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Reproductive factors, exogenous female hormones, and colorectal cancer by subsite Maria Gerhardsson de Verdier and Stephanie London (Received 3 February 1992; accepted in revised form 2 April 1992) The associations between reproductive factors, exogenous hormones, and colorectal cancer were examined among female subjects in a population-based case-control study in Sweden. The study was performed in Stockholm in 1986-88, and included 299 cases and 276 controls. There was little evidence that age at first birth, number of months of breast feeding, age at menarche, or age at menopause influenced the risk of colon or rectal cancer. However, the results indicate that postmenopausal hormone-replacement therapy might reduce the risk of colorectal cancer (age-adjusted relative risk [RR] = 0.4, 95 percent confidence interval [CI] = 0.2-0.9). Compared with nulliparous women, women with at least four births were at reduced risk for colon cancer (RR = 0.5, CI = 0.2-1.2) but not rectal cancer (RR = 1.0, CI = 0.4-2.6). However, no trend across increasing parity was observed. Adjustments for diet, body mass, and physical activity had little influence on the results.
Key words: Colon cancer, hormone, menarche, menopause, oral contraceptives, parity, rectal cancer, replacement therapy, Sweden.
Introduction Colorectal cancer is one of the most common cancers in Western populations? High fat intake, low fiber intake, low physical activity, and being overweight are thought to increase risk of this disease. 2 An early suggestion that hormonal factors may play a role in colorectal cancer etiology came from a geographic comparison of mortality rates showing positive correlations between colon and breast cancer? This theory has been supported by descriptive data which show differences in colorectal cancer incidence by age and gender, 4,sand higher than expected rates of colon cancer in nuns? A plausible mechanism also has been suggested: increased concentrations of secondary bile acids within the colon are thought to enhance colon carcinogenesis,7,8 and progestins, pregnancy, and
exogenous estrogens may reduce bile acid production? In addition, animal experimental data have shown that multiparous rats are at lower risk of 1,2-dimethylhydrazine-induced colon cancer relative to nulliparous rats. t0 Epidemiologic analytical studies on reproductive factors and colorectal cancer have shown conflicting results (see Discussion). Few cohort studies have been presented. In several case-control studies, selection bias is a concern due to not selecting the controls as a random sample of the study base and/or a low response rate. We investigated the relationship between reproductive factors and risk of colorectal cancer among women enrolled in a population-based case-control
The authors are with the Department of Preventive Medicine, University of Southern CaliforniaSchoolof Medicine. Dr Gerhardsson de Verdier is also in the Department of Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden. Address correspondence to Dr London, University of Southern California School of Medicine, Department of Preventive Medicine, PMB B306, 1420 San Pablo Street, Los Angeles, CA 90033, USA. The study was supported by two grants (2228-B86-O13XA;2228-B87-O2XA)from the Swedish National Cancer Society. © 1992 Rapid Communications of Oxford Ltd
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M. Gerhardsson de Verdier and S. London study conducted in Stockholm, Sweden in 1986-88. Previously published reports from this study have addressed the importance of diet ~ and physical activity? ~
Materials and methods Study base and cases The study population included subjects living in a geographically defined part of Stockholm County for all, or part of, the observation period 1986-88. Eligibility was limited to men and women born in Sweden between 1907 and 1946 who had lived at least half their lives within Sweden. Cases had newly diagnosed, histopathologically confirmed, adenocarcinoma of the colon or rectum (ICD-7 t~ codes 153-154). All such cases in the county in 1986-88 were identified through local hospitals (81 percent) and the Regional Cancer Registry (19 percent). Although reporting of cases to the Cancer Registry is mandatory, cases were identified primarily through hospitals to minimize the time between diagnosis and interview. Every four months during the study, controls were selected at random from a complete register of the population of Stockholm County. The distribution of year of birth (four categories: 1907-16; 1917-26; 1927-36; 1937-46) and gender in controls was frequency-matched to that expected for cases. The analysis of reproductive factors was limited to female cases and controls. The questionnaire Information on reproductive factors, diet, weight, height, and physical activity was obtained through a questionnaire. Eligible cases were handed the questionnaire during their hospitalization by a visiting study nurse. Cases who were too ill to complete the questionnaire (44 percent) were assisted by the study nurse who read the questions aloud to them. One percent of controls also received this assistance. The cases who were identified through the Regional Cancer Registry received the questionnaire by mail, as did the controls. Postal questionnaires returned with missing information were followed up by a telephone interview. Further details in the collection of data have been reported previously. "a2 Age at menarche was recorded as less than 13 years, 13-16 years, and more than 16 years. Parity was recorded as the total number of births. Parous women were asked maternal age at first birth, and whether and for how long they breast fed. Age at menopause was recorded as less than 50 years, 50-59 years, and more than 59 years. The history of hormone use was ascertained by a question which read: "Have you ever regularly taken hormone pills for birth control, menstrual dis356
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orders, or because of postmenopausal symptoms?" If yes, the time period of use was sought. This question did not allow for separation of types of hormones, specifically oral contraceptives and postmenopausal estrogens. Dietary data were obtained by a quantitative foodfrequency questionnaire concerning average consumption during the previous five years, excluding any periods of altered dietary habits due to illness." The ordinary frequency of consumption was scored for 55 different food items, covering more than 80 percent of foods in the Swedish diet. Average daily intakes of total energy and selected nutrients were computed using the nutrient database at the Swedish National Food Administration. TMWeight at five years prior to answering the questionnaire was used to calculate body mass index (BMI, kg/m2).
