Skip Navigation


Annals of Oncology Advance Access originally published online on September 24, 2007
Annals of Oncology 2008 19(1):168-172; doi:10.1093/annonc/mdm446
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
19/1/168    most recent
mdm446v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (8)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Lucenteforte, E.
Right arrow Articles by Negri, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lucenteforte, E.
Right arrow Articles by Negri, E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2007 European Society for Medical Oncology. For Permissions, please email: journals.permissions@oxfordjournals.org

epidemiology

Macronutrients, fatty acids and cholesterol intake and endometrial cancer

E. Lucenteforte1,*, R. Talamini2, M. Montella3, L. Dal Maso2, A. Tavani1, S. Deandrea1,4, C. Pelucchi1, S. Greggi5, A. Zucchetto2, F. Barbone6, M. Parpinel6, S. Franceschi7, C. La Vecchia1,8 and E. Negri1

1 Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan
2 Unità di Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Aviano
3 Unità di Epidemiologia, Istituto Nazionale Tumori ‘Fondazione Giovanni Pascale’, Naples
4 Scuola di Specializzazione in Igiene e Medicina Preventiva, Università degli Studi di Pavia, Pavia
5 Unità operativa di ginecologia, Istituto Nazionale Tumori ‘Fondazione Giovanni Pascale’, Naples
6 Istituto di Igiene ed Epidemiologia, Dipartimento di Patologia e Medicina Sperimentale e Clinica, Università degli studi di Udine, Udine, Italy
7 International Agency for Research on Cancer, Lyon Cedex, France
8 Istituto di Statistica Medica e Biometria ‘G. A. Maccacaro’, Università degli Studi di Milano, Milan, Italy

* Correspondence to: Dr E. Lucenteforte, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via La Masa 19, 20156 Milan, Italy. Tel: +39-02-39014652; Fax: +39-02-33200231; E-mail: lucenteforte{at}marionegri.it


   Abstract
Top
 Abstract
introduction
 materials and methods
 results
 discussion
 Acknowledgements
 References
 
Background: There is some evidence that dietary habits may influence the risk of endometrial cancer independently of body mass, although the role of diet on endometrial carcinogenesis is unclear.

Patients and methods: We carried out a multicenter case–control study from 1992 to 2006 in Italy on 454 women with incident, histologically confirmed endometrial cancer (age range 18–79 years) and 908 controls (age range 19–79 years) admitted to hospitals for acute, non-neoplastic diseases. A validated food-frequency questionnaire was used to estimate macronutrients, fatty acids and cholesterol intake. Logistic regression models, conditioned on age and study centre, and adjusted for major known risk factor of endometrial cancer and residual of energy intake were used to estimate odds ratios (OR) and 95% confidence intervals (CI).

Results: Significant direct associations were observed with intake of energy (OR = 1.7 for the highest versus the lowest quintile, 95% CI = 1.1–2.5), and cholesterol (OR = 2.1, 95% CI = 1.4–3.2), while a direct borderline association emerged with saturated fatty acids (OR = 1.3, 95% CI = 0.9–2.0). There was no association with proteins, sugars, starch, total fat and other selected fatty acids.

Conclusion: Energy and cholesterol intake were associated with endometrial cancer.

Key words: case–control study, cholesterol, endometrial cancer, energy, macronutrients


   introduction
Top
 Abstract
 introduction
materials and methods
 results
 discussion
 Acknowledgements
 References
 
Endometrial cancer is the seventh most common cancer among women worldwide [1]. Excessive unopposed estrogen use is the major risk factor for endometrial cancer. Among factors influencing estrogen levels, and consequently endometrial cancer risk, there are overweight and obesity, menstrual and reproductive events and use of exogenous hormones, including estrogen hormonal replacement therapy (HRT) and oral contraceptives (OC) [2–6]. Selected dietary factors, including the intake of total energy, fats and other macronutrients have been associated to endometrial cancer [7–17], although the evidence is still controversial.

Four case–control studies found a direct association between total energy intake and endometrial cancer [7, 13, 14, 16], but one cohort [11] and three case–control studies found no consistent relation [10, 12, 17]. There was a direct relation between total protein intake and endometrial cancer in two case–control studies [7, 16], an inverse one emerged in two other case–control studies [12, 17] and no notable association in four case-control [8, 10, 13, 15] and in one cohort study [11]. Fourt studies found no relation with fat intake [8, 11, 12, 17], although in four case–control studies [7, 10, 13, 16] there was a direct association, and in a case–control study [15] an inverse one with intake of monounsaturated fats. Carbohydrate intake was not associated with endometrial cancer in most studies [8, 11–13, 15–17], but one case–control study found an inverse association [10].

