Menopausal hormones and risk of ovarian cancer - ResearchGate

American Journal of Obstetrics and Gynecology (2005) 193, 76–82
www.ajog.org
Menopausal hormones and risk of ovarian cancer
Patricia G. Moorman, PhD, a, * Joellen M. Schildkraut, PhD, a Brian Calingaert, MS, a
Susan Halabi, PhD, b Andrew Berchuck, MD c
Departments of Community and Family Medicine, a Biostatistics and Bioinformatics, b and Obstetrics and Gynecology, c
Duke University Medical Center, Durham, NC
Received for publication August 23, 2004; revised October 18, 2004; accepted November 4, 2004
KEY WORDS
Ovarian cancer
Hormone replacement
therapy
Estrogen
Progestin
Menopause
Objective: The objective of this study was to determine if use of menopausal hormones was
associated with ovarian cancer and if risk varied by type of hormone used.
Study design: Data from a population-based, case-control study of ovarian cancer in North
Carolina (364 cases, 370 controls, all postmenopausal) were analyzed to evaluate the relationship
between menopausal hormones and ovarian cancer. Logistic regression analyses were used to
calculate odds ratios (OR) and 95% CIs associated with various patterns of hormone use.
Results: Ovarian cancer cases were more likely than controls to report long-term use (R10 years)
of unopposed estrogens (OR 2.2; 95% CI 1.2–4.1). No relationship was observed for estrogen
always used with progestin.
Conclusion: Hormone replacement therapy used according to current recommendations should
not increase risk of ovarian cancer; however, clinicians should be aware of possible increased risk
among women with a long history of estrogen replacement therapy.
Ó 2005 Elsevier Inc. All rights reserved.
Supported by grants from the National Cancer Institute
(CA76016), and the Department of Defense (DAMD17-02-1-0666).
* Reprint requests: Patricia G. Moorman, PhD, 2424 Erwin Road,
Suite 602, Box 2949, Duke University Medical Center, Durham, NC
27710.
E-mail: patricia.moorman@duke.edu
It is well established that ovarian cancer risk is
affected by exogenous hormones. One of the most
consistently reported findings from etiologic studies of
ovarian cancer is that women who have used oral
contraceptives are at reduced risk for ovarian cancer. 1
Although the relationship between menopausal hormone
use and ovarian cancer has been reported in
a number of investigations, the findings have been much
less consistent than studies of oral contraceptives and
ovarian cancer. 2,3-12 Many studies evaluating menopausal
hormones and ovarian cancer have not found
a statistically significant relationship; however, some
have suggested increased risk in various subgroups
defined by patterns of use of hormones or histologic
subtypes of ovarian cancer. 7,10,11,13-15
The interpretation of studies describing the association
between menopausal hormones and ovarian cancer
is complicated by differences in hormone regimens used
and temporal changes in patterns of use. Before the
description of the association between estrogen use and
endometrial cancer, 16 the majority of menopausal hormone
use in the United States was unopposed estrogen.
17 Therefore, many of the earlier published studies
on menopausal hormones and ovarian cancer were
based primarily on use of unopposed estrogen, and
many did not distinguish between estrogen alone and
estrogen used in combination with progestin or other
0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.ajog.2004.11.013

Moorman et al 77
hormones. Since the late 1970s, physicians have tended
to prescribe lower dose estrogens, and a much larger
proportion of women have used menopausal hormones
consisting of both an estrogen and progestin. 17,18 Given
that the effects of progestins on the ovaries may be very
different from that of estrogens, with some investigators
hypothesizing a protective effect of progestins, 19,20 the use
of combination therapy could have very different effects
on ovarian cancer risk than estrogen alone. However,
relatively few studies have assessed the association
between different hormone regimens and ovarian cancer.
