Woman with uterine cancer holding her pelvic pain

Uterine (Endometrial) Cancer

Last Section Update: 09/2013

Table of Contents

1 Introduction

Summary and Quick Facts for Endometrial Cancer

Cancers of the uterus, including endometrial cancer, are diagnosed in about 60,000 women each year in the United States. Fortunately, many cases of uterine cancer are diagnosed relatively early, when the long-term survival rate is good.
This protocol will outline the background and biology of endometrial cancer and its conventional diagnosis and treatment. Several emerging strategies that may improve patient outcomes will also be discussed. For instance, circulating-tumor-cell analysis may help doctors develop a tailored treatment plan well-suited to an individual’s cancer.
Progestogen therapy is often used for uterine cancer. Intriguing research suggests that vitamin D may compliment the anti-cancer effects of progestogens in uterine cancer.

Uterine cancer includes cancer of the inner lining (endometrium) as well as tumors involving the outer muscular margin of the uterus (uterine sarcomas). Uterine cancer of the inner lining of the uterus, called endometrial cancer, comprises about 95% of uterine cancers, and is the most common gynecologic cancer in the Western world (Bakkum-Gamez 2008; Plataniotis 2010; Llaurado 2012; Amant 2005; Rahaman 2003). American Cancer Society estimates for 2013 indicate that 49 560 women in the United States will develop endometrial cancer and 8190 will lose their lives to this disease (ACS 2013a). Most endometrial cancers appear in women between ages 60 and 70, but some occur before age 40 (A.D.A.M. 2012). Cancer of the uterus most frequently involves the endometrium; therefore, endometrial cancer will be the focus of this protocol (Acharya 2005; Amant 2005; A.D.A.M. 2012).

Endometrial cancer is a multifactorial disease, but one of the strongest risk factors is exposure to excess estrogen and/or a relative lack of progesterone (Amant 2005; Lee 2012; Carlson 2012). This is because estrogen stimulates rapid growth of endometrial cells, whereas progesterone counters this action. Long-term exposure to unopposed estrogen can lead to accelerated or abnormal growth of endometrial cells, and in some cases may lead to tumor formation. Numerous studies have shown that treatment with conventional hormone replacement therapy consisting of unopposed estrogen (estrogen without a progestogen) leads to an increased risk of developing endometrial cancer (Berstein 2002; Amant 2005; Woodruff 1994; Beral 2005). In addition to unopposed estrogen therapy, other risk factors that have been associated with endometrial cancer include obesity, diabetes, and diets high in sugar, animal fats, and cholesterol (Goodman, Hankin 1997; Hu 2003; Friberg 2011; Nakamura 2011; Fader 2009; McTiernan 2010).

Fortunately, the survival and cure rates for endometrial cancer are relatively high (Duong 2011; A.D.A.M. 2012). This is because abnormal vaginal bleeding is often among the first signs of endometrial cancer, prompting women to visit their gynecologist and typically receive an early diagnosis and treatment (Duong 2011, El-Sahwi 2012). Surgery to remove the uterus (hysterectomy) as well as the fallopian tubes and ovaries (bilateral salpingo-oophorectomy [BSO]) usually provides a good outcome for women with early stage cancer (A.D.A.M. 2012). Alternatively, for women with cellular overgrowth (hyperplasia) suggestive of pre-cancerous changes, a more conservative approach consisting of relatively high-dose progestogen therapy may be effective (Denschlag 2010; Baker 2007).

This protocol will outline the background and biology of endometrial cancer and discuss its conventional diagnosis and treatment. Several cutting-edge strategies that may improve patient outcomes will also be discussed. For example, intriguing evidence for potential synergism between progesterone, which is sometimes used in the treatment of some types of endometrial cancer, and vitamin D will be presented (Nguyen 2011; Montz 2002; Lotze 1982; Lee 2013), as will several novel diagnostic and therapeutic tools that may enhance the success rates of endometrial cancer care. You will also learn about some shortcomings of conventional hormone replacement therapy and how bioidentical hormone replacement may overcome some of these challenges.

2 Understanding Endometrial Cancer

The uterus is a hollow organ located in the female lower abdomen/pelvis, between the bladder and rectum; it serves as the site for fetal development during pregnancy (Vorvick 2012). Uterine tissue, especially that of the inner lining of the uterus, the endometrium, is very dynamic in that it adapts and changes in response to hormonal fluctuations throughout a woman’s menstrual cycle. This manifests as cycles of rapid cellular growth followed by tissue shedding during menstruation (Huang 2012; Rosenblatt 2007).

