Taking an integrated approach: managing women with phytoestrogens

ABSTRACT

An integrated approach can be employed when counselling women about menopausal management options, where lifestyle, complementary therapies and hormone replacement therapy (HRT) are discussed. Women might opt to use an alternative approach to HRT for a variety of reasons, e.g. fear of side-effects and risks or contraindications to HRT.

There are many choices of dietary and herbal approaches for menopausal symptoms, which essentially divide into food supplements and herbal medicines. The choice can often be overwhelming and confusing for the woman. Of concern, the evidence for efficacy and safety of some of these complementary therapies can be extremely limited or non-existent. In order to enable women to make a fully informed choice, it is important that, when a recommendation is made regarding a specific complementary therapy, it should focus on preparations for which a significant dataset exists for efficacy and safety and in which there is ongoing research and development.

One of the most extensively studied food supplements has been the phytoestrogenic preparation containing red clover isoflavones. There have been six randomized trials thus far studying the impact on vasomotor symptoms, three of which have shown a significant benefit compared to placebo. There are also data from small randomized and observational trials showing positive outcomes for surrogate markers of osteoporosis and cardiovascular disease. A recent study using validated depression scales has shown that women using red clover isoflavones may also derive psychological benefits. Safety data are reassuring for the endometrium and breast, although further studies would be welcome, particularly in women with significant medical risks.

Key words::

• MENOPAUSE
• PHYTOESTROGEN
• isoflavones
• red clover
• soy
• hrt
• complementary

KEY POINTS: TAKING AN INTEGRATED APPROACH

• Women should be given information on HRT and alternatives so that they can make a fully informed choice.

• Awareness of the data for alternative preparations is essential to support women in making a choice.

• There is an extensive dataset showing the benefits of red clover isoflavones in the management of menopausal women, although longer-term, larger trials are desirable. Many other food supplements and herbal preparations have few, if any, data on efficacy and safety.

• Recommending 3 months’ use of red clover isoflavones may be a useful start to see whether this treatment benefits an individual patient who is interested in an alternative to HRT.

KEY POINTS: EFFICACY AND SAFETY DATA FOR RED CLOVER ISOFLAVONES

Efficacy

Vasomotor symptoms: Significant benefit for reducing vasomotor symptoms compared to placebo.

Bone: No fracture data, but attenuation of the loss of bone density that occurs post menopause with smaller decreases in spine bone mineral density and bone mineral content compared to placebo.

Cardiovascular: No hard outcome data, but reduction in triglyceride and LDL levels and improvement in the LDL/HDL ratio; small but significant improvement in arterial stiffness and in compliance.

Psychological: Reduction in symptoms of anxiety and depression.

Safety

Breast: Studies have shown a small decrease in mammographic density, which we would expect to see in women not on treatment; a study in women with at least one first-degree relative with breast cancer showed no significant changes in breast density or endometrial thickness. No trials with breast cancer as an outcome measure have been conducted to date.

Endometrium: No increase in endometrial thickness or hyperplasia observed.

Safety and tolerability: Pooled data from 15 published clinical trials, in more than 1000 women, have shown no difference in adverse events compared to placebo; there are no reports of serious adverse events or safety issues related to all Promensil products sold worldwide for 12 years.

INTRODUCTION

There are several reasons why women might not want to use hormone replacement therapy (HRT), and we need to be adequately informed to discuss the options and to individualize therapy. The main reason is the concern generated among women and health professionals, fuelled by media terror, by the spin-off trials coming from the Women's Health Initiative, which is continuing to drive women to look for alternatives to hormone therapy. Other reasons for not using HRT may be genuine contraindications such as suspected or active breast or endometrial cancer, active liver disease or a recent myocardial infarction and simply that the woman wants to use a ‘natural’ approach. Whatever the reason, an alternative to HRT might be the correct option for a particular individual.

WHAT ARE THE OPTIONS FOR DIETARY AND HERBAL APPROACHES?

There are various choices of dietary and herbal approaches for menopausal symptoms, which essentially divide into food supplements and herbal medicines. Food supplements include red clover isoflavones, soy isoflavones and vitamins; herbal medicines include Ginkgo biloba, ginseng, Black cohosh, Agnus castus and St John's wort. For the purpose of this paper, the focus will be mainly on the data for red clover isoflavones, because these active ingredients have the largest and most impressive dataset of the alternatives available.

RED CLOVER ISOFLAVONES

Isoflavones are ‘smart’ molecules, found in significant quantities in soy beans, legumes and red clover (Trilifolium pratense). Red clover has a high content of the isoflavones biochanin A and formononetin, while soy contains predominantly genistein, daidzein and glycitein. Isoflavone molecules have a similar chemical structure to steroidal estrogens (Figure 1). Preclinical data and some clinical data suggest that they have a selective effect on estrogen receptors, binding preferentially to β-receptors rather than α-receptors, but with much lower affinity than conventional estrogenic compounds. Soy isoflavones and red clover isoflavones display different affinities for these steroid receptors¹.

