Vol. 4, 21-28, January/February 1995 Cancer Epidemiology, Biomarkers & Prevention 21 Menopausal Hormone Use and Colorectal Cancer in Saskatchewan: A Record Linkage Cohort Study1 Harvey A. Risch2 and Geoffrey R. Howe treatment of osteoporosis and the prevention of its sequelae. Department of Epidemiology and Public Health, Yale University School of Estrogen use may have potentially important consequences, Medicine, New Haven, Connecticut 06510 (H. A. RI, and National because long-term usage has been related to increased Cancer Institute of Canada Epidemiology Unit, Department of Preventive incidence of endometrial cancer (1) and possibly breast Medicine and Biostatistics, University of Toronto, Toronto, Ontario cancer (2). It has also been suggested that estrogen use, M5S 1A8, Canada IC. R. H.l through effects on bile acid production, may be associated with the development of colorectal cancer (3), although the Abstrad risks seem to be small and to vary somewhat between studies. If estrogen usage were to be associated with in- It has been suggested that usage of menopausal creased risk, because of the relatively common occurrence estrogens may be associated with risk of colorectal of colorectal cancer among older women and the large cancer. This association was examined in a record number of women using menopausal estrogens, an appre- linkage cohort study using the Saskatchewan Health Plan ciable number of cases could be attributed to this exposure. Databases. All women ages 43-49 who were residents The purpose of the present study was to examine colorectal in Saskatchewan in 1 976 were identified from the cancer incidence and use of estrogens and other meno- Saskatchewan Health master registration file. These pausal hormones among all women (of suitable age) in the 33,003 women were linked by registration beneficiary province of Saskatchewan. number to the Prescription Drug Plan Database for the period January 1 976 through June 1 987, and to the Provincial Cancer Registry Database for the period Subjeds and Methods March 1 960 through December 1 990. Thirty women in The following descriptions apply to the operation of the cohort had colon or redal cancer diagnosed before Saskatchewan Health prior to 1 991 . Since that time, minor 1 976 and were omitted from the analysis; exposures changes have taken place. These changes are of no impor- within 3.5 years of diagnosis or end of follow-up were tance for the present study, and their discussion is omitted. also omitted. Between 1 976 and 1 990, 230 first primary Cohort Definition. Residents of the province become eli- coloredal cancer cases occurred. Women who took gible for health care system benefits once they establish estrogens had nonsignificantly elevated risk of colon residence and apply to Saskatchewan Health for a Health cancer in general (age-adjusted relative risk = 1.29; Services Card. Each person is assigned a unique six-digit 95% confidence interval, 0.86-1 .93) and of cancer of identification number denoting their family unit, and a two- the distal colon (relative risk = 1 .51 ; 95% confidence digit extension identifying them within the family unit. This interval, 0.90-2.54). Women who took p.o. information, plus their name, sex, address, and birthdate, is contraceptives during this follow-up period seemed to stored in a computer registry, the HIRF.’ Saskatchewan be at higher risk of cancer of the proximal colon Health maintains an active follow-up program for review of (relative risk = 2.1 2; 95% confidence interval, 1.00- eligibility and reissuance of the Health Services Card. Be- 4.53), though this apparent association could very well tween January 1989 and December 1990, the review was have occurred by chance. No associations were seen performed biennially; before 1989 it was done annually. between hormone use and risk of redal cancer. This Because family status may have changed over time, the study provides little evidence that usage of menopausal registration beneficiary number for a resident may also have hormones may be related to risk of coloredal cancer changed. For example, children were issued new family (either positively or negatively), though further follow- numbers at age 1 8. After marriage, women took the family up of the cohort appears warranted. number of their husband. Also, individuals may have pen- odically changed name. However, for each person, the Introduction HIRF contains a list of all previous registration numbers, so Among older women, estrogen medications are commonly that individuals may be traced over time through the sys- taken for alleviating menopause symptoms, and for the tem. HIRF information is directly accessible to all of the provincial health care agencies except Vital Statistics. To define the cohort, the HIRF was used to create a list of all women, ages 43-49 years, who were residents