Data analysis Odds ratios (relative risks [RR]) and 95 percent confidence intervals (CI) were calculated using unconditional logistic regression ~5with the EGRET software package? 6All RRs were adjusted for year of birth (four categories). In addition, we adjusted for factors that were associated with the risk of colorectal cancer in these data: total energy intake; total fat intake; protein intake; dietary fiber intake; BMI; and physical activity. 1~,~2 The potentially confounding variables were included in the model as indicator variables with either three or five categories. Subjects were classified according to quintile of energy intake, nutrient intake, and BMI. The cutpoints between quintiles were: total energy (kcal/day) 1,299,1,562,1,791, 2,122; total fat (g/ day) = 43.9, 55.7, 65.2, 80.7; protein (g/day)= 44.5, 57.1, 64.6, 78.5; dietary fiber (g/day) = 11.1, 13.6, 16.2, 19.4; BMI=21.4, 23.0, 24.6, 26.5. Total physical activity in 1980 was categorized as either sedentary, fairly active, or very active? 2 To analyze results by subsite, the following definitions were used: colon includes right colon, left colon, and colon multiple/unknown sites; right colon includes cecum to splenic flexures; left colon includes descending and sigmoid colon; rectum includes the rectosigmoid junction. To investigate whether having assistance in completing the questionnaire might have influenced responses, the data were analyzed including as well as excluding these subjects.
Results Descriptive data During the period of subject accrual, 250 eligible cases of colon cancer, 135 cases of rectal cancer, and 346
Reproductive factors and colorectal cancer potential controls were identified among women. Seventy-eight percent of eligible cases participated. Reasons for nonparticipation were: refusal, 18; disabled, 19; dead, 43; not located, 6. Eighty percent of the potential controls participated. Reasons for nonparticipation were: refusal, 49; disabled, 17; dead, 1; not located, 3. Complete questionnaire data were available for 189 women with colon cancer, 110 women with rectal cancer, and 276 controls. Subsites of colon cancer among the 189 cases were: cecum and ascending colon, 73; transverse colon and flexures, 27; descending colon, 11; sigmoid, 63; multiple or unknown subsites, 15. Ninety-three percent of women, both cases and controls, were postmenopausal at diagnosis. Among cases, 91 percent of women were over 55 years of age at diagnosis, and among controls, 90 percent. The comparison of nulliparous with parous women having four or more births showed a reduced risk of colon cancer but not rectal cancer (Table 1). However, there was no trend across increasing parity. The results did not change when the analysis was adjusted for history of hormone use. Divided by subsite, the reduced risk was evident for both left and fight colon cancer. Due to fewer than five subjects in one strata, the data for right and left colon cancer were reanalyzed with an exact method (RR = 0.7, CI = 0.2-2.4 for right
colon; RR = 0.8, CI = 0.2-2.9 for left colon). Age at first birth was not associated with either colon or rectal cancer risk. Total number of months of breast feeding had no association with colon cancer but a decreased risk for rectal cancer. We observed little association between age at menarche and age at menopause and risk of colon and rectal cancer (Table 2). Due to small numbers in the highest categories, age at menarche was collapsed into less than 13, and greater than or equal to 13; age at menopause was combined into less than 50, or greater than or equal to 50. Subsite analyses did not demonstrate appreciable differences by anatomic location. A decreased risk for both colon and rectal cancer was seen for women who had a history of hormone use (including both oral contraceptives and postmenopausal estrogens). When cases who were assisted by the nurse in completing the questionnaire were excluded, hormone users remained at decreased risk for right colon cancer (RR = 0.5, C I = 0.2-1.1) but not for rectal cancer ( R R = 1.2, CI -- 0.6-2.4). When the history of hormone use was divided into two categories (1-9 years cf 10 or more years), no association with duration of use was evident. In an attempt to distinguish oral contraceptives (OC) from postmenopausal estrogens, the analysis of history of hormone use was stratified by year of hor-
Table 1. Age-adjusted relative risk (RR), with 95% confidence interval (CI), for colorectal cancer by subsite associated with
selected reproductive factors Controls (n = 276) Parity 0 1 2 3 4+ Test of trend
Colon' Cases RR (n = 189)
Right colon b (CI)
Cases RR (n =100)
(CI)
Left colon" Cases (n =74)
RR
68 56 84 47 21
51 41 57 32 8
1.0 1.0 (0.6-1.7) 0.9 (0.6-1.5) 0.9 (0.5-1.7) 0.5 (0.2-1.2) P = 0.3
26 24 29 17 4
1.0 1.1 (0.6-2.2) 0.9 (0.5-1.7) 1.0 (0.5-2.0) 0.5 (0.2-1.6) P = 0.4
20 15 24 11 4
1.0 0.9 1.0 0.9 0.7 P=0.6
Age at first birth 29 51 Test of trend
12 85 41
1.0 1.0 (0.4-2.1) 1.1 (0.5-2.6) P = 0.7
7 49 18
1.0 1.0 (0.4-2.4) 0.8 (0.3-2.2 P = 0.6
4 32 18
1.0 1.2 (0.5-2.7) 1.0 (0.5-2.4) 1.0 (0.4-2.5) P = 0.8
7 29 26 12
1.0 1.2 (0.4-3.1 1.0 (0.4-2.6 0.9 (0.3-2.7) P ~- 0.6
5 19 19 11
Total months of breast feeding 0 18 12 1-9 73 52 10-19 79 50 > 19 38 24 Test of trend
Rectum d (CI)
Cases RR (n =110)
(CI)
25 36 28 13 8
1.0 1.7 (0.9-3.2) 0.9 (0.5-1.6) 0.7 (0.3-1.5) 1.0 (0.4-2.6) P~-0.2
1.0 1.2 (0.4-3.6) 1.6 (0.5-5.3) P=0.4
10 50 25
1.0 0.8 (0.3-1.8) 1.1 (0.4-2.7) P~-0.6
