The Correlation Between Endometrial Cancer and Obesity

The Correlation Between
Endometrial Cancer and Obesity:
The Necessary Public Health Response 

By: Jennifer S. Taillie, NHS ’03

tailliej@georgetown.edu

Endometrial cancer is the most common gynecological cancer. Data from 1999 show that in the United States, endometrial cancer accounted for roughly 6% of all incident cancers and 2% of cancer deaths in women (Purdie & Green, 2001). The American Cancer Society estimated in 2000, that 36,100 new cases of endometrial cancer had been diagnosed in the U.S. and that about 6,500 women had died from the disease (Akhmedkhanov, A., Zeleniuch-Jacquotte, A., and Toniello,P. 2001). Kaaks et al. in 2002, reported that Western, industrialized countries have up to 10 times higher incidence rates than in Asia or Africa. Additionally, industrial development and migration from low-risk to high-risk areas have exacerbated incidence rates over time, suggesting that endometrial cancer has strong environmental risk factors related to the westernization of lifestyle (Kaaks et al., 2002). 

In recent years, the study of obesity as an epigenetic risk factor has revealed a strong correlation to endometrial cancer (Purdie & Green, 2001, Akhmedkhanov et al., 2001, Kaaks et al., 2002, Bergstrom et al., 2001). This is a significant relationship due to the rapid spread of the obesity epidemic in the U.S. A person is considered obese when his or her body mass index (BMI), a number that shows body weight adjusted for height, is greater than or equal to 30 kg/m2. The Centers for Disease Control and Prevention reports that in 2000, the prevalence of obesity among U.S. adults was 19.8%, reflecting a 61% increase since 1991. Obesity prevalence climbed to 20.9% of American adults between 2000 and 2001. Additionally, 20.8% of American women were considered obese. Obesity prevalence rates appear to increase with age until the age of 70 when there is a marked decline (Centers for Disease Control and Prevention, 2003). This is significant because endometrial cancer is commonly found in women between the ages of 50 and 65 years in western populations (Purdie & Green, 2001). It is widely agreed upon that regular physical activity is extremely helpful for the prevention of obesity. Because of the strong correlation between obesity and endometrial cancer, health-promotion and disease-prevention programs need to target physical activity to help lower the incidence of endometrial cancer in the U.S.

Endometrial Cancer

Most risk factors that have been linked to endometrial cancer are associated with excessive estrogen (Table 1). According to Rose (1996), excessive estrogen produces continued stimulation of the endometrium, which can result in endometrial hyperplasia – an abnormal increase in cell number. Several risk factors for endometrial cancer have been identified by epidemiological research, including age, obesity, postmenopausal estrogen replacement, diabetes mellitus, ovarian dysfunction, early menarche, late menopause, infertility, and nulliparity (Akhmedkhanov et al., 2001).

There are two theories of endometrial carcinogenesis. The dualistic model incorporates separate pathways influenced by different epidemiological risk factors, histopathologic lesions, and molecular events. With the traditional mechanism, idle tumors develop from hyperplastic precursors in an estrogen-rich environment. Alternatively, it has been proposed that many aggressive tumors develop in absence of hyperplasia or estrogen excess. There are two main types of endometrial carcinomas that correspond to these pathways. Type I tumors are products of the classic pathway and are “idle neoplasms associated with hyperlipidemia, obesity, and signs of hyperestrogenism, such as anovulatory bleeding, infertility, late menopause, and endometrial and ovarian stromal hyperplasia” (Sherman, 2000). Conversely, type II tumors are associated with the alternative pathway and are largely unrelated to estrogen. Research suggests the majority of type I tumors correspond to endometriod carcinomas while type II tumors include mostly serous carcinomas. Because of these findings, the term type I is interchangeable with endometriod andtype II with serous (Sherman, 2000).

While the pathogenesis of endometriod carcinoma is largely influenced by specific risk factors, the pathogenesis of serous carcinomas is not. Because estrogen promotes type I endometrial carcinoma by stimulating rapid proliferation of epithelial cells, a common risk factor associated with type II tumors is obesity. The only definite risk factor for serous carcinoma is age, since it typically develops in elderly women with atrophic endometrium (Sherman, 2000). Given that type II tumors are less common, and are associated with one, unalterable risk factor, age, emphasis should be placed on the type I tumors and on how to prevent their pathogenesis through risk factor modifications.

