Re: phytoestrogen .. 에스트로겐 대체 치료 2001 jama review

[문형철]

Review

May 14, 2001

A Review of the Evidence for the Use of Phytoestrogens as a Replacement for Traditional Estrogen Replacement Therapy

M. Gina Glazier, MB, BCh; Marjorie A. Bowman, MD, MPA

Author Affiliations Article Information

Arch Intern Med. 2001;161(9):1161-1172. doi:10.1001/archinte.161.9.1161

Abstract

Estrogen replacement therapy (ERT) is recommended for postmenopausal women primarily for reduction of menopausal symptoms and prevention of osteoporosis and cardiovascular disease. However, only 35% to 40% of women ever start ERT, and many do not continue it. One of the reasons women are reluctant to receive postmenopausal ERT is that they perceive prescription estrogens as being "unnatural." Because of this, there is increasing interest in the use of plant-derived estrogens, also known as phytoestrogens. This article reviews the evidence for the potential of phytoestrogens, either in dietary or supplemental form, to replace traditional forms of ERT. A comprehensive search of the English-language literature identified more than 1000 articles published in the past 30 years about phytoestrogens. In total, 74 studies were selected for inclusion in this review based on relevance, inclusion of human subjects wherever possible, and study design. The studies examine phytoestrogens' inhibition of the growth of cancer cell lines in vitro and in animals. They also look at the role of phytoestrogens in the reduction of cholesterol levels, and the use of one phytoestrogen derivative, ipriflavone, in the prevention of osteoporosis. Some small studies examine the role of phytoestrogens in the prevention of menopausal symptoms. Evidence for the potential health benefits of phytoestrogens is increasing. However, the clinically proven health benefits of prescribed ERT far outweigh those of phytoestrogens. Therefore, there is insufficient evidence to recommend the use of phytoestrogens in place of traditional ERT, or to make recommendations to women about specific phytoestrogen products.

초록

에스트로겐 대체 요법(ERT)은 

폐경 후 여성의 폐경기 증상 완화, 골다공증 및 심혈관 질환 예방을 위해 주로 권장됩니다. 

그러나 

여성의 35~40%만이 ERT를 시작하고, 

많은 여성들이 치료를 계속하지 않습니다. 

폐경 후 여성들이 ERT를 꺼리는 이유 중 하나는 

처방 에스트로겐을 “부자연스러운” 것으로 인식하기 때문입니다. 

이 때문에 식물성 에스트로겐(phytoestrogens)이라고도 알려진 

식물 유래 에스트로겐의 사용에 대한 관심이 증가하고 있습니다. 

이 글에서는 식이 또는 보충제 형태로 섭취할 수 있는 

식물성 에스트로겐이 기존의 ERT를 대체할 수 있는 잠재력에 대한 증거를 검토합니다. 

영어로 된 문헌을 종합적으로 검색한 결과, 

지난 30년 동안 식물성 에스트로겐에 관한 1,000개 이상의 논문이 발표된 것으로 확인되었습니다. 

관련성, 가능한 한 인간 대상의 포함, 연구 설계 등을 기준으로 총 74개의 연구가 이 리뷰에 포함되도록 선정되었습니다. 

이 연구들은 식물성 에스트로겐이 시험관 내 및 동물에서 암세포주 성장의 억제에 미치는 영향을 조사합니다. 

또한, 

식물성 에스트로겐이 콜레스테롤 수치를 낮추는 데 미치는 영향과 

골다공증 예방에 사용되는 식물성 에스트로겐 유도체인 이프리플라본의 사용에 대해서도 살펴봅니다. 

일부 소규모 연구에서는 폐경기 증상 예방에 식물성 에스트로겐의 역할에 대해 조사하고 있습니다. 

식물성 에스트로겐의 잠재적인 건강상의 이점에 대한 증거가 증가하고 있습니다. 그러나 임상적으로 입증된 ERT의 건강상의 이점은 식물성 에스트로겐의 이점을 훨씬 능가합니다. 따라서 전통적인 ERT 대신 식물성 에스트로겐을 사용하도록 권장하거나 여성에게 특정 식물성 에스트로겐 제품에 대한 권장 사항을 제시하기에는 증거가 충분하지 않습니다.

Postmenopausal estrogen replacement therapy (ERT) has been used for more than 25 years and combined estrogen-progesterone therapy has been widely used for at least the last 15 years. In this article, ERT will be used to refer to both estrogen and combined estrogen-progesterone replacement therapy. Current knowledge of ERT comes from large observational studies, cohort studies, and randomized controlled trials. Results of these studies show that, if used for primary prevention, ERT is associated with reduced mortality from cardiovascular disease by about 35%,1,2 reduces osteoporosis risk by about 50%;3 and reduces menopausal symptoms.4 Smaller studies suggest that ERT may also improve or reduce the incidence of such diverse medical conditions as memory loss,5 Alzheimer disease,6 tooth loss,7 and colon cancer.8 This list is not exhaustive and continues to expand as further studies are performed. Disadvantages of ERT include a potential increase in the risk of breast cancer (relative risk seems to be about 1.3 after at least 8 years of ERT9) and an increase in vaginal bleeding.10 There is an increased risk of endometrial cancer if women with an intact uterus take unopposed estrogen therapy. However, this risk is negated by the use of combined estrogen-progesterone therapy.11

The potential public health effect of ERT is reduced because only about 35% to 40% of menopausal women ever begin ERT and only about 15% continue taking it long-term.12 There are numerous reasons for this low uptake including physician failure to endorse and patient factors such as fear of breast cancer, dislike of the adverse effect of vaginal bleeding, and the concept of interfering with a "natural" process.13,14

There has been a rapid increase in consumer interest in the use of alternative medicines, particularly in the use of supplements and herbs for the treatment of menopausal symptoms.15 It is reported that 70% of the patients who use complementary therapy do not reveal this to their "traditional" primary care physician because they either do not consider it a medicine or fear primary care physician disapproval.15 When deciding to take complementary therapies, patients frequently base their decisions on anecdotal reports of success in the lay literature more than information from scientific experiments. Many women who are unwilling to take traditional ERT see herbal therapies as natural and, therefore, preferable to "unnatural" prescription medication, despite the fact that traditional ERT is often derived from natural sources such as mare's urine. Herbal and plant-derived therapies are frequently considered safer, although there are no government standards controlling their quality.16 While herbal supplements may be effective, they may also be dangerous, mixed with contaminants, or have unknown or adverse effects.17