1.0 1.0 (0.3-3.1) 1.0 (0.3-3.0) 1.1 (0.3-3.6) P = 0.9
9 34 33 9
1.0 0.9 (0.4-2.2) 0.8 (0.3-2.0) 0.4 (0.2-1.4) P = 0.1
(0.4-1.9) (0.5-2.0) (0.4-2.0) (0.2-2.2)
"Colon includes right colon (n = 100), left colon (n = 74), and colon multiple/unknown sites (n = 15). b Right colon includes cecum to splenic flexures. ° Left colon includes descending and sigmoid colon. d Rectum includes the rectosigmoid junction. Cancer Causes and Control. Vol 3. 1992
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M. Gerhardsson de Verdier and S. London
Table 2. Age-adjusted relative risk (RR), with 95% confidence interval (CI), for colorectal cancer by subsite associated with selected reproductive and hormonal factors Controls (n=276)
Colon •
Right colon b
Cases (n =189)
RR
(CI)
Cases (n =100)
RR
(CI)
Age of menarche ~ < 13 46 13 + 222
42 147
1.0 0.7
(0.4-1.2)
22 78
1.0 0.7
Age of menopause < 50 129 50 + 128
97 83
1.0 0.9
(0.6-1.3)
55 44
Hormone use f None 198 Yes 65
154 29
1.0 0.6
(0.4-1.0)
84 12
Left colon c
Rectum d
Cases (n =74)
RR
(CI)
(0.4-1.3)
15 59
1.0 0.8
1.0 0.8
(0.5-1.3)
34 32
1.0 0.4
(0.2-0.8)
57 16
Cases (n =110
RR
(CI)
(0.4-1.6)
23 84
1.0 0.8
(0.4-1.3)
1.0 1.0
(0.6-1.7)
49 50
1.0 1.0
(0.6-1.6)
1.0 1.0
(0.5-1.9)
84 21
1.0 0.7
(0.4-1.3)
' Colon includes right colon (n = 100), left colon (n = 74), and colon multiple/unknown sites (n = 15). b Right colon includes cecum to splenic flexures. c Left colon includes descending and sigmoid colon. d Rectum includes the rectosigmoid junction. e Eight controls and three rectal cancer cases did not remember their ages at menarche. Thirteen controls, six colon cancer cases, and five rectal cancer cases did not remember if they had used hormones. f Hormone use includes both oral contraceptives and postmenopausal estrogens.
mone use (before 1965, the use of OCs was minimal) and the women's age at hormone use (after 45 years, the use of OCs is minimal) (Table 3). In this analysis, the reduced risk was restricted to women who took hormones at ages under 45, prior to 1965. These women are most likely to have been long-term users of estrogen replacement therapy. The above-mentioned results did not change when the analyses were adjusted for total energy intake, total fat intake, protein intake, dietary fiber intake, BMI, and physical activity. The main results did not change materially when the data were reanalyzed after exclusion of the cases who required help in filling out their questionnaire (data not shown).
Discussion There was little evidence that age at first birth, number of months of breast feeding, age at menarche, age at menopause, and history of hormone use in general influenced the risk of colon or rectal cancer. However, we found that women using hormones at ages under 45 prior to 1965 were at decreased risk, suggesting a possible protective effect of long-term hormone replacement therapy. The results suggested a reduced risk of colon cancer among parous women with at least four births compared with nulliparous women. However, no trend across increasing parity was observed. Few earlier studies on reproductive factors and colorectal 358
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cancer have adjusted for diet, body mass, and physical activity. Adjustments for these potential confounding factors did not materially alter our results. Our data provide limited support for the hypothesis that higher parity may decrease the risk of colon cancer. 4,9,1z The literature on parity and colon cancer is inconsistent. A protective effect of parity has been observed in some studies 18-26but not in others. 27-35A trend across increasing parity was found in some studies 19,2~,24but not in all. ~s,23,26In some studies, a protective effect was limited to women with more than three births 2°;' but, in another, a U-shaped relationship was observed. 28Wu-Williams et al found an effect of parity for Chinese women in North America but not in China. 26 Further, in two studies, 22,24the parity effect was found in men as well as in women suggesting that lifestyle factors rather than female hormonal factors might be the explanation. Overall, parity does not demonstrate a consistent or reproducible effect on colon or rectal cancer risk. We did not find an association between these variables and risk of colorectal cancer. Most previous studies have shown little consistent evidence relating age at menarche to risk of colorectal cancer, 22,25-2z,3Sbut not all. 3°,34 Later age at menopause was associated inversely with colorectal cancer risk in three studies, 22,28,3°but not in two others2 6,34Later age at first birth has been associated with an increased risk of colorectal cancer in some studies, 2°'24'31but not in all, ls'19-u'2sar,2s,33-3sPapadimitriou et aP° even found a decreased risk with increasing age at
Reproductive factors and colorectal cancer
Table 3. Age-adjusted relative risk (RR), with 95% confidence interval (CI), for colorectal cancer associated with history of hormone use stratified by year of hormone use and the women's age at hormone use Year of hormone use Nonusers c 1965 ~< 1965 > 1965 > 1965
Age at hormone use
Controls
Cases
RR*
(CI)
RR b
(CI)
Nonusers 45 ~ 45
198 21 5 12 23
238 10 7 11 22
1.0 0.4 1.2 0.8 0.8
(0.2-0.9) (0.4-3.8) (0.3-1.8) (0.4-1.5)
1.0 0.4 1.2 0.9 0.7
(0.2-0.9) (0.4-3.9) (0.3-2.3) (0.4-1.5)
Adjusted for year of birth. b Adjusted for year of birth and menopause. c Four controls did not remember during which years they had taken hormone pills.