Figure 1 Red clover isoflavones are estrogenic

α-Receptors occur in the breast and the uterus, so selective estrogen β-receptor binding with isoflavones could potentially be of advantage in reducing the impact on these tissues. The selective estrogen receptor modulator (SERM)-type effects with isoflavones enable them to have positive effects on bone, blood vessels, vagina and brain tissue and no effect on uterus or breast^2,3.

There has been some controversy about the potential bioavailability of isoflavones⁴. Dietary isoflavones occur in two forms: glycosides, which are attached to a sugar unit and are typically soy-derived, and aglycones, which are the free form derived from red clover. Aglycones exhibit much higher potency than the equivalent glycosides.

CLINICAL DATA FOR RED CLOVER ISOFLAVONES

Vasomotor symptoms

Six randomized, controlled trials have evaluated the use of red clover isoflavones in the treatment of hot flushes. Three of these six trials have shown a significant benefit for reducing vasomotor symptoms compared to placebo^5–7. Despite the lack of statistical significance in the remaining studies, a meta-analysis of five of the randomized, controlled studies showed significant reduction in vasomotor symptoms with red clover isoflavones over placebo, with a weighted mean difference of 1.5 fewer hot flushes per day (95% confidence interval 22.94 to 0.03, p = 0.05)⁸.

A very recent study⁹ randomized 109 women to red clover isoflavones (80 mg daily) for 3 months, before cross-over to placebo after washout (Group A). A second group (Group B) received placebo first before crossing to red clover isoflavones. Results showed significant improvement in the overall symptom score (Kupperman index) while women were on red clover isoflavone supplementation, and over a 70% reduction in the frequency of hot flushes and night sweats compared to placebo (Figure 2).

Figure 2 The beneficial effects of red clover isoflavone supplementation on vasomotor and menopausal symptoms in postmenopausal women

In summary, peer-reviewed, clinical trial data suggest that there are benefits with red clover isoflavones for symptom relief. In the clinical situation, some patients respond extremely well and others do not respond as well, but it is worth a trial of red clover isoflavones as the optimum way to determine response in an individual patient.

Potential long-term benefits

Bone health

There are no fracture data with red clover isoflavones because studies have been of insufficient size or duration to examine this. However, there are studies using surrogate markers such as bone mineral density¹⁰. One study randomized women to a relatively low dose of red clover isoflavones (40 mg) or placebo. Bone mineral density was assessed with bone density scans at baseline and after 1 year. Results showed an attenuation of the loss of bone density that occurs post menopause. After 12 months, women on red clover isoflavones showed smaller decreases in spine bone mineral density (p < 0.05) and bone mineral content (p = 0.07) than those on placebo (Figure 3). Although bone mineral density did not improve, it was the reduction in bone turnover which led to the attenuation of bone loss.

Figure 3 Attenuation of postmenopausal bone loss with red clover isoflavones (RCI)

Another small trial using a higher dose of red clover isoflavones (80 mg) showed a small increase in bone mineral density¹¹.

Cardiovascular health

There are no major outcome data for coronary heart disease because trials have been relatively small and of short duration, but there are cardiovascular risk marker data. One study randomized women to red clover isoflavones (40 mg) or placebo and studied lipid profiles. Results showed significant reductions in triglyceride and low density lipoprotein (LDL) levels and improvement in the LDL/high density lipoprotein (HDL) ratio⁵. These findings have been replicated in three other trials, showing similar improvement in lipid profiles with red clover isoflavones^7,11.

There are also encouraging data for systemic arterial compliance. An Australian study randomized women to 0, 40 or 80 mg red clover isoflavones (Promensil) and measured systemic arterial compliance every 4 weeks. It found a small but significant improvement in arterial stiffness and in compliance in both the 40- and the 80-mg dosage groups compared to placebo, equivalent to HRT using similar methodology¹². Although these data are encouraging, larger studies of hard cardiovascular outcomes such as coronary heart disease incidence would be ideal.

Breast health

Although there are no trials with red clover isoflavones of sufficient size or duration to study breast cancer as a major outcome measure, there are data on mammographic density, which is used as a surrogate marker for breast cancer risk. These breast density trials have, by and large, been reassuring¹³. Results have shown a small decrease in mammographic density at 12-month follow-up compared to baseline, which would be expected in women not on treatment.

A relatively large trial of alternatives to HRT, including 401 women with at least one first-degree relative with breast cancer who were randomized to red clover isoflavone or placebo and followed for 3 years, showed no significant differences in breast density or endometrial thickness¹⁴. The lead author, Trevor Powles, suggested that there appears to be a growing body of evidence that treatment with red clover isoflavones is safe and well tolerated, but caution should be exercised in the absence of hard outcome data.

