Uterine (Endometrial) Cancer

Uterine (Endometrial) Cancer

1 Introduction

Summary and Quick Facts

  • 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.


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).


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 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). 


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).  

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).

Although qualitative CTC analysis stands at the cutting edge of cancer care currently available, such services are accessible for most cancer patients through organizations such as the International Strategic Cancer Alliance (http://is-canceralliance.com) and Biofocus® (http://www.biofocus.de/de/onkologie/ueberblick/ueberblick). Services such as these allow cancer patients to submit a blood sample to highly specialized labs to undergo qualitative CTC analysis, the results of which are reported back to the patient who can then share them with his or her oncologist (Biofocus 2011).

While the sensitivity and accuracy of these qualitative CTC analyses varies with cancer type, cancers of epithelial cell origin, such as endometrial cancer, are usually good candidates for these procedures (Biofocus 2011). Individuals interested in pursuing CTC testing can contact the International Strategic Cancer Alliance using the contact info below for more information.

International Strategic Cancer Alliance

873 E. Baltimore Pike #333
Kennett Square, PA 19348
Web: http://is-canceralliance.com
Phone: 610-628-3419

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 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

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 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).

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, 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).

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.

A.D.A.M. Medical Encyclopedia. Endometrial cancer. PubMed Health web page. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001908. 2012. Accessed 8/21/2013.

Acharya S, Hensley ML, Montag AC, et al. Rare uterine cancers. Lancet Oncol. 2005 Dec;6(12):961-71.

ACS. American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013a.

ACS. American Cancer Society. Treatment options for endometrial cancer by stage. Updated 1/17/2013b. Available at: http://www.cancer.org/cancer/endometrialcancer/detailedguide/endometrial-uterine-cancer-treating-by-stage. Accessed 8/30/2013.

Agarwal VR, Ashanullah CI, Simpson ER, et al. Alternatively spliced transcripts of the aromatase cytochrome P450 (CYP19) gene in adipose tissue of women. J Clin Endocrinol Metab. 1997 Jan;82(1):70-4.

Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell cycle (Georgetown, Tex.). Sep 2005;4(9):1201-1215.

Aghajanian C, Sill MW, Darcy KM, Greer B, McMeekin DS, Rose PG, . . . Leslie KK. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jun 1 2011;29(16):2259-2265.

Ahn WS, Kim DJ, Chae GT, Lee JM, Bae SM, Sin JI, . . . Lee IP. Natural killer cell activity and quality of life were improved by consumption of a mushroom extract, Agaricus blazei Murill Kyowa, in gynecological cancer patients undergoing chemotherapy. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. Jul-Aug 2004;14(4):589-594.

Akram T, Maseelall P, Fanning J. Carboplatin and paclitaxel for the treatment of advanced or recurrent endometrial cancer. Am J Obstet Gynecol. 2005 May;192(5):1365-7.

Allen NE, Key TJ, Dossus L, et al. Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer. 2008;15(2):485-97.

Altomare R, Cacciabaudo F, Damiano G, Palumbo VD, Gioviale MC, Bellavia M, . . . Lo Monte AI. The mediterranean diet: a history of health. Iranian journal of public health. 2013;42(5):449-457.

Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endometrial cancer. Lancet. Aug 6-12 2005;366(9484):491-505.

Apgar BS, Greenberg G. Using progestins in clinical practice. American family physician. Oct 15 2000;62(8):1839-1846, 1849-1850.

Arem H, Neuhouser ML, Irwin ML, Cartmel B, Lu L, Risch H, . . . Yu H. Omega-3 and omega-6 fatty acid intakes and endometrial cancer risk in a population-based case-control study. Eur J Nutr. Aug 23 2012.

Arora V, Quinn MA. Endometrial cancer. Best Pract Res Clin Obstet Gynaecol. Jun 2012;26(3):311-324.

Avberšek M, Sömen J, Heath E. Dynamics of steroid estrogen daily concentrations in hospital effluent and connected waste water treatment plant. J Environ Monit. 2011 Aug;13(8):2221-6.

Baak JP, Mutter GL, Robboy S, van Diest PJ, Uyterlinde AM, Orbo A, . . . Verheijen RH. The molecular genetics and morphometry-based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health Organization classification system. Cancer. Jun 1 2005;103(11):2304-2312.

Baker TR. Clinical Key. First Consult; Uterine cancer. 2007; www.clinicalkey.com. Accessed 7/18/2013.

Bakkum-Gamez JN, Gonzalez-Bosquet J, Laack NN, et al. Current issues in the management of endometrial cancer. Mayo Clin Proc. 2008 Jan;83(1):97-112

Bandera EV, Gifkins DM, Moore DF, McCullough ML, Kushi LH. Antioxidant vitamins and the risk of endometrial cancer: a dose-response meta-analysis. Cancer Causes Control. Jul 2009;20(5):699-711.

Banno K, Kisu I, Yanokura M, Tsuji K, Masuda K, Ueki A, . . . Aoki D. Progestin therapy for endometrial cancer: the potential of fourth-generation progestin (review). Int J Oncol. Jun 2012;40(6):1755-1762.

Barrenetxe J, Delagrange P, Martinez JA. Physiological and metabolic functions of melatonin. J Physiol Biochem. Mar 2004;60(1):61-72.

Batra S, Bengtsson LP, Grundshell H, et al. Levels of free and protein-bound progesterone in plasma during late pregnancy. J Clin Endocrinol Metab. 1976 Jun;42(6):1041-7.

Beral V, Bull D, Reeves G, Million Women Study C. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet. Apr 30-May 6 2005;365(9470):1543-1551.

Bergman Jungestrom M, Thompson LU, Dabrosin C. Flaxseed and its lignans inhibit estradiol-induced growth, angiogenesis, and secretion of vascular endothelial growth factor in human breast cancer xenografts in vivo. Clinical cancer research : an official journal of the American Association for Cancer Research. Feb 1 2007;13(3):1061-1067.

Bernstein L, Deapen D, Cerhan JR, et al. Tamoxifen therapy for breast cancer and endometrial cancer risk. J Natl Cancer Inst. 1999 Oct 6;91(19):1654-62.

Berstein L, Tsyrlina E, Poroshina T, Bychkova N, Kalinina N, Gamajunova V, . . . Kovalenko I. Switching (overtargeting) of estrogen effects and its potential role in hormonal carcinogenesis. Neoplasma. 2002;49(1):21-25.

Berstein LM, Kvatchevskaya JO, Poroshina TE, Kovalenko IG, Tsyrlina EV, Zimarina TS, . . . Thijssen JH. Insulin resistance, its consequences for the clinical course of the disease, and possibilities of correction in endometrial cancer. J Cancer Res Clin Oncol. Nov 2004;130(11):687-693.

Bhat KP, Pezzuto JM. Resveratrol exhibits cytostatic and antiestrogenic properties with human endometrial adenocarcinoma (Ishikawa) cells. Cancer Res. 2001;61(16):6137-44.

Bidard F-C, Ligthart ST, Decraene C, et al. P4-07-09: Automated Quantitative Assessment of HER2 Expression of Circulating Tumor Cells (CTC) in Metastatic Breast Cancer (IC 2006-04 Study). Poster Session 4 – Detection and Diagnosis – Pathology: Circulating Tumor Cells. Cancer Res. 2011;71(24 Suppl): P4-07-09.

