menopausal hormone use and colorectal cancer in...

Vol. 4, 21-28, January/February 1995 Cancer Epidemiology, Biomarkers & Prevention 21

3 The abbreviations used are: HIRF, health insurance registration file; RR,relative risk; Cl, confidence interval.

Menopausal Hormone Use and Colorectal Cancer in Saskatchewan:A Record Linkage Cohort Study1

Harvey A. Risch2 and Geoffrey R. Howe

Department of Epidemiology and Public Health, Yale University School ofMedicine, New Haven, Connecticut 06510 (H. A. RI, and National

Cancer Institute of Canada Epidemiology Unit, Department of PreventiveMedicine and Biostatistics, University of Toronto, Toronto, Ontario

M5S 1A8, Canada IC. R. H.l

Abstrad

It has been suggested that usage of menopausalestrogens may be associated with risk of colorectalcancer. This association was examined in a recordlinkage cohort study using the Saskatchewan Health PlanDatabases. All women ages 43-49 who were residentsin Saskatchewan in 1 976 were identified from theSaskatchewan Health master registration file. These33,003 women were linked by registration beneficiarynumber to the Prescription Drug Plan Database for theperiod January 1 976 through June 1 987, and to theProvincial Cancer Registry Database for the periodMarch 1 960 through December 1 990. Thirty women inthe cohort had colon or redal cancer diagnosed before1 976 and were omitted from the analysis; exposureswithin 3.5 years of diagnosis or end of follow-up werealso omitted. Between 1 976 and 1 990, 230 first primarycoloredal cancer cases occurred. Women who tookestrogens had nonsignificantly elevated risk of coloncancer in general (age-adjusted relative risk = 1.29;

95% confidence interval, 0.86-1 .93) and of cancer ofthe distal colon (relative risk = 1 .51 ; 95% confidenceinterval, 0.90-2.54). Women who took p.o.contraceptives during this follow-up period seemed tobe at higher risk of cancer of the proximal colon(relative risk = 2.1 2; 95% confidence interval, 1.00-4.53), though this apparent association could very wellhave occurred by chance. No associations were seenbetween hormone use and risk of redal cancer. Thisstudy provides little evidence that usage of menopausalhormones may be related to risk of coloredal cancer(either positively or negatively), though further follow-up of the cohort appears warranted.

IntroductionAmong older women, estrogen medications are commonlytaken for alleviating menopause symptoms, and for the

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 ofHealth 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, 60College Street, P.O. Box 3333, New Haven, CT 06510.

treatment of osteoporosis and the prevention of its sequelae.Estrogen use may have potentially important consequences,because long-term usage has been related to increasedincidence of endometrial cancer (1) and possibly breastcancer (2). It has also been suggested that estrogen use,through effects on bile acid production, may be associatedwith the development of colorectal cancer (3), although therisks seem to be small and to vary somewhat betweenstudies. If estrogen usage were to be associated with in-creased risk, because of the relatively common occurrenceof colorectal cancer among older women and the large

number of women using menopausal estrogens, an appre-ciable number of cases could be attributed to this exposure.The purpose of the present study was to examine colorectalcancer incidence and use of estrogens and other meno-pausal hormones among all women (of suitable age) in theprovince of Saskatchewan.

Subjeds and MethodsThe following descriptions apply to the operation ofSaskatchewan Health prior to 1 991 . Since that time, minorchanges have taken place. These changes are of no impor-tance for the present study, and their discussion is omitted.

Cohort Definition. Residents of the province become eli-gible for health care system benefits once they establishresidence and apply to Saskatchewan Health for a HealthServices Card. Each person is assigned a unique six-digitidentification number denoting their family unit, and a two-digit extension identifying them within the family unit. Thisinformation, plus their name, sex, address, and birthdate, isstored in a computer registry, the HIRF.’ SaskatchewanHealth maintains an active follow-up program for review ofeligibility and reissuance of the Health Services Card. Be-tween January 1989 and December 1990, the review wasperformed biennially; before 1989 it was done annually.