In addition to the possibility that the effect of
menopausal hormones depends on the specific regimen
used, some studies have suggested that the risk may vary
between histologic subtypes of ovarian cancer. Several
studies have reported larger increases in risks for serous
and/or endometrioid than for other subtypes. 13-15
In this report we describe the associations between
menopausal hormone use and ovarian cancer using data
from a population-based, case-control study of ovarian
cancer conducted in North Carolina between 1999 and
2003. The analyses focus on the effects of different
hormone regimens on epithelial ovarian cancer overall,
and on different histologic subtypes of ovarian cancer.
Material and methods
We analyzed data from Phase I of the North Carolina
Ovarian Cancer Study, a population-based case-control
study of newly diagnosed epithelial ovarian cancer cases
in a 48-county area of North Carolina. Cases were
identified using a rapid case ascertainment system
developed by the North Carolina Central Cancer
Registry, a statewide population-based tumor registry.
Pathology reports for all ovarian cancers diagnosed in
the hospitals in the study area were forwarded to the
Central Cancer Registry, and then to the study office
within 2 months of diagnosis. Of the 53 hospitals in the
study area that treat ovarian cancer patients, 52 agreed
to participate in the study. Eligible cases were women
aged 20 to 74 years who were diagnosed with primary
epithelial ovarian cancer between January 1, 1999 and
March 31, 2003, and resided in the 48-county study area.
Both invasive tumors and those with low malignant
potential (borderline tumors) were included. Permission
to contact the ovarian cancer cases was requested from
the physician of record on the pathology report. All
participants were English-speaking, mentally competent
to complete an interview, and able to give informed
consent. All cases underwent standardized pathologic
and histologic review to confirm the diagnosis. Of 883
cases of ovarian cancer identified through the hospitals,
784 were eligible for the study. Reasons for ineligibility
included diagnosis other than epithelial ovarian cancer
(n = 55), date of diagnosis before initiation of study
(n = 11), inability to complete an interview in English
due to language or cognitive issues (n = 16), age greater
than 74 years (n = 12), residence outside of the study
area (n = 4), and institutionalized patient (n = 1). The
overall response rate among eligible cases was 76%,
although 86% of women who were contacted were
successfully recruited into the study. Reasons that cases
were not interviewed included death (4%), debilitating
illness (2%), patient refusal (7%), physician refusal
(3%), and inability to locate the woman (8%). A total
of 594 cases were enrolled in the study.
Controls were identified from the same 48-county
area that generated the cases using random digit dialing
methodology. Controls were frequency matched to cases
by race and age (within 5 years). Race was based on selfreport
by the participant. Health Care Financing and
Administration tapes were initially used to identify
controls aged 65 to 74 years; however, this strategy
was abandoned due to the difficulty in contacting
potential controls because of the absence of telephone
numbers on these tapes. Eligible controls resided in the
same 48-county area as the cases, had no history of
cancer, and had to have at least 1 ovary intact. As was
required for the cases, controls had to be Englishspeaking,
mentally competent to complete an interview,
and able to give informed consent. Seventy-one percent
of controls (n = 628) identified by random digit dialing
who met the eligibility criteria were successfully enrolled
into the study. The study protocol was approved by
institutional review boards at Duke University Medical
Center and all hospitals that participated in the study.
The analyses presented here are restricted to postmenopausal
cases (n = 364) and controls (n = 370). We
included: (1) women who reported their menstrual
periods had stopped naturally; (2) women who reported
they began hormone replacement therapy before their
periods stopped completely; (3) women who had a hysterectomy
without bilateral oophorectomy and were at
least 51 years of age; and (4) women whose periods
stopped due to chemotherapy unrelated to ovarian
cancer. To be eligible for the study, controls were
required to have at least 1 ovary; therefore, none were
postmenopausal due to bilateral oophorectomy. Four of
the cases were postmenopausal due to bilateral oophorectomy
(but still were subsequently diagnosed with
ovarian cancer).
Cases and controls were interviewed in person by
trained nurse interviewers in the home of the study
participant or at another convenient location. A 90-
minute questionnaire was administered to obtain information
on known and suspected risk factors for
ovarian cancer, including family history of cancer in firstand
second-degree relatives, menstrual characteristics,
pregnancy and breastfeeding history, hormone use, and
lifestyle factors such as smoking history, alcohol consumption,
physical activity, and occupational history.

