HORMONE REPLACEMENT THERAPY AND CANCER RISK: A SYSTEMATIC
ANALYSIS FROM A NETWORK OF CASE-CONTROL STUDIES
Esteve FERNANDEZ1–3*, Silvano GALLUS2,4, Cristina BOSETTI2, Silvia FRANCESCHI5, Eva NEGRI2and Carlo LAVECCHIA2,6 1Cancer Prevention and Control Unit, Institut Catala` d’Oncologia, L’Hospitalet (Barcelona), Catalonia, Spain 2Istituto di Ricerche Farmacologiche “Mario Negri,” Milan, Italy
3Department of Public Health, University of Barcelona, Catalonia, Spain 4Servizio di Epidemiologia, Centro di referimento Oncologico, Aviano, Italy
5Field and Intervention Studies Unit, International Cancer for Research on Cancer, Lyon, France 6Istituto di Statistica Medica e Biometria, Universita` di Milano, Milan, Italy
To provide comprehensive and quantitative information on the benefits and risks of hormone replacement therapy (HRT) on several cancer sites, we systematically examined the relation between HRT use and the risk of various cancers in women aged 45–79 by using data from a framework of case-control studies conducted in Italy between 1983 and 1999. The overall data set included the following incident, histologically confirmed neoplasms: oral cavity, pharynx, lar-ynx and esophagus (nⴝ253), stomach (nⴝ258), colon (nⴝ
886), rectum (nⴝ488), liver (nⴝ105), gallbladder (nⴝ31), pancreas (nⴝ122), breast (nⴝ4,713), endometrium (n ⴝ
704), ovary (nⴝ1,614), urinary bladder (n ⴝ106), kidney (n ⴝ 102), thyroid (n ⴝ 65), Hodgkin’s disease (n ⴝ 26), non-Hodgkin’s lymphomas (nⴝ145), multiple myeloma (nⴝ
65) and sarcomas (n ⴝ78). The control group comprised 6,976 women aged 45–79 years, admitted for a wide spec-trum of acute, nonneoplastic conditions. Odds ratios (OR) and the corresponding 95% confidence intervals (CI) for use of HRT were derived from multiple logistic regression equa-tions. There was an inverse association between ever use of HRT and colon (OR ⴝ0.7), rectum (OR ⴝ 0.5) and liver cancer (ORⴝ0.2), with a consistent pattern of protection for duration of use. An excess risk was found for gallbladder (ORⴝ3.2), breast (ORⴝ1.1), endometrial (ORⴝ3.0) and urinary bladder cancer (ORⴝ2.0). These data from a south-ern European population add some useful information on the risk-benefit assessment of HRT among postmenopausal women.
© 2003 Wiley-Liss, Inc.
Key words:hormonal replacement therapy; case-control studies; risk factors; neoplasms
Hormone replacement therapy (HRT) is highly effective to relieve short-term menopause-related symptoms and prevent post-menopausal osteoporosis.1The use of estrogens increases the risk of endometrial cancer, breast cancer, and venous thromboembo-lism and that of ovarian and gallbladder cancer,2– 8 whereas a protective effect on colorectal cancer risk has been reported.9,10 With respect to other cancer sites, there are some indications that HRT is associated with a reduced risk of cervical cancer and stomach cancer and an increased risk of renal cell cancer, whereas there is no consistent effect on the risk of liver, malignant mela-noma, or thyroid cancer.6,11Notwithstanding the widespread use of HRT, relatively few studies have focused on its effect on cancers other than the breast, endometrium, ovary, and colorec-tum.6,11
To provide comprehensive and quantitative information on the benefits and risks of HRT on several cancer sites, we systemati-cally examined the relation between HRT use and the risk of various cancers by using data from an integrated series of hospital-based case-control studies conducted in Italy.
MATERIAL AND METHODS
The data were derived from a network of case-control studies conducted between 1983 and 1999, whose general design has been already described.12Trained interviewers identified and questioned
patients admitted to teaching and general hospitals in the area under surveillance for selected cancers and for a wide spectrum of other acute, nonneoplastic conditions. All interviews were con-ducted during the hospital stay. On average, less than 3% of eligible cases and controls refused to be interviewed. The same study design, criteria of enrollment of cases and controls, and interview setting were adopted for all the diseases studied, and all the questionnaires contained a basic structured section, including sociodemographic characteristics, anthropometric measures and environmental exposures (including smoking and alcohol con-sumption), and frequency of consumption of selected dietary items. For women, information was also collected on menstrual and reproductive factors, and on use of oral contraceptives, meno-pausal HRT, and female hormones for other indications. The time of each episode of use was registered, together with the brand name, whenever available.
