Phytoestrogens are produced by many plants and best investigated are isoflavones that are widely present in soy (Glycine max) and red clover (Trifolium pratense) [1]. During the past 20 years, a remarkable number of research lines about the health effects of soy consumption have been conducted, which in large part can be attributed to the presence of isoflavones in the soybean [2].

Isoflavones first came to the attention of the scientific community in the 1940s based on the fertility problems observed in sheep grazing on an isoflavone-rich clover. In the 1950s, as a result of their estrogenic effects in rodents, isoflavones were studied as possible growth promoters for use by the animal feed industry, although shortly thereafter it was shown that isoflavones could also function as antiestrogens. Despite this early work, it was not until the 1990s, largely because of research sponsored by the U.S. National Cancer Institute that the role of soy foods in disease prevention began to receive widespread attention. Subsequently, isoflavones and soy foods were being studied for their ability to alleviate hot flashes and inhibit bone loss in postmenopausal women. In 1995, soy protein attracted worldwide attention for its ability to lower cholesterol. At the same time, isoflavones began to be widely discussed as potential alternative to conventional hormone therapy. In 2002, it was hypothesized that individuals possessing the intestinal bacteria capable of converting the soybean isoflavone daidzein into the isoflavan equol were more likely to benefit from soy intake. More recently, in vitro and animal research has raised questions about the safety of isoflavone exposure for certain subsets of the population, although the human data are largely inconsistent with these concerns [2].

Isoflavones, which have been known for over 100 years to exist in plants, have a relatively limited distribution in nature. In the commonly consumed human foods, they are present in physiologically relevant amounts only in soybeans and foods derived from this legume [3], although a variety of plants (e.g., red clover) [4] are also rich sources.

Asian populations have consumed foods made from soybeans for centuries, whereas in the West, certain subpopulations, namely Seventh-day Adventists and vegetarians, have used soy foods for ∼100 years although the quintessential soy food tofu was first introduced on a large scale to the general U.S. population beginning only in the early 1970s. Health-conscious and ecologically minded consumers were particularly attracted to soy at that time because it was perceived as being a source of high-quality protein low in saturated fat that was more efficiently produced than animal sources of protein [2].

The mechanism of action of the phytoestrogens are a partial estrogenic receptor agonists; anti-estrogenic effects in premenopausal women, but weak estrogenic effects in postmenopausal women. They also may stimulate osteoblastic activity, increase sex hormone-binding globulin levels, and antioxidant activity. The suggested dosing in symptoms of menopause is between 34 and 120 mg daily [5].

Soy isoflavones are diphenolic compounds that are frequently used for alternative treatment of symptoms of aging in both genders [6].

The impact of soy food intake on risk of breast cancer has been investigated extensively. Much of this focus can be attributed to the soybean being a dietary source that is uniquely rich in isoflavones. The chemical structure of isoflavones is similar to that of estrogen, and isoflavones bind to both estrogen receptors (ER-α and ER-β) (although they preferentially bind to and activate ER-β) and exert estrogen-like effects under some experimental conditions. Isoflavones also possess nonhormonal properties that are associated with the inhibition of cancer cell growth. Thus, there are several possible mechanisms by which soy can reduce the risk of breast cancer. However, the role of isoflavones in breast cancer has become controversial because, in contrast to the possible beneficial effects, some data from in vitro and animal studies suggest that isoflavones, in particular genistein, the aglycone of the main soybean isoflavone genistin, may stimulate the growth of estrogen-sensitive tumors. Limited human data directly address the tumor-promoting effects of isoflavones and soy. Because the use of soy foods and isoflavone supplements is increasing, it is important from a public health perspective to understand the impact of these products on breast cancer risk in women at high risk of the disease and on the survival of breast cancer patients [7]. While moderate isoflavone consumption seems to be safe in the majority of the population, women with breast cancer should avoid long-term use of soy products or isolated isoflavones [8]. Isoflavones protect against mammary cancer, but only when taken peripubertally when the mammary gland develops [1].