Because family status may have changed over time, theregistration beneficiary number for a resident may also havechanged. For example, children were issued new familynumbers at age 1 8. After marriage, women took the familynumber of their husband. Also, individuals may have pen-odically changed name. However, for each person, theHIRF contains a list of all previous registration numbers, sothat individuals may be traced over time through the sys-tem. HIRF information is directly accessible to all of theprovincial health care agencies except Vital Statistics.

To define the cohort, the HIRF was used to create a listof all women, ages 43-49 years, who were residents ofSaskatchewan in 1976. For present purposes, the 30

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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 .3acetate

Ethinyl estradiol/ethynodiol 906 2.7 0.3diacetate

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 1976were omitted, leaving 32,973 women in the cohort.

Exposures. The Saskatchewan Prescription Drug Plan wasinitiated in September 1 975, and through June 30, 1 987, allresidents with a valid Health Services Card were eligible forbenefits (4). A nominal part ofeach prescription was paid bythe consumer, and the Province covered the remainder.Those who could not afford even the nominal cost receivedbenefits without paying. To obtain payment from the Prov-ince, pharmacists submitted claims to the drug plan, mi-tially on paper forms but later through direct electroniccommunication from pharmacy computers. The Prescnip-tion Drug Plan Database consists of information compiledfrom all prescription claims. This database contains recordsof the HIRF registration number of the consumer; the dis-pensed drug identification number; the amount of drug anddate of dispensing; and data regarding the pharmacy, theprescriber, and the cost of the prescription. Informationabout the active ingredients, strength, and form of prepara-tion may be derived from the drug identification number.

For the present study, we obtained all prescriptions for

estrogens, progesti ns, and combi ned estrogen-progestinagents (p.o. contraceptives) found in the Drug Plan Data-base between January 1 , 1 976, and June 30, 1 987, associ-ated with a HIRF number of a member of the cohort. Foreach prescription, the date dispensed, active ingredientnumber, drug units, dosage form, and strength were re-

corded. The various active ingredients of the medicationsfound are shown in Table 1.

This report concerns usage of p.o. medications. In ouranalyses, the term “ever usage” denotes the existence of oneor more filled prescriptions. Other minimum exposureswere considered for defining ever usage, e.g., 2 prescrip-tions, 90 tablets, 1 80 tablets, etc.; however, results werevery similar and have been omitted. In addition, estrogenprescriptions were classified as “opposed” if progestin was

dispensed on the same date; if no such prescriptions werefound, the estrogen was considered “unopposed.” Simi-larly, progestin prescriptions were classified with respect toestrogen. Allowing up to 1 4 days between dates of estrogenand progestin prescriptions in the definition of opposedmedications produced essentially no differences in results.For the analysis of continuous exposures, numbers of tabletstaken prior to the date of interest were cumulated. This

measure is closely related to duration of usage.

Outcomes. Cohort members were followed by Saskatche-wan Health for vital and residence status from January 1,1976 through December 31, 1990. Besides the active fol-low-up program used to gather annual data about eachresident (biennial between January 1989 and December1 990), Saskatchewan Health received vital status informa-tion through death certificates and hospital reports. Notifi-cations of registration from the health plans of neighboringprovinces also provided additional information about emi-



Cancer Epidemiology, Biomarkers & Prevention 23

gration. Thus, fact and date of death or emigration from theprovince were obtained for the members of the cohort.

Cancer was made a reportable disease in Saskatche-wan in 1 934, and from 1 944 the Saskatchewan CancerFoundation has maintained one of the most complete pro-

vincial cancer registries in Canada (4). Cancer diagnoses

are reported to the registry through payment claims filed byphysicians, through patient registrations at the Regina andSaskatoon Provincial Cancer Clinics, and through continu-ous review of death certificates and hospital pathologyreports. Cases ascertained by the registry are identified by

their HIRF number. The registry database contains informa-tion on date of diagnosis, International Classification ofDiseases for Oncology four-digit site code, and five-digit

histology code for each patient, as well as diagnosis and

treatment data. Because of the unique HIRF registrationnumbers, the cancer registry database can identify multiplecancers in the same patient, at the same or different sites,