Alternative medicines that are used for menopause include phytoestrogens, herbs, and nutritional supplements. Herbs traditionally recommended for menopausal symptoms include black and blue cohosh, evening primrose oil, chasteberry, and licorice. Vitamin E is a commonly recommended dietary supplement. A recent review article on these herbs and supplements reveals that the scientific evidence is scant regarding their safety and efficacy.18 Few randomized controlled trials have been done investigating their use and these trials show that none have proved better than placebo.19-22

Phytoestrogens are naturally occurring plant estrogens that have a chemical structure similar to human estrogen and that have the proven ability to attach to estrogen receptors in humans. Interest in these phytoestrogens (referred to in the lay literature as "natural estrogens" or "plant estrogens") as an alternative treatment for menopause recently has increased. Increasing the intake of dietary phytoestrogens is thought to decrease the risk of cancer and cardiovascular disease. Concentrated phytoestrogens are available in pill form and are sold extensively in health food stores and on the Internet. Web sites attest to the fact that these supplements are natural, identical to human hormones, and as effective as prescription ERT. It is claimed that these supplements can lower cholesterol levels, reduce menopausal symptoms, decrease the risk of endometrial cancer, improve sexual enjoyment, and reduce the risk of osteoporosis.

This review summarizes the available published experimental data about the possible benefits and adverse effects of phytoestrogens to see if there are sufficient data to substantiate these claims. We compare this evidence with the known benefits and adverse effects of prescribed ERT. Based on the available scientific data, is there evidence that phytoestrogens could replace traditional ERT?

폐경 후 에스트로겐 대체 요법(ERT)은 25년 이상 사용되어 왔으며, 에스트로겐과 프로게스테론 병용 요법은 적어도 지난 15년 동안 널리 사용되어 왔습니다. 이 글에서는 ERT를 에스트로겐과 에스트로겐과 프로게스테론 병용 요법 모두를 지칭하는 용어로 사용합니다. ERT에 대한 현재의 지식은 대규모 관찰 연구, 코호트 연구, 무작위 대조 시험에서 비롯된 것입니다. 이러한 연구 결과에 따르면, 일차 예방에 사용될 경우, ERT는 심혈관 질환으로 인한 사망률을 약 35% 감소시키고,1,2 골다공증 위험을 약 50% 감소시키며,3 갱년기 증상을 완화하는 것으로 나타났습니다. 4 소규모 연구에 따르면, ERT는 기억력 상실,5 알츠하이머병,6 치아 상실,7 대장암과 같은 다양한 질병의 발생률을 개선하거나 감소시킬 수 있다고 합니다.8 이 목록은 완전한 것이 아니며, 추가 연구가 진행됨에 따라 계속 확장될 것입니다. ERT의 단점은 유방암 발병 위험의 잠재적 증가(ERT를9년 이상 받은 후 상대적 위험도는 약 1.3으로 추정됨)와 질 출혈의 증가를 들 수 있습니다10 자궁이 온전한 여성들이 반대 작용이 없는 에스트로겐 요법을 받는 경우, 자궁내막암 발병 위험이 증가합니다. 그러나, 에스트로겐과 프로게스테론의 병용 요법을 사용하면 이러한 위험이 사라집니다11

갱년기 여성의 약 35%에서 40%만이 ERT를 시작하고, 약 15%만이 장기적으로 복용을 지속하기 때문에 ERT의 잠재적인 공중 보건 효과는 감소합니다.12 이러한 낮은 보급률에는 의사의 지지 부족, 유방암에 대한 두려움, 질 출혈의 부작용에 대한 혐오, “자연스러운” 과정을 방해한다는 개념과 같은 환자 요인 등 여러 가지 이유가 있습니다.13,14

대체 의약품, 특히 폐경기 증상 치료를 위한 보충제와 허브 사용에 대한 소비자의 관심이 급격히 증가하고 있습니다.15 보완 요법을 사용하는 환자의 70%가 이를 “전통적인” 주치의에게 알리지 않는 것으로 보고되었습니다. 그들은 이를 약으로 간주하지 않거나 주치의의 반대를 두려워하기 때문입니다. 15

보완 요법을 선택하는 경우, 환자들은 과학적 실험의 정보보다 일반 문헌에 실린 성공 사례에 근거하여 결정을 내리는 경우가 많습니다. 전통적인 ERT를 꺼리는 많은 여성들은 약초 요법을 자연스러운 것으로 간주하고, 따라서 전통적인 ERT가 종종 암말의 소변과 같은 자연적인 원천에서 유래한다는 사실에도 불구하고, “자연스럽지 않은” 처방약보다 선호합니다. 약초 및 식물 유래 요법은 품질을 관리하는 정부 표준이 없지만, 더 안전한 것으로 간주되는 경우가 많습니다.16 약초 보충제는 효과적일 수 있지만, 오염 물질과 혼합되어 위험하거나, 알려지지 않은 부작용이 있을 수 있습니다.17

폐경기에 사용되는 대체 의약품에는 식물성 에스트로겐, 허브, 영양 보충제가 있습니다.

전통적으로 폐경기 증상에 권장되는 허브에는

블랙코호시, 블루코호시, 달맞이꽃종자유, 챠스티베리, 감초 등이 있습니다.

비타민 E는 일반적으로 권장되는 건강 보조 식품입니다.

최근 이러한 허브와 보조제에 대한 리뷰 기사에 따르면, 안전성과 효능에 관한 과학적 증거는 거의 없다고 합니다.18 이들의 사용을 조사한 무작위 대조 시험은 거의 이루어지지 않았으며, 이러한 시험에서 위약보다 더 나은 효과가 입증된 사례는 없었습니다.19-22

식물성 에스트로겐은

인간 에스트로겐과 유사한 화학 구조를 가지고 있으며,

인간의 에스트로겐 수용체에 결합하는 능력이 입증된 자연 발생 식물 에스트로겐입니다.

폐경의 대체 치료법으로 식물성 에스트로겐(일반 대중을 대상으로 한 문헌에서는 “천연 에스트로겐” 또는 “식물성 에스트로겐”이라고 함)에 대한 관심이 최근 증가하고 있습니다. 식물성 에스트로겐의 섭취를 늘리면 암과 심혈관 질환의 위험을 줄일 수 있다고 여겨집니다. 농축된 식물성 에스트로겐은 알약 형태로 제공되며, 건강식품점과 인터넷에서 널리 판매되고 있습니다. 이러한 보충제는 천연 물질이며, 인체 호르몬과 동일하며, 처방약인 ERT만큼 효과가 있다는 사실이 웹사이트를 통해 입증되고 있습니다. 이러한 보충제는 콜레스테롤 수치를 낮추고, 갱년기 증상을 완화하며, 자궁내막암의 위험을 줄이고, 성생활의 즐거움을 향상시키며, 골다공증의 위험을 줄일 수 있다고 주장되고 있습니다.

