Phytoestrogens in Breast, Endometrial, and Ovarian Cancers
For cancer patients and clinicians, the use of phytoestrogens is perhaps one of the most controversial and fiercely debated topics related to dietary supplements. Phytoestrogens are diphenol compounds that comprise one of the largest groups of "natural" hormonal supplements consumed today. These agents are categorized according to their chemical structures, with isoflavones, lignans, coumestans, and resorcyclic acid lactones comprising the four major classes. Isoflavones are the most abundant compounds in commonly consumed foods, with 230 types identified. Three common isoflavone aglycones”genistein, daidzein, and glycitein”are present in most dietary sources. Coumestrol, another isoflavone, is present in soybeans but in much lower concentrations than genistein, daidzein, and glycitein. Isoflavones also exist as glucosides, acetyl glucosides, and malonyl glucosides. These differing forms of isoflavones determine absorption, with aglycone forms more readily absorbed than the corresponding glucoside conjugates. Glucoside derivatives of isoflavones undergo hydrolization in the large intestine to their corresponding aglycone, which is readily absorbed. These aglycones are then metabolized by the liver to glucorinic acid or sulfate conjugates and enterohepatically circulated through the gut, with potential for further metabolism and reabsorption. The glucuronide fraction of these isoflavone aglycones represents up to 90% of circulating isoflavones in both rats and humans and is considered biologically inactive. Free and sulfated forms, while in lower concentrations, are considered biologically active. Variances in the pharmacokinetics of isoflavones are apparent and based on age, sex, and ethnicity. Details surrounding these differences are beyond the scope of this article but are important indicators of the complex nature of phytoestrogens and represent how individual differences in liver and gut metabolism may play vital roles in determining the activity of these compounds and the potential risks or benefits.
The most significant dietary sources of phytoestrogens include soybeans, clover, alfalfa sprouts, and oilseeds (e.g., flaxseed). Components of these plants vary with geographic location, soil type, year, and environmental conditions of growth. Processing also influences the amount and form of isoflavones in soy products. Processing soybeans for soy-containing food products increases hydrolization to the aglycone forms. Fermenting soybeans to produce products such as tempeh and natto partially hydrolyzes isoflavone glucosides to the aglycone form. The U.S. Department of Agriculture and Iowa State University developed an isoflavone database in 1999 to use as a reference for determining the isoflavone values for many foods. This database expresses all values as aglycones and provides an accurate and comparable estimate of isoflavone content for many different foods. It is important to recognize that eliminating all phytoestrogens from the diet is impossible, but limiting soy-containing foods and supplements is feasible. The effects of supplementation with synthetic sources of phytoestrogens are just beginning to be studied. All of these factors may account for varying results in observational and clinical trials and should be considered when evaluating studies of phytoestrogenic supplements.
The estrogenic activity of phytoestrogens was first observed in Australian ewes. It was found that some animals suffered reproductive disorders, resulting in permanent infertility after eating red clover. Genistein and daidzein, constituents of red clover, were later identified as the agents most likely to have caused this effect in the animals.[117,119] Estrogenic activity has been demonstrated by many soy-containing foods, as well as the individual components discussed above. In vitro and in vivo studies have demonstrated hormonal activity through ER-binding assays. The binding affinity of phytoestrogens to the estrogen receptor has been compared with 17ร-estradiol, illustrating their weaker estrogenic potential (potential in descending order: 17ร-estradiol, coumestrol, genistein, equol, daidzein, and biochanin A). These experiments did not distinguish between agonistic and antagonistic activity after receptor binding or binding differences between the α and ร isoforms of ER. Therefore, corresponding clinical outcomes related to these biochemical activities are uncertain.
Many other mechanisms of biological activity have been demonstrated with various phytoestrogens. Genestein, for example, has demonstrated both proliferative and anti-proliferative effects, depending on the concentrations studied. At low concentrations, genestein stimulates the growth of breast cancer cells; at high concentrations, growth inhibition is seen. Antiestrogenic effects have also been observed with increased concentrations of other phytoestrogens. Mechanisms other than ER binding may also elicit hormonal effects. Daidzein has been shown to inhibit aromatase and 5-α-reductase, while other phytoestrogens have been proposed to decrease estrogen levels via stimulation of sex hormone binding globulin.[117,123] Other hypothesized mechanisms of biological activity include inactivation of tyrosine kinase, inhibition of epidermal growth factor, and inhibition of type II topoisomerase. Corresponding biological outcomes related to these activities have yet to be determined. However, these effects would seem to be beneficial for breast, endometrial, ovarian and prostate cancers, potentially inhibiting cancer cell growth through similar mechanisms as prescription drugs administered as cancer therapy. Evidence supporting or refuting these biological effects in cancer patients has yet to be reported.
