Context Whether menopausal hormone replacement therapy using a combined estrogen-progestin
regimen increases risk of breast cancer beyond that associated with estrogen
alone is unknown.
Objective To determine whether increases in risk associated with the estrogen-progestin
regimen are greater than those associated with estrogen alone.
Design Cohort study of follow-up data for 1980-1995 from the Breast Cancer
Detection Demonstration Project, a nationwide breast cancer screening program.
Setting Twenty-nine screening centers throughout the United States.
Participants A total of 46,355 postmenopausal women (mean age at start of follow-up,
58 years).
Main Outcome Measure Incident breast cancers by recency, duration, and type of hormone use.
Results During follow-up, 2082 cases of breast cancer were identified. Increases
in risk with estrogen only and estrogen-progestin only were restricted to
use within the previous 4 years (relative risk [RR], 1.2 [95% confidence interval
{CI}, 1.0-1.4] and 1.4 [95% CI, 1.1-1.8], respectively); the relative risk
increased by 0.01 (95% CI, 0.002-0.03) with each year of estrogen-only use
and by 0.08 (95% CI, 0.02-0.16) with each year of estrogen-progestin–only
use among recent users, after adjustment for mammographic screening, age at
menopause, body mass index (BMI), education, and age. The P value associated with the test of homogeneity of these estimates
was .02. Among women with a BMI of 24.4 kg/m2 or less, increases
in RR with each year of estrogen-only use and estrogen-progestin–only
use among recent users were 0.03 (95% CI, 0.01-0.06) and 0.12 (95% CI, 0.02-0.25),
respectively. These associations were evident for the majority of invasive
tumors with ductal histology and regardless of extent of invasive disease.
Risk in heavier women did not increase with use of estrogen only or estrogen-progestin
only.
Conclusion Our data suggest that the estrogen-progestin regimen increases breast
cancer risk beyond that associated with estrogen alone.
In a recent collaborative reanalysis of more than 90% of the world's
epidemiological data on the relationship between menopausal hormone replacement
therapy (HRT) and breast cancer risk, it was found that longer durations of
recent, but not past, use of HRT increased breast cancer risk, particularly
among leaner women and for tumors that were less clinically advanced.1 Unresolved issues include the extent to which the
findings were due to a biological effect of hormones rather than issues of
screening and ascertainment. The data were also insufficient to determine
whether a combined estrogen-progestin regimen increased risk beyond that associated
with estrogen alone.
In 1994, we published data on HRT and breast cancer risk from a follow-up
study conducted among former participants in a breast cancer screening program.2 Cases were diagnosed through 1989. Those data were
included in the collaborative analysis.1 In
this article, we expand our previous analysis to include cases diagnosed in
the follow-up study through 1995, almost doubling the total number of cases.
The collection of additional data on mammographic screening and use of the
combined estrogen-progestin regimen allowed us to address some issues left
unresolved.
Study subjects were participants in the Breast Cancer Detection Demonstration
Project (BCDDP) conducted between 1973 and 1980. We previously described a
follow-up study begun in 1979 involving a subset of BCDDP participants.2 In brief, the follow-up study included (1) all screening
participants who underwent breast surgery during the screening period, with
no evidence of malignant disease (n = 25,114); (2) all subjects who had recommendations
by the project for a surgical consultation but did not have either a biopsy
or aspiration performed (n = 9628); and (3) a sample of women who had neither
surgery nor recommendation for surgical consultation during screening participation
(n = 25,165). The follow-up study was approved by the Institutional Review
Board at the National Cancer Institute. Informed consent was obtained from
participants.
The follow-up study was carried out in 3 phases. Our previous analysis
involved the first 2 phases of the study, in which annual telephone interviews
were conducted between 1979 and 1986 and 1 mailed questionnaire was administered
between 1987 and 1989.2 The current analysis
includes data from these earlier phases as well as from the latest phase of
the study, during which 1 mailed questionnaire was administered between 1993
and December 1995 to study subjects not known to be deceased and who completed
a questionnaire in 1987-1989. Nonrespondents to the mailed questionnaire were
interviewed by telephone, if possible.