Biel RK, Csizmadi I, Cook LS, Courneya KS, Magliocco AM, Friedenreich CM. Risk of endometrial cancer in relation to individual nutrients from diet and supplements. Public Health Nutr. Nov 2011;14(11):1948-1960.

Biofocus. Biofocus (Germany). Molecular Oncology. Directory of Services (2011). Available at: http://www.biofocus.de/PDF/Onkologie/BF_111_Brochure_M-Oncology.pdf 2011.

Boshuizen R, Kuhn P, van den Heuvel M. Circulating tumor cells in non-small cell lung carcinoma. J Thorac Dis. 2012 Oct;4(5):456-8.

Bradlow HL, Telang NT, Sepkovic DW, Osborne MP. 2-hydroxyestrone: the 'good' estrogen. The Journal of endocrinology. Sep 1996;150 Suppl:S259-265.

Bradlow HL. Review. Indole-3-carbinol as a chemoprotective agent in breast and prostate cancer. In vivo (Athens, Greece). Jul-Aug 2008;22(4):441-445.

Brinton LA, Sakoda LC, Frederiksen K, Sherman ME, Kjaer SK, Graubard BI, . . . Mellemkjaer L. Relationships of uterine and ovarian tumors to pre-existing chronic conditions. Gynecologic oncology. Dec 2007;107(3):487-494.

Brtko J, Thalhamer J. Renaissance of the biologically active vitamin A derivatives: established and novel directed therapies for cancer and chemoprevention. Current pharmaceutical design. 2003;9(25):2067-2077.

Bulun SE, Simpson ER. Competitive RT-PCR analysis indicates levels of aromatase cytochrome P450 transcripts in adipose tissue of buttocks, thighs, and abdomen of women increase with advancing age. J Clin Endocrinol Metab 1988;7:1379-85.

Burzawa JK, Schmeler KM, Soliman PT, Meyer LA, Bevers MW, Pustilnik TL, . . . Lu KH. Prospective evaluation of insulin resistance among endometrial cancer patients. Am J Obstet Gynecol. Apr 2011;204(4):355 e351-357.

Calder PC. Omega-3 fatty acids and inflammatory processes. Nutrients. Mar 2010;2(3):355-374.

Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL. Metformin is a potent inhibitor of endometrial cancer cell proliferation--implications for a novel treatment strategy. Gynecologic oncology. Jan 2010;116(1):92-98.

Carlson MJ, Thiel KW, Yang S, Leslie KK. Catch it before it kills: progesterone, obesity, and the prevention of endometrial cancer. Discovery medicine. Sep 2012;14(76):215-222.

Cavalli LR, Urban CA, Dai D, et al. Genetic and epigenetic alterations in sentinel lymph notes metastatic lesions compared to their corresponding primary breast tumors. Cancer Genet Cytogenet. 2003; 146(1):33-40.

Cederroth CR, Nef S. Soy, phytoestrogens and metabolism: A review. Mol Cell Endocrinol. May 25 2009;304(1-2):30-42.

Ciszko B, Zdrojewicz Z. [Compliance endogenous and exogenous estriol in clinical practice]. Ginekol Pol. 2006 Jul;77(7):559-65.

Clarke CL, Sutherland RL. Progestin regulation of cellular proliferation. Endocr Rev. May 1990;11(2):266-301.

Cleland WH, Mendelson CR, Simpson ER. Effects of aging and obesity on aromatase activity of human adipose cells. J Clin Endocrinol Metab 1985;60:174-7.

Cohen SJ, Punt CJ, Iannotti N, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008 Jul 1;26(19):3213-21.

Creasman WT. Prognostic significance of hormone receptors in endometrial cancer. Cancer. Feb 15 1993;71(4 Suppl):1467-1470.

Creutzberg CL, Nout RA. The role of radiotherapy in endometrial cancer: current evidence and trends. Curr Oncol Rep. 2011;13(6):472-8.

Cristofanilli M, Broglio KR, Guarneri V, Jackson S, Fritsche HA, Islam R, . . . Valero V. Circulating tumor cells in metastatic breast cancer: biologic staging beyond tumor burden. Clinical breast cancer. Feb 2007;7(6):471-479.

Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, . . . Hayes DF. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. The New England journal of medicine. Aug 19 2004;351(8):781-791.

Cunzhi H, Jiexian J, Xianwen Z, Jingang G, Shumin Z, Lili D. Serum and tissue levels of six trace elements and copper/zinc ratio in patients with cervical cancer and uterine myoma. Biological trace element research. Aug 2003;94(2):113-122.

Cust AE. Physical activity and gynecologic cancer prevention. Recent Results Cancer Res. 2011;186:159-185.

Dai D, Albitar L, Nguyen T, et al. A therapeutic model for advanced endometrial cancer: systemic progestin in combination with local adenoviral-mediated progesterone receptor expression. Mol Cancer Ther. 2005 Jan;4(1):169-75.

Dai D, Wolf DM, Litman ES, White MJ, Leslie KK. Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. Cancer research. Feb 1 2002;62(3):881-886.

Dalvi TB, Canchola AJ, Horn-Ross PL. Dietary patterns, Mediterranean diet, and endometrial cancer risk. Cancer causes & control : CCC. Nov 2007;18(9):957-966.

Dann JM, Sykes PH, Mason DR, et al. Regulation of Vascular Endothelial Growth Factor in endometrial tumor cells by resveratrol and EGCG. Gynecol Oncol. 2009;113(3):374-8.

Darb-Esfahani S, Wirtz RM, Sinn BV, et al. Estrogen receptor 1 mRNA is a prognostic factor in ovarian carcinoma: determination by kinetic PCR in formalin-fixed paraffin-embedded tissue. Endocr Relat Cancer. 2009 Dec;16(4):1129-39.

Decensi A, Fontana V, Bruno S, et al. Effect of tamoxifen on endometrial proliferation. J Clin Oncol. 1996 Feb; 14(2):434-40.

Denschlag D, Ulrich U, Emons G. The diagnosis and treatment of endometrial cancer: progress and controversies. Deutsches Arzteblatt international. Aug 2010;108(34-35):571-577.

Dong X, Alpaugh KR, Cristofanilli M. Circulating tumor cells (CTCs) in breast cancer: a diagnostic tool for prognosis and molecular analysis. Chinese journal of cancer research = Chung-kuo yen cheng yen chiu. Dec 2012;24(4):388-398.

Duong LM, Wilson RJ, Ajani UA, Singh SD, Eheman CR. Trends in endometrial cancer incidence rates in the United States, 1999-2006. J Womens Health (Larchmt). Aug 2011;20(8):1157-1163.

Duska LR, Berkowitz R, Matulonis U, et al. A pilot trial of TAC (paclitaxel, doxorubicin, and carboplatin) chemotherapy with filgastrim (r-metHuG-CSF) support followed by radiotherapy in patients with “high-risk” endometrial cancer. Gynecol Oncol. 2005 Jan;96(1):198-203.