The present paper provides further insight on the relation between endometrial cancer and intake of total energy and macronutrients, including selected fatty acids and cholesterol, using data from a case–control study conducted in Italy and based on a validated food-frequency questionnaire (FFQ).


   materials and methods
Top
 Abstract
 introduction
 materials and methods
results
 discussion
 Acknowledgements
 References
 
The data were derived from a case–control study of endometrial cancer conducted from 1992 to 2006 in three Italian areas: the provinces of Pordenone and Milan, in northern Italy and Naples, in southern Italy. Trained interviewers regularly visited selected medical wards of the major hospitals of the areas under study and identified cases and controls.

Cases were 454 women (median age 60 years, range 18–79) with incident, histologically confirmed endometrial cancer, with no previous diagnosis of cancer. Only women whose first diagnosis of endometrial cancer occurred <1 year earlier were eligible. Controls were 908 women (median age 61 years, range 19–79) admitted to the same network of hospitals of cases for a wide spectrum of non-neoplastic, acute illnesses. Women admitted for gynaecological or hormone-related conditions, or any medical condition associated with long-term dietary changes were not eligible as controls. Women with a history of hysterectomy were excluded from the control group. Controls were admitted for traumatic orthopaedic disorders (36%), other orthopaedic disorders (32%), acute surgical conditions (9%) and miscellaneous other illnesses, including eye, nose, ear, skin or dental disorders (23%). Controls were frequency matched to cases with a 2 : 1 ratio on age and study centre. Less than 5% of cases and controls approached refused to be interviewed.

Data were collected by trained interviewers using a structured questionnaire including information on sociodemographic characteristics, anthropometric measures, selected lifestyle habits, including tobacco smoking and alcohol drinking, a personal medical history, family history of cancer, menstrual and reproductive factors, history of OC and HRT use. A FFQ was used to assess the usual diet during the 2 years preceding the interview to estimate the intake of total energy and of selected nutrients. The questionnaire included 78 foods, food groups or dishes divided into six sections: (i) bread, cereals, first courses; (ii) second courses (i.e. meat, fish and other main dishes); (iii) side dishes (i.e. vegetables); (iv) fruits; (v) sweets, desserts and soft drinks; (vi) milk, hot beverages and sweeteners. A validated section for alcoholic beverages was also included [18]. Information on alcohol consumption included the number of days per week on which each type of alcoholic beverage (i.e. wine, beer and spirits, including amari, grappa, whisky, cognac and brandy) was consumed, the average number of drinks per week, and the age at starting and stopping consumption. For a few vegetables and fruit, seasonal consumption and the corresponding duration were elicited. At the end of each section, one or two open questions were used to include other foods eaten at least once per week. Specific questions aimed to assess the ‘fat intake pattern’, e.g. the type of fat used for dressing or cooking various types of food, and the avoidance of visible fat in meat and ham [19]. The intake of energy (including the contribution from alcoholic beverages), macronutrients, fatty acids and cholesterol was computed, using an Italian food composition database [20]. The FFQ was reproducible and satisfactorily valid [21, 22].

Odds ratios (OR) of endometrial cancer and their corresponding 95% confidence intervals (CIs) were estimated using conditional multiple logistic regression models [23] conditioned on age and study centre, adjusted for year of interview, education, physical activity at work at age 30–39 years, body mass index (BMI: kg/m2), history of diabetes, age at menarche, age at menopause, parity, OC and HRT use and energy intake. To control for energy intake, the residuals of the linear regression of nutrients on energy intake were computed [24]. The quintiles of nutrient intake were computed on the distribution of controls, and the unit for the continuous variables corresponded to one standard deviation (SD) of the distribution of controls. Tests for trend for the nutrient quintiles were based on the likelihood-ratio test between the models with and without a linear term giving the nutrient's quintile for each subject. To test for interactions, the differences in –2 x log(likelihood) of the models with and without interaction term were compared with the {chi}2 distribution with one degree of freedom.


   results
Top
 Abstract
 introduction
 materials and methods
 results
discussion
 Acknowledgements
 References
 
Table 1 shows the distribution of 454 endometrial cancer cases and 908 controls according to matching variables (age and study centre) and other selected variables. By design, cases and controls had equal distribution of age and study centre. No clear association was found with education or physical activity. Cases reported a BMI ≥30 kg/m2, history of diabetes and HRT use more frequently than controls, and less frequent OC use.