In humans, phytoestrogens have been shown to alter endocrine function in premenopausal, perimenopausal, and postmenopausal women. Studies investigating the effects of different forms of isoflavone supplementation have found conflicting results regarding changes in menstrual cycle, hormone levels, and other measures of endocrine function (e.g., changes in vaginal epithelium). Many studies investigating the endocrine effects of phytoestrogens in healthy women have been of short duration and are not designed to determine the presence (or absence) of clinical benefit based on their findings. This information could be extrapolated to individual patient scenarios, but caution should be used when making these assumptions, as these are complex interactions.
Breast cancer. The effects of phytoestrogens on breast tissue are not well understood. Early epidemiologic studies appeared to indicate an inverse association between soy consumption and breast cancer incidence;[124-129] however, other studies have failed to confirm these results.[130-133] This result may be due to study design, a true lack of effect, or variability in other factors related to phytoestrogen metabolism or processing. Studies investigating the timing of phytoestrogen exposure appear to indicate that consumption early in life, especially during breast development, may indeed be protective against breast cancer. This may be due to enhanced mammary gland development, leading to fewer terminal end buds, which are the most vulnerable to carcinogenesis. These inferences are based on animal studies and have yet to be substantiated in humans. However, a small retrospective study conducted in China to evaluate soy food intake during childhood and adolescence found an inverse association with adult breast cancer risk. These results appeared to be significant, regardless of menopausal status. It is, therefore, postulated that early exposure to a diet high in phytoestrogens may be beneficial, but supplementation or increases in dietary phytoestrogens later in life may offer no established benefit on breast tissue.
Effects of phytoestrogens on breast tumors have been studied in cell lines and animal models. Conflicting reports exist, demonstrating both protective and procarcinogenic effects with phytoestrogens.[134-138] A study investigating the effects of dietary genistein in combination with tamoxifen in an athymic nude mouse model demonstrated a decrease in tumor growth inhibition with tamoxifen when given in combination with the phytoestrogen. At least two human studies have demonstrated a stimulatory effect on breast tissue with soy supplementation.[140,141] All of these data raise concerns about phytoestrogen supplementation in women with a history of breast cancer, regardless of whether they are currently receiving active hormonal therapy.
Endometrial and ovarian cancers. The effects of phytoestrogens on the endometrium are even less well understood. Unopposed estrogen replacement therapy has long been known to increase the risk of endometrial hyperplasia and cancer. This effect is not evident when either continual or cyclic progesterone therapy is added to the replacement regimen. Epidemiologic evidence seems to support the notion that increased consumption of phytoestrogens decreases the risk of endometrial cancer.[142,143] However, in vitro data have shown that high concentrations of phytoestrogens induce stromal cell proliferation to nearly the same degree as estradiol. In the presence of estradiol, phytoestrogens antagonize the proliferative effects of estradiol by 10“20%. This demonstrates the SERM-like qualities of phytoestrogens on the endometrium. A recent randomized, double-blind, placebo-controlled clinical trial investigating the use of a soy tablet (150 mg of isoflavone daily) in 376 postmenopausal women found 6 patients (4%) with endometrial hyperplasia, compared with none of the patients receiving placebo. The phytoestrogen supplement was administered for five years, and the cases of hyperplasia were diagnosed at five years through a scheduled endometrial biopsy that was part of the study. Another study investigating the rates of endometrial hyperplasia with conventional HRT also reported rates as high as 3% in the placebo group of the trial. Therefore, the overall risk of endometrial cancer with phytoestrogen supplementation seems rather low, but one case of endometrial cancer has been reported in a woman who was ingesting many herbs and vitamins with known phytoestrogenic components. This information would lead to the conclusion that phytoestrogens should be avoided in patients with endometrial cancer. No data regarding the effects of phytoestrogens on ovaries or ovarian cancer could be found, making it difficult to ascertain the risks associated with phytoestrogen supplementation in ovarian cancer.
