Targeted Natural Interventions
Vitamin A and Carotenoids
Carotenoids are a family of yellow pigments found in plants. One of the most prominent carotenoids – beta-carotene – is converted to active vitamin A within the body. Vitamin A and its derivatives bind and activate specialized receptors that contribute to regulating a process called transcription, which is the reading of information encoded within DNA (Nagpal 1998). The activation of these receptors exerts several chemopreventive effects including inhibition of carcinogenesis, induction of tumor cell death (apoptosis), and suppression of tumor growth and invasion (Brtko 2003). Greater consumption of vitamin A or beta-carotene has been associated with a lower risk of developing endometrial cancer (Pelucchi 2008; Xu 2007; Bandera 2009; Yeh 2009). In one analysis of dietary factors associated with endometrial cancer, greater consumption of beta-carotene (along with vitamin C) was associated with a 50% reduced risk of the disease (Levi 1993).
Vitamin C, also referred to as ascorbic acid, is associated with a significantly lower risk of developing endometrial cancer (Xu 2007; Berstein 2002; Goodman, Hankin 1997; McCann 2000; Kuiper 2010; Bandera 2009). Vitamin C has been proposed to reduce the activity of a key protein called hypoxia inducible factor-1 alpha (HIF-1α), which is involved in endometrial tumor cell survival (Kuiper 2010; Traber 2011). In addition to its direct inhibitory effects on tumor cells, vitamin C was also proposed to boost anti-tumor immunity. Specifically, it has been suggested that vitamin C may aide the immune system’s surveillance of tumor cells and promote tumor cell killing (Yu, Bae 2011). Several studies have shown that consumption of foods rich in vitamin C is associated with not only significant reductions in endometrial cancer incidence, but also the disease grade (Bandera 2009; Kuiper 2010; Xu 2007). For example, one study showed that at the level of 50 mg per 1000 calories consumed, vitamin C reduced risk of endometrial cancer by 15% (Bandera 2009). Another study showed that the highest quintile (1/5th) of vitamin C intake from food, which was defined as ≥72.7 mg of vitamin C per 1000 calories/day, was associated with a 20% reduced risk of endometrial cancer compared to the lowest quintile of intake, which was defined as ≤29.8 mg per 1000 calories/day (Xu 2007).
Consumption of foods rich in vitamin E is associated with a significantly decreased risk of developing endometrial cancer (Xu 2007; Yeh 2009; USDA 2013). Wheat germ oil is very high in natural vitamin E, nuts like almonds and hazelnuts are moderately high in vitamin E, and tomatos and spinach contain lower levels of vitamin E. In one study, the highest intake of dietary vitamin E was associated with a 56% reduced risk of endometrial cancer compared to the lowest intake levels (Yeh 2009).
Naturally occurring vitamin E exists in eight chemical forms (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol) that have varying levels of biological activity. Gamma-tocopherol has been shown to possess significant anti-inflammatory and anti-tumor effects in a rat model of breast cancer (Smolarek 2013). Of interest in the context of endometrial cancer, the anti-tumor effects of gamma-tocopherol appeared to be dependent on inhibiting the activities of estrogen. Given that endometrial cancer can be driven by excess estrogen or imbalances in estrogen and progesterone levels, it is tempting to speculate that gamma-tocopherol may also have therapeutic activities against endometrial cancer, though studies are needed to explore this possibility. However, evidence has shown that gamma-tocopherol consumption may reduce risk of other gynecologic cancers. A study conducted in Korea found that women who consumed the highest levels of gamma-tocopherol had a 72% lower risk of ovarian cancer compared to women with the lowest intake of the nutrient (Jeong 2009).
Omega-3 Fatty Acids
Some studies have examined the link between omega-3 fatty acid consumption and endometrial cancer risk. In one such study on 556 women with endometrial cancer and 533 healthy controls, greater consumption of the omega-3’s eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are abundant in fatty, cold-water fish, was associated with significantly lower risk of endometrial cancer. Specifically, women whose EPA consumption fell within the top one-fourth of distribution had a 43% lower risk of endometrial cancer compared to women whose consumption was within the lowest one-fourth. Similarly, those consuming the most DHA had a 36% lower risk compared to those consuming the least. In addition, having a higher dietary ratio of omega-3 to omega-6 fatty acids was also associated with reduced risk. Finally, those women who consumed fish oil supplements had a 37% lower risk of endometrial cancer (Arem 2012). Another study involving over 3500 women found that women whose consumption of fatty fish (which are rich in omega-3 fatty acids) fell into the highest quarter of distribution had a 40% lower risk of endometrial cancer compared to women whose consumption ranged within the lowest quarter of distribution (Terry, Wolk 2002).