The cases were women between 45 and 79 years who were admitted to the National Cancer Institute and the Ospedale Mag-giore, which includes the 4 largest teaching and general hopitals of the Greater Milan area (northern Italy) and the Oncologic Refer-ence Hospital of the province of Pordenone (northeastern Italy) with histologically confirmed incident (i.e., diagnosed within the year prior to interview) cancers of the oral cavity, pharynx, larynx and esophagus (n⫽253), stomach (n⫽258), colon (n⫽886), rectum (n⫽488), liver (n⫽105), gallbladder (n⫽31), pancreas (n⫽122), breast (n⫽4,713), endometrium (n⫽704), ovary (n⫽
1,614), urinary bladder (n⫽106), kidney (n⫽102), thyroid (n⫽
65), Hodgkin’s disease (n⫽26), non-Hodgkin’s lymphomas (n⫽
145), multiple myeloma (n⫽65) and sarcomas (n⫽78). The control group comprised 6,976 women aged 45 to 79 years admitted for a wide spectrum of acute conditions in the same hospitals where cases were identified. For admission diagnoses, specific exclusions were made for malignant tumors, digestive tract diseases, or any disorder related to alcohol or tobacco con-sumption, or which might have induced a long-term modification of diet. Overall, controls were admitted for traumatic conditions (21%), nontraumatic orthopedic disorders (25%), acute surgical conditions (35%), and other miscellaneous diseases (19%), such as ear, nose, and throat, skin or dental disorders. For endometrial and
Grant sponsor: Italian Association for Cancer Research; Grant sponsor: the Italian League Against Cancer.
*Correspondence to: Cancer Prevention and Control Unit, Institut Catal`a d’Oncologia, Av. Gran Via s/n Km 2.7, 08907 L’Hospitalet (Barcelona), Spain. Fax:⫹34-93-2607956. E-mail: [email protected]
Received 1 October 2002; Revised 16 January 2003; Accepted 20 January 2003
DOI 10.1002/ijc.11083 © 2003 Wiley-Liss, Inc.
breast, endometrium, ovary, gallbladder and colorectal cancer, further adjustment for other reproductive factors (i.e., parity) was done but no meaningful differences emerged.
RESULTS
The distribution of cases according to ever use and duration of HRT use is shown in Table I. The frequency of exposure among cases ranged from 2.8% (among liver cancer) to 16.1% (among gallbladder cancer), and the overall frequency of ever use among controls was 7.6%.
Figure 1 and Table II give the OR and 95% CI of various neoplasms for evervs.never use of HRT. There was an inverse relation between ever use of HRT and colon (OR⫽0.7; 95% CI⫽ 0.5– 0.9), rectal (OR⫽0.5; 95% CI⫽0.3– 0.8) and liver cancer (OR⫽0.2; 95% CI⫽0.1– 0.8). A nonsignificant reduction in risk was observed for cancers of the oral cavity, esophagus, pharynx and larynx, as well as for thyroid cancer, Hodgkins’s, non-Hodgkin’s lymphomas and myelomas. A nonsignificant increased risk of pancreatic cancer, kidney cancer and sarcomas for women who had ever used HRT was present. An excess risk was found for gallbladder (OR ⫽3.2; 95% CI⫽ 1.1–9.3), breast (OR⫽1.1; 95% CI⫽1.0 –1.3), endometrial (OR⫽3.0; 95% CI⫽2.2– 4.0) and urinary bladder cancer (OR⫽2.0; 95% CI⫽1.1–3.5).
