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 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).
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.”