The endometrium is lined by a thin layer of tightly-packed cells called the epithelium. The endometrial epithelium contains densely-packed epithelial cells and stromal cells (connective tissue) enclosed by two layers of smooth muscle cells (Huang 2012). Epithelial and stromal cells of the endometrium undergo cycles of rapid growth, shedding, and regeneration in response to fluctuating levels of estrogen and progesterone during the menstrual cycle (Rosenblatt 2007; Huang 2012). Sometimes, after many rounds of repeated growth and shedding, genetic changes may occur, leading to alterations in the shape and size of the endometrium. In some cases this causes a thickening of the endometrium, termed endometrial hyperplasia, while in others it can eventually lead to endometrial intraepithelial neoplasia (EIN), which precedes the development of a type of endometrial cancer (Baak 2005; Mutter 2000).

Endometrial cancers can occur in two distinct ways (Duong 2011). Type I endometrial carcinoma, also known as endometrioid endometrial carcinoma, accounts for 70-80% of endometrial cancers, occurs most frequently in pre- and peri-menopausal women, is estrogen dependent, and has a good prognosis if discovered prior to metastasis (spreading of the cancer to other organs or tissues) (Amant 2005; Tao 2010; Duong 2011; El-Sahwi 2012). In contrast, type II carcinoma, also known as non-endometrioid endometrial carcinoma, is most frequent in older postmenopausal women, is not estrogen dependent, is more aggressive, and has a poorer outcome (Duong 2011; El-Sahwi 2012). Women with type II carcinoma tend to be older when the diagnosis is made (Duong 2011). Type II endometrial cancers include uterine clear cell carcinoma, uterine papillary serous carcinoma, and grade 3 endometrioid carcinoma (Hamilton 2006; El-Sahwi 2012; Kim 2013).

If undiscovered, type I and II endometrial carcinomas may eventually metastasize from the endometrium to other parts of the abdomen or elsewhere in the body via the bloodstream or lymphatic system (Amant 2005; The Merck Manual 2013). Once any cancer metastasizes, prognosis worsens.

3 Causes and Risk Factors

Unopposed Conventional Estrogen Therapy

The two major female sex hormones, estrogen and progesterone, control the menstrual cycle, and a balance between these two hormones is crucial for maintenance of a healthy endometrium (Yang 2011). Estrogen promotes endometrial epithelial cell growth, while progesterone inhibits estrogen-mediated epithelial cell growth in the endometrium (Clarke 1990; Carlson 2012).

Given the efficacy of estrogen replacement therapy in controlling the symptoms of menopause, estrogen therapy composed of conjugated equine (horse-derived) estrogens without progesterone (unopposed estrogen therapy) gained popularity as a treatment for the symptoms of menopause in the United States in the 1960s and 70s (Ross 2000). This was associated with a dramatic increase in the rates of endometrial cancer in the 1960s and 70s (Weiss 1976; Woodruff 1994; Jick 1980). Since these discoveries, unopposed estrogen has been shown to cause endometrial hyperplasia by promoting epithelial cell growth in the endometrium (Amant 2005; Beral 2005; Woodruff 1994).

It is important to recognize that the levels of estrogen and progesterone need to be balanced against each other (Carlson 2012; Allen 2008). In fact, unopposed conventional estrogen replacement therapy increases the risk of endometrial cancer by up to 70-fold, but adding progesterone reduces risk to equal that of the population in general (Baker 2007).

A potential method for mitigating this risk may be to use bioidentical hormone replacement therapy (HRT) with estriol rather than conventional HRT with equine (horse urine-derived) estrogens. There are three main estrogens – estrone, estradiol, and estriol (Avberšek 2011). Of these, estriol is considered the “weakest,” that is, it binds and activates estrogen receptors more weakly than the other two primary estrogens (Ciszko 2006). In fact, when estriol is administered along with estradiol, it counters some of the more potent estrogenic activity of the stronger estrogen (estradiol). Nonetheless, administered long term, estriol may still exert enough estrogenic activity to combat menopausal symptoms (Melamed 1997; Takahashi 2000).

However, research suggests that route of administration of estrogen is very important to maximize benefit and minimize risk. Specifically, oral estriol may increase the relative risk of endometrial neoplasia (Weiderpass 1999) likely through the first-pass effect with hepatic (liver) metabolism that occurs with oral administration. In contrast, vaginal estriol appears to be the optimal route of administration to optimize benefit and minimize risk; a review of 12 studies determined that use of intravaginal low-dose estriol did not result in endometrial cell proliferation (Vooijs 1995). However, conventional HRT with conjugated equine estrogen, which contains estrone in combination with equine (horse-derived) estrogens such as equilin and equilenin, is associated with increased endometrial cancer risk (Ziel 1975).

Overall, evidence suggests that bioidentical HRT with hormones natural to a woman’s body administered topically is the better option versus conventional HRT with horse-derived estrogen hormones ingested orally with regard to patient satisfaction and risk of breast cancer and cardiovascular disease (Holtorf 2009). A comprehensive overview of bioidentical hormone therapy is available in the Female Hormone Restoration protocol.

