Drug-herb interactions with herbal medicines for menopause

Herbal medicine is one of most popular choices of complementary therapies for women, particularly as an alternative treatment for menopausal symptoms. The most commonly used herbal medicines for the menopause is probably black cohosh (Actaea/Cimcifuga racemosa); other preparations used include red clover (Trifolium pratense), dong quai (Angelica sinesis) and evening primrose (Oenothera biennis). Some of these herbal medicines have a very good safety profile with little or no suggestion of interaction with conventional drugs. For others, there are many and significant drug-herb interactions. This article outlines the major known and theoretical drug-herb interactions of herbal medicines thought to be of benefit for menopausal symptoms, as well as discussing the implications for the medical profession.     

Red clover isoflavones in practice: a clinician's view

The subject of phytoestrogen use must be seen against the background of increasing controversy surrounding the role of hormone replacement therapy. Phytoestrogens such as those derived from red clover may help with hot flushes, which are a common menopausal complaint. Red clover isoflavones have more evidence base than most herbal medicinal products, although the literature is beset by difference in methodologies making direct comparison between studies difficult. There certainly does not appear to be any increased risk for women with breast cancer, who often suffer severely from sweats and flushes. There is currently insufficient evidence to recommend its use for bone protection in a group of women who are at high risk.     

Non-hormonal therapy of post-menopausal vasomotor symptoms: a structured evidence-based review

Background Interest in non-hormonal therapies for the treatment of menopausal symptoms has increased since the publication of adverse effects of estrogen replacement therapy. Objective To provide information on the efficacy of non-hormonal therapies for menopausal vasomotor symptoms based on evidence from published randomised controlled studies. Methods The Cochrane Database of Systematic Reviews (CDSR), MEDLINE, Alternative Therapies in Health and Medicine database (ATHMD) and Allied and Complementary Medicine database (AMED) were searched for randomised controlled trials in the English language reporting data on treatment of menopausal vasomotor symptoms. Trials including cancer breast patients were included. Results Our search identified 58 randomised controlled trials of which 11 involved the use of clonidine, six for SSRIs, four for gabapentin, seven for black cohosh, seven for red clover, 18 for phytoestrogens, two for ginseng, one for evening primrose, one for dong quai and one for vitamin E. Most trials had methodological deficiencies. Conclusion There is evidence that clonidine, paroxetine, venlafaxine, gabapentin and black cohosh may be beneficial in the treatment of menopausal vasomotor symptoms in some women. Current evidence does not support the use of fluoxetine, red clover, phytoestrogens, Ginseng, evening primrose, dong quai and vitamin E. The side effects profile of these therapies should be considered.     

The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: a randomized, double-blind, placebo-controlled study.

Background: The unexpected results of the Women's Health Initiative study have decreased the use of conventional hormone therapy (HT), changing physicians' and patients' attitudes towards HT and increasing their interest in alternative options. OBJECTIVE: The present study aimed to evaluate the effect of isoflavones contained in red clover extracts (Trifolium pratense) on menopausal symptoms, lipids and vaginal cytology in menopausal women. METHODS: Sixty postmenopausal women aged >40 years, non-users of HT, with Kupperman index score 15, were double-blindly randomized to receive either a commercially available red clover isoflavone supplement (80 mg/day) or placebo for 90 days. Subsequently, after a 7-day washout period, subjects switched to receive the opposite treatment for a further 90 days. Kupperman index score was determined and fasting blood and vaginal cytologic sampling performed at baseline, 90 and 180 days. RESULTS: Fifty-three women (88.3%) completed the trial. Mean age was 51.3 +/- 3.5 years, 69.7% of the women were aged 50 years or more. There was no significant effect on body mass index, weight or blood pressure after either treatment phase. Baseline Kupperman index score decreased significantly after each treatment phase, with the decrease more pronounced after the isoflavone phase (baseline: 27.2 +/- 7.7; after isoflavone: 5.9 +/- 3.9; after placebo: 20.9 +/- 5.3, p < 0.05). Red clover isoflavone supplementation significantly decreased the rate of menopausal symptoms and had a positive effect on vaginal cytology as expressed by improvement in karyopyknotic, cornification and basal cell maturation indices. Mean total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels also decreased; however, only the latter was significantly lower compared with placebo. CONCLUSIONS: Compared with placebo, red clover isoflavone supplementation in postmenopausal women significantly decreased menopausal symptoms and had a positive effect on vaginal cytology and triglyceride levels.     