first birth. Thus the evidence for an effect of ages at menarche, menopause, and at first childbirth is not convincing. To our knowledge, the association between lactation and colorectal cancer has not been evaluated in earlier studies, although one study2° noted that their colon cancer cases lactated less often than their controls, without specifying the point estimates of the relative risks. However, the results in our study gave little support for this association. Unfortunately, our information on hormone use does not allow us to determine with certainty whether women used OCs or postmenopausal estrogens. However, Table 3 suggests that the reduced risk was concentrated in women using hormones prior to 1965 at ages under 45. Because OCs were not available then, it is reasonable to assume that these women used hormones for estrogen replacement for an early menopause. It is also reasonable to assume that these women who started using replacement hormones at a young age would have used them for longer periods than other women in the study group. However, this is speculative because small numbers do not allow further analysis of duration of use in this small subgroup. Furthermore, women using hormones for estrogen replacement prior to 1965 also may have been exposed to relatively high doses of hormones compared with women using them later. Earlier studies addressing this issue have found little support for an association between O C s 25'35'37o r estrogen replacement",~2a3;5 and risk of colorectal cancer. Two studiesz°," reported that OC use was protective, while Weiss et a119found the opposite. However, four studies have found estrogen replacement to be inversely associated with colon cancer~°,35,36or colorectal cancer risk," indicating that this issue may benefit from further investigation. Differences in the descriptive epidemiology of colorectal cancer by subsite have led to the speculation that risk factors have different effects in the different parts
of the large bowel? s Recent results also have suggested that different subsites within the large bowel may have differing susceptibilities to neoplastic transformation due to developmental and biologic differences." Although we found no consistent patterns of subsite differences in the association between reproductive factors and colorectal cancer risk, we did observe sporadic differences by subsite. Given small numbers of exposed cases within some strata, these results are not stable. However, the findings suggest the importance of examining the effects of reproductive factors in datasets large enough to produce stable estimates within subsites. Variations in the associations by subsite due to small numbers may explain some of the inconsistences across studies. In conclusion, we found little evidence for an association between risk for colon or rectal cancer in women and age at first birth, number of months of breast-feeding, age of menarche, and age of menopause. However, our results add to the still inconclusive body of evidence that high parity and postmenopausal hormonereplacement therapy might reduce the risk of colorectal cancer.
AcknowledgementsmWe thank Mss Inga Romanus and Gun-Inger Loboda for their excellent work in collecting the data, and the Departments of Surgery at the hospitals involved (Danderyd, Ersta, Karolinska, Nacka, Sabbatsberg, St G6ran, and S6dersjukhuset), for their cooperation.
References 1. Parkin DM, L~iiir~iE, Muir CS. Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer 1988; 41: 184-97. 2. Rogers AE, Longnecker MP. Dietary and nutritional influences on cancer: a review of epidemiologic and experimental data. Lab Invest 1988; 59: 72%59. 3. Wynder EL, Hyams L, Shigematsu T. Correlations of Cancer Causes and Control. Vol 3. 1992
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M. Gerhardsson de Verdier and S. London international cancer death rates. An epidemiological exercise. Cancer 1967; 20: 113-26. 4. McMichael AJ, Potter DJ. Host factors in carcinogenesis: certain bile-acid metabolic profiles that selectively increase the risk of proximal colon cancer. JNCI 1985; 75: 185-91. 5. Gerhardsson M, Steineck G, Norell SE. Colorectal cancer in Sweden--a descriptive epidemiologic study. Acta Oncologica 1990; 29: 855-61. 6. FraumeniJF, LloydJW, Smith EM, WagonerJK. Cancer mortality among nuns: role of marital status in etiology of neoplastic disease in women. JNCI 1969; 42: 455-68. 7. Reddy BS, Watanabe K, Weisburger JH, Wynder EL. Promoting effect of bile acids in colon carcinogenesis in germfree and conventional F344 rats. Cancer Res 1977; 37: 3238-42. 8. Hill MJ. Bile acids in colorectal carcinogenesis. In: Bruce WR, Correa P, Lipkin M, Tannenbaum SR, Wilkins TD, eds. Banbury Report No. 7. Gastrointestinal Cancer: Endogenous Factors. New York: Cold Spring Harbor Laboratory, 1981; 365-77. 9. McMichael AJ, Potter JD. Reproduction, endogenous and exogenous sex hormones, and colon cancer: a review and hypothesis. JNCI 1980; 65" 1201-7. 10. Sj6gren HO. Overview: the application of immunology to the development of immunotherapeutic programs for patients with large bowel cancer. Cancer 1977; 40" 2710-5. 11. Gerhardsson de Verdier M, Hagman U, Steineck G, Rieger J~, Norell SE. Diet, body mass and colorectal cancer: a case-referent study in Stockholm. Int J Cancer 1990; 46: 832-8. 12. Gerhardsson de Verdier M, Steineck G, Hagman U, Rieger J~, Norell SE. Physical activity and colon cancer: a case-referent study in Stockholm. IntJ Cancer 1990; 46: 985-9. 13. World Health Organisation. Manual of the Inter-