Obesity

The development of endometrial cancer is not only caused by unopposed estrogen therapy, but also by endogenous estrogens (estrogens produced by the body). A number of studies have shown that fat stores can generate estrogen precursors that are able to drive endometrial hyperplasia and carcinoma (Agarwal 1997; Cleland 1985; Bulun 1988; Hemsell 1974; Goodman, Hankin 1997; Nelson 2001; Nakamura 2011; McTiernan 2010; Lukanova, Lundin 2004; Lukanova, Zeleniuch-Jacquotte 2004). Some studies have shown that as many as 40% of endometrial cancer cases may be attributable to obesity (Kaaks 2002). Weighing more than 200 lbs increases risk by about 7-fold (Baker 2007). In a 2007 analysis of data on 1.2 million women, each 10-unit increment in body mass index (BMI) was associated with a nearly 3-fold increase in endometrial cancer risk (Reeves 2007). Other mechanisms by which obesity may increase endometrial cancer risk include perturbation of glucose regulation and promotion of an inflammatory state throughout the body (Schmandt 2011; Carlson 2012).

Polycystic Ovary Syndrome (PCOS)

Polycystic ovary syndrome (PCOS), a hormonal-metabolic disorder, has been shown to promote endometrial cancer development; it is associated with about a 5-fold increased risk on average across several studies (Kaaks 2002; Baker 2007). Similar to the way that obesity contributes to excessive estrogen stimulation of the endometrium, PCOS causes excessive production of male sex hormones called androgens, which can be converted into estrogens. Moreover, it has been suggested that the androgens themselves, when present in excess, may increase the risk, although this has yet to be clearly established (Navaratnarajah 2008; Giudice 2006).

Never Having Been Pregnant

Pregnancy allows for a beneficial change in the hormonal balance of progesterone and estrogen. As pregnancy progresses, levels of progesterone increase (Batra 1976). If a woman never becomes pregnant, she will not benefit from the prolonged period of increased progesterone production. This is illustrated by data showing that women who have never been pregnant are at greater risk for endometrial cancer than women who have had children (Pocobelli 2011). Likewise, the risk to develop endometrial cancer appears to decrease further in women with several childbirths (Hinkula 2002).

Early or Irregular Menstruation and Late Onset of Menopause

Menstruation occurring before age 11 or 12 and irregular menstruation are associated with a higher risk of developing endometrial cancer (Purdie 2001; Kaaks 2002). Since menopause is marked by decreased production of estrogen in the female body, the delayed commencement of menopause has also been shown to be associated with endometrial cancer; for example, onset of menopause after age 52 increases risk 2.4 times (Fader 2009). An increased length of the “menstruation span,” which is the time between the first menstruation and menopause, excluding time related to pregnancy, was also shown to heighten the risk for endometrial cancer (Purdie 2001).

Tamoxifen Treatment

Tamoxifen is a drug that binds to estrogen receptors and has estrogenic effects in some tissues (eg, bone) and anti-estrogenic effects in others (eg, breast) (Turner 1987; Goodsell 2002; Lymperatou 2013). It is widely used in breast cancer treatment. Despite its anti-breast cancer activities, tamoxifen treatment has been shown to be associated with a 2- to 3-fold higher risk of developing endometrial cancer, and the risk increases with duration of treatment (Mourits 2001). For example, in one study, tamoxifen treatment for at least 3 months was associated with 2.4-fold increased odds of developing endometrial cancer, and treatment for more than 5 years was associated with over 3-fold increased odds (Swerdlow 2005). In another study, women with 5 years or more of tamoxifen treatment showed over 4-fold increased odds of developing endometrial cancer (Bernstein 1999). The increased risk of endometrial cancer in pre- and post-menopausal women (both during and at least 5 years after the last tamoxifen treatment) demands aggressive, consistent monitoring to include transvaginal ultrasonography or hysteroscopy following a baseline exam because the effects of increasing tamoxifen doses for breast cancer treatment can be cumulative (Decensi 1996; Neven 2000).

Diabetes and Insulin Resistance

Diabetes mellitus and hyperinsulinemia (elevated insulin levels) have been shown in many studies to be associated with endometrial cancer (Lai 2013; Zhang, Su 2013; Brinton 2007; Berstein 2004). Diabetic postmenopausal women are twice as likely to develop endometrial cancer as their non-diabetic counterparts (Friberg 2007). In addition, diabetics often develop insulin resistance, which results in hyperinsulinemia. Hyperinsulinemia and the insulin-resistant state are associated with an increased endometrial cancer risk. Moreover, a low level of the hormone adiponectin, which may be a surrogate marker for insulin resistance, has also been associated with increased endometrial cancer risk in some but not all studies (Carlson 2012; Soliman 2006; Soliman 2011).

