(Hypertension. 1999;34:320-325.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
From the Istituto di Ricerche Farmacologiche "Mario Negri" (M.S., L.C., E.N., F.P., C. La V.), Milan; Prima Clinica Ostetrico-ginecologica, Università di Milano (F.P.), Milan; Servizio di Epidemiologia, Centro di Riferimento Oncologico (S.F.), Aviano; and Istituto di Statistica Medica e Biometria, Università degli Studi di Milano (C. La V.), Milan, Italy.
Correspondence to Maria Soler, MD, Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157 Milan, Italy.
| Abstract |
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5 years since diagnosis of hypertension.
No significant association was observed for ovarian and thyroid
cancer. For breast cancer, the association was apparently stronger at
age 55 years or over and consequently after menopause. No appreciable
effect modification was evident for endometrial cancer. Allowance for
BMI did not explain the association of postmenopausal breast cancer and
endometrial cancer with hypertension. The OR of postmenopausal breast
cancer was 1.5 (95% CI, 1.1 to 2.0) in hypertensive women with BMI
30 kg/m2 compared with normotensive women with BMI <25
kg/m2. The corresponding figure for all endometrial cancers
was 4.9 (95% CI, 3.4 to 6.9). Even in the absence of a clear
understanding of biological mechanisms, the definition of a role of
hypertension on female hormonerelated cancers can have relevant
implications on individual risk assessment.
Key Words: hypertension, essential breast neoplasms endometrial neoplasms ovarian neoplasms thyroid neoplasms case-control studies
| Introduction |
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With regard to the possible relation between hypertension and cancer risk in women, specific attention has also been paid to the possible association with breast, endometrial, and ovarian neoplasms.6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Available evidence for breast cancer allows exclusion of a strong association with hypertension.7 8 9 However, the possibility of a moderately increased risk remains open to discussion, mainly for hypertension early in life,7 8 9 10 including hypertension in pregnancy. Talamini et al8 found a RR of 2.3 for hypertension in pregnancy in a case-control study. Furthermore, some treatment for hypertension has been associated with breast cancer risk. Armstrong et al,11 Heinonen et al,12 and Stanford et al13 suggested that rauwolfia derivatives may increase the risk of breast cancer, but other case-control14 15 16 and cohort studies17 did not support this association. In postmenopausal women, the association between hypertension and breast cancer risk may be partly or largely due to residual confounding by overweight, which is related to both hypertension and postmenopausal breast cancer.7 18
Stronger and more consistent is the relation between hypertension and endometrial cancer risk. Thus, several studies reported a higher risk of the disease in hypertensive women, with odds ratios (ORs) ranging from 1.2 to 2.1.19 20 21 22 23 24 25 26 27 28 The association generally persisted after allowance for covariates.27 Because endometrial cancer is strongly related to overweight and obesity, and although most recent studies allowed for measures of body mass index (BMI) in the analysis, the possibility of some residual confounding by BMI remains open to discussion for this neoplasm as well.
Little data exist on the possible relation between hypertension, overweight, and ovarian cancer risk.29 The RR of ovarian cancer death was 1.6 in obese women in the prospective American Cancer Society One Million Study.30 Thyroid cancer has also been related to overweight, mainly in postmenopausal women.31 32 Consequently, an association with hypertension is possible for this neoplasm as well.
To provide further information on this issue, we systematically analyzed the relation between treated hypertension and cancers of the breast, endometrium, ovary, and thyroid, with the use of data from a network of case-control studies conducted in Italy.
| Methods |
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Trained interviewers identified and questioned cases and controls with
a structured questionnaire, including information on personal
characteristics and habits, education and other socioeconomic factors,
smoking, alcohol and coffee consumption, food frequency, and menstrual
and reproductive history. The questionnaire included data on age at
first diagnosis of selected medical conditions (or procedures),
including a specific question on the age at first diagnosis of treated
hypertension, ie, hypertension diagnosed by a physician and regularly
treated with antihypertensive drugs for
1 year (excluding
hypertension in pregnancy only).
The cases included in the present analysis were women younger than 75 years with incident, histologically confirmed cancer of the breast (n=3406; median age, 53 years), endometrium (n=745; median age, 61 years), ovary (n=970; median age, 54 years), or thyroid (n=145; median age, 43 years). The patients were admitted to the National Cancer Institute, to several university clinics, or to the Ospedale Maggiore of Milan, which includes the 4 largest teaching and general hospitals in Milan.