Other potential uses. In terms of efficacy, there is an abundance of information related to the efficacy of phytoestrogens for a number of physiological or pathophysiological states. Physiological changes in women related to phytoestrogen consumption have been reported relative to their use as "natural" HRT (in postmenopausal women) or as a cancer prevention strategy (for all women), primarily focusing on breast cancer prevention.
The effects on menopausal symptoms, primarily vasomotor symptoms (hot flashes), have been a major focus of research in this arena as well. It is prudent to recognize the importance of a placebo effect (nearly 20“30% reduction in vasomotor symptoms) in these studies. Soy supplementation through foods, soy protein isolate,[148,149] or soy extracts[150-152] appears to add an additional 10“20% improvement above that seen with placebo. However, conflicting evidence from other studies demonstrate no benefit over placebo with a soy protein isolate,[153,154] a soy beverage supplement, or a soy extract. Also, two studies of red clover extracts have been published and failed to find a benefit over placebo for the management of hot flashes.[157,158] The soy products used in these studies had differing amounts of isoflavone content, which may have led to discrepancies in the outcomes. Again, these varying results could be due to individual differences in metabolism or the source of phytoestrogens used. As little as 30 mg daily of soy isoflavones (intact with soy protein or as a semipurified extract) may reduce the frequency of hot flashes. However, the placebo effect should be taken into account, and each individual woman must evaluate the relatively small additional benefit of soy phytoestrogen used to treat hot flashes. Of greater concern, no safety information exists regarding this type of supplementation in women with a history of breast, endometrial, or ovarian cancer. One of the above-mentioned studies included breast cancer patients, but neither cancer status nor disease recurrence rates were mentioned. Most of these studies addressing hot flashes were of short duration, and the overall effect of continued supplementation on cancer recurrence is unknown.
Other proposed benefits of HRT include positive effects on cardiovascular disease and osteoporosis. While even large, prospective, randomized, placebo-controlled trials investigating prescription HRT have failed to substantiate epidemiologic and case“control data relating to these positive effects, investigations have commenced with "natural" HRT. In 1999, the Food and Drug Administration (FDA) approved the health claim "Diets low in saturated fat and cholesterol that include 25 g of soy protein/day may reduce the risk of heart disease." This approval was based on data from numerous studies indicating that an average of 47 g daily of soy protein lowers total and low-density-lipoprotein cholesterol and produces a trend toward increased high-density-lipoprotein cholesterol. Since this approval, studies have questioned whether isoflavones are responsible for the lipid-lowering effects of soy. Isoflavones have been shown to participate in this effect but must be consumed with other components of soy protein to see a benefit.[152,162-171] Isoflavone extracts may have other effects on the cardiovascular system that may be beneficial (e.g., improved arterial compliance), but these are just beginning to be investigated.[171,172]
The effects of phytoestrogens on bone health are not as strongly supported by human evidence. Animal studies investigating effects on bone mineral density and bone turnover have been conducted, but little human evidence is available to substantiate these claims.[173-175] Reports from clinical trials appear mixed, demonstrating mild benefit or no effect. Studies suggest a short-term benefit with soy protein supplementation, but clinical outcomes (e.g., fracture rates) related to these benefits have not been demonstrated. Further studies are required to establish whether these effects are sustained over a prolonged period and whether they translate into decreased fracture rates and an overall improvement in postmenopausal health. Also, the question of whether bone loss can be prevented with soy supplementation has not been answered. Again, women included in these studies did not have a history of breast, endometrial, or ovarian cancer; hence, the effects on cancer recurrence with soy protein supplementation are not known. Therefore, risk benefit analyses have not adequately been accomplished and safety concerns still exist.
Based on this information, recommendations for individual patients are very complex. For patients faced with a myriad of menopause- or cancer-treatment-related symptoms, the question of whether to use a "natural" hormonal preparation is fraught with anxiety and confusion. Communication surrounding this issue should be sensitive to these anxieties and attempt to fully explain the controversial nature of the evidence available to date. Discussion of the conflicting evidence presented previously and the fact that there are still many unanswered questions is paramount to ensure that patients make informed decisions. Generally, recommendations include an emphasis on moderation and stress the lack of information with synthetic or concentrated forms of phytoestrogens. As stated previously, lower concentrations of phytoestrogens appear to be estrogenic and stimulate cancer cell growth in vitro. However, it is important to reiterate that it is impossible to eliminate phytoestrogens from the diet. For food sources with high phytoestrogenic concentrations or high isoflavone content (e.g., soy milk, tofu), no more than one serving of these products per day is recommended. This recommendation is based on other published recommendations that will be discussed later.