and occurring at the same or different times. The databasebecame computerized in the early 1 970s. In addition to thecontinuous input of new cases, the Cancer Foundation hasbeen retrospectively entering older patient files into the

database. At the time that the database file linkages for thepresent study were performed, cancer diagnoses extendingback through March 1960 were available. Women in thecohort having a first diagnosis of primary colon or rectumcancer [International Classification of Diseases (Ninth Re-vision) codes 153 and 154] between January 1, 1976 andDecember 31 , 1 990 were considered cases. As noted pre-viously, 30 women had a diagnosis of colorectal cancermade between March 1, 1960 and December 31, 1975 andwere excluded from the cohort for the present analysis;incidence of the disease before age 33 (i.e., the age of the

oldest women in the cohort in 1960) is essentially zero.Thus, the cohort was followed until cancer outcome, death,emigration, or the end ofthe study period on December 31,1990.

Record Linkage. Because the same unique registrationnumbers were used to identify individuals in the master file(HIRF), the Prescription Drug Plan Database, and the Can-cer Foundation Registry, linkage was based on exact matchof the HIRF registration number. For quality control andbilling purposes, the Saskatchewan Health agencies pen-odically conduct internal linkages of their registries onname, date of birth, and other identifiers. These linkageshave shown the identifying information to be more than99.99% accurate. Therefore, the HIRF registration numbersprovide a valid method of identifying the same individual inthe various databases.

Data Analysis. Initially, descriptive analysis of the cohortwas performed by counting the numbers of prescriptions foreach of the medications used. To examine associationsbetween ever/never usage of the various hormones and riskof colon and rectum cancer, numbers of cases and totalperson-years of exposure were cumulated within each1 -year interval of age over the follow-up period for each ofthe exposure groups. Separate analyses were done for ever/never use of estrogens, progestins, and p.o. contraceptives.Based on biological plausibility grounds, a lag interval of3.5 years was used. That is, person-years continued toaccrue to each woman in the unexposed category of hor-mone use until 3.5 years after the date of the first prescrip-tion. Other lag intervals from 0 to 5 years were considered;however, the results were essentially unchanged. For each

type of hormone, in cumulating person-years for the ever-used and never-used groups, we disregarded usage of theother kinds of hormones. Thus, for example, some women(and person-years) in both the ever-used p.o. contraceptivesgroup and the never-used p.o. contraceptives group reflectusage of noncontraceptive estrogens. Because readers maywish to make comparisons with respect to women in thecohort who had no prescriptions for any of the varioushormones, person-years and rates for this group have beengiven as well. Finally, we used the GLIM program (RoyalStatistical Society, Oxford, UK) with Poisson regression tocalculate age-adjusted relative risks and their confidencelimits.

For the multivaniate analysis of continuous measures ofhormone exposure, Cox regression with time-dependentcovariates was used (5). A modified version of the programRCOX, based on the one shown in Appendix 3 of Ref. 5,was used. Again, an exposure lag of 3.5 years was assumed.In this case, for each failure (case diagnosis) time in theregression, exposure status for a subject was based on thenumber of tablets taken since 1 976, excluding tablets takenwithin the immediately preceding 3.5 years. In cumulatingthe number of tablets taken before a certain date, it wasassumed that one tablet was taken per day, beginning withthe date dispensed.

Results

Almost one-third of the women in the cohort had estrogenprescriptions during the 1 1 .5-year period included in thedrug database. The great majority of these prescriptionswere for conjugated estrogen (Table 1 ). Users of estrogenshad recorded prescriptions totaling on average about 588tablets each, corresponding to 28 months of usage at 21tablets/month. On the other hand, p.o. progestins weretaken by relatively few women, approximately 5% of thecohort, and in smaller amounts than estrogen, about 1 1 5tablets (1 6 months at 7 tablets/month) per user. An evensmaller fraction of the cohort, 2.6-2.7%, had used estro-gens opposed by progestins. Over 90% opposed estrogenuse reflected estrogen and progestin prescriptions on thesame date. Finally, Table 1 shows that even in the age groupof this cohort, there was appreciable usage of p.o. contra-ceptives: 9% of the women had prescriptions for the com-bined agents, a mean of 472 tablets (22.5 months) per user.

