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Original Contribution

Risks of Endometrial Cancer Associated With Different Hormone Replacement

Therapies in the E3N Cohort, 1992

2008

Agns Fournier, Laure Dossus, Sylvie Mesrine, Alice Vilier, Marie-Christine Boutron-Ruault,Franoise Clavel-Chapelon*, and Nathalie Chabbert-Buffet

*Correspondence to Dr. Franoise Clavel-Chapelon, INSERM U108, Team 9, Institut Gustave Roussy, 114 rue Edouard Vaillant,

94805 Villejuif Cedex, France (e-mail: [email protected]).

Initially submitted November 27, 2013; accepted for publication May 12, 2014.

We assessed whether different oral progestogens in hormone replacement therapy may differentially affect the

risk of endometrial cancer, using data from the Etude Epidmiologique auprs de femmes de lEducation Nationale

(E3N), a French cohort study (19922008). Hazard ratios and their confidence intervals were derived from Cox

models. Among 65,630 postmenopausal women (mean follow-up: 10.8 years), 301 endometrial cancers occurred.

Compared with never use, ever use of estrogen + micronized progesterone was associated with an increased risk

of endometrial cancer (hazard ratio (HR) = 1.80, 95% confidence interval (CI): 1.38, 2.34) that was significantly

more marked with longer duration of use (for5 years, HR = 1.39 (95% CI: 0.99, 1.97); for >5 years, HR = 2.66

(95% CI: 1.87, 3.77)). Although use of estrogen + dydrogesterone was not associated overall with endometrial can-

cer risk (HR = 1.05, 95% CI: 0.76, 1.45), there was a significantly increased risk with long-term use compared with

never use (for >5 years, HR = 1.69, 95% CI: 1.06, 2.70). Users of preparations containing other progesterone de-

rivatives or a norsteroid derivative were not at significantly increased risk (HR = 0.79 (95% CI: 0.60, 1.05) and

HR = 1.30 (95% CI: 0.85, 1.99), respectively). In conclusion, micronized progesterone and, to a lesser extent, dy-

drogesterone at the doses used in France may not be sufficient to prevent estrogen-induced endometrial cancers.

cohort studies; dydrogesterone; endometrial neoplasms; hormone replacement therapy; progesterone; progestins

Abbreviations: BMI, body mass index; CI, confidence interval; E3N, Etude Epidmiologique auprs de femmes de l Education

Nationale; EPT, estrogen-progestogen therapy; HR, hazard ratio; HRT, hormone replacement therapy.

Endometrial cancer is one of the factors to be consideredwhen evaluating the risk-benet ratio associated with hor-mone replacement therapy (HRT). The estrogen:progesterone

ratio plays a critical role in endometrial carcinogenesis (1), andendometrial cancer is ranked fourth in terms of incidence and11th in terms of mortality among malignant disorders ofwomen in the more developed regions of the world (2).

HRT initially consisted of estrogens. After their use wasshown to be associated with a marked increase in endo-metrial cancer risk (3,4), progestogens were added to pre-vent estrogen-induced endometrial proliferation. Numerousestrogen-progestogen therapies (EPTs), administered at vari-ous doses and frequencies and containing various types ofprogestogens, are now available for treating menopausalsymptoms.

To date, the epidemiologic evidence suggests that thesafety of EPTs with regard to endometrial cancer dependson the number of days per month on which the progestogen

component is used (57). Less is known about the impact ofprogestogen type. In 2 observational studies, the risk of endo-metrial cancer was not signicantly increased (comparedwith never users) among users of cyclic combined HRT, re-gardless of whether it contained medroxyprogesterone ace-tate, norethisterone acetate, or norgestrel/levonorgestrel, andthe risk was lower among users of continuous combined HRTthan in never users, regardless of whether it contained nor-ethisterone acetate or medroxyprogesterone acetate (8,9).