View this table:
[in this window]
[in a new window]

  		Table 1. Distribution of 454 cases of endometrial cancer and 908 controls according to age, centre and other selected variables, Italy, 1992–2006.

 
Table 2 gives the mean daily intake among controls of energy, macronutrients, selected fatty acids and cholesterol, and the corresponding ORs of endometrial cancer according to quintile of intake, and as a continuous variable, for an increment of intake equal to one SD of the distribution of controls. Cases reported higher energy intake than controls (OR = 1.7 for intake ≥2554.1 kcal/day versus intake <1597.9 kcal/day; 95% CI 1.1–2.5). The adjusted OR for energy intake was similar to the crude OR (1.6 for the highest versus lowest quintile of intake; 95% CI 1.1–2.4). There was a borderline direct association with saturated fatty acids (OR = 1.3, 95% CI: 0.9–2.0, P for trend = 0.08). Proteins, sugars, starch, total fat, monounsaturated fatty acids and polyunsaturated fatty acids were unrelated to endometrial cancer. Among specific fatty acids, oleic, linoleic and linolenic acids were unrelated to endometrial cancer. Cholesterol intake was associated with endometrial cancer (OR = 2.1 for intake ≥356 mg/day, versus intake of <192 mg/day; 95% CI 1.4–3.2) and the OR increased in each subsequent quintile of intake (P for trend <0.0001). For an increase in intake equal to one SD, the ORs were 1.2 (95% CI: 1.0–1.3) for total energy, 1.1 (95% CI: 1.0–1.2) for total proteins, 1.1 (95% CI: 1.0–1.2) for saturated fatty acids and 1.2 (95% CI: 1.1–1.3) for cholesterol intake.


View this table:
[in this window]
[in a new window]

  		Table 2. ORsa and corresponding 95% CIs of 454 endometrial cancer cases and 908 controls according to intake of energy, macronutrient, selected fatty acids and cholesterol, Italy 1992–2006

 
The relation between energy and cholesterol with endometrial cancer was further examined in Table 3 in strata of age (<55 and ≥55 years), BMI (<26 and ≥26 kg/m2), history of diabetes (yes and no), menopausal status (pre/peri and post), parity (nulliparous and parous), OC use (yes and no), HRT use (yes and no) and energy intake. There was a significant interaction between cholesterol and HRT, and the association with cholesterol appeared to be confined to nonusers of HRT. No notable differences emerged across strata of the other covariates included in the table.


View this table:
[in this window]
[in a new window]

  		Table 3. ORsa, b and corresponding 95% CIs of 454 endometrial cancer cases and 908 controls according to intake of energy and cholesterol in strata of age, BMI and other characteristics

 

   discussion
Top
 Abstract
 introduction
 materials and methods
 results
 discussion
Acknowledgements
 References
 
The large study size and the collection of extensive dietary information using a reproducible and valid FFQ [21, 22] are major strengths of this study. Further strengths include the comparable catchment areas of cases and controls, the high participation rate and the possibility of allowance for intake of energy and for several covariates in the analyses. However, as in most case–control studies, some selection and recall biases are possible. A recent cancer diagnosis may influence recall of diet for cases, although awareness of dietary hypothesis in endometrial cancer etiology was unknown to the general population and the interviewers, and the comparability of information between cases and controls was improved by interviewing subjects in the same hospital setting. Another limitation might be that dietary habits of hospital controls may be different from those of the general population. However, we excluded from the control group any subject admitted for conditions associated with long-term modifications of diet.

The relation between energy and endometrial cancer has been evaluated previously [7, 10–14, 16, 17]. In four case–control studies conducted in Shanghai on 1454 cases [7], in Hawaii on 332 cases [13], in the Swiss Canton of Vaud and Northern Italy on 368 cases [14], and in the United States on 296 cases [16], there was a direct association with total energy intake, although no association was found in three other case–control studies [10, 12, 17] and in one cohort study based on 221 cases [11].