Information collected from phase 1 of the study included recognized
breast cancer risk factors; breast cancer screening practices, including number
of mammograms for a routine reason or because of a problem since the last
interview; and breast procedures undergone since the last examination by the
screening program or the last interview. In addition, information was collected
on age at first use and duration of use of female hormones (excluding creams)
other than oral contraceptives. Information was not obtained on type of hormone
used. During phase 2 of the study, information on breast procedures and previously
collected risk factors was updated. Information was obtained on use of menopausal
hormones in the form of shots, creams, patches, or pills since the last interview;
those who had used pills provided information on ever use of menopausal estrogens
and progestins in the same month, duration of use of estrogens and progestins,
and number of days in the month progestins were used. Information on breast
cancer screening practices was not collected during phase 2. In phase 3 of
follow-up, previously collected information, including use of estrogens and
progestins, was updated; information was also collected on mammographic and
physical examinations of the breast for a routine reason or because of a problem
in the 5 years prior to the interview.
Level of education was recorded on a form completed at entry to the
screening program. Height and weight measurements were recorded on forms at
each screening visit. Current height and weight measurements were available
from the 1987-1989 questionnaire.
This analysis was limited to women who were menopausal before the start
of the follow-up period or who became menopausal during the course of the
study. Menopausal women were defined as those who did not have a menstrual
period for at least 3 months prior to an interview because of natural menopause
or a bilateral oophorectomy. In addition, women who stopped menstruating because
of a hysterectomy but who retained at least 1 ovary or whose ovarian status
was uncertain were considered to have reached menopause by age 57 years (the
75th percentile for age at menopause in the study population) or their age
at hysterectomy, whichever was later. However, they were assigned an unknown
value for their specific ages at menopause in the analyses. Those reporting
prophylactic bilateral mastectomies or a diagnosis of breast cancer before
the start of follow-up were excluded. Those reporting use of menopausal hormones
in the form of shots, patches, or creams (n = 6212) were also excluded because
detailed information regarding timing of use was not available. Most study
subjects (86%) were white. There were small percentages of black (5%), Hispanic
(2%), and Asian American (5%) women, as well as those with other or unknown
race/ethnicity (1%).
After all exclusions, 46,355 subjects were available for analysis. A
total of 39,427 (85%) of these subjects completed a phase 2 questionnaire;
33,004 (84%) of those who completed a phase 2 questionnaire also completed
a phase 3 questionnaire. Phase 3 questionnaires were not completed by those
who completed phase 2 for reasons including death (6%); loss to follow-up
(0.5%); and illness, refusal, or because contact with study subjects at a
current telephone number was not made by the end of the study period (9.5%).
During follow-up, 2082 breast cancer cases were identified in study
subjects through self-reports or reports of breast cancer on death certificates;
1054 of these cases were included in our previous analysis.2
Pathology reports were obtained for 1713 of these cases (82%); reports were
not obtained for 237 cases (11%) because they were not received before the
end of the study period, because of nonresponse of physicians or hospitals,
or because permission to retrieve medical records was not received from the
study subject. Pathology reports for the 132 cases (6%) identified by death
certificate also were not retrieved. A total of 255 (15%) cancers for which
pathology reports were available were in situ and 1456 (85%) were invasive.
It was uncertain whether 2 cases were in situ or invasive. Invasive tumors
were further classified into 2 groups based on histology: (1) mucinous, medullary,
tubular, or papillary carcinomas (n = 76) or (2) ductal or lobular carcinomas
(n = 916). A total of 788 in the second group were ductal carcinomas, 104
were lobular carcinomas, and 24 were comedocarcinomas or Paget disease with
infiltrating ductal carcinoma. Histology was not available for 464 invasive
cases, largely from those whose disease was diagnosed during phase 1 of the
study, because pathology reports were no longer available from which to code
histology. Because the accuracy of self-reporting was high among those with
pathology reports (97% were confirmed as cancers), cancers without pathology
reports (n = 369) were included in the analyses but were not categorized as
in situ or invasive.
Nodal status was available for 1253 (86%) of the invasive cases; 903
(72%) were node negative and 350 were (28%) node positive. Tumor size was
available for 1041 (71%) of invasive cases: 680 (65%) were smaller than 2
cm and 361 (35%) were 2 cm or larger.
Follow-up began at the date of the baseline interview or date of menopause,
whichever was later. Person-years accrued until the earliest of the following
dates: diagnosis of breast cancer, a second prophylactic mastectomy, death
(including cases identified by death certificate), or date of last contact.
