Abstract
Introduction
Menopausal hormone therapy (MHT) is a well established factor in endometrial carcinogenesis, and therefore, could have prognostic implications. We investigated the effects of ever use of MHT on tumour grade and depth of myometrial invasion, and 5-year relative survival in postmenopausal endometrial cancer patients.
Materials and Methods
We used a nationwide, population-based case-case design, of 683 Swedish women aged 50–74 years diagnosed with endometrial cancer during 1994 to 1995, followed up to 5 years after diagnosis. We applied polytomous multiple logistic regression to investigate the associations between use of MHT and tumour grade, and myometrial invasion and Poisson regression for modelling 5-year excess mortality.
Results
Compared to never use, ever use of any MHT entailed lower risks of having moderately and poorly differentiated tumours. The lowest odds ratios for poorly differentiated tumours were seen for ever users of cyclically combined oestrogen-progestin [OR = 0.23 (95% CI = 0.07–0.73)]. Ever users of any form of MHT; particularly, medium potency MHT users, had significantly lower risks for tumours with deep myometrial invasion. Adjusted estimated relative excess hazard ratios revealed significantly improved survival for ever users of any form of MHT [RER = 0.40 (95% CI = 0.16–0.97)]; in particular ever users of any form of oestrogens [RER = 0.38 (95% CI = 0.15–0.99)].
Conclusion
Endometrial cancer patients who were ever users of MHT had more favourable tumour characteristics and better survival compared to never users of MHT. These findings support the notion that MHT induces endometrial cancer with less aggressive characteristics.
Keywords: Endometrial cancer, menopause hormone therapy, postmenopausal, tumour grade, myometrial invasion, relative survival, mortality
INTRODUCTION
Exogenous hormones are well established factors in endometrial carcinogenesis. The use of menopausal hormone therapy (MHT) has been found to variably, increase risk - with variable doses of unopposed oestrogens 1–5, cyclically combined oestrogens and progestins 6–9, or continuously combined oestrogens and progestins 3; decrease risk - with use of continuously combined regimes 6; or findings of no increased risk - for users of continuous combined regimes 6,8,10,11, or cyclically combined regimes. 10
The influence of MHT on endometrial cancer histopathologic characteristics and survival is less well addressed in large sample populations, and the results are conflicting. 12–21 Two studies found improved survival among users of oestrogens 14,21, one study found higher survival rates among oestrogen users before accounting for grade only 18, and two studies found an increased mortality in ever users of exogenous hormones 15, and among unopposed oestrogen users. 19 All previous studies investigating MHT, tumour characteristics and mortality have had limited power, with the exception of one study. 14
The association of MHT with a better prognosis in many cancers has been hypothesized to be due to the development of less aggressive tumours among MHT users. 14 On the other hand, it has been reasoned that findings of improved survival among users of oestrogens could be attributed to earlier detection of tumours due to increased medical surveillance among hormone users 14,18, or users being from higher socio-economic classes with better access to health care. 18 Using the unique equitable nature of the Swedish health care system, and a large population-based cohort, we addressed the effects of MHT use on the histopathological characteristics, and mortality in postmenopausal endometrial cancer patients.
PATIENTS AND METHODS
Study design
This study is an extension of a population-based case-control study of all Swedish women born in Sweden, aged 50 to 74 years of age between January 1, 1994 and December 31, 1995 and described in detail elsewhere. 5,9,22 To investigate the relationships between use of MHT, tumour characteristics and endometrial cancer relative survival, we used a case-case design; in which we obtained odds ratios and estimated excess hazard ratios as measures of relative risk comparing endometrial cancer cases’ ever and never use of MHT.
Parent study
During the study period, all endometrial cancer cases were identified through the six Regional Cancer Registries in Sweden, which provides complete information on incident cancers. The study was restricted to women who had not undergone hysterectomy or who had a previous diagnosis of breast or endometrial cancer. Eligible patients were those women with a histopathologically confirmed endometrial cancer as reported to the cancer registry. Of all eligible cases, 802 (76%) women participated in this initial questionnaire-based study. The primary reasons for non-participation were patient and physician refusal. Detailed information on the use of MHT, including the brand, dose and dates of use for each type of treatment were collected. Recall of MHT was facilitated by colour picture charts of all brands commercially available throughout Sweden during 1950 to 1995. Other relevant information collected covered data on medical, reproductive, lifestyle and anthropometric factors, including age at diagnosis, age at menarche, total parity, age at first and last births, age at natural menopause, body mass index, and smoking. Findings from this study have been previously published. 5,9,22–26
Present study – participants
For our current study, we performed additional linkage with the Swedish Cause of Death Register. In order to confirm previous endometrial cancers from the parent study, we linked the cohort of 802 cases to the national Swedish Cancer Register for confirmed endometrial cancers with an International Classification of Diseases (ICD) codes 172, 182 and C54 (7th, 9th and 10th editions respectively). Of the original 802 cases, two had missing personal identification numbers, making record linkage impossible, whilst 19 cases did not have a primary diagnosis of endometrial cancer, and 10 cases were benign. After restricting our analyses to postmenopausal women, the final cohort comprised 683 endometrial cancer patients born and resident in Sweden. Out of 1055 eligible women in the parent study, the participation rate in the current study was 65%.
Protocol
The study was approved by the ethical review board at the Karolinska Institute. Prior to participation via a mailed questionnaire, written consent was obtained from all patients. The mean interval between diagnosis and data collection was 8.4 months (standard deviation 4.6 months).
Classification of MHT
MHT use was categorized as having ever used the therapy, or never. Ever use of any particular MHT was not mutually exclusive; meaning a woman could be considered an ever user of more than one type of hormone therapy. The classification of MHT was as follows:
Any form of medium potency MHT
Any form of medium potency conjugated or synthetic oestrogens (oestradiol or other synthetic oestrogens); with or without progestins
-
Combined medium potency conjugated or synthetic oestrogens and progestins (progesterone-like progestins, i.e. 17-hydroxy-progesterone derivatives; or testosterone-like progestins, i.e. 19-nor-testosterone derivatives):
In cyclic form (cyclic progestins added to oestrogens for less than 16 days per cycle, mostly for 10 to 14 days per cycle)
In continuous form (progestins added to oestrogens for 19 or more days per cycle, typically daily)
Low potency vaginal oestrogens (oestriol 0.5 mg, dienoestrol 0.5 mg, or oestradiol 0.25 μg) applied daily during the initial two to three weeks of treatment, and followed by bi-weekly applications
Low potency oral oestrogens consisting of one or two milligrams per day
All hormone exposures were censored after an index date; defined as six months before the date of diagnosis.