High-energy intake causes obesity, which, in turn, is a strong risk factor for endometrial cancer. In this and other studies, however, the association with energy intake persisted even after adjustment for BMI. Whether energy intake has an effect independent of BMI on endometrial cancer risk is still open to discussion, since underadjustment for BMI is possible.

We observed a borderline association with saturated fatty acids, although total fat was unrelated to endometrial cancer. A case–control study from Shanghai [7] found a direct relation with total fat and saturated fatty acids. Thus, the role of fat intake on development of endometrial cancer is yet not clear [9, 25].

The role of cholesterol has been investigated in previous studies [8, 10, 12, 13, 15–17]. Cholesterol was strongly associated with endometrial cancer in a case–control study from Hawaii (OR = 2.2) [13], and in a case–control study from Alabama based on 103 cases [17] there was a moderate direct association between endometrial cancer and cholesterol, after adjustment for protein intake (OR = 1.9). However, other case–control studies did not confirm this association [8, 10, 12, 15, 16]. Intake ranges and main food sources of macronutrients may differ between populations, and must be considered in the interpretation of the findings from various studies. In this Italian population, the main sources of cholesterol were eggs, chicken/turkey, cheeses and fish/molluscs [19].

Cholesterol is involved in several metabolic pathways leading to estrogen [26] and is the major substrate leading to steroid hormone synthesis including estrogens. This indicates a link between cholesterol and endometrial cancer, as it has been reported previously for prostate cancer [27]. A study found increased cholesterol serum levels in endometrial cancer patients [28], but another study did not confirm this result [29]. In our study, cholesterol was associated with endometrial cancer only in women who had never used HRT. This association can be due to chance, given the small number of ever users and the many interaction tests carried out. However, this is compatible with a role for dietary cholesterol on steroid hormone levels in women who had not used exogenous hormones.


   Acknowledgements
Top
 Abstract
 introduction
 materials and methods
 results
 discussion
 Acknowledgements
References
 
The authors thank Ms I. Garimoldi for editorial assistance. This work was conducted with the contributions from the Italian Association for Cancer Research , Italian League Against Cancer and Italian Ministry of Research (PRIN 2005). CLV was a Senior Fellow at the International Agency for Research on Cancer.

Received for publication April 13, 2007. Revision received July 24, 2007. Accepted for publication August 13, 2007.


   References
Top
 Abstract
 introduction
 materials and methods
 results
 discussion
 Acknowledgements
 References
 
1. Parkin DM, Whelan SL, Ferlay J, Thomas DB. Cancer Incidence in Five Continents (2002) Volume VIII. Lyon Cedex, France: IARC Scientific Publication no. 155.

2. Cook LS, Weiss NS, Doherty JA, Chen C. Endometrial cancer. In: Cancer Epidemiology and Prevention—Schottenfeld D, Fraumeni JF Jr, eds. (2006) 3rd edition. New York, NY: Oxford University Press. 1027–1043.

3. Amant F, Moerman P, Neven P, et al. Endometrial cancer. Lancet (2005) 366:491–505.[CrossRef][Web of Science][Medline]

4. Pike MC, Pearce CL, Wu AH. Prevention of cancers of the breast, endometrium and ovary. Oncogene (2004) 23:6379–6391.[CrossRef][Web of Science][Medline]

5. Purdie DM, Green AC. Epidemiology of endometrial cancer. Best Pract Res Clin Obstet Gynaecol (2001) 15:341–354.[CrossRef][Medline]

6. Parazzini F, La Vecchia C, Bocciolone L, Franceschi S. The epidemiology of endometrial cancer. Gynecol Oncol (1991) 41:1–16.[CrossRef][Web of Science][Medline]

7. Xu WH, Dai Q, Xiang YB, et al. Nutritional factors in relation to endometrial cancer: a report from a population-based case-control study in Shanghai, China. Int J Cancer (2007) 120:1776–1781.[CrossRef][Web of Science][Medline]

8. Salazar-Martinez E, Lazcano-Ponce E, Sanchez-Zamorano LM, et al. Dietary factors and endometrial cancer risk. Results of a case-control study in Mexico. Int J Gynecol Cancer (2005) 15:938–945.[CrossRef][Web of Science][Medline]

9. Bosetti C, Altieri A, La Vecchia C. Diet and environmental carcinogenesis in breast/gynaecological cancers. Curr Opin Obstet Gynecol (2002) 14:13–18.[CrossRef][Web of Science][Medline]