A further study, the Shanghai Breast Cancer Survival Study, investigated soy isoflavone in 5042 breast cancer survivors¹⁵. Follow-up for a median of 3.9 years showed that women in the highest quartile of soy intake appeared to have lower mortality and breast cancer recurrence rates compared to those in the lowest intake quartile (7.4% vs. 10.3% for mortality; 8.0% vs. 11.2% for recurrence). In view of the large number of women in this trial, the hazard ratios of 0.71 for mortality and 0.68 for recurrence were significant. The study suggests that soy consumption appears to be associated with a reduction in death and recurrence in this population. However, these data would be best confirmed by a larger trial over a longer period of time, ideally collecting data prospectively.

Endometrial/urogenital health

Red clover isoflavones appear to affect the endometrium, but the data are limited. There is one short, randomized, placebo-controlled trial studying 3-month treatment with isoflavones in which endometrial biopsies showed no evidence of hyperplasia¹⁶. Numerous trials with red clover isoflavones have assessed endometrial thickness using ultrasonography and have shown no increase in endometrial thickness^11,17–19.

Interesting findings from an 8-week study that assessed the vaginal maturation index showed that red clover isoflavones were associated with a reduced number of parabasal cells and an increased number of superficial cells¹⁹. The study found improvement in the vaginal maturation index, with some resolution in atrophic symptoms and improvement of lubrication.

Psychological health

A relatively recent trial conducted in Austria assessed the impact of treatment with red clover isoflavones on a large group of postmenopausal women (n = 109) with symptoms of anxiety and depression, although this was not a depressed population²⁰. One group of women was treated for 90 days with isoflavones (80 mg) before crossing over to placebo, while a second group was treated first with placebo before crossing over to isoflavones. The researchers assessed symptoms using the Hospital Anxiety and Depression Scale (HADS) questionnaire and also a self-rating depression scale (SDS). Encouragingly, women on active treatment showed nearly a 76.9% reduction in the total HADS score and 80.6% reduction in the total SDS score. HADS and SDS scores for the placebo group also decreased in comparison to baseline but only by an average of 21.7%. These data require confirmation, but look promising. The authors of the study postulate a role for isoflavones in protection against neuron damage by inhibiting pro-inflammatory pathways. This could potentially result in central nervous system and psychological benefits.

SAFETY AND TOLERABILITY OF RED CLOVER ISOFLAVONES

Pooled adverse event data from 15 published clinical trials, including a total of more than 1000 women using red clover isoflavones, have shown no difference compared to placebo. There have been no reports of serious adverse events or safety issues related to all Promensil products sold worldwide for 12 years.

For complementary therapies in general, it is important not to assume that all products are necessarily safe. We know that there are potential risks and interactions with other preparations. St John's wort has possible interactions with selective serotonin reuptake inhibitors and warfarin and may reduce efficacy of antiepileptics and oral contraceptives. In high doses, Black cohosh may cause vomiting, headaches, dizziness, low blood pressure and limb pain and, in exceptional cases, has been associated with liver dysfunction. Gingko biloba may cause mild gastrointestinal complaints and, rarely, allergic skin reactions.

For women who have a past history or particular risk for venous thromboembolism or with hormone-sensitive tumors, we need to be cautious with phytoestrogens and carefully weigh up the pros and cons as we would for HRT.

CONCLUSION

We should counsel postmenopausal women about HRT and alternatives so that they can make a fully informed choice. If we do not advise women regarding alternative preparations, then they will simply choose anything over the counter. In order to be able to advise women appropriately, it is our duty to be aware of the latest data for safety and efficacy.

Although many trials have been performed with soy isoflavones, there is a lack of consistency in the data for standardized soy-derived preparations. The dataset for red clover isoflavones is relatively extensive, more consistent and generally favorable, although randomized studies of longer duration would be desirable. Beneficial effects have been shown for vasomotor symptoms, cardiovascular risk markers, bone density, psychological and urogenital health. Safety data are reassuring, including lack of effect on the endometrium and breast.

ONGOING RESEARCH

At the moment, there is ongoing work to examine the role of dietary phytoestrogens, not only for vasomotor symptom relief but also for the impact on metabolism, diabetes, osteoporosis and carcinogenesis. There are currently two large European Union Study Programmes, examining the role of dietary phytoestrogens in metabolism, osteoporosis and cancer: PHYTOS is investigating the potential role of phytoestrogens in osteoporosis prevention in postmenopausal women; PHYTOPREVENT is studying the preventive role of phytoestrogens on breast and prostate cancers.

Conflict of interest The author has received honoraria from Novogen for lecturing and advisory work.

Source of funding No funding was received for the preparation of this manuscript.