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Cigarette smoking and the risk of endometrial cancer
Review
Smoking and endometrial cancer
Cigarette smoking and the risk of endometrial cancer Paul D Terry, Thomas E Rohan, Silvia Franceschi, and Elisabete Weiderpass
Epidemiological studies have shown that cigarette smoking is associated with a reduced risk of endometrial cancer, in contrast to the increased risks observed with many other non-respiratory-tract cancers, including those of the bladder, pancreas, and cervix uteri. Some studies of endometrial cancer suggest that the inverse association with smoking is limited to certain groups of women, such as those who are postmenopausal or those taking hormone-replacement therapy. The biological mechanisms that might underlie this association remain unclear, although several have been proposed, including an antioestrogenic effect of cigarette smoking on circulating oestrogen concentrations, a reduction in relative bodyweight, and an earlier age at menopause. We have examined the evidence for an association between cigarette smoking and risk of endometrial cancer, including studies related to the proposed biological mechanisms.
Figure 1. In this example of an endometrial carcinoma, the tumour forms an exophytic mass that fills the endometrial cavity.
Lancet Oncol 2002; 3: 470–80
Endometrial adenocarcinoma accounts for roughly one of every ten cancers diagnosed among women worldwide, and it is the most commonly diagnosed cancer of the female genital tract in the more developed countries (figure 1).1 Exogenous oestrogens unopposed by progesterone have been hypothesised to increase the risk of this cancer through increased mitotic activity of endometrial cells, increased number of DNA replication errors, and somatic mutations resulting in the malignant phenotype.2 The use of exogenous oestrogens, and of oestrogen-replacement therapy in particular, has been strongly related to increased risk in epidemiological studies and has also been linked to trends in endometrial-cancer incidence in more developed countries.3 Other factors associated with increased risk include obesity, ovarian dysfunction, and nulliparity, which are thought to act through increased circulating concentrations of unopposed oestrogens.2 The vast majority of endometrial cancers are adenocarcinomas (figure 2). Since oestrogens have a role in endometrial adenocarcinoma,2 factors associated with low concentrations of circulating oestrogens may reduce the risk of this malignant disorder. In this regard, a hypothesis has been put forward that smoking might exert antioestrogenic effects—through reduced relative bodyweight, lowered age at menopause,4 or differences in metabolism of oestrogens between smokers and non-smokers—and through this mechanism might reduce the risk of endometrial cancer. Support for this hypothesis comes from studies showing that smoking is associated with increased risk of osteoporosis,5–8
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an oestrogen-deficient condition, and that it may attenuate the decrease in serum-total and LDL cholesterol associated with hormone-replacement therapy (HRT). In view of the importance of understanding endometrial-cancer aetiology, epidemiological studies have continued to address the association with cigarette smoking, both directly in studies of the association between smoking and risk of the cancer and indirectly through studies of the possible association between smoking and oestrogen concentrations and metabolism. Our aim was to review the available evidence on cigarette smoking and endometrial-cancer risk. We began by examining studies that used qualitative measures of smoking (never, ever, former, and current), studies that used quantitative measures of smoking related to intensity and duration (cigarettes smoked per day, years of smoking, and pack-years), and studies that stratified their results according to potentially important effect-modifying variables (primarily menopausal status, use of HRT, and relative bodyweight). In light of what may be important PDT and TER are cancer epidemiologists in the Department of Epidemiology and Social Medicine at the Albert Einstein College of Medicine, Bronx, NY, USA; TER is chairman of the department. SF and EWV are epidemiologists and medical officers in the Unit of Field and Intervention Studies at the International Agency for Research on Cancer (IARC), Lyon, France; SF is head of the unit. Correspondence: Dr Paul Terry, Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 13th Floor, Bronx, NY 10461, USA. Tel: +1 718 430 3038. Fax: +1 718 430 8653. Email: [email protected]
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Smoking and endometrial cancer
recall bias and are less susceptible to selection bias, but very few prospective cohort studies have provided information on smoking. Current, former, ever, and never smokers
Qualitative measures of smoking, such as ever or never, or current or former, have been used in most previous studies of endometrial-cancer risk. However, such measures are difficult to interpret. For example, current smoking may reflect a more intense exposure of much longer duration in one study population than in another. There is even greater ambiguity inherent in the measure “ever smoked”, since the timing of the exposure to Figure 2. This medium-power photomicrograph shows an endometrial carcinoma that is composed of closely packed, well-formed glands. cigarette smoke and its extent are not clear. Therefore, the results of studies underlying mechanisms, we then reviewed studies that that used qualitative smoking measures should be viewed in examined the associations between smoking and light of these limitations. concentrations of hormones in the blood and urine, including oestrogens (particularly oestrone, oestradiol, and Cohort studies oestriol) and androgens (particularly androstenedione and To date, there have been three prospective cohort dehydroepiandrosterone). We also reviewed studies that studies13,28,33 of the association between cigarette smoking examined the association between cigarette smoking and and endometrial-cancer risk (table 1). With qualitative sex-hormone-binding globulin (SHBG)—concentrations of smoking measures, these studies do not clearly support an which can influence oestrogen activity. Finally, we reviewed inverse association between smoking and risk of studies that examined the association between cigarette endometrial cancer. The results of two of these studies13,28 smoking and age at menopause, which itself is positively were based on small numbers of cases (36 and 12 cases among current smokers) and the confidence intervals were related to endogenous oestrogen exposure. wide.
Cigarette smoking and endometrial-cancer risk To date, at least 26 epidemiological studies have examined this association.9–34 The studies fall into two major categories—case-control and prospective cohort studies. Most of those published to date have used the case-control design; some were hospital based and some were population based. To ensure that the selection of controls is independent of the exposure of interest is particularly difficult in a hospital setting, where many disorders (or hospital admission for those disorders) may be related to smoking. Population-based case-control studies are not subject to this problem, but participation rates among controls are generally lower than in hospital-based studies. Wide differences in participation rates with respect to exposure (most notably a lower participation rate among smoking women who are eligible to participate) could spuriously drive a study’s results towards or away from a null association; a lower rate of participation among potential controls who are cigarette smokers would tend to mask a true inverse association. Furthermore, both types of case-control studies are vulnerable to recall bias, such as would occur if case women systematically recalled more exposure to cigarettes than control women did (which would also tend to mask a true inverse association). Prospective cohort studies, by contrast, are not vulnerable to THE LANCET Oncology Vol 3 August 2002
Population-based case-control studies
The results of 12 population-based case-control studies,11,12,14,15,22–26,29,30,34 which included between 46 and 740 cases of endometrial cancer, have been fairly consistent in showing no association with risk among former smokers compared with never smokers and slightly to moderately lower risks among current smokers than never smokers (table 1). Nine studies also, or exclusively, examined former and current smokers combined (ie, ever smokers) and mostly showed small, non-significant reductions in risk compared with never smokers. Hospital-based case-control studies
The six hospital-based case-control studies9,16,17,20,21,27 included between 83 and 1374 cases of endometrial cancer and examined qualitative measures of cigarette smoking (table 1). In these studies, former smokers generally had a slightly, not statistically significant, lower risk than never smokers (on average about 10–20% lower); but the reduced risk among current (ie, active smokers at assessment) compared with never smokers was more pronounced, on average about 30–40% lower. The largest of the hospital-based studies,27 with 1374 cases and 3921 controls, found that both former and current smokers were
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Smoking and endometrial cancer
Table 1. Epidemiological studies of cigarette smoking and endometrial-cancer risk in current, former, and never smokers Reference
Number of cases/controls (or number in cohort)
Age range at recruitment (years)
13
140/26 000
28
123/11 659
33
403/70 591
Odds ratio (95% CI) for smoking category Ever vs never
Variables adjusted for*
Former vs never
Current vs never
32–72
1·2 (0·6–2·2)
1·1 (0·7–1·6)
Not specified
42–82
0·7 (0·3–2·0)
0·9 (no CI)†
Age, weight, parity
40–59
1·0 (0·8–1·3)
0·8 (0·6–1·1)
Age, BMI, HRT, parity
1·1 (0·7–1·6)
0·4 (0·2–0·7)
Age, weight, HRT, parity, diabetes, age at menopause
1·4 (0·6–3·5)
0·2 (0·1–0·6)
Age, BMI, HRT, parity, diabetes
Prospective cohort
Population case-control 11
405/297
20–74
0·8 (0·5–1·1)
12
46/138
14
79/416
20–55
0·5 (0·3–0·8)
Age, BMI, HRT, parity, diabetes, age at menopause
15
332/511
18–84
0·8 (0·6–1·2)
Age, BMI, HRT, parity, diabetes
22
220/223
30–79
1·0 (0·8–1·3)
None
23
236/639
40–85
0·6 (0·4–0·8)
24
740/2372
40–79
0·8 (0·7–0·9)
25
196/986
20–54
34
553/752
45–64
26
70/612
20–54
0·8 (0·4–1·5)
29
437/3200
20–54
0·9 (0·7–1·1)
30
709/3368
Age 0·8 (0·7–1·0)
0·8 (0·6–1·0)
Age, BMI, HRT, parity, diabetes
0·8 (0·5–1·2)
0·7 (0·5–1·0)
Age, BMI, treatment for diabetes
0·8 (0·6–1·2)‡
0·6 (0·4–0·8)‡
Age, BMI Age, BMI, HRT, parity, age at menopause
1·0 (0·7–1·4)
0·8 (0·7–1·1)
Age, weight, HRT, age at menopause
50–74
0·9 (0·7–1·1)
0·6 (0·5–0·8)
Age, BMI, HRT, parity, diabetes, age at menopause
0·8 (0·5–1·5)
0·7 (0·4–1·2)
Age, BMI, HRT, parity, diabetes
Hospital case-control 9
168/334
40–82
16§
167/903
45–74
17
83/164
40–79
20
510/727
18–69
21
357/1122
31–74
27
1374/3921
0·8 (no CI)
Age, HRT, age at menopause 0·5 (0·2–1·3)¶
Age, height, weight, HRT, parity, age at menopause
0·9 (0·6–1·2)
0·8 (no CI)†
Age, BMI, HRT, age at menopause, parity, diabetes
0·9 (0·5–1·5)
0·5 (0·3 – 0·7)
Age, BMI, HRT, parity, age at menopause
0·6 (0·5–0·8)
0·7 (no CI)†
Age
*Covariates considered here were age, BMI, HRT, age at menopause, parity, and diabetes; †Crude measures of association were calculated from the data provided. ‡Results shown are for women not taking unopposed oestrogens. Among oestrogen users, smokers were also at higher risk than non-smokers. §Results reported in reference 5 ¶Former smokers were combined with never smokers in this analysis. BMI, body-mass index; HRT, hormone replacement therapy.