이 리뷰는 식물성 에스트로겐의 가능한 이점과 부작용에 대한 발표된 실험 데이터를 요약하여 이러한 주장을 입증할 수 있는 충분한 데이터가 있는지 확인합니다. 우리는 이 증거를 처방된 ERT의 알려진 이점과 부작용과 비교합니다. 이용 가능한 과학적 데이터를 바탕으로, 식물성 에스트로겐이 전통적인 ERT를 대체할 수 있다는 증거가 있습니까?

Methods

The MEDLINE, CINAHL, and Cochrane databases from January 1, 1966, through September 30, 1999, were searched for articles using the terms "phytoestrogen," "isoflavones," "coumestans," "lignans," and "soy," and cross-referenced with the terms "cholesterol," "hyperlipidemia," "endometrial cancer," "breast cancer," "osteoporosis," "hot flashes," "coronary heart disease," "menopause," and "prevention." The reference lists of published articles were searched for relevant English-language articles about phytoestrogens that were not found on the database searches. Lay literature concerning phytoestrogens was obtained through Internet searches, and directly from the companies who supply plant-derived estrogens in pill form.

Criteria for the selection of articles included English language and human subjects wherever available. As far as possible, we endeavored to consider only evidence from randomized, blinded, controlled studies in preference to observational or epidemiological studies. Animal studies were included to support human data or if there were no relevant human studies available. In vitro studies were used to support animal or human data, or if there were no in vivo data available. As the interest in phytoestrogens has increased, the number of studies has also increased. Where important, the weakness in the trials and experiments cited are noted. Using these criteria, a total of 74 articles were considered relevant.

What are phytoestrogens?

Phytoestrogens are a diverse group of nonsteroidal plant compounds that can behave as estrogens and occur naturally in most plants, fruits, and vegetables.23 They were first noted in 1926 to have estrogenic activity.24 Because they possess a phenolic ring, this enables them to bind to estrogen receptors in humans. They bind to both types of estrogen receptor, Erα receptors and the more recently discovered Erβ receptors.25 Many phytoestrogens seem to have a higher affinity for the Erβ receptor than steroidal estrogens, which suggests that they may exert their actions through distinctly different pathways.25 However, despite their ability to bind to the estrogen receptor, they are much weaker than human estrogens, with 102 to 105 times less activity.26 They seem to possess both estrogenic and antiestrogenic behavior, but whether they act primarily as an estrogen or as an antiestrogen seeems to depend on an individual's amount of circulating endogenous estrogens and the number and type of estrogen receptors.27,28 Even though they have low estrogenic activity, they are frequently present in the body in much higher quantities than endogenously produced estrogens.29 Some have also demonstrated progesterone receptor activity.30

There are 3 main types of phytoestrogens—the isoflavones (the most potent), coumestans, and lignans (Figure 1). There are more than 1000 types of isoflavones, but the most commonly investigated are genistein and daidzein, which are also thought to have the highest estrogenic properties. They are found in legumes such as soy, chickpeas, clover, lentils, and beans.26 The amount of phytoestrogen found in each soy protein depends on the processing techniques used and its relative abundance in the specific soy product of interest. The secondary soy products (milk or flour) contain lower amounts of isoflavones than the primary products.30 The isoflavones are bound to glucose, and when ingested by humans, are enzymatically cleaved in the gut to the active forms.25 The metabolism of the phytoestrogens varies from person to person, and there is also a sex difference, with women appearing to metabolize them more efficiently.31 The estrogenic activity of the various isoflavones varies greatly. We do not yet know which is the most biologically active form.

The lignans (enterolactone or enterodiol) are found in flaxseed (in huge quantities), lentils, whole grains, beans, fruits, and vegetables.26 Other classes, which are much more rarely ingested, are the coumestans (found in sprouting plants), flavones, flavanones, chalcones, terpenoids, and saponins.

식물성 에스트로겐이란 무엇입니까?

식물성 에스트로겐은 에스트로겐처럼 작용할 수 있는 다양한 비스테로이드 식물 화합물 그룹으로, 대부분의 식물, 과일, 채소에서 자연적으로 발생합니다.23 1926년에 에스트로겐 활성이 있는 것으로 처음 발견되었습니다.24

페놀 고리를 가지고 있기 때문에 인간의 에스트로겐 수용체에 결합할 수 있습니다.

이들은 에스트로겐 수용체의 두 가지 유형,

즉 Erα 수용체와 최근에 발견된 Erβ 수용체에 모두 결합합니다.25

많은 식물성 에스트로겐은 스테로이드성 에스트로겐보다

Erβ 수용체에 더 높은 친화성을 보이는 것으로 보이며,

이는 식물성 에스트로겐이 뚜렷하게 다른 경로를 통해 작용할 수 있음을 시사합니다.25

그러나

에스트로겐 수용체에 결합하는 능력에도 불구하고,

식물성 에스트로겐은 인간 에스트로겐보다 훨씬 약하며,

활성이 102~105배 낮습니다. 26

그들은 에스트로겐과 항에스트로겐의 양쪽 성질을 모두 가지고 있는 것으로 보이지만, 그들이 주로 에스트로겐으로 작용하는지 아니면 항에스트로겐으로 작용하는지는 순환하는 내인성 에스트로겐의 양과 에스트로겐 수용체의 수와 유형에 따라 달라지는 것으로 보입니다.27,28 비록 에스트로겐 활성이 낮지만, 체내에서 내인성 에스트로겐보다 훨씬 더 많은 양으로 존재하는 경우가 많습니다. 29 일부는 프로게스테론 수용체 활성도 입증했습니다.30

식물성 에스트로겐에는 세 가지 주요 유형이 있습니다.

가장 강력한 이소플라본, 쿠메스탄, 리그난(그림 1).

이소플라본에는 1,000가지 이상의 종류가 있지만,

가장 일반적으로 연구되는 것은

제니스테인(genistein)과 다이제인(daidzein)으로,

이 두 가지가 가장 높은 에스트로겐 특성을 가지고 있는 것으로 여겨집니다.