Phytoestrogens in Prostate Cancer
The normal growth and differentiation of the prostate require the presence of androgens, specifically testosterone. The most physiologically active form of testosterone is dihydrotestosterone (DHT). Conversion of testosterone to the more active moiety occurs through a reaction catalyzed by the enzyme 5-α-reductase. Testosterone production is regulated through the release of LHRH, which interacts with the pituitary gland to release FSH and LH, ultimately regulating the level of testosterone through a negative feedback mechanism. LHRH agonists have been developed to target this pathway, activating the negative feedback mechanism and decreasing serum testosterone levels. Similar outcomes can be achieved through surgery (orchiectomy) or with other types of drugs, such as ketoconazole ( Table 7 ). Directly targeting prostate cancer cells may also be accomplished with antiandrogens (e.g., flutamide, bicalutamide) that bind to the androgen receptor and prevent DHT from acting and stimulating growth. Another mechanism to target prostate cancer is to block the conversion to the active form of testosterone (DHT) through 5-α-reductase inhibition. This mechanism has not proven effective as prostate cancer treatment but may play a role in prostate cancer prevention.
Men in the general population commonly take supplements for symptoms of prostatitis, treatment of benign prostatic hypertrophy, or symptoms of sexual dysfunction. Others use these products for the treatment and prevention of prostate cancer. Some dietary supplements may effectively treat these problems but may also pose a risk for prostate cancer patients, rendering their cancer treatment ineffective or stimulating cancer cell growth.
Phytoestrogen supplementation is also extremely controversial for the treatment of prostate cancer yet may prove to be more beneficial than for patients with breast, endometrial, or ovarian cancer. Epidemiologic and laboratory evidence seems to support the idea that phytoestrogens are protective against prostate cancer. Asian men have been shown to have a decreased incidence of prostate cancer, which is believed to be a result of a diet high in phytoestrogens. The full mechanism of protection has not been clearly elucidated, but most studies suggest a relationship to the inhibition of 5-α-reductase in genital skin fibroblasts and prostate tissue. ER-ร receptors have been identified in the prostate, but expression of this protein is lost in malignant prostate cells and prostate cancer tissues. Some phytoestrogens may alter expression of ER-receptor proteins over a mans life span, but the clinical outcomes of these biological events are unknown. A study using a mouse xenograft model for prostate cancer incorporated increasing concentrations of soy protein into the animals diet to determine the effects on prostate tumor growth. Diets with the highest concentrations of phytoestrogens were associated with tumor growth inhibition, while diets containing lower levels of phytoestrogens were associated with reduced tumor growth compared with diets without supplementation. Tumor growth inhibition in this study was associated with apoptotic mechanisms and decreased angiogenesis. Whether the mechanisms are active and these concentrations of phytoestrogens achievable in humans has yet to be determined. Urban and colleagues failed to find any effect on prostate specific antigen (PSA) in men with baseline elevations in PSA who were undergoing supplementation with a soy protein beverage. This was a small study and does not eliminate the potential for beneficial effects on the prostate by similar phytoestrogenic compounds. Until more evidence is available, phytoestrogenic supplements should be used with caution in men with a history of prostate cancer and their use should be accurately recorded for any patient, particularly patients who are participating in clinical trials. Dietary sources of phytoestrogens may also pose some risk, but eliminating all dietary sources of phytoestrogens is impossible. Therefore, moderation would still be a prudent course of action based on other published recommendations.