Endogenous hormones and growth factors are thought to influence endometrial cancer risk through regulatory effects on the balance among cell proliferation, differentiation, and apoptosis. The relationship between endogenous hormones and endometrial cancer can be effectively explained within the

framework of the unopposed estrogen hypothesis (Kaaks et al., 2002). 

This hypothesis proposes that “exposure to endogenous or exogenous estrogens [unopposed] by progesterone or synthetic progestins increases the mitotic activity of endometrial cells, resulting in increased DNA replication errors and somatic mutations, ultimately easing to endometrial hyperplasia and malignant phenotype” (Akhmedkhanov et al., 2001).  While most endometrial cancer risk factors affect premenopausal orpostmenopausal women, obesity is a widely accepted endogenous risk factor affecting both (Akhmedkhanov et al.,2001)

Obesity

It is proposed that obesity increases the risk of endometrial cancer by increasing the conversion of androgens to estrogens in the adipose tissue of postmenopausal women.  In premenopausal women, increased anovulatory cycles and associated progesterone insufficiency resulting from obesity are the theoretical causes of endometrial cancer (Potischman et al., 1996).  Additionally, factors involving energy balance, BMI and sex hormone-binding globulin (SHBG) contribute to the increased risk of endometrial cancer in conjunction with obesity.

Evidence by Potischam et al. (1996) suggests that obesity is “linked to higher circulating levels of free estradiol as a consequence of lower concentrations of SHBG that tightly binds estrogens.”  Thomas et al. (1997) replicated this study and confirmed the results. SHBG is a glycoprotein, which has specific binding sites for both estrogens and androgens.  Several studies have shown that increasing BMI is coupled with decreasing SHBG in premenopausal women as well as in postmenopausal women.  Though the exact mechanism is unknown, this effect may be due to the rise in insulin levels associated with increasing BMI.  As BMI increases above 30 kg/m2 in premenopausal women, SHBG falls and there is an increase in circulating levels of free estradiol, regulated by homeostatic control.  Normally, the ovaries in a premenopausal woman also produce progesterone; however the incidence of anovulatory cycles increases with clinical obesity, resulting in low levels of progesterone due to the failure to produce a corpus luteum.  Thus, the exposure to high levels of estradiol unopposed by progesterone in obese premenopausal women increases the risk of endometrial cancer up to 20-fold (Key et al., 2001).

In post-menopausal women the ovaries do not produce progesterone or estradiol.  Postmenopausal women obtain the needed estradiol from androstenedione, which is secreted by the adrenal glands.  Aromatase converts androstenedione to estrone in the peripheral adipose tissue, with some of the estrone then converted to estradiol.  Postmenopausal women, however, do not  have the feedback mechanism to regulate estradiol and consequently, obese postmenopausal women have much higher serum estradiol concentrations.  Coupled with the lack of ovarian progesterone production, obese postmenopausal women have a 5- to 10-fold increased risk of developing endometrial cancer (Key et al., 2001).

According to the first law of thermodynamics, obesity results from an imbalance between energy expenditure and energy intake.  Energy expenditure is comprised of resting energy expenditure, physical activity and thermic effect of food.  Energy expenditure is strongly linked to fat-free body mass.   Higher basal energy expenditure indicates there is more fat-free body mass (Bray, 2002).  Energy balance can affect the risk of endometrial cancer due to its ability to alter sex hormones.  Excessive energy intake relative to expenditure leads to a high BMI (Key et al., 2001).  If a woman’s BMI increases to the point of clinical obesity unopposed, excessive estrogen results, causing an increased risk of endometrial cancer.

Leptin is a hormone synthesized and secreted by adipose tissue that acts a signal in a feedback loop to suppress body fat by decreasing food intake or increasing energy expenditure.  Because leptin is strongly, positively associated with obesity, researchers in Greece recently attempted to examine the relationship between leptin and endometrial cancer (Petridou et al., 2002).  Petridou et al. (2002), found that leptin was indeed strongly, positively associated with endometrial cancer, but these researchers were unable to determine whether leptin elevation, as a consequence of obesity, plays a role in endometrial carcinogenesis or whether it is a simple correlate of obesity.  An additional theory proposes that leptin may adversely affect luteal phase progesterone output, thus leaving the endometrium less protected than in normal weight individuals (Hale et al., 2002).