at moderately (about 30%) lower risk of endometrial cancer. Although most of these studies adjusted their estimates of relative risk for potentially confounding variables such as body–mass index, use of HRT, parity, diabetes, and age at menopause (table 1), those that did not, tended to show similar inverse associations. Within individual studies, statistical adjustment for the effects of body–mass index and other covariates made little difference, although some attenuation of relative-risk estimates has been noted.30,33
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Quantitative measures of smoking
Quantitative measures of smoking include frequency (cigarettes per day), duration (years smoked), the product of smoking frequency and duration (pack-years), latency (years since smoking started), and recency (years since smoking ceased). The examination of these measures is important, since potentially adverse effects of the many carcinogens in tobacco smoke have been observed in some studies. If a dose-response association with cigarette smoking could be shown with increasing values of a particular smoking
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Smoking and endometrial cancer
measure, the role of smoking in prevention of endometrial cancer could be established more firmly. Cohort studies
Two28,33 of the three13,28,33 prospective cohort studies mentioned in the previous section examined quantitative smoking measures in relation to endometrial-cancer risk, the results of these investigations are consistent with the inverse associations with current smoking (but not former smoking) observed in the case-control studies (table 2). One of these two studies28 found a 50% lower risk among current smokers in the highest intensity category (11 cigarettes per day or more) than in non-smokers, but the number of cases
was low and the confidence intervals were correspondingly wide. The more recent and larger of the two cohort studies33 found a significant 40% lower risk among current smokers who smoke more than 20 cigarettes per day, but somewhat weaker and non-significant reductions in risk with smoking of long duration or high number of pack-years. By contrast, the risk among former smokers was similar to that among never smokers. Population-based case-control studies
To date, six population-based case-control studies11,18,19,24,29,30 have examined quantitative measures of smoking in relation to endometrial-cancer risk, with most showing the strongest
Table 2. Epidemiological studies of cigarette smoking and endometrial-cancer risk in terms of smoking frequency, duration, and pack-years Reference
Number of Age range cases/controls (years) (or number in cohort)
Comparison odds ratio (95% CI) Smoking intensity Smoking duration (cigarettes per day) (years)
Pack-years (packs per day x years)
Prospective cohort 28
123/11 659
42–82
Current ⭓11 vs never 0·5 (0·1–2·0)
33
403/70 591
40–59
Former >20 vs never 0·9 (0·6–1·3)
Former >20 vs never 1·1 (0·8–1·6)
Former >20 vs never 1·0 (0·7–1·5)
Current >20 vs never 0·6 (0·4–0·9)*
Current >20 vs never 0·8 (0·6–1·1)
Current >20 vs never 0·7 (0·5–1·1)
Ever ⭓30 vs never 0·7 (0·4–1·4)
Ever ⭓40 vs never 0·5 (0·3–0·9)*
Former ⭓30 vs never 1·4 (no CI)
Former ⭓40 vs never 0·5 (no CI)
Current ⭓30 vs never 0·3 (no CI)
Current ⭓40 vs never 0·5 (no CI)
Population case-control 11
18
405/297
301/289
20–74
40–69
Former >20 vs never 0·6 (no CI) Current >20 vs never 0·5 (no CI)
19
84/168
40–69
Former >20 vs never 1·0 (no CI) Current >20 vs never 1·0 (no CI)
24
740/2372
40–79
Ever ⭓80 vs never 0·9 (0·5–1·4)
29
437/3200
20–54
Ever ⭓15 vs never 1·0 (0·7–1·2)
30
709/3368
50–74
Maximum ⭓20 vs never 0·7 (0·4–1·3)
Lifelong ⭓45 vs never 0·6 (0·3–0·9)
Hospital case-control Ever ⭓15 vs never 0·6 (0·4–0·9)*
10
476/2128
40–89
17
83/164
40–79
20
510/727
18–69
Current ⭓25 vs never 0·5 (0·3–0·8)
21
357/1122
31–74
Current ⭓15 vs never 0·4 (0·2–0·9)*
27
1374/3921
32
358/3189
⭓20 (continuous variable) 0·5 (0·3–0·9)*
Current >40 vs never 0·5 (0·3–0·9) 25–76
Ever ⭓40 vs never 0·7 (NS)
*Statistically significant. NS, not significant.
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Smoking and endometrial cancer
inverse associations among current smokers of high intensity or long duration (table 2). However, one population-based study of late-stage endometrial cancer19 did not show an association with any measure of smoking (although the number of cases in that study was small); in another small study,18 the same investigators found that smoking more than 20 cigarettes per day was associated with a lower risk of early-stage endometrial cancer among both current and former smokers.
In many of these studies, the number of cases in the highest smoking category was small. The issue of statistical imprecision, along with the likely correlations between smoking measures and the scarcity of studies that examined more than one smoking measure, make comparisons among the various studies difficult. Overall, however, the findings of epidemiological studies of smoking and endometrial cancer support an inverse association among current smokers, especially those who reported smoking of high intensity or long duration.
Hospital-based case-control studies
Six hospital-based case-control studies of endometrial cancer that examined quantitative measures of smoking mostly showed significant 30–60% lower risks with current or recent smoking of high intensity,20,21,27 with smoking of long duration,17 or with a high number of pack-years (table 2).10,32 However, the intercorrelation between the various smoking measures complicates the differentiation of their independent effects. For example, smokers of high intensity also tend to be smokers of long duration,33 and the latter also tend to have started smoking at an early age. Although studies to date have generally shown that high levels of smoking are associated with a reduced risk of endometrial cancer, the results have not been as consistent about which of the quantitative smoking measures is the most important. For example, two population-based casecontrol studies11,30 found a greater reduction in risk with smoking of long duration than with smoking of high intensity, whereas a large prospective cohort study33 found a greater reduction in risk with smoking of high intensity. Few of the studies examined more than one quantitative smoking measure. In addition, two studies11,33 found non-significantly reduced endometrial-cancer risk with smoking commencement at an early age. As mentioned above, this smoking measure is correlated with smoking duration.
Effect modification
Several studies have examined the association between smoking and endometrial-cancer risk according to factors that are known determinants of endogenous hormone concentrations, and which may counteract or augment possible tobacco-related hormonal changes. These factors include menopausal status, use of HRT, and relative bodyweight. Effect modification can reflect true underlying differences in the association, for example, if cigarette smoking acts to decrease or modify oestrogen concentrations differently in two groups. Effect modification can also reflect methodological factors, such as differences that occur by chance or through the varying frequency of confounding variables. However, similarities in the relative risks may still reflect important differences in the absolute number of cases associated with smoking if the baseline risk in the two groups differs. For example, a 30% lower risk among HRT users would affect a greater number of women than the same proportional reduction among women not taking HRT, since the baseline risk is higher among HRT users.2 This factor is important to bear in mind in comparison of relative measures of association over strata defined by factors that are themselves associated with risk.
Table 3. Epidemiological studies of cigarette smoking and endometrial-cancer risk according to menopausal status Reference
Number of cases/controls (or number in cohort)
Smoking comparison
Odds ratio (95% CI) Premenopausal
Postmenopausal
403/70 591
Current >20 /day vs never
0·7 (0·4–1·3)
0·6 (0·3–1·1)
Prospective cohort 33 Population case-control 11
405/297
Former vs never
3·0 (1·2–7·4)
0·8 (0·4–1·2)
Current vs never
0·5 (0·1–1·7)
0·4 (0·2–0·7)
Ever ⭓30 years vs never
6·2 (0·9–42·3)
0·6 (0·4–1·0)†
Ever ⭓30 /day vs never
1·3 (0·2–7·1)
0·6 (0·3–1·3)†
14
79/416
Ever vs never
18
301/289
Current vs never
0·6 (no CI)
0·5 (0·3–0·8) 0·6 (no CI)
26
70/612
Ever vs never
1·3 (0·7–2·5)
0·4 (0·2–1·0)
30
709/3368
Current (highest duration category)
0·9 (0·4–2·0)
0·4 (0·2–0·8)
17
83/164
Current vs former and non-smokers
2·3 (no CI)
0·2 (no CI)
20
510/727
Current ⭓25 vs never
0·9 (0·4–2·2)
0·5 (0·2–0·9)
Hospital case-control
21
357/1122
Current vs never
0·5 (0·2–0·9)
0·4 (0·3–0·7)
27*
1374/3921
Current >40 vs never
1·9 (0·5–7·8)
0·4 (0·2–0·8)
*In this study the stratification categories were <50 vs ⭓50 years; †Statistically significant.
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Table 4. Epidemiological studies of cigarette smoking and endometrial-cancer risk according to HRT use Reference
Number of cases/controls (or number in cohort)
Smoking comparison
Odds ratio (95% CI) No HRT
HRT
403/70 591
Current >20 /day vs never
0·6 (0·4–1·0)*
0·6 (0·3–1·3)
14 18
79/416
Ever vs never
0·5 (0·3–0·9)
0·3 (0·1–0·8)
301/289
Current vs never
0·6 (no CI)
31
0·6 (no CI)
322/289
Ever vs never
0·4 (0·2–0·7)
357/1122
Current vs never
0·5 (0·3–0·7)
Prospective cohort 33 Population case-control
Hospital case-control 21
0·2 (0·1–0·7)
*Statistically significant. HRT, hormone replacement therapy.
Menopausal status
Menopausal status can be viewed as a proxy for age and ovarian function. Although endometrial cancer is rare among premenopausal women, several studies have examined the association between cigarette smoking and risk of endometrial cancer according to menopausal status, including one prospective cohort study,33 five populationbased case-control studies,11,14,18,26,30 and four hospital-based case-control studies17,20,21,27 (table 3). In all but one of these studies, a study of early-stage endometrial cancer,18 the inverse association was stronger among postmenopausal than premenopausal women. Among premenopausal women, the relative-risk estimates for cigarette smoking have been inconsistent, some showing increased risks with certain measures of cigarette smoking,11,17,26,27 some showing decreased risks,11,18,21,33 and some showing practically no association.20,30 In analyses limited to postmenopausal women, by contrast, all showed between 20% and 80% reduced risks of endometrial cancer with the various smoking measures. HRT
The possibility that cigarette smoking lowers blood hormone concentrations mostly among women who are taking HRT7,8,35 leads to the idea that an inverse association between smoking and endometrial-cancer risk would be stronger among HRT users than among non-users. However, the results of studies that have examined the association according to HRT use14,18,21,31,33 are equivocal in showing such a pattern (table 4). Two studies14,21 observed a larger reduction in risk among smokers taking HRT than among smokers not taking HRT; two other studies18,33 found no difference in the association according to HRT status, including a large prospective cohort study.33 Thus, although effect modification by HRT status is biologically plausible, the available epidemiological evidence is equivocal. Relative bodyweight
Obesity is an established risk factor for endometrial cancer.36 Smokers tend to have lower body–mass indices than nonsmokers (although former smokers tend to have a higher relative bodyweight than current or never smokers).6 Two studies have examined the association between cigarette smoking and endometrial-cancer risk according to measures THE LANCET Oncology Vol 3 August 2002
of relative bodyweight, such as body–mass index.12,21 Neither a hospital-based21 nor a population-based12 case-control study found any clear differences in the association according to relative bodyweight. Another study,18 a population-based case-control study of early-stage endometrial cancer, observed that the inverse association with cigarette smoking became stronger with increasing absolute, rather than relative, bodyweight.