Soy isoflavones may prevent postmenopausal osteoporosis and improve bone strength thus decreasing risk of fracture in menopausal women by increasing lumbar spine in the bone mineral density (BMD) and decreasing bone resorption marker urine deoxypyridinoline. Further studies are needed to address factors affecting the magnitude of the beneficial effects of soy isoflavones and to assess the possible interactions between soy isoflavones and anti-osteoporosis drugs, and to verify effects on BMD of other skeletal sites and other bone turnover markers [9].

Isoflavones have been investigated in detail for their role in the prevention and therapy of prostate cancer. This is primarily because of the overwhelming data connecting high dietary isoflavone intake with reduced risk of developing prostate cancer. A number of investigations have evaluated the mechanism(s) of anticancer action of isoflavones (e.g., genistein, daidzein, biochanin A, equol) in various prostate cancer models, both in vitro and in vivo. Genistein quickly jumped to the forefront of isoflavone cancer research, but the initial enthusiasm was followed by reports on its contradictory prometastatic and tumor-promoting effects. Recent research indicates a novel role of genistein and other isoflavones in the potentiation of radiation therapy, epigenetic regulation of key tumor suppressors and oncogenes, and the modulation of mRNA, epithelial-to-mesenchymal transition, and cancer stem cells, which has renewed the interest of cancer researchers in this class of anticancer compounds [10].

The most promising news for soy may be its positive effect on lipid profiles. Soy protein has also been the subject of considerable investigation, especially in regard to its hypocholesterolemic effects [9]; recent scientific interest in soy largely parallels the interest in isoflavones. Of the ∼2,000 soy-related papers currently published annually, more than one half are related to isoflavones [2].

A meta-analysis of 38 controlled human studies of soy consumption provides compelling evidence for its positive effect on improved lipid profiles including reduction in low-density lipid and triglycerides and an increase in high-density lipid levels [11, 12].

The U.S. Food and Drug Administration has approved a health claim for isoflavone-rich soy protein to reduce cholesterol with 25 g of soy protein consumption daily [13]. However, it is important to note that it appears to require that soy isoflavones are consumed intact in soy protein [14].

There are other aspects to investigate regarding soy isoflavones which have been less studied. These are the psychotropic effects in anxiety, depression, and cognitive symptoms in the menopausal women. The following is a brief overview based on evidence of the past decade about the use of soy isoflavones in the treatment of these menopausal psychological symptoms.

Transitioning into menopause is a natural part of life. All women, if they live long enough, will experience menopause. A variety of symptoms are reported frequently associated with menopause. These include hot flashes, night sweats, menstrual irregularities, vaginal dryness, depression, nervous tension, palpitations, headaches, insomnia, lack of energy, difficulty concentrating, and dizzy spells. How a woman experiences or reports symptomatology is greatly influenced by a multitude of variables including race, ethnicity, and other psychosocial factors. Her ability to manage symptoms associated with this life transition affects her quality of life and imposes physical, psychological, and economic burdens [15, 16].

The menopausal transition can be categorized into several stages. In the Study of Women’s Health Across the Nation (SWAN) and the Four Major Ethnic Groups (FMEG) study, the menopausal status was categorized into pre-, early peri-, late peri-, and postmenopausal [17, 16]. Both studies examined the prevalence of various symptoms by menopausal status in a multiethnic sample of women transitioning to menopause states. The study comprised two stages. The first was a cross-sectional telephone or in-home survey conducted between November 1995 and October 1997. The second was a longitudinal investigation to track changes in women’s physical and mental health as they age and traverse the menopausal transition. FMEG used an Internet survey and qualitative online forums [16].

Literature reviews consistently report a relationship between culture and menopause. The sociocultural organization of one’s life course in specific geographical locations profoundly affects the menopausal experience for women. Many factors are hypothesized to influence the menopause experience (e.g., diet, smoking, exercise, attitude, expectation, marital status, socioeconomic status, etc.) [4, 17].

