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,3
Department of Epidemiology and Preventive Medicine and
* Department of Tumor and General Surgery, Gifu University Graduate School of Medicine, Gifu, Japan; and
Gihoku General Hospital, Gifu, Japan
2To whom correspondence should be addressed. E-mail: chisato{at}cc.gifu-u.ac.jp.
ABSTRACT
A reduction in fat intake has been associated with decreased estrogen levels in dietary intervention studies. However, previous cross-sectional studies conducted mainly among Western populations did not find a positive association between fat intake and postmenopausal estrogen levels. This study examined the cross-sectional association of fat intake with serum levels of estrone, estradiol, testosterone, and dehydroepiandrosterone sulfate (DHEAS) in women. Study subjects were 324 healthy postmenopausal Japanese women. Diet including fat intake was assessed by a validated semiquantitative FFQ. After controlling for age and other potential breast cancer risk factors, serum estrone was positively associated with the percentage of energy from total fat (P = 0.04). The associations of serum estrone with monounsaturated fat and polyunsaturated fat were of borderline significance (P = 0.05). Serum DHEAS was positively associated with the percentage of energy from total fat (P = 0.007), saturated fat (P = 0.009), monounsaturated fat (P = 0.006), and polyunsaturated fat (P = 0.04). Serum estrone and DHEAS concentrations increased 11.8 and 9.3%, respectively, with a 5% increase in the percentage of energy from total fat. These data suggest that a high intake of fat is associated with higher serum levels of estrone and DHEAS in postmenopausal women.
KEY WORDS: • diet • dietary fat • estrogens • androgens • postmenopausal women
Diet has been implicated in the etiology of breast cancer. It was hypothesized that a high fat intake increases the risk of breast cancer (1). However, conflicting findings from cohort studies have created uncertainty over the role of dietary fat in the development of breast cancer (2). Endogenous hormones, especially estrogens, are important determinants of breast cancer (3). If fat intake can increase circulating hormone levels, this may be the explanation for the link between fat intake and breast cancer. Although a meta-analysis of intervention studies revealed significantly lower estradiol levels in the low-fat diet groups (4), cross-sectional studies among postmenopausal women did not find a positive association between fat intake and estrogen levels (5–9). In a recent large study among the Nurses Health Study participants (8), plasma estradiol levels were significantly inversely associated with fat intake, which was consistent with the inverse association between fat intake and breast cancer risk observed in a cohort study conducted in this population (10).
Most of the previous studies on dietary fat and endogenous estrogens or breast cancer risk were conducted among Western populations. The purpose of the present study was to determine whether estrogen levels are associated with fat intake in postmenopausal Japanese women. We also examined the relations between fat intake and testosterone and dehydroepiandrosterone sulfate (DHEAS)4 because breast cancer risk has been associated with these androgens in postmenopausal women (11). Few studies have addressed the relations of dietary fat to hormones other than estrogens.
SUBJECTS AND METHODS
Study population
Study subjects were women attending a mammographic breast cancer screening at a general hospital in Gifu, Japan. This particular hospital has conducted a mass screening campaign for breast cancer since the early 1980s. Women 
30 y old residing near the hospital were invited by the city to take part in the screening. Approximately 20% of women residing in the catchments area of the hospital receive a screening mammogram. From 2000 to 2002, the women attending the breast cancer screening at the hospital were recruited for a study of mammographic breast density that sought to identify its determinants. A total of 1061 women who were free of breast cancer agreed to participate in the study (the estimated participation rate was 70.3%) (12). The study also aimed to examine the associations of various biomarkers with breast cancer risk factors as well as the risk of breast cancer using subsets of this population. The study period for each component study was predetermined. The present study included postmenopausal women from whom blood samples were obtained for measurements of estrogen and androgen levels. Women who had not had a menstrual cycle in the past 12 mo were classified as postmenopausal. Information was sought about the type of menopause (natural or surgical) and age at menopause. Exclusion criteria included the following: 1) use of hormone replacement therapy; 2) prior malignancy; 3) coexisting medical condition including diabetes mellitus, chronic hepatitis, and thyroid disease; or 4) 
49 y old and had had surgical menopause with ovarian conservation. Informed consent was obtained from each woman. This study was approved by the institutional review board of Gifu University Graduate School of Medicine.