Data were analyzed using Poisson regression methods. We calculated relative
risks (RRs) and 95% confidence intervals (CIs) for categorized variables using
standard likelihood ratio methods.3 For a continuous
variable (eg, duration of estrogen use), the RR was modeled as a linear excess
RR (ERR) as follows: λ(t, z, d) = λ(t, z, 0) (1 + βd),
where d is duration of hormone use, the parameter β is the change in
the ERR (RR −1) per unit d, λ(t, z, 0) is the risk at time t
for those with covariate vector z and no hormone use, and λ(t, z, d)
is the risk at time t for those with covariate vector z and d years of hormone
use. The background risk λ(t, z, 0) was modeled by means of stratification.
Likelihood-based methods were used to obtain CIs for the linear ERR model.4 Score tests were used to test for the statistical
significance of trends and to assess quadratic departures from linearity in
the linear ERR model. No such departures were detected. Tests of homogeneity
of the effects of estrogen and estrogen-progestin were assessed by score tests
in which the effects of the 2 regimens were first assumed to be the same and
then were allowed to vary. Similarly, score tests were used to assess the
homogeneity of hormonal effects by categories of body mass index (BMI).
Variables included as time-dependent factors were attained age, BMI,
use of female hormones for menopausal reasons, and mammographic examinations
of the breast. Hormone use was calculated to 1 year prior to attained (or
current) age to eliminate exposure that was most likely not causal. Data on
BMI and mammographic examinations were calculated to attained age.
Because information on progestin use was not collected until the 1987-1989
interview, progestin use was unknown for the 6928 subjects who did not answer
this interview. For these subjects and those who were uncertain whether they
had used progestins, person-years and cases associated with estrogen use were
included in the estrogen (progestin unknown) category
if the subject had undergone a natural menopause; otherwise, they were included
in the estrogen only category because women with
a surgical menopause were less likely to have used progestins. Information
on episodes of hormone use that occurred before breast cancer diagnosis may
have been reported by study subjects after diagnosis. For instance, a subject
may have reported on a 1994 interview that she had been diagnosed as having
breast cancer in 1993 and that she had used hormones between 1991 and 1992
(before diagnosis). For this same study subject, all hormone use that was
reported on interviews completed prior to 1993 would have been reported before
breast cancer diagnosis. An individual who responded to the 1994 interview
but did not report breast cancer on that interview would have reported any
hormone use in a manner similar to this hypothetical case.
We assessed the influence of mammographic screening (ie, mammograms
as part of routine screening rather than for a problem) during the follow-up
period by categorizing person-years and cases in a time-dependent manner into
1 of the following 4 groups: (1) no mammographic screening, defined as the
period of time from the start of the follow-up study to the first screening
mammogram during the follow-up study; (2) sporadic mammographic screening,
defined as the period of 1 year following the first screening mammogram and
subsequent periods more than 1 year after a screening mammogram; (3) annual
mammographic screening, defined as the period of time within 1 year of the
second and subsequent screening mammograms; and (4) unknown mammographic screening
type. We chose to adjust for mammographic screening in this manner, rather
than controlling for number of screening mammograms, because cancer detection
rates associated with the first mammogram during the BCDDP screening program
were markedly higher than those associated with subsequent mammograms, while
cancer detection rates were remarkably constant for the second and subsequent
mammograms.5 A similar variable was created
for clinical breast examinations by a health care professional during the
follow-up period.
For the follow-up period until the 1987-1989 questionnaire, we calculated
BMI from information obtained from the screening visit closest in time to
the baseline follow-up interview; for the subsequent period we calculated
BMI from current height and weight from the 1987-1989 questionnaire.
For analytic purposes, BMI data were grouped into quintiles. Because
there was virtually no difference in the prevalence of hormone use in the
lowest 2 quintiles, they were combined in the analyses. To control as completely
as possible for the confounding effects of age at menopause, we created narrow
categories for the most commonly reported ages at menopause and broader categories
for the less commonly reported ages. We performed selected analyses excluding
subjects with unknown age at menopause to address theoretical concerns that
including these women would seriously underestimate the risk associated with
HRT.6
The mean duration of follow-up was 10.2 years, with a median of 12.3
years, a maximum of 16.0 years, and a minimum of less than 1 year. During
follow-up, 473,687 person-years were accumulated for the 46,355 subjects.
The average age at start of follow-up was 58 years.