Studies of cigarette smoking and blood hormone concentrations Whether mediated through changes in the amount of adipose tissue, altered age at menopause, or antioestrogenic effects, blood hormone concentrations might be an important link between smoking and the reduced risk of endometrial cancer observed in most of the studies discussed above. The oestrogens that have typically been studied include oestrone, SHBG-bound oestradiol, and oestriol. Blood concentrations of androgens, mostly androstenedione and dehydroepiandrosterone, have also been studied, since these are biological precursors of oestrone. Studies that have examined blood concentrations of SHBG are less common, and studies of unbound (free) oestradiol are scarce. Smoking and blood oestrogen concentrations
Studies of cigarette smoking and blood hormone concentrations have been undertaken mostly among postmenopausal women who were not taking HRT (table 5).4,7–9,35,37–47 Of these studies, nine examined serum or plasma oestrone, ten serum or plasma oestradiol, and two serum or plasma free oestradiol. These studies have been very consistent in showing little or no association between smoking and blood oestrogen concentrations among postmenopausal women who were not taking HRT. Among premenopausal women, three studies44–46 found no clear association between cigarette smoking and oestrogen concentrations. Studies that adjusted hormone measurements for the effects of relative bodyweight (and other covariates) showed similar results to those that did not, suggesting that relative bodyweight is not a strong confounding variable in this association. Two studies examined the association between cigarette smoking and blood oestrogen concentrations after randomisation of women to groups receiving either oestradiol
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Table 5. Studies of cigarette smoking and blood hormone concentrations Reference
Study population and non-smokers
Sex hormones examined
Major differences in blood hormone concentrations between smokers and non-smokers
Additional adjustment for BMI
39
209 postmenopausal women not taking HRT
Serum E1, E2, ∆4A
None
Yes
46
694 premenopausal women with BMI <25 kg/m2 Plasma E1, E2
None
No
35
25 postmenopausal women randomised to 1 mg or 2 mg micronised E2
Serum E1, E2, unbound E2, Unbound E2 lower and SHBGSHBG binding capacity higher in smokers
37
38 postmenopausal women not taking HRT
Serum E1, E2, SHBG, non-SHBG-bound E2, ∆4A, DHEAS
∆4A and DHEAS higher in smokers
Yes
38
143 postmenopausal women not taking HRT
Serum E1, E2, ∆4A
∆4A higher in smokers
Yes
39
25 postmenopausal women not taking HRT
Serum E1, E2, ∆ A, DHEAS
∆4A and DHEAS higher in smokers
Yes
8
136 postmenopausal women randomised to 4 mg, 2 mg, or 1 mg E2 or placebo
Serum E1, E2
E1 and E2 lower in smokers
Randomisation
7
110 postmenopausal women randomised to oral or percutaneous E2 or placebo
Serum E1, E2
E1 and E2 lower in smokers after oral E2
Randomisation
45
147 premenopausal and postmenopausal women not taking HRT
Serum E2, DHEAS
None
Yes
43
233 postmenopausal women not taking HRT
Plasma DHEAS, ∆4A, E1, E2, SHBG
∆4A and DHEAS higher in
Yes
4
Randomisation
smokers
47
253 postmenopausal women not taking HRT
Serum SHBG
None
Yes
41
1219 premenopausal and postmenopausal women not taking HRT
Serum E1, E2, ∆4A, DHEAS, SHBG
None
Yes
44
88 premenopausal and postmenopausal women not taking HRT
Plasma ∆4A, E1, E2, free E2, SHBG
∆4A higher in smokers
Yes
4
27 premenopausal women not taking HRT, BMI <25 kg/m2
2-hydroxylation of injected radiolabelled E2
2-hydroxylation of E2 higher in smokers
No
40
267 women in the early postmenopause
Serum E1, E2, ∆4A
∆4A higher in smokers
No
42
84 perimenopausal and postmenopausal women Serum E1, E2, ∆4A
∆4A higher in smokers
No
BMI, body–mass index; E1, oestrone; E2, oestradiol; ∆ A, androstenedione; DHEAS, dehydroepiandrosterone. 4
or placebo (table 5).7,35 In a study of 25 postmenopausal women,35 unbound oestradiol was significantly lower among smokers than non-smokers both at baseline and shortly after micronised oestradiol taken orally. No important differences were observed between smokers and non-smokers in serum concentrations of oestrone or bound oestradiol. By contrast, a study in which 110 postmenopausal women were randomly assigned hormones (orally or percutaneously) or placebo7 found that smokers had lower concentrations of both oestrone and bound oestradiol than non-smokers after oral but not percutaneous hormone treatment for at least a year (concentrations of free oestrogens were not examined). These results indicate that smoking may affect the absorption or metabolism of hormones used in replacement therapy. Smoking and blood SHBG concentrations
Of the five studies that have examined the association between cigarette smoking and serum or plasma SHBG, none found any clear association. However, one of these studies43 found an inverse association between smoking and the ratio of oestradiol to SHBG, a measure of oestrogen activity. Cassidenti and colleagues35 found that unbound (but not SHBG-bound) oestradiol was significantly lower among smokers than non-smokers both at baseline and after oral oestradiol, suggesting an increased SHBG-binding capacity in the women who smoked.
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Smoking and blood androgen concentrations
In postmenopausal women, androgens are the major source of oestrogens, converted through an aromatisation process in fat deposits. Thus, adiposity is positively correlated with oestrogen concentrations in postmenopausal women. Of the nine studies that examined blood concentrations of androstenedione in smokers, all found higher circulating concentrations among current than never or former smokers (table 5). However, these same studies did not show clear variation in blood oestrogen concentrations by smoking status. Of the five studies that have examined cigarette smoking and dehydroepiandrosterone concentrations, three37,39,43 found increased blood concentrations among current smokers, and the other two41,45 found no clear differences according to smoking status. Studies of cigarette smoking and urinary hormone concentrations
Seven studies have examined cigarette smoking and urinary oestrogen concentrations (table 6);4,46,48–52 three found no major differences according to smoking status.46,49,52 The remaining four studies showed lower urinary oestriol concentrations among smokers than non-smokers, but mixed results for urinary oestrone and oestradiol.4,48,50,51 Although based on small sample sizes, the finding of lowered
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oestriol excretion among smokers, along with the increased excretion of 2-hydroxyoestrone among smokers observed in two studies of catecholoestrogens,49,51 may support the hypothesis that smoking decreases the formation of active oestrogen metabolites along the 16α-hydroxylation pathway.49 However, as mentioned earlier, only one study has directly examined 2-hydroxylation in relation to cigarette smoking.4
the weak, non-significant inverse associations observed in three other studies.17,26,29 The earlier age at natural menopause observed among smokers may be caused by the toxic effects on the ovaries of compounds contained in tobacco smoke, or by a deregulation in gonadotropin or sex-hormone metabolism caused by nicotine.74 Therefore, if viewed as a link in the causal chain between smoking and endometrialcancer risk, age at menopause should not be considered as a confounding variable.
Cigarette smoking and age at menopause Age at natural menopause varies substantially under the influence of genetic and environmental factors.53 A young age at menopause has been associated with reduced risk of endometrial cancer.2,5,6,16 For example, a 1-year decrease in age at menopause was associated with a decrease in risk of about 7%.16 Smoking may decrease the age at natural menopause.6 The reduced exposure to endogenous oestrogens after menopause may therefore account for the lower endometrial-cancer risk among smokers. At least 19 studies have examined the association between cigarette smoking and age at menopause,54–72 particularly age at natural (as opposed to surgical) menopause (table 7). In these studies, differences in age at menopause between smokers and non-smokers were measured in terms of differences in means54,59–61,63,67,71,73 medians,56–58,70,72 or the proportion of women who reached menopause by a certain age55,62,64–66,68,69 (these latter studies are not shown in table 7). These studies have shown that, on average, smokers have menopause 1·0–1·5 years earlier than non-smokers. There were no clear differences in the results between studies that adjusted estimates for obesity (and other covariates) and those that did not. In many studies of smoking and endometrial-cancer risk, age at menopause was not taken to be a potentially confounding variable. However, a significant inverse association between cigarette smoking and endometrialcancer risk was not altered by adjustment for age at menopause in four epidemiological studies,14,20,21,30 and adjustment for age at menopause did not appreciably alter
Comments The results of at least 26 epidemiological studies to date suggest that current or recent smoking is associated with a slightly to moderately decreased risk of endometrial cancer, particularly among postmenopausal women, and especially when smoking is of high intensity or long duration. Associations between cigarette smoking and increased risk of osteoporosis5–8 and attenuated effects of HRT among smokers7 suggest an antioestrogenic effect of smoking.5,6 However, circulating concentrations of oestrogen do not differ clearly between current smokers and former smokers or non-smokers. Possibly the type, rather than the absolute concentrations, of circulating oestrogens is important. Oestrogen can be metabolised along two major pathways, to 16␣-hydroxyoestrone or to 2-hydroxyoestrone.75 16␣-hydroxyoestrone is thought to be the more biologically active of the two oestrogen metabolites; it increases mammary epithelial proliferation rates in experimental studies.75 By contrast, 2-hydroxyoestrone might decrease proliferation and cancer risk.75 Therefore, if cigarette smoking increases oestradiol 2-hydroxylation, this mechanism may explain to some extent the observed inverse association between cigarette smoking and endometrialcancer risk. However, only one study4 has directly examined 2-hydroxylation in relation to cigarette smoking. Radiolabelled oestradiol was injected, and there was 50% more oestradiol 2-hydroxylation in premenopausal women who smoked at least 15 cigarettes per day than in nonsmokers.
Table 6. Studies of cigarette smoking and urinary hormone concentrations Reference
Study population
Sex hormones examined
Differences in urinary hormone excretion concentrations between smokers and non-smokers
Additional adjustment for BMI
51
16 postmenopausal women before and after taking 2 mg/day oral E2
Urinary E1, E2, E3, 16␣OHE1, 2OHE1
E1 and E3 lower, E2 and 2OHE1 higher in smokers after treatment
No
46
694 premenopausal women, BMI <25 kg/m2
Urinary E1, E2, E3
None
No
50
367 premenopausal and postmenopausal women
Urinary E1, E2, E3
E3 lower in postmenopausal smokers
Yes
48
106 premenopausal women not taking HRT
Urinary E1, E2, E3
E1, E2, and E3 lower in smokers in the luteal phase of the menstrual cycle
No
49
29 premenopausal women not taking HRT, BMI <25 kg/m2
Urinary E1, E2, E3, 16␣OHE1, 2OHE1
E3 lower and 2OHE1 higher in smokers
No
4
27 premenopausal women not taking HRT, BMI <25 kg/m2
Urinary E1, E3
E3 lower and the ratio of E3 to E1 lower in smokers
No
52
220 postmenopausal women not taking HRT
Urinary E1, E2, E3
None
Height and weight
BMI, body–mass index; E1, oestrone; E2, oestradiol; E3, oestriol; 16␣OHE1, 16␣-hydroxyoestrone; 2OHE1, 2-hydroxyoestrone.