Omega-3 fatty acids like EPA and DHA may prevent cancer development through multiple mechanisms. These may include changes in the activity of gene expression and estrogen metabolism, as well as improved insulin sensitivity and reduced inflammation (Larsson 2004; Arem 2012).
Selenium is an essential micronutrient required for numerous metabolic processes throughout the body. Studies have shown that selenium can disrupt estrogen signaling in cancer cells (Shah 2005). Not only has selenium been shown to slow tumor growth, but it also decreases the risk of developing a variety of gynecological cancers such as cancer of the uterus and cervix (Lou 1995; Cunzhi 2003). In 2009, a randomized prospective clinical trial showed sodium selenite supplementation to be beneficial for patients with cervical and uterine cancer who have selenium deficiency and radiotherapy-induced diarrhea (Micke 2009). In addition, a laboratory study on cervical cancer reported that sodium selenite induces the death of cancer cells by apoptosis (Rudolf 2008).
Calcium is an important mineral involved in hormone signaling, muscle contraction, and bone health. While calcium plays a variety of roles in cellular signaling, it acts as a critical messenger in protein kinase C (PKC) signaling. PKC signaling controls a variety of pathways related to cellular growth and the regulation of cellular death. Calcium also plays a role in several other metabolic pathways related to cellular differentiation and proliferation, which must be carefully regulated in order to avoid cancer (McCullough 2008). Women taking calcium supplements or who consumed calcium-rich foods were shown to have a significant reduction in the risk of developing endometrial cancer (Biel 2011; Salazar-Martinez 2005; Terry, Vainio 2002).
Lignans are a group of natural phytoestrogens found in plants like flaxseed and sesame. After consumption, lignans can be metabolized into enterolactone – a compound that promotes cancer cell death and decreases the capacity of hormone-responsive cancer cells to grow new blood vessels to facilitate tumor growth. While several studies are currently aimed at determining how enterolactone may promote endometrial cancer cell death, it has been postulated that phytoestrogens may compete with endogenous estrogen for binding to the estrogen receptor (Bergman Jungestrom 2007; Cederroth 2009). Given the estrogen-dependence of endometrial cancer, this hypothesis is consistent with studies showing that women who consume high amounts of lignans have a 32% lower risk of developing uterine cancer. In postmenopausal women, this risk was 43% lower (Horn-Ross 2003).
Isoflavones are a class of plant phytochemicals found in soy and other legumes. Greater intake of isoflavones is associated with reduced endometrial cancer risk (Ollberding 2012). Soy isoflavones bind to estrogen receptors and modulate estrogen signaling. Thus, they may act in a manner similar to lignans to compete with endogenous estrogens, which exert more pronounced estrogenic activity (Wood 2006; Cederroth 2009). In 2011, a clinical study of postmenopausal women found that those consuming higher amounts of soy isoflavones (including genistein and daidzein) and total isoflavones were significantly less likely to develop endometrial cancer (Ollberding 2012). Additionally, data from several case-control studies showed that soy and legume consumption was associated with a lower risk of developing endometrial cancer (Goodman, Wilkens 1997; Xu 2004; Tao 2005).
Soy and Estrogen: The Real Story
At the center of the controversy surrounding soy is the “estrogen-like” molecular profile of some soy-based compounds—and whether they increase the risk of certain hormone-dependent cancers and other adverse effects associated with hormonal imbalance.
Soy contains antioxidant polyphenols (plant-based compounds) known as isoflavones. Isoflavones are considered “phytoestrogens” or “dietary estrogens” because of their molecular similarity to estrogen as estradiol (17-β-estradiol), the female sex hormone. The ability of isoflavones to “mimic” some of estrogen’s effects has led many doctors and scientists to characterize isoflavones as “weak estrogens.”
This is incorrect, according to Dr. Mark F. McCarty, an internationally recognized expert in soy isoflavones (McCarty 2006). Advances in our understanding of how the body responds to estrogen (and estrogen-like compounds) explains why.
Estrogen exerts its influence upon cells directly through the presence of estrogen receptors. Until relatively recently, only one receptor was known to exist, now called the estrogen receptor alpha or ER-alpha. Overexpression of ER-alpha has been implicated in a variety of cancers in humans, including breast cancer, ovarian cancer, endometrial cancer, and colon cancer (Hayashi 2003; Darb-Esfahani 2009; Fujimoto 2009; Nussler 2008).
In the late 1990s, a second estrogen receptor was discovered, now known as ER-beta (McCarty 2006; Hartman 2009). Expression of this receptor appears to counteract many of the cancer-causing activities of ER-alpha (Hartman 2009).
As Dr. McCarty points out, genistein, one of the most abundant isoflavones in soy, is a highly potent activator of ER-beta. Critics of soy regard isoflavones’ action on estrogen receptors as the source of concern, without recognizing there is more than one type of estrogen receptor in the body, and that they exert very different effects.