Histopathological classification
Information regarding tumour characteristics was retrieved from all 35 pathology departments in Sweden and reviewed and reclassified by the study pathologist, who was blinded to hormone use and other exposures. The histological specimens of patients were reclassified as: endometrioid adenocarcinoma (n = 624 or 91%), or non-endometrioid adenocarcinoma comprising; seropapillary carcinoma (n = 36 or 5%), clear-cell carcinoma (n = 8 or 1%), adenoacanthoma (n = 3 or 0.4%), or adenosquamous carcinoma (n = 12 or 2%). Endometrioid adenocarcinomas were further classified as Grade 1 (well differentiated, n = 230 or 37%), Grade 2 (moderately differentiated, n = 281 or 45%), or Grade 3 (poorly differentiated, n = 113 or 18%). All endometrioid adenocarcinomas were analyzed separately to non-endometrioid adenocarcinomas. However, due to low power among the specific sub-types of non-endometrioid adenocarcinomas, we analyzed these carcinomas as one entity. Hysterectomy specimens were obtainable for 525 women (77%). Among these women, the depth of myometrial invasion was classified as none or less than 50% (n = 348 or 51%), and 50% or more of myometrial thickness or penetration through the serosa (n = 177 or 26%).
Follow-up data on survival
The Swedish National Registration Number, a unique 12-digit number for each Swedish resident was used to link the cohort with the Swedish National Population Register, and the Swedish Cause of Death Register, to obtain data on emigrations, and the dates of death respectively. The latter register covers all residents in Sweden. Patients were followed up to five years after the date of diagnosis of endometrial cancer. One woman was found to have emigrated during follow-up and was consequently censored at the date of emigration.
Statistical analyses
Tumour presentation
The significance of differences between tumour characteristics and use of MHT was evaluated using frequencies with Chi-square tests of association. All probability values of P<0.05 were considered significant. Odds ratios (OR) with 95% confidence intervals (CI) were calculated using polytomous multiple logistic regression 27 with tumour characteristics as the dependent variables; with the reference group being the category of tumour characteristic with the best prognosis, and the remaining categories as the outcome. Potential confounders were included in the models in a step-wise approach based on established biological knowledge of confounders particular to the associations of interest between MHT and prognostic tumour characteristics, rather than solely based on a 10% percentage shift in the estimates.
Relative survival analyses
Relative survival ratios, defined as the observed survival among patients divided by the expected survival of a directly comparable group from the general Swedish population and assumed to be free of endometrial cancer, were used to estimate excess mortality. The calculation of relative survival ratios accounts for competing causes of death. Observed survival for the cohort was based on deaths from all causes. The expected survival proportion was estimated from the Swedish population’s life tables stratified by age, sex, and calendar time. Estimates of the expected survival proportions are based on tables of annual probabilities of all-cause mortality in the general Swedish population. We used the Ederer II method 28 for estimating expected survival, in which the matched individuals were considered to be at risk until the corresponding endometrial cancer patient died or was censored. Estimated relative excess hazard ratios (RER), a measure of excess mortality, were modelled in the structure of generalized linear models using Poisson regression, and adjusted for age and calendar time of diagnosis, with never users of MHT as the reference group.
RESULTS
Background characteristics of the study participants in relation to ever use of MHT are summarized in Table 1. Age at diagnosis was significantly associated with use of all forms of MHT, with the exception of oestrogens. Ages at menarche, last birth and natural menopause were not associated with use of any MHT. A low body mass index was also significantly associated with increased use of all MHT, except low potency vaginal oestrogens. Medium potency MHT was more commonly used by non-smokers than smokers.
Table 1.
Distribution of background factors with ever use of menopausal hormone therapy for postmenopausal women diagnosed with endometrial cancer in Sweden between 1993 and 1995.
