IJE Advance Access originally published online on January 4, 2006
International Journal of Epidemiology 2006 35(1):166-168; doi:10.1093/ije/dyi301
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Commentary |
Commentary: Weight gain, weight loss, and endometrial cancer
Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, Qld 4029, Australia. E-mail: Penny.webb{at}qimr.edu.au
It has long been recognized that women who develop endometrial cancer are often overweight1 and obesity is now clearly established as a major risk factor for the disease.2 In pre-menopausal women, obesity is associated with an increased frequency of anovulatory cycles and, as a result, the endometrium is exposed to oestrogen in the absence of progesterone. Among post-menopausal women, obesity is again associated with exposure to higher levels of endogenous oestrogen as a result of increased conversion of androstenedione to oestrone in adipose tissue and lower levels of sex-hormone binding globulin (SHBG). In the absence of progesterone, unopposed oestrogen stimulates cellular proliferation in the endometrium leading to hyperplasia and, potentially, cancer.3
It has been estimated that up to 40% of all endometrial cancers could be related to obesity,2 a figure that is rising as the prevalence of obesity increases.4 More than 1.1 billion adults worldwide are now classified as overweight according to the WHO criteria5 [body mass index (BMI) 
25 kg/m2] and approximately one-third of middle-aged women in Europe and North America are classified as obese (BMI 30 kg/m2).6 In the US, it is predicted that obesity will soon overtake smoking as the main preventable cause of illness and premature death.6
Endometrial cancer is now the fourth most common cancer in women and the most common gynaecological cancer in Western countries.7 Rates in the US were very high in the mid-1970s, owing to the common use of oestrogens for relief of menopausal symptoms, but they then fell dramatically in the late 1970s and 1980s with the recognition that unopposed oestrogen use increased endometrial cancer risk.8 In contrast, in the UK, the incidence of endometrial cancer has remained fairly constant over the last 40–50 years. There is now a suggestion, however, that rates are starting to rise and one likely explanation for any such increase is the rise in prevalence of obesity.4,7 Furthermore, given that endometrial cancer is predominantly a disease of older age whereas obesity is currently more common among middle-aged women,6,9 it is likely that the full effects of the obesity epidemic on endometrial cancer rates have yet to be seen.
Two papers published in this issue of the International Journal of Epidemiology have addressed the role of obesity in endometrial cancer, paying particular attention to the timing of obesity and the effects of weight change.10,11 What makes these two case–control studies particularly interesting is that they were conducted in very different populations yet show essentially identical results. The study by Xu et al.10 was conducted in Shanghai, China where endometrial cancer rates are among the lowest in the world,7 use of oestrogen replacement therapy is rare and obesity is, as yet, uncommon. In contrast, the study by Trentham-Dietz et al.11 was conducted in the US where endometrial cancer rates are the highest in the world7 and use of oestrogen replacement therapy and obesity are very common. Despite these differences, both groups reported 3-fold increases in risk of endometrial cancer among the heaviest women compared with the lightest. It is noteworthy that in the US study, which was conducted in the early 1990s, 50% of control women were overweight or obese and, if that study had been conducted 10 years later, the figure would have been closer to 60–65%.9 In contrast, only 25% of control women in the Chinese study (conducted from 1997–2001) were overweight.
A number of studies have shown that although body size in adolescence is associated with an increased risk of endometrial cancer, the associations all but disappear after controlling for recent body-mass, which appears to be the most important determinant of risk.12,13 Xu et al.10 reported a similar effect but went one step further to evaluate the effects of obesity and weight change at different ages during adulthood. They found that the association between endometrial cancer and high BMI at any given decade of age was stronger than that for the previous decade, with the strongest effect seen for recent BMI (1 year prior to diagnosis/interview). While this pattern might be due in part to better recall of more recent weights, and thus less non-differential misclassification, and/or to the gradual increase in the average BMI in the highest group with increasing age, the data do provide evidence that recent weight is important. The authors also found that weight gain in recent decades was associated with an increased risk of endometrial cancer after adjusting for initial weight. Importantly, these effects were not restricted to those who were currently overweight suggesting that any appreciable weight gain may increase a woman's risk even if this does not take her over the threshold of 25 kg/m2.
The solution would appear to be clear—preventing obesity should prevent a large proportion of endometrial cancers. The challenge, however, is enormous; the increasingly calorie-rich diets and sedentary lifestyles of the West are highly conducive to weight gain and reversing this trend is far from simple. Furthermore, many women are already obese and for them the more relevant question is whether losing weight will reduce their risk of endometrial cancer or if this is already pre-determined by their body-size earlier in life. Oestrogen appears to act relatively late in the carcinogenic process, thereby explaining the very rapid rise and fall in endometrial cancer rates seen in the US following the increase and subsequent decrease in use of oestrogen replacement therapy.8 If, as thought, the effects of obesity are largely mediated by the associated increases in exposure to endogenous oestrogen then it is likely that obesity also acts at a late stage as a cancer promoter. This is good news for prevention because, in theory, weight loss should then reduce a woman's risk of endometrial cancer.