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national Statistical Classification of Disease, Injuries, and Causes of Death. Seventh Revision (1955). Geneva: WHO, 1957. Bergstr6m L, Kylberg E, Hagman U, Eriksson H-B, Bruce .~. The use of the Swedish national food administration nutrient data base for information on nutrient values of food items. Vdr F6da 1991; 43: 439-47. Breslow NE, Day NE. Statistical Methods in Cancer Research. Vol. I. The Analysis of Case-Control Studies. Lyon, France: International Agency for Research on Cancer, 1980; IARC Sci. Pub. No 32. Statistics and Epidemiology Research Corporation. Epidemiological Graphics, Estimation, and Testing Package. Seattle, WA: SERC, 1991. McMichael AJ, Potter DJ. Do intrinsic sex differences in lower alimentary tract physiology influence the sex-specific risks of bowel cancer and other biliary and intestinal diseases? AmJ Epidemio11983; 118: 620-7. Dales LG, Friedman GD, Ury HK, Grossman S, Williams SR. A case-control study of relationships of diet and other traits to colorectal cancer in American Blacks. AmJ Epidemio11978; 109: 132-44. Weiss NS, Daling JR, Chow WH. Incidence of cancer of the large bowel in women in relation to reproductive and hormonal factors. JNCI 1981; 67: 57-60. Potter JD, McMichael AJ. Large bowel cancer in women
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Reproductive factors, exogenous female hormones, and colorectal cancer by subsite Maria Gerhardsson de Verdier and Stephanie London (Received 3 February 1992; accepted in revised form 2 April 1992) The associations between reproductive factors, exogenous hormones, and colorectal cancer were examined among female subjects in a population-based case-control study in Sweden. The study was performed in Stockholm in 1986-88, and included 299 cases and 276 controls. There was little evidence that age at first birth, number of months of breast feeding, age at menarche, or age at menopause influenced the risk of colon or rectal cancer. However, the results indicate that postmenopausal hormone-replacement therapy might reduce the risk of colorectal cancer (age-adjusted relative risk [RR] = 0.4, 95 percent confidence interval [CI] = 0.2-0.9). Compared with nulliparous women, women with at least four births were at reduced risk for colon cancer (RR = 0.5, CI = 0.2-1.2) but not rectal cancer (RR = 1.0, CI = 0.4-2.6). However, no trend across increasing parity was observed. Adjustments for diet, body mass, and physical activity had little influence on the results.
Key words: Colon cancer, hormone, menarche, menopause, oral contraceptives, parity, rectal cancer, replacement therapy, Sweden.
Introduction Colorectal cancer is one of the most common cancers in Western populations? High fat intake, low fiber intake, low physical activity, and being overweight are thought to increase risk of this disease. 2 An early suggestion that hormonal factors may play a role in colorectal cancer etiology came from a geographic comparison of mortality rates showing positive correlations between colon and breast cancer? This theory has been supported by descriptive data which show differences in colorectal cancer incidence by age and gender, 4,sand higher than expected rates of colon cancer in nuns? A plausible mechanism also has been suggested: increased concentrations of secondary bile acids within the colon are thought to enhance colon carcinogenesis,7,8 and progestins, pregnancy, and
exogenous estrogens may reduce bile acid production? In addition, animal experimental data have shown that multiparous rats are at lower risk of 1,2-dimethylhydrazine-induced colon cancer relative to nulliparous rats. t0 Epidemiologic analytical studies on reproductive factors and colorectal cancer have shown conflicting results (see Discussion). Few cohort studies have been presented. In several case-control studies, selection bias is a concern due to not selecting the controls as a random sample of the study base and/or a low response rate. We investigated the relationship between reproductive factors and risk of colorectal cancer among women enrolled in a population-based case-control
The authors are with the Department of Preventive Medicine, University of Southern CaliforniaSchoolof Medicine. Dr Gerhardsson de Verdier is also in the Department of Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden. Address correspondence to Dr London, University of Southern California School of Medicine, Department of Preventive Medicine, PMB B306, 1420 San Pablo Street, Los Angeles, CA 90033, USA. The study was supported by two grants (2228-B86-O13XA;2228-B87-O2XA)from the Swedish National Cancer Society. © 1992 Rapid Communications of Oxford Ltd
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3~5
M. Gerhardsson de Verdier and S. London study conducted in Stockholm, Sweden in 1986-88. Previously published reports from this study have addressed the importance of diet ~ and physical activity? ~