Avis et al., [18] from SWAN reported that two consistent clusters of clearly symptoms of menopause emerged from the data. The first was vasomotor symptoms such as hot flashes and night sweats, and the second consisted of psychological and psychosomatic symptoms. There were racial/ethnic differences in symptom reporting as well as differences of menopausal status. Controlling for the following variables (e.g., age, education, health, and economic strain), Caucasian women reported significantly more psychosomatic symptoms than other racial/ethnic groups. African American women reported significantly more vasomotor symptoms. Tension feelings, depression, irritability, headaches, and stiffness were all frequently reported symptoms. In some studies, fatigue, muscle/joint pain, back/neck aches, and headaches exceeded reports of hot flashes [12, 18]. In general, Japanese and Chinese women were less likely than the other groups to report any symptoms.

Im et al., from the FMEG study, also reported statistically significant ethnic differences in the total number of symptoms experienced during the menopausal transition [19].

Hispanics reported significantly larger numbers of total symptoms, physical symptoms, and psychosomatic symptoms than Asians. Caucasians reported significantly larger numbers of total symptoms, physical symptoms, psychological symptoms, and psychosomatic symptoms than Asians. African Americans reported a significantly larger number of psychosomatic symptoms than Asians. There were statistically significant ethnic differences in the frequencies of 41 individual symptoms [20].

Both studies reported racial and ethnic differences in symptoms experienced in menopause transition in different groups of women. The racial and ethnic differences are consistent and serve as evidence against a universal menopausal syndrome [18]. It must be pointed out that both studies had limitations related to the selection of participants [20]. Thus, the generalizability of the study findings is limited. Nonetheless, these studies support racial and ethnic differences in how women experience menopause [20].

All women reach menopause and approximately two thirds of women develop symptoms of menopause, primarily hot flashes. Hormone therapy was long considered the first line of treatment for vasomotor symptoms. However, given the results of the Women’s Health Initiative (WHI), many women are reluctant to use exogenous hormones for symptomatic treatment and are turning to botanicals and dietary supplement (BDS) products for relief. Despite the fact that there is limited scientific evidence describing efficacy and long-term safety of such products, many women find these “natural treatments” appealing. Peri- and postmenopausal women are among the highest users of these products, but 70 % of women do not tell their healthcare providers about their use. Compounding this issue is the fact that few clinicians ask their patients about use of BDS, largely because they have not been exposed to alternative medical practices in their training and are unfamiliar with these products [21].

In a National Health and Nutrition Examination Survey, researchers confirmed ethnic differences in the use of hormone replacement therapy (HRT); white women were more likely to use HRT than non-Hispanic, African American, or Mexican American women [22].

This finding is consistent with trends noted by other investigators. In 2001, Avis et al., from SWAN reported that hormone use was highest among Caucasian women and lowest among African American and Hispanic women [18]. Multiple investigators cited similar findings indicating white women were more likely to use HRT than non-Hispanic, African American, or Mexican American women. Additionally, white women were prescribed or offered HRT more often [15, 23]. This trend is interesting given the SWAN data, which reported white women having fewer vasomotor complaints when compared with African American and Hispanic women. In addition, post WHI, there was a significant decline in hormone prescribing across all ethnic groups [24].

Over the years, the number of prescriptions for hormone therapy has reflected scientific findings. In the 1970s, the number of prescriptions increased to approximately 30 million per year. This practice was likely because of data describing the cardioprotective effects of hormone therapy [25].

In the 1980s, reports of increased rates of endometrial cancer with unopposed estrogen led to a decrease in annual prescriptions to about 15 million. Then, the addition of progesterone for endometrial protection renewed interest in hormone therapy, and prescriptions again increased [25].

Between 1995 and 2002, annual prescriptions peaked at about 91 million. Termination of the estrogen-progestin arm of the WHI in July 2002 and release of the Heart and Estrogen/Progestin Replacement Study data received considerable media attention and raised serious questions about the safety of hormone therapy in postmenopausal women. Many women stopped taking hormones and began to seek out alternative therapies. Prescriptions for hormone treatment immediately decreased [25].

The use of complementary and alternative medicine (CAM) is very common. In 1999, the National Health Interview Survey data estimated approximately 40 % of women in the United States used some form of CAM in the past 12 months. More than $600 million was spent on CAM for treatment of menopause [11].

Women commonly use soy products, herbs, and other CAM therapies for symptoms of menopause. Randomized, controlled trials have evaluated the efficacy and short-term safety of these therapies [9].