Between 1976 and 1990, 230 first primary colorectalcancer cases occurred in the cohort. Ofthese, three had twosubsites specified at diagnosis, and two others went on tohave a second primary during the follow-up. Age-adjustedrelative risks for colon and rectal cancer according to ever-usage of the various types of hormones are presented inTable 2. For both tumor sites grouped together, there was noevidence of increased risk for women using estrogens.Among the 1 436 women who used estrogens for 5 years orlonger, (7005 person-years), a total of 3 cases occurred,giving an age-adjusted relative risk (compared to never use)of 0.65 (95% Cl, 0.21-2.03). No cases of colon or rectalcancer occurred for women who had used estrogens only asopposed by progestins, although the number of suchwomen, 171, was small (540.8 person-years); 1 case ofcolon cancer occurred among the 648 women who hadused both opposed and unopposed estrogens, giving acrude rate of 57.5/1 0� person-years. Three cases of cob-rectal cancer occurred among women who had ever usedprogestins, either as opposed or unopposed. Finally, usage



Table 2 Relative risk of colon or rectal cancer according to previous hormone usage among 32,973 women ages 43-49 years in 1 976 in Saskatchewan,1976-1990

Colon or rectum

EstrogensNever

Ever


No. ofHormone usag& No. of subjects Person-years cases

Crude

Rate/i 0� RR

Age-adjusted

RR 95% CI

Progestins

Never

Ever


Never

Ever

Any of the above medications

Never

Ever

Colon

Estrogens

Never

Ever

Progestins

Never

Ever


Never

Ever


Never

Ever

Rectum

Estrogens

Never

Ever


Never

Ever


Never

Ever

23,145 382,395 187 48.9 1 i

9,828 71,805 43 59.9 1.22 1.04 0.74-1.46

31,412 446,931 227 50.8 1 1

1,561 7,270 3 41.3 0.8i 0.64 0.21-2.01

30,105 425,818 212 49.8

2,868 28,383 18 63.4

20,870 357,265 171 47.9

12,103 96,936 59 60.9

23,138 382,628 ii7 30.6 1 1

9,835 71,840 32 44.5 1.46 1.29 0.86-1.93

31,411 447,195 146 32.6 1 1

1,562 7,273 3 4i.3 1.26 1.04 0.33-3.29

30,104 426,053 138 32.4

2,869 28,415 11 38.7

20,863 357,469 107 29.9

12,110 96,998 42 43.3

23,138 382,776 72 18.8 1 1

9,835 71,956 11 15.3 0.81 0.64 0.33-i.22

30,104 426,316 76 i7.8 1 1

2,869 28,415 7 24.6 1.38 1.16 0.53-2.52

20,864 357,621 66 18.5 1 1

12,109 97,iio 17 17.5 0.95 0.74 0.43-1.28

1 1

1.27 1.12 0.69-1.81

1 1

1.27 1.08 0.79-1.46

1 1

1.20 1.07 0.58-1.99

1 1

1 .45 1 .28 0.88-1 .86

a Exposure latency, 3.5 years.

of p.o. contraceptives within the age range of follow-up forexposure in this cohort, 43-61 years, was not significantlyassociated with risk for both sites grouped together.

For colon cancer considered separately, ever-usage ofestrogen appeared to be associated with an approximate30% risk increase, which was statistically nonsignificant(P = 0.22). However, use longer than 5 years was notassociated with increased risk (RR = 0.70; 95% CI, 0.17-2.85). No significant associations were observed for use ofthe various hormones and risk of rectal cancer.

In Table 3, age-adjusted relative risks are given for theproximal (including cecum through splenic flexure), and

distal (including descending and sigmoid) colons. Little as-sociation with ever-use of estrogens appeared for cancer of

the proximal colon, but a somewhat higher, though notstatistically significant, 51 % increase in risk was seen for thedistal colon. An opposing pattern of association appearedfor ever-usage of p.o. contraceptives, with relative risk lessthan unity for the distal colon and greater than unity for theproximal colon (P = 0.050 for the latter).