Materials and methods Study base and cases The study population included subjects living in a geographically defined part of Stockholm County for all, or part of, the observation period 1986-88. Eligibility was limited to men and women born in Sweden between 1907 and 1946 who had lived at least half their lives within Sweden. Cases had newly diagnosed, histopathologically confirmed, adenocarcinoma of the colon or rectum (ICD-7 t~ codes 153-154). All such cases in the county in 1986-88 were identified through local hospitals (81 percent) and the Regional Cancer Registry (19 percent). Although reporting of cases to the Cancer Registry is mandatory, cases were identified primarily through hospitals to minimize the time between diagnosis and interview. Every four months during the study, controls were selected at random from a complete register of the population of Stockholm County. The distribution of year of birth (four categories: 1907-16; 1917-26; 1927-36; 1937-46) and gender in controls was frequency-matched to that expected for cases. The analysis of reproductive factors was limited to female cases and controls. The questionnaire Information on reproductive factors, diet, weight, height, and physical activity was obtained through a questionnaire. Eligible cases were handed the questionnaire during their hospitalization by a visiting study nurse. Cases who were too ill to complete the questionnaire (44 percent) were assisted by the study nurse who read the questions aloud to them. One percent of controls also received this assistance. The cases who were identified through the Regional Cancer Registry received the questionnaire by mail, as did the controls. Postal questionnaires returned with missing information were followed up by a telephone interview. Further details in the collection of data have been reported previously. "a2 Age at menarche was recorded as less than 13 years, 13-16 years, and more than 16 years. Parity was recorded as the total number of births. Parous women were asked maternal age at first birth, and whether and for how long they breast fed. Age at menopause was recorded as less than 50 years, 50-59 years, and more than 59 years. The history of hormone use was ascertained by a question which read: "Have you ever regularly taken hormone pills for birth control, menstrual dis356
Cancer Causes and Control. Vol 3. 1992
orders, or because of postmenopausal symptoms?" If yes, the time period of use was sought. This question did not allow for separation of types of hormones, specifically oral contraceptives and postmenopausal estrogens. Dietary data were obtained by a quantitative foodfrequency questionnaire concerning average consumption during the previous five years, excluding any periods of altered dietary habits due to illness." The ordinary frequency of consumption was scored for 55 different food items, covering more than 80 percent of foods in the Swedish diet. Average daily intakes of total energy and selected nutrients were computed using the nutrient database at the Swedish National Food Administration. TMWeight at five years prior to answering the questionnaire was used to calculate body mass index (BMI, kg/m2).
Data analysis Odds ratios (relative risks [RR]) and 95 percent confidence intervals (CI) were calculated using unconditional logistic regression ~5with the EGRET software package? 6All RRs were adjusted for year of birth (four categories). In addition, we adjusted for factors that were associated with the risk of colorectal cancer in these data: total energy intake; total fat intake; protein intake; dietary fiber intake; BMI; and physical activity. 1~,~2 The potentially confounding variables were included in the model as indicator variables with either three or five categories. Subjects were classified according to quintile of energy intake, nutrient intake, and BMI. The cutpoints between quintiles were: total energy (kcal/day) 1,299,1,562,1,791, 2,122; total fat (g/ day) = 43.9, 55.7, 65.2, 80.7; protein (g/day)= 44.5, 57.1, 64.6, 78.5; dietary fiber (g/day) = 11.1, 13.6, 16.2, 19.4; BMI=21.4, 23.0, 24.6, 26.5. Total physical activity in 1980 was categorized as either sedentary, fairly active, or very active? 2 To analyze results by subsite, the following definitions were used: colon includes right colon, left colon, and colon multiple/unknown sites; right colon includes cecum to splenic flexures; left colon includes descending and sigmoid colon; rectum includes the rectosigmoid junction. To investigate whether having assistance in completing the questionnaire might have influenced responses, the data were analyzed including as well as excluding these subjects.
Results Descriptive data During the period of subject accrual, 250 eligible cases of colon cancer, 135 cases of rectal cancer, and 346
Reproductive factors and colorectal cancer potential controls were identified among women. Seventy-eight percent of eligible cases participated. Reasons for nonparticipation were: refusal, 18; disabled, 19; dead, 43; not located, 6. Eighty percent of the potential controls participated. Reasons for nonparticipation were: refusal, 49; disabled, 17; dead, 1; not located, 3. Complete questionnaire data were available for 189 women with colon cancer, 110 women with rectal cancer, and 276 controls. Subsites of colon cancer among the 189 cases were: cecum and ascending colon, 73; transverse colon and flexures, 27; descending colon, 11; sigmoid, 63; multiple or unknown subsites, 15. Ninety-three percent of women, both cases and controls, were postmenopausal at diagnosis. Among cases, 91 percent of women were over 55 years of age at diagnosis, and among controls, 90 percent. The comparison of nulliparous with parous women having four or more births showed a reduced risk of colon cancer but not rectal cancer (Table 1). However, there was no trend across increasing parity. The results did not change when the analysis was adjusted for history of hormone use. Divided by subsite, the reduced risk was evident for both left and fight colon cancer. Due to fewer than five subjects in one strata, the data for right and left colon cancer were reanalyzed with an exact method (RR = 0.7, CI = 0.2-2.4 for right