Controls were 3054 women resident in the same geographic area as cases, younger than 75 years (median age, 53 years), admitted for a wide spectrum of acute, nonneoplastic conditions in the same hospitals in which cases had been identified. For admission diagnosis, specific exclusions were made for malignant tumors, hormone-related and gynecological conditions, or any long-term chronic disease. Controls were admitted for orthopedic disorders (33%), traumatic conditions (32%), acute surgical conditions (16%), and other miscellaneous diseases, such as ear, nose, throat, skin, or dental disorders (19%).
Data Analysis
ORs and the corresponding 95% CIs in relation to history of
treated hypertension, age at first diagnosis, and time since diagnosis
of hypertension were derived from unconditional multiple logistic
regression, fitted by the method of maximum likelihood.34
To allow for possible confounding, all the regression equations
included terms for area of residence, age (in quinquenniums),
education, smoking habits, alcohol consumption, parity, menopausal
status, and BMI (<20; 20 to 24; 25 to 29;
30
kg/m2).
The potential modifying effect of selected covariates was evaluated by
comparing the increase in the -2 log likelihood between the models
with and without interaction terms with the
2
distribution, with degrees of freedom given by the number of
interaction terms.34
| Results |
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Table 2 gives the distribution of cases of the 4 neoplasms and the comparison group according to hypertension. The corresponding multivariate ORs were 1.2 (95% CI, 1.1 to 1.4) for breast cancer and 1.6 (95% CI, 1.3 to 1.9) for endometrial cancer. No significant association was observed for ovarian (OR=0.9; 95% CI, 0.7 to 1.2) and thyroid (OR=1.0; 95% CI, 0.6 to 1.8) cancer.
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Table 3 shows the relation between age at first diagnosis of hypertension and time since diagnosis for breast and endometrial cancer. No appreciable differences were found according to age at the first diagnosis of hypertension. With reference to time since diagnosis, the ORs for duration of hypertension <5 years were 1.1 (95% CI, 0.9 to 1.4) for breast cancer and 1.5 (95% CI, 1.2 to 2.0) for endometrial cancer. Corresponding values for duration of hypertension >5 years were 1.3 (95% CI, 1.1 to 1.6) for breast cancer and 1.7 (95% CI, 1.3 to 2.1) for endometrial cancer. The trends in risk were significant for both neoplasms.
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To address the issue of effect modification, Table 4 considers the relation between
hypertension, breast cancer, and endometrial cancer in strata of age at
cancer diagnosis and other selected covariates. For breast cancer, the
association was stronger at age 55 and over, and consequently in
postmenopausal women, and in alcohol drinkers. No appreciable effect
modification was evident for education, smoking, and parity (data not
shown). The association between treated hypertension and breast cancer
risk was significantly stronger in overweight women, with an OR of 1.1
in women with BMI <25 kg/m2 and 1.4 in those
with BMI
25 kg/m2 (
2
for heterogeneity obtained from the logistic
model=4.689; 1 df; P=0.03). Likewise, the
association between hypertension and breast cancer tended to be
stronger in subjects with diabetes mellitus, although the interaction
term was not significant (OR=1.7;
2 for
heterogeneity=2.877; 1 df;
P=0.099). No significant effect modification of any of the
covariates considered was observed for endometrial cancer.
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To investigate further the combined effect of BMI and
hypertension on endometrial and postmenopausal breast cancer, the joint
ORs of hypertension and BMI are presented in Table 5. In normotensive women, there was no
trend in OR with increasing BMI with respect to breast cancer, but a
marked trend with respect to endometrial cancer was observed. Compared
with women who did not report hypertension and had a BMI <25
kg/m2, the OR of postmenopausal breast cancer was
1.0 in obese (BMI
30) normotensive women but rose to 1.5 (95% CI,
1.1 to 2.0) in hypertensive and obese women. Corresponding ORs for
all endometrial cancers were 2.9 (95% CI, 2.1 to 3.8) and 4.9 (95%
CI, 3.4 to 6.9).
|
| Discussion |
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5 years since diagnosis. The strength of the association
was consistent across strata of several covariates considered
for breast and endometrial cancer, but in both cases this relation
tended to be stronger in overweight (25 to 29
kg/m2) and obese (
30
kg/m2) patients. The potential confounding effect
of several covariates, including age, area of residence, education,
tobacco smoking, alcohol consumption, parity, menopausal status, and
BMI, was controlled for in the analysis. It is conceivable that
some aspect of diet, such as a relative absence of fruits and
vegetables, is correlated with both hypertension35 and the
risk of these neoplasms.36 However, further allowance for
these factors was unable to totally account for the association.