In Table 4, we consider dose-response models of hor-mone usage and risk of colon or rectal cancer. In the Model1 5 of this table, for each failure (case diagnosis) time in theCox regression, the hormone exposure variables were thecumulative number of tablets taken between 1 976 and 3.5years in the past. Neither use of estrogens nor p.o. contra-ceptives appeared to be associated with significant trends inrisk for colon cancer in general or rectal cancer. We also




Table 3 Relative risk of colon cancer subsites according to previous hormone usage among 32,973 women ages 43-49 years in 1976 in Saskatchewan,

1976-1990

Hormone usag& No. of subjects Person-years No. of casesCrude

Rate/i05 RR

Age

RR

-adjusted

95%Cl

Proximal colon5

Estrogens

Never

Ever

23,133

9,840

382,886

71,939

43

12

11.2

16.7

1

1.49

1

1.17 0.60-2.25

Progestins

Never

Ever

31,409

1,564

447,544

7,280

54

1

12.1

13.7

1

1.14

1

0.80 0.11-S.84

Combined Agents (p.o. contraceptives)

Never

Ever

30,103

2,870

426,397

28,427

47

8

11.0

28.1

1

2.55

1

2.12 1.00-4.53


Never

Ever

20,858

12,115

357,7i9

97,105

37

18

10.3

18.5

1

1.79

1

1.42 0.79-2.55

Distal coIon�

Estrogens

Never

Ever

23,136

9,837

382,760

71,892

69

20

18.0

27.8

1

1.54

1

1.51 0.90-2.54

Progestins

Never

Ever

31,4ii

1,562

447,378

7,274

87

2

19.4

27.5

i

1.41

1

1.32 0.32-5.37

Combined Agents (p.o. contraceptives)

Never

Ever

30,104

2,869

426,214

28,437

88

1

20.6

3.52

1

0.17

1

0.16 0.02-1.15


Never

Ever

20,862

i2,iil

357,583

97,068

67

22

i8.7

22.7

1

1.21

1

1.16 0.70-1.92

a Exposure latency, 3.5 years.b Proximal colon includes cecum through splenic flexure.

C Distal colon includes descending and sigmoid colon.

found no association between risk of colorectal cancer andeither “current” use of estrogens (i.e., use immediately be-fore the lag period of 3.5 years) or average tablet dose ofconjugated estrogen. In order to examine possible patternsof dose-response for levels of usage of estrogens and p.o.contraceptives (Model 2s), the cumulated numbers of tab-letswere divided into categories of use, with roughly similar

numbers of users in each category at the end of the follow-up. That is, for each failure time in the regression, a womanwas assigned a category of use based on the cumulativenumber of tablets taken between 1 976 and 3.5 years in thepast. In these models, some increase in risk of colon cancerwas seen according to category of estrogen usage, althoughthe trend (Model 1 ) was not significant. Little evidence oftrend was present for usage of p.o. contraceptives or foreither type of hormone use and rectal cancer. Cox regres-sion models for colon or colorectal cancer that includedcategories of estrogen use longer than 5 years in durationdid not show such usage to convey increased risk; therelative risks were 0.69 (95% CI, 0.1 7-2.82) and 0.62 (95%CI, 0.20-1 .97), respectively.

Finally, the Cox regression trend analyses for coloncancer subsites are given in Table 5. Similar to the resultfor colon cancer as a whole, a pattern of increasing riskwith category of estrogen use was present for cancer of

the distal colon. Some suggestion of an increase in riskof proximal colon cancer also appeared for usage ofp.o. contraceptives. Neither trend was statisticallysignificant.

Discussion

A few points are worth considering before conclusions aredrawn from this study. To begin with, the cohort of allwomen ages 43-49 in 1 976 in the Saskatchewan HIRF,represents all women of this age range in the province. Inactuality, it included about 96% of women at the time, theremaining 4% covered by other health care plans (for fed-eral or military employees, etc.). Among the women in-cluded in the cohort, some errors could have occurred inthe database information and linkages, and it is possiblethat exposures or outcomes could have happened outsideof Saskatchewan. However, for the following reasons, thelikelihood of substantial errors of these types seems quitesmall.