In the Etude Epidmiologique auprs de femmes delEducation Nationale (E3N) cohort study, we previouslyfound that the excess risk of breast cancer associated with

508 Am J Epidemiol. 2014;180(5):508517

American Journal of Epidemiology

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Vol. 180, No. 5

DOI: 10.1093/aje/kwu146

Advance Access publication:

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EPTs was less elevated when they included micronized pro-gesterone or dydrogesterone rather than other progestogens(10). On the other hand, analyses from the European Prospec-tive Investigation into Cancer and Nutrition suggested thatestrogen-micronized progesterone combinations might bemore deleterious to the endometrium than other EPTs (11).Exposure was assessed only once in that study, however

8 years before diagnosis, on averageand only 26 cases ofendometrial cancer were diagnosed among women exposedto estrogen-micronized progesterone (11). The exposed womenwere almost exclusively participants in the studys Frenchcomponent, namely, E3N.

We present here an extended analysis of data from the E3Ncohort. The longer follow-up period, combined with the avail-ability of regularly updated information on HRT use, more thantripled the number of endometrial cancer cases with exposure toestrogen-micronized progesterone and allowed us to separatelyevaluate EPTs containing different types of progestogens.

METHODS

The E3N cohort

The E3N, a prospective cohort study, began in 1990 whenhalf a million women aged 4065 years who were residing incontinental France and were insured by a national health in-surance fund that mainly covers teachers and their familymembers were invited to participate. In all, 98,995 womengave written informed consent and completed the rst ques-tionnaire. Thereafter, the women received follow-up ques-tionnaires (available atwww.e3n.fr) every 23 years. Thequestionnaire mailed in June 2008 is the last one that wasused for this analysis. Response rates were 75% for eachfollow-up questionnaire. The French National Commission

for Data Protection and Privacy approved the study protocol.

Definition of cases

The occurrence of endometrial cancer was identied mainlyfrom self-reports in the questionnaires; a few additional casescame from next-of-kin reports and the French national cause-of-death registry. These analyses included only cases conrmedby a pathology report (91% of the reported incident cases).

Assessment of HRT use

Information on lifetime use of hormonal treatments was re-

corded on the 1992 questionnaire. We asked for brand names,starting dates, and duration of use for each treatment episode.The information was updated in all subsequent question-naires. Information about dosage and number of days of useper month was not requested.

Exposure was classied as: 1) estrogen only (systemicestradiol or conjugated equine estrogens); 2) EPTs containingoral micronized progesterone; 3) EPTs containing oral dydro-gesterone; 4) EPTs containing another oral progesteronederivative; 5) EPTs containing an oral norsteroid derivative;6) weak estrogens (i.e., orally or vaginally administered pro-mestriene or estriol); 7) tibolone; or 8) other (i.e., HRT contain-ing an androgen, or which was intramuscularly administered,

or with the progestogen component delivered through apatch, or with no specied formulation).

Study population and follow-up

The study population was restricted to postmenopausalwomen. Menopausal status and date of menopause were de-

termined from regularly updated data on menstrual periods,hysterectomy, oophorectomy, HRT use, self-reported meno-pausal status, and menopausal symptoms, as detailed else-where (12).

Follow-up started at the date on which the 1992 question-naire was returned for postmenopausal women and the dateon which menopause was rst reported for the other women.Follow-up ended at the date of diagnosis of any cancer, thedate of hysterectomy, the date of the last completed question-naire, or June 2008, whichever occurred rst.

Of the 98,995 E3N women, we excluded those who had nofollow-up (n = 9,541), were diagnosed with cancer (other thanbasal-cell carcinoma) before follow-up started (n= 4,832),

were premenopausal at the end of follow-up (n= 2,763), un-derwent hysterectomy before follow-up started (n = 13,530),did not respond to the 1992 questionnaire about lifetime HRTuse while already postmenopausal (n= 2,668), or reporteda diagnosis of endometrial carcinoma for which no pathol-ogy report could be obtained (n= 31). Accordingly, 65,630women remained for analysis.

Statistical analysis

Hazard ratios for endometrial cancer and their 95% con-dence intervals were estimated using Cox proportional haz-ards models with age as the time scale.