El-Sahwi KS, Schwartz PE, Santin AD. Development of targeted therapy in uterine serous carcinoma, a biologically aggressive variant of endometrial cancer. Expert Rev Anticancer Ther. Jan 2012;12(1):41-49.

Emons G, Heyl W. Hormonal treatment of endometrial cancer. J Cancer Res Clin Oncol. Nov 2000;126(11):619-623.

Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:1304–1305.

Fader AN, Arriba LN, Frasure HE, von Gruenigen VE. Endometrial cancer and obesity: epidemiology, biomarkers, prevention and survivorship. Gynecologic oncology. Jul 2009;114(1):121-127.

Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nature reviews. Drug discovery. Aug 2006;5(8):671-688.

Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature reviews. Drug discovery. May 2004;3(5):391-400.

Fram KM, Sumrein IM. Laparoscopic versus abdominal hysterectomy in the treatment of endometrial cancer. Saudi medical journal. Jan 2013;34(1):11-18.

Friberg E, Mantzoros CS, Wolk A. Diabetes and risk of endometrial cancer: a population-based prospective cohort study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Feb 2007;16(2):276-280.

Friberg E, Orsini N, Mantzoros CS, et al. Coffee drinking and risk of endometrial cancer--a population-based cohort study. Int J Cancer. 2009 Nov 15;125(10):2413-7.

Friberg E, Wallin A, Wolk A. Sucrose, high-sugar foods, and risk of endometrial cancer--a population-based cohort study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Sep 2011;20(9):1831-1837.

Fujimoto J, Sato E. Clinical implication of estrogen-related receptor (ERR) expression in uterine endometrial cancers. J Steroid Biochem Mol Bol. 2009 Aug;116(1-2):71-5.

Fukuda K, Mori M, Uchiyama M, et al. Prognostic significance of progesterone receptor immunohistochemistry in endometrial carcinoma. Gynecol Oncol. 1998 Jun;69(3):220-5.

Galizia G, Gemei M, Orditura M, Romano C, Zamboli A, Castellano P, . . . Lieto E. Postoperative Detection of Circulating Tumor Cells Predicts Tumor Recurrence in Colorectal Cancer Patients. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. Jun 28 2013.

Galuska D, Nolte LA, Zierath JR, Wallberg-Henriksson H. Effect of metformin on insulin-stimulated glucose transport in isolated skeletal muscle obtained from patients with NIDDM. Diabetologia. Aug 1994;37(8):826-832.

Gazzaniga P, Gianni W, Raimondi C, Gradilone A, Lo Russo G, Longo F, Gandini O, Tomao S, Frati L. Circulating tumor cells in high-risk nonmetastatic colorectal cancer. Tumour Biol. 2013 Mar 29.

Genkinger JM, Friberg E, Goldbohm RA, et al. Long-term dietary heme iron and red meat intake in relation to endometrial cancer risk. Am J Clin Nutr. 2012 Oct;96(4):848-54.

Giri A, Sturgeon SR, Luisi N, et al. Caffeinated coffee, decaffeinated coffee and endometrial cancer risk: a prospective cohort study among US postmenopausal women. Nutrients. 2011 Nov;3(11):937-50.

Giudice LC. Endometrium in PCOS: Implantation and predisposition to endocrine CA. Best practice & research. Clinical endocrinology & metabolism. Jun 2006;20:235-244.

Goodman MT, Hankin JH, Wilkens LR, Lyu LC, McDuffie K, Liu LQ, Kolonel LN. Diet, body size, physical activity, and the risk of endometrial cancer. Cancer research. Nov 15 1997;57(22):5077-5085.

Goodman MT, Wilkens LR, Hankin JH, Lyu LC, Wu AH, Kolonel LN. Association of soy and fiber consumption with the risk of endometrial cancer. American journal of epidemiology. Aug 15 1997;146(4):294-306.

Goodsell DS. The molecular perspective: tamoxifen and the estrogen receptor. Oncologist. 2002;7(2):163-4.

Grushko TA, Filiaci VL, Mundt AJ, Ridderstrale K, Olopade OI, Fleming GF, Gynecologic Oncology G. An exploratory analysis of HER-2 amplification and overexpression in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecologic oncology. Jan 2008;108(1):3-9.

Gunter MJ, Schaub JA, Xue X, et al. A prospective investigation of coffee drinking and endometrial cancer incidence. Int J Cancer. 2012 Aug 15;131(4):E530-6.

Gupta M, McDougal A, Safe S. Estrogenic and antiestrogenic activities of 16alpha- and 2-hydroxy metabolites of 17beta-estradiol in MCF-7 and T47D human breast cancer cells. The Journal of steroid biochemistry and molecular biology. Dec 1998;67(5-6):413-419.

Hadziabdić MO, Bozikov V, Pavić E, et al. The antioxidative protecting role of the Mediterranean diet. Coll Antropol. 2012 Dec;36(4):1427-34.

Hamilton CA, Cheung MK, Osann K, et al. Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrial corpus cancers. Br J Cancer. 2006 Mar;94(5):642-6.

Hartman J, Strom A, Gustafsson JA. Estrogen receptor beta in breast cancer—diagnostic and therapeutic implications. Steroids. 2009 Aug;74(8):635-41.

Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. Aug 15 2004;18(16):1926-1945.

Hayashi SI, Eguchi H, Tanimoto K, et al. he expression and function of estrogen receptor alpha and beta in human breast cancer and its clinical application. Endocr Relat Cancer. 2003 Jun;10(2):193-202.

Hemsell DL, Grodin JM, Brenner PF, et al. Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age. J Clin Endocrinol Metab. 1974;38:476-9.

Hesselius I, Johansson ED. Medroxyprogesterone acetate (MPA) plasma levels after oral and intramuscular administration in a long-term study. Acta Obstet Gynecol Scand Suppl. 1981;101:65-70.

Hetzel DJ, Wilson TO, Keeney GL, et al. HER-2/neu expression: a major prognostic factor in endometrial cancer. Gynecol Oncol. 1992 Nov;47(2):179-85.

Hinkula M, Pukkala E, Kyyrönen P, et al. Grand multiparity and incidence of endometrial cancer: a population-based study in Finland. Int J Cancer. 2002 Apr 20;98(6):912-5.

Holtorf K. The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgraduate medicine. Jan 2009;121(1):73-85.

Horn-Ross PL, John EM, Canchola AJ, Stewart SL, Lee MM. Phytoestrogen intake and endometrial cancer risk. Journal of the National Cancer Institute. Aug 6 2003;95(15):1158-1164.

Hu FB. Overweight and obesity in women: health risks and consequences. J Womens Health (Larchmt). Mar 2003;12(2):163-172.

Huang CC, Orvis GD, Wang Y, Behringer RR. Stromal-to-epithelial transition during postpartum endometrial regeneration. PloS one. 2012;7(8):e44285.

Hung CM, Garcia-Haro L, Sparks CA, Guertin DA. mTOR-dependent cell survival mechanisms. Cold Spring Harb Perspect Biol. 2012 Dec 1;4(12).

Ishimi Y. Soybean isoflavones in bone health. Forum Nutr. 2009;61:104-16.

Jackman KA, Woodman OL, Sobey CG. Isoflavones, equol and cardiovascular disease: pharmacological and therapeutic insights. Curr Med Chem. 2007;14(26):2824-30.

Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, Tsimberidou AM, . . . Kurzrock R. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol. Mar 10 2012;30(8):777-782.

Je Y, Hankinson SE, Tworoger SS, DeVivo I, Giovannucci E. A prospective cohort study of coffee consumption and risk of endometrial cancer over a 26-year follow-up. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Dec 2011;20(12):2487-2495.

Jeong NH, Song ES, Lee JM, Lee KB, Kim MK, Cheon JE, . . . Kwon YI. Plasma carotenoids, retinol and tocopherol levels and the risk of ovarian cancer. Acta obstetricia et gynecologica Scandinavica. 2009;88(4):457-462.

Jick H, Walker AM, Rothman KJ. The epidemic of endometrial cancer: a commentary. Am J Public Health. 1980 Mar;70(3):264-7.

Jiralerspong S, Gonzalez-Angulo AM, Hung MC. Expanding the arsenal: metformin for the treatment of triple-negative breast cancer? Cell cycle (Georgetown, Tex.). Sep 1 2009;8(17):2681.

Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, . . . Gonzalez-Angulo AM. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. Jul 10 2009;27(20):3297-3302.

Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease.Nature. 2013 Jan 17;493(7432):338-45.

Jung B, Ahmad N. Melatonin in cancer management: progress and promise. Cancer research. Oct 15 2006;66(20):9789-9793.

Juretzka MM, Chi DS, Sonoda Y. Update on surgical treatment for endometrial cancer. Expert Rev Anticancer Ther. Feb 2005;5(1):113-121.

Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Dec 2002;11(12):1531-1543.

Kaiser Permanente. What is a laparoscopic hysterectomy? [undated]. Available at: http://mydoctor.kaiserpermanente.org/ncal/facilities/region/eastbay/area_master/departments/laparoscopy/laparoscopy_gyn/laparoscopic_hysterectomy.jsp. Accessed 8/30/2013.

Kakuta Y, Nakaya N, Nagase S, Fujita M, Koizumi T, Okamura C, . . . Tsuji I. Case-control study of green tea consumption and the risk of endometrial endometrioid adenocarcinoma. Cancer causes & control : CCC. Jul 2009;20(5):617-624.

Kallianpur AR, Lee SA, Xu WH, Zheng W, Gao YT, Cai H, Ruan ZX, Xiang YB, Shu XO. Dietary iron intake and risk of endometrial cancer: a population-based case-control study in Shanghai, China. Nutr Cancer. 2010;62(1):40-50.

Kang S, Dong SM, Kim BR, et al. Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells. Apoptosis. 2012 Sep;17(9):989-97.

Katoh M, Nakagama H. FGF Receptors: Cancer Biology and Therapeutics. Med Res Rev. 2013 May 21. doi: 10.1002/med.21288. [Epub ahead of print]

Kaunitz AM. Long-acting injectable contraception with depot medroxyprogesterone acetate. Am J Obstet Gynecol. 1994 May;170(5 Pt 2):1543-9.

Kawana K, Yamada M, Jimbo H, et al. Diagnostic usefulness of endometrial aspiration cytology for endometrial cancer cases with normal cutterage findings. Acta Cytol. 2005 Sep-Oct;49(5):507-12.

Kim HJ, Kim TJ, Lee YY, et al. A comparison of uterine papillary serous, clear cell carcinomas, and grade 3 endometrioid corpus cancers using 2009 FIGO staging system. J Gynecol Oncol. 2013 Apr;24(2):120-7.

Kojima T, Tanaka T, Mori H. Chemoprevention of spontaneous endometrial cancer in female Donryu rats by dietary indole-3-carbinol. Cancer research. Mar 15 1994;54(6):1446-1449.

Kotsopoulos J, Eliassen AH, Missmer SA, Hankinson SE, Tworoger SS. Relationship between caffeine intake and plasma sex hormone concentrations in premenopausal and postmenopausal women. Cancer. Jun 15 2009;115(12):2765-2774.

Kristensen G, Tropé C. Endometrial cancer: the management of high-risk disease. Current Oncology Reports. 2004;6(6):471-475.

Kuiper C, Molenaar IG, Dachs GU, Currie MJ, Sykes PH, Vissers MC. Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. Cancer research. Jul 15 2010;70(14):5749-5758.

Lai GY, Park Y, Hartge P, Hollenbeck AR, Freedman ND. The Association Between Self-Reported Diabetes and Cancer Incidence in the NIH-AARP Diet and Health Study. The Journal of clinical endocrinology and metabolism. Feb 13 2013.

Larkin T, Price WE, Astheimer L. The key importance of soy isoflavone bioavailability to understanding health benefits. Crit Rev Food Sci Nutr. 2008 Jun;48(6):538-52.

Larsson SC, Kumlin M, Ingelman-Sundberg M, Wolk A. Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms. The American journal of clinical nutrition. Jun 2004;79(6):935-945.

Laschke MW, Schwender C, Scheuer C, et al. Epigallocatechin-3-gallate inhibits estrogen-induced activation of endometrial cells in vitro and causes regression of endometriotic lesions in vivo.Hum Reprod. 2008 Oct;23(10):2308-18.

Laviano A, Rianda S, Molfino A, Rossi Fanelli F. Omega-3 fatty acids in cancer. Current opinion in clinical nutrition and metabolic care. Mar 2013;16(2):156-161.

Lee LR, Teng PN, Nguyen H, Hood BL, Kavandi L, Wang G, . . . Syed V. Progesterone enhances calcitriol antitumor activity by upregulating vitamin d receptor expression and promoting apoptosis in endometrial cancer cells. Cancer prevention research. Jul 2013;6(7):731-743.

Lee WL, Lee FK, Su WH, Tsui KH, Kuo CD, Hsieh SL, Wang PH. Hormone therapy for younger patients with endometrial cancer. Taiwanese journal of obstetrics & gynecology. Dec 2012;51(4):495-505.

Lentz GM, Lobo RA, Gershenson DM, et al. Comprehensive Gynecology: Expert Consult – Online and Print, Sixth Edition, 32, 713-730, 2012.

Leong H, Firestone GL, Bjeldanes LF. Cytostatic effects of 3,3'-diindolylmethane in human endometrial cancer cells result from an estrogen receptor-mediated increase in transforming growth factor-alpha expression. Carcinogenesis. Nov 2001;22(11):1809-1817.

Levi F, Franceschi S, Negri E, La Vecchia C. Dietary factors and the risk of endometrial cancer. Cancer. Jun 1 1993;71(11):3575-3581.

Lewandowski G, Torrisi J, Potkul RK, et al. Hysterectomy with extended surgical staging and radiotherapy versus hysterectomy alone and radiotherapy in stage I endometrial cancer: a comparison of complication rates. Gynecol Oncol. 1990;36(3):401-4.

Lewis GC, Jr., Slack NH, Mortel R, Bross ID. Adjuvant progestogen therapy in the primary definitive treatment of endometrial cancer. Gynecologic oncology. Aug 1974;2(2-3):368-376.

Li X, Kumar A, Zhang F, Lee C, Li Y, Tang Z, Arjuna P. VEGF-independent angiogenic pathways induced by PDGF-C. Oncotarget. 2010 Aug;1(4):309-314.