Hormone replacement therapy: curse or blessing?

There is a controversial discussion on the risks and benefits of hormonal replacement therapy (HRT), and many women and doctors have revised their opinions of HRT over the last few years. Complementary and alternative therapies can be considered an option to treat menopausal symptoms. The following issue summarizes the actual knowledge of treatment options of menopausal symptoms.     

Complementary medicine: phytotherapy and soyaisoflavones as phytoestrogens

After a introduction concerning complementary medicine, naturopathy and phytotherapy a general view of soy isoflavones as phytoestrogens will be given. In german speaking countries the term and topic naturopathy has a tradition of 150 years regarding theoretical development and practical use among lay people and health professionals in European culture. In contrary the term complementary medicine has been used for approximately 15 years in englisch speaking countries as a kind of collective name for European and Non-European medical cultures and traditions. Complementay medicine summarizes a huge variety of cultural, medical and qualitywise different medical methods and treatments which can be a contribution to conventional medicine. One of the oldest and intensly researched fields in European and Non-European complementary medicine is the use of herbal drugs (phytotherapy). Soy isoflavones serve as an example to show the differences between phytotherapy based on multicompounds and dietary supplements (neutraceuticals) based on monosubstances. The differing preparations of soy isoflavones are not phytotherapeutic medicine. A review of the experimental and clinical data concerning soy isoflavones as phytoestrogens for the prevention of cancer, menopausal complaints, osteoporosis or cardiovascular diseases indicates that the consumption of food containing phytoestrogens seems to be health protective. Yet, the relevance of supplementation of single phytoestrogens for an additional health effect is not sufficiently proven.     

Soy and red clover for mid-life and aging.

INTRODUCTION: Menopause is associated with mid-life, a time when many women begin to experience the signs and symptoms of aging, such as increases in blood pressure, changes in lipid profiles, loss of bone mass density, and diminished memory and cognition. Given the result of the Women's Health Initiative, many women no longer consider hormone therapy the first option for promoting healthy aging. Instead, they are turning to botanical and dietary supplement (BDS) products in place of hormone therapy. This paper reviews the evidence available for use of isoflavones from soy and red clover for the treatment or prevention of these health issues. METHODS: The MEDLINE and EMBASE databases were searched for articles relating to soy or red clover supplement use for prevention and/or treatment of heart disease, hyperlipidemia, osteoporosis, mood disorders and cognitive abilities. Studies were included if they were randomized, controlled trials and included peri- or postmenopausal women. RESULTS: Isoflavone products appear to be the most useful for improving lipid profiles; however, the evidence suggests that isoflavone extracts from soy are less effective than products containing soy protein or red clover isoflavones. Soy protein appears to reduce levels of total cholesterol and low density lipoprotein cholesterol, while red clover reduces levels of triglycerides and increases high density lipoprotein cholesterol. The data were somewhat less convincing, although promising, for increasing bone mass density and improving cognitive abilities. CONCLUSIONS: Research suggests that isoflavones found in soy foods and red clover appear to have a small but positive health effect on plasma lipid concentrations, bone mass density, and cognitive abilities. Given the lack of serious safety concerns in the short term, it would appear that including soy and red clover in the diet of postmenopausal women, not withstanding a soy allergy, might be beneficial.     

Use of alternative and complementary medicine in menopause.

OBJECTIVES: To review the clinical evidence available for the treatment of menopausal symptoms with alternative and complementary medicine. METHODS: The MEDLINE, PREMEDLINE and COCHRANE electronic databases for the years 1980-2002 were searched for articles concerning soy products, black cohosh, dong quai, acupuncture, ginseng and evening primrose oil. Studies pertaining to menopausal vasomotor symptoms, lipid profiles and bone mineral densities of postmenopausal women were included. The data from clinical trials were reviewed. RESULTS: Soy isoflavones slightly decrease total cholesterol and LDL levels. The clinical significance of this small change is yet to be determined. The synthetic isoflavone derivative ipriflavone increases bone mineral density in healthy peri- and postmenopausal women with moderate bone mineral densities. Although earlier reports have claimed that soy is beneficial for the improvement of vasomotor symptoms, recent data do not support this claim. There are insufficient data on the other alternative therapies for treating menopausal symptoms at this time. CONCLUSION: Alternative and complementary medicine may play a role in the management of menopause, however, well-designed large studies are still needed.     