콩, 병아리콩, 클로버, 렌즈콩, 콩과 같은 콩과 식물에서 발견됩니다.26

각 콩 단백질에 함유된 식물성 에스트로겐의 양은 사용되는 가공 기술과 관심 있는 특정 콩 제품의 상대적 풍부도에 따라 다릅니다. 2차 콩 제품(우유 또는 밀가루)은 1차 제품보다 이소플라본의 양이 적습니다. 30

이소플라본은

포도당에 결합되어 있으며,

사람이 섭취하면 장에서 효소에 의해 활성 형태로 분해됩니다.25

식물성 에스트로겐의 대사는 사람마다 다르며, 성별에 따라 차이가 있는데,

여성은 더 효율적으로 대사하는 것으로 보입니다.31

다양한 이소플라본의 에스트로겐 활성은 매우 다양합니다.

어떤 형태가 생물학적으로 가장 활동적인지는 아직 밝혀지지 않았습니다.

리그난(엔테로락톤 또는 엔테로디올)은

아마씨(대량으로 함유되어 있음),

렌즈콩, 통곡물, 콩, 과일, 채소에 함유되어 있습니다.26

그밖에 섭취되는 빈도가 훨씬 더 적은 종류로는

쿠메스탄(발아 식물에서 발견됨), 플라본, 플라바논, 칼콘, 테르페노이드, 사포닌 등이 있습니다.

Potential benefits of phytoestrogens

Rates of certain diseases, particularly cancers, vary greatly between various geographic regions. In epidemiological observational studies, it was noted that the rates of colon, prostate, and breast cancers were much lower in Japan and other southeast Asian societies than in the United States.32,33 Similar differences were also noted for cardiovascular diseases.34 Interest in the phytoestrogens as therapy for menopausal symptoms began when it was noted that Asian women had approximately 10% the incidence of hot flashes that American women had, but this may be complicated by cultural definitions and beliefs.35,36 These are observational studies with many confounding factors including genetics, psychology, and diet. However, migration studies of Japanese moving to the United States showed the Japanese developed an increased incidence of "Western" disease within 1 or 2 generations.37 Therefore, genetics do not seem to be the only factor and attention has turned to diet. In comparing the Asian diet with that consumed in the West, one of the most significant differences is the high quantity of soy in the Asian diet. The average diet resulted in the ingestion of between 20 and 150 mg/d of soy compared with women in the United States who ingest 1 to 3 mg/d.38

Soy contains high levels of phytoestrogens, particularly the isoflavones. As a result of these observational studies, isoflavones, and particularly soy, are marketed as food supplements and drinks, and also as nonprescription-requiring natural hormone replacement therapy. Is it possible that by supplementing the diet with phytoestrogens that we can improve disease profiles?

식물성 에스트로겐의 잠재적 이점

특정 질병, 특히 암의 발병률은 지역에 따라 크게 다릅니다. 역학 관찰 연구에 따르면, 대장암, 전립선암, 유방암의 발병률은 미국보다 일본과 다른 동남아시아 사회에서 훨씬 낮았습니다. 32,33 유사한 차이가 심혈관 질환에서도 관찰되었습니다.34 폐경기 증상 치료제로서의 식물성 에스트로겐에 대한 관심은 아시아 여성들이 미국 여성들에 비해 약 10% 정도만 일과성 열감을 경험한다는 사실이 밝혀졌을 때 시작되었지만, 이는 문화적 정의와 신념에 의해 복잡해질 수 있습니다.35,36 이 연구는 유전학, 심리학, 식습관 등 많은 혼란 요인을 포함한 관찰 연구입니다. 그러나 미국으로 이주한 일본인의 이주 연구에 따르면 일본인은 1~2세대 내에 “서양” 질병의 발생률이 증가하는 것으로 나타났습니다.37 따라서 유전학이 유일한 요인은 아닌 것으로 보이며, 식단에 대한 관심이 높아지고 있습니다.

아시아의 식단과 서양의 식단을 비교해 보면,

가장 큰 차이점 중 하나는 아시아의 식단에서 대두가 많이 사용된다는 것입니다.

평균적인 식단을 섭취한 사람들은 하루에 20~150mg의 대두를 섭취한 반면,

미국 여성들은 하루에 1~3mg의 대두를 섭취했습니다.38

콩에는

특히 이소플라본이라는

식물성 에스트로겐이 많이 함유되어 있습니다.

이러한 관찰 연구 결과, 이소플라본, 특히 콩은 건강 보조 식품과 음료, 그리고 처방전이 필요 없는 자연 호르몬 대체 요법으로 판매되고 있습니다.

식물성 에스트로겐을 식단에 보충함으로써

질병의 프로파일을 개선할 수 있을까요?

The evidence is discussed below.

Cancer prevention

Phytoestrogens have several potential anticarcinogenic activities. Early studies focused on their estrogenic activity, particularly in their potential ability to reduce the risk of breast cancer, but recent studies have found that their actions are not purely estrogenic, and their nonhormonal activities could be more important in cancer prevention.39 The proposed mechanisms by which they may inhibit cancer cells include the following: (1) inhibition of DNA topoisomerase, (2) suppression of angiogenesis, (3) induction of differentiation in cancer cell lines, and (4) induction of apoptosis.40 Numerous in vitro cell culture studies and in vivo animal experiments have demonstrated that phytoestrogens can inhibit tumors.32 In a comprehensive review on the potential of phytoestrogens to reduce tumor growth, Fournier et al41 noted that 16 of 17 animal studies showed that the addition of soy products reduced tumor incidence or multiplicity in tumor models of the breast, prostate, liver, esophagus, and lung. Isoflavones were the most common soy constituent added (11 studies), but various other components of soy (genistein, soybean saponin, and soy flour) were also used.

Many studies have focused on the isoflavone, genistein, which seems to be the primary anticancer soy constituent. It has antioxidant properties that may also play a role in its anticarcinogenic effects. It can inhibit hydrogen peroxide–induced tumor promoter activity in vitro and in vivo42 and has been shown to inhibit tyrosine kinase.43 Its activity as an anticancer agent probably results from its suppression of enzymes that promote cell growth.

Caution in the interpretation of the available evidence is necessary. Many, but not all, of the tumor-inhibiting effects have been obtained with huge doses of the phytoestrogens, far larger than could be obtained by diet alone. Experimental conditions and isoflavone concentrations varied widely. Cell lines were different and the presence or absence of estradiol also varied. We have no idea what doses and what types of phytoestrogens should be used for tumor suppression, their duration of use, their frequency of use, and the potential or real adverse effects or toxicities. To date, there are no intervention trials using soy or its products in humans for primary or secondary prevention of cancer. These studies are needed, but will be difficult to perform and control. In addition, it is difficult to conduct retrospective epidemiological studies on soy intake. Assessments of the amount and types of soy products consumed 3 or 4 decades prior to the study are unreliable, as is the ability to link this information to the development of cancer years later.