Similar to what occurs in healthy cells during diabetes and insulin resistance, endometrial cancer cells develop abnormalities in the insulin and insulin-like growth factor-1 (IGF-1) signaling pathways, both of which are involved in cancer cell growth. Thus, it is not surprising that the anti-diabetic drug metformin, which helps improve insulin sensitivity, has received considerable attention from researchers investigating new ways to combat endometrial cancer, as will be discussed later in this protocol (Cantrell 2010; Carlson 2012; Soliman 2005; Soliman 2006; Faivre 2006).

Diet Composition

Endometrial cancer appears to be especially influenced by dietary and lifestyle factors (Amant 2005). A variety of factors related to diet and lifestyle can increase the chances of developing endometrial cancer; chief among them is the consumption of foods high in animal fats and sugars whereas diets high in vegetables and fruits (especially those high in lutein) have lower risk (Friberg 2011; Goodman, Hankin 1997; Bandera 2009; McTiernan 2010). High intake of iron from red meat has also been modestly associated with increased risk (Kallianpur 2010; Genkinger 2012).

Copious research has shown that dietary omega fatty acid composition also influences risk of several diseases, including cancer. There are two primary omega fatty acids: omega-3’s and omega-6’s, differentiated by their chemical structure. Omega-3’s are generally viewed as exerting anti-inflammatory action, whereas their omega-6 counterparts are easily metabolized into proinflammatory end products (Calder 2010). Given that inflammation plays a major role in tumor initiation, omega-3 fatty acids have gained considerable attention in the context of cancer prevention and treatment (Laviano 2013). Indeed, evidence suggests a higher dietary ratio of omega-3’s to omega-6’s is associated with a lower risk of endometrial cancer (Arem 2012). Several studies on omega-3 fatty acid consumption and endometrial cancer risk are reviewed later in this protocol in the “Targeted Natural Interventions” section under “Omega-3 Fatty Acids.”

4 Signs and Symptoms

The most common symptom of endometrial cancer is abnormal vaginal bleeding that occurs independently of normal menstrual bleeding, especially postmenopausal bleeding. Other symptoms include (Amant 2005; Lentz 2012; Tannus 2009; Denschlag 2010; A.D.A.M. 2012):

Lower abdominal or pelvic pain/ cramps
Urinary difficulty
Pain during sexual intercourse
White or clear vaginal discharge

If a woman (whether peri-, pre-, or postmenopausal) experiences any of these symptoms, she should consult with her healthcare provider.

5 Diagnosis and Staging

Endometrial cancer is often detected at an early stage since abnormal vaginal bleeding, the most common symptom, prompts women to visit their doctor soon after it begins. If a doctor suspects endometrial cancer, several tests can help confirm the diagnosis, including (Amant 2005; Kawana 2005; Lentz 2012; A.D.A.M. 2012; MayoClinicStaff 2013; NCI 2010; Denschlag 2010):

A procedure called dilation and curettage (D & C), which involves widening of the cervix and scraping the endometrium to retrieve a sample of cells
Biopsy of the endometrium
Examination of endometrial fluids
Pelvic examination (although results are often normal in early stages of endometrial cancer)
Transvaginal ultrasound
Hysteroscopy (a procedure that allows for examination of the inside of the uterus)

Although abnormal test results from a Pap smear may raise the suspicion of endometrial cancer, Pap smear results are not sufficient for a definitive diagnosis of endometrial cancer. Pap smears are not screening tests for endometrial cancer, and when they show abnormal results additional tests are necessary (A.D.A.M. 2012; NCI 2010).

If endometrial cancer is discovered, then other diagnostic tests are used to determine the stage of the disease. Currently, magnetic resonance imaging (MRI) scans of the abdomen are an important non-invasive diagnostic imaging approach to obtain an accurate evaluation of the extent of the disease (Shweel 2012; Tong 2012). The first stage of endometrial cancer refers to cancer that is still confined to the uterus; the second stage involves cancer spreading to the cervix; the third stage involves cancer spreading beyond the uterus but not outside the pelvic area, which may also involve spreading to the local lymph nodes in the pelvis or near the aorta; and the fourth stage of endometrial cancer involves spreading to other organs in the abdominal cavity and beyond, including the bowel and bladder (Wright 2012; Amant 2005; NCI 2013).

Seventy five percent of endometrial cancer cases are diagnosed in stage I, where cure rates as high as 75-90% have been reported. However, 5-year survival rates are only 50% in stage II and up to 30% and less than 10% in stages III and IV, respectively (Emons 2000).

In addition to staging, endometrial cancer is scored by a numerical grading system (grade 1-3). Grade 1 is the least aggressive, while grade 3 is the most aggressive. Higher-grade tumors grow faster and are more likely to spread (metastasize) than low-grade tumors (NCI 2013; A.D.A.M. 2012).