In this study, some sources were consulted. The MEDLINE searches were directed to articles published from January 1966 through March 2002. The Alternative and Complementary Database (AMED) of the British Library was used to search for articles published from January 1985 through December 2000. The authors’ own extensive files were also used. The chosen research terms were hot flash/flush, menopause, and climacteric, combined with phytoestrogens, alternative medicine, herbal medicine, traditional medicine, Traditional Chinese Medicine, Ayurveda, naturopathy, chiropractic, osteopathy, massage, yoga, relaxation therapy, homeopathy, aromatherapy, and therapeutic touch [9].

A number of 29 randomized, controlled clinical trials of CAM therapies for hot flashes and other symptoms of menopause were selected. A group of 12 trials dealt with soy or soy extracts, 10 with herbs, and 7 with other CAM therapies. In the data synthesis, soy seemed to have modest benefit for hot flashes, but studies were not conclusive. Isoflavone preparations seemed to be less effective than soy foods. Black cohosh may be effective for symptoms of menopause, especially hot flashes, but the lack of adequate long-term safety data (mainly on estrogenic stimulation of the breast or endometrium) precludes recommending long-term use. Single clinical trials have found that dong quai, evening primrose oil, a Chinese herb mixture, vitamin E, and acupuncture do not affect hot flashes; two trials have shown that red clover has no benefit for treating hot flashes. It was concluded that black cohosh and foods that contain phytoestrogens show promissory properties for the treatment of symptoms of menopause. Clinical trials do not support the use of other herbs or CAM therapies. Long-term safety data on individual isoflavones or isoflavone concentrates are not available [9].

The use of botanical and dietary supplements (BDS) among menopausal women has increased in recent years in the US, with the largest increase in the use of so-called “natural hormonal agents” [26, 27]. Most women report use of these treatments because they find these alternatives to traditional medicine more congruent with their values, beliefs, and lifestyles [28, 29].

A recent survey of 500 peri- and postmenopausal women conducted at the University of Illinois Medical Center found that 70 % of women between the ages of 40 and 60 years reported using BDS to treat symptoms or diseases; however, fewer than 10 % of users could actually verbalize the health benefits of these supplements [4].

Asian diets are high in soy-based foods (40–80 mg per day of isoflavones in Asian diets as compared with <3 mg per day in American diets), and many women in these countries express few menopausal complaints [30]. It is unknown if the lower prevalence of hot flashes and other symptoms of menopause are due to dietary make-up, cultural factors, or a combination of both [21].

Historically, investigators have noted differences in use of CAM. Hirata et al. reported Asian women, especially Chinese women, were more likely to use acupuncture and dong quai, a Chinese herb traditionally prescribed as a tonic for women [25]. Korean women commonly use red ginger, which reportedly improves fatigue and depression [31, 32]. Asian women were more likely to use soy products [31]. Of note, however, is that a major predictor of subsequent CAM use in menopausal transition is the use of CAM before menopausal transition [24].

Chemically, isoflavones belong to the group of polyphenols. The most important food source is soy, which contains mainly genistein and daidzein in the form of glycosides. The absorption rate ranges from 20 to 55 %. Isoflavones are selectively incorporated in certain tissues such as the breasts and ovaries. They are able to bind to the alpha (ER-α) and beta (ER-β) estrogen receptors. However, the binding affinity for genistein to ER-α is only 4 %, and the affinity to ER-β is 87 % compared with 17 β-estradiol. Thus, depending on the estradiol concentration, they exhibit weak estrogenic or antiestrogenic activity. Isoflavones can influence transcription and cell proliferation. They modulate enzyme activities as well as signal transduction, and have antioxidant properties. Epidemiological studies have shown that the prevalence of hot flashes is lower in women from countries with high dietary isoflavone intake such as Japan than in Western nations with low isoflavone intake. Results of clinical studies on the effects of soy products or isolated isoflavones on vasomotor symptoms are contradictory. Due to a strong placebo effect and a time-dependent reduction of hot flashes, phytoestrogens were seen to have no significant effect in most studies. However, the use of soy isoflavones could be considered for women with intense disorders [8].