Lignan-rich Food for Menopausal Symptom Relief: A Flash in the Pan?

Abstract & Commentary

By Susan T. Marcolina, MD, FACP. Dr. Marcolina is a physician at the HealthPoint Community Health Clinic in Kent, WA; she reports no financial relationship to this field of study.

Synopsis: Middle-aged, postmenopausal women with significant symptomatic vasomotor events (VMEs) experienced equivalent significant relief of symptoms after 3 months of treatment with a flaxseed-enriched or an isocaloric control whole wheat- and barley-enriched diet. The VMEs in each group of recently menopausal patients were measured by a validated global scale, the Kupperman Menopausal Index, and a vasomotor diary at a Brazilian public health clinic over 12 weeks. It would have been interesting to have included an estradiol-treated arm to compare to these dietary manipulations since flaxseeds contain lignans, a type of phytoestrogen that chemically resembles the structure of estradiol (E2), the gold standard for climacteric-related VME relief. The flaxseed-enriched diet caused no significant change in ultrasound-measured endometrial thickness or serum levels of sex steroid hormones or cholesterol fractions.

Source: Simbalista RL, et al. Consumption of a flaxseed-rich food is not more effective than a placebo in alleviating the climacteric symptoms of postmenopausal women. J Nutr 2010;140:293-297.

With the aging of the world's population, many women will live up to one-third of their lives after ovarian failure or cessation of ovulatory function. The most common complaints for which women seek medical care during this time of life are hot flashes and night sweats, termed vasomotor events (VMEs). Approximately 80% of all menopausal women, particularly in Western countries, have VMEs, and approximately 9% will have 7 or more moderate-to-severe VMEs per day that negatively impact their quality of life, particularly sleep quality.1

Such symptoms are not uniformly perceived by women worldwide and a review by Freeman and Sherif showed that perception of VMEs can be variable depending upon climate, diet, and lifestyle, as well as cultural attitudes toward aging.2 As a matter of fact, epidemiological studies have shown VMEs to be much less prevalent and intense for women from Asian countries.3 One possible reason for this difference is thought to be the increased consumption of dietary phytoestrogens compared to Western counterparts.4

Phytoestrogens are unique nutrients present in plant-based foods such as beans, grains, and seeds. Two types of phytoestrogens are the isoflavones found in soy foods, such as soybeans, tofu, miso, and tempeh, and the lignans found in foods such as whole grains, legumes, fruits, sea vegetables, and seeds, particularly flaxseeds, which are the richest source of dietary lignans.5 The primary lignan in flaxseed is secoisolariciresinol diglycoside (SDG), which is converted into the biologically active mammalian lignans enterolactone and enterodiol by human intestinal microflora. Phytoestrogens share a similar diphenolic chemical structure to the mammalian hormone 17-beta estradiol, and can, therefore, behave as selective estrogen receptor modulators (SERMs) in estrogen- sensitive tissue.6

In this double-blind, placebo-controlled, 12-week clinical trial of 38 recently postmenopausal (average age, 52 years) women, Simbalista et al randomized 20 to treatment with a flaxseed-enriched bread and 18 to the control group, whose diet was supplemented with an isocaloric wheat bran-containing bread with equivalent fiber, fat, energy, and micronutrient content. Hot flashes and menopausal symptoms in all patients were evaluated with a numerical diary log of daily hot flashes and night sweats as well as with the Kupperman Menopausal Index (KMI), which is a validated global measurement of the primary discomforts of menopause. Scores in this index range from 0 to 51, with cutoffs for mild symptoms at < 20, moderate at 20-30, and severe at > 30. The bread received by the treatment group contained 25 g of flaxseed (approximately 2.5 tablespoons or 46 mg lignans) vs. the control bread, which contained wheat bran with < 1 mg lignans. The primary objective was to evaluate the effects of the lignan-enriched daily diet on endometrial thickness and control of VMEs in postmenopausal women.

Both flaxseed and control groups had similar KMI scores of 21 each with an average of 8.5 hot flash events per day at baseline. After the 3 months, both groups experienced significant decreases in both KMI scores (40% decrease for flaxseed group and 39% decrease for control wheat group) and number of diary-recorded VME events (39% decrease for flaxseed and 53% decrease for control wheat group) compared to the beginning of the study, but there were no statistically significant differences between the groups. Also, there were no significant changes in serum levels of FSH, estradiol, free testosterone, cholesterol levels, or endometrial thickness, as measured via transabdominal ultrasound after 12 weeks of lignan supplementation. These are important data because they document the effects of daily dietary phytoestrogen (lignan) supplementation on estrogen-sensitive tissues such as the endometrium and on blood levels of sex steroid hormones. This study also underscores the importance of the placebo effect on VMEs. This strong placebo effect is prevalent in all studies of interventions for VMEs, with some reporting a placebo response rate of 50%.7,8

The results of this study are concordant with an earlier randomized, double-blind controlled trial of 87 postmenopausal women (average age, 53 years) by Lewis et al, which demonstrated a significant improvement in VMEs for all three groups consuming either daily soy flour muffins (42 mg isoflavones daily), flaxseed muffins (25 g flaxseed or 50 mg/d of mammalian lignan precursor SDG), or wheat flour control muffins without any statistically significant intergroup differences.9 It is important to note, however, that the small size and short duration of this study limits definitive conclusions regarding the efficacy of this treatment for VMEs.