Summary and Recommendations
There are no easy answers regarding the use of dietary supplements with hormonal properties in people with a history of cancer. Hopefully, the concerns outlined above are adequate for clinicians to establish a template with which to evaluate these types of compounds. Due to the lack of conclusive evidence regarding both safety and efficacy, patients should be counseled on the theoretical risks and potential benefits and need to recognize that our understanding of this subject is lacking. Overall, it is important to review each patient’s disease and the goals of cancer therapy and supplement therapy while addressing these concerns. Moderation would appear to be a prudent course of action related to phytoestrogens, limiting the amount of soy and avoiding the use of synthetic or concentrated forms of phytoestrogens. Some countries have established maximum daily allowances for phytoestrogens based on the available scientific evidence. Much of the widespread concern surrounds thyroid alterations found in adolescents who received soy-based infant formulas and decreases in the number of proliferating cells in the intestine of piglets fed soy-based formulas compared with cow’s-milk formulas. The French have issued a public statement recommending a maximum daily intake of 1 mg/kg of phytoestrogens. According to Sirtori and colleagues, the Italian Health Authority released a public statement recommending a daily intake of phytoestrogens as dietary supplements below 80 mg, which represents approximately 1 mg of phytoestrogens per kilogram of body weight. Utilizing the isoflavone database mentioned previously, foods and supplements can be categorized based on their isoflavone components, and patients can be counseled on the appropriate amounts of foods and supplements to intake to stay within these limits. Working closely with a dietitian who specializes in this type of education and counseling is very helpful. As a more generalized recommendation for cancer patients, clinicians may recommend no more than one serving of soy per day with a well-balanced diet that includes fruits, vegetables, and grains. After reviewing all of the important information, patients must decide whether to take such supplements.
Supplements with Known Safety Issues
Over the years, many supplements have been associated with severe adverse events, leading to deaths or serious life-threatening complications. These supplements are occasionally removed from the market by FDA but may be available in other countries. In retrospective analyses, it is nearly impossible to prove that an agent caused an adverse event. However, FDA is responsible for investigating and determining causality or risks in these situations. Many commonly used supplements are associated with serious adverse reactions (e.g., kava kava [Piper methysticum] and ma huang [Ephedra]).[183-185] As pharmacists, we are very aware that any drug can cause an untoward reaction and lead to serious complications. Supplements should be viewed similarly. While the window of safety may be quite wide for many dietary supplements, many of these compounds have true pharmacologic activities that may cause harm or provide valuable benefits. Only through diligent reporting efforts will these harmful and beneficial effects be realized.
Supplements with Known or Theoretical Drug Interactions
Many reviews have been published about drug“nutrient and drug supplement interactions.[186-189] It has become apparent that effects on absorption, metabolism, and excretion are not restricted to prescription drugs. Research has revealed substantial interactions between many prescription medications and the consumption of grape-fruit juice. The effects of St. John’s wort on CYP isoenzymes have also been well-defined through diligent observations and detailed research. These interactions are typically reported involving a prescription medication, but supplement supplement interactions are also possible and much more difficult to identify. Caution should be taken whenever more than one medication or supplement is added or dietary intake significantly altered. Information regarding these types of effects may be found in many databases and the primary literature.
The ability to identify and locate reliable information regarding dietary supplements is vital. There are numerous resources that clinicians can consult when caring for patients who wish to use dietary supplements. There are a few systematic reviews and evaluations of dietary supplement references that are useful to consult when making a decision regarding the purchase and use of such resources.[192-195] However, these references are continuously updated, especially the electronic resources, and the conclusions may subsequently change.
For clinical practice, the Natural Medicines Comprehensive Database (Therapeutic Research Faculty), Natural Standard (Natural Standard, Inc.) (not allowed class="postlink" href="http://www.naturalstandard.com">http://www.naturalstandard.com), and Review of Natural Products (component of Facts and Comparisons 4.0, not allowed class="postlink" href="http://online.factsandcomparisons.com/">http://online.factsandcomparisons.com/) are useful databases. The Natural Medicines Comprehensive Database is also available as a print reference, which is useful in some clinical settings. All databases require a subscription, and practicality will vary for different practice sites. There are advantages and disadvantages associated with each database, so access to more than one database or another reference is essential. The scope of products included in the Natural Medicines Comprehensive Database is extensive and a very valuable asset of the database. Another very helpful feature is the ability to search by proprietary name to identify product ingredients, often eliminating the need to track down the product through an Internet search engine. It provides very useful information for each supplement, including its scientific name, safety profile, adverse reactions, interactions with drugs and diseases (known and theoretical), mechanism of action, and dosage and ranks the efficacy for proposed indications. The Natural Standard offers similar sections within each monograph, but there are fewer products in the database. The strength of the Natural Standard database is the extensive evidence-based review for proposed indications. The Review of Natural Products database provides similar sections within each monograph; however, the clinical information may not always be as detailed. The AltMedDex System of Micromedex (Thomson Healthcare Inc.) is also useful.
