Reproductive Factors, Hormone Use, and Risk for Lung
Cancer in Postmenopausal Women, the Nurses' Health Study
Christina S. Baik1, Gary M. Strauss1, Frank E. Speizer2,3, and Diane Feskanich2
Background: There is increasing evidence suggesting that female hormones may play a significant role in
lung cancer development. We evaluated the associations between reproductive factors, exogenous hormone
use, and lung cancer incidence in the Nurses' Health Study.
Methods: We assessed age at menopause, age at menarche, type of menopause, parity, age at first birth,
postmenopausal hormone (PMH) use, and past oral contraceptive use in 107,171 postmenopausal women. Cox
models were used to estimate the hazard ratios for each exposure, adjusting for smoking and other covariates.
Results: We identified 1,729 lung cancer cases during follow-up from 1984 to 2006. Menopause onset before
44 years of age (hazard ratio, 1.39; 95% confidence interval, 1.14-1.70) and past oral contraceptive use for >5
years (hazard ratio, 1.22; 95% confidence interval, 1.05-1.42) were associated with increased lung cancer risk.
These associations were strongest in current smokers and small cell histology. In never smokers, increased
parity was associated with decreased risk among parous women (P trend = 0.03), whereas in current smokers,
older age at first birth was associated with increased risk (P trend = 0.02). PMH use was not associated with
overall lung cancer incidence. However, nonsignificant results of increased risk in adenocarcinoma were seen
with current PMH use.
Conclusions: Our findings suggest female hormones may influence lung carcinogenesis, although the effect
is likely modest, varied by histologic subtype, and altered by smoking.
Impact: Further investigation of the pathophysiology of female hormones in lung cancer subtypes and their
interaction with smoking will lead to better understanding of lung carcinogenesis. Cancer Epidemiol Biomarkers
Prev; 19(10); 2525–33. ©2010 AACR.
Lung cancer is the leading cause of cancer mortality in
U.S. women. The American Cancer Society estimates that
70,490 women will die of lung cancer in 2009, which ex-
ceeds combined breast and colorectal cancer mortality in
women (1). There is increasing evidence that lung cancers
in women are biologically distinct from those of men,
with the observation that they exhibit different distribu-
tion of histologic subtypes and molecular characteristics.
Women are more likely to develop adenocarcinoma com-
pared with men, especially among never smokers (2, 3).
In comparison with men, women with lung cancer are
also more likely to be lifelong nonsmokers (4). Moreover,
adenocarcinoma in women are more likely to harbor epi-
dermal growth factor receptor mutations (5, 6) and thus
more likely to respond to epidermal growth factor recep-
tor tyrosine kinase inhibitors (7-9).
These gender differences raise the question of whether
female hormones could play a role in lung carcinogene-
sis. In fact, estrogen-β and progesterone receptors have
been found on lung cancer cells (10, 11), and in a preclin-
ical study by Stabile et al. (10, 12), a significant increase in
cellular proliferation was seen in lung cancer-derived cell
lines when they were incubated with β-estradiol, and this
was inhibited by antiestrogens. Similar results have been
seen in lung adenocarcinomamouse models in whichovari-
ectomized mice treated with estradiol developed higher tu-
These findings suggest that a woman's reproductive
history and exogenous hormone use could affect her risk
for developing lung cancer. Several epidemiologic stud-
ies have investigated the association between postmeno-
pausal hormone (PMH) use and lung cancer incidence.
However, results have been conflicting. Although several
studies reported decreased risk with hormone replace-
ment therapy (14-18), others reported no effect (19-22) and
a few others reported a trend toward increased risk (23-25).
Many have also investigated the effect of reproductive
Authors' Affiliations:1Division of Hematology-Oncology, Tufts Medical
Center;2Channing Laboratory, Department of Medicine, Brigham and
Women's Hospital and Harvard Medical School;3Department of
Environmental Health, Harvard School of Public Health, Boston,
Note: Presented in part at the American Society of Clinical Oncology
Annual Meeting, 2009, Orlando, Florida.
Corresponding Author: Christina S. Baik, Fred Hutchinson Cancer
Research Center, 1100 Fairview Avenue N/M3-A410, P.O. Box 19024,
Seattle, WA 98109. Phone: 857-998-2861 and 206-667-2975; Fax: 206-
667-4142. E-mail: email@example.com and firstname.lastname@example.org
©2010 American Association for Cancer Research.
factors,but these resultshavebeeninconsistent(16, 19,20,
22-29). Most of these studies were retrospective in design,
and varying adjustment for covariates may have con-
tributed to the inconsistent results. Thus, our aim was to
conduct a prospective and comprehensive analysis of re-
to lung cancer incidence in the Nurses' Health Study
(NHS).We furtherevaluated these associations separately
by smoking status and histologic subtypes.