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Table 7. Studies of cigarette smoking and age at menopause Reference
Sample size
Median or mean age at menopause (in years) Non-smokers Ever smokers Former smokers
Current smokers
Difference non-smokers minus current smokers (years)
49·9
1·0
50·5
Adjustment for BMI
54
15 464
50·9
56
1930
50·6
50·5
No
57
2149
50·3
49·9
58
9402
Cases 50·5 Controls 49·9
59
1279
49·1
47·6
Yes
67
236
49·4
47·4
Yes
60
3234
Cases 50·3 Controls 49·3
Cases 49·3 Controls 48·8
No
No 50·1
49·6
0·7
No
Cases 50·6 Controls 49·6
Cases 49·3 Controls 48·7
1·2 1·2
No
61
84 172
48·9
48·4
48·0*
0·9
Yes
63
656
49·4
49·2
47·7*
1·7
Yes
70
7828
52·0
50·3
1·7
No
71
1405
50·1
49·3
0·8
72
3497
51
73
3368
Cases 52 Controls 50
50
No No
Cases 51 Controls 50
1 0
No
*Crude values were calculated from the data provided. BMI, body–mass index.
A positive association between cigarette smoking and blood androgen concentrations has been observed consistently, especially with androstenedione, although its relevance to the association between smoking and endometrial-cancer risk is unknown.9 There has been speculation about the possible inhibitory effects of androgens on oestrogens,43 although there is currently no evidence to support such effects. Smoking is associated with lower relative bodyweight (body–mass index),5,18,40 yet positive associations have also been observed between smoking and waist-to-hip ratio,74 which may stem from the positive association between smoking and androgen concentrations. However, the latter association may be confounded by such factors as physical inactivity and higher intake of calories, total fat, and alcohol.74 Since adipose tissue is the main determinant of oestrogen concentrations among postmenopausal women and is inversely associated with smoking, relative bodyweight may partly mediate the inverse association between cigarette smoking and oestrogen. Indeed, statistical adjustment for the effects of body–mass index has attenuated the association between smoking and endometrial-cancer risk in some studies, which is consistent with the potential role of this variable as a mediator of the association between cigarette smoking and endometrial cancer. Most studies have adjusted for current relative bodyweight, although more relevant measures may include changes in bodyweight over time, waist-to-hip ratio, or duration of obesity. These measures may ultimately explain more of the association between smoking and endometrialcancer risk than does current relative bodyweight. The data presented here suggest that smoking lowers the age at which women reach menopause by an average of about 1·0–1·5 years, an association that appears to weaken with time since smoking cessation. Statistical adjustment for
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the effects of age at menopause does not alter appreciably the inverse associations between smoking and endometrialcancer risk observed in several epidemiological studies.14,17,20,21,26,29,30 Although a lower average bodyweight and earlier age at menopause among current smokers than nonsmokers certainly mediates some of the inverse association, the extent of this mediation remains unclear. Methodological issues, such as the potential for selection and recall bias in studies of retrospective design, may explain some or all of the association between smoking and endometrial-cancer risk. Prospective cohort studies of the association, in which the problems of selection and recall are minimised, have been scarce. Indeed, only three prospective studies of endometrial-cancer incidence have examined cigarette smoking,13,28,33 and their results have been null,13 equivocal,28 or have supported the hypothesised inverse association33 (the latter being the only large study of the three). Thus, the association between cigarette smoking and endometrial-cancer risk might be clarified further through the analysis of data from large prospective cohort studies. Cohort studies are not without limitations, however. For example, changes in smoking habits during follow-up can lead to misclassification of the exposure if, as has generally been the case, exposure is not updated after the baseline assessment. Cohort studies can also be limited by losses to follow-up, for which assumptions about the lack of bias due to systematic losses must be made. Moreover, whether smokers are more or less likely than non-smokers to have their endometrial cancers detected during follow-up is unknown. If an association is observed to differ according to values of another variable, such effect modification may provide clues to the mechanisms underlying the association. In relation to effect modification in the association between cigarette smoking and endometrial cancer by factors related to
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Search strategy and selection criteria We reviewed the published studies of smoking and endometrial-cancer risk obtained through searches of the Medline and Cancerlit databases, using keywords such as “smoking”, “endometrial cancer”, “endometrial neoplasms”, “oestrogens”, and “menopause”. We obtained additional published reports by cross-matching the references of relevant articles. We included unpublished data only when they have been cited as a “personal communication” in a published report (provided that an odds ratio or relative risk estimate was included). Virtually all published reports are in English, and we have restricted our review to those.
endogenous or exogenous hormones, the epidemiological data remain equivocal. On the one hand, ten studies have shown a reduced risk with current smoking that is stronger among, or limited to, postmenopausal women,11,20,26,30 women using HRT,14,21,31 parous women,33 and women who are obese.11,18 On the other hand, nine studies have found no important differences in the association according to menopausal status,18,21,33 obesity,21,33 or HRT use.11,18,30,33 However, the validity of a single oestrogen measurement as an indicator of a woman’s usual concentrations is unclear. Furthermore, none of the published reports have had sufficient statistical power to address meaningfully the issue of effect modification. In summary, the bulk of evidence from epidemiological studies suggests that cigarette smoking is associated with reduced risk of endometrial cancer among current smokers, perhaps mainly among postmenopausal women, and that the association weakens with time since quitting. Studies that have examined quantitative measures of exposure to cigarette smoke show greater reductions in risk among women who smoke either more intensely or for a longer duration than women who smoke relatively less. Thus far, the mechanisms by which this association may be driven remain unclear. Conflict of interest
None declared. References
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9 Austin H, Drews C, Partridge EE. A case-control study of endometrial cancer in relation to cigarette smoking, serum estrogen levels, and alcohol use. Am J Obstet Gynecol 1993; 169: 1086–91. 10 Baron JA, Byers T, Greenberg ER, et al. Cigarette smoking in women with cancers of the breast and reproductive organs. J Natl Cancer Inst 1986; 77: 677–80. 11 Brinton LA, Barrett RJ, Berman ML, et al. Cigarette smoking and the risk of endometrial cancer. Am J Epidemiol 1993; 137: 281–91. 12 Elliott EA, Matanoski GM, Rosenshein NB, et al. Body fat patterning in women with endometrial cancer. Gynecol Oncol 1990; 39: 253–58. 13 Engeland A, Andersen A, Haldorsen T, Tretli S. Smoking habits and risk of cancers other than lung cancer: 28 years’ follow-up of 26,000 Norwegian men and women. Cancer Causes Control 1996; 7: 497–506. 14 Franks AL, Kendrick JS, Tyler CW Jr. Postmenopausal smoking, estrogen replacement therapy, and the risk of endometrial cancer. Am J Obstet Gynecol 1987; 156: 20–23. 15 Goodman MT, Hankin JH, Wilkens LR, et al. Diet, body size, physical activity, and the risk of endometrial cancer. Cancer Res 1997; 57: 5077–85. 16 Kelsey JL, LiVolsi VA, Holford TR, et al. A case-control study of cancer of the endometrium. Am J Epidemiol 1982; 116: 333–42. 17 Koumantaki Y, Tzonou A, Koumantakis E, et al. A case-control study of cancer of endometrium in Athens. Int J Cancer 1989; 43: 795–99. 18 Lawrence C, Tessaro I, Durgerian S, et al. Smoking, body weight, and early-stage endometrial cancer. Cancer 1987; 59: 1665–69. 19 Lawrence C, Tessaro I, Durgerian S, et al. Advanced-stage endometrial cancer: contributions of estrogen use, smoking, and other risk factors. Gynecol Oncol 1989; 32: 41–45. 20 Lesko SM, Rosenberg L, Kaufman DW, et al. Cigarette smoking and the risk of endometrial cancer. N Engl J Med 1985; 313: 593–96. 21 Levi F, la Vecchia C, Decarli A. Cigarette smoking and the risk of endometrial cancer. Eur J Cancer Clin Oncol 1987; 23: 1025–29. 22 Jain MG, Howe GR, Rohan TE. Nutritional factors and endometrial cancer in Ontario, Canada. Cancer Control 2000; 7: 288–96. 23 McCann SE, Freudenheim JL, Marshall JR, et al. Diet in the epidemiology of endometrial cancer in western New York (United States). Cancer Causes Control 2000; 11: 965–74. 24 Newcomer LM, Newcomb PA, Trentham-Dietz A, Storer B. Hormonal risk factor for endometrial cancer: modification by cigarette smoking (United States). Cancer Causes Control 2001; 12: 829–35. 25 Rubin GL, Peterson HB, Lee NC, et al. Estrogen replacement therapy and the risk of endometrial cancer: remaining controversies. Am J Obstet Gynecol 1990; 162: 148–54. 26 Smith EM, Sowers MF, Burns TL. Effects of smoking on the development of female reproductive cancers. J Natl Cancer Inst 1984; 73: 371–76. 27 Stockwell HG, Lyman GH. Cigarette smoking and the risk of female reproductive cancer. Am J Obstet Gynecol 1987; 157: 35–40. 28 Terry P, Baron JA, Weiderpass E, et al. Lifestyle and endometrial cancer risk: a cohort study from the Swedish Twin Registry. Int J Cancer 1999; 82: 38–42. 29 Tyler CW Jr, Webster LA, Ory HW, Rubin GL. Endometrial cancer: how does cigarette smoking influence the risk of women under age 55 years having this tumor? Am J Obstet Gynecol 1985; 151: 899–905. 30 Weiderpass E, Baron JA. Cigarette smoking, alcohol consumption, and endometrial cancer risk: a population-based study in Sweden. Cancer Causes Control 2001; 12: 239–47. 31 Weiss NS, Farewall VT, Szekely DR, et al. Oestrogens and endometrial cancer: effect of other risk factors on the association. Maturitas 1980; 2: 185–90. 32 Williams RR, Horm JW. Association of cancer sites with tobacco and alcohol consumption and socioeconomic status of patients: interview study from the Third National Cancer Survey. J Natl Cancer Inst 1977; 58: 525–47. 33 Terry P, Miller AB, Rohan TE. A prospective cohort study of cigarette smoking and the risk of endometrial cancer. Br J Cancer 2002; 86: 1430–35. 34 Shields TS, Weiss NS, Voigt LF, Beresford SA. The additional risk of endometrial cancer associated with unopposed estrogen use in women with other risk factors. Epidemiology 1999; 10: 733–38. 35 Cassidenti DL, Vijod AG, Vijod MA, et al. Short-term effects of smoking on the pharmacokinetic profiles of micronized estradiol in
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postmenopausal women. Am J Obstet Gynecol 1990; 163: 1953–60. 36 International Agency for Research on Cancer. Weight control and physical activity. IARC handbook of cancer prevention, vol 6. Lyon: IARC Press, 2002. 37 Cassidenti DL, Pike MC, Vijod AG, et al. A reevaluation of estrogen status in postmenopausal women who smoke. Am J Obstet Gynecol 1992; 166: 1444–48. 38 Cauley JA, Gutai JP, Kuller LH, et al. The epidemiology of serum sex hormones in postmenopausal women. Am J Epidemiol 1989; 129: 1120–31. 39 Friedman AJ, Ravnikar VA, Barbieri RL. Serum steroid hormone profiles in postmenopausal smokers and nonsmokers. Fertil Steril 1987; 47: 398–401. 40 Schlemmer A, Jensen J, Riis BJ, Christiansen C. Smoking induces increased androgen levels in early post-menopausal women. Maturitas 1990; 12: 99–104. 41 Law MR, Cheng R, Hackshaw AK, et al. Cigarette smoking, sex hormones and bone density in women. Eur J Epidemiol 1997; 13: 553–58. 42 Slemenda CW, Hui SL, Longcope C, Johnston CC Jr. Cigarette smoking, obesity, and bone mass. J Bone Miner Res 1989; 4: 737–41. 43 Khaw KT, Tazuke S, Barrett-Connor E. Cigarette smoking and levels of adrenal androgens in postmenopausal women. N Engl J Med 1988; 318: 1705–09. 44 Longcope C, Johnston CC Jr. Androgen and estrogen dynamics in pre- and postmenopausal women: a comparison between smokers and nonsmokers. J Clin Endocrinol Metab 1988; 67: 379–83. 45 Key TJ, Pike MC, Baron JA, et al. Cigarette smoking and steroid hormones in women. J Steroid Biochem Mol Biol 1991; 39: 529–34. 46 Berta L, Frairia R, Fortunati N, et al. Smoking effects on the hormonal balance of fertile women. Horm Res 1992; 37: 45–48. 47 Lapidus L, Lindstedt G, Lundberg PA, et al. Concentrations of sexhormone binding globulin and corticosteroid binding globulin in serum in relation to cardiovascular risk factors and to 12-year incidence of cardiovascular disease and overall mortality in postmenopausal women. Clin Chem 1986; 32: 146–52. 48 MacMahon B, Trichopoulos D, Cole P, Brown J. Cigarette smoking and urinary estrogens. N Engl J Med 1982; 307: 1062–65. 49 Michnovicz JJ, Naganuma H, Hershcopf RJ, et al. Increased urinary catechol estrogen excretion in female smokers. Steroids 1988; 52: 69–83. 50 Key TJ, Pike MC, Brown JB, et al. Cigarette smoking and urinary oestrogen excretion in premenopausal and post-menopausal women. Br J Cancer 1996; 74: 1313–16. 51 Berstein LM, Tsyrlina EV, Kolesnik OS, et al. Catecholestrogens excretion in smoking and non-smoking postmenopausal women receiving estrogen replacement therapy. J Steroid Biochem Mol Biol 2000; 72: 143–47. 52 Trichopoulos D, Brown J, MacMahon B. Urine estrogens and breast cancer risk factors among post-menopausal women. Int J Cancer 1987; 40: 721–25.