78 Moorman et al
A life-event calendar on which major events in the
woman’s life, such as pregnancies and marriages, were
recorded was used to aid recall. Body mass index (BMI)
was calculated based on measured height and selfreported
weight from 1 year ago (kg/m 2 ). BMI from 1
year ago was used because many cases reported recent
weight changes related to the cancer or its treatment.
In regard to hormone use, women were asked if they
had used PremarinÒ or conjugated estrogens, other estrogen
pills, or estrogen patches. If they responded affirmatively
to use of any of these types of estrogen, they were
asked if they had used progestin along with the estrogen.
The women also were asked about use of progestin alone,
testosterone, or any other hormone pills. For each
hormone used, we obtained the name of the hormone,
ages at first and last use, total duration of use, and dosing
regimen (every day, R21 days/month, or !21 days/
month). We examined the type of hormone used (estrogen
only; progestin only; estrogen always taken with progestin;
estrogen taken sometimes with progestin, sometimes
alone; testosterone with estrogen and/or
progestin), the total duration of use, and the time since
last use.
Statistical analyses
Cases and controls were compared in regard to demographic
characteristics and ovarian cancer risk factors
using t tests for continuous variables and chi-square
tests for categorical variables. Unconditional logistic
regression analyses were used to calculate odds ratios
(ORs) and 95% CIs for the association between
hormone use and ovarian cancer, taking into account
potential confounders. Variables considered as potential
confounders in the multivariable models included age
(continuous), race (black/non-black), parity (continuous),
tubal ligation (yes/no), oral contraceptive use (yes/
no), history of breastfeeding (yes/no), hysterectomy
(yes/no), history of breast or ovarian cancer in a firstdegree
relative (yes/no), BMI 1 year before interview
(continuous), and educational level (less than high
school, high school graduate, or greater than high
school). To test for trend across categories of duration,
we created an ordinal variable by assigning nonusers
a value of 0, users in the shortest duration category
a value of 1, the next highest duration category a value
of 2, etc. We then included this ordinal term in our
logistic regression model, and took the P value corresponding
to this variable as our test of trend. All
analyses were performed using SAS 8.0 (SAS Institute,
Inc, Cary, NC).
Results
Table I presents selected characteristics of the cases and
controls. Although not all differences were statistically
Table I Selected characteristics of cases and controls, the
North Carolina Ovarian Cancer Study
Cases
(n = 364)
Controls
(n = 370)
n (%) n (%) P value*
Age (y)
!40 0 (0) 1 (0) .006
40-49 12 (3) 8 (2)
50-59 145 (40) 116 (31)
60-69 148 (41) 158 (43)
O70 59 (16) 87 (24)
Race
White 312 (86) 308 (83) .56
African American 47 (13) 54 (15)
Other 5 (1) 8 (2)
Type of menopause
Natural 191 (52) 194 (52) .40
Began hormones before 51 (14) 65 (18)
periods stopped
Surgical 119 (33) 110 (30)
Chemotherapy 3 (1) 1 (0)
Months of pregnancy
None 47 (13) 30 (8) .006
!9 13 (4) 8 (2)
9-18 125 (34) 135 (36)
19-36 140 (39) 141 (38)
O36 38 (10) 56 (15)
Missing 1 0
Months of breastfeeding
None 260 (72) 247 (67) .68
!6 37 (10) 48 (13)
6-12 36 (10) 35 (9)
O12 29 (8) 39 (11)
Missing 2 1
Oral contraceptive use (m)
None 158 (43) 175 (47) .22
!12 38 (10) 30 (8)
12-36 62 (17) 66 (18)
O36 96 (26) 92 (25)
Unknown duration of use 10 (3) 7 (2)
Tubal ligation
No 281 (77) 259 (70) .027
Yes 83 (23) 111 (30)
1st degree family history of
ovarian cancer
No 344 (95) 357 (96) .18
Yes 19 (5) 12 (3)
Missing 1 1
Body mass index (kg/m 2 )
Quartile 1 82 (23) 90 (25) .16
Quartile 2 94 (26) 91 (25)
Quartile 3 75 (21) 90 (25)
Quartile 4 104 (29) 91 (25)
Missing 9 8
Education
!High school 36 (10) 62 (17) .062
High school graduate 122 (34) 99 (27)
OHigh school 206 (57) 209 (56)
* P values based on t tests for continuous variables (age, months
of pregnancy, months of breastfeeding, months of oral contraceptive
use, body mass index) and chi-square tests for categorical variables.