Forty-two percent of person-years were associated with no use of hormones,
38% with estrogen-only use, 4% with combined estrogen-progestin–only
use, 6% with estrogen-progestin use among those who also used estrogen alone,
5% with estrogen use with uncertain or unascertained progestin use, 1% with
progestin-only use or progestin use with uncertain estrogen use, and 5% with
uncertain hormone use. The primary type of estrogen used was conjugated estrogens
(Premarin) and the primary progestin was medroxyprogesterone acetate.
Ever Use and Recency of Use
Relative risks associated with ever use of different hormone regimens
after adjustment for attained age, age at menopause, education, BMI, and mammographic
screening are shown in Table 1.
Adjustment for race, period of follow-up, age at first live birth, family
history of breast cancer, history of benign breast disease, and clinical breast
examinations did not alter these estimates. There were slight increases in
risk associated with all regimens of use except progestin only. Most subsequent
analyses are restricted to nonhormone use, use of estrogen only, and use of
estrogen-progestin only.
Increases in risk associated with use of estrogen only and estrogen-progestin
only were largely restricted to recent use of hormones (defined as current
use and past use occurring within the previous 4 years)
(Table 1). Relative risks were 1.2 (95% CI, 1.0-1.4) and 1.4 (95%
CI, 1.1-1.8), respectively. The mean person-year weighted duration of combined
estrogen-progestin use among recent users was less than half that among recent
users of estrogens alone (3.6 vs 10.3 years).
Observed and predicted RRs associated with duration of estrogen-only
use and estrogen-progestin–only use among recent users are shown in Figure 1. Based on the linear excess risk
model, the RR of breast cancer increased by 0.01 (95% CI, 0.002-0.03) for
each year of estrogen-only use (P = .01 for trend)
and by 0.08 (95% CI, 0.02-0.16) for each year of estrogen-progestin–only
use (P = .01 for trend). The P value for the test of homogeneity of these estimates was .02. Results
were similar when analyses were restricted to the category of annual mammographic
screening, which included 24% of the person-years in the study.
To assess the impact of excluding women with an unknown age at menopause
on the analysis, we restricted data to recent users with a known age at menopause.
Relative risks were changed only slightly; in contrast with estimates of 0.01
and 0.08 for all data, the increase in RR for each year of estrogen-only use
was 0.02 (95% CI, 0.002-0.04) and for each year of estrogen-progestin–only
use was 0.06 (95% CI, −0.002 to 0.15). The P
value for the test of homogeneity of these associations was .23. We also examined
associations among women with a known age at menopause but unadjusted for
age at menopause; the increase in RR for each year of estrogen-only use was
0.01 (95% CI, 0.002-0.24) and for estrogen-progestin–only use was 0.07
(95% CI, 0.001-0.16), suggesting that ignoring age at menopause entirely had
little effect on the estimates.
When analyses included all recent users of estrogen-progestin (ie, including
those who also used estrogen alone and those with an unknown age at menopause),
the RR increased by 0.05 (95% CI, 0.003-0.11) with each year of use. The P value associated with the test of homogeneity of this
estimate and that associated with duration of use of estrogen alone was .07.
There was no association between duration of use of estrogen alone and
risk of breast cancer among past users.
Duration by Days in the Month Progestins Were Used
Among recent users who used progestins for fewer than 15 days per month,
the RRs associated with less than 4 and 4 or more years of use of estrogen-progestin
only were 1.1 (95% CI, 0.8-1.7) and 1.5 (95% CI, 1.0-2.4), respectively, based
on 26 and 22 cases. The median number of days progestins were used in this
group was 10.
There were too few cases who had used progestins for 15 or more days
per month (n = 12) to derive stable estimates according to duration of use.
A substantial number of cases (n = 33) were uncertain how many days in the
month they had used progestin.
Associations with duration of estrogen-only use among recent users varied
significantly according to BMI (P = .002 for score
test), with increases in risk evident only in women with a BMI of 24.4 kg/m2 or less
(Table 2). The
RRs increased by 0.03 (95% CI, 0.01-0.06) for each year of estrogen-only use
in this group.
Associations with duration of estrogen-progestin–only use among
recent users did not vary significantly according to BMI (P = .42 for score test), although there was a significant increase
in risk among lean women but not heavier women. The RR among lean women increased
by 0.12 (95% CI, 0.02-0.25) for each year of use. The P value associated with the test of homogeneity of this estimate and
that associated with estrogen-only use in lean women was .06.