Liberko M, Kolostova K, Bobek V. Essentials of circulating tumor cells for clinical research and practice. Critical reviews in oncology/hematology. Jul 4 2013.

Liehr JG. Is estradiol a genotoxic mutagenic carcinogen? Endocrine reviews. Feb 2000;21(1):40-54.

Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. Journal of pineal research. Aug 2003;35(1):12-15.

Lissoni P, Malugani F, Brivio F, Piazza A, Vintimilla C, Giani L, Tancini G. Total pineal endocrine substitution therapy (TPEST) as a new neuroendocrine palliative treatment of untreatable metastatic solid tumor patients: a phase II study. Neuro endocrinology letters. Jun-Aug 2003;24(3-4):259-262.

Llaurado M, Ruiz A, Majem B, Ertekin T, Colas E, Pedrola N, . . . Reventos J. Molecular bases of endometrial cancer: new roles for new actors in the diagnosis and the therapy of the disease. Molecular and cellular endocrinology. Jul 25 2012;358(2):244-255.

Lodish H, Berk A, Zipursky SL, et al. New York: W. H. Freeman; 2000. Molecular Cell Biology. 4th Edition.

Lotze W, Richter P, Sarembe B. [High-dose progesterone therapy in advanced endometrial cancer]. Archiv fur Geschwulstforschung. 1982;52(7):569-574.

Lou H, Wu R, Fu Y. [Relation between selenium and cancer of uterine cervix]. Zhonghua zhong liu za zhi [Chinese journal of oncology]. Mar 1995;17(2):112-114.

Lu L, Risch H, Irwin ML, Mayne ST, Cartmel B, Schwartz P, . . . Yu H. Long-term overweight and weight gain in early adulthood in association with risk of endometrial cancer. International journal of cancer. Journal international du cancer. Sep 1 2011;129(5):1237-1243.

Lukanova A, Lundin E, Micheli A, Arslan A, Ferrari P, Rinaldi S, . . . Zeleniuch-Jacquotte A. Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women. International journal of cancer. Journal international du cancer. Jan 20 2004;108(3):425-432.

Lukanova A, Zeleniuch-Jacquotte A, Lundin E, Micheli A, Arslan AA, Rinaldi S, . . . Kaaks R. Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer. International journal of cancer. Journal international du cancer. Jan 10 2004;108(2):262-268.

Lymperatou D, Giannopoulou E, Koutras AK, et al. The exposure of breast cancer cells to fulvestrant and tamoxifen modulates cell migration differently. Biomed Res Int. 2013;2013:147514.

Mann GE, Bonacasa B, Ishii T, et al. Targeting the redox sensitive Nrf2-Kaep1 defense pathway in cardiovascular disease: protection afforded by dietary isoflavones. Curr Opin Pharmacol. 2009 Apr;9(2):139-45.

Mann GE, Rowlands DJ, Li FY, et al. Activation of endothelial nitric oxide synthase by dietary isoflavones: role of NO in Nrf2-mediated antioxidant gene expression. Cardiovasc Res. 2007 Jul 15;75(2):261-74.

Manohar M, Fatima I, Saxena R, et al. (-)-Epigallocatechin-3-gallate induces apoptosis in human endometrial adenocarcinoma cells via ROS generation and p38 MAP kinase activation. J Nutr Biochem. 2013 Jun;24(6):940-7.

Mateos-Aparicio I, Redondo Cuenca A, Villanueva-Suarez MJ, et al. Soybean, a promising health source. Nutr Hosp. 2008 Jul-Aug;23(4):305-12.

MayoClinicStaff. Mayo Clinic. Endometrial Cancer; Tests and diagnosis. Available at: http://www.mayoclinic.com/health/endometrial-cancer/DS00306/DSECTION=tests-and-diagnosis. 2013.

McCann SE, Freudenheim JL, Marshall JR, Brasure JR, Swanson MK, Graham S. Diet in the epidemiology of endometrial cancer in western New York (United States). Cancer causes & control : CCC. Dec 2000;11(10):965-974.

McCarty MF. Isoflavones made simple – genistein’s agonist activity for the beta-type estrogen receptor mediates their health benefits. Med Hypotheses. 2006;66(6):1093-114.

McCullough ML, Bandera EV, Moore DF, Kushi LH. Vitamin D and calcium intake in relation to risk of endometrial cancer: a systematic review of the literature. Preventive medicine. Apr 2008;46(4):298-302.

McTiernan A, Irwin M, Vongruenigen V. Weight, physical activity, diet, and prognosis in breast and gynecologic cancers. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Sep 10 2010;28(26):4074-4080.

Melamed M, Castano E, Notides AC, Sasson S. Molecular and kinetic basis for the mixed agonist/antagonist activity of estriol. Molecular endocrinology (Baltimore, Md.). Nov 1997;11(12):1868-1878.

Michnovicz JJ, Adlercreutz H, Bradlow HL. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. Journal of the National Cancer Institute. May 21 1997;89(10):718-723.

Micke O, Schomburg L, Buentzel J, et al. Selenium in oncology: from chemistry to clinics. Molecules. 2009;14(10):3975-88.

Montz FJ, Bristow RE, Bovicelli A, Tomacruz R, Kurman RJ. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol. Apr 2002;186(4):651-657.

Moreno-Bueno G, Sánchez-Estévez C, Cassia R, et al. Differential gene expression profile in endometrioid and nonendometrioid endometrial carcinoma: STK15 is frequently overexpressed and amplified in nonendometrioid carcinomas. Cancer Res. 2003 Sep 15;63(18):5697-702.

Morotti M, Valenzano Menada M, Venturini PL, Ferrero S. Bevacizumab in endometrial cancer treatment. Expert Opin Biol Ther. May 2012;12(5):649-658.

Morrison C, Zanagnolo V, Ramirez N, Cohn DE, Kelbick N, Copeland L, Maxwell GL, Fowler JM. HER-2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients. J Clin Oncol. 2006 May 20;24(15):2376-85.

Mourits MJ, De Vries EG, Willemse PH, Ten Hoor KA, Hollema H, Van der Zee AG. Tamoxifen treatment and gynecologic side effects: a review. Obstetrics and gynecology. May 2001;97(5 Pt 2):855-866.

Mu N, Zhu Y, Wang Y, Zhang H, Xue F. Insulin resistance: a significant risk factor of endometrial cancer. Gynecol Oncol. Jun 2012;125(3):751-757.

Mulvey L, Chandrasekaran A, Liu K, et al. Interplay of genes regulated by estrogen and diindolylmethane in breast cancer cell lines. Mol Med. 2007 Jan-Feb;13(1-2):69-78.

Mutter GL. Endometrial intraepithelial neoplasm (EIN): will it bring order to chaos? The Endometrial Collaborative Group. Gynecol Oncol. 2000;76(3):287-90.

Nag S, Erickson B, Thomadsen B, Orton C, Demanes JD, Petereit D. The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. International journal of radiation oncology, biology, physics. Aug 1 2000;48(1):201-211.

Nagpal S, Chandraratna RA. Vitamin A and regulation of gene expression. Current opinion in clinical nutrition and metabolic care. Jul 1998;1(4):341-346.