colon; RR = 0.8, CI = 0.2-2.9 for left colon). Age at first birth was not associated with either colon or rectal cancer risk. Total number of months of breast feeding had no association with colon cancer but a decreased risk for rectal cancer. We observed little association between age at menarche and age at menopause and risk of colon and rectal cancer (Table 2). Due to small numbers in the highest categories, age at menarche was collapsed into less than 13, and greater than or equal to 13; age at menopause was combined into less than 50, or greater than or equal to 50. Subsite analyses did not demonstrate appreciable differences by anatomic location. A decreased risk for both colon and rectal cancer was seen for women who had a history of hormone use (including both oral contraceptives and postmenopausal estrogens). When cases who were assisted by the nurse in completing the questionnaire were excluded, hormone users remained at decreased risk for right colon cancer (RR = 0.5, C I = 0.2-1.1) but not for rectal cancer ( R R = 1.2, CI -- 0.6-2.4). When the history of hormone use was divided into two categories (1-9 years cf 10 or more years), no association with duration of use was evident. In an attempt to distinguish oral contraceptives (OC) from postmenopausal estrogens, the analysis of history of hormone use was stratified by year of hor-
Table 1. Age-adjusted relative risk (RR), with 95% confidence interval (CI), for colorectal cancer by subsite associated with
selected reproductive factors Controls (n = 276) Parity 0 1 2 3 4+ Test of trend
Colon' Cases RR (n = 189)
Right colon b (CI)
Cases RR (n =100)
(CI)
Left colon" Cases (n =74)
RR
68 56 84 47 21
51 41 57 32 8
1.0 1.0 (0.6-1.7) 0.9 (0.6-1.5) 0.9 (0.5-1.7) 0.5 (0.2-1.2) P = 0.3
26 24 29 17 4
1.0 1.1 (0.6-2.2) 0.9 (0.5-1.7) 1.0 (0.5-2.0) 0.5 (0.2-1.6) P = 0.4
20 15 24 11 4
1.0 0.9 1.0 0.9 0.7 P=0.6
Age at first birth 29 51 Test of trend
12 85 41
1.0 1.0 (0.4-2.1) 1.1 (0.5-2.6) P = 0.7
7 49 18
1.0 1.0 (0.4-2.4) 0.8 (0.3-2.2 P = 0.6
4 32 18
1.0 1.2 (0.5-2.7) 1.0 (0.5-2.4) 1.0 (0.4-2.5) P = 0.8
7 29 26 12
1.0 1.2 (0.4-3.1 1.0 (0.4-2.6 0.9 (0.3-2.7) P ~- 0.6
5 19 19 11
Total months of breast feeding 0 18 12 1-9 73 52 10-19 79 50 > 19 38 24 Test of trend
Rectum d (CI)
Cases RR (n =110)
(CI)
25 36 28 13 8
1.0 1.7 (0.9-3.2) 0.9 (0.5-1.6) 0.7 (0.3-1.5) 1.0 (0.4-2.6) P~-0.2
1.0 1.2 (0.4-3.6) 1.6 (0.5-5.3) P=0.4
10 50 25
1.0 0.8 (0.3-1.8) 1.1 (0.4-2.7) P~-0.6
1.0 1.0 (0.3-3.1) 1.0 (0.3-3.0) 1.1 (0.3-3.6) P = 0.9
9 34 33 9
1.0 0.9 (0.4-2.2) 0.8 (0.3-2.0) 0.4 (0.2-1.4) P = 0.1
(0.4-1.9) (0.5-2.0) (0.4-2.0) (0.2-2.2)
"Colon includes right colon (n = 100), left colon (n = 74), and colon multiple/unknown sites (n = 15). b Right colon includes cecum to splenic flexures. ° Left colon includes descending and sigmoid colon. d Rectum includes the rectosigmoid junction. Cancer Causes and Control. Vol 3. 1992
357
M. Gerhardsson de Verdier and S. London
Table 2. Age-adjusted relative risk (RR), with 95% confidence interval (CI), for colorectal cancer by subsite associated with selected reproductive and hormonal factors Controls (n=276)
Colon •
Right colon b
Cases (n =189)
RR
(CI)
Cases (n =100)
RR
(CI)
Age of menarche ~ < 13 46 13 + 222
42 147
1.0 0.7
(0.4-1.2)
22 78
1.0 0.7
Age of menopause < 50 129 50 + 128
97 83
1.0 0.9
(0.6-1.3)
55 44
Hormone use f None 198 Yes 65
154 29
1.0 0.6
(0.4-1.0)
84 12
Left colon c
Rectum d
Cases (n =74)
RR
(CI)
(0.4-1.3)
15 59
1.0 0.8
1.0 0.8
(0.5-1.3)
34 32
1.0 0.4
(0.2-0.8)
57 16
Cases (n =110
RR
(CI)
(0.4-1.6)
23 84
1.0 0.8
(0.4-1.3)
1.0 1.0
(0.6-1.7)
49 50
1.0 1.0
(0.6-1.6)
1.0 1.0
(0.5-1.9)
84 21
1.0 0.7
(0.4-1.3)
' Colon includes right colon (n = 100), left colon (n = 74), and colon multiple/unknown sites (n = 15). b Right colon includes cecum to splenic flexures. c Left colon includes descending and sigmoid colon. d Rectum includes the rectosigmoid junction. e Eight controls and three rectal cancer cases did not remember their ages at menarche. Thirteen controls, six colon cancer cases, and five rectal cancer cases did not remember if they had used hormones. f Hormone use includes both oral contraceptives and postmenopausal estrogens.
mone use (before 1965, the use of OCs was minimal) and the women's age at hormone use (after 45 years, the use of OCs is minimal) (Table 3). In this analysis, the reduced risk was restricted to women who took hormones at ages under 45, prior to 1965. These women are most likely to have been long-term users of estrogen replacement therapy. The above-mentioned results did not change when the analyses were adjusted for total energy intake, total fat intake, protein intake, dietary fiber intake, BMI, and physical activity. The main results did not change materially when the data were reanalyzed after exclusion of the cases who required help in filling out their questionnaire (data not shown).