No recommendations can be made regarding phytoestrogens' use in cancer prevention or treatment other than the fact that they seem to have encouraging effects in vitro. Based on this evidence, no conclusive statement can be made about the protective effect of dietary phytoestrogens other than most in vitro and animal studies suggest that the soy constituents, particularly the isoflavones, have antineoplastic activity.

Breast cancer

One of the reasons women are reluctant to take traditional ERT is the fear of developing breast cancer. Recent studies have suggested that the risk of breast cancer in patients receiving ERT increases with the duration of therapy. The magnitude of this association remains controversial, but relative risks are in the range of 1.3 to 2.4 after a minimum of 5 years of therapy.9

Phytoestrogens have structural similarity to estrogens, and it is, therefore, theoretically possible that ingestion could also increase the risk of breast cancer. However, epidemiological studies suggest that phytoestrogen consumption is inversely associated with the development of breast cancer. Countries in which the dietary intake of phytoestrogens is high have some of the world's lowest incidences of breast cancer.44 These are observational studies only.

Studies on breast cancer and phytoestrogens are summarized in Table 1. Early studies looking at the associations of phytoestrogens, particularly genestein, with breast cancer looked at its action on hormone receptors. In one study 48 women who were about to undergo resection of breast masses were given either a daily supplement of isoflavones (45 mg/d) or a placebo for 2 weeks prior to the surgery. The isoflavone-supplemented group had increased growth in the breast lobular epithelium and increased progesterone-receptor expression‎.45 The significance of this is unknown.

We know that phytoestrogens can bind to estrogen receptors in vitro, and, like tamoxifen, they have both mild estrogenic and antiestrogenic effects. Therefore, if their antiestrogenic activity is prominent, they could, in theory, reduce the potential carcinogenic effect of prolonged estrogenic activity.46 Zava and Duwe46 compared the dose-response to genestein with that of estradiol, tamoxifen, and several other structurally similar iso- and bioflavonoids (equol, kaempferol, and quercetin) in human breast cancer cells in vitro. The results showed that genistein was the only isoflavonoid with potent estrogen agonist and cell growth inhibitory actions over a physiologically obtainable concentration range. The growth-inhibitory action of genestein was distinctly different from those of tamoxifen.46

However, an experiment done in ovariectomized mice found that genestein actually stimulated mammary cancer growth.47 The postulated theory was that phytoestrogens, acting as weak estrogens, exhibit estrogenic activity in a low-estrogen environment. These animals, although ovariectomized, were sexually immature. A study by Wang et al48 investigated the effects of increasing genestein concentrations on estrogen receptor–positive human breast cancer cells. Genistein produced a concentration-dependent effect on their growth. At levels similar to those produced by soy in the diet, DNA synthesis in breast cancer cell lines appeared to be stimulated,48 but at higher concentrations, genistein inhibited growth. The effects of genistein on growth at lower concentrations appeared to be via the estrogen receptor pathway, while the effects at higher concentrations were independent of the estrogen receptor. It seems as if phytoestrogens could act at other levels in the cell and have the potential, in low concentrations, of inducing breast cancer.

Despite some evidence that genestein has the potential to be a cancer promoter, most in vivo and in vitro studies show that genestein inhibits the growth of breast cancer cells and induces apoptosis in breast cancer cell lines.49,50 In one study,51 newborn female rats fed a known mammary carcinogen were randomized to receive supplementary genestein, and there was a 50% reduction in the number of breast cancers in the genestein-exposed group. The timing of genestein administration seemed to be critical in reducing the incidence of breast cancer. Mice fed genestein prior to 35 days of age had a greatly reduced incidence of breast tumors compared with those exposed later in life.52 Despite encouraging study results in animals, experimental human studies have yet to be performed.

Although there are no experimental human studies, some case-control studies have attempted to link soy intake and breast cancer risk. Most recently, a case-control study of 288 subjects by Ingram et al53 looked at the association between the urinary excretion of phytoestrogens and breast cancer. Patients were women 30 to 84 years old recently diagnosed as having breast cancer; controls were matched for demographic variables. They found that the increased urinary excretion of some phytoestrogens was associated with a substantial decrease in the risk of breast cancer (odds ratio, 0.27; 95% confidence interval, 0.10-0.69).53 The amount absorbed is more important than the amount ingested. A study from China of 60 patients with breast cancer showed similar findings, where the median excretion of isoflavones in the patients was 50% to 65% less than in the control subjects.54 A criticism of these studies is the lack of information on a temporal relationship between soy intake and breast cancer development. We do not know if the patients ate diets high in soy before they were diagnosed as having cancer, or whether they had changed their diets over time.

The conflicting results make it difficult to interpret the studies—do phytoestrogens prevent or promote breast cancer growth? It is possible that they demonstrate estrogenic activity in a low-estrogen environment and antiestrogenic activity in a high-estrogen environment. It is, therefore, possible that they have the potential to protect against breast cancer before menopause (high-estrogen environment) and be procancer agents after menopause (low-estrogen environment). This theory is partly supported by a study from Singapore that showed an inverse relationship between soy intake and breast cancer in premenopausal women but not in postmenopausal women.55 Again, caution in the interpretation of the evidence is necessary. Most of the studies have been conducted in vitro and, owing to conflicting evidence, further research is needed to confirm‎ the action of phytoestrogens. The real worry is that phytoestrogens seem to have the ability to actually promote some breast tumor growth. Further in vitro studies are needed to sort out the conflicting data and, following this, well-designed intervention studies should be performed to confirm‎ whether phytoestrogens can in fact reduce the risk of breast cancer.

Cardiovascular disease

The incidence of cardiovascular disease increases steeply in women after menopause. Studies have shown that traditional ERT lowers the total serum cholesterol level and increases the high-density lipoprotein cholesterol (HDL-C) level. If used for primary prevention, it is associated with a 35% to 40% decrease in cardiovascular disease mortality.1,56 These epidemiological data are supported both by clinical trials and basic science research.2 The "healthy-user" effect has been hypothesized to affect these correlations, but so far, there is no definitive evidence to disprove these large studies.