The known risk factors for endometrial cancer (13) and po-

tential confounders that we included in our models are listed inTable1 (in the same categories, except for body mass index(BMI) and age at menopause, both included as continuous var-iables). The proportional hazards assumption was not violatedfor any of these covariates, except for premenopausal use oforal contraceptives or progestogens alone. However, the intro-duction into our models of interaction terms between these var-iables and the time scale only marginally affected the hazardratios associated with HRT exposure (data not shown).

We present only the results from fully adjusted modelsand note that the hazard ratios derived from these modelsdiffered quite a bit from those derived from age-adjustedmodels (e.g., for ever use of HRT, the hazard ratio was

1.33 (95% con

dence interval (CI): 1.01, 1.76) in the fullyadjusted model and 1.08 (95% CI: 0.83, 1.41) in the age-adjusted model). However, no strong individual confounderswere identied: The removal of any given covariate from thefully adjusted model resulted in variations in the hazard ratiosassociated with HRT ever use of less than 10%.

BMI (calculated as weight (kg)/height (m)2), smoking,history of benign disease of the uterus (endometriosis,broids,or polyps), recent gynecological examination, history of diabe-tes, and history of high blood pressure, all updated duringfollow-up, were included in the models as time-varying vari-ables. Models were further stratied by year of birth in 5-yearcategories.

HRT and Endometrial Cancer 509

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Information on HRT exposure was updated on the date

of each questionnaire completion and dealt with prospec-tively: To characterize exposure for the period precedingthe completion of a given questionnaire, we used only the in-formation reported in the previous questionnaires. The sameapproach was used for time-varying covariates. At the time ofeach questionnaire, a woman was considered a past user of agiven type of HRT when she reported any use (ever) but nouse in the preceding 3 months. For past users at the time of agiven questionnaire, time since last use increased with timeelapsed since questionnaire completion. For current users,duration of use increased with time elapsed since question-naire completion, as we made the assumption that HRT usedid not stop until completion of the subsequent questionnaire.

We performed a sensitivity analysis evaluating whether that

assumption was robust to other hypotheses. It appeared to beso, since our results were only marginally altered when we as-sumed instead that HRT use was stopped halfway between thequestionnaires (data not shown). If a woman successively tookdifferent types of HRT, she simultaneously contributed to eachof the relevant categories (e.g., past user of estrogen-only ther-apy and current user of estrogen-micronized progesterone).

When a covariate had a low percentage of missing values(5%), imputation to the median (for continuous variables)or mode (for discrete variables) was used to replace missingvalues. Missing values exceeded 5% for duration of oral con-traceptives use; accordingly, we created an unknown dura-tioncategory (Table1). When a woman did not respond to

Table 1. Baseline Characteristics of Participants According to HRT Exposure Status at the End of the Follow-up

Period, E3N Study, France, 19922008

All Women(n= 65,630a)

Never Users of HRT(n= 17,107)

Ever Users of HRT(n= 42,460)

No. % No. % No. %

Body mass indexb

20 8,945 13.6 2,059 12.0 6,153 14.520.124.9 41,785 63.7 9,808 57.3 28,436 67.0

2529.9 11,963 18.2 3,935 23.0 6,670 15.7

30 2,937 4.5 1,305 7.6 1,201 2.8

Education

No high school diploma 9,691 14.8 3,077 18.0 5,390 12.7

High school diploma,with or withoutpostsecondaryeducation

55,939 85.2 14,030 82.0 37,070 87.3

Physical activity,MET-hours/weekc

57 16,106 24.5 4,851 28.4 9,734 22.9

Smoking status

Never smoker 34,957 53.3 9,740 56.9 22,034 51.9

Ever smoker 30,673 46.7 7,367 43.1 20,426 48.1

Familial history ofendometrial cancerin first-degree relatives

No 63,190 96.3 16,483 96.3 40,840 96.2

Yes 2,440 3.7 624 3.7 1,620 3.8

History of benign diseaseof the uterus

(endometriosis,fibroids, or polyps)

No 50,615 77.1 13,470 78.7 32,339 76.2

Yes 15,015 22.9 3,637 21.3 10,121 23.8

Age at menarche, years


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a questionnaire, her HRTexposure was classied as unknownforthe period between the questionnairesmailingdateandthedate of the next questionnaire that she answered. Therefore,during that period, she contributed person-years neither tothe HRT never-use category nor to any HRT ever-use cate-gory, but rather contributed to the unknown exposure statuscategory. In a sensitivityanalysis in which we replaced missingexposure data with exposure reported on the previous question-naire, our conclusions were unaltered (data not shown).