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53 McKinlay SM. The normal menopause transition: an overview. Maturitas 1996; 23: 137–45. 54 Adena MA, Gallagher HG. Cigarette smoking and the age at menopause. Ann Hum Biol 1982; 9: 121–30. 55 Bailey A, Robinson D, Vessey M. Smoking and age of natural menopause. Lancet 1977; 2: 722. 56 Brinton LA, Schairer C, Stanford JL, Hoover RN. Cigarette smoking and breast cancer. Am J Epidemiol 1986; 123: 614–22. 57 Brownson RC, Blackwell CW, Pearson DK, et al. Risk of breast cancer in relation to cigarette smoking. Arch Intern Med 1988; 148: 140–44. 58 Chu SY, Stroup NE, Wingo PA, et al. Cigarette smoking and the risk of breast cancer. Am J Epidemiol 1990; 131: 244–53. 59 Daniell HW. Osteoporosis of the slender smoker. Vertebral compression fractures and loss of metacarpal cortex in relation to postmenopausal cigarette smoking and lack of obesity. Arch Intern Med 1976; 136: 298–304. 60 Field NA, Baptiste MS, Nasca PC, Metzger BB. Cigarette smoking and breast cancer. Int J Epidemiol 1992; 21: 842–48. 61 Hiatt RA, Fireman BH. Smoking, menopause, and breast cancer. J Natl Cancer Inst 1986; 76: 833–38. 62 Jick H, Porter J. Relation between smoking and age of natural menopause. Lancet 1977; 1: 1354–55. 63 Kaufman DW, Slone D, Rosenberg L, et al. Cigarette smoking and age at natural menopause. Am J Public Health 1980; 70: 420–22. 64 Lindquist O, Bengtsson C. Menopausal age in relation to smoking. Acta Med Scand 1979; 205: 73–77. 65 van Keep PA, Brand PC, Lehert P. Factors affecting the age at menopause. J Biosoc Sci Suppl 1979: 37–55. 66 Willett W, Stampfer MJ, Bain C, et al. Cigarette smoking, relative weight, and menopause. Am J Epidemiol 1983; 117: 651–58. 67 Daniell HW. Smoking, obesity, and the menopause. Lancet 1978; 2: 373. 68 Andersen FS, Transbol I, Christiansen C. Is cigarette smoking a promotor of the menopause? Acta Med Scand 1982; 212: 137–39. 69 Hammond EC. Smoking in relation to physical complaints. Arch Environ Health 1961; 3: 28–164. 70 McKinlay SM, Bifano NL, McKinlay JB. Smoking and age at menopause in women. Ann Intern Med 1985; 103: 350–56. 71 McNamara PM, Hjortland MC, Gordon T, Kannel WB. Natural history of menopause: the Framingham Study. J Cont Ed Obstet Gynecol 1978; 20: 27–35. 72 Stanford JL, Hartge P, Brinton LA, et al. Factors influencing the age at natural menopause. J Chronic Dis 1987; 40: 995–1002. 73 Weiderpass E, Adami HO, Baron JA, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999; 91: 1131–37. 74 US Department of Health and Human Services. Women and smoking: a report of the Surgeon General. Rockville, Maryland: Department of Health and Human Services, 2001. 75 Bradlow HL, Telang NT, Sepkovic DW, Osborne MP. 2hydroxyestrone: the ‘good’ estrogen. J Endocrinol 1996; 150 (suppl): S259–65.
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Smoking and endometrial cancer
Cigarette smoking and the risk of endometrial cancer Paul D Terry, Thomas E Rohan, Silvia Franceschi, and Elisabete Weiderpass
Epidemiological studies have shown that cigarette smoking is associated with a reduced risk of endometrial cancer, in contrast to the increased risks observed with many other non-respiratory-tract cancers, including those of the bladder, pancreas, and cervix uteri. Some studies of endometrial cancer suggest that the inverse association with smoking is limited to certain groups of women, such as those who are postmenopausal or those taking hormone-replacement therapy. The biological mechanisms that might underlie this association remain unclear, although several have been proposed, including an antioestrogenic effect of cigarette smoking on circulating oestrogen concentrations, a reduction in relative bodyweight, and an earlier age at menopause. We have examined the evidence for an association between cigarette smoking and risk of endometrial cancer, including studies related to the proposed biological mechanisms.
Figure 1. In this example of an endometrial carcinoma, the tumour forms an exophytic mass that fills the endometrial cavity.
Lancet Oncol 2002; 3: 470–80
Endometrial adenocarcinoma accounts for roughly one of every ten cancers diagnosed among women worldwide, and it is the most commonly diagnosed cancer of the female genital tract in the more developed countries (figure 1).1 Exogenous oestrogens unopposed by progesterone have been hypothesised to increase the risk of this cancer through increased mitotic activity of endometrial cells, increased number of DNA replication errors, and somatic mutations resulting in the malignant phenotype.2 The use of exogenous oestrogens, and of oestrogen-replacement therapy in particular, has been strongly related to increased risk in epidemiological studies and has also been linked to trends in endometrial-cancer incidence in more developed countries.3 Other factors associated with increased risk include obesity, ovarian dysfunction, and nulliparity, which are thought to act through increased circulating concentrations of unopposed oestrogens.2 The vast majority of endometrial cancers are adenocarcinomas (figure 2). Since oestrogens have a role in endometrial adenocarcinoma,2 factors associated with low concentrations of circulating oestrogens may reduce the risk of this malignant disorder. In this regard, a hypothesis has been put forward that smoking might exert antioestrogenic effects—through reduced relative bodyweight, lowered age at menopause,4 or differences in metabolism of oestrogens between smokers and non-smokers—and through this mechanism might reduce the risk of endometrial cancer. Support for this hypothesis comes from studies showing that smoking is associated with increased risk of osteoporosis,5–8
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an oestrogen-deficient condition, and that it may attenuate the decrease in serum-total and LDL cholesterol associated with hormone-replacement therapy (HRT). In view of the importance of understanding endometrial-cancer aetiology, epidemiological studies have continued to address the association with cigarette smoking, both directly in studies of the association between smoking and risk of the cancer and indirectly through studies of the possible association between smoking and oestrogen concentrations and metabolism. Our aim was to review the available evidence on cigarette smoking and endometrial-cancer risk. We began by examining studies that used qualitative measures of smoking (never, ever, former, and current), studies that used quantitative measures of smoking related to intensity and duration (cigarettes smoked per day, years of smoking, and pack-years), and studies that stratified their results according to potentially important effect-modifying variables (primarily menopausal status, use of HRT, and relative bodyweight). In light of what may be important PDT and TER are cancer epidemiologists in the Department of Epidemiology and Social Medicine at the Albert Einstein College of Medicine, Bronx, NY, USA; TER is chairman of the department. SF and EWV are epidemiologists and medical officers in the Unit of Field and Intervention Studies at the International Agency for Research on Cancer (IARC), Lyon, France; SF is head of the unit. Correspondence: Dr Paul Terry, Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 13th Floor, Bronx, NY 10461, USA. Tel: +1 718 430 3038. Fax: +1 718 430 8653. Email: [email protected]
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recall bias and are less susceptible to selection bias, but very few prospective cohort studies have provided information on smoking. Current, former, ever, and never smokers
Qualitative measures of smoking, such as ever or never, or current or former, have been used in most previous studies of endometrial-cancer risk. However, such measures are difficult to interpret. For example, current smoking may reflect a more intense exposure of much longer duration in one study population than in another. There is even greater ambiguity inherent in the measure “ever smoked”, since the timing of the exposure to Figure 2. This medium-power photomicrograph shows an endometrial carcinoma that is composed of closely packed, well-formed glands. cigarette smoke and its extent are not clear. Therefore, the results of studies underlying mechanisms, we then reviewed studies that that used qualitative smoking measures should be viewed in examined the associations between smoking and light of these limitations. concentrations of hormones in the blood and urine, including oestrogens (particularly oestrone, oestradiol, and Cohort studies oestriol) and androgens (particularly androstenedione and To date, there have been three prospective cohort dehydroepiandrosterone). We also reviewed studies that studies13,28,33 of the association between cigarette smoking examined the association between cigarette smoking and and endometrial-cancer risk (table 1). With qualitative sex-hormone-binding globulin (SHBG)—concentrations of smoking measures, these studies do not clearly support an which can influence oestrogen activity. Finally, we reviewed inverse association between smoking and risk of studies that examined the association between cigarette endometrial cancer. The results of two of these studies13,28 smoking and age at menopause, which itself is positively were based on small numbers of cases (36 and 12 cases among current smokers) and the confidence intervals were related to endogenous oestrogen exposure. wide.