The quality of information in the Saskatchewan HIRFand other provincial databases is excellent, since thesedatabases are used for the accounting and financial admin-istration of the provincial health services. It is possible thatcases of multiple unconnected HIRF numbers identifying a



Table 4 Relative risk of colon or rectal cancer according to dose-response models of hormone

Saskatchewan, 1976-1990

usage among 32,973 women ages 43-49 years in 1976 in

Exposure RR At unir’ 95% CI

a Exposure variables with number of tablets appearing in this column are continuous and time dependent, and represent cumulative number of tablets between

1 976 and Case Diagnosis Date -3.5 years. Variables with “yes/no” are time-dependent indicators for having reached exactly that category of exposure between1 976 and Case Diagnosis Date -3.5 years. Age (in 1 976) is continuous but not time dependent in these Cox regression models.b 252 tablets = 21 tablets/month for 12 months.C Use up to 1 year, assuming 2i tablets/month.d One to 2 years of use, assuming 21 tablets/month.

,. More than 2 years of use, assuming 21 tablets/month.


Colon or rectum

Model 1

Age (in 1976)

Estrogens

Combined p.o. contraceptives

Model

Age (in 1976)

Estrogens

1-252 tabletsc

253-504 tablets”

505 + tablets’


1-252 tablets

253-504 tablets

505 + tablets

Colon

Model

Age (in 1976)

Estrogens


Model 2

Age (in 1976)

Estrogens

1-252 tablets

253-504 tablets

505 + tablets

Combined OralContraceptives

1-252 tablets

253-504 tablets

505 + tablets

Rectum

Model 1

Age (in 1976)

Estrogens


Model 2

Age (in 1976)

Estrogens

1-252 tablets

253-504 tablets

505 + tablets

Combined p.o. contraceptives1-252 tablets

253-504 tablets

505 + tablets

1.112

0.976

0.938

1.113

0.799

1.033

0.953

1.OOi

1.780

0.790

1.isi

i.0i6

0.934

i.15i

0.879

1.258

1.325

0.953

1.874

0.628

1.052

0.867

0.936

1.056

0.639

0.641

0.356

1.066

1.568

1.030

lyear

252 tablets”

252 tablets

1 year

yes/no

yes/no

yes/no

yes/no

yes/no

yes/no

1 year

252 tablets

252 tablets

1 year

yes/no

yes/no

yes/no

yes/no

yes/no

yes/no

1 year

252 tablets

252 tablets

1 year

yes/no

yes/no

yes/no

yes/no

yes/no

yes/no

i.04-i.i9

0.87-i .09

0.74-i.i8

1.04-i.i9

0.51-i .25

0.51-2.11

0.�4-1.69

0.49-2.03

0.79-4.02

0.29-2.13

1.06-1.25

0.90-i .1S

0.69-1.26

1.06-1.25

0.51-i .52

0.55-2.88

0.70-2.49

0.39-2.33

0.69-5.08

0.1 5-2.55

0.94-i .17

0.67-1 .i 2

0.6�-1.36

0.95-i .i 8

0.29-1.40

0.16-2.63

0.09-1.47

0.33-3.40

0.38-6.42

0.25-4.23

single person could exist, particularly for women leavingthe province and returning after a span of more than 2 years.These errors are rare, because of the low total emigrationrate of less than 0.8%/year for the cohort over the 15 yearsof follow-up, and because of the frequent internal validity

checking of the HIRF. Database information could alsocontain errors from incomplete follow-up of individualswho died, moved within Saskatchewan, or emigrated. FromJanuary 1989 through December 1990, individuals in thehealth plan were issued health plan identification cards at



Table 5 Relativerisk of colon-cancer subsites according to dose-responsemodels of hormone usage among 32,973 women ages 43-49 years in

1976 in Saskatchewan, 1976-1 990

RR At unit’

a Exposure variables with number of tablets appearing in this column are

continuous and time dependent, and represent cumulative number of tabletsbetween i 976 and Case Diagnosis Date -3.5 years. Variables with “yes/no”are time-dependent indicators for having reached exactly that category ofexposure between 1976 and Case Diagnosis Date -3.5 years. Age (in 1976)

is continuous but not time dependent.b Proximal colon includes cecum through splenic flexure.C 252 tablets = 21 tablets/month for 1 2 months.d Distal colon includes descending and sigmoid colon.