These references are useful as first-line resources but are not the only good references available. It is important to understand that none of them offers "one-stop shopping," and the use of more than one reference is necessary to complete the analysis of dietary supplements for a patient. Searches of secondary databases, other tertiary references, and an Internet search engine are also necessary. The other caveat is that not all information will be explicitly stated in the reference (or even known), necessitating making professional judgment and extrapolation based on pharmacologic actions and available evidence.
Most patients who take dietary supplements or CAM do so in conjunction with conventional cancer therapies. This complementary use poses some potential risks. Once a supplement is deemed safe for a patient, efficacy must be addressed. The oncology community is focused on evidence to support efficacy with traditional therapies and supplements. Burstein stated that "the role of CAM extends far beyond the purported medicinal value of any CAM, and in fact, may have little to do with whether or not CAM works as a traditional medicine." In other words, many cancer patients have multiple legitimate needs that are not being met by conventional medical practices, including emotional and existential discomforts. The use of CAM may not be about treating their cancer but rather "feeling better and having greater control over ones destiny." When looking at our algorithm (Figure 1) for reviewing supplements, this fact is reflected in the recommendation to "accept" practices or supplements that are safe despite the lack of or inconsistent evidence to support efficacy. This reasoning suggests that talking about CAM is of the utmost importance. Ask every patient at every point in his or her care about the use of CAM. Ask why they are using these therapies. When listening to their responses, sensitivity for social, cultural, and ethnic differences is required. While the rate of CAM use was similar among whites, African Americans, Latinos, and Chinese patients in one study, the types of therapies chosen differed substantially. The need to consistently assess patients differently for physical discomfort or emotional distress should be addressed with development of better clinical tools. This is an opportunity to have an open and honest dialogue with patients and empower them to be involved in their conventional medical treatment decisions as well as their complementary ones.
According to Burstein, "the interest in CAM is an understandable expression of the hopes, concerns and symptoms experienced by our patients." In our approach to this conundrum, we have tried to take the emotional and overwhelming process of reviewing individual products and make it more manageable and objective without negating the beliefs and hopes of our patients. By focusing first on safety, we leave the question of efficacy to the patient. Only in light of convincing evidence of lack of efficacy would a suggestion to discourage use be made if a product were safe. The reasons for a patients use of a dietary supplement and the clinical setting should also be taken into account when addressing risks and benefits. Individual patient goals and prognosis should always be addressed in the context of the available evidence, as the perception of risk versus benefit may differ greatly from one patient to another and from one clinical setting to another (e.g., curative versus palliative setting). This approach allows for open discussion of the available evidence, utilizing objective information and theoretical conjecture when available. If the information is presented to the patient as it stands, with gaps and inconsistencies, patients remain empowered to make informed health care decisions and do not feel ignored or dismissed.
The difficulties surrounding this issue are apparent in both the complex nature of the information and the enormous emotional investment patients have in seeking to help themselves through the use of dietary supplements. Harpham, physician and cancer survivor, wrote, "When faced with a life-threatening disease requiring highly toxic treatments with no guarantees, or when dying because there are no effective conventional treatments, it takes guts to reject something or someone claiming to be able to save you, just in case you might be wrong." As pharmacists, we need to remember this statement when counseling patients on dietary supplements and respect their views and beliefs. This open communication with patients makes them more likely to divulge all of the CAM therapies they are using. At the same time, Harpham wrote that "not all hope is equal. Realistic hope”hope based on fact”is stronger than that born of wishful thinking." It is our job to give each patient the facts as we know them, recognizing that this requires more time and effort on our part. However, this time is well spent and will encourage patients to continue to ask for information about CAM before using it, further reducing the chances for a serious interaction with a drug or disease. We believe that this approach allows patients to make informed, objective decisions while maintaining their realistic hope for the future.
Counseling patients with cancer about dietary supplements requires a systematic thought process that considers the available theories and data, as well as the patients views about the agents.