For any given type of HRT, we tested BMI as a potentialeffect modier by incorporating a cross-product term of everuse of that type of HRT (yes/no) BMI (25, yes/no).

Model parameters were estimated and compared by meansof likelihood methods and Wald tests. Tests of statistical sig-nicance were 2-sided, and signicance was set at the 0.05level. SAS software, version 9.3 (SAS Institute, Inc., Cary,North Carolina), was used to perform the analyses.

RESULTS

A total of 301 histologically conrmed rst primary endo-metrial cancers were diagnosed during 709,018 person-yearsof follow-up (mean = 10.8 years). Mean age at diagnosis was64.3 years (standard deviation, 6.5). Extension, according to

Table 1. Continued

All Women(n= 65,630a)

Never Users of HRT(n= 17,107)

Ever Users of HRT(n= 42,460)

No. % No. % No. %

Age at menopause, years

10 years 11,714 17.9 2,361 13.8 8,473 20.0

Unknown duration 14,499 22.1 3,083 18.0 9,799 23.1Premenopausal use of

progestogen alone

Never 38,308 58.4 11,861 69.3 22,349 52.6

Ever 27,322 41.6 5,246 30.7 20,111 47.4

Recent gynecologicalexaminationd

No 9,221 14.1 4,788 28.0 3,455 8.1

Yes 56,409 85.9 12,319 72.0 39,005 91.9

History of diabetes

No 64,837 98.8 16,769 98.0 42,092 99.1

Yes 793 1.2 338 2.0 368 0.9

History of high blood

pressuree

No 59,734 91.0 15,244 89.1 39,017 91.9

Yes 5,896 9.0 1,863 10.9 3,443 8.1

Abbreviations: E3N, Etude Epidmiologique auprs de femmes de lEducation Nationale; HRT, hormone

replacement therapy; MET, metabolic equivalent of task.a During the last follow-up cycle, there were 6,063 women in the unknownHRT exposure category.b Weight (kg)/height (m)2.c From selected recreational and household activities.d Papanicolaou smear performed during the previous follow-up period, used as an indicator of gynecological

monitoring.e Includes self-reported use of antihypertensive medication and history of high blood pressure.


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the International Federation of Gynecology and Obstetricsclassication (14,15), was mostly local (7 cancers werein situ, 237 were stage T1, 23 were stage T2, and 21 werestage T3; information was not available for 13 cancers).

Table1gives the baseline characteristics of the study pop-ulation. Table 2 shows that HRT consisted mostly of estradiolassociated with micronized progesterone, dydrogesterone, or

other progesterone-derived compounds. Many women usedmore than 1 type of HRT: Of those who had ever used estro-gen only, 85% had also ever used EPTs; of those who hadever used estrogen-micronized progesterone, estrogen-dydrogesterone, estrogen-other progesterone derivative, orestrogen-norsteroid derivative, 68%, 72%, 63%, and 80%, re-spectively, had also used another EPT or estrogen only.

Any use of HRT was associated with a signicant increasein the risk of endometrial cancer (hazard ratio (HR) = 1.33,95% CI: 1.01, 1.76) compared with never use of HRT. How-ever, associations differed signicantly across ever use ofthe different types of HRT shown in Table3 (P for homo-geneity < 0.001), including across the different types of pro-

gestogens in EPTs (Pfor homogeneity < 0.001).Compared with never users, ever users of estrogen onlyand ever users of estrogen-micronized progesterone both hadsignicantly increased risks of endometrial cancer (HR =1.80 (95% CI: 1.31, 2.49) and HR = 1.80 (95% CI: 1.38,2.34), respectively) that also differed signicantly fromthe risks associated with any use (ever) of either estrogen-dydrogesterone or estrogen-other progesterone derivative(Table3). Signicant trends of increasing risks with increas-ing durations of use were observed for estrogen only andestrogen-micronized progesterone (Table3). Hazard ratiosassociated with any use of EPTs containing dydrogesterone,other progesterone derivatives, and norsteroid derivativesdid not differ signicantly from unity and did not differ

signicantly from one another (Table3 ). However, therewas a signicantly increased risk with long-term use ofestrogen-dydrogesterone (for >5 years, HR = 1.69, 95% CI:1.06, 2.70).