| MHT^ | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Any form of MHT | Oestrogens†∞ | Oestrogens with progestins∞‡∫Ω | Low potency vaginal oestrogens§ | Low potency oral oestrogens~ | |||||||
| Background factors | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | |
| n (%) | n (%) | n (%) | n (%) | n (%) | |||||||
| All 683 cases▲ | 486 | 196 | 499 | 182 | 556 | 110 | 584 | 98 | 546 | 135 | |
| Age at diagnosis | |||||||||||
| 50–59 years | 94 (64) | 53 (36) | 101 (69) | 45 (31) | 102 (71) | 42 (29) | 136 (93) | 11 (7) | 134 (92) | 12 (8) | |
| 60–69 years | 247 (72) | 94 (28) | 253 (74) | 88 (26) | 285 (86) | 48 (14) | 283 (83) | 58 (17) | 269 (79) | 72 (21) | |
| ≥70 years | 145 (75) | 49 (25) | 145 (75) | 49 (25) | 169 (89) | 20 (11) | 165 (85) | 29 (15) | 143 (74) | 51 (26) | |
| p-value* | 0.074 | 0.447 | 0.000 | 0.022 | 0.000 | ||||||
| Age at menarche | |||||||||||
| <12 years | 104 (74) | 36 (26) | 106 (76) | 34 (24) | 114 (83) | 23 (17) | 121 (86) | 19 (14) | 117 (84) | 23 (16) | |
| 12–14 years | 240 (68) | 112 (32) | 247 (70) | 105 (30) | 282 (83) | 60 (18) | 302 (86) | 50 (14) | 276 (78) | 76 (22) | |
| >14 years | 94 (74) | 33 (26) | 96 (76) | 30 (24) | 109 (87) | 16 (13) | 105 (83) | 22 (17) | 104 (83) | 22 (17) | |
| p-value* | 0.269 | 0.280 | 0.467 | 0.635 | 0.342 | ||||||
| Parity | |||||||||||
| nulliparous | 71 (72) | 28 (28) | 73 (74) | 26 (26) | 80 (82) | 18 (18) | 87 (88) | 12 (12) | 78 (79) | 21 (21) | |
| 1–2 children | 284 (70) | 123 (30) | 290 (71) | 116 (29) | 324 (82) | 72 (18) | 350 (86) | 57 (14) | 320 (79) | 86 (21) | |
| ≥3 children | 131 (74) | 45 (26) | 136 (77) | 40 (23) | 152 (88) | 20 (12) | 147 (84) | 29 (16) | 148 (84) | 28 (16) | |
| p-value* | 0.519 | 0.341 | 0.134 | 0.581 | 0.318 | ||||||
| Age at last birth | |||||||||||
| <25 years | 67 (66) | 34 (34) | 67 (67) | 33 (33) | 81 (84) | 16 (16) | 89 (88) | 12 (12) | 84 (84) | 16 (16) | |
| 25–34 years | 275 (72) | 105 (28) | 284 (75) | 96 (25) | 305 (82) | 66 (18) | 321 (84) | 59 (16) | 307 (81) | 73 (19) | |
| >34 years | 73 (72) | 28 (28) | 75 (74) | 26 (26) | 90 (91) | 9 (9) | 86 (85) | 15 (15) | 76 (75) | 25 (25) | |
| p-value* | 0.478 | 0.290 | 0.110 | 0.656 | 0.278 | ||||||
| Age at natural menopause | |||||||||||
| <50 years | 129 (72) | 49 (27) | 131 (74) | 47 (26) | 150 (86) | 24 (14) | 152 (85) | 26 (15) | 137 (77) | 41 (23) | |
| 50–54 years | 257 (70) | 108 (30) | 266 (73) | 99 (27) | 291 (82) | 65 (18) | 314 (86) | 51 (14) | 297 (81) | 68 (19) | |
| >54 years | 94 (75) | 32 (25) | 96 (76) | 30 (24) | 104 (84) | 20 (16) | 109 (87) | 17 (13) | 103 (82) | 23 (18) | |
| p-value* | 0.646 | 0.767 | 0.425 | 0.961 | 0.432 | ||||||
| Body mass index| | |||||||||||
| Underweight/normal | 158 (61) | 100 (39) | 165 (64) | 93 (36) | 193 (76) | 61 (24) | 215 (83) | 43 (17) | 196 (76) | 62 (24) | |
| overweight | 163 (73) | 61 (27) | 168 (75) | 56 (25) | 191 (87) | 29 (13) | 188 (84) | 36 (16) | 176 (79) | 48 (21) | |
| obese | 165 (82) | 35 (18) | 166 (83) | 33 (17) | 172 (90) | 20 (10) | 181 (90) | 19 (10) | 174 (87) | 25 (13) | |
| p-value* | 0.000 | 0.000 | 0.000 | 0.064 | 0.007 | ||||||
| Smoking | |||||||||||
| No | 139 (61) | 88 (39) | 142 (63) | 84 (37) | 167 (76) | 52 (24) | 200 (88) | 27 (12) | 185 (82) | 41 (18) | |
| Yes | 347 (76) | 108 (24) | 357 (78) | 98 (21) | 389 (87) | 58 (13) | 384 (84) | 71 (16) | 361 (79) | 94 (21) | |
| p-value* | 0.000 | 0.000 | 0.000 | 0.193 | 0.438 | ||||||
Menopausal hormone therapy. Ever use of MHT are not mutually exclusive; medium potency exogenous hormones unless otherwise stated
Ever use of oestrogens with or without progestins
Conjugated oestrogens; oestradiol; or other synthetic
Use of oestrogens and progestins, cyclic and/or continuous
Cyclic progestins: added to oestrogens for less than 16 days/cycle, mostly for 10–14 days; continuous progestins: added to oestrogens for 19 or more days per cycle, mostly daily
Progesterone-like progestins (17-hydroxy-progesterone derivatives); or testosterone-like progestins (19-nor-testosterone derivatives)
Oestriol 0.5 mg; dienoestrol 0.5 mg; oestradiol 0.25 μg. Daily applications during initial 2–3 weeks of treatment, followed by applications twice per week
1–2 mg daily
MHT users and non-users may not total to 683 cases due to missing values
p-value: Pearson Chi-squared tests of association between groups
Body mass index categories of underweight and normal were combined as only 4 cases were underweight
Ever use of MHT and tumour characteristics
The association of ever use of MHT with tumour grade and depth of myometrial invasion are shown in Table 2. We found ever use of any form of MHT was significantly associated with tumour grade (p-value = 0.02). Specific subtypes of MHT showed no significant associations with tumour grade. The depth of myometrial invasion was significantly associated with ever use of any form of MHT (p-value = 0.001); oestrogens (p-value = 0.002); oestrogens and progestins (p-value = 0.001); and in particular oestrogens with cyclic progestins (p-value = 0.001).
Table 2.
Distribution of ever use of menopausal hormone therapy with endometrial cancer tumour-defined characteristics in postmenopausal women.