Nakamura K, Hongo A, Kodama J, Hiramatsu Y. Fat accumulation in adipose tissues as a risk factor for the development of endometrial cancer. Oncology reports. Jul 2011;26(1):65-71.

Navaratnarajah R, Pillay OC, Hardiman P. Polycystic ovary syndrome and endometrial cancer. Semin Reprod Med. Jan 2008;26(1):62-71.

NCI. National Cancer Institue (NCI). What you need to know about Cancer of the Uterus; Diagnosis. Available at: http://www.cancer.gov/cancertopics/wyntk/uterus/page6. 2010. Accessed 8/28/2013.

NCI. National Cancer Institute (NCI). Stages of Endometrial Cancer. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/endometrial/Patient/page2. Last updated 6/18/2013. Accessed 8/28/2013.

Negin BP, Cohen SJ. Circulating tumor cells in colorectal cancer: past, present, and future challenges. Curr Treat Options Oncol. 2010 Jun;11(1-2):1-13.

Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol. 2001 Sep;45(3 Suppl):S116-24.

Neven P and Vernaeve H. Guidelines for Monitoring Patients Taking Tamoxifen Treatment. Drug Saf. 2000;22(1):1-11.

Nguyen H, Ivanova VS, Kavandi L, Rodriguez GC, Maxwell GL, Syed V. Progesterone and 1,25-dihydroxyvitamin D(3) inhibit endometrial cancer cell growth by upregulating semaphorin 3B and semaphorin 3F. Molecular cancer research : MCR. Nov 2011;9(11):1479-1492.

Nout RA, Smit VT, Putter H, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet. 2010 Mar 6;375(9717):816-23.

Nussler NC, Reinbacher K, Shanny N, et al. Sex-specific differences in the expression levels of estrogen receptor subtypes in coloectal cancer. Gend Med. 2008 Sep;5(3):209-17.

Odagiri T, Watari H, Hosaka M, Mitamura T, Konno Y, Kato T, . . . Sakuragi N. Multivariate survival analysis of the patients with recurrent endometrial cancer. J Gynecol Oncol. Mar 31 2011;22(1):3-8.

Ohno S, Sumiyoshi Y, Hashine K, Shirato A, Kyo S, Inoue M. Phase I Clinical Study of the Dietary Supplement, Agaricus blazei Murill, in Cancer Patients in Remission. Evidence-based complementary and alternative medicine : eCAM. 2011;2011:192381.

Ollberding NJ, Lim U, Wilkens LR, Setiawan VW, Shvetsov YB, Henderson BE, . . . Goodman MT. Legume, soy, tofu, and isoflavone intake and endometrial cancer risk in postmenopausal women in the multiethnic cohort study. Journal of the National Cancer Institute. Jan 4 2012;104(1):67-76.

Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM, . . . Eisenhauer EA. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Aug 20 2011;29(24):3278-3285.

Parajuli B, Shin SJ, Kwon SH, Cha SD, Lee HG, Bae I, Cho CH. The synergistic apoptotic interaction of Indole-3-Carbinol and Genistein with TRAIL on endometrial cancer cells. Journal of Korean medical science. Apr 2013;28(4):527-533.

Park JY, Kim DY, Kim TJ, Kim JW, Kim JH, Kim YM, Kim YT, Bae DS, Nam JH. Hormonal therapy for women with stage IA endometrial cancer of all grades. Obstet Gynecol. 2013 Jul;122(1):7-14.

Peach G, Kim C, Zacharakis E, et al. Prognostic significance of circulating tumour cells following surgical resection of colorectal cancers: a systematic review.Br J Cancer. 2010 Apr 27;102(9):1327-34.

Pelucchi C, Dal Maso L, Montella M, Parpinel M, Negri E, Talamini R, . . . La Vecchia C. Dietary intake of carotenoids and retinol and endometrial cancer risk in an Italian case-control study. Cancer causes & control : CCC. Dec 2008;19(10):1209-1215.

Plataniotis G, Castiglione M, ESMO Guidelines Working Group. Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010 May;21 Suppl 5:v41-5.

Pocobelli G, Doherty JA, Voigt LF, Beresford SA, Hill DA, Chen C, . . . Weiss NS. Pregnancy history and risk of endometrial cancer. Epidemiology (Cambridge, Mass.). Sep 2011;22(5):638-645.

Punnonen R, Mattila J, Kuoppala T, Koivula T. DNA ploidy, cell proliferation and steroid hormone receptors in endometrial hyperplasia and early adenocarcinoma. J Cancer Res Clin Oncol. 1993;119(7):426-429.

Purdie DM, Green AC. Epidemiology of endometrial cancer. Best Pract Res Clin Obstet Gynaecol. Jun 2001;15(3):341-354.

Rahaman J and Cohen CJ. Gynecologic Sarcomas. In Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6h Edition. Chapter 120. Hamilton (ON): BC Decker; 2003. <http://www.ncbi.nlm.nih.gov/books/NBK13954/>

Rahbari NN, Bork U, Kircher A, Nimitz T, Schölch S, Kahlert C, Schmidt T, Steinert G, Ulrich AB, Reissfelder C, Büchler MW, Koch M, Weitz J. Compartmental differences of circulating tumor cells in colorectal cancer.Ann Surg Oncol. 2012 Jul;19(7):2195-202.

Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS, Fowler J, . . . Gynecologic Oncology Group S. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jan 1 2006;24(1):36-44.

Rüdiger N, Stein EL, Schill E, et al. Chemosensitivity Testing of Circulating Epithelial Tumor Cells (CETC) in Vitro: Correlation to in Vivo Sensitivity and Clinical Outcome. J Cancer Therapy 2013, 4:597-605.

Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. Bmj. Dec 1 2007;335(7630):1134.

Reiter RJ. Mechanisms of cancer inhibition by melatonin. Journal of pineal research. Oct 2004;37(3):213-214.

Rimbach G, Boesch-Saadatmandi C, Frank J, et al. Dietary isoflavones in the prevention of cardiovascular disease—a molecular perspective. Food Chem Toxicol. 2008 Apr;46(4):1308-19.

Rosenblatt PL. The Merck Manual. Menstrual Cycle. Available at:  http://www.merckmanuals.com/home/womens_health_issues/biology_of_the_female_reproductive_system/menstrual_cycle.html. Last updated July 2007. Accessed 8/28/2013.  

Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. Journal of the National Cancer Institute. Feb 16 2000;92(4):328-332.

Rudolf E, Rudolf K, Cervinka M. Selenium activates p53 and p38 pathways and induces caspase-independent cell death in cervical cancer cells. Cell Biol Toxicol. 2008;24(2):123-41.

Sainz RM, Mayo JC, Tan DX, et al. Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism. Prostate. 2005 Apr 1;63(1):29-43.

Salazar-Martinez E, Lazcano-Ponce E, Sanchez-Zamorano LM, Gonzalez-Lira G, Escudero DELRP, Hernandez-Avila M. Dietary factors and endometrial cancer risk. Results of a case-control study in Mexico. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. Sep-Oct 2005;15(5):938-945.

Sanchez-Barcelo EJ, Cos S, Mediavilla D, Martinez-Campa C, Gonzalez A, Alonso-Gonzalez C. Melatonin-estrogen interactions in breast cancer. Journal of pineal research. May 2005;38(4):217-222.

Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S. Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu. Int J Gynaecol Obstet. Aug 2008;102(2):128-131.

Saydmohammed M, Joseph D, Syed V. Curcumin suppresses constitutive activation of STAT-3 up-regulating protein inhibitor of activated STAT-3 (PIAS-3) in ovarian and endometrial cancer cells. J Cell Biochem. 2010;110(2):447-56.

Schiavone MB, Bashir S, Herzog TJ. Biologic therapies and personalized medicine in gynecologic malignancies. Obstet Gynecol Clin North Am. 2012 Jun;39(2):131-44.

Schmandt RE, Iglesias DA, Co NN, Lu KH. Understanding obesity and endometrial cancer risk: opportunities for prevention. Am J Obstet Gynecol. Dec 2011;205(6):518-525.

Schouten LJ, Goldbohm RA, van den Brandt PA. Anthropometry, physical activity, and endometrial cancer risk: results from the Netherlands Cohort Study. Journal of the National Cancer Institute. Nov 3 2004;96(21):1635-1638.

Sexton E, Van Themsche C, LeBlanc K, et al. Resveratrol interferes with AKT activity and triggers apoptosis in human uterine cancer cells. Mol Cancer. 2006;5:45.

Shah YM, Al-Dhaheri M, Dong Y, Ip C, Jones FE, Rowan BG. Selenium disrupts estrogen receptor (alpha) signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells. Molecular cancer therapeutics. Aug 2005;4(8):1239-1249.

Shehzad A, Khan S, Sup Lee Y. Curcumin molecular targets in obesity and obesity-related cancers. Future Oncol. 2012;8(2):179-90.

Shimada M, Kigawa J, Terakawa N, et al. Phase I trial of paclitaxel, doxorubicin, and carboplatin (TAC) for the treatment of endometrial cancer. Int J Gynecol Cancer. 2007 Jan-Feb;17(1):210-4.

Shweel MA, Abdel-Gawad EA, Abdel-Gawad EA, et al. Uterine cervical malignancy: diagnostic accuracy of MRI with histopathologic correlation. J Clin Imag Sci. 2012;2:42.

Slomovitz BM, Broaddus RR, Burke TW, Sneige N, Soliman PT, Wu W, . . . Lu KH. Her-2/neu overexpression and amplification in uterine papillary serous carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Aug 1 2004;22(15):3126-3132.

Slomovitz BM, Coleman RL. The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer.  Clin Cancer Res. 2012 Nov 1;18(21):5856-64.

Smiraglia DJ, Smith LT, Lang JC, et al. Differential targets of CpG island hypermethylation in primary and metastatic head and neck squamous cell carcinoma (HNSCC). J Med Genet. 2003 Jan; 40(1):25-33.

Smolarek AK, So JY, Thomas PE, Lee HJ, Paul S, Dombrowski A, . . . Suh N. Dietary tocopherols inhibit cell proliferation, regulate expression of ERalpha, PPARgamma, and Nrf2, and decrease serum inflammatory markers during the development of mammary hyperplasia. Mol Carcinog. 2013 Jul;52(7):514-25.

Soliman PT, Cui X, Zhang Q, Hankinson SE, Lu KH. Circulating adiponectin levels and risk of endometrial cancer: the prospective Nurses' Health Study. Am J Obstet Gynecol. Feb 2011;204(2):167.e161-165.

Soliman PT, Oh JC, Schmeler KM, Sun CC, Slomovitz BM, Gershenson DM, . . . Lu KH. Risk factors for young premenopausal women with endometrial cancer. Obstetrics and gynecology. Mar 2005;105(3):575-580.

Soliman PT, Wu D, Tortolero-Luna G, Schmeler KM, Slomovitz BM, Bray MS, . . . Lu KH. Association between adiponectin, insulin resistance, and endometrial cancer. Cancer. Jun 1 2006;106(11):2376-2381.

Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Therapeutic actions of melatonin in cancer: possible mechanisms. Integr Cancer Ther. Sep 2008;7(3):189-203.

Suh DH, Kim JW, Kim K, Kim HJ, Lee KH. Major clinical research advances in gynecologic cancer in 2012. J Gynecol Oncol. Jan 2013;24(1):66-82.

Swerdlow AJ, Jones ME, British Tamoxifen Second Cancer Study G. Tamoxifen treatment for breast cancer and risk of endometrial cancer: a case-control study. Journal of the National Cancer Institute. Mar 2 2005;97(5):375-384.

Takahashi K, Okada M, Ozaki T, Kurioka H, Manabe A, Kanasaki H, Miyazaki K. Safety and efficacy of oestriol for symptoms of natural or surgically induced menopause. Human reproduction (Oxford, England). May 2000;15(5):1028-1036.

Tang NP, Li H, Qui YL, et al. Tea consumption and risk of endometrial cancer: a metaanalysis. Am J Obstet Gynecol. 2009;201(6):605.e1-8.

Tang YZ, Liu ZQ. Chemical kinetic behavior of chlorogenic acid in protecting erythrocyte and DNA against radical-induced oxidation. J Agric Food Chem. 2008;56(22):11025-9.

Tannus SR, Atlas I. Endometrial cancer presenting as acute urinary retention: a case report and review of the literature. Cases J. 2009 Dec 22;2:9382.

Tao MH, Freudenheim JL. DNA methylation in endometrial cancer. Epigenetics. 2010 Aug 16;5(6):491-8.

Tao MH, Xu WH, Zheng W, Gao YT, Ruan ZX, Cheng JR, . . . Shu XO. A case-control study in Shanghai of fruit and vegetable intake and endometrial cancer. British journal of cancer. Jun 6 2005;92(11):2059-2064.

Terry P, Baron JA, Weiderpass E, Yuen J, Lichtenstein P, Nyren O. Lifestyle and endometrial cancer risk: a cohort study from the Swedish Twin Registry. International journal of cancer. Journal international du cancer. Jul 2 1999;82(1):38-42.

Terry P, Vainio H, Wolk A, Weiderpass E. Dietary factors in relation to endometrial cancer: a nationwide case-control study in Sweden. Nutrition and cancer. 2002;42(1):25-32.

Terry P, Wolk A, Vainio H, Weiderpass E. Fatty fish consumption lowers the risk of endometrial cancer: a nationwide case-control study in Sweden. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Jan 2002;11(1):143-145.

The Merck Manual. Endometrial Cancer. The Merck Manual online version. Available at: http://www.merckmanuals.com/professional/gynecology_and_obstetrics/gynecologic_tumors/endometrial_cancer.html. Last updated 5/2013. Accessed 8/21/2013.

Tong T, Yajia G, Huaying W, et al. Application of 1.5 T magnetic resonance imaging in endometrial cancer. Arch Gynecol Obstet. 2012;285(4):1113-8.

Traber MG, Stevens JF. Vitamins C and E: beneficial effects from a mechanistic perspective. Free radical biology & medicine. Sep 1 2011;51(5):1000-1013.

Trichopoulou A, Lagiou P, Kuper H, Trichopoulos D. Cancer and Mediterranean dietary traditions. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Sep 2000;9(9):869-873.