Cigarette smoking and endometrial-cancer risk To date, at least 26 epidemiological studies have examined this association.9–34 The studies fall into two major categories—case-control and prospective cohort studies. Most of those published to date have used the case-control design; some were hospital based and some were population based. To ensure that the selection of controls is independent of the exposure of interest is particularly difficult in a hospital setting, where many disorders (or hospital admission for those disorders) may be related to smoking. Population-based case-control studies are not subject to this problem, but participation rates among controls are generally lower than in hospital-based studies. Wide differences in participation rates with respect to exposure (most notably a lower participation rate among smoking women who are eligible to participate) could spuriously drive a study’s results towards or away from a null association; a lower rate of participation among potential controls who are cigarette smokers would tend to mask a true inverse association. Furthermore, both types of case-control studies are vulnerable to recall bias, such as would occur if case women systematically recalled more exposure to cigarettes than control women did (which would also tend to mask a true inverse association). Prospective cohort studies, by contrast, are not vulnerable to THE LANCET Oncology Vol 3 August 2002
Population-based case-control studies
The results of 12 population-based case-control studies,11,12,14,15,22–26,29,30,34 which included between 46 and 740 cases of endometrial cancer, have been fairly consistent in showing no association with risk among former smokers compared with never smokers and slightly to moderately lower risks among current smokers than never smokers (table 1). Nine studies also, or exclusively, examined former and current smokers combined (ie, ever smokers) and mostly showed small, non-significant reductions in risk compared with never smokers. Hospital-based case-control studies
The six hospital-based case-control studies9,16,17,20,21,27 included between 83 and 1374 cases of endometrial cancer and examined qualitative measures of cigarette smoking (table 1). In these studies, former smokers generally had a slightly, not statistically significant, lower risk than never smokers (on average about 10–20% lower); but the reduced risk among current (ie, active smokers at assessment) compared with never smokers was more pronounced, on average about 30–40% lower. The largest of the hospital-based studies,27 with 1374 cases and 3921 controls, found that both former and current smokers were
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Table 1. Epidemiological studies of cigarette smoking and endometrial-cancer risk in current, former, and never smokers Reference
Number of cases/controls (or number in cohort)
Age range at recruitment (years)
13
140/26 000
28
123/11 659
33
403/70 591
Odds ratio (95% CI) for smoking category Ever vs never
Variables adjusted for*
Former vs never
Current vs never
32–72
1·2 (0·6–2·2)
1·1 (0·7–1·6)
Not specified
42–82
0·7 (0·3–2·0)
0·9 (no CI)†
Age, weight, parity
40–59
1·0 (0·8–1·3)
0·8 (0·6–1·1)
Age, BMI, HRT, parity
1·1 (0·7–1·6)
0·4 (0·2–0·7)
Age, weight, HRT, parity, diabetes, age at menopause
1·4 (0·6–3·5)
0·2 (0·1–0·6)
Age, BMI, HRT, parity, diabetes
Prospective cohort
Population case-control 11
405/297
20–74
0·8 (0·5–1·1)
12
46/138
14
79/416
20–55
0·5 (0·3–0·8)
Age, BMI, HRT, parity, diabetes, age at menopause
15
332/511
18–84
0·8 (0·6–1·2)
Age, BMI, HRT, parity, diabetes
22
220/223
30–79
1·0 (0·8–1·3)
None
23
236/639
40–85
0·6 (0·4–0·8)
24
740/2372
40–79
0·8 (0·7–0·9)
25
196/986
20–54
34
553/752
45–64
26
70/612
20–54
0·8 (0·4–1·5)
29
437/3200
20–54
0·9 (0·7–1·1)
30
709/3368
Age 0·8 (0·7–1·0)
0·8 (0·6–1·0)
Age, BMI, HRT, parity, diabetes
0·8 (0·5–1·2)
0·7 (0·5–1·0)
Age, BMI, treatment for diabetes
0·8 (0·6–1·2)‡
0·6 (0·4–0·8)‡
Age, BMI Age, BMI, HRT, parity, age at menopause
1·0 (0·7–1·4)
0·8 (0·7–1·1)
Age, weight, HRT, age at menopause
50–74
0·9 (0·7–1·1)
0·6 (0·5–0·8)
Age, BMI, HRT, parity, diabetes, age at menopause
0·8 (0·5–1·5)
0·7 (0·4–1·2)
Age, BMI, HRT, parity, diabetes
Hospital case-control 9
168/334
40–82
16§
167/903
45–74
17
83/164
40–79
20
510/727
18–69
21
357/1122
31–74
27
1374/3921
0·8 (no CI)
Age, HRT, age at menopause 0·5 (0·2–1·3)¶
Age, height, weight, HRT, parity, age at menopause
0·9 (0·6–1·2)
0·8 (no CI)†
Age, BMI, HRT, age at menopause, parity, diabetes
0·9 (0·5–1·5)
0·5 (0·3 – 0·7)
Age, BMI, HRT, parity, age at menopause
0·6 (0·5–0·8)
0·7 (no CI)†
Age
*Covariates considered here were age, BMI, HRT, age at menopause, parity, and diabetes; †Crude measures of association were calculated from the data provided. ‡Results shown are for women not taking unopposed oestrogens. Among oestrogen users, smokers were also at higher risk than non-smokers. §Results reported in reference 5 ¶Former smokers were combined with never smokers in this analysis. BMI, body-mass index; HRT, hormone replacement therapy.
at moderately (about 30%) lower risk of endometrial cancer. Although most of these studies adjusted their estimates of relative risk for potentially confounding variables such as body–mass index, use of HRT, parity, diabetes, and age at menopause (table 1), those that did not, tended to show similar inverse associations. Within individual studies, statistical adjustment for the effects of body–mass index and other covariates made little difference, although some attenuation of relative-risk estimates has been noted.30,33
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Quantitative measures of smoking
Quantitative measures of smoking include frequency (cigarettes per day), duration (years smoked), the product of smoking frequency and duration (pack-years), latency (years since smoking started), and recency (years since smoking ceased). The examination of these measures is important, since potentially adverse effects of the many carcinogens in tobacco smoke have been observed in some studies. If a dose-response association with cigarette smoking could be shown with increasing values of a particular smoking
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measure, the role of smoking in prevention of endometrial cancer could be established more firmly. Cohort studies
Two28,33 of the three13,28,33 prospective cohort studies mentioned in the previous section examined quantitative smoking measures in relation to endometrial-cancer risk, the results of these investigations are consistent with the inverse associations with current smoking (but not former smoking) observed in the case-control studies (table 2). One of these two studies28 found a 50% lower risk among current smokers in the highest intensity category (11 cigarettes per day or more) than in non-smokers, but the number of cases
was low and the confidence intervals were correspondingly wide. The more recent and larger of the two cohort studies33 found a significant 40% lower risk among current smokers who smoke more than 20 cigarettes per day, but somewhat weaker and non-significant reductions in risk with smoking of long duration or high number of pack-years. By contrast, the risk among former smokers was similar to that among never smokers. Population-based case-control studies
To date, six population-based case-control studies11,18,19,24,29,30 have examined quantitative measures of smoking in relation to endometrial-cancer risk, with most showing the strongest
Table 2. Epidemiological studies of cigarette smoking and endometrial-cancer risk in terms of smoking frequency, duration, and pack-years Reference
Number of Age range cases/controls (years) (or number in cohort)
Comparison odds ratio (95% CI) Smoking intensity Smoking duration (cigarettes per day) (years)
Pack-years (packs per day x years)
Prospective cohort 28
123/11 659
42–82
Current ⭓11 vs never 0·5 (0·1–2·0)
33
403/70 591
40–59
Former >20 vs never 0·9 (0·6–1·3)
Former >20 vs never 1·1 (0·8–1·6)
Former >20 vs never 1·0 (0·7–1·5)
Current >20 vs never 0·6 (0·4–0·9)*
Current >20 vs never 0·8 (0·6–1·1)
Current >20 vs never 0·7 (0·5–1·1)
Ever ⭓30 vs never 0·7 (0·4–1·4)
Ever ⭓40 vs never 0·5 (0·3–0·9)*
Former ⭓30 vs never 1·4 (no CI)
Former ⭓40 vs never 0·5 (no CI)
Current ⭓30 vs never 0·3 (no CI)
Current ⭓40 vs never 0·5 (no CI)
Population case-control 11
18
405/297
301/289
20–74
40–69
Former >20 vs never 0·6 (no CI) Current >20 vs never 0·5 (no CI)
19
84/168
40–69
Former >20 vs never 1·0 (no CI) Current >20 vs never 1·0 (no CI)
24
740/2372
40–79
Ever ⭓80 vs never 0·9 (0·5–1·4)
29
437/3200
20–54
Ever ⭓15 vs never 1·0 (0·7–1·2)
30
709/3368
50–74
Maximum ⭓20 vs never 0·7 (0·4–1·3)
Lifelong ⭓45 vs never 0·6 (0·3–0·9)
Hospital case-control Ever ⭓15 vs never 0·6 (0·4–0·9)*
10
476/2128
40–89
17
83/164
40–79
20
510/727
18–69
Current ⭓25 vs never 0·5 (0·3–0·8)
21
357/1122
31–74
Current ⭓15 vs never 0·4 (0·2–0·9)*
27
1374/3921
32
358/3189
⭓20 (continuous variable) 0·5 (0·3–0·9)*
Current >40 vs never 0·5 (0·3–0·9) 25–76
Ever ⭓40 vs never 0·7 (NS)
*Statistically significant. NS, not significant.
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inverse associations among current smokers of high intensity or long duration (table 2). However, one population-based study of late-stage endometrial cancer19 did not show an association with any measure of smoking (although the number of cases in that study was small); in another small study,18 the same investigators found that smoking more than 20 cigarettes per day was associated with a lower risk of early-stage endometrial cancer among both current and former smokers.
In many of these studies, the number of cases in the highest smoking category was small. The issue of statistical imprecision, along with the likely correlations between smoking measures and the scarcity of studies that examined more than one smoking measure, make comparisons among the various studies difficult. Overall, however, the findings of epidemiological studies of smoking and endometrial cancer support an inverse association among current smokers, especially those who reported smoking of high intensity or long duration.
Hospital-based case-control studies
Six hospital-based case-control studies of endometrial cancer that examined quantitative measures of smoking mostly showed significant 30–60% lower risks with current or recent smoking of high intensity,20,21,27 with smoking of long duration,17 or with a high number of pack-years (table 2).10,32 However, the intercorrelation between the various smoking measures complicates the differentiation of their independent effects. For example, smokers of high intensity also tend to be smokers of long duration,33 and the latter also tend to have started smoking at an early age. Although studies to date have generally shown that high levels of smoking are associated with a reduced risk of endometrial cancer, the results have not been as consistent about which of the quantitative smoking measures is the most important. For example, two population-based casecontrol studies11,30 found a greater reduction in risk with smoking of long duration than with smoking of high intensity, whereas a large prospective cohort study33 found a greater reduction in risk with smoking of high intensity. Few of the studies examined more than one quantitative smoking measure. In addition, two studies11,33 found non-significantly reduced endometrial-cancer risk with smoking commencement at an early age. As mentioned above, this smoking measure is correlated with smoking duration.