Moorman et al 79
Table II Odds ratios for ovarian cancer associated with hormone use
Cases
(n = 364)
Controls
(n = 370)
n n OR* 95% CI OR y 95% CI
Never users 129 152 1.0 (Reference) 1.0 (Reference)
Ever user 235 218 1.2 (0.9-1.6) 1.2 (0.8-1.6)
Duration of use
!12 months 11 14 0.8 (0.4-1.9) 0.8 (0.3-1.9)
12-59 months 68 64 1.1 (0.7-1.6) 1.2 (0.7-1.9)
60-119 months 42 42 1.0 (0.6-1.7) 1.0 (0.6-1.6)
O119 months 96 78 1.5 (1.0-2.2) 1.5 (1.0-2.3)
Missing 18 20
Time since last use
!12 months 147 145 1.1 (0.8-1.5) 1.1 (0.7-1.5)
12-59 months 41 31 1.4 (0.8-2.4) 1.6 (0.9-2.8)
60-119 months 15 7 2.4 (0.9-6.1) 2.6 (1.0-7.0)
O119 months 11 12 1.1 (0.5-2.7) 1.2 (0.5-2.8)
Missing 21 23
* ORs (odds ratios) adjusted for age and race using logistic regression modeling.
y ORs adjusted for age, race, parity, tubal ligation, hysterectomy, BMI 1 year before interview, 1st degree family history of breast or ovarian cancer,
breastfeeding (yes/no), oral contraceptive use (yes/no), and educational level using logistic regression modeling.
Table III Odds ratios for ovarian cancer by hormone regimen used and duration of use
Cases
(n = 364)
Controls
(n = 370)
n n OR* 95% CI OR y 95% CI
Never use 129 152 Referent Referent
Estrogen only
Ever use 105 79 1.2 (0.7-2.0) 1.5 (0.9-2.3)
!12 months 5 6 0.8 (0.2-2.9) 0.9 (0.3-3.2)
12-59 months 23 24 1.0 (0.5-1.8) 1.2 (0.6-2.3)
60-119 months 17 11 1.7 (0.7-3.7) 1.5 (0.6-3.5)
O119 months 52 32 2.1 (1.2-3.4) 2.2 (1.2-4.1)
Missing duration 8 6
Estrogen always with progestin
Ever use 70 87 0.8 (0.6-1.3) 0.9 (0.6-1.4)
!12 months 3 7 0.5 (0.1-1.8) 0.5 (0.1-2.0)
12-59 months 29 31 0.9 (0.5-1.7) 1.0 (0.6-1.9)
60-119 months 14 14 1.0 (0.4-2.2) 1.1 (0.5-2.6)
O119 months 20 28 0.9 (0.5-1.7) 1.0 (0.5-2.0)
Missing duration 4 7
Estrogen and progestin, not always
used together
Ever use 44 38 1.2 (0.7-2.0) 1.3 (0.8-2.2)
!12 months 0 1 - -
12-59 months 9 4 1.8 (0.5-6.3) 2.2 (0.6-7.9)
60-119 months 10 14 0.7 (0.3-1.6) 0.7 (0.3-1.9)
O119 months 22 14 1.9 (0.9-4.0) 2.4 (1.1-5.3)
Missing duration 3 5
Progestin only
Ever use 7 1 6.9 (0.8-57.3) 6.7 (0.8-57.9)
Testosterone
Ever use 9 13 0.7 (0.3-1.6) 0.6 (0.3-1.6)
* ORs (odds ratios) adjusted for age and race using logistic regression modeling.
y ORs adjusted for age, race, parity, tubal ligation, hysterectomy, BMI 1 year before interview, 1st degree family history of breast or ovarian cancer,
breastfeeding (yes/no), oral contraceptive use (yes/no), and educational level using logistic regression modeling.