When those with an unknown age at menopause were excluded, the RR increased
by 0.05 for each year of estrogen-only use (95% CI, 0.02-0.08) among lean
women; the increase in the RR for each year of estrogen-progestin–only
use in lean women was 0.11 (95% CI, 0.01-0.27). The P
value associated with the test of homogeneity of these estimates was .36.
Extent of Disease and Tumor Histology
In recent estrogen-only users with BMI of 24.4 kg/m2 or less,
duration of use was associated with significant increases in risk of both
early- and later-stage invasive disease (Table 3). Estrogen-progestin–only use was also associated
with significant increases in risk of invasive cancer, but numbers were too
small to draw conclusions regarding associations according to extent of invasive
disease. There were no significant increases in risk of in situ disease associated
with either regimen, but the number of cases was small. In recent users with
BMI of 24.4 kg/m2 or less, use of estrogen only and estrogen-progestin
only were both associated with significant increases in risk of invasive tumors
with ductal and/or lobular histologies (Table 4). Similar associations were evident when analyses were limited
to invasive tumors with ductal histology. There were too few cases with other
histologies to examine these associations.
Our results suggest that the combined estrogen-progestin regimen is
associated with greater increases in breast cancer risk than estrogen alone.
These results are consistent with those from the recent collaborative analysis,
although in that analysis, the effect of the combined estrogen-progestin regimen
was evaluated among women who may also have used estrogen alone.1
Recently published data also support a more adverse effect on the breast with
the estrogen-progestin regimen than with estrogen alone.7
Assessing the comparative risk of estrogen alone vs estrogen-progestin
was complicated by the fact that use of estrogen alone was associated with
increased risk in lean but not heavy women. We found differences between the
2 regimens among lean women but were unable to draw conclusions among heavier
women. In the collaborative reanalysis, associations without regard to type
of hormone were evident in lean but not heavy women.1
Among lean women, we found no evidence that associations differed according
to extent of disease. In the collaborative reanalysis, increases in risk were
greater for localized than distant disease, but results according to extent
of disease were not reported in lean women.1
We also found significant increases in risk for the vast majority of invasive
tumors classified as lobular and/or ductal carcinomas, results that are not
consistent with those of Gapstur et al.8 Their
categories for duration of use (≤5 or >5 years) may have obscured an effect
of long-term use; in addition, they did not present results among lean women.
In a survival analysis based on a different series of cases, we found that
the reduction in breast cancer mortality among current hormone users at diagnosis
was not due to earlier-stage disease or tumors with more favorable histologies
in hormone users compared with nonusers,9 consistent
with the current analysis.
The biological mechanisms underlying an effect of exogenous hormones
on the breast are complex. In a study of proliferation of normal human breast
tissue implanted into athymic nude mice, there appeared to be a maximally
effective dosage of estradiol in regard to breast cell proliferation beyond
which higher dosages had no effect.10 This
phenomenon may explain the lack of effect of exogenous estrogen on breast
cancer risk in heavy women, who have relatively higher endogenous estrogen
levels than lean women due to nonovarian synthesis of estrone as a result
of the peripheral conversion of androgens. The fact that progesterone does
not down-regulate estrogen and progesterone receptors in the breast may contribute
to its adverse effects.10,11 Moreover,
the isozyme of 17β-hydroxysteroid dehydrogenase induced by progesterone
in the breast predominantly catalyzes the conversion of the less potent estrone
to the more potent estradiol.12
Several methodological issues need to be considered in interpreting
our results. The pattern of greater increases in risk associated with the
estrogen-progestin regimen than with estrogen alone was evident when subjects
with an unknown age at menopause were both included and excluded, although
the disparity between the associations was slightly smaller when they were
excluded. The lack of statistical significance for the test of the homogeneity
of the associations of the 2 regimens after exclusion of those with an unknown
age at menopause most likely resulted from the elimination of 17% of person-years
and 20% of cases in the study, which reduced the information available for
estimating increases in the RRs. We chose to present our main findings including
women with an unknown age at menopause because age at menopause was not a
substantial confounder of the hormone associations in these data and because
excluding these women resulted in a substantial loss of information. Moreover,
the estimates including and excluding these women were not meaningfully different,
given the uncertainty in the estimates.