Risks did not vary signicantly with increasing time sincelast use (Table 3). Although ndings were limited by thesmall numbers of cases in some strata, additional strati-cation by duration of use (5 years or >5 years) and timesince last use (10 years) enabledus to evaluate the persistence of risks several years aftertreatment stopped: Signicant increases in risk were still ob-served 10 or more years after the last use of estrogen only(HR = 1.76, 95% CI: 1.01, 3.07; 15 cases among exposed

women) and 5

10 years after the last use of long-term (>5years) estrogen-micronized progesterone (HR = 2.99, 95%CI: 1.18, 7.57; 5 cases) (data not shown).

Among women who had ever used estrogen only, we ob-served no signicant difference in risks between differentroutes of estrogen administration: For oral administration (11cases diagnosed among exposed women), the hazard ratiowas 1.46 (95% CI: 0.78, 2.72), and for gel or a patch (44cases), it was 1.77 (95% CI: 1.26, 2.50) (data not shown).

Ever use of weak estrogens (i.e., promestriene or estriol)was not associated with a signicant increase in risk of endo-metrial cancer (HR = 1.28, 95% CI: 0.87, 1.89; 31 cases di-agnosed among exposed women). Ever use of tibolone was

associated with a nonsignicantly increased risk (HR = 1.78,95% CI: 0.87, 3.65; 8 cases) (data not shown).

Table4 shows the associations for the dichotomous BMI

strata (


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medroxyprogesterone acetate, and containing norgestrel/levonorgestrel. In our study, EPTs containing oral micronizedprogesterone or dydrogesterone were the only types of EPTsassociated with duration-dependent increases in endometrialcancer risk, with signicantly elevated hazard ratios for treat-ment durations of more than 5 years.

In the Postmenopausal Estrogen/Progestin Interventions

Trial, researchers investigated the risk of atypical hyperplasiaand endometrial cancer among users of 0.625 mg/day of con-jugated equine estrogens associated with 200 mg/day of mi-cronized progesterone for the rst 12 days, but during 3 yearsof follow-up, only a single case of endometrial cancer wasobserved in the placebo group and 1 case of atypia in thetreatment group (17). Studies evaluating short-term treat-ments suggest that micronized progesterone might notprevent estrogen-induced endometrial cell proliferation, par-ticularly at 100200 mg/day (18,19), but that higher dosesmight be more effective for that purpose (1820). This maybe due to considerable interindividual variability in the ab-sorption of oral micronized progesterone (21). In France,

the recommended daily doses of micronized progesteronein EPTs are 100 mg for continuous schemes and 200 mgfor sequential schemes (22,23), based on evaluation of theprogestational potencies of the different progestogenic com-pounds available (24).

After micronized progesterone, dydrogesterone is theprogestogen with the lowest bioavailability and potency

(25). In a record-linkage cohort study with limited statisticalpower, Jaakkola et al. (26) found that ever use of estrogen-dydrogesterone was associated with a hazard ratio for endo-metrial cancer of 1.33 (95% CI: 0.69, 2.33) when used forless than 5 years and a hazard ratio of 4.81 (95% CI: 0.58,17.4) when used longer. Among 5 trials that evaluated hy-perplasia in estrogen-dydrogesterone users, only 1 case of hy-perplasia was reported (2731), perhaps because of the lownumber of women included and the short follow-up periods.Clinical data show that 10 mg of dydrogesterone sequentiallycombined with 2 mg of estradiol for 14 days per month or5 mg of dydrogesterone administered daily (doses typicallyused in France) is effective in protecting the endometrium