In order to reduce the incidence of endometrial cancer in American women, the public health sector needs to target physical activity as a way of addressing obesity.  Physical activity is a modifiable risk factor for obesity-related endometrial cancer.  Nine out of 13 studies of endometrial cancer found evidence for decreased risk and an average reduction of 30-40% with increased physical activity (Friedenreich and Orenstein, 2002).  Understanding the operative biological

mechanisms of physical activity and cancer are needed to better understand how alterations in activity levels can influence cancer risk.  This understanding is essential in the development public health recommendations that will maximize the effectiveness of physical activity for cancer risk reduction (Friedenreich & Orenstein, 2002). 

Prevention

In order to reduce the incidence of endometrial cancer in American women, the public health sector needs to target physical activity as a way of addressing obesity.  Physical activity is a modifiable risk factor for obesity-related endometrial cancer.  Nine out of 13 studies of endometrial cancer found evidence for decreased risk and an average reduction of 30-40% with increased physical activity (Friedenreich and Orenstein, 2002).  Understanding the operative biological mechanisms of physical activity and cancer are needed to better understand how alterations in activity levels can influence cancer risk.  This understanding is essential in the development public health recommendations that will maximize the effectiveness of physical activity for cancer risk reduction (Friedenreich & Orenstein, 2002).

There are several proposed biological mechanisms, which address changes in endogenous sexual and metabolic hormone levels and growth factors, decreased obesity and central adiposity, as well as changes in immune function.  To combat obesity, physical activity lowers the levels of biologically available sex hormones, which contribute to endometrial carcinogenesis.  Not only does physical activity decrease endogenous production of estrogens, it also increases the amount of circulating SHGB, which binds to these estrogens, reducing their ability to influence target tissues (Friedenreich & Orenstein, 2002).

Weight control is a particularly important link between physical activity and cancer prevention.   The concept of energy balance illustrates the direct association between physical activity and weight control.  A positive energy balance results in increased weight and increased adiposity, while a negative energy balance results in weight loss.  Stable body weight is achieved when there is energy balance between energy intake and expenditure.  Because internal body processes govern energy expended through metabolism and the thermic effect of food, physical activity needs to be targeted as a way to increase energy expenditure (Friedenreich & Orenstein, 2002).

Within the past ten years, numerous studies have demonstrated the association between upper-body or central fat distribution and increased risk for endometrial cancer (Potischman et al., 1996).  Physical activity may also prevent endometrial carcinogenesis through a reduction in abdominal fat mass.  While decreasing dietary intake and increasing physical activity both contribute to weight loss, evidence suggests physical activity may preferentially reduce intra-abdominal fat, which is more strongly associated with long term weight loss and maintenance (Friedenreich & Orenstein, 2002).

Conclusion

Following recommendations from former U.S. Surgeon General, Dr. C. Everett Koop, NIH recently lowered the threshold BMI to 25.0. The economic impact of obesity is now comparable to that of diabetes, and ranks with what is spent nationally on heart disease and hypertension (Wellness Junction, 2001). A study from 1995 reported that total U.S. healthcare expenditures attributable to obesity were $51.6 billion dollars in direct costs, while a study from 2000 estimated annual medical care costs for endometrial cancer was $10,375 (Oster et al., 2000).

The obesity epidemic, combined with endometrial cancer implications, has created an enormous financial burden for the U.S. health care system. The strong relationship between obesity and endometrial cancer signifies the need for health-promotion and disease-prevention programs to target physical activity in addressing these health problems. In addition to lowering the incidence of both obesity and endometrial cancer and saving healthcare dollars, physical activity improves several aspects of health-related quality of life in obese individuals, including psychological functioning and perceived health (Rissanen & Fogelholm, 1999). The economic and health burdens on society related to obesity and endometrial cancer demonstrate the urgent need for health promotion and disease prevention programs to target physical activity in order to reduce the incidence of obesity and endometrial cancer.

References

Copyright © 2003  Georgetown Journal of Health Sciences. All rights reserved.
Revised: 12/03/03.