Tunnicliffe JM, Shearer J. Coffee, glucose homeostatis, and insulin resistance: physiological mechanisms and mediators. Appl Physiol Nutr Metab. 2008 Dec;33(6):1290-1300.

Turner RT, Wakley GK, Hannon KS, et al. Tamoxifen prevents the skeletal effects of ovarian hormone deficiency in rats. J Bone Miner Res. 1987 Oct; 2(5):449-56.

USDA  (U.S. Department of Agriculture). USDA National Nutrient Database for Standard Reference, Release 24. Available at: http://www.nutrition.gov/whats-food/vitamins-minerals/individual-vitamins. Last updated 8/26/2013. Accessed 8/28/2013.

Ushijima K, Yahata H, Yoshikawa H, et al. Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women. Journal of Clinical Oncology. 2007;25(19):2798–2803.

van Dijk AE, Olthof MR, Meeuse JC, et al. Acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on glucose tolerance.Diabetes Care. 2009 Jun;32(6):1023-5.

Vooijs GP, Geurts TB. Review of the endometrial safety during intravaginal treatment with estriol. European journal of obstetrics, gynecology, and reproductive biology. Sep 1995;62(1):101-106.

Vorvick LJ, Zieve D. MedlinePlus website; uterus. Updated 2/26/2012. Available at: http://www.nlm.nih.gov/medlineplus/ency/imagepages/19263.htm. Accessed 8/30/20123.

Wang S, Liu K, Liu J, et al. Highly efficient capture of circulating tumor cells by using nanostructured silicon substrates with integrated chaotic micromixers. Angew Chem Int Ed Engl. 2011 Mar 21;50(13):3084-8.

Weiderpass E, Baron JA, Adami HO, Magnusson C, Lindgren A, Bergstrom R, . . . Persson I. Low-potency oestrogen and risk of endometrial cancer: a case-control study. Lancet. May 29 1999;353(9167):1824-1828.

Weiderpass E, Persson I, Adami HO, Magnusson C, Lindgren A, Baron JA. Body size in different periods of life, diabetes mellitus, hypertension, and risk of postmenopausal endometrial cancer (Sweden). Cancer causes & control : CCC. Feb 2000;11(2):185-192.

Weiss NS, Szekely DR, Austin DF. Increasing incidence of endometrial cancer in the United States. The New England journal of medicine. Jun 3 1976;294(23):1259-1262.

Westin SN, Broaddus RR. Personalized therapy in endometrial cancer: challenges and opportunities. Cancer Biol Ther. Jan 1 2012;13(1):1-13.

Williams CJ, Fargnoli JL, Hwang JJ, van Dam RM, Blackburn GL, Hu FB, Mantzoros CS. Coffee consumption is associated with higher plasma adiponectin concentrations in women with or without type 2 diabetes: a prospective cohort study. Diabetes care. Mar 2008;31(3):504-507.

Wood CE, Register TC, Franke AA, et al. Dietary soy isoflavones inhibit estrogen effects in the postmenopausal breast. Cancer Res. 2006 Jan 15;66(2):1241-9.

Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. The Menopause Study Group. Am J Obstet Gynecol. May 1994;170(5 Pt 1):1213-1223.

Wright JD, Barrena Medel NI, Sehouli J, Fujiwara K, Herzog TJ. Contemporary management of endometrial cancer. Lancet. Apr 7 2012;379(9823):1352-1360.

Wu T, Willett WC, Hankinson SE, Giovannucci E. Caffeinated coffee, decaffeinated coffee, and caffeine in relation to plasma C-peptide levels, a marker of insulin secretion, in U.S. women. Diabetes care. Jun 2005;28(6):1390-1396.

Wulfing P, Borchard J, Buerger H, Heidl S, Zanker KS, Kiesel L, Brandt B. HER2-positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients. Clinical cancer research : an official journal of the American Association for Cancer Research. Mar 15 2006;12(6):1715-1720.

Wynder EL, Escher GC, Mantel N. An epidemiological investigation of cancer of the endometrium. Cancer. Apr 1966;19(4):489-520.

Xiao CW. Health effects of soy protein and isoflavones in humans. J Nutr. 2008 Jun;138(6):1244S-9S.

Xie Y, Wang YL, Yu L, Hu Q, Ji L, Zhang Y, Liao QP. Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells. J Steroid Biochem Mol Biol. Sep 2011;126(3-5):113-120.

Xu WH, Dai Q, Xiang YB, Zhao GM, Ruan ZX, Cheng JR, . . . Shu XO. Nutritional factors in relation to endometrial cancer: a report from a population-based case-control study in Shanghai, China. International journal of cancer. Journal international du cancer. Apr 15 2007;120(8):1776-1781.

Xu WH, Zheng W, Xiang YB, Ruan ZX, Cheng JR, Dai Q, . . . Shu XO. Soya food intake and risk of endometrial cancer among Chinese women in Shanghai: population based case-control study. Bmj. May 29 2004;328(7451):1285.

Yang S, Thiel KW, De Geest K, et al. Endometrial cancer: reviving progesterone therapy in the molecular age. Discov Med. 2011;12(64):205-12.

Yeh M, Moysich KB, Jayaprakash V, Rodabaugh KJ, Graham S, Brasure JR, McCann SE. Higher intakes of vegetables and vegetable-related nutrients are associated with lower endometrial cancer risks. The Journal of nutrition. Feb 2009;139(2):317-322.

Yu M, Stott S, Toner M, et al. Circulating tumor cells: approaches to isolation and characterization.J Cell Biol. 2011 Feb 7;192(3):373-82.

Yu Y, Bae S, Kim H, et al. The Anti-tumor Activity of Vitamin C via the Increase of Fas (CD95) and MHC I Expression on Human Stomach Cancer Cell Line, SNU1. Immune Netw. 2011 Aug;11(4):210-5.

Yu Z, Shah DM. Curcumin down-regulates Ets-1 and Bcl-2 expression in human endometrial carcinoma HEC-1-A cells. Gynecol Oncol. 2007;106(3):541-8.

Zagouri F, Bozas G, Kafantari E, Tsiatas M, Nikitas N, Dimopoulos MA, Papadimitriou CA. Endometrial cancer: what is new in adjuvant and molecularly targeted therapy? Obstet Gynecol Int. 2010;2010:749579.

Zhang H, Gao C, Fang L, Zhao HC, Yao SK. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a meta-analysis. Scand J Gastroenterol. Jan 2013;48(1):78-87.

Zhang P, Li H, Tan X, Chen L, Wang S. Association of metformin use with cancer incidence and mortality: A meta-analysis. Cancer Epidemiol. Jan 23 2013.

Zhang Z, Dong L, Sui L, Yang Y, Liu X, Yu Y, . . . Feng Y. Metformin reverses progestin resistance in endometrial cancer cells by downregulating GloI expression. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. Feb 2011;21(2):213-221.

Zhang ZH, Su PY, Hao JH, Sun YH. The role of preexisting diabetes mellitus on incidence and mortality of endometrial cancer: a meta-analysis of prospective cohort studies. Int J Gynecol Cancer. Feb 2013;23(2):294-303.

Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. The New England journal of medicine. Dec 4 1975;293(23):1167-1170.