80 Moorman et al
Table IV Odds ratios* for ovarian cancer associated with hormone use by type of hormone and histologic subtype of ovarian cancer
Controls
Serous Endometrioid or clear cell Mucinous Other
n n OR 95% CI n OR 95% CI n OR 95% CI n OR 95% CI
Never user 152 68 1.0 (reference) 31 1.0 (reference) 13 1.0 (reference) 17 1.0 (reference)
Estrogen only 79 73 2.0 (1.3-3.1) 17 1.0 (0.5-2.0) 6 0.9 (0.3-2.5) 9 1.1 (0.5-2.7)
Estrogen always with 87 48 1.1 (0.7-1.8) 9 0.4 (0.2-0.9) 5 0.4 (0.1-1.3) 8 1.0 (0.4-2.4)
progestin
Estrogen and progestin,
not always used together
38 27 1.4 (0.8-2.5) 8 0.9 (0.4-2.1) 2 0.4 (0.1-2.0) 7 2.0 (0.7-5.4)
* All ORs adjusted for age and race using logistic regression modeling.
significant, the characteristics of the cases and controls
were generally consistent with established risk factors
for ovarian cancer. Cases tended to have fewer months
of pregnancy, were less likely to have had a tubal
ligation, were more likely to have a family history of
ovarian cancer, and had higher educational levels. In
contrast to many studies, we observed little difference in
oral contraceptive use between cases and controls.
When comparing characteristics of hormone users
and nonusers among the control women, we found few
significant differences (data not shown). However, the
trends were consistent with published data, suggesting
that hormone users are more likely to be nulliparous,
have used oral contraceptives, have lower BMI, have
higher educational level, and drink alcohol.
Table II shows the ORs for ovarian cancer associated
with use of any type of menopausal hormones. There
was not a statistically significant relationship between
ever use of menopausal hormones and ovarian cancer.
There was a suggestion of a modestly increased risk for
women who reported long-term use, but no clear
relationship with time since last use. Because we
hypothesized that the effects of hormones on ovarian
cancer could vary by the specific regimen used, we
examined various categories of hormone use separately
(Table III). The OR associated with ever use of estrogen
only was only slightly elevated; however, analyses by
duration of use showed significantly increased ORs with
longer duration of use (P for trend = .03). Ovarian
cancer cases were twice as likely to report 10 years or
more of unopposed estrogen use as the control women.
There was no suggestion of increased risk for women
who had taken estrogen and progestin always in
combination, whether considering ever use or duration
of use. Among women who had taken both estrogen and
progestin but not always at the same time, there was no
clear trend with duration of use. This was a diverse
exposure category in which some of the women took
a progestin for nearly all of the time when they took
estrogen, whereas other women took progestins for
relatively short periods of time and were mostly exposed
to unopposed estrogen. There were no significant
associations with use of progestin alone (which was
taken by only 7 cases and 1 control) or with testosterone
(which was taken by 9 cases and 13 controls and was
always taken in combination with estrogen and/or
progestin).
Table IV shows associations between the hormone
regimens and histologic subtypes of ovarian cancer.
Among users of estrogen only, the elevated risk was
confined to the serous subtype, with no indication of
increased risk in other histologic types. There was not
a strong indication of increased risk within any histologic
subtype among users of estrogen and progestin. It
must be noted that with the exception of the serous
subtype there was a small number of cases within any
given category defined by histology and hormone use.
Therefore, it is difficult to say whether some of the
observed differences in the ORs by histologic type were
true differences or chance variation due to the small
numbers.