Table 4. Immunomodulatory Effects of Commonly Used Dietary Supplements[31,90-92]
Dietary SupplementReported Immunomodulatory Effect(s)a
Echinacea (Echinacea purpurea)Increases phagocytosis, lymphocyte activity, TNF-α, IL-1, and IFN-ร-2b
North American ginseng (Panax quinquefolius)Monocyte activation, TNF-αinductionb
Asian or Korean ginseng (Panax ginseng)Increases NK cell activity,b,c decreases TNF-α,c increases lymphocyte proliferationb and total leukocytesd
Milk thistle (Silybum marianum)Increases lymphocyte proliferation,b inhibits TNF-αb
Garlic (Allium sativum)Increases T-cell proliferation,b IL-2,c TNF-α,c and IFN-γc
Ginger (Zingiber officinale)Decreases lymphocyte proliferation and IL-2b
Melatonin (N-acetyl-5-methoxytryptamine)Increases IL-2 and IL-2-induced lymphocytosis, monocyte activationd
Dong quai (Angelica sinensis)Increases lymphocyte proliferationb
Coriolus mushroom Coriolus versicolorIncreases IgG, IgM, leukocytes, and neutr d
a TNF = tumor necrosis factor; IL = interleukin; IFN = interferon; NK = natural killer; Ig = immunoglobulin.
Table 5. Selected Supplements with Hormonal Properties
Alfalfa (Medicago sativa)Estrogenic
Black cohosh (Cimicifuga racemosa)Estrogenic (controversial)
Chasteberry (Vitex agnus-castus)Estrogenic, progestogenic
Dehydroepiandrosterone (DHEA)Estrogenic, androgenic
Dong quai (Angelica sinensis)Estrogenic
Flaxseed (not flaxseed oil)Estrogenic, phytoestrogens, antiestrogenic
Ginseng (American, Siberian, Asian)Estrogenic
Hops (Humulus lupulus)Estrogenic, estrogen constituents
Licorice (Glycyrrhiza glabra)Estrogenic, estrogen constituents, antiestrogenic
Oregano (Oregano spp.)Progestogenic
Red clover (Trifolium pratense)Estrogenic, isoflavones
Saw palmetto (Seronoa replens)Antiestrogenic
Table 6. Traditional Hormonal Therapies for Breast Cancer
Traditional Hormonal TherapyAntitumor Mechanism of Actiona
FulvestrantBlocks and downregulates ER
Megestrol acetateBlocks ER and PR
Estrogen synthesis inhibitors
AnastrozoleInhibits peripheral estrogen synthesis
ExemestaneInhibits peripheral estrogen synthesis
LetrozoleInhibits peripheral estrogen synthesis
Leuprolide acetateInhibits ovarian production of estrogen through negative feedback mechanism (HPA axis)
GoserelinInhibits ovarian production of estrogen through negative feedback mechanism (HPA axis)
TriptorelinInhibits ovarian production of estrogen through negative feedback mechanism (HPA axis)
AminoglutethimideInhibits adrenal production of estrogen
Megestrol acetateInhibits ovarian production of estrogen through negative feedback mechanism (HPA axis)
FluoxymesteronePrevents peripheral estrogen synthesis
a ER = estrogen receptor; SERM = selective estrogen-receptor modulator; PR = progesterone receptor; HPA = hypothalamic, pituitary, adrenal.
Table 7. Traditional Hormonal Therapies for Prostate Cancer
Traditional Hormonal TherapyAntitumor Mechanism of Actiona
BicalutamideBlocks androgen receptor
FlutamideBlocks androgen receptor
Megestrol acetateBlocks androgen receptor
NilutamideBlocks androgen receptor
Androgen synthesis inhibitors
AminoglutethimideInhibits adrenal production of androgens
KetoconazoleInhibits adrenal production of androgens
EstrogensInhibits testicular production of androgens through negative feedback mechanism (HPA axis)
GoserelinInhibits testicular production of androgens through negative feedback mechanism (HPA axis)
LeuprolideInhibits testicular production of androgens through negative feedback mechanism (HPA axis)
Megestrol acetateInhibits testicular production of androgens through negative feedback mechanism (HPA axis)
TriptorelinInhibits testicular production of androgens through negative feedback mechanism (HPA axis)
a HPA = hypothalamic, pituitary, adrenal.
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