This highly selective mode of action explains why soy isoflavones promote beneficial estrogen-like effects in tissues where the ER-beta receptor predominates, but do not provoke the harmful effects of conventional estrogen replacement therapy in tissues where the ER-alpha receptor predominates.
For example, soy isoflavones have been shown to exert positive effects in tissues such as bone, vascular endothelium (blood vessel lining), and breast cells without the negative effects in those and other tissues such as liver and uterus, where side effects of estrogen therapy have been observed (McCarty 2006). In fact, in breast tissue possessing both estrogen receptor types, ER-beta is now known to exert a restraining influence on cell proliferation stimulated by estrogen at ER-alpha sites, reducing the risk of breast cancer (Hartman 2009). This balance helps to explain why soy isoflavones do not increase breast cancer risk despite their estrogen-like activity (McCarty 2006).
Dozens of epidemiological (population-level) studies document the broad array of health benefits associated with a high-soy diet (Mann 2007; Larkin 2008; Mateos-Aparicio 2008). Diets rich in soy isoflavones are associated with lower rates of cardiovascular disease, osteoporosis, cancer, and obesity-related complications such as type 2 diabetes (Xiao 2008; Cederroth 2009; Ishimi 2009).
Soy isoflavones have relaxing effects on blood vessels, mediated by their influence on nitric oxide synthase (NOS), as well as powerful antioxidant effects, which together explain their potential for treatment and prevention of hypertension and stroke (Mann 2007; Jackman 2007). Acting via yet another distinct mechanism, the isoflavones modulate signaling in pathways that control the interaction of oxidant stress with inflammation, leading to upregulation of detoxifying and antioxidant defense genes (Mann 2009).
The cumulative weight of the evidence for soy’s health benefits led to the remarkable decision by the FDA to approve a food-labeling health claim for products containing 25 grams of soy proteins in the prevention of coronary heart disease in 1999 (Xiao 2008). This claim was based on a wealth of clinical trials as well as epidemiological data showing that high soy isoflavone intake could reduce LDL cholesterol, inhibit pro-inflammatory cytokines, reduce cell adhesion proteins, inhibit platelet aggregation, and improve blood vessel reactivity (Rimbach 2008). Many nations throughout the world have now similarly endorsed soy products based on these data (Hartman 2009).
Melatonin, a hormone produced by the pineal gland, is responsible for regulating sleep patterns and is important for energy balance (Barrenetxe 2004). Melatonin may also help prevent cancers that are responsive to sex hormones, including prostate, breast, and gynecologic cancers such as endometrial cancer; it also improves the efficacy of chemotherapy in patients with non-small cell lung cancer (Sanchez-Barcelo 2005; Reiter 2004; Lissoni, Chilelli 2003; Lissoni, Malugani 2003; Sainz 2005). The anti-cancer activities of melatonin appear to be multi-factorial, since several studies have shown that melatonin can directly promote cancer cell death and indirectly promote immune responses against tumor cells (Srinivasan 2008). In addition, activation of the melatonin receptor, by binding to melatonin, modulates a number of cellular metabolic pathways crucial for healthy cell growth and differentiation (Jung 2006).
Coffee and Chlorogenic Acid
Coffee contains a variety of phytochemicals and polyphenols that exert an array of health effects. One such polyphenol in particular, called chlorogenic acid (CGA), has been hypothesized to protect cells from oxidative DNA damage (Tang 2008). In addition to being found in modest quantities in brewed coffee, chlorogenic acid is also richly concentrated in green coffee bean extracts. Coffee, is associated with a reduction in the risk of developing estrogen-driven cancers like endometrial cancer (Wu 2005; Williams 2008; Kotsopoulos 2009; Friberg 2009; Giri 2011; Gunter 2012). Consumption of at least 4 cups of coffee per day is associated with a 25% reduction in the likelihood of developing endometrial cancer as compared to consuming less than 1 cup per day. Interestingly, researchers also found that consumption of two or more cups of decaffeinated coffee per day was associated with a 22% reduction in the risk of developing endometrial cancer (Je 2011).
While coffee likely possesses direct anti-cancer activities, it may also have indirect effects in preventing endometrial cancer. Since coffee has been shown to lower insulin production and improve insulin resistance (Tunnicliffe 2008), and because insulin resistance leads to weight gain and excess estrogen production by fat deposits in the body (Carlson 2012), coffee may lower the risk of developing endometrial cancer by preventing weight gain and modulating glucose metabolism (van Dijk 2009; Fader 2009; Je 2011).