With reference to duration of use (Table II), a pattern of greater protection for longer duration was present for cancers of the liver, colon, and rectum (pfor trend⬍0.05). A pattern of increasing risk with duration was also present for endometrium and bladder can-cer, whereas a nonsignificant trend was present for cancer of the gallbladder, breast and ovary. The pattern of cancer risk was consistent across age strata and no appreciable effect modification was found.
use.14,15 A healthy user effect or prevention bias has been sug-gested,16since HRT users may differ from nonusers in ways that influence colorectal cancer risk. However, the results from ran-domized clinical trials showed a decreased risk of colorectal can-cer after several years of follow-up, supporting that the inverse association was real.4Different biological mechanisms have been postulated. Female hormones confer a protection against colorectal cancer, possibly as a result of changes in bile synthesis, which lead to reduced concentration of bile acids in the colon.17 Estrogens inhibit the growth of colon cancer cells in vitro,18and estrogen receptors have been identified in normal and neoplastic colon epithelial cells.19The estrogen receptor (ER) gene might play a tumor suppressor role, since the hypermethylation of the promotor region of the ER gene results in a reduced expression and dereg-ulated growth in colonic mucosa.20 Estrogens may also reduce serum insulin-like growth factor-I (IGF-I) levels,21–24a mitogen that may play an important role in the pathophysiology of colo-rectal and other cancers.25–27
There are scarce epidemiological data available on the associa-tion between HRT and liver cancer.6,11,28 In a Swedish cohort study based on prescription information, the relative risk of pri-mary liver cancer was 0.7.29No association between conjugated estrogen and other estrogen use and hepatocellular carcinoma was observed in a case-control study in Los Angeles County (RR⫽1.1 for ever use).30The use of female hormone preparations was not associated with the risk of liver cancer (RR⫽1.29) in the Japanese cohort of atomic bomb survivors.31In a previous analysis of this Italian case-control study, which included 82 liver cancer cases (with 1 exposed case to HRT),32a nonsignificant decreased risk was observed (OR⫽0.2), while in the present updated report, the OR and the pattern in risk are significant. These results, however, are based on small numbers. Estrogen receptors may be involved in the inhibition of malignant transformation of preneoplastic liver cells, and experimental studies have shown that exogenous estro-gens can suppress chemical hepatocarcinogenesis.33Moreover, the liver is the major source of IGF-I, and deregulation of the IGF axis has been identified in the development of hepatocellular carcino-ma.34Thus, downregulation of IGF-I by HRT may exert a protec-tive effect against hepatocellular carcinoma, as also hypothesized for colorectal cancer.
Analytical studies to date have provided scanty information on the relation between HRT and the risk of gallbladder cancer.35. In a case-control study conducted in Los Angeles County, including 105 histologically confirmed gallbladder cases, no association was found,36whereas the pooled analysis from 5 case-control studies included in the SEARCH program37showed a nonsignificant re-duction in risk based in 10 exposed cases and 126 exposed controls (OR ⫽ 0.5). Gallstones are the main risk factor for gallbladder cancer,35,37and gallstones are associated with HRT.38 – 40Thus, the pathogenic link between HRT and gallbladder is colelithiasis. Some kind of surveillance bias is possible since HRT stimulates gallbladder motility, making gallstones symptomatic, which in turn may determine an early diagnosis of gallbladder cancer in subjects with clinical cholelithiasis.8
The relationship between HRT and endometrial cancer has been firmly established in experimental and epidemiological studies since the 1970s.11The RR of endometrial cancer is 2 to 3 times greater in ever than in never users, is directly related to the duration of use, and is inversely related with time since last TABLE I– DISTRIBUTION OF CASES OF SELECTED CANCERS AND OF
CONTROLS ACCORDING TO DIFFERENT MEASURES OF HORMONE REPLACEMENT THERAPY USE, ITALY, 1983–99
Never use Ever use
Duration of use1 ⬍2 years ⱖ
2 years Oral cavity, esophagus,
pharynx and larynx
237 16 8 6 Stomach 245 13 8 5 Colon 832 54 33 20 Rectum 466 22 15 7 Liver 102 3 1 2 Gallbladder 26 5 2 2 Pancreas 110 12 9 2 Breast 4,354 359 241 115 Endometrium 617 87 61 26 Ovary 1,498 116 69 46 Bladder 89 17 11 6 Kidney 89 13 9 3 Thyroid 61 4 3 1 Hodgkin’s disease 23 3 2 1 Non-Hodgkin’s lymphomas 132 13 11 2 Multiple myeloma 62 3 0 2 Sarcomas 68 10 7 3 Controls 6,439 537 344 180 1In some strata, sum does not add up to the total because of some missing values.
use.2,6,11,41– 44 The present findings, therefore, confirm the avail-able evidence.