| TUMOR CHARACTERISTICS | ||||||||
|---|---|---|---|---|---|---|---|---|
| Grade§ Frequency n(%) |
Depth of myometrial invasion Frequency n(%) |
|||||||
| Use of MHT| | 1 | 2 | 3 | other carcinomas | p-value*~ | none/<50% thick | ≥50% thick/through serosa | p-value* |
| Any form of MHT¶ | ||||||||
| No | 150 (31) | 203 (42) | 89 (18) | 44 (9) | 229 (62) | 141 (38) | ||
| Yes | 80 (41) | 78 (40) | 23 (12) | 15 (8) | 0.020 | 119 (77) | 36 (23) | 0.001 |
| Any form of oestrogens¶†∞ | ||||||||
| No | 157 (31) | 208 (42) | 89 (18) | 45 (9) | 238 (62) | 144 (38) | ||
| Yes | 72 (40) | 73 (40) | 23 (13) | 14 (7) | 0.090 | 109 (77) | 33 (23) | 0.002 |
| Oestrogens and Progestins¶∞‡∫Ω | ||||||||
| No | 182 (33) | 228 (41) | 96 (17) | 50 (9) | 272 (63) | 157 (37) | ||
| Yes | 43 (39) | 48 (44) | 13 (12) | 6 (5) | 0.256 | 68 (83) | 14 (17) | 0.001 |
| Oestrogens with cyclic progestins¶∞∫Ω | ||||||||
| No | 186 (32) | 240 (42) | 101 (18) | 50 (9) | 284 (64) | 161 (36) | ||
| Yes | 36 (42) | 36 (42) | 8 (9) | 5 (6) | 0.080 | 54 (86) | 9 (14) | 0.001 |
| Oestrogens with continuous progestins¶∞∫Ω | ||||||||
| No | 209 (34) | 257 (41) | 101 (16) | 52 (8) | 310 (65) | 165 (35) | ||
| Yes | 10 (27) | 17 (46) | 8 (22) | 2 (5) | 0.559 | 23 (79) | 6 (21) | 0.121 |
| Low potency vaginal oestrogens▲ | ||||||||
| No | 198 (34) | 242 (41) | 94 (16) | 50 (9) | 290 (65) | 157 (35) | ||
| Yes | 32 (33) | 39 (40) | 18 (18) | 9 (9) | 0.837 | 58 (74) | 20 (26) | 0.102 |
| Low potency oral oestrogens^ | ||||||||
| No | 175 (32) | 224 (41) | 95 (17) | 52 (10) | 274 (65) | 149 (35) | ||
| Yes | 54 (40) | 57 (42) | 17 (13) | 7 (5) | 0.194 | 73 (72) | 28 (28) | 0.152 |
Endometrioid carcinoma grades1–3 correspond to histological differentiation: well, moderate, and poor, respectively; other carcinomas include: seropapillary carcinoma, clear cell carcinoma, adenoacanthoma, and adenosquamous carcinoma
Ever use of menopausal hormone therapies are not mutually exclusive
p-value: Pearson Chi-squared tests of association between groups
p-value association does not include other carcinomas
Medium potency MHT
Ever use of oestrogens with or without progestins
Conjugated oestrogens; oestradiol; or other synthetic
Use of oestrogens and progestins, cyclic and/or continuous
Cyclic progestins: added to oestrogens for less than 16 days/cycle, mostly for 10–14 days; continuous progestins: added to oestrogens for 19 or more days per cycle, mostly daily
Progesterone-like progestins (17-hydroxy-progesterone derivatives); or testosterone-like progestins (19-nor-testosterone derivatives)
Oestriol 0.5 mg; dienoestrol 0.5 mg; oestradiol 0.25 μg. Daily applications during initial 2–3 weeks of treatment, followed by applications twice per week
1–2 mg daily
Overall, ever use of any MHT entailed lower risk estimates of having tumours of moderate and poorly differentiated grade compared to never use (Table 3). After multivariate adjustment, we found ever users of cyclic oestrogens and progestins, and low potency oral oestrogens to have significantly lower risks of having the poorest differentiation of tumour grade [OR = 0.23 (95% CI = 0.07–0.73)]; and [OR = 0.44 (95% CI = 0.21–0.91)]; respectively.
Table 3.
The relation of ever use of menopausal hormone therapy to endometrial cancer tumour grade in postmenopausal women.
| TUMOR GRADE^ |
||||
|---|---|---|---|---|
| Unadjusted OR (95% CI)∫ | Adjusted OR (95% CI)∫▲ | |||
| Use of MHT| | 2 | 3 | 2 | 3 |
| Any form of MHT¶ | ||||
| No | ||||
| Yes | 0.72 (0.49–1.05) | 0.48 (0.28–0.82) | 0.82 (0.47–1.45) | 0.52 (0.23–1.20) |
| Any form of oestrogens¶†∞ | ||||
| No | ||||
| Yes | 0.76 (0.52–1.13) | 0.56 (0.33–0.96) | 0.74 (0.42–1.32) | 0.59 (0.27–1.31) |
| Oestrogens and Progestins¶∞‡∫Ω | ||||
| No | ||||
| Yes | 0.89 (0.56–1.40) | 0.57 (0.29–1.12) | 0.89 (0.50–1.57) | 0.55 (0.22–1.33) |
| Oestrogens with cyclic progestins¶∞∫Ω | ||||
| No | ||||
| Yes | 0.78 (0.47–1.28) | 0.41 (0.18–0.91) | 0.64 (0.34–1.18) | 0.23 (0.07–0.73) |
| Low potency vaginal Oestrogens§ | ||||
| No | ||||
| Yes | 1.00 (0.60–1.65) | 1.18 (0.63–2.22) | 0.91 (0.50–1.64) | 1.00 (0.48–2.07) |
| Low potency oral oestrogens~ | ||||
| No | ||||
| Yes | 0.82 (0.54–1.26) | 0.58 (0.32–1.05) | 0.74 (0.45–1.20) | 0.44 (0.21–0.91) |
Endometrioid carcinoma grades1–3 correspond to histological differentiation: well, moderate, and poor, respectively
Ever use of menopausal hormone therapies are not mutually exclusive
OR: odds ratio; CI: confidence interval; reference group: grade 1 endometrioid carcinoma and never users of each type of MHT
All MHT exposure models adjusted for age at diagnosis, parity, age at natural menopause, body mass index, use of oral contraceptives, age at last birth, and smoking; with additional adjustments for the following models:
Any form of MHT - duration of use of oestrogens only, duration of use of progestins only, and duration of use of low potency oral oestrogens
Any form of oestrogens - duration of use of oestrogens and progestins (cyclic and/or continuous), duration of use of progestins only, and duration of use of low potency oral oestrogens
Oestrogens and Progestins (cyclic and continuous) - duration of use of oestrogens only, duration of use of progestins only, duration of use of low potency oral oestrogens; and for the analyses of cyclic addition of progestins also adjusted for duration of use of continuous use of progestins, and vice versa
Low potency vaginal and oral oestrogens - duration of use of oestrogens only, duration of use of progestins only, and duration of use of oestrogens and progestins (cyclic and/or continuous)
Medium potency MHT
Ever use of oestrogens with or without progestins
Conjugated oestrogens; oestradiol; or other synthetic
Use of oestrogens and progestins, cyclic and/or continuous
Cyclic progestins: added to oestrogens for less than 16 days/cycle, mostly for 10–14 days; continuous progestins: added to oestrogens for 19 or more days per cycle, mostly daily
Progesterone-like progestins (17-hydroxy-progesterone derivatives); or testosterone-like progestins (19-nor-testosterone derivatives)
Oestriol 0.5 mg; dienoestrol 0.5 mg; oestradiol 0.25 μg. Daily applications during initial 2–3 weeks of treatment, followed by applications twice per week
1–2 mg daily
The protective effect of ever use of MHT against tumours with a potential poor prognosis was observed for the depth of myometrial invasiveness (Table 4). After multivariate adjustment, we found ever users of any form of MHT; in particular, users of any form of oestrogens, combined oestrogens and progestins, and cyclic use of oestrogens and progestins; to have significantly lower risks of having tumours with the deepest myometrial invasion.