Table 3. Hazard Ratios for Endometrial Cancer Associated With Different Types of HRT, E3N Study, France,

19922008

HRT Type and Usage No. of

CasesaPerson-Yearsof Follow-up

HazardRatiob

95%Confidence

Interval

Pfor Trendc

With IncreasingDuration

Pfor Trendc

With IncreasingTimeSince Last

Use

Estrogen only

Ever used 51 72,645 1.80 1.31, 2.49

Duration 5 years 39 51,918 1.81 1.27, 2.58 5 years 5 4,223 3.53 1.44, 8.66

Current use 8 8,188 3.30 1.61, 6.76 0.33

Past use 37 53,927 1.67 1.16, 2.41

Estrogen + micronizedprogesterone

Ever used 91 149,806 1.80 1.38, 2.34

Duration 5 years 42 76,303 1.39 0.99, 1.97 5 years 46 59,278 2.66 1.87, 3.77

Current use 54 87,366 1.96 1.41, 2.73 0.77

Past use 37 61,210 1.44 0.99, 2.08

Estrogen + dydrogesterone

Ever used 47 117,216 1.05 0.76, 1.45

Duration 5 years 25 66,212 0.87 0.57, 1.32 0.006

Duration >5 years 21 39,207 1.69 1.06, 2.70

Current use 11 55,442 0.67 0.36, 1.25 0.96

Past use 36 60,390 1.30 0.90, 1.88

Estrogen + otherprogesteronederivative

Ever used 79 257,095 0.79 0.60, 1.05

Duration 5 years 49 132,269 0.81 0.59, 1.13 0.76

Duration >5 years 28 97,979 0.94 0.62, 1.44

Current use 24 131,653 0.65 0.41, 1.02 0.54

Past use 55 123,185 0.89 0.65, 1.23

Table continues


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from estrogenic effects for up to 3 years (32). Data for longerdurations are not available.

Our results suggest that micronized progesterone and long-term dydrogesterone as used in France are not sufcient toprevent estrogen-induced endometrial cell proliferation. Al-ternatively, failure to control for various forms of bias mayexplain our results. First, although the evidence derivedfrom trials assessing endometrial hyperplasia yielded no stat-istically signicant difference between continuous and se-quential EPTs including at least 10 days of progestogen permonth (16), observational data suggest that the risk of endo-metrial cancer increases when the number of days per month

on which the progestogen is taken decreases (5

7). We couldnot control for that parameter in our cohort, in which most(approximately 80%) EPTs containing progesterone or itsderivatives used 2 distinct brands of estrogen and of pro-gestogen (e.g., estrogen patch + progestogen pill) ratherthan single-pill combinations, because the number of daysof hormone use was not recorded on the self-administeredquestionnaires used to assess HRT exposure for the presentstudy. Although this may have changed over time, in 2008,micronized progesterone and dydrogesterone were nottaken for fewer days than other progestogens: Data fromthe questionnaire sent in 2008, which recorded that informa-tion, showed that the 5,493 women who were current users of

EPT (either as a single-pill combination or with distinctbrands of estrogen and of oral progestogen) took the proges-togen component for a mean of 22.5 days for micronizedprogesterone, 23.5 days for dydrogesterone, 18.9 days forother progesterone derivatives, and 26.8 days for testosteronederivatives (unpublished data). Thus, if this observation heldtrue for the entire follow-up of our cohort, it would be un-likely that differences regarding endometrial cancer risk be-tween estrogen-micronized progesterone/dydrogesterone andother EPTs are explained by the number of days per month onwhich the progestogen is taken. Second, a prescription biascould have affected our results if women at higher risk of

endometrial cancer were more often prescribed micronizedprogesterone/dydrogesterone than other progestogens. How-ever, our analyses were systematically adjusted for known en-dometrial cancer risk factors, and we observed no markeddifference in their distribution according to the progestogencomponent of EPT (data not shown). Finally, a diagnosticbias due to excess bleeding in women using estrogen-micronized progesterone, which may entail an increasednumber of endometrial biopsies, could have affected our re-sults, since irregular bleeding has previously been reportedin these women (33). However, this result was not found inthe 2 trials that assessed unscheduled biopsies in these users(34,35).