Discussion There was little evidence that age at first birth, number of months of breast feeding, age at menarche, age at menopause, and history of hormone use in general influenced the risk of colon or rectal cancer. However, we found that women using hormones at ages under 45 prior to 1965 were at decreased risk, suggesting a possible protective effect of long-term hormone replacement therapy. The results suggested a reduced risk of colon cancer among parous women with at least four births compared with nulliparous women. However, no trend across increasing parity was observed. Few earlier studies on reproductive factors and colorectal 358
Cancer Causes and Control. Vol 3. 1992
cancer have adjusted for diet, body mass, and physical activity. Adjustments for these potential confounding factors did not materially alter our results. Our data provide limited support for the hypothesis that higher parity may decrease the risk of colon cancer. 4,9,1z The literature on parity and colon cancer is inconsistent. A protective effect of parity has been observed in some studies 18-26but not in others. 27-35A trend across increasing parity was found in some studies 19,2~,24but not in all. ~s,23,26In some studies, a protective effect was limited to women with more than three births 2°;' but, in another, a U-shaped relationship was observed. 28Wu-Williams et al found an effect of parity for Chinese women in North America but not in China. 26 Further, in two studies, 22,24the parity effect was found in men as well as in women suggesting that lifestyle factors rather than female hormonal factors might be the explanation. Overall, parity does not demonstrate a consistent or reproducible effect on colon or rectal cancer risk. We did not find an association between these variables and risk of colorectal cancer. Most previous studies have shown little consistent evidence relating age at menarche to risk of colorectal cancer, 22,25-2z,3Sbut not all. 3°,34 Later age at menopause was associated inversely with colorectal cancer risk in three studies, 22,28,3°but not in two others2 6,34Later age at first birth has been associated with an increased risk of colorectal cancer in some studies, 2°'24'31but not in all, ls'19-u'2sar,2s,33-3sPapadimitriou et aP° even found a decreased risk with increasing age at
Reproductive factors and colorectal cancer
Table 3. Age-adjusted relative risk (RR), with 95% confidence interval (CI), for colorectal cancer associated with history of hormone use stratified by year of hormone use and the women's age at hormone use Year of hormone use Nonusers c 1965 ~< 1965 > 1965 > 1965
Age at hormone use
Controls
Cases
RR*
(CI)
RR b
(CI)
Nonusers 45 ~ 45
198 21 5 12 23
238 10 7 11 22
1.0 0.4 1.2 0.8 0.8
(0.2-0.9) (0.4-3.8) (0.3-1.8) (0.4-1.5)
1.0 0.4 1.2 0.9 0.7
(0.2-0.9) (0.4-3.9) (0.3-2.3) (0.4-1.5)
Adjusted for year of birth. b Adjusted for year of birth and menopause. c Four controls did not remember during which years they had taken hormone pills.
first birth. Thus the evidence for an effect of ages at menarche, menopause, and at first childbirth is not convincing. To our knowledge, the association between lactation and colorectal cancer has not been evaluated in earlier studies, although one study2° noted that their colon cancer cases lactated less often than their controls, without specifying the point estimates of the relative risks. However, the results in our study gave little support for this association. Unfortunately, our information on hormone use does not allow us to determine with certainty whether women used OCs or postmenopausal estrogens. However, Table 3 suggests that the reduced risk was concentrated in women using hormones prior to 1965 at ages under 45. Because OCs were not available then, it is reasonable to assume that these women used hormones for estrogen replacement for an early menopause. It is also reasonable to assume that these women who started using replacement hormones at a young age would have used them for longer periods than other women in the study group. However, this is speculative because small numbers do not allow further analysis of duration of use in this small subgroup. Furthermore, women using hormones for estrogen replacement prior to 1965 also may have been exposed to relatively high doses of hormones compared with women using them later. Earlier studies addressing this issue have found little support for an association between O C s 25'35'37o r estrogen replacement",~2a3;5 and risk of colorectal cancer. Two studiesz°," reported that OC use was protective, while Weiss et a119found the opposite. However, four studies have found estrogen replacement to be inversely associated with colon cancer~°,35,36or colorectal cancer risk," indicating that this issue may benefit from further investigation. Differences in the descriptive epidemiology of colorectal cancer by subsite have led to the speculation that risk factors have different effects in the different parts
of the large bowel? s Recent results also have suggested that different subsites within the large bowel may have differing susceptibilities to neoplastic transformation due to developmental and biologic differences." Although we found no consistent patterns of subsite differences in the association between reproductive factors and colorectal cancer risk, we did observe sporadic differences by subsite. Given small numbers of exposed cases within some strata, these results are not stable. However, the findings suggest the importance of examining the effects of reproductive factors in datasets large enough to produce stable estimates within subsites. Variations in the associations by subsite due to small numbers may explain some of the inconsistences across studies. In conclusion, we found little evidence for an association between risk for colon or rectal cancer in women and age at first birth, number of months of breast-feeding, age of menarche, and age of menopause. However, our results add to the still inconclusive body of evidence that high parity and postmenopausal hormonereplacement therapy might reduce the risk of colorectal cancer.
AcknowledgementsmWe thank Mss Inga Romanus and Gun-Inger Loboda for their excellent work in collecting the data, and the Departments of Surgery at the hospitals involved (Danderyd, Ersta, Karolinska, Nacka, Sabbatsberg, St G6ran, and S6dersjukhuset), for their cooperation.
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