Data collection
Dietary data. At recruitment, women responded to a self-administered questionnaire seeking information about diet, basic demographic characteristics, physical activity, smoking and drinking habits, medical history, and reproductive history. Information on height and weight was based on self-report. Diet including fat intake was assessed with a validated 169-item semiquantitative FFQ (13). The questionnaire asked participants how often on average they consumed each of the food item listed and what was the usual serving size of each item during the year before the study. The intakes of foods and nutrients were estimated from the frequency of ingestion and portion size using the Japanese Standard Tables of Food Composition (14). Fatty acid composition was evaluated using data published by Sasaki and others (15). Long-chain (n-3) fatty acid intake was calculated as the sum of eicosapentaenoic and docosahexaenoic acids. Detailed information on the questionnaire including its validity and reproducibility was described elsewhere (13). For example, the Spearman correlation coefficients between this questionnaire and 12 daily diet records kept over a 1-y period for intakes of energy, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, eicosapentaenoic acid, and docosahexaenoic acid were 0.53, 0.52, 0.54, 0.56, 0.51, 0.54, and 0.58, respectively (P < 0.05). Exercise was assessed by asking the average time spent per week over the past year in various kinds of activities including strenuous sports (such as jogging, bicycling on hills, tennis, racquetball, swimming, or aerobics), vigorous work (such as moving heavy furniture, loading or unloading trucks, shoveling, weight lifting, or equivalent manual labor), and moderate activities (such as housework, brisk walking, golfing, bowling, bicycling on level ground, or gardening). Strenuous sports were regarded as those requiring 5 metabolic equivalent tasks (METs). The corresponding METs were 4 for vigorous work and 3 for moderate activities. The details including the questionnaire’s validity are described elsewhere (16).
Serum hormone concentrations.
Blood samples for an endogenous hormone assay were obtained from subjects at 
1400 h. After centrifugation at 1500 x g for 10 min, the sera were separated and stored at –80°C until assayed. Serum estrone was measured by RIA using kits purchased from Diagnostic Systems (DSL-8700) at 1500 x g for 10 min. The sensitivity and interassay CV were 4.4 pmol/L and 8.4–24.5% for high to low levels, respectively. Serum estradiol, testosterone, and DHEAS were measured by RIA using kits purchased from Diagnostic Products (KE2D, TKDS, and TKTT, respectively). The sensitivity and the interassay CV, respectively, were 5.1 pmol/L and 13.7% for estradiol; 0.14 nmol/L and 8.4–23.9% for high to low levels of testosterone; and 3.8 nmol/L and 8.12% for DHEAS.
Estradiol was measured in all 328 postmenopausal women after excluding 26 women because of incomplete or unreliable responses to the dietary questionnaire (n = 25) [see (17) for FFQ criteria] or because of missing data for BMI (n = 1). Estrone and testosterone were not measured in 1 woman, and DHEAS was not measured in 4 women. In addition, 4 women were excluded from the present study because their estradiol levels suggested unreported estrogen use (>367 pmol/L). The remaining 324 women are the focus of this report. Of these women, 160 (49.4%) had estradiol levels, 26 (8.0%) had estrone levels, and 55 (17.0%) had testosterone levels below the sensitivity of the assay; the values of assay sensitivity were assigned for them.
Data analysis
All hormone levels were transformed into logarithmic values for statistical analysis. We used analysis of covariance to provide adjusted estimates of the means of logarithmically transformed hormone levels according to the quartile of percentage of energy from fat. The geometric means are presented. The relations between hormone levels and the percentage of energy from fat were assessed by linear regression models. Based on the ß-coefficients obtained from the models, the percentage of change of hormone levels with a 5% increase of total fat or types of fats [0.1% for long-chain (n-3) fatty acid] were calculated. Potential confounding factors were included in the models as covariates. The selection of potential confounders was based primarily on prior consideration of their associations with both fat intake and hormone levels. The variables included were as follows: age, years of education, age at menarche, parity, age at first birth, type of menopause (natural or surgical), years since menopause, BMI, smoking status, alcohol intake, physical activity, and family history of breast cancer among first-degree relatives. The achieved sample size was sufficient to detect (at the 5% level) a 16% change of estrone with a 5% increase in the percentage of energy from total fat with 80% power. The corresponding value for DHEAS was 9%. All statistical analyses were performed using SAS (SAS Institute).
