).
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. The changes in LDL-cholesterol correspond to a significant 15.9% decrease after HRT and to a 1.6% diminution after flaxseed. HDL-cholesterol and apolipoprotein A-1 were significantly increased by 10.7% and 18.7%, respectively, after HRT. The overall change in the atherogenic index (cholesterol/HDL-cholesterol) corresponds to a significant 13.9% decrease with HRT compared with a 2.0% diminution with flaxseed. The HRT significantly increased triglycerides by 19.2%, whereas flaxseed decreased it by 1.2%.
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, both HRT and flaxseed were effective in causing apparent reductions of glucose, insulin, and factor VIII. The thrombin antithrombin III complex was increased by HRT, whereas it was decreased by flaxseed without reaching a significant difference between the two interventions. The HRT decreased fibrinogen and plasminogen activator inhibitor type 1 to a significantly greater extent than flaxseed. A significant difference was also revealed between HRT, which markedly increased sex hormone binding globulin and flaxseed, which did not change this liver protein.
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illustrates main differences in results of laboratory tests observed between the beginning and the end of treatment periods. The HRT caused significant reductions of blood glucose (-8.4%) and insulin (-13.7%). Flaxseed also significantly reduced blood glucose (-5.3%), but the 10.7% decrease in insulin did not reach statistical significance. The 9.0% and 5.9% reductions of factor VIII, respectively, by HRT and flaxseed were not statistically significant. The 23% decrease in thrombin antithrombin III by HRT was also not significant. The changes in serum levels of fibrinogen and plasminogen activator inhibitor type 1 corresponded to respective significant 13.4% and 44.1% reductions after HRT and to nonsignificant 0.5% and 7.4% decreases after flaxseed. There was also a 132% increase of sex hormone binding globulin (P < .001) by HRT compared with the 1.7% change by flaxseed (data not shown).
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DISCUSSION |
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Only a few studies have looked at the effects of flaxseed on serum lipids in humans. One study, carried out on nine nonsmoking female undergraduate students, reported a 18% decrease in LDL-cholesterol after 4 weeks of consumption of raw, ground flaxseed or bread made with flaxseed flour having a high content of -linolenic acid.9 In another trial, five men and ten women aged 25–65 with mild elevation of serum cholesterol greater than 6.2 mmol/L (240 mg/dL) and taking 800 IU/day of vitamin E consumed 15 g of ground flaxseed (3.4 g of linolenic acid and 5.5 g of fiber) and three slices of 10% flaxseed-containing bread (1.2 g of linolenic acid, 10 g fiber) during 3 months.10 The LDL-cholesterol was reduced by 10% and triglycendes by 12%. The results of a double-blind cross-over study in 38 postmenopausal women with mild hypercholesterolemia indicated a 14.7% decrease of LDL-cholesterol after 6 weeks of addition of 38 g of whole flaxseed in bread and muffins compared with the addition of a similar amount of sunflower seeds.11 In another controlled cross-over trial, 22 men and seven postmenopausal women were given muffins that contributed 20 g of fiber per day from either flaxseed (50 g of partially defatted flaxseed per day, less than 10% fat by weight, mainly the viscous seed coat gum) or wheat bran (controls), while they consumed self-selected National Cholesterol Education Program step 2 diet.12 Compared with controls, partially defatted flaxseed significantly reduced LDL-cholesterol by 7.6%, apolipoprotein B by 5.4%, and apolipoprotein A-1 by 5.8% but had no effects on HDL-cholesterol and serum lipoproteins ratios.
These results from the literature are in contrast to the absence of effects observed in the present study. Several explanations for the lack of effects in our study would be possible but would also be only speculative (type and composition of flaxseeds, characteristics of patients, lifestyle habits, pretreatment diet, etc). In the previous studies, subjects were not submitted to a diet, or possible changes in the diet were not evaluated. In our study, the 4-month pretreatment phase did not have an effect on the lipid profile but did reduce significantly the lipid constituents in the diet. The lack of effects of crushed flaxseed on lipids in our study would not be a result of poor compliance in the intake of flaxseed because women consumed 86.7 ± 12.7% of the targeted intake of flaxseed. Byproducts of flaxseed were not measured in the blood or in the urine, but the single increases in polyunsaturated fat and fibers observed only during the flaxseed period of treatment are indicative of significant absorption of flaxseed constituents. However, because neither the flaxseed protein nor phenolic flaxseed lignans nor the fiber content has been tested individually or in combination with one another for their hypolipidemic effect, one or several flaxseed components may be required in absolute or relative amounts to achieve modifications of the lipid profile.