Table 4.
The relation of ever use of menopausal hormone therapy to endometrial cancer depth of myometrial invasion in postmenopausal women.
| DEPTH OF MYOMETRIAL INVASION |
||
|---|---|---|
| Unadjusted OR (95% CI)Σ | Adjusted OR (95% CI)Σ▲ | |
| Use of MHT| | ≥50% thick/through serosa | ≥50% thick/through serosa |
| Any form of MHT¶ | ||
| No | ||
| Yes | 0.49 (0.32–0.75) | 0.34 (0.17–0.71) |
| Any form of oestrogens¶†∞ | ||
| No | ||
| Yes | 0.50 (0.32–0.78) | 0.46 (0.23–0.91) |
| Oestrogens and Progestins¶∞‡∫Ω | ||
| No | ||
| Yes | 0.36 (0.19–0.65) | 0.34 (0.15–0.76) |
| Oestrogens with cyclic progestins¶∞∫Ω | ||
| No | ||
| Yes | 0.29 (0.14–0.61) | 0.27 (0.10–0.73) |
| Low potency vaginal oestrogens§ | ||
| No | ||
| Yes | 0.63 (0.37–1.10) | 0.67 (0.36–1.23) |
| Low potency oral oestrogens~ | ||
| No | ||
| Yes | 0.70 (0.44–1.14) | 0.60 (0.34–1.03) |
Ever use of menopausal hormone therapies are not mutually exclusive
OR: odds ratio; CI: confidence interval; reference group: myometrial invasion <50% thick or none, and never users of each type of MHT
All MHT exposure models adjusted for age at diagnosis, parity, age at natural menopause, body mass index, use of oral contraceptives, age at last birth, and smoking; with additional adjustments for the following models:
Any form of MHT - duration of use of oestrogens only, duration of use of progestins only, and duration of use of low potency oral oestrogens
Any form of oestrogens - duration of use of oestrogens and progestins (cyclic and/or continuous), duration of use of progestins only, and duration of use of low potency oral oestrogens
Oestrogens and Progestins (cyclic and continuous) - duration of use of oestrogens only, duration of use of progestins only, duration of use of low potency oral oestrogens; and for the analyses of cyclic addition of progestins also adjusted for duration of use of continuous use of progestins, and vice versa
Low potency vaginal and oral oestrogens - duration of use of oestrogens only, duration of use of progestins only, and duration of use of oestrogens and progestins (cyclic and/or continuous)
Medium potency exogenous hormones
Ever use of oestrogens with or without progestins
Conjugated oestrogens; oestradiol; or other synthetic
Use of oestrogens and progestins, cyclic and/or continuous
Cyclic progestins: added to oestrogens for less than 16 days/cycle, mostly for 10–14 days; continuous progestins: added to oestrogens for 19 or more days per cycle, mostly daily
Progesterone-like progestins (17-hydroxy-progesterone derivatives); or testosterone-like progestins (19-nor-testosterone derivatives)
Oestriol 0.5 mg; dienoestrol 0.5 mg; oestradiol 0.25 μg. Daily applications during initial 2–3 weeks of treatment, followed by applications twice per week
1–2 mg daily
MHT and relative survival
Overall, we observed 96 deaths during 3179 person-years at risk during five years of follow-up (Table 5). We found that all never users of any MHT had slightly lower relative survival ratios at five years. Analyses of the adjusted estimated relative excess hazard ratios revealed significantly improved survival for ever users of any form of MHT [RER = 0.40 (95% CI = 0.16–0.97)]; in particular ever users of any form of oestrogens [RER = 0.38 (95% CI = 0.15–0.99)]. All estimates for specific forms of MHT were below unity. We additionally conducted analyses of the adjusted excess hazard ratio model excluding non-endometrioid Type II tumours, and the significance of results remained unchanged.
Table 5.
Observed and relative survival ratios using the Ederer II method, and adjusted estimated relative excess hazard ratios (RER) from the relative survival model using Poisson regression for postmenopausal women diagnosed with endometrial cancer in Sweden during 1993–1995 with 5-year follow-up; in relation to menopausal hormone therapy use.