RESULTS
The characteristics of 324 women are shown in Table 1; 15.2% of the women had a percentage of energy from total fat < 20%, and 14.8% had an intake > 30%.
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50% of the women, the results were omitted from Table 2. There was a positive association of estrone levels with the percentage of energy from total fat (P = 0.04). The associations between serum estrone levels and the percentages of energy from monounsaturated fat and polyunsaturated fat were of borderline significance (P = 0.05, respectively). DHEAS levels were significantly associated with the percentage of energy from total fat, saturated fat, monounsaturated fat, and polyunsaturated fat. Additional adjustment for protein intake and total energy did not alter the results substantially, although some associations were no longer significant; the percentages of increase in serum estrone were 12.3% (P = 0.11), 25.0% (P = 0.27), 29.9% (P = 0.12), and 33.9% (0.19) with a 5% increase in energy from total fat, saturated fat, monounsaturated fat, and polyunsaturated fat, respectively. The corresponding figures for DHEAS were 10.6% (P = 0.02), 31.1% (P = 0.03), 27.1% (P = 0.02), and 20.3% (P = 0.17), respectively.
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23 kg/m2 after controlling for the covariates.
The present study may have included perimenopausal women whose hormone status might be similar to those of premenopausal women. Therefore, we conducted a subanalysis after excluding 126 women 55 y old and those whose hormone values were greater than the absolute value of the 75th percentile plus 3 times the interquartile range (> 162 pmol/L for estrone and > 9019 nmol/L for DHEAS). The results were not altered substantially except that the association between estrone and monounsaturated fat was somewhat strengthened; the estrone level was 48.9% (P = 0.03) higher with a 5% increase in the percentage of energy from monounsaturated fat after controlling for the covariates (n = 198).
Intakes of dietary fiber and soy products, which were also suggested to be related to estrogen levels, were not associated with levels of any hormone measured in the present study.
DISCUSSION
We observed significant positive associations between serum estrone and fat intake in these postmenopausal Japanese women. Most of the previous dietary fat intervention studies did not include measurements of estrone. In a study by Prentice et al. (18), there was no significant change in estrone after consumption of a low-fat diet. To our knowledge, 5 cross-sectional studies (5–9) examined the relation between fat intake and hormone levels, and all of them included estrone measurements. No significant association of fat intake with estrone or estradiol occurred. Fat intake was unrelated to urinary estrone and estradiol in 88 postmenopausal women in Greece (5). There were no significant correlations between any measure of fat (total fat, saturated fat, and linoleic acid) and serum estrone and estradiol in 325 climacteric U.S. women. Neither total fat nor saturated fat was significantly correlated with serum estrone in 253 postmenopausal U.S. women (7). Total fat and types of fat (saturated fat, monounsaturated fat, and polyunsaturated fat) were not associated with serum estrone and estradiol in 144 postmenopausal Chinese women (9). There is no obvious explanation for the different outcomes of the present and previous studies. Fat intake was relatively low in our study subjects compared with those reported in the previous studies (5–9). We postulate that the effect of fat on estrone levels may be more evident at the lower intake range. We also previously observed significant associations of total fat and monounsaturated fat intake with serum estrone and estradiol among premenopausal Japanese women (19). It is also possible that fat intake is associated with serum estrone levels in lean populations, such as this Japanese population. There was a suggestion that the associations between fat intake and serum hormone concentrations were somewhat stronger in the leaner women in our study. However, the cross-sectional studies that found no association of fat with estrogen, as described above, included one conducted among postmenopausal Chinese women. Their intake levels of fat and each type of fat as well as BMI were similar to those of subjects in our study. Their estrogen levels were higher than those observed in our study subjects. This difference may explain in part the discrepancy in the results.