However, despite the evidence that weight gain and current obesity are strongly associated with endometrial cancer risk, there is currently very limited information regarding the effects of weight loss. This may be due in part to the challenges associated with losing weight and maintaining that weight loss over time and, in addition, it can be difficult to separate the effects of weight change from current weight. In the Iowa Women's Health Study, a previous episode of intentional weight loss of >20 pounds (9 kg) had a negligible effect on the incidence of endometrial cancer during follow-up.14 It is important to note, however, that 83% of the women who reported an episode of intentional weight loss were overweight at the start of follow-up suggesting that most had regained the weight they had previously lost. It is perhaps, therefore, not surprising that they did not experience any reduction in endometrial cancer, although an effect was seen for breast cancer. On a more positive note, women in the Netherlands whose BMI at the start of follow-up was lower than their BMI at age 20 (12% of the cohort) did have a 50% lower risk of going on to develop endometrial cancer than those whose BMI had remained constant or increased slightly.15
Some further support for a beneficial effect of weight loss comes from the study in this issue by Trentham-Dietz et al.11 who attempted to evaluate the effects of weight loss by comparing women's maximum and minimum weights during adulthood. They concluded that women who had sustained some degree of weight loss (the amount was not specified) for 5 years or more had a 25% lower risk of developing endometrial cancer than those who had not lost weight.11 Nevertheless, although it seems logical that weight loss should reduce risk of endometrial cancer (as well as many other health conditions), there is still insufficient evidence to conclude this with any certainty and further studies that pay particular attention to the effects of sustained weight loss among obese individuals are required.
Finally, it is important to note that the vast majority of studies have considered endometrial carcinoma as a single disease. There are, however, several different histological subtypes of endometrial carcinoma, and these are broadly classified into two major groups. The type I or oestrogen-dependent cancers are predominantly low-grade endometrioid tumours that are associated with good prognosis. In contrast, the less common type II or non-oestrogen-dependent cancers are mostly high-grade serous papillary, clear cell or adenosquamous carcinomas that develop in older women and have a much poorer prognosis.16 A similar spectrum of tumour types is seen for ovarian cancer and there is increasing evidence that these different subtypes may differ in their aetiology.17,18 As more than 80% of endometrial cancers are endometrioid tumours the observed effects of obesity (and exogenous oestrogens) may relate only to this subtype. Although much less common, the type II tumours are usually more aggressive than the endometrioid cancers, thus they account for a relatively greater proportion of endometrial cancer deaths. Very little is currently known about their aetiology, although limited data suggest that they may not be associated with either obesity or oestrogen use,19 and further investigation is warranted.
 |
References |
|---|
 Top References |
|---|
1 Twombly G, Scheiner S, Levitz M. Endometrial cancer, obesity and estrogenic excretion in women. Am J Obstet Gynecol 1961;82:424–27.[Web of Science][Medline]
2 Vainio H, Bianchini F. Weight Control and Physical Activity IARC Handbooks of Cancer Prevention. Vol. 6. Lyon: IARC, 2002.
3 Key TJ, Pike MC. The dose-effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. Br J Cancer 1988;57:205–12.[Web of Science][Medline]
4 Polednak AP. Trends in incidence rates for obesity-associated cancers in the US. Cancer Detect Prev 2003;27:415–21.[CrossRef][Web of Science][Medline]
5 WHO Expert Committee. Physical Status: The Use and Interpretation of Anthropometry. Geneva: WHO, 1995.
6 Haslam DW, James WP. Obesity. Lancet 2005;366:1197–209.[CrossRef][Web of Science][Medline]
7 Ferlay J, Bray F, Pisani P, Parkin D. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide, Version 2.0.: IARC CancerBase No. 5. Lyon: IARC Press, 2004.
8 Austin DF, Roe KM. The decreasing incidence of endometrial cancer: public health implications. Am J Public Health 1982;72:65–68.
9 Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002;288:1723–27.
10 Xu W, Xiang Y-B, Zheng W et al. Weight history and risk of endometrial cancer among Chinese women. Int J Epidemiol 2006;35:159–66.
11 Trentham-Dietz A, Nichols H, Hampton J, Newcomb P. Weight change and risk of endometrial cancer. Int J Epidemiol 2006;35:151–58.
12 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 2000;11:185–92.[CrossRef][Web of Science][Medline]
13 Shu X, Brinton L, Zheng W et al. Relation of obesity and body fat distribution to endometrial cancer in Shanghai, China. Cancer Res 1992;52:3865–70.
14 Parker ED, Folsom AR. Intentional weight loss and incidence of obesity-related cancers: the Iowa Women's Health Study. Int J Obes Relat Metab Disord 2003;27:1447–52.[CrossRef][Web of Science][Medline]
15 Schouten LJ, Goldbohm RA, van den Brandt PA. Anthropometry, physical activity, and endometrial cancer risk: results from The Netherlands Cohort Study. J Natl Cancer Inst 2004;96:1635–38.
16 Tavassoli F, Devilee P. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Lyon: IARC Press, 2003.
17 Purdie DM, Siskind V, Bain CJ, Webb PM, Green AC. Reproduction-related risk factors for mucinous and nonmucinous epithelial ovarian cancer. Am J Epidemiol 2001;153:860–64.
18 Risch H, Marrett L, Jain M, Howe G. Differences in risk factors for epithelial ovarian cancer by histologic type. results of a case–control study. Am J Epidemiol 1996;144:363–72.
19 Sherman ME, Sturgeon S, Brinton LA et al. Risk factors and hormone levels in patients with serous and endometrioid uterine carcinomas. Mod Pathol 1997;10:963–68.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Wang, P. Hanifi-Moghaddam, E. E. Hanekamp, H. J. Kloosterboer, P. Franken, J. Veldscholte, H. C. van Doorn, P. C. Ewing, J. J. Kim, J. A. Grootegoed, et al. Progesterone Inhibition of Wnt/{beta}-Catenin Signaling in Normal Endometrium and Endometrial Cancer Clin. Cancer Res., September 15, 2009; 15(18): 5784 - 5793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. Rodriguez, B.J. Rimel, W. Watkin, J. M. Turbov, C. Barry, H. Du, G. L. Maxwell, and J.M. Cline Progestin Treatment Induces Apoptosis and Modulates Transforming Growth Factor-{beta} in the Uterine Endometrium Cancer Epidemiol. Biomarkers Prev., March 1, 2008; 17(3): 578 - 584. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||