Commentary

Although VMEs fluctuate over time and can resolve spontaneously for most women after 3-5 years, the 9% of women for whom these symptoms remain intense and persistent will look to their primary care physicians for a safe, long-term effective treatment.10 Hormone replacement therapy remains the most effective and widely studied treatment for vasomotor symptoms and reduces both the frequency and severity compared with placebo for women afflicted with moderate-to-severe symptoms.11 There has been decreased enthusiasm from physicians and patients for initiation or continuation of hormone replacement, however, since the Women's Health Initiative trial found increased risks for breast cancer, heart disease, strokes, and other thromboembolic diseases in older women (more than 10-15 years postmenopause) on oral, nonphysiologic estrogen therapy for more than 5 years.12

Additionally, the Hormonal Replacement After Breast Cancer: Is It Safe? (HABITS) trial has highlighted the fact that women with a previous diagnosis of hormone-sensitive breast cancer have a threefold increased relative risk of a recurrent breast cancer event when treated with a variety of oral estrogen/progestin regimens for VMEs. This was noted after 2.1 years of follow-up and resulted in the early termination of the trial by the Data Monitoring and Safety Committee.13

For this reason, estrogen replacement is not recommended after a diagnosis of breast cancer or for women with a history of or undergoing active treatment for a hormone-sensitive cancer. Hormone suppression is often a treatment option associated with VMEs as adverse effects. For such women, hypnosis may provide a nonpharmacologic option for treatment-induced VMEs. Elkins et al performed a randomized controlled trial of hypnotherapy as an intervention for hot flashes. Hypnotherapy provided a 68% reduction in hot flash scores in 60 breast cancer survivors compared to the control group. Additionally, there were improvements in sleep, anxiety, and depressive symptoms.14

Due to concerns about the use of estrogen-containing hormone regimens, nonprescription botanicals such as black cohosh (Cimicifuga racemosa) have been used for VME symptom treatment. There have been mixed results from clinical trials regarding the efficacy of this herbal intervention. Although the preparations of black cohosh used were standardized for triterpine glycoside content, it is not clear that this is the active ingredient. Nappi et al performed a 12-week, randomized study comparing an isopropanolic extract of C. racemosa (40 mg) to low-dose transdermal estradiol (TTSE2; 25 mg) in 60 postmenopausal women. Both C. racemosa and TTSE2 significantly reduced the number of hot flashes per day (P < 0.001) and VMEs per day (P < 0.001) within the first 4 weeks of treatment, an effect sustained throughout the study.15

In the Herbal Alternatives for Menopause Trial (HALT), however, Newton et al randomly assigned 351 peri- or postmenopausal women (45-55 years of age) to one of five different treatment arms for climacteric-associated VMEs as follows: 1) black cohosh (160 mg of an ethanolic extract); 2) multibotanical alone (consisting of black cohosh, alfalfa, boron, chaste tree, licorice, oats, and Siberian ginseng); 3) multibotanical plus 2 servings of soy-containing foods daily (12-20 g soy protein); 4) placebo, or 5) oral conjugated equine estrogen (CEE) supplementation. At the conclusion of the one-year trial, it was clear that the only statistically significant improvement in VMEs occurred in the CEE arm with an average decrease of 4 episodes per day vs. placebo at all follow-up visits.16 There was no evidence of significant side effects during either study. The different black cohosh products, processed by different extraction techniques, may have been responsible for the different clinical outcomes.

It is notable that the great majority of the patients in the HALT study were white, well-educated, and had mild symptoms (< 2 daily VMEs); therefore, the results of this study may not generalize to other populations. However, since women with mild VMEs are the primary users of herbal therapy, the lack of response in this trial to black cohosh alone or in conjunction with other botanicals and an isoflavone-enriched diet suggests that these interventions are unlikely to provide relief for women with symptomatic VMEs.

Additionally, there have been a few serious case reports of hepatotoxicity associated with the use of black cohosh.17,18 As a result, the National Institutes of Health has suggested routine monitoring of serum liver functions tests for patients taking black cohosh in clinical trials.19 There is a wide-range of quality for nonprescription herbal remedies, some of which have been shown to contain contaminants, which could account for the adverse effects seen in some case reports, as with black cohosh.

Although several pharmacologic therapies such as selective serotonin reuptake inhibitors/serotonin norepinephrine reuptake inhibitors (SSRI/SNRIs, especially paroxetine and venlafaxine) and gabapentin are more effective in alleviating VMEs than placebo, they are not as effective as hormone interventions that include estrogen replacement and have been studied only in short-duration trials.20,21

For women with persistent, severe VMEs and a history of hormone-sensitive cancers, it is important to identify and treat certain clinical problems and to initiate lifestyle modifications that may improve symptoms. Thyroid function disorders (hypo and hyper) can present with vasomotor symptoms such as hot flashes; it is important to evaluate each patient's thyroid status and treat accordingly. Since smoking can exacerbate hot flashes, it is important to counsel patients with regard to smoking cessation and point them to helpful resources such as state-run free telephone QuitLines (1-800-QUIT-NOW or 1-800-784-8669) and on-line resources such as the National Institute of Health "Clearing the Air" informational brochure developed in conjunction with the National Cancer Institute.22,23

A benefit of the Simbalista study is its use of flaxseed as a whole food ingredient in a dietary modification strategy. Flaxseeds are rich in lignans, fiber, and alpha-linolenic acid (ALA), the precursor to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 fatty acids from cold-water fish, and, therefore, may be beneficial for heart health, an important consideration for women in midlife and later years.

There are currently no U.S. Public Health recommendations for daily intake levels for phytoestrogens such as lignans, although 25 g of flaxseed has been used as a daily supplement in clinical studies over 3-4 months. This dose was generally well-tolerated, with mild gastrointestinal side effects of increased flatulence, fullness, and stool bulk. Flaxseed dietary supplementation, however, appears unlikely to offer women symptomatic from VMEs significant relief over placebo and may not be safe for long-term use in women with a history of estrogen-sensitive breast or uterine cancers.

References

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