| 5 YEARS | 5-YEAR FOLLOW-UP | |||
|---|---|---|---|---|
| Use of MHT| | Observed survival | Relative survival ratio (95% CI) | Observed number of deaths | RER (95% CI)▲ |
| All 683 cases with 3179 person-years at risk for 5-year follow-up | - | - | 96 | - |
| Any form of MHT¶ | ||||
| No | 0.84 | 0.90 (0.87–0.94) | 75 | 1.00 (reference) |
| Yes | 0.89 | 0.95 (0.90–0.99) | 21 | 0.40 (0.16–0.97) |
| Any form of oestrogens¶†∞ | ||||
| No | 0.85 | 0.91 (0.87–0.94) | 76 | 1.00 (reference) |
| Yes | 0.89 | 0.95 (0.89–0.99) | 20 | 0.38 (0.15–0.99) |
| Oestrogens and Progestins¶∞‡∫Ω | ||||
| No | 0.85 | 0.91 (0.87–0.94) | 84 | 1.00 (reference) |
| Yes | 0.93 | 0.98 (0.91–1.02) | 8 | 0.17 (0.01–1.96) |
| Oestrogens with cyclic progestins¶∞∫Ω | ||||
| No | 0.85 | 0.91 (0.88–0.94) | 86 | 1.00 (reference) |
| Yes | 0.94 | 0.99 (0.92–1.04) | 5 | 0.23 (0.04–1.47) |
| Low potency vaginal oestrogens§ | ||||
| No | 0.86 | 0.92 (0.88–0.94) | 83 | 1.00 (reference) |
| Yes | 0.87 | 0.93 (0.84–0.99) | 13 | 0.95 (0.39–2.29) |
| Low potency oral oestrogens~ | ||||
| No | 0.86 | 0.91 (0.88–0.94) | 78 | 1.00 (reference) |
| Yes | 0.87 | 0.94 (0.86–0.99) | 18 | 0.76 (0.34–1.71) |
Ever use of menopausal hormone therapies are not mutually exclusive
Adjusted for age and year of diagnosis
Medium potency MHT
Ever use of oestrogens with or without progestins
Conjugated oestrogens; oestradiol; or other synthetic
Use of oestrogens and progestins, cyclic and/or continuous
Cyclic progestins: added to oestrogens for less than 16 days/cycle, mostly for 10–14 days; continuous progestins: added to oestrogens for 19 or more days per cycle, mostly daily
Progesterone-like progestins (17-hydroxy-progesterone derivatives); or testosterone-like progestins (19-nor-testosterone derivatives)
Oestriol 0.5 mg; dienoestrol 0.5 mg; oestradiol 0.25 μg. Daily applications during initial 2–3 weeks of treatment, followed by applications twice per week
1–2 mg daily
DISCUSSION
In our study, ever use of any MHT seemed to induce less aggressive tumours - as measured by tumour grade and depth of myometrial invasion; with consequently better survival observed among ever users compared to never users. We found stronger associations of increased 5-year survival among medium potency MHT users than among low potency vaginal and oral oestrogens.
Our study’s findings showing that MHT users have less aggressive tumours are in agreement with all previous studies investigating MHT and endometrial tumour characteristics, despite methodological differences 13,14,16,17,20,21, with the exception of two studies. 12,20 One example of a study showing consistent results with our findings is the large study by Collins and colleagues 14, where oestrogen use was associated with earlier stage, lower grade of tumour and less frequent myometrial invasion. On the other hand, the most recent study, the Women’s Health Initiative Randomized Trial 12, found no ascertainable differences in the distribution of tumour histology, stage or grade of endometrial cancer between users and non-users of MHT.
Previous studies investigating MHT and endometrial cancer survival have been conflicting. Similar to our findings of significantly better survival among users of MHT are the majority of other studies. 13,14,18,21,29,30 Contrastingly, some studies found an increased mortality with MHT use. 15,19 The study by Schairer and colleagues 19 found that mortality from endometrial cancer was not related to the prescription of weak oestrogens with or without progestins; however mortality was reportedly 40% higher in women prescribed more potent unopposed oestrogens. In the recent study by Khan and colleagues 15, a significant increased risk of endometrial cancer mortality was found for ever users of sex hormones, however, this study was severely hampered by a small number of deaths.
Previously, it has been argued that the findings of improved survival among users of MHT could be attributable to earlier detection of tumours due to increased medical surveillance among ever users of hormone therapies 14,18, or hormone therapy users being from more socio-economically advantaged classes with greater accessibility to health care. 18 In our study, we utilized data from Sweden with the unique equitable nature of the Swedish health care system, which would be less prone to inequalities in health and health care evident in other European countries. 31–34 In recent comparisons of 23 European countries using the EUROCARE study investigating cancer patient survival, Sweden had the second highest 5-year relative survival for breast, ovarian and endometrial cancers. 31,33,34 Similarly, in a recent study investigating the socioeconomic inequalities in health in 22 European countries, Sweden is one of the few countries in Europe with the lowest average rate of death from any cause, and one of the lowest due to causes amenable to medical intervention. 32 Consequently, the improved survival observed in our study would be unlikely to be due to earlier detection of tumours as a result of increased medical surveillance among ever users of MHT.
In the present study, we have been able to show findings consistent with the interpretation of a better prognosis for both tumour characteristics and survival with ever use of MHT. Furthermore, when comparing the particular MHT compounds used in this study, for use of any type of medium potency ingested MHT; the estimates for survival are fairly similar and well below unity. In comparison, low potency oral and vaginal oestrogens are closer to unity, with low potency vaginal oestrogens showing almost no effect. This is biologically plausible given that expected effects would be weaker for lower potency preparations, and the weakest with topical vaginal applications. This additionally provides further evidence of our findings not being due to detection and surveillance bias.
Cancers associated with prior MHT use may result in less aggressive tumours, thereby resulting in potentially improved survival. 14 This hypothesis is supported by the bulk of recent evidence for both breast 35–38 and ovarian 39 cancers, but contrasted by a few studies. 40,41 Despite the extent of evidence reporting favourable tumour characteristics and survival among users of MHT for endometrial, breast and ovarian cancers, this does not imply that MHT use is safe, simply because of an illusive improvement in survival. 14
Strengths and limitations
Our study is one of the largest population-based studies of endometrial cancer cases, with detailed information on MHT exposures and confounding factors. The histopathological classification of tumours was consistent, and undifferentiated in relation to the use of MHT. We censored exposures at an index date of 6 months prior to diagnosis, thereby reducing the possibility of detection bias. However, some limitations of the study included limited power to analyze in detail the use of continuous combined oestrogens and progestins therapy, as well as exclusive use of the hormone regimes, in addition to evaluating the effects of differing doses, duration, and recency of use of hormonal treatments. We cannot exclude the possibility that women receiving menopausal hormone therapies could have a greater likelihood of more intense surveillance; as oestrogens are established in the causation of endometrial cancer. However, the nature of the Swedish health care system would be less prone to such differences with equitable access to all citizens, and would ensure that primary symptoms result in an immediate endometrial biopsy, regardless of hormonal exposures. Our findings of a better prognosis among users of MHT may partly be explained by a selection process in which women who were healthier and had fewer risk factors for endometrial cancer, may have been more likely to be prescribed MHT, as opposed to nonusers. Finally, selection bias in the parent study may account for our findings of a better prognosis. It is conceivable that patients with advanced stages of disease may have been less willing to participate. However, all comparisons in our study were made between women who participated and could therefore be considered internally valid.