Because the incidence of cardiovascular disease is lower in countries in which large quantities of soy are consumed in the diet, phytoestrogens, particularly soy, have been investigated as cholesterol-lowering agents since the early 1940s.2,57 Trials of phytoestrogens in cardiovascular disease prevention are outlined in Table 2. In a large epidemiological study on the relationship between soy product intake and total serum cholesterol concentration, 4838 Japanese men and women had their serum cholesterol levels measured and were interviewed regarding their dietary intake of soy and soy products.58 A significant trend (P<.001) was observed for decreasing total serum cholesterol concentration with an increasing intake of soy products in both men and women suggesting a dose-response relationship. However, it is also possible that persons who use soy as a protein source may have a lower intake of animal proteins and, therefore, a concomitant reduction in cholesterol and saturated fat intake.

There are several mechanisms by which dietary phytoestrogens could prevent or reduce atherosclerosis including antioxidant activity,59 improvement in plasma lipid concentrations,60,61 reduction of thrombus formation,62 and improvement in vascular compliance.63 The mechanisms by which they could improve plasma lipid profiles are poorly understood. Proposed mechanisms of action include the following: increased bile acid secretion,60 direct action on estrogen receptors,64 inhibition of endogenous cholesterol synthesis,65 up-regulation of the cholesterol receptors,66 and enhanced thyroid function (an elevated thyroxine level reduces the cholesterol level).67,68 Studies investigating the potential cardioprotective effects of phytoestrogens have been done on both primate and human subjects. In 1996, Anthony et al69 studied 27 peripubertal male and female rhesus monkeys fed moderately atherogenic diets with soy protein as the protein source. In a crossover design, the monkeys were fed a phytoestrogen-depleted soy protein for 6 months and a phytoestrogen-containing soy protein for 6 months. The phytoestrogen diet significantly decreased the low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein cholesterol levels in both male and female monkeys by 30% to 40% and increased the HDL-C level by 15% in females. In addition, the total serum cholesterol level–HDL-C ratio decreased by 20% in the male monkeys and 50% in the female monkeys. A similar study was conducted in 1997 on ovariectomized female monkeys fed 1 of the following 4 diets: animal protein (casein) alone, animal protein with 17β-estradiol, soy isolate alone (which contained soy phytoestrogens), or soy isolate with 17β-estradiol.70 Soy protein improved the plasma lipid profiles, and soy protein combined with estradiol improved the lipid profiles even further. In one further study by Anthony et al71 young male cynomolgous monkeys were fed 1 of the following 3 diets for 14 months: animal protein, phytoestrogen-depleted soy, or phytoestrogen-containing soy. Again, those fed phytoestrogen-containing soy had improved lipid profiles compared with the other 2 groups. In addition, autopsy studies done on a random sample of each group showed that the group fed phytoestrogens had 90% less atherosclerosis than those fed animal protein.

There are numerous small sample size studies on human looking at the potential cardiovascular benefits of phytoestrogens. In an attempt to combine these, Anderson et al72 performed a meta-analysis of 38 controlled trials of soy protein use for cholesterol reduction in humans. Thirty-four of 38 studies showed an improvement in lipid values. Overall, an average of 47 g of soy protein intake per day resulted in statistically significant reductions of 9.3% in the total serum cholesterol level, 12.9% in LDL level, and 10.5% in triglyceride levels. There was no overall change noted in HDL-C or very low-density lipoprotein levels. In addition, the higher the patient's initial total serum cholesterol level, the better their response to soy intake. Those with normal cholesterol levels with initial cholesterol values below 5.2 mmol/L (<200 mg/dL) had nonsignificant decreases of 4.4%, whereas subjects with initial values above 8.66 mmol/L (>335 mg/dL) had significant reductions of 19.6%. There was insufficient data to analyze the effects based on sex.

Since 1995, further small human studies have been conducted. Washburn et al73 carried out a randomized, double-blind, crossover trial in 51 perimenopausal women. Subjects received the following 3 diets in sequence, each given for 6 weeks: a comparison carbohydrate-based diet; a diet with 34 mg of supplemental phytoestrogens in a single dose; and a diet with 34 mg of phytoestrogens split in 2 doses. Significant declines in total serum cholesterol (6%) and LDL-C (7%) levels were noted in the 2 groups receiving the soy diets as compared with the group receiving the carbohydrate diet. A significant decrease of 5 mm Hg in systolic blood pressure was also noted in the subjects receiving twice daily soy supplements compared with the carbohydrate only diet. To establish whether soy protein lowered the total cholesterol level in normocholesterolemic subjects on a National Cholesterol Education Panel Step I diet, Wong et al74 conducted a randomized crossover study. Thirteen normocholesterolemic and 13 hypercholesterolemic men aged between 20 and 50 years were fed either an National Cholesterol Education Panel Step I soy protein diet or an National Cholesterol Education Panel Step I animal protein diet for 5 weeks, followed by a washout period of 10 to 15 weeks, and then the alternate diet for 5 weeks. The hypocholesterolemic effect of soy protein was found to be independent of age and body weight. Regardless of original lipid status, the soy protein diet was associated with a statistically significant decrease in the plasma concentrations of LDL-C (P = .03) and the ratio of plasma LDL-C to HDL-C (P = .005).

Following from the primate studies, interest has centered on finding the component of soy that is most responsible for its cholesterol-lowering ability, primarily the isoflavones—genestein and daidzein. In 15 healthy young women with normal cholesterol levels, it was found that 45 mg/d of isoflavonoids, but not 23 mg/d, resulted in a significant decrease in total serum cholestrol and LDL-C levels.61 In a noncontrolled trial Nestel et al63 studied 15 perimenopausal and postmenopausal women fed 45 mg/d of genestein over 10 weeks. Although there was no significant change in LDL-C levels after treatment, arterial compliance improved by 26%, a similar degree to that encountered in women who receive conventional ERT. Not all trials have shown an improvement in lipid profiles. Hodgson et al75 looked at 46 men and 13 postmenopausal women who were given 55 mg/d of isoflavonoids (mainly genestein) in pill form over 8 weeks in a 2-way parallel design. There was no difference noted in baseline and posttreatment cholesterol levels and it was concluded in this study that patients with normal cholesterol levels at baseline do not have a significant improvement when fed isoflavonoids.

Variability in study design (particularly the type and amount of phytoestrogen used); study subjects (age and sex varies greatly); and outcomes studied make the studies done on cholesterol lowering associated with phytoestrogens hard to synthesize. The numbers of subjects studied are generally small (usually <100, often <30). It seems as if the beneficial effects are greater in those with elevated, rather than normal, cholesterol levels. Overall, phytoestrogen supplementation seems to have a beneficial effect on lipid values, but the magnitude of that effect, its clinical significance, and the amount of soy isoflavones required to obtain it are still in question. Despite the inconsistencies, there are no studies to date showing an elevation of lipid values with the use of these diets.