Our finding of a positive association between DHEAS and total fat and types of fat is of interest in light of the fact that DHEAS, independently of estradiol, has been associated with an increased risk of breast cancer (11). Few studies examined the association of DHEAS with fat intake among postmenopausal women. In an intervention study reported by Ingram et al. (20), a low-fat diet had no effect on serum DHEAS among postmenopausal Australian women. Serum DHEAS was measured in 2 cross-sectional studies (7,8). Although total fat was not associated with DHEAS in either study, monounsaturated fat was significantly positively association with DHEAS in one of the studies (8).
The limitation of measuring low levels of estrogens must be considered. Estradiol was undetectable in 50% of the women in our study. Similarly low levels of estradiol and estrone were reported in postmenopausal Japanese women (21–23).
The use of only 1 sample/women in the present analysis is arguable. We obtained blood samples from 36 women 55 y old 1 y later. The intraclass correlation coefficients (ICC) for estrone and DHEAS were 0.52 and 0.85, respectively. These values did not differ greatly from those reported previously among elderly white women: ICC = 0.56 for estrone over 2 y in women with a mean of 9 y since the onset of menopause (24) and ICC = 0.90 for DHEAS over 1 y among women aged 55–69 y (25).
The lack of support for the association between fat and breast cancer from the pooled analysis of 7 prospective studies (2) may cast doubt on a positive association between fat intake and estrogens. Although we found no positive association between serum estradiol and fat intake, it is possible that the lack of association was due to an artifact arising from the measurement of estradiol. The findings from this study of a positive association between estrone and fat, together with those from intervention studies, suggest that the fat-estrogen hypothesis warrants further study. In addition, further studies are required to examine the relations of DHEAS with fat and other dietary factors.
FOOTNOTES
1 Supported by a grant from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. 
3 Present address: Asahi University School of Dentistry, Gifu, Japan.
4 Abbreviations used: DHEAS, dehydroepiandrosterone; ICC, intraclass correlation coefficient; MET, metabolic equivalent task.
Manuscript received 31 May 2005. Initial review completed 8 July 2005. Revision accepted 13 September 2005.
LITERATURE CITED
1. Wynder EL, Cohen LA, Muscat JE, Winters B, Dwyer JT, Blackburn GL. Breast cancer: weighing the evidence for a promoting role of dietary fat. J Natl Cancer Inst. 1997;89:766-775.[Medline]
2. Hunter DJ, Spiegelman D, Adami H-O, Beeson L, van den Brandt PA, Folson A, Fraser GE, Goldbohm A, Graham S, et al. Cohort studies of fat intake and the risk of breast cancer—a pooled analysis. N Engl J Med. 1996;334:356-361.
3. Bernstein L, Ross RK. Endogenous hormones and breast cancer risk. Epidemiol Rev. 1993;15:48-65.
4. Wu AH, Pike MC, Stram DO. Meta-analysis: dietary fat intake, serum estrogen levels, and the risk of breast cancer. J Natl Cancer Inst. 1999;91:529-534.
5. Katouyanni K, Boyle P, Trichopoulos D. Diet and urine estrogens among postmenopausal women. Oncology. 1991;48:490-494.[Medline]
6. London S, Willett W, Longcope C, Mckinlay S. Alcohol and other dietary factors in relation to serum hormone concentrations in women at climacteric. Am J Clin Nutr. 1991;53:166-171.
7. Newcomb PA, Klein R, Klein BEK, Haffner S, Mares-Perlman J, Cruickshanks KJ, Marcus PM. Association of dietary and life-style factors with sex hormones in postmenopausal women. Epidemiology. 1995;6:318-321.[Medline]
8. Holmes MD, Spigelman D, Willett WC, Manson JE, Hunter DJ, Barbieri RL, Colditz GA, Hankinson SE. Dietary fat intake and endogenous sex steroid hormone levels in postmenopausal women. J Clin Oncol. 2000;18:3668-3676.