6 Conventional Treatment

Surgery is the mainstay of treatment in most cases of isolated endometrial cancer. Radiation therapy, hormone therapy, and chemotherapy may be used to complement surgery in these cases, but play more of a role in the treatment of recurrent or disseminated cancer for which surgery is unlikely to be curative (Wright 2012; Arora 2012; Baker 2007).

Surgery

Patients with stage I endometrial cancer typically undergo hysterectomy (ie, removal of the uterus). In order to allow for maximal removal of cancerous lesion(s), the fallopian tubes and ovaries are also removed in a procedure called a bilateral salpingo-oophorectomy (BSO) (Lewandowski 1990; Juretzka 2005). Removal of the uterus through the abdomen (abdominal hysterectomy) may offer some advantages over vaginal hysterectomy, since the former procedure allows the surgeon to directly examine the abdominal wall and cavity and to remove tissues for biopsy (Wright 2012; Amant 2005; Arora 2012; Kristensen 2004). Laparoscopic hysterectomy is a less invasive option which has gained popularity. This technique involves small incisions in the abdomen and specialized instruments for visualization and removal of tissue (Fram 2013; Kaiser Permanente [undated]).

Radiation Therapy

While surgery alone is a good treatment option in women with low-risk endometrial cancer, patients with later stages of the disease typically undergo BSO in combination with radiation therapy (RT), especially if they have high-risk disease (Creutzberg 2011). Radiation is typically delivered either through the use of an external beam (EBRT) or via a device implanted internally (ie, vaginal brachytherapy) (Nag 2000; Nout 2010; Creutzberg 2011).

Chemotherapy

Chemotherapy may be prescribed to patients after the uterus and locally affected tissues are surgically removed. Women with advanced and/or recurrent endometrial cancer are typically prescribed chemotherapeutic drugs which may include carboplatin (Paraplatin®), paclitaxel (Taxol®), doxorubicin (Adriamycin®), and others (Akram 2005; Duska 2005; Randall 2006; Shimada 2007).

Although as many as 40-60% of endometrial cancer patients initially respond to chemotherapy, recurrences may appear after only a few months. Approximately 10-15% of patients with early stage endometrial cancer experience recurrences. Some studies reported recurrence rates of about 50% in advanced disease (Emons 2000; Amant 2005; Odagiri 2011).

Hormone Therapy

Since estrogens can promote the development and progression of endometrial cancer, treatment with synthetic progesterone-like drugs called progestins was one of the first pharmacologic interventions developed (Lewis 1974; Apgar 2000).

Synthetic progestins are typically administered orally in pill form, but can also be intramuscularly injected, as in the case of medroxyprogesterone acetate (MPA, or Depo-Provera®) (Hesselius 1981; Kaunitz 1994; Apgar 2000; Ushijima 2007; Park 2013). Synthetic progestin therapy has only been shown to be effective in endometrial cancer patients whose tumor(s) express progesterone’s target molecule, the progesterone receptor (Dai 2002; Dai 2005; Punnonen 1993; Creasman 1993; Fukuda 1998; Banno 2012).

This form of cancer treatment is typically administered to patients who cannot undergo surgery, require palliative treatment, or when cancer occurs in women of childbearing age who want to have children after diagnosis (Apgar 2000; Emons 2000; Banno 2012). Patients on synthetic progestin therapy need to be monitored closely as the disease can progress during or after this treatment (ACS 2013b).

Natural progesterone also exerts several anti-cancer effects in endometrial tissue, primarily related to cell differentiation. In one experimental study, administration of progesterone to endometrial cancer cells reduced cancer cell proliferation by activating metabolic regulators known as p21 and p27. In addition, treatment with progesterone led to a reduction in the expression of several cellular adhesion molecules that cancer cells use to attach to normal tissues and spread (Dai 2002). In one study that followed 12 women with stage I, grade 1 endometrial cancer for up to 36 months, placing a progesterone-containing intrauterine device resulted in negative biopsies at 12 months in 6 of 8 patients (Montz 2002).

An experimental study using endometrial cancer cells found that progesterone augmented the anti-tumor effects of vitamin D by upregulating the expression of vitamin D’s target, the vitamin D receptor (Lee 2013). In another laboratory study, simultaneous administration of a metabolically active form of vitamin D (ie, 1,25-dihydroxyvitamin D3) and progesterone led to a significant upregulation of proteins that help restrain tumor growth and metastasis in endometrial cancer cells (Nguyen 2011). These intriguing results suggest that women undergoing progesterone therapy for endometrial cancer may be able to achieve a more desirable outcome by ensuring their blood levels of 25-hydroxyvitamin D are in the optimal range, although studies have yet to test this hypothesis.

7 Novel and Emerging Strategies

The Power and Promise of Personalized Medicine

Although conventional treatment strategies for stage I endometrial cancer are quite successful, major advances in the areas of endometrial oncology and chemotherapy research have allowed for the development of several promising therapies for recurrent and late stage endometrial cancer patients (Schiavone 2012; Zagouri 2010).