Table 3. Continued

HRT Type and Usage No. of

CasesaPerson-Yearsof Follow-up

HazardRatiob

95%Confidence

Interval

Pfor Trendc

With IncreasingDuration

Pfor Trendc

With IncreasingTimeSince Last

Use

Estrogen + norsteroidderivative

Ever used

24 50,698 1.30 0.85, 1.99Duration 5 years 18 32,795 1.32 0.81, 2.15 0.51

Duration >5 years 3 12,579 0.98 0.31, 3.07

Current use 6 20,403 1.10 0.48, 2.49 0.38

Past use 17 28,955 1.34 0.81, 2.22

Abbreviations: E3N, Etude Epidmiologique auprs de femmes de lEducation Nationale; HRT, hormone

replacement therapy.a Eighty-eight cases were diagnosed among never users of HRT (232,726 person-years), 23 among women with

an unknown exposure status at the time of diagnosis, 25 among women ever exposed to another HRT (i.e., HRT

containing an androgen, or intramuscularly administered, or with the progestogen component delivered through a

patch, or with no specified formulation), 31 among ever users of weak estrogens, and 8 among ever users of

tibolone. The total number of endometrial cancer cases exceeds 301 because a woman could contribute person-

years to several categories of exposure simultaneously (e.g., past use of estrogen-only therapy and current use of

estrogen-micronized progesterone).b Adjusted for age (years; time scale), all variables listed in Table 1, and the equivalent exposure categories for the

other types of HRT. Reference category: never use.c Ever use, duration of use (years; continuous), and recency of use (years since last use (continuous); equaled 0

when use was current) were entered simultaneously into the model.d PairwisePvalues for heterogeneity of hazard ratios associated with ever use were as follows: between estrogen

only and estrogen-micronized progesterone, 0.99; between estrogen only and estrogen-dydrogesterone, 0.03;

between estrogen only and estrogen-other progesterone derivative,


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The epidemiologic evidence shows that estrogen-only

therapy is associated with an increased risk of endometrialcancer, which is more marked with prolonged duration ofuse and persists for several years after treatment discontinua-tion (36). It also suggests that the increase in risk is connedto nonobese women (8, 3740). Ourndings agree with theseconclusions.

Most epidemiologic studies suggest an increased riskof endometrial cancer associated with tibolone (8,11, 41).In our study, we observed a nonsignicantly increased riskin tibolone users, but the number of exposed cases was toolimited to permit arm interpretation.

Consistent with the reassuring data available about endo-metrial hyperplasia with the use of vaginal estrogens (42), we

found no signi

cantly increased risk of endometrial cancerwith the use of weak estrogens (mostly vaginally adminis-tered promestriene or estriol in our cohort).

We found no signicant variations in the risk of endome-trial cancer according to time since last use of EPT, and therisk remained signicantly elevated many years after the useof estrogen-micronized progesterone. Although relativelyscarce, previous epidemiologic data similarly suggest thatthe effect (whether deleterious, neutral, or protective) ofEPT on the risk of endometrial cancer persists for severalyears after treatment ends (8,38,4345).

Strengths of our study include our ability to evaluate dif-ferent types of HRT and the regular exposure updates. These

updates limited classication bias and allowed us to take into

account possible changes over time in the types of hormonesused, by adjusting our models simultaneously for the differ-ent HRT types each woman could have ever used. Hence, it isunlikely that our results for a given HRT type were insteaddue to the previous use of other types of HRT. Finally, expo-sure was dealt with prospectively: The exposure precedingthe completion of a given questionnaire was characterizedusing only the information reported in the previous ques-tionnaires. In particular, this implies for cases that the informa-tion on exposure used in our models was only that collectedbefore any diagnosis of cancer (e.g., for a woman with cancerdiagnosed between the fth and sixth follow-up question-naires, only the exposure information collected up to the

fth follow-up questionnaire was used), thus eliminatingthe possibility that differential recall between cases and non-cases may have affected our results.