Conclusion
The findings of our study show that ever users of MHT have favourable tumour characteristics and improved survival compared to never users of MHT with endometrial cancer. Notwithstanding the bulk of evidence whereby users of MHT have been shown to have improved tumour characteristics and survival for endometrial, breast, and ovarian cancers, evidence to the contrary from large studies has been reported and continues to be cause for concern. Caution is imperative in the decision to prescribe MHT to women seeking relief for climacteric symptoms, and should be based on a thorough work up of female cancer risk factors, as well as the overall health of patients seeking MHT treatments.
Acknowledgments
We are indebted to Dr Anders Lindgren for performing the histopathological review of all endometrial cancers, and to the health care staff collaborating in patient recruitment.
Acknowledgements of research support for the study: The data collection for this study was supported by the United States National Institute of Health, the American Cancer Society, and the Swedish Cancer Society.
Footnotes
Conflict of interest statement: None declared.
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References
- 1.Cushing KL, Weiss NS, Voigt LF, McKnight B, Beresford SA. Risk of endometrial cancer in relation to use of low-dose, unopposed estrogens. Obstet Gynecol. 1998;91:35–9. doi: 10.1016/s0029-7844(97)00577-2. [DOI] [PubMed] [Google Scholar]
- 2.Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol. 1995;85:304–13. doi: 10.1016/0029-7844(94)00383-O. [DOI] [PubMed] [Google Scholar]
- 3.Lacey JV, Jr, Brinton LA, Lubin JH, Sherman ME, Schatzkin A, Schairer C. Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2005;14:1724–31. doi: 10.1158/1055-9965.EPI-05-0111. [DOI] [PubMed] [Google Scholar]
- 4.Persson I, Weiderpass E, Bergkvist L, Bergstrom R, Schairer C. Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes Control. 1999;10:253–60. doi: 10.1023/a:1008909128110. [DOI] [PubMed] [Google Scholar]
- 5.Weiderpass E, Baron JA, Adami HO, et al. Low-potency oestrogen and risk of endometrial cancer: a case-control study. Lancet. 1999;353:1824–8. doi: 10.1016/S0140-6736(98)10233-7. [DOI] [PubMed] [Google Scholar]
- 6.Beral V, Bull D, Reeves G. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2005;365:1543–51. doi: 10.1016/S0140-6736(05)66455-0. [DOI] [PubMed] [Google Scholar]
- 7.Beresford SA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet. 1997;349:458–61. doi: 10.1016/S0140-6736(96)07365-5. [DOI] [PubMed] [Google Scholar]
- 8.Pike MC, Peters RK, Cozen W, et al. Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst. 1997;89:1110–6. doi: 10.1093/jnci/89.15.1110. [DOI] [PubMed] [Google Scholar]
- 9.Weiderpass E, Adami HO, Baron JA, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst. 1999;91:1131–7. doi: 10.1093/jnci/91.13.1131. [DOI] [PubMed] [Google Scholar]
- 10.Lacey JV, Jr, Leitzmann MF, Chang SC, et al. Endometrial cancer and menopausal hormone therapy in the National Institutes of Health-AARP Diet and Health Study cohort. Cancer. 2007;109:1303–11. doi: 10.1002/cncr.22525. [DOI] [PubMed] [Google Scholar]
- 11.Sturdee DW, Ulrich LG, Barlow DH, et al. The endometrial response to sequential and continuous combined oestrogen-progestogen replacement therapy. BJOG. 2000;107:1392–400. doi: 10.1111/j.1471-0528.2000.tb11654.x. [DOI] [PubMed] [Google Scholar]
- 12.Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial. JAMA. 2003;290:1739–48. doi: 10.1001/jama.290.13.1739. [DOI] [PubMed] [Google Scholar]
- 13.Chapman JA, DiSaia PJ, Osann K, Roth PD, Gillotte DL, Berman ML. Estrogen replacement in surgical stage I and II endometrial cancer survivors. Am J Obstet Gynecol. 1996;175:1195–200. doi: 10.1016/s0002-9378(96)70027-3. [DOI] [PubMed] [Google Scholar]
- 14.Collins J, Donner A, Allen LH, Adams O. Oestrogen use and survival in endometrial cancer. Lancet. 1980;2:961–4. doi: 10.1016/s0140-6736(80)92115-7. [DOI] [PubMed] [Google Scholar]
- 15.Khan M, Mori M, Sakauchi F, et al. Risk of endometrial cancer mortality by ever-use of sex hormones and other factors in Japan. Asian Pac J Cancer Prev. 2006;7:260–6. [PubMed] [Google Scholar]
- 16.Mittal KR, Barwick KW. Endometrial adenocarcinoma involving adenomyosis without true myometrial invasion is characterized by frequent preceding estrogen therapy, low histologic grades, and excellent prognosis. Gynecol Oncol. 1993;49:197–201. doi: 10.1006/gyno.1993.1107. [DOI] [PubMed] [Google Scholar]
- 17.Nyholm HC, Nielsen AL, Norup P. Endometrial cancer in postmenopausal women with and without previous estrogen replacement treatment: comparison of clinical and histopathological characteristics. Gynecol Oncol. 1993;49:229–35. doi: 10.1006/gyno.1993.1112. [DOI] [PubMed] [Google Scholar]
- 18.Robboy SJ, Bradley R. Changing trends and prognostic features in endometrial cancer associated with exogenous estrogen therapy. Obstet Gynecol. 1979;54:269–77. [PubMed] [Google Scholar]