Is there other evidence for improvement in cardiovascular disease? Although soy protein may reduce the lipid values, there are no studies to date studying the long-term effects of soy in coronary heart disease prevention. There is strong epidemiological evidence that the risk of heart disease in Asian countries is significantly lower than the United States, but this is confounded by the fact that the Asian diet also has low saturated fat.76 There is only one primate study that shows that a diet high in soy reduced atherosclerosis, which could affect the rate of heart disease.77 There is also interest in the platelet inhibitory function of genestein in vitro. Nakashima et al78 showed that platelets incubated in vitro with genestein completely inhibited platelet aggregation induced by thromboxane A2 and collagen analogues.78 The mechanisms by which this occurs are poorly understood, and the clinical significance and application of this requires further study. Additional studies are needed to look at the effect of isoflavones and other phytoestrogens on lipoproteins, hemostasis, and vascular function.

Hot flashes or menopausal symptoms

Hot flashes are preval‎ent at menopause and are the most common reason cited by menopausal women for starting ERT. Their preval‎ence varies greatly with geographic distribution from 70% to 80% of women in the United States to 10% to 14% in Singapore and Japan.36,79 Interestingly, it appears that ERT does not seem to reduce the incidence of menopausal hot flashes in Asian women. Chung et al80 carried out a double-blind study on 83 Hong Kong Chinese women with a surgical menopause randomized to receive treatment with 0.625 mg/d of estradiol. There was a significant increase in the serum estradiol concentration with treatment compared with placebo (P<.001) but no significant difference in the frequency of hot flashes between the groups. It was hypothesized that the dietary intake of phytoestrogens could have negated the effects of estradiol on menopausal symptoms, but actual dietary habits of the subjects were not recorded in this study.

Few controlled studies have been done looking at the effects of phytoestrogens on menopausal symptoms (Table 3). Washburn et al73 noted a statistically significant decrease in vasomotor symptoms and hypoestrogenic symptoms in 51 patients fed phytoestrogen supplements (17 mg) twice daily compared with patients receiving placebo. However, this supplement did not improve other menopausal symptoms, such as mood swings, and did not affect the overall quality of life.73 Albertazzi et al81 looked at the effect of daily dietary supplementation of soy protein isolate powder on hot flashes in 104 postmenopausal women in a 12-week, double-blind, parallel, randomized placebo-controlled trial. Patients were assigned to either 60 g/d of isolated soy protein or 60 g/d of placebo (casein). By the end of the 12th week, patients taking soy had a 45% reduction in their daily hot flashes vs a 30% reduction obtained with placebo (P<.01). Murkies et al82 randomized 58 postmenopausal women in a double-blind study design. Patients received either a supplement of wheat or soy flour (45 g/d) over 12 weeks. Overall, those receiving soy flour had a reduction of 40% in the frequency of hot flashes compared with a reduction of 25% in those receiving wheat flour. Although both studies had statistically significant results, the clinical significance is unclear. A 15% reduction in hot flashes would mean a reduction of 1 hot flash per day in patients experiencing 10 or 12 hot flashes per day. This would be of limited practical benefit.

Osteoporosis

Estrogen replacement therapy is highly effective at reducing the rate of bone loss and can also replace lost bone.83 Epidemiological data suggest that osteoporosis is about one third as common in Japanese women (who consume a diet rich in soy products) compared with those consuming a Western diet.84 The extent to which this is genetic is unknown.

To date, few controlled trials have been done specifically looking at phytoestrogens and osteoporosis in women. Kardinaal et al85 in the Netherlands hypothesized that the rate of bone loss is inversely associated with urinary excretion of phytoestrogens used as a surrogate marker of dietary intake. They compared the excretion of flavonoids in the urine of 35 women who had a high rate of bone loss (>2.5% per year) with the excretion of flavonoids in 35 women with a low rate of bone loss (<0.5% per year). There was no difference in the excretion of isoflavonoids between the 2 groups and it was concluded that there did not seem to be a protective effect. However, animal models have demonstrated possible positive effects of isoflavones on bone.86 It has been shown recently in a placebo-controlled trial that ovariectomized rats fed a diet of genestein had a significant decrease in bone loss.87

All phytoestrogens are unlikely to be the same when it comes to osteoporosis prevention. Interest is centered on ipriflavone in the prevention of bone loss. It is a synthetic nonhormonal drug produced commercially from the isoflavone daidzein. Ipriflavone does not seem to act through direct estrogen receptor activity and, therefore, is not strictly a phytoestrogen.88 However, approximately 10% of the ingested dose is converted back to daidzein in the body.88 Its lack of estrogenic properties was investigated in a study of 15 postmenopausal women given ipriflavone treatment. The levels of follicle-stimulating hormone, luteinizing hormone, prolactin, and estradiol did not change following administration of 600 mg/d and 1000 mg/d to 2 groups of women, even after 21 days of treatment. In addition, there was no change in vaginal cytology after 21 days of treatment.89 To date, this apparent lack of hormonal activity has not been investigated using higher doses of ipriflavone. Most of the studies about ipriflavone efficacy have been done in Italy, Hungary, and Japan. Ipriflavone has been shown to inhibit bone resorbtion by mouse osteoclasts and to inhibit parathyroid hormone activity.90 It has been shown that the 5 metabolites of ipriflavone can increase alkaline phosphatase activity and collagen formation in vitro.91

Several double-blind human studies have shown a beneficial effect of ipriflavone in reducing bone loss. In 1997 Gambacciani et al92 observed the effect of ipriflavone combined with ERT in postmenopausal women. The study consisted of 4 groups of postmenopausal women treated for 2 years with one of the following: (1) only a calcium supplementation (500 mg/d), (2) ipriflavone (600 mg/d) plus the same calcium dose, (3) low-dose conjugated estrogens (0.3 mg/d) plus calcium, or (4) low-dose ipriflavone (400 mg/d) plus low-dose conjugated estrogens plus calcium. The most beneficial effects in reducing bone loss were seen in patients who received the low-dose ipriflavone with estrogens and the ipriflavone with calcium with a significant (P<.05) increase in vertebral bone density seen in these groups. In another placebo-controlled study, 98 women with an established diagnosis of osteoporosis were given ipriflavone, 200 mg, 3 times daily. After 2 years of treatment, the placebo-treated group had lost 3.5% of bone mass, but those treated with ipriflavone had maintained or slightly increased their bone density.93 A further placebo-controlled study with 453 participants and the same study design also showed similar results after 2 years.94

There is some evidence that, in addition to slowing bone loss, ipriflavone treatment can increase bone mass. In a 1-year, double-blind, placebo-controlled, parallel group clinical trial, 41 postmenopausal women received ipriflavone and 50 received placebo.95 Six months later the ipriflavone-treated group had a statistically significant increase in vertebral bone mineral density, whereas it decreased in the placebo-treated group. In a smaller Italian study, 28 women older than 65 years, having a diagnosis of osteoporosis and radiographic evidence of at least one vertebral fracture, were treated with ipriflavone (600 mg/d) or placebo in a randomized, double-blind, parallel group design.96 All patients received 1000 mg/d of calcium. After 12 months there was a 6% increase in bone mineral density at the distal radius in the ipriflavone-treated group (P<.05). Bone mineral density values did not change in the placebo group.