Comment
Analyses from this population-based, case-control study
showed no association between ovarian cancer and
menopausal hormone use overall, but suggested that
long-term users of unopposed estrogen may be at increased
risk. Although these findings are consistent with
some studies reporting increased risk for long-term
users, 7,11,21 the overall picture of the relationship between
estrogen use and ovarian cancer is far from consistent,
with a number of studies finding no increased risk for
hormone users. At a biological level, the relationship
between estrogens and ovarian cancer is similarly unclear.
It has been shown that both normal and malignant
ovarian epithelial cells have estrogen receptors; however,
in vitro studies have not consistently found that estradiol
increases proliferation of the ovarian epithelium. 9 Our
findings suggested that any increased risk related to
estrogen use was confined to the serous histologic subtype.
Some investigators have reported a similar increase
in risk for the serous subtype, 7,13,14 but they tended to report
increased risk for endometrioid tumors as well. 7,13-15
We saw no indication of increased risk for endometrioid

Moorman et al 81
or clear cell tumors; however, we had few women with
these histologic subtypes.
Women who reported taking estrogen always with
progestin did not appear to be at increased risk. The
overall lack of association with combination estrogenprogestin
therapy is consistent with the hypothesis that
progestin protects against ovarian cancer. 19,20 The wellestablished
protective effects of pregnancy or oral
contraceptive use are beyond what can be explained
simply through suppression of ovulation, and it has
been suggested that high progesterone levels during
pregnancy and the progestin component of oral contraceptives
contribute significantly to reducing ovarian
cancer risk. 19,22 A possible mechanism for the protective
effect of progestins was demonstrated in an in vivo study
that showed that the progestin component of oral
contraceptives has a potent apoptotic effect on the
ovarian epithelium. 20 It must be noted, however, that
the lack of association between ovarian cancer and
estrogen-progestin therapy that we observed contrasts
with recently published findings from the Women’s
Health Initiative randomized clinical trial in which there
was a suggestion of increased risk associated with
estrogen plus progestin use (hazard ratio 1.58; 95% CI
0.77–3.24) based on a total of 32 cases of invasive
ovarian cancer. 12
The overall findings from the Women’s Health
Initiative, in which the risks for coronary heart disease,
stroke, pulmonary embolism, and breast cancer were all
statistically significantly elevated among estrogen plus
progestin users, 23 have resulted in changes in recommendations
for use of menopausal hormones. Given the
observed lack of benefit for cardiovascular conditions,
there is no longer a strong justification for long-term use
of menopausal hormones for prevention of chronic
diseases, and many women discontinued them after
publication of the Women’s Health Initiative findings.
Current recommendations for use of estrogen and/or
progestin limited to short-term treatment of menopausal
symptoms with the lowest effective dose 24 would not be
expected to have an important effect on ovarian cancer
risk based on our findings and the findings of most other
studies, in which any increased risk of ovarian cancer
seemed to be most pronounced among long-term users.
An important strength of this study was that we were
able to examine different hormone regimens in relation
to ovarian cancer risk. However, our analyses were
somewhat limited by the number of women who had
taken any specific regimen, which prevented us from
more thoroughly considering issues of latency, recency,
and duration of use with any given hormone regimen.
Another limitation was in our ability to do race-specific
analyses. Although our study population was closer to
the US population in terms of representation of African
Americans (approximately 14%) than many other
studies that have addressed this question, the number
of African Americans was still too low to do meaningful
analyses.
Although it would be expected that in the future there
should be relatively few women who would have exposure
to the patterns of menopausal hormone use that would
likely increase their risk for ovarian cancer, clinicians
should be aware of the past histories of hormone use
among their patients. Based on data suggesting both
a latency effect of 10 or more years and a persistence of
effect such that users continue to be at increased risk for
some years after stopping hormones, 25 it is important that
women and their physicians be alert to possible risks for
cancer among long-term users of menopausal hormones,
particularly among women who used unopposed estrogens.
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