Likewise, allowance for parity, age at first birth, and age at menarche
and menopause, which are recognized risk factors for breast and
endometrial cancer,27 37 38 did not appreciably modify any
of the risk estimates. Although information on treated hypertension was not independently validated,39 the choice of a hospital-based design is optimal to investigate aspects of medical history, because cases and controls were similarly sensitized toward recalling diseases in the past.39 Moreover, the fact that the association was observed in only 2 of the 4 cancers considered is reassuring regarding generalized recall bias. With reference to selection bias, cases and controls were identified in the major teaching and general hospitals in the greater Milan area, and the participation of cases and controls was almost complete. The proportion of controls with hypertension (17%) is consistent with that of the 19901991 Italian National Health Survey, when similar age ranges were considered.40 Also, there is no reason to assume different recall in relation to age at first treatment for hypertension on the basis of disease status. A limitation of the present study is the absence of information on values of blood pressure, severity of the disease, and treatment for hypertension.
The observation that the ORs were higher in subjects who had been diagnosed with hypertension for a longer time argues against surveillance bias, ie, more careful screening for breast or endometrial neoplasms in the few years around the diagnosis of hypertension. This pattern of risk is also consistent with a duration-risk relation, thus suggesting the existence of a real association between hypertension and the risk of these neoplasms.
Detailed discussion on biological mechanisms underlying the possible influence of treated hypertension and female hormonerelated cancers goes beyond the scope of this work. Hamet41 42 suggested that hypertension may increase the cancer risk by blocking and subsequently modifying apoptosis, thereby affecting the regulation of cell turnover. Hypertension has also been related to insulin resistance and hence to insulin-like growth factor 1,43 which has been related to cell growth and neoplastic progression.44 45 Other possible interpretations for breast cancer include the relation between treatment for hypertension and increased secretion of prolactin, a hormone with recognized effect on breast tissue differentiation.12 13 Hormonal mechanisms are also possible for breast cancer and primarily for endometrial cancer, because hypertension is related to overweight, which in turn is associated with elevated estrogen levels and availability46 and consequently with the risk of endometrial27 and postmenopausal breast cancer.18 30 However, strict allowance for BMI was unable to totally explain the association observed, and women reporting both risk factors (BMI and hypertension) had an appreciably elevated risk of breast cancer. The 2 factors (BMI and hypertension) appeared to have a synergistic effect47 on the risk of endometrial cancer and produced appreciably elevated risk (almost 5-fold) in women exposed to both factors.
| Acknowledgments |
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Received January 13, 1999; first decision February 9, 1999; accepted March 29, 1999.
| References |
|---|
|
|
|---|
2.
Raynor WR Jr, Shekelle RB, Rossof AH, Maliza C, Paul
O. High blood pressure and 17-year cancer mortality in the Western
Electric Health Study. Am J Epidemiol. 1981;113:371377.
3.
Khaw KT, Barrett-Connor E. Systolic
blood-pressure and cancer mortality in an elderly population.
Am J Epidemiol. 1984;120:550558.
4. Goldbourt U, Holtzman E, Yaari S, Cohen L, Katz L, Neufeld HN. Elevated systolic blood pressure as a predictor of long-term cancer mortality: analysis by site and histologic subtype in 10,000 middle-aged and elderly men. J Natl Cancer Inst. 1986;77:6370.
5.
Wannamethee G, Shaper AG. Blood pressure and cancer in
the middle-aged British men. Int J Epidemiol. 1996;25:2231.
6.
Kelsey JL, LiVolsi VA, Holford TR, Fischer DB, Mostow
ED, Schwartz PE, O'Connor T, White C. A case-control study of cancer
of the endometrium. Am J Epidemiol. 1982;116:333342.