95% ClExposure

Proximal colon”

Model 1

Age (in 1976) 1.079 1 year 0.9S-i .23

Estrogens 0.905 252 tabletsc 0.69-1 .18

Combined p.o. contraceptives 1.141 252 tablets 0.88-i .48

Model 2

Age (in 1976) 1.079 1 year 0.95-1.23

Estrogens

1-252 tablets 1.074 yes/no 0.50-2.30

253-S04tablets 0.993 yes/no 0.24-4.13

505 + tablets 0.534 yes/no 0.1 3-2.23


1-252 tablets 0.944 yes/no 0.23-3.90

253-504 tablets 5.21 1 yes/no 1 .87-1 4.6

505 + tablets 1 .534 yes/no 0.37-6.36

Distal colon”

Model 1

Age (in 1976) 1.205 1 year 1.08-i .35

Estrogens 1 .093 252 tablets 0.95-i .26

Combined p.o. contraceptives 0.205 252 tablets 0.02-2.45

Model 2

Age (in 1976) 1.202 1 year 1.07-i .35

Estrogens

1-252 tablets 0.8i0 yes/no 0.37-1.79

253-504 tablets 1 .61 7 yes/no 0.58-4.49

505 + tablets 2.202 yes/no 1 .07-4.54


Ever-use 0.i65 yes/no 0.02-1.18

2-year intervals; before 1989, the cards were issued annu-ally. To track the status of each individual, SaskatchewanHealth used an active follow-up program; using identifica-tion card returns by Canada Post, they attempted contact ofindividuals by telephone and by field inspectors, contact ofrelatives or neighbors, information from physician deathreports, and through comparisons with town lists. For mdi-viduals who moved from Saskatchewan to the neighboringprovinces of Manitoba, Alberta, or British Columbia andregistered for the health insurance plans there, those prov-inces notified Saskatchewan Health about the change inresidence.

It is possible that some exposures or outcomes couldhave occurred outside of Saskatchewan. However, from1976 to 1987, there was a strong financial incentive forSaskatchewan residents to obtain prescription medicationsthrough the drug plan. Similarly, because the health plancovered the costs of medical work-ups for the conditionsrelevant to the hormones considered in this study, a finan-cial incentive existed for having these work-ups done by

physicians in the province. In addition, even if some pro-cedures for cancer diagnosis were performed elsewhere(e.g., Florida), there was a financial incentive for patients tohave treatment done in Saskatchewan, thus giving caseidentification.

Also, this study did not record hormone usage prior to1 976. Thus, some nondifferential misclassification of themenopausal exposures could have occurred, especially forthe older women in the cohort, although we estimate thatless than 5% of estrogen use may have been missed (6).Nevertheless, on this basis, results could be attenuatedsomewhat.

Another potential error is that an incorrect HIRF regis-tration number could have been recorded when a prescnip-tion was dispensed at a pharmacy. Between 1976 and1 987, a 1% random sample of all individuals whose regis-tration numbers were listed on filled prescriptions were sentmail questionnaire cards in which they verified the pre-scniption data. This prevented pharmacists from billing thedrug plan for nonexistent prescriptions, and the results ofthe questionnaire cards indicated that the prescription andidentifying information was appreciably more than 99%accurate.