Some limitations of our study must also be acknowledged.Exposure assessment was based on self-reports. However,recall bias was probably limited, since data on HRT usewere updated every 23 years. Furthermore, previous studieshave shown good agreement between self-reported HRT ex-posure and prescription data, especially for recent use ( 46,47). However, the risk of endometrial cancer associatedwith estrogen-only therapy might have been underestimatedif some women who were using a combination of progesto-gen and estrogen as 2 distinct brands rather than a single-pill

Table 4. Hazard Ratios for Endometrial Cancer Associated With Ever Use of Different Types of HRT, by Body Mass

Indexa, E3N Study, France, 19922008

HRT Type and Body Mass Indexb No. of

CasesPerson-Yearsof Follow-up

HazardRatioc

95% ConfidenceInterval

PforHomogeneity

Estrogen only 0.06


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combination (approximately 80% of EPT use) neglected toreport the use of the progestogen component; they wouldtherefore have been misclassied as estrogen-only users. Wealso acknowledge that there were relatively few cases in somesubgroups, due to the limited incidence of the diseasein our cohort, 4 cases among 1,000 women over a 10-yearperiod in HRT never users, far fewer than for invasive

breast cancer (around 34 cases). Finally, the small percent-age of overweight or obese women limited our ability toassess whether the effects of HRT varied across BMI catego-ries, as consistently suggested by previous epidemiologicstudies (reviewed by Brinton and Felix (7)). Our resultsshould therefore be viewed as pertaining mostly to womenwho are neither obese nor overweight, in whom the HRT-associated hazard ratio for endometrial cancer appears to behighest (7).

In conclusion, our study suggests that estrogen-micronizedprogesterone and long-term use (5 years) of estrogen-dydrogesterone at the doses/frequencies employed in Franceare not sufcient to prevent estrogen-induced endometrial

cancers. Such an insuf

cient progestational potency wouldalso explain the lack of difference regarding breast cancerrisk we observed in the same cohort between users of estro-gen only and users of estrogen-micronized progesterone orestrogen-dydrogesterone (10). Although endometrial canceris far less frequent than breast cancer, further studies are re-quired to dene an optimal HRT regimen that minimizes therisks of both breast and endometrial cancer.

ACKNOWLEDGMENTS

Author afliations: Nutrition, Hormones and Womens

Health Team, U1018, Centre for Research in Epidemiologyand Population Health, Institut National de la Sant et de laRecherche Mdicale (INSERM), Villejuif, France (AgnsFournier, Laure Dossus, Sylvie Mesrine, Alice Vilier, Marie-Christine Boutron-Ruault, Franoise Clavel-Chapelon);Unit Mixte de Recherche Scientique 1018, UniversitParis-Sud, Villejuif, France (Agns Fournier, Laure Dossus,Sylvie Mesrine, Alice Vilier, Marie-Christine Boutron-Ruault, Franoise Clavel-Chapelon); Institut GustaveRoussy, Villejuif, France (Agns Fournier, Laure Dossus,Sylvie Mesrine, Alice Vilier, Marie-Christine Boutron-Ruault, Franoise Clavel-Chapelon); and Department ofObstetrics-Gynaecology and Reproductive Medicine, Hpi-

tal Tenon APHP, Universit Pierre et Marie Curie, Paris,France (Nathalie Chabbert-Buffet).This work was supported by a grant from the Institut de

Recherche en Sant Publique (as part of the Plan Cancer20092013). The E3N cohort is being studied with thenancial support of the Mutuelle Gnrale de lEducationNationale, the European Community, the Ligue NationaleContre le Cancer, the Institut Gustave Roussy, INSERM,and the Fondation de France.

We thank the medical practitioners for providing pathologyreports. We are grateful to R. Chait, M. Fangon, L. Hoang,and M. Niravong for technical assistance; to Dr. Alban Fabre,who performed the preliminary statistical analyses; to the

E3N Study Group; and to JoAnn Cahn for assistance withtranslation.

Conict of interest: none declared.

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