Complementary/alternative therapies for premenstrual syndrome: a systematic review of randomized controlled trials

Complementary/alternative therapies are popular with women who have premenstrual syndrome. This systematic review was designed to determine whether use of such therapies is supported by evidence of effectiveness from rigorous clinical trials. Trials were located through searching 7 databases and checking the reference lists of articles. Randomized controlled trials investigating a complementary/alternative therapy in women with premenstrual syndrome published in the peer-reviewed literature were included in the review. Twenty-seven trials were included investigating herbal medicine (7 trials), homeopathy (1), dietary supplements (13), relaxation (1), massage (1), reflexology (1) chiropractic (1), and biofeedback (2). Despite some positive findings, the evidence was not compelling for any of these therapies, with most trials suffering from various methodological limitations. On the basis of current evidence, no complementary/alternative therapy can be recommended as a treatment for premenstrual syndrome.     

Menopausal symptoms and alternative medicine

With the large number of women entering the perimenopausal and menopausal age range in the next decade, use of alternatives to standard hormone replacement therapy will increase. Women’s views of conventional hormone replacement and trends toward “complementary and alternative medicines” have contributed to an increased use of alternative treatments for menopausal symptoms. Growing media coverage and lay literature available on “natural” therapies for the climacteric are making it virtually impossible for practitioners to remain unfamiliar with the various regimens. Information on phytoestrogens, natural progesterones, mineral and vitamin supplements, herbal treatments, exercise, relaxation, acupuncture and homeopathy is flooding the market. Although alternatives to conventional hormone therapy are becoming mainstream, scientific evidence on the safety and efficacy of “natural” therapies is limited. Lack of standardization of alternative supplements and lack of regulation also make it difficult for both consumers and practitioners to evaluate these therapies. Well-designed, controlled studies are needed to obtain further information about these regimens. This, however, is no excuse for practitioners to be unaware of what products are available and their possible benefits and adverse effects. The evidence for various alternative therapies for menopausal symptoms is reviewed in both the lay and medical literature.     

Hormone replacement therapy in gynecologic cancer survivors: why not?

Purpose

As a result of treatment, many women with gynecologic malignancies will go through menopause and display climacteric symptoms at an earlier age than occurs naturally. Iatrogenic menopause may adversely affect quality of life and health outcomes in young female cancer survivors. Hormone replacement therapy (HRT) has often been withheld from women with gynecologic cancer because of concern that it might increase the risk of relapse or the development of new primary cancers. The purpose of this review was to examine the published literature on menopause management in gynecologic cancer survivors and highlight the risks and benefits of conventional and alternative HRT in this population.

Methods

A comprehensive literature search of English language studies on menopause management in gynecologic cancer survivors and women with a hereditary predisposition to a gynecologic malignancy was performed in MEDLINE databases through December 2010.

Results

Both our review and a 2008 Cochrane review of randomized trials on the effects of long-term HRT demonstrate that for menopausal women in their 40s or 50s with and without gynecologic cancer, the absolute risks of estrogen-only HRT are low. Several prospective observational studies and randomized trials on HRT use in women with a genetic predisposition for or development of a gynecologic malignancy suggest benefits in quality of life with no proven adverse oncologic effects as a result of short-term HRT use.

Conclusion

In select women, it is reasonable to discuss and offer conventional HRT for the amelioration of menopausal symptoms and to improve quality of life. HRT does not appear to increase the risk of gynecologic cancer recurrences; however, this conclusion was largely based on observational data and smaller prospective studies.     