Ever use of HRT has also been associated to the risk of breast cancer in women.28,45A pooled analysis of individual data of 51 epidemiological studies from 21 different countries showed a significant 35% excess risk of breast cancer for ever HRT use.46 The Women’s Health Initiative Randomized Controlled Trial has recently confirmed that women with a uterus at randomization who were using combined estrogen plus progestin had a significant 26% increased incidence rate of developing breast cancer.2
With reference to HRT and bladder cancer risk, the available literature is scanty.6,11 Although risk factors for bladder cancer have been investigated,47,48 only the above-mentioned Swedish cohort29has evaluated the role of HRT on bladder cancer risk. In that study, a total of 58 cases of bladder cancer were observedvs.
67.7 expected, corresponding to a nonsignificant RR of 0.9. The role of sexual hormones in bladder cancer risk is controversial. Whereas a study from Iowa49found a protective association with menstrual and reproductive factors, results from this Italian case-control study showed no consistent association with parity and late
age at birth.50 Detection bias is possible, since HRT users are referred to the medical system more frequently for menopausal bleeding,28but the risk was not higher in recent users.
An excess risk of ovarian cancer has been established among ever HRT users.7,51,52 In our study, a nonsignificant 20% excess risk was found among women with 2 or more years of HRT use. The biological mechanisms that support this epidemiological ob-servation are related to the rise in estradiol and decrease in gonad-otropins levels.53Moreover, estrogen receptors are present in hu-man ovarian cells, and estrogens stimulate the proliferation of normal ovarian epithelial cells and the malignant differentiation of ovarian cellular lines.54
The interest and importance of this comprehensive analysis are given by the possibility of assessing the pattern of risk for various cancer sites. The overall pattern is unlikely to be due only to random or systematic error since the pattern was consistent across cancer sites that share common etiologic characteristics. Among the strengths of this study, there is the comparable catchment area of cases and controls, and the almost complete participation, which are reassuring against selection bias. Thus, the control series
FIGURE1– Odds ratio and 95% confi-dence intervals of selected cancers accord-ing to hormone replacement therapy use. Estimates from multiple logistic regres-sion equations including terms for age, study center, year of interview, education, smoking, drinking, type of menopause, age at menopause and body mass index. The reference category is never use of hormone replacement therapy.
represents the person-time distribution of exposure in the source population. For each women contributing time to the source pop-ulation, the time that she is eligible to be selected as a control is the same time during which she is eligible to become a case if the disease should occur. Selection bias due to overrepresentation of women with traumatic conditions in the control group (who could be more frequently HRT nonusers than other types of controls) is unlikely, since the analysis excluding the controls with trauma or other orthopedic conditions did not meaningfully alter the results. Cases and controls were interviewed in the same setting, which enabled us to obtain comparable information. Due to the low prevalence of HRT in this population, and the low incidence of some of the cancer sites studied, the statistical power is however limited. The study power and the information collected were also inadequate to address the issue of different types of administration and of estrogen-onlyvs.progestin-combined therapy.
Information bias due to a systematic underreporting of HRT is unlikely, since the potential association between HRT and cancer risk was unknown to the interviewers as well as to the patients. Differential reporting of HRT according to the period of study could also have biased the association observed. However, a similar protection was present when separate analysis according to study period was performed and the results were adjusted for the
year of interview. Furthermore, although the frequency of use of HRT in Italy has increased over the last decade, the correlates of use have not changed appreciably.55Finally, the choice of hospital controls has advantages in relation to the reliability and validity of drug use information, since cases and controls should be similarly sensitized toward various aspects of their past medical history, and reproducibility of the information was satisfactory.56 –58With ref-erence to confounding, the regression equations included major potential confounders, including use of oral contraceptives for cancers of the colon, rectum, liver, gallbladder, breast, endome-trium and ovary.
In summary, this study shows a consistent protective effect of ever use of HRT against colorectal and liver cancers and an increased risk for gallbladder, breast, endometrium and bladder cancers. In addition to the results already published from obser-vational studies and U.S. clinical trials2,40,42 this data from a southern European population could be of help in the risk-benefit assessment of HRT among postmenopausal women.
ACKNOWLEDGEMENTS
The authors thank Dr. Carmen Rodrı´guez for useful comments to a preliminary version of this article.
REFERENCES 1. Kenemans P. Menopause, HRT and menopausal symptoms. J
Epide-miol Biostat 1999;4:141– 6.
2. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321–33.