Effect modification
Several studies have examined the association between smoking and endometrial-cancer risk according to factors that are known determinants of endogenous hormone concentrations, and which may counteract or augment possible tobacco-related hormonal changes. These factors include menopausal status, use of HRT, and relative bodyweight. Effect modification can reflect true underlying differences in the association, for example, if cigarette smoking acts to decrease or modify oestrogen concentrations differently in two groups. Effect modification can also reflect methodological factors, such as differences that occur by chance or through the varying frequency of confounding variables. However, similarities in the relative risks may still reflect important differences in the absolute number of cases associated with smoking if the baseline risk in the two groups differs. For example, a 30% lower risk among HRT users would affect a greater number of women than the same proportional reduction among women not taking HRT, since the baseline risk is higher among HRT users.2 This factor is important to bear in mind in comparison of relative measures of association over strata defined by factors that are themselves associated with risk.
Table 3. Epidemiological studies of cigarette smoking and endometrial-cancer risk according to menopausal status Reference
Number of cases/controls (or number in cohort)
Smoking comparison
Odds ratio (95% CI) Premenopausal
Postmenopausal
403/70 591
Current >20 /day vs never
0·7 (0·4–1·3)
0·6 (0·3–1·1)
Prospective cohort 33 Population case-control 11
405/297
Former vs never
3·0 (1·2–7·4)
0·8 (0·4–1·2)
Current vs never
0·5 (0·1–1·7)
0·4 (0·2–0·7)
Ever ⭓30 years vs never
6·2 (0·9–42·3)
0·6 (0·4–1·0)†
Ever ⭓30 /day vs never
1·3 (0·2–7·1)
0·6 (0·3–1·3)†
14
79/416
Ever vs never
18
301/289
Current vs never
0·6 (no CI)
0·5 (0·3–0·8) 0·6 (no CI)
26
70/612
Ever vs never
1·3 (0·7–2·5)
0·4 (0·2–1·0)
30
709/3368
Current (highest duration category)
0·9 (0·4–2·0)
0·4 (0·2–0·8)
17
83/164
Current vs former and non-smokers
2·3 (no CI)
0·2 (no CI)
20
510/727
Current ⭓25 vs never
0·9 (0·4–2·2)
0·5 (0·2–0·9)
Hospital case-control
21
357/1122
Current vs never
0·5 (0·2–0·9)
0·4 (0·3–0·7)
27*
1374/3921
Current >40 vs never
1·9 (0·5–7·8)
0·4 (0·2–0·8)
*In this study the stratification categories were <50 vs ⭓50 years; †Statistically significant.
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Table 4. Epidemiological studies of cigarette smoking and endometrial-cancer risk according to HRT use Reference
Number of cases/controls (or number in cohort)
Smoking comparison
Odds ratio (95% CI) No HRT
HRT
403/70 591
Current >20 /day vs never
0·6 (0·4–1·0)*
0·6 (0·3–1·3)
14 18
79/416
Ever vs never
0·5 (0·3–0·9)
0·3 (0·1–0·8)
301/289
Current vs never
0·6 (no CI)
31
0·6 (no CI)
322/289
Ever vs never
0·4 (0·2–0·7)
357/1122
Current vs never
0·5 (0·3–0·7)
Prospective cohort 33 Population case-control
Hospital case-control 21
0·2 (0·1–0·7)
*Statistically significant. HRT, hormone replacement therapy.
Menopausal status
Menopausal status can be viewed as a proxy for age and ovarian function. Although endometrial cancer is rare among premenopausal women, several studies have examined the association between cigarette smoking and risk of endometrial cancer according to menopausal status, including one prospective cohort study,33 five populationbased case-control studies,11,14,18,26,30 and four hospital-based case-control studies17,20,21,27 (table 3). In all but one of these studies, a study of early-stage endometrial cancer,18 the inverse association was stronger among postmenopausal than premenopausal women. Among premenopausal women, the relative-risk estimates for cigarette smoking have been inconsistent, some showing increased risks with certain measures of cigarette smoking,11,17,26,27 some showing decreased risks,11,18,21,33 and some showing practically no association.20,30 In analyses limited to postmenopausal women, by contrast, all showed between 20% and 80% reduced risks of endometrial cancer with the various smoking measures. HRT
The possibility that cigarette smoking lowers blood hormone concentrations mostly among women who are taking HRT7,8,35 leads to the idea that an inverse association between smoking and endometrial-cancer risk would be stronger among HRT users than among non-users. However, the results of studies that have examined the association according to HRT use14,18,21,31,33 are equivocal in showing such a pattern (table 4). Two studies14,21 observed a larger reduction in risk among smokers taking HRT than among smokers not taking HRT; two other studies18,33 found no difference in the association according to HRT status, including a large prospective cohort study.33 Thus, although effect modification by HRT status is biologically plausible, the available epidemiological evidence is equivocal. Relative bodyweight
Obesity is an established risk factor for endometrial cancer.36 Smokers tend to have lower body–mass indices than nonsmokers (although former smokers tend to have a higher relative bodyweight than current or never smokers).6 Two studies have examined the association between cigarette smoking and endometrial-cancer risk according to measures THE LANCET Oncology Vol 3 August 2002
of relative bodyweight, such as body–mass index.12,21 Neither a hospital-based21 nor a population-based12 case-control study found any clear differences in the association according to relative bodyweight. Another study,18 a population-based case-control study of early-stage endometrial cancer, observed that the inverse association with cigarette smoking became stronger with increasing absolute, rather than relative, bodyweight.
Studies of cigarette smoking and blood hormone concentrations Whether mediated through changes in the amount of adipose tissue, altered age at menopause, or antioestrogenic effects, blood hormone concentrations might be an important link between smoking and the reduced risk of endometrial cancer observed in most of the studies discussed above. The oestrogens that have typically been studied include oestrone, SHBG-bound oestradiol, and oestriol. Blood concentrations of androgens, mostly androstenedione and dehydroepiandrosterone, have also been studied, since these are biological precursors of oestrone. Studies that have examined blood concentrations of SHBG are less common, and studies of unbound (free) oestradiol are scarce. Smoking and blood oestrogen concentrations
Studies of cigarette smoking and blood hormone concentrations have been undertaken mostly among postmenopausal women who were not taking HRT (table 5).4,7–9,35,37–47 Of these studies, nine examined serum or plasma oestrone, ten serum or plasma oestradiol, and two serum or plasma free oestradiol. These studies have been very consistent in showing little or no association between smoking and blood oestrogen concentrations among postmenopausal women who were not taking HRT. Among premenopausal women, three studies44–46 found no clear association between cigarette smoking and oestrogen concentrations. Studies that adjusted hormone measurements for the effects of relative bodyweight (and other covariates) showed similar results to those that did not, suggesting that relative bodyweight is not a strong confounding variable in this association. Two studies examined the association between cigarette smoking and blood oestrogen concentrations after randomisation of women to groups receiving either oestradiol
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Table 5. Studies of cigarette smoking and blood hormone concentrations Reference
Study population and non-smokers
Sex hormones examined
Major differences in blood hormone concentrations between smokers and non-smokers
Additional adjustment for BMI
39
209 postmenopausal women not taking HRT
Serum E1, E2, ∆4A
None
Yes
46
694 premenopausal women with BMI <25 kg/m2 Plasma E1, E2
None
No
35
25 postmenopausal women randomised to 1 mg or 2 mg micronised E2
Serum E1, E2, unbound E2, Unbound E2 lower and SHBGSHBG binding capacity higher in smokers
37
38 postmenopausal women not taking HRT
Serum E1, E2, SHBG, non-SHBG-bound E2, ∆4A, DHEAS
∆4A and DHEAS higher in smokers
Yes
38
143 postmenopausal women not taking HRT
Serum E1, E2, ∆4A
∆4A higher in smokers
Yes
39
25 postmenopausal women not taking HRT
Serum E1, E2, ∆ A, DHEAS
∆4A and DHEAS higher in smokers
Yes
8
136 postmenopausal women randomised to 4 mg, 2 mg, or 1 mg E2 or placebo
Serum E1, E2
E1 and E2 lower in smokers
Randomisation
7
110 postmenopausal women randomised to oral or percutaneous E2 or placebo
Serum E1, E2
E1 and E2 lower in smokers after oral E2
Randomisation
45
147 premenopausal and postmenopausal women not taking HRT
Serum E2, DHEAS
None
Yes
43
233 postmenopausal women not taking HRT
Plasma DHEAS, ∆4A, E1, E2, SHBG
∆4A and DHEAS higher in
Yes
4
Randomisation
smokers
47
253 postmenopausal women not taking HRT
Serum SHBG
None
Yes
41
1219 premenopausal and postmenopausal women not taking HRT
Serum E1, E2, ∆4A, DHEAS, SHBG
None
Yes
44
88 premenopausal and postmenopausal women not taking HRT
Plasma ∆4A, E1, E2, free E2, SHBG
∆4A higher in smokers
Yes
4
27 premenopausal women not taking HRT, BMI <25 kg/m2
2-hydroxylation of injected radiolabelled E2
2-hydroxylation of E2 higher in smokers
No
40
267 women in the early postmenopause
Serum E1, E2, ∆4A
∆4A higher in smokers
No
42
84 perimenopausal and postmenopausal women Serum E1, E2, ∆4A
∆4A higher in smokers
No
BMI, body–mass index; E1, oestrone; E2, oestradiol; ∆ A, androstenedione; DHEAS, dehydroepiandrosterone. 4
or placebo (table 5).7,35 In a study of 25 postmenopausal women,35 unbound oestradiol was significantly lower among smokers than non-smokers both at baseline and shortly after micronised oestradiol taken orally. No important differences were observed between smokers and non-smokers in serum concentrations of oestrone or bound oestradiol. By contrast, a study in which 110 postmenopausal women were randomly assigned hormones (orally or percutaneously) or placebo7 found that smokers had lower concentrations of both oestrone and bound oestradiol than non-smokers after oral but not percutaneous hormone treatment for at least a year (concentrations of free oestrogens were not examined). These results indicate that smoking may affect the absorption or metabolism of hormones used in replacement therapy. Smoking and blood SHBG concentrations
Of the five studies that have examined the association between cigarette smoking and serum or plasma SHBG, none found any clear association. However, one of these studies43 found an inverse association between smoking and the ratio of oestradiol to SHBG, a measure of oestrogen activity. Cassidenti and colleagues35 found that unbound (but not SHBG-bound) oestradiol was significantly lower among smokers than non-smokers both at baseline and after oral oestradiol, suggesting an increased SHBG-binding capacity in the women who smoked.