Phytoestrogens for treatment of menopausal symptoms: a systematic review

OBJECTIVE: To assess the efficacy and tolerability of phytoestrogens for treatment of menopausal symptoms. DATA SOURCES: We searched the Cochrane Library and MEDLINE from 1966 to March 2004, using a detailed list of terms related to phytoestrogens and menopausal symptoms and also hand-searched abstracts from relevant meetings. METHODS OF STUDY SELECTION: Randomized trials were eligible if they involved symptomatic perimenopausal or postmenopausal women, compared phytoestrogen with placebo or control, reported hot flush frequency or menopausal symptom scores, and were at least 4 weeks in duration. TABULATION, INTEGRATION, AND RESULTS: Data were extracted onto standardized forms using a prospectively developed protocol. Twenty-five trials involving 2,348 participants met criteria. At baseline, the mean age was 53.1 years, mean duration of menopause was 4.3 years, and mean daily hot flush frequency was 7.1. Mean study duration was 17 weeks. Trials were grouped into categories according to type of phytoestrogen: soy foods, beverages, or powders (n = 11); soy extracts (n = 9); and red clover extracts (n = 5). Of the 8 soy food trials reporting hot flush frequency outcomes, 7 were negative. Five trials of soy foods provided information to calculate effect sizes; these were in the small-to-medium range, favoring placebo in 3 trials and soy in 2. Of the 5 soy extract trials reporting hot flush frequency, 3 (including the 2 largest trials) were negative. Effect sizes were calculated for 2 soy extract trials: one favored placebo with small effect size and the other favored soy with moderate effect size. Red clover trials showed no improvement in hot flush frequency (weighted mean difference -0.60, 95% confidence interval -1.71 to 0.51). Adverse effects were primarily gastrointestinal and taste intolerance in the soy food and beverage trials. CONCLUSION: The available evidence suggests that phytoestrogens available as soy foods, soy extracts, and red clover extracts do not improve hot flushes or other menopausal symptoms.     

The effect of red clover isoflavone supplementation over vasomotor and menopausal symptoms in postmenopausal women

Objective. To evaluate the effect of red clover isoflavone supplementation over vasomotor and overall menopausal symptoms in postmenopausal women. Methods. One hundred and nine postmenopausal women aged 40 or more were assigned to randomly receive either two daily capsules of the active compound (80?mg red clover isoflavones, Group A) or placebo of equal appearance (Group B) for a 90-day period. After a washout period of 7 days, medication was crossed over and taken for 90 days more. Daily hot flush and night sweat frequency and overall menopausal symptom intensity (Kupperman Index) were measured at baseline, 90, 97 and 187 days. Results. Daily hot flush/night sweat frequency and Kupperman Index values were similar in both studied groups at baseline. All indices significantly decreased after red clover phase in Group A, corresponding, respectively to a 73.5%, 72.2% and 75.4% average decrement. These decrements were significantly higher than those observed for Group B after placebo phase (8.2%, 0.9% and 6.7% respectively). In Group A, after washout and placebo phases all values significantly increased. In Group B, all indices remained similar after placebo and washout phases, however significantly dropping after red clover treatment. These values were also significantly lower than those observed in Group A after placebo phase. No side effects were encountered after treatment with the active compound or placebo. Conclusion. Red clover isoflavone supplementation was more effective than placebo in reducing daily vasomotor frequency and overall menopausal intensity in postmenopausal women.     

Red clover isoflavones and menopausal health

Menopausal symptoms such as hot flushes and night sweats can be very disrupting. While hormone replacement therapy is an effective therapy, concerns about side effects and breast cancer risk have stimulated interest into alternative therapies such as phytoestrogens. These are oestrogen-like compounds made by plants. Two major sources of phytoestrogens are soy and red clover. Data on randomised controlled trials of red clover for the control of menopausal symptoms are presented. The conflicting data are encouraging and suggest that phytoestrogens are a treatment modality that needs pursuing.     

ACOG Practice Bulletin no. 28: Clinical Management Guidelines for Obstetrician-Gynecologists. Use of botanicals for management of menopausal symptoms

Lack of confidence in the espoused benefits of hormone replacement therapy (HRT) coupled with a significant array of side effects of HRT, results in fewer than 1 in 3 women choosing to take HRT. The use of alternatives to conventional HRT has become more accessible and acceptable to many women. As more women choose these alternatives, physicians are confronted with the challenges of how to advise patients about alternative medicine and how to determine which therapies may be safe and effective. This document will examine available scientific information on alternative therapies for treatment of menopausal symptoms and provide recommendations on efficacy and potential adverse consequences.     