3. Hulley S, Furberg C, Barrett-Connor E. Heart and Estrogen/Progestin Replacement Study Follow-Up (HERS II): noncardiovascular disease outcomes during 6.8 years of hormone therapy. JAMA 2002;288:58 – 66.
4. Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet 2002;360: 942– 4.
5. Manson JE, Martin KA. Clinical practice: postmenopausal hormone-replacement therapy. N Engl J Med 2001;345:34 – 40.
6. IARC. Monographs on the evaluation of carcinogenic risks to human. Hormonal contraception and post-menopausal hormonal therapy. vol. 72. Lyon: IARC, 1999.
7. Rodriguez C, Patel AV, Calle EE, Jacob EJ, Thun MJ. Estrogen replacement therapy and ovarian cancer mortality in a large prospec-tive study of US women. JAMA 2001;285:1460 –5.
8. Gallus S, Negri E, Chatenoud L, Bosetti C, Franceschi S, La Vecchia C. Post-menopausal hormonal therapy and gallbladder cancer risk. Int J Cancer 2002;99:762–3.
9. Fernandez E, La Vecchia C, Braga C, Talamini R, Negri E, Parazzini F, Franceschi S. Hormone replacement therapy and risk of colon and rectal cancer. Cancer Epidemiol Biomarkers Prev 1998;7:329 –33. 10. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone
therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 1999;106:574 – 82.
11. Beral V, Banks E, Reeves G, Appleby P. Use of HRT and the subsequent risk of cancer. J Epidemiol Biostat 1999;4:191–210. 12. Chatenoud L, Tavani A, La Vecchia C, Jacobs DR Jr, Negri E, Levi
F, Franceschi S. Whole grain food intake and cancer risk. Int J Cancer 1998;77:24 – 8.
13. Breslow NE, Day NE. Statistical methods in cancer research. The analysis of case-control studies. vol 1. Lyon: IARC, Sci Publ, Vol. 32; 1980.
14. Franceschi S, La Vecchia C. Colorectal cancer and hormone replace-ment therapy: an unexpected finding. Eur J Cancer Prev 1998;7:427– 38. Liver 0.2 (0.1–0.8) 0.2 (0.0–1.1) 0.3 (0.1–1.7) 4.45 Gallbladder 3.2 (1.1–9.3) 2.3 (0.5–10.5) 3.0 (0.6–15.0) 2.47 Pancreas 1.6 (0.9–3.1) 2.0 (1.0–4.1) 0.7 (0.2–3.1) 0.43 Breast3 1.1 (1.0–1.3) 1.2 (1.0–1.4) 1.1 (0.9–1.4) 2.60 Endometrium3 3.0 (2.2–4.0) 3.3 (2.3–4.6) 2.5 (1.4–4.3) 38.292 Ovary3 1.0 (0.8–1.3) 0.9 (0.7–1.2) 1.2 (0.8–1.7) 0.10 Bladder 2.0 (1.1–3.5) 1.9 (1.0–3.8) 2.2 (0.9–5.6) 5.702 Kidney 1.3 (0.7–2.4) 1.3 (0.6–2.8) 0.9 (0.3–3.2) 0.06 Thyroid 0.8 (0.3–2.3) 1.0 (0.3–3.4) 0.5 (0.1–4.0) 0.26 Hodgkin’s disease 0.8 (0.2–3.1) 0.8 (0.2–3.8) 1.2 (0.1–10.7) 0.01 Non-Hodgkin’s lymphomas 0.7 (0.3–1.3) 0.9 (0.4–1.8) 0.2 (0.0–1.6) 2.18 Multiple myeloma 0.5 (0.1–1.6) — — Sarcomas 1.1 (0.5–2.7) 1.8 (0.7–4.6) 0.5 (0.1–2.1) 0.06 1Estimates from multiple logistic regression equations including terms for age, study center, year of interview, education, smoking, drinking, type of menopause, age at menopause and body mass index. The reference category is never use of hormone replacement therapy.–2p⬍ 0.05.–3Estimates further adjusted for oral contraceptive use.
15. Hebert-Croteau N. A meta-analysis of hormone replacement therapy and colon cancer in women. Cancer Epidemiol Biomark Prev 1998; 7:653–9.
16. Barrett-Connor E. Postmenopausal estrogen and prevention bias. Ann Intern Med 1991;115:455– 6.
17. McMichael AJ, Potter JD. Host factors in carcinogenesis: certain bile-acid metabolic profiles that selectively increase the risk of prox-imal colon cancer. J Natl Cancer Inst 1985;75:185–91.