By capitalizing on advances in DNA sequencing and genomics, researchers and clinicians are now able to individualize endometrial cancer treatments in accordance with the unique biology of each patient’s cancer (Westin 2012). For example, if genetic profiling of a patient’s tumor sample indicates a reliance on a specific growth signaling pathway that healthy endometrial cells do not rely heavily upon, then proteins important to this pathway would represent promising drug targets (Moreno-Bueno 2003; Westin 2012; Katoh 2013).

In addition, there are a variety of other pathways being identified as important in the development of endometrial cancer, such as the phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways (Slomovitz 2012). These pathways can be modulated by pharmaceutical agents, and research is underway to identify agent(s) that favorably alter the course of this disease (Janku 2012; Kang 2012; Suh 2013).

Personalized Medicine and Trastuzumab. One promising drug target in endometrial cancer is the Human Epidermal Growth Factor Receptor 2 (HER2) protein (Grushko 2008). This receptor, which transverses the outside surface of cells (ie, plasma membrane), is critical for growth signaling. In the case of certain subsets of endometrial cancer, the HER2 gene gets copied excessively, and the ensuing overabundance of HER2 protein has independent prognostic significance (Hetzel 1992; Morrison 2006; Grushko 2008; Slomovitz 2004).

By sequencing the DNA of endometrial cancer patients and using additional cellular and molecular biology tools, researchers and clinicians are now able to determine which endometrial cancer patients would benefit from treatment with trastuzumab (Herceptin®), a synthetic antibody that targets HER2 (Santin 2008).

Temsirolimus and the Inhibition of Endometrial Cancer Cell Metabolism

mTOR is a key protein involved in cellular growth, aging, survival, and metabolism (Hay 2004; Hung 2012; Johnson 2013). Cancer cells have developed a variety of means to modulate mTOR activity to help drive their high growth and metabolic rate. Given the links between cellular growth and metabolism on one hand, and cancer development on the other, inhibitors of mTOR have been hypothesized to have potent anti-cancer properties, and specific compounds showed positive responses in clinical trials (Faivre 2006). With respect to endometrial cancer, the mTOR inhibitor temsirolimus (Torisel®) was shown to have significant anti-cancer properties; response rates as high as 83% were reported in a phase II clinical trial involving women with recurrent or metastatic endometrial cancer (Oza 2011; Suh 2013).

Metformin

Given the significant metabolic changes that occur during endometrial cancer development and the greater prevalence of endometrial cancer among patients with metabolic and endocrine diseases, including diabetes, anti-diabetic drugs have received interest for endometrial cancer prevention (Berstein 2004; Brinton 2007; Friberg 2007; Lai 2013; Zhang, Su 2013). One such anti-diabetic agent is metformin, a drug that lowers blood glucose levels by reducing the ability of the liver to produce new glucose and also increases the ability of muscle cells to uptake glucose from the blood (Mu 2012; Galuska 1994).

A variety of epidemiological studies have shown that diabetic patients taking metformin are significantly less likely to develop a variety of cancers, including pancreatic, liver, colorectal, and breast cancer (Evans 2005; Jiralerspong, Gonzalez-Angulo 2009; Jiralerspong, Palla 2009; Zhang, Gao 2013; Zhang, Li 2013). A variety of preclinical studies have shown that metformin inhibits the proliferation and promotes the death of endometrial cancer cells (Cantrell 2010; Xie 2011; Zhang 2011).

Prominent mechanisms by which metformin combats endometrial cancer appear to be through promotion of progesterone receptor expression and the reversal of progestin resistance in endometrial cancer cells (Zhang 2011; Xie 2011). Since endometrial cancer is largely an estrogen-driven disease, one of the treatments is to administer progesterone or synthetic progestins, which counter the action of estrogen in the endometrium. However, a major hurdle for this treatment approach is that the target for progesterone and synthetic progestins, the progesterone receptor, is often downregulated in endometrial cancer cells, especially following long-term treatment with a synthetic progestin. This negates the effects of progesterone or synthetic progestins, even if ample concentrations are available. In an experimental study, scientists administered metformin along with the synthetic progestin medroxyprogesterone acetate (MPA). They found that metformin markedly increased the expression of the progesterone receptor and had synergistic activity with MPA to decrease proliferation of the cancerous cells (Xie 2011). Likewise, researchers in China conducted an experimental study and concluded similarly that metformin “reversed progestin resistance, enhanced progestin-induced cell proliferation inhibition, and induced apoptosis in progestin-resistant [endometrial cancer] cells” (Zhang 2011).

More Information about repurposing drugs for use in the context of cancer in general is available at Life Extension’s Drug Repurposing in Cancer protocol.