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Smoking and blood androgen concentrations
In postmenopausal women, androgens are the major source of oestrogens, converted through an aromatisation process in fat deposits. Thus, adiposity is positively correlated with oestrogen concentrations in postmenopausal women. Of the nine studies that examined blood concentrations of androstenedione in smokers, all found higher circulating concentrations among current than never or former smokers (table 5). However, these same studies did not show clear variation in blood oestrogen concentrations by smoking status. Of the five studies that have examined cigarette smoking and dehydroepiandrosterone concentrations, three37,39,43 found increased blood concentrations among current smokers, and the other two41,45 found no clear differences according to smoking status. Studies of cigarette smoking and urinary hormone concentrations
Seven studies have examined cigarette smoking and urinary oestrogen concentrations (table 6);4,46,48–52 three found no major differences according to smoking status.46,49,52 The remaining four studies showed lower urinary oestriol concentrations among smokers than non-smokers, but mixed results for urinary oestrone and oestradiol.4,48,50,51 Although based on small sample sizes, the finding of lowered
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oestriol excretion among smokers, along with the increased excretion of 2-hydroxyoestrone among smokers observed in two studies of catecholoestrogens,49,51 may support the hypothesis that smoking decreases the formation of active oestrogen metabolites along the 16α-hydroxylation pathway.49 However, as mentioned earlier, only one study has directly examined 2-hydroxylation in relation to cigarette smoking.4
the weak, non-significant inverse associations observed in three other studies.17,26,29 The earlier age at natural menopause observed among smokers may be caused by the toxic effects on the ovaries of compounds contained in tobacco smoke, or by a deregulation in gonadotropin or sex-hormone metabolism caused by nicotine.74 Therefore, if viewed as a link in the causal chain between smoking and endometrialcancer risk, age at menopause should not be considered as a confounding variable.
Cigarette smoking and age at menopause Age at natural menopause varies substantially under the influence of genetic and environmental factors.53 A young age at menopause has been associated with reduced risk of endometrial cancer.2,5,6,16 For example, a 1-year decrease in age at menopause was associated with a decrease in risk of about 7%.16 Smoking may decrease the age at natural menopause.6 The reduced exposure to endogenous oestrogens after menopause may therefore account for the lower endometrial-cancer risk among smokers. At least 19 studies have examined the association between cigarette smoking and age at menopause,54–72 particularly age at natural (as opposed to surgical) menopause (table 7). In these studies, differences in age at menopause between smokers and non-smokers were measured in terms of differences in means54,59–61,63,67,71,73 medians,56–58,70,72 or the proportion of women who reached menopause by a certain age55,62,64–66,68,69 (these latter studies are not shown in table 7). These studies have shown that, on average, smokers have menopause 1·0–1·5 years earlier than non-smokers. There were no clear differences in the results between studies that adjusted estimates for obesity (and other covariates) and those that did not. In many studies of smoking and endometrial-cancer risk, age at menopause was not taken to be a potentially confounding variable. However, a significant inverse association between cigarette smoking and endometrialcancer risk was not altered by adjustment for age at menopause in four epidemiological studies,14,20,21,30 and adjustment for age at menopause did not appreciably alter
Comments The results of at least 26 epidemiological studies to date suggest that current or recent smoking is associated with a slightly to moderately decreased risk of endometrial cancer, particularly among postmenopausal women, and especially when smoking is of high intensity or long duration. Associations between cigarette smoking and increased risk of osteoporosis5–8 and attenuated effects of HRT among smokers7 suggest an antioestrogenic effect of smoking.5,6 However, circulating concentrations of oestrogen do not differ clearly between current smokers and former smokers or non-smokers. Possibly the type, rather than the absolute concentrations, of circulating oestrogens is important. Oestrogen can be metabolised along two major pathways, to 16␣-hydroxyoestrone or to 2-hydroxyoestrone.75 16␣-hydroxyoestrone is thought to be the more biologically active of the two oestrogen metabolites; it increases mammary epithelial proliferation rates in experimental studies.75 By contrast, 2-hydroxyoestrone might decrease proliferation and cancer risk.75 Therefore, if cigarette smoking increases oestradiol 2-hydroxylation, this mechanism may explain to some extent the observed inverse association between cigarette smoking and endometrialcancer risk. However, only one study4 has directly examined 2-hydroxylation in relation to cigarette smoking. Radiolabelled oestradiol was injected, and there was 50% more oestradiol 2-hydroxylation in premenopausal women who smoked at least 15 cigarettes per day than in nonsmokers.
Table 6. Studies of cigarette smoking and urinary hormone concentrations Reference
Study population
Sex hormones examined
Differences in urinary hormone excretion concentrations between smokers and non-smokers
Additional adjustment for BMI
51
16 postmenopausal women before and after taking 2 mg/day oral E2
Urinary E1, E2, E3, 16␣OHE1, 2OHE1
E1 and E3 lower, E2 and 2OHE1 higher in smokers after treatment
No
46
694 premenopausal women, BMI <25 kg/m2
Urinary E1, E2, E3
None
No
50
367 premenopausal and postmenopausal women
Urinary E1, E2, E3
E3 lower in postmenopausal smokers
Yes
48
106 premenopausal women not taking HRT
Urinary E1, E2, E3
E1, E2, and E3 lower in smokers in the luteal phase of the menstrual cycle
No
49
29 premenopausal women not taking HRT, BMI <25 kg/m2
Urinary E1, E2, E3, 16␣OHE1, 2OHE1
E3 lower and 2OHE1 higher in smokers
No
4
27 premenopausal women not taking HRT, BMI <25 kg/m2
Urinary E1, E3
E3 lower and the ratio of E3 to E1 lower in smokers
No
52
220 postmenopausal women not taking HRT
Urinary E1, E2, E3
None
Height and weight
BMI, body–mass index; E1, oestrone; E2, oestradiol; E3, oestriol; 16␣OHE1, 16␣-hydroxyoestrone; 2OHE1, 2-hydroxyoestrone.
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Table 7. Studies of cigarette smoking and age at menopause Reference
Sample size
Median or mean age at menopause (in years) Non-smokers Ever smokers Former smokers
Current smokers
Difference non-smokers minus current smokers (years)
49·9
1·0
50·5
Adjustment for BMI
54
15 464
50·9
56
1930
50·6
50·5
No
57
2149
50·3
49·9
58
9402
Cases 50·5 Controls 49·9
59
1279
49·1
47·6
Yes
67
236
49·4
47·4
Yes
60
3234
Cases 50·3 Controls 49·3
Cases 49·3 Controls 48·8
No
No 50·1
49·6
0·7
No
Cases 50·6 Controls 49·6
Cases 49·3 Controls 48·7
1·2 1·2
No
61
84 172
48·9
48·4
48·0*
0·9
Yes
63
656
49·4
49·2
47·7*
1·7
Yes
70
7828
52·0
50·3
1·7
No
71
1405
50·1
49·3
0·8
72
3497
51
73
3368
Cases 52 Controls 50
50
No No
Cases 51 Controls 50
1 0
No
*Crude values were calculated from the data provided. BMI, body–mass index.
A positive association between cigarette smoking and blood androgen concentrations has been observed consistently, especially with androstenedione, although its relevance to the association between smoking and endometrial-cancer risk is unknown.9 There has been speculation about the possible inhibitory effects of androgens on oestrogens,43 although there is currently no evidence to support such effects. Smoking is associated with lower relative bodyweight (body–mass index),5,18,40 yet positive associations have also been observed between smoking and waist-to-hip ratio,74 which may stem from the positive association between smoking and androgen concentrations. However, the latter association may be confounded by such factors as physical inactivity and higher intake of calories, total fat, and alcohol.74 Since adipose tissue is the main determinant of oestrogen concentrations among postmenopausal women and is inversely associated with smoking, relative bodyweight may partly mediate the inverse association between cigarette smoking and oestrogen. Indeed, statistical adjustment for the effects of body–mass index has attenuated the association between smoking and endometrial-cancer risk in some studies, which is consistent with the potential role of this variable as a mediator of the association between cigarette smoking and endometrial cancer. Most studies have adjusted for current relative bodyweight, although more relevant measures may include changes in bodyweight over time, waist-to-hip ratio, or duration of obesity. These measures may ultimately explain more of the association between smoking and endometrialcancer risk than does current relative bodyweight. The data presented here suggest that smoking lowers the age at which women reach menopause by an average of about 1·0–1·5 years, an association that appears to weaken with time since smoking cessation. Statistical adjustment for
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the effects of age at menopause does not alter appreciably the inverse associations between smoking and endometrialcancer risk observed in several epidemiological studies.14,17,20,21,26,29,30 Although a lower average bodyweight and earlier age at menopause among current smokers than nonsmokers certainly mediates some of the inverse association, the extent of this mediation remains unclear. Methodological issues, such as the potential for selection and recall bias in studies of retrospective design, may explain some or all of the association between smoking and endometrial-cancer risk. Prospective cohort studies of the association, in which the problems of selection and recall are minimised, have been scarce. Indeed, only three prospective studies of endometrial-cancer incidence have examined cigarette smoking,13,28,33 and their results have been null,13 equivocal,28 or have supported the hypothesised inverse association33 (the latter being the only large study of the three). Thus, the association between cigarette smoking and endometrial-cancer risk might be clarified further through the analysis of data from large prospective cohort studies. Cohort studies are not without limitations, however. For example, changes in smoking habits during follow-up can lead to misclassification of the exposure if, as has generally been the case, exposure is not updated after the baseline assessment. Cohort studies can also be limited by losses to follow-up, for which assumptions about the lack of bias due to systematic losses must be made. Moreover, whether smokers are more or less likely than non-smokers to have their endometrial cancers detected during follow-up is unknown. If an association is observed to differ according to values of another variable, such effect modification may provide clues to the mechanisms underlying the association. In relation to effect modification in the association between cigarette smoking and endometrial cancer by factors related to
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Search strategy and selection criteria We reviewed the published studies of smoking and endometrial-cancer risk obtained through searches of the Medline and Cancerlit databases, using keywords such as “smoking”, “endometrial cancer”, “endometrial neoplasms”, “oestrogens”, and “menopause”. We obtained additional published reports by cross-matching the references of relevant articles. We included unpublished data only when they have been cited as a “personal communication” in a published report (provided that an odds ratio or relative risk estimate was included). Virtually all published reports are in English, and we have restricted our review to those.
endogenous or exogenous hormones, the epidemiological data remain equivocal. On the one hand, ten studies have shown a reduced risk with current smoking that is stronger among, or limited to, postmenopausal women,11,20,26,30 women using HRT,14,21,31 parous women,33 and women who are obese.11,18 On the other hand, nine studies have found no important differences in the association according to menopausal status,18,21,33 obesity,21,33 or HRT use.11,18,30,33 However, the validity of a single oestrogen measurement as an indicator of a woman’s usual concentrations is unclear. Furthermore, none of the published reports have had sufficient statistical power to address meaningfully the issue of effect modification. In summary, the bulk of evidence from epidemiological studies suggests that cigarette smoking is associated with reduced risk of endometrial cancer among current smokers, perhaps mainly among postmenopausal women, and that the association weakens with time since quitting. Studies that have examined quantitative measures of exposure to cigarette smoke show greater reductions in risk among women who smoke either more intensely or for a longer duration than women who smoke relatively less. Thus far, the mechanisms by which this association may be driven remain unclear. Conflict of interest
None declared. References
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