In general, ipriflavone seems safe. However, most studies look at its use over a 2-year period only. Because it seems to have no estrogenic effects, ipriflavone may be less likely to increase the risk of estrogen-dependent cancers but it is also unlikely to help prevent cardiovascular disease. Caution is urged in the interpretation of these studies, as ipriflavone is synthetic, and not a naturally occurring substance, and the amount of ipriflavone per pill is far higher than any amount that could be obtained from dietary phytoestrogens. Whether dietary phytoestrogens could have the same or similar effects remains to be seen. In vitro studies are being conducted on the effects of daidzein and genestein on bone growth, but there are no human studies available.

Adverse effects

Although the evidence is increasing that there may be some benefits to the addition of soy and soy products to the diet, there are many questions left unanswered. One of the most important is the potential adverse effects. The potential for inducing breast cancer growth in a low-estrogen environment needs to be investigated further. Use of phytoestrogens has also been found to affect concentrations of thyroxine, insulin, and glucagon.97,98 Therefore, they have the potential to act as endocrine disrupters. Evidence from animal studies suggests that ingestion of larger quantities of phytoestrogens can adversely affect fertility. Original studies done on phytoestrogens involved some studies where sheep, exposed to high levels of clover in their fodder, became infertile.99 Rats fed a diet high in coumestrol maintained a state of chronic anovulation.100 Six premenopausal women fed soy milk daily for 1 month had significantly decreased levels of estradiol, which persisted for 2 to 3 months after stopping the intervention.101 The menstrual cycle length also increased by about 4 days in the patients fed soy, although there was no statistical significance possibly owing to the small size of the study. Despite these concerns, there is no definitive evidence that the consumption of phytoestrogens at the levels normally encountered in the diet is likely to be harmful in adults.

Summary

Interest in the use of phytoestrogens as an alternative to traditional ERT has increased tremendously over the past 3 to 5 years owing to the popular perception that they could be a natural alternative to prescription medication. Most evidence on the benefits of phytoestrogens comes from in vitro and animal studies. Little research has been done in humans, and the current epidemiological evidence could be confounded by many factors. Without human data, little can be extrapolated to the potential effects in humans.

Although evidence of the beneficial effects of phytoestrogens is increasing, current evidence for the benefits of taking traditional ERT is far more convincing that that for phytoestrogen consumption. There is epidemiological and in vitro evidence, but no human clinical trials, linking phytoestrogen ingestion to the lower rates of certain cancers. However, the specific dietary elements that provide cancer protection have not been elucidated. In addition the temporal relationships of phytoestrogens and cancer protection have yet to be established, and these may be important. For example, it seems that developing breast tissue responds most to phytoestrogens. Animal studies suggest that the cholesterol level is lowered by increased phytoestrogen intake and there is also some evidence from human studies to suggest that phytoestrogens may reduce cholesterol levels in persons with preexisting hypercholesterolemia. Evidence is weak for the phytoestrogens' ability to reduce menopausal symptoms. Ipriflavone, a synthetic isoflavone, may be helpful for osteoporosis prevention.

What doses and what types of phytoestrogens are best? Current evidence is too preliminary to even suggest doses that may have the maximum benefit. Even if patients switch to soy products, several factors affect the bioavailability. Xu et al102,103 found that daidzein is more bioavailable than genestein. The efficacy can vary considerably based on the type of gut microflora present.104 The doses may vary considerably depending on whether the aim is cancer prevention or prevention of menopausal symptoms. Are there particular phytoestrogens that protect or treat certain diseases? Do these effects increase as dose increases? Could the unopposed estrogens from phytoestrogens actually produce cancers in persons who are susceptible? What are needed are prospective randomized controlled trials, particularly to observe the effect on vascular tissue, breast tissue, and endometrium.

It is a simplistic view that by adopting the diet of another country one can automatically assume the disease profile of that country. Multiple confounders make this premise unlikely. Phytoestrogens consumed alone may not be helpful, but may require combination with other dietary elements to exert their effects. Their beneficial effects could also be unique to Asian populations and not work so well in Western populations because of genetic differences. In addition, changing disease profiles does not mean an increase in longevity. Japan has a life expectancy greater than that of the United States, but Mediterranean countries, such as Italy, have a better life expectancy than Japan.

Safety of phytoestrogens is also a concern. Although these substances are consumed in large quantities in certain countries and, therefore, dietary phytoestrogen consumption appears to be "safe," we do not know their effects when taken long-term or in high doses such as those found in supplements. Phytoestrogens' estrogenic activity could potentially result in the problems seen with unopposed estrogens, including an elevated risk of endometrial and breast cancer. This risk could theoretically increase with ingestion of larger quantities.

Conclusions

Recommending replacement of ERT with soy-based or plant-based phytoestrogens is premature. Current evidence does not permit us to draw firm conclusions owing to small sample sizes, frequent lack of control and placebo groups, variability of study designs, and huge variations in the amount and types of phytoestrogens used. Evidence for the beneficial effects of phytoestrogens is increasing, but further studies are needed. There is insufficient evidence to recommend specific quantities or types of phytoestrogens for the prevention or the treatment of any diseases. The most prudent recommendation is to eat a diet high in fruit, vegetables, and fiber, and low in meat and saturated fat content. This is consistent with current recommendations and would increase overall dietary phytoestrogen intake. Further recommendations cannot be made.

Accepted for publication November 7, 2000.

Corresponding author: Marjorie A. Bowman MD, MPA, Department of Family Practice and Community Medicine, University of Pennsylvania, Second Floor, Gates Bldg, 3400 Spruce St, Philadelphia, PA 19104 (e-mail: bowmanm@uphs.upenn.edu).

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