Green Tea and (-)-Epigallocatechin-3-gallate
Epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, was shown in preclinical studies to inhibit proliferation and induce cell death in endometrial carcinoma cells, emerging as a potentially important compound to be considered for this condition (Manohar 2013). An analysis that included 7 published studies on the effects of green tea on endometrial cancer reported that an increase of 2 cups/day was associated with a 25% decrease in endometrial cancer risk, and the protective effect of green tea was stronger than that of black tea (Tang 2009). Also, a study published in 2009 reported that the protective effect of green tea consumption against endometrial cancer was independent of risk factors such as obesity or menopause (Kakuta 2009). An animal study revealed that EGCG inhibits blood vessel formation and prevents the formation of new lesions in endometriosis (Laschke 2008).
The agaricus mushroom (Agaricus blazei Murill Kyowa) possesses immunomodulatory properties and has been studied in cancer patients in at least 2 clinical trials. In one study conducted on 100 women with gynecological cancers, including endometrial cancer, supplementation for 6 months with agaricus in addition to chemotherapy led to an increase in the activity of anti-cancer immune cells called natural killer cells. Moreover, agaricus treatment was associated with a reduction in chemotherapy side effects such as emotional instability, hair loss, and loss of appetite (Ahn 2004). Another trial conducted on 78 patients in cancer remission found supplementation with 1.8–5.4 g per day of agaricus to be well tolerated in most subjects, indicating that this product is generally safe (Ohno 2011).
Preclinical studies that used several uterine cancer cell lines reported that resveratrol, a polyphenol found in Japanese knotweed (Polygonum cuspidatum) and grapes, can inhibit cell growth and stimulate the death of uterine cancer cells (Sexton 2006). In endometrial adenocarcinoma cells, resveratrol inhibited cell growth, and the effects appear to be both estrogen-dependent and estrogen-independent (Bhat 2001). In addition, resveratrol and EGCG significantly reduced the VEGF secreted by endometrial cancer cells in a concentration-dependent manner, indicating these two compounds are promising in inhibiting angiogenesis in endometrial cancers (Dann 2009).
Curcumin was reported to significantly inhibit the proliferation of a type of uterine cancer cells. Also, due to its ability to improve insulin metabolism, which is implicated in cancers linked to obesity, it was proposed to be useful in preventing several obesity-related cancers such as endometrial cancer (Shehzad 2012). Curcumin was shown to hinder the growth of cancer cells by inhibiting the phosphorylation of a protein (STAT-3) that is important for the uncontrolled growth of cancer cells (Saydmohammed 2010). Moreover, curcumin was shown to induce apoptosis of human endometrial carcinoma cells through another mechanism of anti-cancer action involving proto-oncogenes (Yu 2007).
Indole-3-Carbinol and Diindoylmethane
Indole-3-carbinol, or I3C, is a phytochemical concentrated in cruciferous vegetables such as cabbage, cauliflower, radishes, broccoli, and Brussels sprouts. When ingested, it is quickly converted into diindoylmethane (DIM) (Aggarwal 2005). Several studies suggest these compounds may possess anti-cancer properties, especially in malignancies in which hormones exert considerable influence, such as breast, endometrial, and prostate cancer (Aggarwal 2005; Bradlow 2008). A variety of mechanisms have been explored, but much of the available evidence suggests that it is the ability of I3C and DIM to modulate estrogen metabolism and signaling that protects against estrogen-mediated cancers. Specifically, these compounds reduce the conversion of estrogens into 16-hydroxyestrogens, which more strongly promote cellular proliferation, and promote conversion into 2-hydroxyestrogens, which are weaker, and far less proliferative on hormone-responsive cell growth (Bradlow 1996; Bradlow 2008; Michnovicz 1997; Mulvey 2007; Liehr 2000)(Gupta 1998). In addition, the I3C derivative DIM appears to influence estrogen receptor signaling in endometrial cancer cells (Leong 2001). In one experimental study, I3C in combination with the soy isoflavone genistein enhanced the cancer-cell-killing properties of a protein called TRAIL, which induces cell death in endometrial cancer cells (Parajuli 2013). Other evidence suggests I3C and/or its metabolites promote cell death in tumor cells by modulating several metabolic pathways critical to cancer cell survival (Aggarwal 2005). In an animal experiment conducted on rats genetically prone to developing endometrial cancer, a diet supplemented with I3C was compared to a standard diet for 660 days. In the group of rats that received the highest I3C dose, the endometrial cancer rate at the end of the study was 14%, whereas the rate in the standard-diet group was 38%. It was also found that feeding I3C significantly increased the 2-hydroxylation of estradiol. These data led the researchers to conclude “These results suggest that dietary I3C inhibits spontaneous occurrence of endometrial adenocarcinoma as well as preneoplastic lesions […] This […] may be due to its induction of estradiol 2-hydroxylation” (Kojima 1994).