It is also possible that while prescriptions were validlyrecorded by the drug plan, the recipients may not havetaken all of the medications. This is an issue for manyobservational epidemiological studies. Because of the non-zero cost to the purchaser for each prescription, cohortmembers had some motivation either to use the medica-tions or to discontinue purchase. Also, women in the cohortwho obtained hormone prescriptions may have differed intheir health behaviors, for example with respect to physi-cian visits, as compared to women without such prescnip-tions. However, 96% of women in the cohort had at least 1

database prescription record for some type of medication.Finally, over the follow-up period ofthis study, most of

the noncontraceptive estrogen use among cohort memberswas of unopposed medications. Thus, results for opposed

preparations are limited and may not be the same as thosefor estrogens taken alone.

Allowing for the previous considerations, the findingspresented here differ little from the results of previous stud-es, in that significant associations have not generally been

seen. Most work has shown no relationship between use ofnoncontraceptive estrogens and risk of colon or colorectalcancer (7-1 4). Two studies have noted decreased risks (1 5,1 6). Slightly increased relative risks, typically in the 1 .4-1 .6range, have been seen for rectal cancer in some reports (7,8, 1 0, 1 1 , 1 3); however, those associations were not statis-tically significant, and other studies have shown somewhatdecreased risk with usage (1 7, 1 8). Studies examining riskseparately for cancers of the proximal and distal colon alsoshowed little association with estrogen usage (1 0, 1 2, 1 3,17), although decreased risk (RR = 0.4-0.5) for the proxi-mal colon was observed in two reports (1 6, 19).

Slightly fewer studies have examined risks for womenusing p.o. contraceptives, particularly in their 40s and SOs.For colon or colorectal cancer overall, one study observedslightly increased risk with usage (7) and two others some-what decreased risk (8, 1 7); however, most studies have

demonstrated essentially no association with risk (1 1-13,18). Observed relative risks for proximal and distal colonsubsites have been a little more variable, with studies re-porting both risk increases and decreases, though againnone has been statistically significant (1 1 -1 3).



28 Menopausal Hormone Use and Coloredal Cancer

One concern in the present study is that data on po-tentially confounding reproductive and other factors werenot available to be used in model adjustments for the hor-mone variables of interest. For both noncontraceptive es-trogens and p.o. contraceptives, a number of reports havegiven adjusted and unadjusted results or noted differencesafter adjustment, and thus relate to whether our resultswould be likely to change had we been able to adjust. Onepaper, giving relative risk of colorectal cancer according toever usage of menopausal estrogens, showed a reduction ofabout 16% (RR changing from 0.57 to 0.49) with adjust-ment for parity, hysterectomy, and cholecystectomy (1 7).However, the same study showed the relative risk accord-ing to ever-usage of p.o. contraceptives to increase towardunity (RR, 0.61-0.80) with adjustment for the same van-ables. Overall, most studies have shown essentially no dif-ferences in results controlling for various factors, includingdietary variables, parity, family history of colorectal cancer,socioeconomic status, physical activity, past weight, orbody-mass index (8, 1 0, 1 1-1 3). Thus, it appears unlikelythat the risks related to hormone usage seen in the presentwork would change appreciably had they been adjusted.

In summary, this cohort study of the Saskatchewanpopulation provides little evidence for increased risk ofcolorectal cancer with menopausal usage of either estro-gens or p.o. contraceptives. No significant dose-responsetrends were observed. The one significant risk association,between ever-use of p.o. contraceptives and cancer of theproximal colon, could very well have occurred by chancegiven the number of independent associations examined.The incidence of colon cancer rises steeply after age 60.Because of the relatively small numbers of cases in thepresent study, particularly for the colon subsite analyses,further follow-up of our cohort through the seventh decadeof lifeseems warranted.

AcknowledgmentsWe gratefully acknowledge the contributions at Saskatchewan Health of

Edith Malcolm, Dwayne Senft, Winanne Downey, Diane Robson, SusanKraft, and Drs. Linda Strand and Roy West. This study is based in part on data

provided by the Saskatchewan Department of Health. The interpretations

and conclusions contained herein do not necessarily represent those of theGovernment of Saskatchewan, or the Saskatchewan Department of Health.

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1995;4:21-28. Cancer Epidemiol Biomarkers Prev H A Risch and G R Howe Saskatchewan: a record linkage cohort study.Menopausal hormone use and colorectal cancer in

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