10. Littman AJ, Beresford SA, White E. The association of dietary fat and plant foods with endometrial cancer (United States). Cancer Causes Control (2001) 12:691–702.[CrossRef][Web of Science][Medline]

11. Jain MG, Rohan TE, Howe GR, Miller AB. A cohort study of nutritional factors and endometrial cancer. Eur J Epidemiol (2000) 16:899–905.[CrossRef][Web of Science][Medline]

12. McCann SE, Freudenheim JL, Marshall JR, et al. Diet in the epidemiology of endometrial cancer in western New York (United States). Cancer Causes Control (2000) 11:965–974.[CrossRef][Web of Science][Medline]

13. Goodman MT, Hankin JH, Wilkens LR, et al. Diet, body size, physical activity, and the risk of endometrial cancer. Cancer Res (1997) 57:5077–5085.[Abstract/Free Full Text]

14. Negri E, La Vecchia C, Franceschi S, et al. Intake of selected micronutrients and the risk of endometrial carcinoma. Cancer (1996) 77:917–923.[CrossRef][Web of Science][Medline]

15. Tzonou A, Lipworth L, Kalandidi A, et al. Dietary factors and the risk of endometrial cancer: a case–control study in Greece. Br J Cancer (1996) 73:1284–1290.[Web of Science][Medline]

16. Potischman N, Swanson CA, Brinton LA, et al. Dietary associations in a case-control study of endometrial cancer. Cancer Causes Control (1993) 4:239–250.[Web of Science][Medline]

17. Barbone F, Austin H, Partridge EE. Diet and endometrial cancer: a case-control study. Am J Epidemiol (1993) 137:393–403.[Abstract/Free Full Text]

18. Ferraroni M, Decarli A, Franceschi S, et al. Validity and reproducibility of alcohol consumption in Italy. Int J Epidemiol (1996) 25:775–782.[Abstract/Free Full Text]

19. Favero A, Salvini S, Russo A, et al. Sources of macro- and micronutrients in Italian women: results from a food frequency questionnaire for cancer studies. Eur J Cancer Prev (1997) 6:277–287.[Web of Science][Medline]

20. Salvini S, Parpinel MT, Gnagnarella P, et al. Banca Dati di Composizione degli Alimenti per Studi Epidemiologici in Italia (1998) Milano, Italy: Istituto Europeo di Oncologia.

21. Decarli A, Franceschi S, Ferraroni M, et al. Validation of a food-frequency questionnaire to assess dietary intakes in cancer studies in Italy. Results for specific nutrients. Ann Epidemiol (1996) 6:110–118.[CrossRef][Web of Science][Medline]

22. Franceschi S, Barbone F, Negri E, et al. Reproducibility of an Italian food frequency questionnaire for cancer studies. Results for specific nutrients. Ann Epidemiol (1995) 5:69–75.[CrossRef][Medline]

23. Breslow NE, Day NE. Statistical Methods in Cancer Research. Volume I—The Analysis of Case-Control Studies (1980) Lyon Cedex, France: IARC Scientific Publication no. 32.

24. Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol (1986) 124:17–27.[Free Full Text]

25. Bandera EV, Kushi LH, Moore DF, et al. Dietary lipids and endometrial cancer: the current epidemiologic evidence. Cancer Causes Control (2007) 18:687–703.[CrossRef][Web of Science][Medline]

26. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility (2004) Baltimora: Lippincott Williams & Wilkins.

27. Bravi F, Scotti L, Bosetti C, et al. Self-reported history of hypercholesterolaemia and gallstones and the risk of prostate cancer. Ann Oncol (2006) 17:1014–1017.[Abstract/Free Full Text]

28. Kucuk O, Churley M, Goodman MT, et al. Increased plasma level of cholesterol-5 beta,6 beta-epoxide in endometrial cancer patients. Cancer Epidemiol Biomarkers Prev (1994) 3:571–574.[Abstract]

29. Swanson CA, Potischman N, Barrett RJ, et al. Endometrial cancer risk in relation to serum lipids and lipoprotein levels. Cancer Epidemiol Biomarkers Prev (1994) 3:575–581.[Abstract]


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
19/1/168    most recent
mdm446v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (8)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Lucenteforte, E.
Right arrow Articles by Negri, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lucenteforte, E.
Right arrow Articles by Negri, E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?