Bevacizumab and the Inhibition of New Blood Vessel Formation in Endometrial Tumors

As tumors grow, they constantly form new blood vessels to provide cancerous cells with a blood supply that can deliver nutrients, energy sources, and oxygen, and remove waste products (Lodish 2000). This process of generating new blood vessels, called angiogenesis, appears to be promoted by several pathways, the most intensively studied one being dependent on a protein called vascular endothelial growth factor (VEGF) (Lodish 2000; Li 2010). Bevacizumab (Avastin®), a synthetic antibody that binds to VEGF, was developed to block angiogenesis and hence decrease tumor growth (Ferrara 2004). Preclinical studies showed promising results for bevacizumab in inhibiting endometrial cancer growth and clinical trial results documented the efficacy of this new anti-cancer treatment modality. Additional clinical trials are ongoing and further studies are needed to explore this therapeutic agent (Aghajanian 2011; Suh 2013; Morotti 2012).

Personalizing Cancer Care with Circulating Tumor Cell Testing

The one word that cancer patients dread most is “metastasis.” Metastasis is the spread of cancer cells from the primary tumor into distant organs or tissues. In most cases of cancer-related death, it is not the primary tumor but rather the emergence of distant metastasis that claims the lives of cancer victims (Liberko 2013).

In order for cancer to metastasize, cells of the primary tumor must break away and infiltrate the circulatory system to be transported to another part of the body. These cancer cells flowing through the bloodstream are called circulating tumor cells (CTCs) (Wang 2011). In recent years, technological advances have given clinicians the ability to collect and evaluate CTCs from a cancer patient’s blood sample. These innovations have paved the way for new diagnostic and therapeutic strategies based upon quantitative and qualitative analyses of CTCs (Liberko 2013).

Counting the number of CTCs in a blood sample, which is described as quantitative CTC analysis, has emerged as a powerful prognostic tool: more CTCs correlate with a poorer outcome, and the prognostic information provided by CTCs can supplement the information obtained by imaging studies (Cristofanilli 2004; Cohen 2008; Negin 2010; Bidard 2011). CTCs can originate either from the primary tumor or metastatic tumors, and they are extremely rare, with one CTC being estimated to exist for one billion normal blood cells even in a person with advanced cancer (Yu, Stott 2011). Quantitative CTC testing provides prognostic value in several ways. For example, it can help predict tumor recurrences after surgical treatment (Peach 2010; Galizia 2013; Liberko 2013; Negin 2010; Cristofanilli 2007; Wulfing 2006). Moreover, CTCs can be used as a “surrogate marker” to indicate the potential spread of the tumor even in the absence of visible metastases (Gazzaniga 2013). It is important to remember that the number of CTCs is not simply an indication of tumor size, but it reflects other characteristics, such as vascularity and invasiveness (Yu, Stott 2011).

While quantitative CTC testing has been a boon in the battle against cancer, another aspect of CTC testing – qualitative CTC analysis – is emerging as a powerful tool. Cutting edge technology has allowed methods for evaluating CTCs to evolve from simply counting their number to characterizing their intricate molecular properties (Dong 2012; Rahbari 2012; Boshuizen 2012).

A major hurdle in the treatment of metastatic cancer is that tumor cells that break away from the primary site often evolve and develop different metabolic properties than the original tumor from which they emerged. This presents several problems because physicians often rely upon molecular analysis of a tissue sample from a primary tumor to guide treatment. For example, once a patient is diagnosed with cancer and a tumor is identified, a tissue sample (biopsy) is often taken from the tumor and sent to a pathologist for molecular analysis. This elucidates the metabolic properties of the tumor cells and allows oncologists to select interventions with a higher likelihood of success based upon the molecular characteristics of the cancer cells. However, in several cancer types, molecular differences have been observed between primary and metastatic tumors even within the same patient (Cavalli 2003; Smiraglia 2003). Interventions developed based upon molecular analysis of the primary tumor may, therefore, not be effective against metastatic tumors due to these differences (Biofocus 2011).

Qualitative CTC analysis represents a major step toward overcoming this barrier. Characterization of the molecular and genetic properties of CTCs allows oncologists to select a drug regimen that may be more effective against metastatic tumors. Using a process known as “chemosensitivity testing,” pathologists can analyze the properties of CTCs and determine which chemotherapeutic drugs are likely to kill the cells based upon their specific genetic makeup. Oncologists can then develop a treatment regimen consisting of drugs to which the patient’s CTCs are susceptible (Biofocus 2011; Rüdiger 2013).