- 19.Schairer C, Adami HO, Hoover R, Persson I. Cause-specific mortality in women receiving hormone replacement therapy. Epidemiology. 1997;8:59–65. doi: 10.1097/00001648-199701000-00010. [DOI] [PubMed] [Google Scholar]
- 20.Shapiro JA, Weiss NS, Beresford SA, Voigt LF. Menopausal hormone use and endometrial cancer, by tumor grade and invasion. Epidemiology. 1998;9:99–101. [PubMed] [Google Scholar]
- 21.Smith DC, Prentice RL, Bauermeister DE. Endometrial carcinoma: histopathology, survival, and exogenous estrogens. Gynecol Obstet Invest. 1981;12:169–79. doi: 10.1159/000299600. [DOI] [PubMed] [Google Scholar]
- 22.Weiderpass E, Adami HO, Baron JA, Magnusson C, Lindgren A, Persson I. Use of oral contraceptives and endometrial cancer risk (Sweden) Cancer Causes Control. 1999;10:277–84. doi: 10.1023/a:1008945721786. [DOI] [PubMed] [Google Scholar]
- 23.Moradi T, Weiderpass E, Signorello LB, Persson I, Nyren O, Adami HO. Physical activity and postmenopausal endometrial cancer risk (Sweden) Cancer Causes Control. 2000;11:829–37. doi: 10.1023/a:1008919717930. [DOI] [PubMed] [Google Scholar]
- 24.Weiderpass E, Adami HO, Baron JA, et al. Organochlorines and endometrial cancer risk. Cancer Epidemiol Biomarkers Prev. 2000;9:487–93. [PubMed] [Google Scholar]
- 25.Weiderpass E, Persson I, Adami HO, Magnusson C, Lindgren A, Baron JA. Body size in different periods of life, diabetes mellitus, hypertension, and risk of postmenopausal endometrial cancer (Sweden) Cancer Causes Control. 2000;11:185–92. doi: 10.1023/a:1008946825313. [DOI] [PubMed] [Google Scholar]
- 26.Weiderpass E, Persson I, Melhus H, Wedren S, Kindmark A, Baron JA. Estrogen receptor alpha gene polymorphisms and endometrial cancer risk. Carcinogenesis. 2000;21:623–7. doi: 10.1093/carcin/21.4.623. [DOI] [PubMed] [Google Scholar]
- 27.Begg C, Gray R. Calculation of polychotomous logistic regression parameters using individualized regressions. Biometrika. 1984;71:11–18. [Google Scholar]
- 28.Ederer F, Axtell LM, Cutler SJ. The relative survival rate: a statistical methodology. Natl Cancer Inst Monogr. 1961;6:101–21. [PubMed] [Google Scholar]
- 29.Persson I, Yuen J, Bergkvist L, Schairer C. Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy--long-term follow-up of a Swedish cohort. Int J Cancer. 1996;67:327–32. doi: 10.1002/(SICI)1097-0215(19960729)67:3<327::AID-IJC4>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
- 30.Suriano KA, McHale M, McLaren CE, Li KT, Re A, DiSaia PJ. Estrogen replacement therapy in endometrial cancer patients: a matched control study. Obstet Gynecol. 2001;97:555–60. doi: 10.1016/s0029-7844(00)01221-7. [DOI] [PubMed] [Google Scholar]
- 31.Berrino F, De Angelis R, Sant M, et al. Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995–99: results of the EUROCARE-4 study. Lancet Oncol. 2007;8:773–83. doi: 10.1016/S1470-2045(07)70245-0. [DOI] [PubMed] [Google Scholar]
- 32.Mackenbach JP, Stirbu I, Roskam AJ, et al. Socioeconomic inequalities in health in 22 European countries. N Engl J Med. 2008;358:2468–81. doi: 10.1056/NEJMsa0707519. [DOI] [PubMed] [Google Scholar]
- 33.Verdecchia A, Baili P, Quaglia A, et al. Patient survival for all cancers combined as indicator of cancer control in Europe. Eur J Public Health. 2008;18:527–32. doi: 10.1093/eurpub/ckn022. [DOI] [PubMed] [Google Scholar]
- 34.Karim-Kos HE, de Vries E, Soerjomataram I, Lemmens V, Siesling S, Coebergh JW. Recent trends of cancer in Europe: a combined approach of incidence, survival and mortality for 17 cancer sites since the 1990s. Eur J Cancer. 2008;44:1345–89. doi: 10.1016/j.ejca.2007.12.015. [DOI] [PubMed] [Google Scholar]
- 35.Collins JA, Blake JM, Crosignani PG. Breast cancer risk with postmenopausal hormonal treatment. Hum Reprod Update. 2005;11:545–60. doi: 10.1093/humupd/dmi028. [DOI] [PubMed] [Google Scholar]
- 36.Daling JR, Malone KE, Doody DR, et al. Association of regimens of hormone replacement therapy to prognostic factors among women diagnosed with breast cancer aged 50–64 years. Cancer Epidemiol Biomarkers Prev. 2003;12:1175–81. [PubMed] [Google Scholar]
- 37.Gapstur SM, Morrow M, Sellers TA. Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa Women’s Health Study. JAMA. 1999;281:2091–7. doi: 10.1001/jama.281.22.2091. [DOI] [PubMed] [Google Scholar]
- 38.Rosenberg LU, Granath F, Dickman PW, et al. Menopausal hormone therapy in relation to breast cancer characteristics and prognosis: a cohort study. Breast Cancer Res. 2008;10:R78. doi: 10.1186/bcr2145. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Mascarenhas C, Lambe M, Bellocco R, et al. Use of hormone replacement therapy before and after ovarian cancer diagnosis and ovarian cancer survival. Int J Cancer. 2006;119:2907–15. doi: 10.1002/ijc.22218. [DOI] [PubMed] [Google Scholar]
- 40.Beral V, Bull D, Green J, Reeves G. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet. 2007;369:1703–10. doi: 10.1016/S0140-6736(07)60534-0. [DOI] [PubMed] [Google Scholar]
- 41.Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–33. doi: 10.1001/jama.288.3.321. [DOI] [PubMed] [Google Scholar]