Materials and Methods
The NHS was established in 1976 with 121,700 female
U.S. nurses of ages between 30 and 55 years who re-
sponded to the initial mailed questionnaire. The women
were asked questions about their medical history and
lifestyle, which included detailed reproductive and hor-
mone use information, as well as smoking history. Follow
up questionnaires have been sent every 2 years to update
information about exposure status and to identify newly
diagnosed medical conditions, and the response rate has
been at least 90% for each cycle.
We have previously shown that fruit and vegetable
consumption was associated with lower risk for lung
cancer among women (30). Thus, we used 1984 as the
baseline year because this was the first cycle in which diet
assessment with extensive questions on fruits and vegeta-
bles was available. At baseline, we included women who
werepostmenopausal and had notreportedadiagnosis of
cancer (except nonmelanoma skin cancers) and women
entered analysis during follow-up when they reached
menopause. Women were classified as postmenopausal
at the age when natural menopause or bilateral oophorec-
tomy occurred. For women whose periods stopped after a
hysterectomy or unilateral oophorectomy, we classified
them as postmenopausal at the age of 54 years if a current
which90% ofNHSparticipants with anatural menopause
had become postmenopausal.
pital Institutional Review Board in Boston, Massachusetts.
This investigation was also approved by Tufts University
Institutional Review Board in Boston, Massachusetts.
Lung cancers were reported by the participants or
identified on their death certificates, and they were sub-
sequently confirmed by hospital records and pathology
reports. The cases were classified as confirmed only if a
pathology report indicated that the lesion was a primary
lung tumor. The confirmed lung cancer cases were then
classified by predominant histologic subtype. Of the self-
reported cases, 88% were confirmed with medical re-
cords, and an additional 6% were confirmed by death
certificates. All self-reported lung cancers were included
in the primary analyses because results were very similar
when limited to cases confirmed by medical records.
Analyses by histologic subtype included only those
confirmed by medical record review.
During the 22-year follow up, 1,729 incident lung
cancer cases were identified. Of the 1,505 cases for which
histology information was available, 47% were adenocar-
cinoma, 18% were small cell carcinoma, 17% were squa-
mous cell carcinoma, 5% were large cell carcinoma, 10%
were unspecified non–small cell lung cancer, and 3%
were other histologies, including carcinoid and sarcoma.
The histology distribution is comparable with the Sur-
veillance Epidemiology and End Results data reported
for female lung cancer (31).
There were 8% never smokers, 45% former smokers
and 47% current smokers among the cases as determined
by their smoking status on the biennial questionnaire be-
fore lung cancer diagnosis. Of the 138 cases among never
smokers, adenocarcinoma was the predominant histol-
ogic subtype in 81 cases (62%), and there were no cases
with small cell histology.
Reproductive and hormonal exposures
The exposure variables assessed in this analysis were
age at menarche, age at menopause, type of menopause,
parity, age at first birth, oral contraceptive (OCP), use
and PMH use.
Age at menarche was reported on the initial 1976 ques-
tionnaire, and number of pregnancies lasting >6 months
was assessed from 1976 through the 1984 questionnaire
and reconfirmed in 1996. In each biennial questionnaire,
women were asked whether their menstrual periods had
stopped, age at which they stopped, and whether the rea-
son was natural or surgical. PMH and OCP use were first
assessed on the initial 1976 questionnaire and were up-
dated in each biennial questionnaire, which asked details
about current or past use, duration of use, and type of
hormones used. At each 2-year follow up cycle, we calcu-
lated total duration of use and time since last use. We
stopped collecting additional OCP information in 1984
when <1% of the premenopausal women were currently
using the medication. Missing information about expo-
sure variables was included as a separate category.
Smoking exposure and other covariates
Participants were asked on the initial questionnaire
whether they were current or former smokers and, if
so, their age at initiation. Former smokers were asked
the age at which they discontinued smoking, and current
smokers were asked to report their average number of
cigarettes smoked per day. Participants with missing
smoking status were excluded at baseline. Smoking sta-
tus and quantity of cigarettes have been updated every 2
years. In 1982, participants were asked for information
about environmental tobacco exposure, including wheth-
er one or both parents smoked, number of years living
with someone who smoked, and whether exposed to
smoke at work and/or at home. Other covariates includ-
ed body mass index (BMI), calculated each questionnaire
cycle from current weight and from height reported at
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Reproductive Factors and Lung Cancer
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