8 Dietary And Lifestyle Management Strategies

Increase Physical Activity and Maintain a Healthy Weight

Epidemiological studies have shown that increased physical activity is associated with an up to 30% reduction in the risk of developing endometrial cancer (Cust 2011). Physical inactivity and obesity are well-documented risk factors associated with the development of endometrial cancer (Terry 1999; Goodman, Hankin 1997; Fader 2009). This can be attributed to significant increases in exposure of the endometrium to estrogen generated by fatty tissue deposits. Several studies have shown that obesity increases the risk of endometrial cancer by over 4-fold, and sedentary lifestyle can increase the risk by up to 46% (Wynder 1966; Goodman, Hankin 1997; Fader 2009; Terry 1999; Schouten 2004). A study completed in 2011 found that while overweight women had 1.5 times the risk of developing endometrial cancer compared to women at a healthy weight, obese women had almost 5 times a normal-weight woman’s risk of developing the disease. Importantly, women who experienced a 35% weight gain in their 20s developed endometrial cancer approximately 10 years earlier compared to women without such weight changes early in their lives (Lu 2011).

Achieving a healthy weight may be one of the most impactful lifestyle changes women can make to reduce endometrial cancer risk and potentially improve treatment outcomes. Life Extension® has developed a comprehensive Weight Loss protocol that outlines several strategies that may help achieve a healthy weight.

Reduce Sugar Intake and Avoid Type 2 Diabetes

Although type 2 diabetic women have for many decades been observed to have a higher risk of developing endometrial cancer, the actual contribution of insulin resistance and diabetes toward developing endometrial cancer has only relatively recently been appreciated (Soliman 2006; Berstein 2004). Since diabetes typically leads to weight gain, and because fat deposits in overweight and obese people secrete estrogen that promotes endometrial cancer development, it was thought that the contribution of diabetes to endometrial cancer risk was only indirect. It is now understood that diabetic, non-obese women who are otherwise healthy continue to be at a higher risk of developing endometrial cancer (Weiderpass 2000; Burzawa 2011; Soliman 2006; Berstein 2004). This information is supported by the fact that metformin, an anti-diabetic agent, appears to hold considerable promise in the prevention of endometrial cancer (Zhang 2011; Xie 2011). A number of strategies for achieving healthy glucose regulation are available in the Diabetes and Glucose Control protocol.

Adhere to a Mediterranean Dietary Pattern

The traditional dietary pattern of populations of the Mediterranean region has come to be regarded as one of the healthiest eating styles in the world. Centering upon whole grains, vegetables, fruits, olive oil, fish, moderate dairy, and wine, the Mediterranean diet has been shown in a large body of published scientific literature to reduce the risk of several of today’s most prominent ailments including obesity, cardiovascular disease, and cancer (Hadziabdić 2012; Altomare 2013). Accordingly, rates of endometrial cancer in the Mediterranean region are lower than in the United States and United Kingdom, and this discrepancy is thought to be due, at least in part, to differences in eating styles between these regions. In fact, it has been estimated that 10% of endometrial cancer cases could be prevented if “Western” societies shifted to a Mediterranean diet (Trichopoulou 2000). In one study, adherence to a “Western” diet, which is high in saturated and animal fats as well as refined carbohydrates, was associated with a 60% increased risk of endometrial cancer (Dalvi 2007).

9 Nutrients

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

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).

Vitamin E

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

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

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

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).

Soy Isoflavones

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

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).

Agaricus

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).

Resveratrol

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

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).

2013

Sept: Comprehensive update & review

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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Uterine (Endometrial) Cancer

Uterine (Endometrial) Cancer

1 Introduction

Summary and Quick Facts for Endometrial Cancer

2 Understanding Endometrial Cancer

3 Causes and Risk Factors

Unopposed Conventional Estrogen Therapy

Obesity

Polycystic Ovary Syndrome (PCOS)

Never Having Been Pregnant

Early or Irregular Menstruation and Late Onset of Menopause

Tamoxifen Treatment

Diabetes and Insulin Resistance

Diet Composition

4 Signs and Symptoms

5 Diagnosis and Staging

6 Conventional Treatment

Surgery

Radiation Therapy

Chemotherapy

Hormone Therapy

7 Novel and Emerging Strategies

The Power and Promise of Personalized Medicine

Temsirolimus and the Inhibition of Endometrial Cancer Cell Metabolism

Metformin

Bevacizumab and the Inhibition of New Blood Vessel Formation in Endometrial Tumors

Personalizing Cancer Care with Circulating Tumor Cell Testing

8 Dietary And Lifestyle Management Strategies

Increase Physical Activity and Maintain a Healthy Weight

Reduce Sugar Intake and Avoid Type 2 Diabetes

Adhere to a Mediterranean Dietary Pattern

9 Nutrients

Vitamin A and Carotenoids

Vitamin C

Vitamin E

Omega-3 Fatty Acids

Selenium

Calcium

Lignans

Soy Isoflavones

Soy and Estrogen: The Real Story

Melatonin

Coffee and Chlorogenic Acid

Green Tea and (-)-Epigallocatechin-3-gallate

Agaricus

Resveratrol

Curcumin

Indole-3-Carbinol and Diindoylmethane

Update History

2013

Disclaimer and Safety Information

References

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