A putative action of flaxseed is its potential ability to interact with estrogen receptor and as a phytoestrogen to cause hypolipidemic effects similar to those of selective estrogen receptor modulators. Recent data indicate that administration of 60 mg of the selective estrogen receptor modulator raloxifen decreased LDL-cholesterol to the same extent as 0.625 mg of conjugated equine estrogens but had no significant effect on HDL-cholesterol and triglycerides.20 Our results indicate that addition of 40 g of flaxseed to the diet during 8 weeks does not reproduce any of the effects on lipids obtained with oral HRT as observed in this direct comparison in the same women. Thus, the modality of flaxseed dietary supplementation used in this study did not bring lipid changes expected from a phytoestrogen or a selective estrogen receptor modulator.
It is interesting to consider that both HRT and flaxseed brought a significant diminution of serum glucose and insulin in hypercholesterolemic women. A few studies have reported similar reductions of glucose and insulin in eulipemic women by HRT.21,22 One study reported that flaxseed has a hypoglycemic effect in decreasing postmeal blood glucose levels by about 27%.9 Other evaluations and dynamic tests would be required to more adequately assess the effect of flaxseed and HRT interventions on carbohydrate tolerance.
The decrease in fibrinogen and in plasminogen activator inhibitor type 1 obtained in this study is in agreement with data from several other studies of oral HRT on the hemostatic balance (Conard J, Samama M, Basdevant A, Guy-Grand B, de Lignieres B. Differential AT III-response to oral and parenteral administration of 17 beta-estradiol [letter]. Thromb Haemost 1983; 49:252).23–26 Such changes would be considered favorable especially in the presence of hypercholesterolemia. The amount of flaxseed used in this study did not affect any of the hemostatic tests. The clinical significance of these findings remains to be correlated with cardiovascular endpoints in larger cross-sectional, prospective, or randomized studies.
Only one previous study reported a marked increase in sex hormone binding globulin after 12 weeks of a phytoestrogenrich diet consisting of soybean and flaxseed.27 In our study, HRT more than doubled the levels of sex hormone binding globulin, whereas flaxseed did not change the sex hormone carrier. This liver protein has been shown to increase with rising doses of oral estrogens but not of transdermal estrogens.28–30 Our results contrast with the significant positive correlation reported between intake of fibers, urinary excretion of lignans, and the concentration of plasma sex hormone binding globulin by Adlercreutz et al.31 Compared with these data from the literature, the crushed flaxseed ingested in our study had a rather limited estrogenic effect on the liver, as also mentioned in the work of Baird et al,32 who reported no changes in sex hormone binding globulin and a small estrogenic effect on vaginal cytology in menopausal women on a soy-supplemented diet. The possibility of increasing sex hormone binding globulin at menopause would be of clinical significance because low levels of this protein are currently associated with an atherogenic lipid profile and with increased risks of cardiovascular disease and breast cancer in menopausal women.33–35
The modifications obtained in the serum lipid profile cannot be attributed to changes in dietary intake. Analysis of 3-day food diary records done repeatedly during the study did not reveal any apparent or significant variations in types of lipids, carbohydrates, proteins, and alcohol intake. There were also no obvious fluctuations in energy expenditure and physical fitness as assessed by repeated physical activity scores. No changes in weight, body mass index waist, hip girth, or waist-hip ratio could be invoked to explain the modifications in serum lipid constituents.
Overall, results of this 10-month cross-over study indicate that although 40 g of crushed flaxseed is as effective as 0.625 mg of conjugated equine estrogens with or without 100 mg of micronized progesterone in relieving mild menopausal symptoms and in lowering serum levels of glucose and insulin, only oral HRT is effective in improving the lipid profile and in achieving favorable changes in biochemical markers related to cardiovascular health in hypercholesterolemic postmenopausal women. Other studies will be required to evaluate the effects of whole flaxseed and flaxseed constituents compared with placebo and various HRT formulations not only on other cardiovascular risk factors but also on other tissues (mainly the endometrium, bone, and breast), the integrity and function of which are affected by hormonal deprivation and replacement at menopause. Results of such studies would be most important not only for healthy menopausal women but most importantly for women presenting with metabolic problems related to cardiovascular diseases or for those who for clinical reasons are unable to use conventional HRT.
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Footnotes |
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Received October 17, 2001. Received in revised form February 8, 2002. Accepted February 28, 2002.
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REFERENCES |
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