7. Franceschi S, La Vecchia C, Negri E, Parazzini F, Boyle P. Breast cancer risk and history of selected medical conditions linked with female hormones. Eur J Cancer. 1990;26:781785.
8. Talamini R, Franceschi S, Favero A, Negri E, Parazzini F, La Vecchia C. Selected medical conditions and risk of breast cancer. Br J Cancer. 1997;75:16991703.[Medline] [Order article via Infotrieve]
9. de Waard F, Baanders-van Halewijn EA. A prospective study in general practice on breast-cancer risk in menopausal women. Int J Cancer. 1974;14:153160.[Medline] [Order article via Infotrieve]
10.
Moseson M, Koenig KL, Shore RE, Pasternack BS. The
influence of medical conditions associated with hormones on the risk of
breast cancer. Int J Epidemiol. 1993;22:10001009.
11. Armstrong B, Stevens N, Doll R. Retrospective study of the association between use of rauwolfia derivates and breast cancer in English women. Lancet. 1974;2:672675.[Medline] [Order article via Infotrieve]
12. Heinonen OP, Shapiro S, Tuominen L, Turunen MI. Reserpine use in relation to breast cancer. Lancet. 1974;2:675677.[Medline] [Order article via Infotrieve]
13. Stanford JL, Martin EJ, Brinton LA, Hoover RN. Rauwolfia use and breast cancer: a case-control study. J Natl Cancer Inst. 1986;76:817822.
14. Laska EM, Siegel C, Meisner M, Fischer S, Wanderling J. Matched-pairs study of reserpine use and breast cancer. Lancet. 1975;2:296300.[Medline] [Order article via Infotrieve]
15. Aromaa A, Hakama M, Hakulinen T, Saxén E, Teppo L, Idänpään-Heikkilä J. Breast cancer and use of rauwolfia and other antihypertensive agents in hypertensive patients: a nationwide case-control study in Finland. Int J Cancer. 1976;18:727738.[Medline] [Order article via Infotrieve]
16. O'Fallon WM, Labarthe DR, Kurland LT. Rauwolfia derivates and breast cancer: a case-control study in Olmstedt County, Minnesota. Lancet. 1975;2:292296.[Medline] [Order article via Infotrieve]
17. Mack TM, Henderson BE, Gerkins VR, Arthur M, Baptista J, Pike MC. Reserpine and breast cancer in a retirement community. N Engl J Med. 1975;292:13661371.[Abstract]
18. La Vecchia C, Negri E, Franceschi S, Talamini R, Bruzzi P, Palli D, Decarli A. Body mass index and post-menopausal breast cancer: an age-specific analysis. Br J Cancer. 1997;75:441444.[Medline] [Order article via Infotrieve]
19. Elwood JM, Cole P, Rothman KJ, Kaplan SD. Epidemiology of endometrial cancer. J Natl Cancer Inst. 1977;59:10551060.
20. Hoogerland DL, Buchler DA, Crowley JJ, Carr WF. Estrogen use: risk of endometrial carcinoma. Gynecol Oncol. 1978;6:451458.[Medline] [Order article via Infotrieve]
21. Jelovsek FR, Hammond CB, Woodard BH, Draffin R, Lee KL, Creasman WT, Parker RT. Risk of exogenous estrogen therapy and endometrial cancer. Am J Obstet Gynecol. 1980;137:8591.[Medline] [Order article via Infotrieve]
22. Schwartz Z, Dgani R, Flugelman MY, Lancet M, Gelerenter I. A novel approach to the analysis of risk factors in endometrial carcinoma. Gynecol Oncol. 1985;21:228234.[Medline] [Order article via Infotrieve]
23. Tyler CW Jr, Webster LA, Ory HW, Rubin GL. Endometrial cancer: how does cigarette smoking influence the risk of women under age 55 years having this tumor? Am J Obstet Gynecol. 1985;151:899905.[Medline] [Order article via Infotrieve]
24. Franks AL, Kendrick JS, Tyler CW Jr. The Cancer and Steroid Hormone Study Group: postmenopausal smoking, estrogen replacement therapy, and the risk of endometrial cancer. Am J Obstet Gynecol. 1987;156:2023.[Medline] [Order article via Infotrieve]