18. Lointier P, Wildrick DM, Boman BM. The effects of steroid hor-mones on a human colon cancer cell line in vitro. Anticancer Res 1992;12:1327–30.
19. Meggouh F, Lointier P, Pezet D, Saez S. Status of sex steroid hormone receptors in large bowel cancer. Cancer 1991;67:1964 –70. 20. Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson EN, Baylin SB. Methylation of the oestrogen receptor CpG islands links ageing and neoplasia in human colon. Nat Genet 1994;7:536 – 40. 21. Goodman-Gruen D, Barrett-Connor E. Effect of replacement estrogen
on insulin-like growth factor-I in postmenopausal women: the Rancho Bernardo Study. J Clin Endocrinol Metab 1996;81:4268 –71. 22. Campagnoli C, Biglia N, Cantamessa C, Lesca L, Lotano MR,
Sis-mondi P. Insulin-like growth factor I (IGF-I) serum level modifica-tions during transdermal estradiol treatment in postmenopausal wom-en: a possible bimodal effect depending on basal IGF-I values. Gynecol Endocrinol 1998;12:259 – 66.
23. Vestergaard P, Hermann AP, Orskov H, Mosekilde L. Effect of sex hormone replacement on the insulin-like growth factor system and bone mineral: a cross-sectional and longitudinal study in 595 peri-menopausal women participating in the Danish Osteoporosis Preven-tion Study. J Clin Endocrinol Metab 1999;84:2286 –90.
24. Kam GY, Leung KC, Baxter RC, Ho KK. Estrogens exert route- and dose-dependent effects on insulin-like growth factor (IGF)-binding protein-3 and the acid-labile subunit of the IGF ternary complex. J Clin Endocrinol Metab 2000;85:1918 –22.
25. Baghdiguian S, Verrier B, Gerard C, Fantini J. Insulin like growth factor I is an autocrine regulator of human colon cancer cell differ-entiation and growth. Cancer Lett 1992;62:23–33.
26. Giovannucci E. Insulin-like growth factor-I and binding protein-3 and risk of cancer. Horm Res 1999;51(Suppl 3):34 – 41
27. McCarty MF. Androgenic progestins amplify the breast cancer risk associated with hormone replacement therapy by boosting IGF-I activity. Med Hypotheses 2001;56:213– 6.
28. La Vecchia C, Brinton LA, McTiernan A. Menopause, hormone replacement therapy and cancer. Maturitas 2001;39:97–115. 29. Persson I, Yuen J, Bergkvist L, Schairer C. Cancer incidence and
mortality in women receiving estrogen and estrogen-progestin re-placement therapy: long-term follow-up of a Swedish cohort. Int J Cancer 1996;67:327–32.
30. Yu MC, Tong MJ, Govindarajan S, Henderson BE. Nonviral risk factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California. J Natl Cancer Inst 1991;83:1820 – 6.
31. Goodman MT, Moriwaki H, Vaeth M, Akiba S, Hayabuchi H, Ma-buchi K. Prospective cohort study of risk factors for primary liver cancer in Hiroshima and Nagasaki, Japan. Epidemiology 1995;6:36 – 41.
32. Tavani A, Negri E, Parazzini F, Franceschi S, La Vecchia C. Female hormone utilisation and risk of hepatocellular carcinoma. Br J Cancer 1993;67:635–7.
33. Shimizu I, Yasuda M, Mizobuchi Y, Ma YR, Liu F, Shiba M, Horie T, Ito S. Suppressive effect of oestradiol on chemical hepatocarcino-genesis in rats. Gut 1998;42:112–9.
34. Scharf JG, Dombrowski F, Ramadori G. The IGF axis and hepato-carcinogenesis. Mol Pathol 2001;54:138 – 44.
35. Fraumeni JF Jr, Devesa SS, McLaughlin JK, Standford JL. Biliary tract cancers. In: Schotenfeld D, Fraumeni JF Jr, eds. Cancer epide-miology and prevention, 2nd ed. New York: Oxford University Press, 1996. 794 – 805.
36. Chow WH, McLaughlin JK, Menck HR, Mack TM. Risk factors for extrahepatic bile duct cancers: Los Angeles County, California (USA). Cancer Causes Control 1994;5:267–72.