Although we were not able to completely account for differences in mammographic
screening according to hormone use, it is reassuring that results were similar
when we restricted analyses to those who had undergone annual mammographic
screening. Moreover, similar differences have been noted in other populations
where mammographic screening is widespread7
or where differences in mammographic screening have been taken into account
in assessing risk of HRT.13
Although our study may be subject to problems of recall in the reporting
of menopausal hormone use,14 such misclassification
would most likely dilute the magnitude of the relationship between HRT and
breast cancer risk. The fact that some episodes of hormone use that occurred
before breast cancer diagnosis were reported after diagnosis raises the possibility
of differential recall by cases and noncases. However, our results with regard
to recency of use are very similar to those from a cohort study in which all
hormone use was reported before diagnosis.13
Moreover, in another cohort study in which all hormone use was reported before
diagnosis, the estrogen-progestin regimen also was associated with greater
increases in risk than estrogens alone.7 Finally,
in an early case-control study based on this study population in which hormone
use was validated, there was no evidence of differential reporting of hormone
use by cases and controls.15
Our results, as well as those of others, suggest that in weighing the
risks and benefits of menopausal HRT, it is important to consider the type
of hormone regimen as well as individual characteristics of the woman, such
as body mass index.
1.Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy.
Lancet.1997;350:1047-1059.Google Scholar 2.Schairer C, Byrne C, Keyl PM.
et al. Menopausal estrogen and estrogen-progestin replacement therapy and
risk of breast cancer (United States).
Cancer Causes Control.1994;5:491-500.Google Scholar 3.Breslow NE, Day NE. Statistical Methods in Cancer Research: The Design
and Analysis of Cohort Studies. Lyon, France: International Agency for Research on Cancer; 1987.
4.Preston DL, Lubin JH, Pierce DA, McConney ME. EPICURE [software]. Release 2.0. Seattle, Wash: HiroSoft International Corp; 1996.
5.Baker LH. Breast Cancer Detection Demonstration Project.
CA Cancer J Clin.1982;32:194-225.Google Scholar 6.Pike MC, Ross RK, Spicer DV. Problems involved in including women with simple hysterectomy in epidemiologic
studies measuring the effects of hormone replacement therapy on breast cancer
risk.
Am J Epidemiol.1998;147:718-721.Google Scholar 7.Persson I, Weiderpass E, Bergstrom R, Schairer C. Risks of breast and endometrial cancer after estrogen and estrogen-progestin
replacement therapy.
Cancer Causes Control.1999;10:253-260.Google Scholar 8.Gapstur SM, Morrow M, Sellers TA. Hormone replacement therapy and breast cancer with a favorable pathology.
JAMA.1999;281:2091-2097.Google Scholar 9.Schairer C, Gail M, Byrne C.
et al. Estrogen replacement therapy and breast cancer survival in a large
screening study.
J Natl Cancer Inst.1999;91:264-270.Google Scholar 10.Laidlaw IJ, Clarke RB, Howell A.
et al. The proliferation of normal human breast tissue implanted into athymic
nude mice is stimulated by estrogen but not progesterone.
Endocrinology.1995;136:164-171.Google Scholar 11.Hargreaves DF, Knox F, Swindell R, Potten CS, Bundred NJ. Epithelial proliferation and hormone receptor status in the normal
post-menopausal breast and the effects of hormone replacement therapy.
Br J Cancer.1998;78:945-949.Google Scholar 12.Poutanen M, Isomaa V, Peltoketo H, Vihko R. Role of 17β-hydroxysteroid dehydrogenase type 1 in endocrine and
intracrine estradiol biosynthesis.
J Steroid Biochem Mol Biol.1995;55:525-532.Google Scholar 13.Colditz GA, Hankinson SE, Hunter DJ.
et al. The use of estrogens and progestins and the risk of breast cancer in
postmenopausal women.
N Engl J Med.1995;332:1589-1593.Google Scholar 14.Greendale GA, James MK, Espeland MA, Barrett-Connor E.for the PEPI Investigators. Can we measure prior postmenopausal estrogen/progestin use?
Am J Epidemiol.1997;146:763-770.Google Scholar 15.Brinton LA, Hoover RN, Szklo M.
et al. Menopausal estrogen use and risk of breast cancer.
Cancer.1981;47:2517-2522.Google Scholar