25. Ewertz M, Schou G, Boice JD Jr. The joint effect of risk factors on endometrial cancer. Eur J Cancer Clin Oncol. 1988;24:189194.[Medline] [Order article via Infotrieve]
26. Parazzini F, Negri E, La Vecchia C, Bruzzi P, Decarli A. Population attributable risk for endometrial cancer in Northern Italy. Eur J Cancer Clin Oncol. 1989;25:14511456.[Medline] [Order article via Infotrieve]
27. Parazzini F, La Vecchia S, Bocciolone L, Franceschi S. The epidemiology of endometrial cancer. Gynecol Oncol. 1991;41:110.[Medline] [Order article via Infotrieve]
28. Rubin GL, Peterson HB, Lee NC, Maes EF, Wingo PA, Becker S. Estrogen replacement therapy and the risk of endometrial cancer: remaining controversies. Am J Obstet Gynecol. 1990;162:148154.[Medline] [Order article via Infotrieve]
29. Parazzini F, Franceschi S, La Vecchia C, Fasoli M. The epidemiology of ovarian cancer. Gynecol Oncol. 1991;43:923.[Medline] [Order article via Infotrieve]
30. Garfinkel L. Overweight and cancer. Ann Intern Med. 1985;103:10341036.
31. Goodman MT, Kolonel LN, Wilkens LR. The association of body size, reproductive factors and thyroid cancer. Br J Cancer. 1992;66:11801184.[Medline] [Order article via Infotrieve]
32. Preston-Martin S, Jin F, Duda MJ, Mack WJ. A case-control study of thyroid cancer in women under age 55 in Shangai (People's Republic of China). Cancer Causes Control. 1993;4:431440.[Medline] [Order article via Infotrieve]
33. Chatenoud L, Tavani A, La Vecchia C, Jacobs DR, Negri E, Levi F, Franceschi S. Whole grain food intake and cancer risk. Int J Cancer. 1998;77:2428.[Medline] [Order article via Infotrieve]
34. Breslow EN, Day EN. Statistical Methods in Cancer Research. Vol 1. Lyon, France: IARC; 1980. IARC Scientific Publication 32.
35.
McCarron DA. Diet and blood pressure: the paradigm
shift. Science. 1998;281:933934.
36. Negri E, La Vecchia C, Franceschi S, D'Avanzo B, Parazzini F. Vegetable and fruit consumption and cancer risk. Int J Cancer. 1991;48:350354.[Medline] [Order article via Infotrieve]
37.
Kelsey JL, Gammon MD, John EM. Reproductive factors
and breast cancer. Epidemiol Rev. 1993;15:3641.
38. Lipworth L. Epidemiolgy of breast cancer. Eur J Cancer Prev. 1995;4:730.[Medline] [Order article via Infotrieve]
39.
Kelly JP, Rosenberg L, Kaufman DW, Shapiro S.
Reliability of personal interview data in a hospital-based case-control
study. Am J Epidemiol. 1990;131:7990.
40. Pagano R, La Vecchia C. Overweight and obesity in Italy, 19901991. Int J Obes. 1994;18:665669.
41.
Hamet P. Cancer and hypertension: an unresolved issues.
Hypertension. 1996;28:321324.
42. Hamet P. Cancer and hypertension: a potential for crosstalk? J Hypertens. 1997;15:15731577.[Medline] [Order article via Infotrieve]
43. Giovannucci E. Insulin and colon cancer. Cancer Causes Control. 1995;6:164179.[Medline] [Order article via Infotrieve]
44. Nagamani M, Stuart CA. Specific binding and growth-promoting activity of insulin in endometrial cancer cells in culture. Am J Obstet Gynecol. 1998;179:612.[Medline] [Order article via Infotrieve]
45. Mantzoros CS, Tzonou A, Signorello LB, Stampfer M, Trichopoulos D, Adami H-O. Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. Br J Cancer. 1997;76:11151118.[Medline] [Order article via Infotrieve]
46.
Siiteri PK. Adipose tissue as a source of hormones.
Am J Clin Nutr. 1987;45:277282.
47.
Rothman KJ, Greenland S, Walker AM. Concepts of
interaction. Am J Epidemiol. 1980;112:467470.
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