37. Zatonski WA, Lowenfels AB, Boyle P, Maisonneuve P, Bueno de Mesquita HB, Ghadirian P, Jain M, Przewozniak K, Baghurst P, Moerman CJ, Simard A, Howe GR, McMichael AJ, Hsieh CC, Walker AM. Epidemiologic aspects of gallbladder cancer: a
case-control study of the SEARCH Program of the International Agency for Research on Cancer. J Natl Cancer Inst 1997;89:1132– 8. 38. La Vecchia C, Negri E, D’Avanzo B, Parazzini F, Gentile A,
France-schi S. Oral contraceptives and non-contraceptive oestrogens in the risk of gallstone disease requiring surgery. J Epidemiol Comm Health 1992;46:234 – 6.
39. Uhler ML, Marks JW, Judd HL. Estrogen replacement therapy and gallbladder disease in postmenopausal women. Menopause 2000;7: 162–7.
40. Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, Haskell W, Knopp R, Lowery M, Satterfield S, Schrott H, Vittinghoff E, Hunninghake D. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study Follow-Up (HERS II). JAMA 2002;288:58 – 66.
41. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hor-mone replacement therapy and endometrial cancer risk: a meta-anal-ysis. Obstet Gynecol 1995;85:304 –13.
42. Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA 1996;275:370 –5.
43. Weiderpass E, Adami HO, Baron JA, Magnusson C, Bergstrom R, Lindgren A, Correia N, Persson I. Risk of endometrial cancer follow-ing estrogen replacement with and without progestins. J Natl Cancer Inst 1999;91:1131–7.
44. Lethaby A, Farquhar C, Sarkis A, Roberts H, Jepson R, Barlow D. Hormone replacement therapy in postmenopausal women: endome-trial hyperplasia and irregular bleeding. Cochrane Database Syst Rev 2000;2:CD000402.
45. Stanford JL, Thomas DB. Exogenous progestins and breast cancer. Epidemiol Rev 1993;15:98 –107.
46. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350: 1047–59.
47. Silverman DT, Morrison AS, Devesa SS. Bladder cancer. In: Scho-tenfeld D, Fraumeni JF Jr, eds. Cancer epidemiology and prevention, 2nd ed. New York: Oxford University Press, 1996. 1156 –79. 48. Negri E, La Vecchia C. Epidemiology and prevention of bladder
cancer. Eur J Cancer Prev 2001;10:7–14.
49. Cantor KP, Lynch CF, Johnson D. Bladder cancer, parity, and age at first birth. Cancer Causes Control 1992;3:57– 62.
50. Pelucchi C, La Vecchia C, Negri E, Dal Maso L, Franceschi S. Smoking and other risk factors for bladder cancer in women. Prev Med 2002;35:114 –20.
51. Riman T, Dickman PW, Nilsson S, Correia N, Nordlinder H, Mag-nusson CM, Weiderpass E, Persson IR. Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. J Natl Cancer Inst 2002;94:497–504.
52. Lacey JV Jr, Mink PJ, Lubin JH, Sherman ME, Troisi R, Hartge P, Schatzkin A, Schairer C. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002;288:334 – 41.
53. Syed V, Ulinski G, Mok SC, Ho SM. Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells. J Natl Cancer Inst 2002;94:617–29. 54. Persson I. Estrogens in the causation of breast, endometrial and
ovarian cancers: evidence and hypotheses from epidemiological find-ings. J Steroid Biochem Mol Biol 2000;74:357– 64.
55. Parazzini F, La Vecchia C, Negri E, Bianchi C, Fedele L. Determi-nants of estrogen replacement therapy use in northern Italy. Rev Epidem Sante Publ 1993;41:53– 8.
56. Banks E, Beral V, Cameron R, Hogg A, Langley N, Barnes I, Bull D, Elliman J, Harris CL. Agreement between general practice prescrip-tion data and self-reported use of hormone replacement therapy and treatment for various illnesses. J Epidemiol Biostat 2001;6:357– 63. 57. Kelly JP, Rosenberg L, Kaufman DW, Shapiro S. Reliability of
personal interview data in a hospital-based case-control study. Am J Epidemiol 1990;131:79 –90.
58. Bosetti C, Tavani A, Negri E, Trichopoulos D, La Vecchia C. Reli-ability of data on medical conditions, menstrual and reproductive history provided by hospital controls. J Clin Epidemiol 2001;54: 902– 6.