A comprehensive approach to the menopause: so far, one size should fit all

Although extensive studies have indicated that the benefits of hormone replacement therapy outweigh the risks, many women and health care providers have concerns about safety and side effects. Many alternative therapies are popular with patients, and menopausal women in the United States spent more than $600 million in 1999 alone purchasing these therapies. Several of the more commonly used alternative therapies for the menopause are critically appraised in this article. For women who choose not to take estrogen, and for those who do, the additional benefits of calcium, vitamin D, exercise, stress reduction, and different dietary and lifestyle adaptations may enhance the quality of life as they age. Although they have the potential for being effective and safe options, there has been limited clinical research for the other alternative therapies. Gynecologists and other health care providers should be aware of the lack of evidence for the effectiveness of most of these therapies when they address patient's questions and concerns. Our information about alternative therapies will increase in the coming years. Ultimately, the growing number of available treatment choices will allow individualization of the treatment. Nevertheless, until prospective studies with prolonged follow-up are conducted to evaluate the risks and benefits of different alternative therapies, hormone replacement therapy, which is better studied, will remain the treatment of first choice, and "one size fits all" will continue to describe the management plan for most peri- and postmenopausal women at least in the near future. LEARNING OBJECTIVES: After completion of this article, the reader will be able to summarize the various alternatives to hormonal therapy for menopausal symptoms, describe the effects of phytoestrogens in the management of menopausal symptoms, and explain the origin and clinical use of the more common herbal therapies.     

Proposal for an informed consent form for hormonal replacement therapy in ambulatory care]

Hormonal Replacement Therapy (HRT) represents a valid therapeutic approach for menopausal symptoms and for the prevention of cardiovascular disease and osteoporosis. Nevertheless, an informed consent, after a complete information, must be obtained from the patient. This procedure is generally adopted in any medical activity, but the modality of the consent in the HRT administration is not well established (verbal or written?, timing of administration?). The authors propose an informed written consent model to be utilized in menopausal centers; this model synthetically informs about HRT benefits and risks and must be red and signed by the patient. The written consent should be explained through a verbal detailed discussion about it, during which the patient's comprehension must be assured. The informed consent procedure should be renewed every year in long term-users. The influence of the HRT informed consent in menopausal centers must be analyzed in particular as far as women compliance is concerned.     

Consensus: soy isoflavones as a first-line approach to the treatment of menopausal vasomotor complaints

The association between an increased uptake of isoflavones and a reduced frequency of menopausal hot flushes was first described in 1992, based on a lower incidence of hot flushes in countries with a high consumption of soy. Since then, numerous clinical trials with various sources of isoflavones including soy and red clover have been presented, with practically all of the studies with adequate design delivering an outcome in favour of isoflavone supplementation. An in-depth risk assessment (EFSA 2015) concludes that the amply available human data does not indicate any suspected harmful effects from a potential interaction of isoflavones with hormone-sensitive tissues in the mammary gland, the uterus and the thyroid gland. Safety was ascertained with long-term intake of up to 150?mg isoflavones per day ingested for the duration of at least 3 years. Moreover, high isoflavone intake was found to have preventive effects with respect to breast cancer. Clinical findings indicate potential benefits of isoflavone exposure even during breast cancer treatment with tamoxifen or anastrozole.     

The effects of dietary supplementation with isoflavones from red clover on cognitive function in postmenopausal women.

OBJECTIVE: To examine the effects of dietary isoflavone supplementation with an extract from red clover on cognitive function in postmenopausal women. DESIGN: Thirty postmenopausal women aged greater than 60 years received either two tablets of an extract of aglycone isoflavones from red clover (each containing formononetin 25 mg, biochanin 2.5 mg and less than 1 mg of daidzein and genistein) for 6 months in a randomized, controlled clinical trial. Cognitive function tests were performed at baseline and at the end of isoflavone or placebo therapy. RESULTS: Isoflavone supplementation was associated with an apparent improvement in block design (a test of visual-spatial intelligence) compared to placebo (isoflavone +12%, placebo -3%; p = 0.03), no improvement in verbal memory compared to an improvement on placebo (isoflavone +1%, placebo +29%; p = 0.023) and a deterioration in digit recall compared to placebo (isoflavone -6%, placebo +12%; p = 0.029). However, these findings were not statistically significant when corrections were made for potential chance findings due to multiple comparisons. CONCLUSION: Isoflavone supplementation does not appear to have major short-term effects on cognitive function in postmenopausal women. However, further clinical trials are required to determine whether small effects or long-term effects on cognitive function occur during isoflavone supplementation.