9. Wu AH, Stanczyk FZ, Seow A, Lee H-P, Yu MC. Soy intake and other lifestyle determinants of serum estrogen levels among postmenopausal Chinese women in Singapore. Cancer Epidemiol. Biomarkers Prev. 2002;11:844-851.
10. Holmes MD, Hunter DJ, Colditz GA, Stampfer MJ, Hankinson SE, Spizer FE, Rosner B, Willett WC. Association of dietary intake of fat and fatty acids with risk of breast cancer. J Am Med Assoc. 1999;281:914-920.
11. The Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 2002;94:606-616.
12. Nagata C, Nagao Y, Shibuya C, Kashiki T, Shimizu H. Urinary cadmium and serum levels of estrogens and androgens in postmenopausal women. Cancer Epidemiol. Biomarkers Prev. 2005;14:705-708.
13. Shimizu H, Ohwaki A, Kurisu Y, Takatsuka N, Ido M, Kawakai N, Nagata C, Inaba S. Validity and reproducibility of a quantitative food frequency questionnaire for a cohort study in Japan. Jpn J Clin Oncol. 1999;29:38-44.
14. The Science and Technology Agency of Japan Standard Tables of Food Composition in Japan, 4th and 5th rev. eds. Kagawa Nutrition University Press Tokyo, Japan.
15. Sasaki S, Kobayashi M, Tsugane S. Development of substituted fatty acid composition table for the use in nutritional epidemiologic studies for Japanese populations: its methodological backgrounds and the evaluation. J Epidemiol. 1999;9:190-207.[Medline]
16. Suzuki I, Kawakami N, Shimizu H. Reliability and validity of a questionnaire for physical activity in epidemiological studies. J Epidemiol. 1998;8:152-159 (supplementary comment: J Epidemiol. 2002;12:54).[Medline]
17. Shimizu H. Reliability and validity of a questionnaire for physical activity in epidemiological studies. The Basic Report on Takayama Study Gifu. Department of Public Health, Gifu University School of Medicine Japan.
18. Prentice R, Thompson D, Clifford C, Gorbach S, Goldin B, Byar D. Dietary fat reduction and plasma estradiol concentration in healthy postmenopausal women. J Natl Cancer Inst. 1990;82:129-134.
19. Nagata C, Takatsuka N, Kawakami N, Shimizu H. Total and monounsaturated fat intake and serum estrogen concentrations in premenopausal Japanese women. Nutr Cancer. 2000;38:37-39.[Medline]
20. Ingram DM, Bennett FC, Willcox D, de Klerk N. Effect of low-fat diet on female sex hormone levels. J Natl Cancer Inst. 1987;79:1225-1229.[Medline]
21. Dowsett M, Donaldson K, Tsuboi M, Wong J, Yates R. Effects of the aromatase inhibitor anastrozole on serum oestrogens in Japanese and Caucasian women. Cancer Chemother. Pharmacol. 2000;45:35-39.
22. Yoshimura N, Kasamatsu T, Sakata K, Hashimoto T, Cooper C. The relationship between endogenous estrogen, sex hormone-binding globulin, and bone loss in female residents of a rural Japanese community: the Taiji Study. J Bone Miner Metab. 2002;20:303-310.[Medline]
23. Miyoshi Y, Tanji Y, Taguchi T, Tamaki Y, Noguchi S. Association of serum estrone levels with estrogen receptor-positive breast cancer risk in postmenopausal Japanese women. Clin Cancer Res. 2003;9:2229-2233.
24. Cauley JA, Gutal JP, Kuller LH, Powell JG. Reliability and interrelations among serum sex hormones in postmenopausal women. Am J Epidemiol. 1991;133:50-57.
25. Muti P, Trevisan M, Micheli A, Krogh V, Bolelli G, Sciajno R, Berrino F. Reliability of serum hormones in premenopausal and postmenopausal women over a one-year period Cancer Epidemiol. Biomarkers Prev. 1996;5:917-922.
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