of Received 8/1/94; revised 1 0/1 3/94; accepted 1 0/1 3/94. I Supported by National Health Research and Development Program of Saskatchewan in 1 976. For present purposes, the 30 Health and Welfare Canada Grant 6613-1324-53 (H. A. R.), and by BRSG 507 RR05443 awarded by the Biomedical Research Support Grant Program, Division of Research Resources, NIH. 2 To whom requests for reprints should be addressed, at the Department of Epidemiology and Public Health, Yale University School of Medicine, 60 3 The abbreviations used are: HIRF, health insurance registration file; RR, College Street, P.O. Box 3333, New Haven, CT 06510. relative risk; Cl, confidence interval. Downloaded from cebp.aacrjournals.org on September 25, 2021. © 1995 American Association for Cancer Research. 22 Menopausal Hormone Use and Colorectal Cancer Table 1 Hormone prescriptions in provincial Drug Plan Database for cohort: 32,973 women ages 43-49 years in 1 976 in Saskatchewan, Canada, 1976-1 987 Hormone No. of prescriptions Percent of total Percent of cohort Estrogens Conjugated estrogens 1 1 6,427 91 .4 29.0 Estenified estrogens 5,536 4.3 2.1 Piperazine estrone sulfate 3,096 2.4 1 .4 Ethinyl estradiol 1,126 0.9 0.5 Estradiol 612 0.5 0.3 Stilboestrol 355 0.3 0.3 Methallenestril 251 0.2 0.1 Chlorotrianisene 32 0.03 <0.1 Any estrogens 127,435 100.0 30.9 Opposed estrogens Prescriptions on same date 3,585 2.6 Prescriptions >1, 7 days 160 0.04 Prescriptions >7, 14 days 156 0.04 Progestins Medroxyprogesterone acetate 6,724 97.9 4.8 Norethindrone 141 2.0 0.1 Norethindrone acetate 4 0.1 <0.1 Any progestins 6,869 100.0 4.9 Combined agents (p.o. contraceptives) Ethinyl estradiol/D-norgestrel 9,201 27.4 3.1 Ethinyl estradiol/norethindrone 4,524 1 3.4 1 .3 acetate Ethinyl estradiol/ethynodiol 906 2.7 0.3 diacetate Ethinyl estradiol/norethindrone 213 0.6 0.2 Ethinyl estradiol/dimethisterone 1 43 0.4 0.2 Mestranol/norethindrone 1 6,531 49.2 4.5 Mestranol/ethynodiol diacetate 1,810 5.4 0.6 Mestranol/norethynodrel 304 0.9 0.2 Any combined 33,632 100.0 9.0 women with colon or rectal cancer diagnosed before 1976 corded. The various active ingredients of the medications were omitted, leaving 32,973 women in the cohort. found are shown in Table 1. Exposures. The Saskatchewan Prescription Drug Plan was This report concerns usage of p.o. medications. In our initiated in September 1 975, and through June 30, 1 987, all analyses, the term “ever usage” denotes the existence of one residents with a valid Health Services Card were eligible for or more filled prescriptions. Other minimum exposures benefits (4). A nominal part ofeach prescription was paid by were considered for defining ever usage, e.g., 2 prescrip- the consumer, and the Province covered the remainder. tions, 90 tablets, 1 80 tablets, etc.; however, results were Those who could not afford even the nominal cost received very similar and have been omitted. In addition, estrogen benefits without paying. To obtain payment from the Prov- prescriptions were classified as “opposed” if progestin was ince, pharmacists submitted claims to the drug plan, mi- dispensed on the same date; if no such prescriptions were tially on paper forms but later through direct electronic found, the estrogen was considered “unopposed.” Simi- communication from pharmacy computers. The Prescnip- larly, progestin prescriptions were classified with respect to tion Drug Plan Database consists of information compiled estrogen. Allowing up to 1 4 days between dates of estrogen from all prescription claims. This database contains records and progestin prescriptions in the definition of opposed of the HIRF registration number of the consumer; the dis- medications produced essentially no differences in results. pensed drug identification number; the amount of drug and For the analysis of continuous exposures, numbers of tablets date of dispensing; and data regarding the pharmacy, the taken prior to the date of interest were cumulated. This prescriber, and the cost of the prescription. Information measure is closely related to duration of usage. about the active ingredients, strength, and form of prepara- Outcomes. Cohort members were followed by Saskatche- tion may be derived from the drug identification number. wan Health for vital and residence status from January 1, For the present study, we obtained all prescriptions for 1976 through December 31, 1990. Besides the active fol- estrogens, progesti ns, and combi ned estrogen-progestin low-up program used to gather annual data about each agents (p.o. contraceptives) found in the Drug Plan Data- resident (biennial between January 1989 and December base between January 1 , 1 976, and June 30, 1 987, associ- 1 990), Saskatchewan Health received vital status informa- ated with a HIRF number of a member of the cohort. For tion through death certificates and hospital reports.