Tubal sterilization and the risk of endometrial cancer

Several animal and human studies suggest that tubal occlusion may curtail ovarian function, altering the production and balance of endogenous estrogens and progesterone, 2 hormones closely related to endometrial carcinogenesis. Despite this, and the increasing world-wide popularity of this method of contraception, little is known about its relationship with the risk of developing endometrial cancer. To assess whether tubal sterilization influences a woman's risk of developing epithelial endometrial carcinoma, data from a large multicenter population-based case-control study of endometrial cancer were analyzed. Cases were 437 women aged 20 to 54 years with histologically confirmed epithelial endometrial cancer ascertained through 6 population-based cancer registries in the United States. Controls were 3200 women selected at random from the populations of the areas from which the cases were detected. As compared with women who had never had tubal sterilization, women who had had this surgery had a crude odds ratio of 0.58 [95% confidence interval (CI), 0.43–0.78]. However, after adjusting for the combined confounding effects of age and parity, the magnitude of the protective association decreased to 0.87 (95% CI, 0.63–1.20). The magnitude of the protective effect did not significantly change with years since surgery or age at surgery. Although a modest, non-significant protective effect is suggested, these findings indicate that tubal sterilization does not substantially alter the risk of developing epithelial endometrial cancer in women 20 to 54 years of age. If there is an increase in risk, these data indicate that it is unlikely to be any greater than 20%. © 1996 Wiley-Liss, Inc.     

Oral contraceptives and endometrial cancer: Do other risk factors modify the association?

The joint effect of use of combination-type oral contraceptives and other exposure factors on risk of endometrial cancer was examined in data from a multicenter case-control study conducted in 5 areas of the United States. Cases were 405 women with histologically confirmed invasive epithelial endometrial cancer first treated at one of 7 participating hospitals. A total of 297 population-based controls of similar age, race, and geographic area were selected as a comparison group. Information on exposure factors was derived from in-person interviews. Combination-type oral contraceptive (COC) use was associated with a significant reduction in risk of endometrial cancer, with an adjusted odds ratio (OR) of 0.4 (95% confidence interval 0.3 to 0.7) for ever compared to never use. Long-term (≥ 10 years) users experienced a markedly lower risk (OR = 0.2). Women who discontinued COC use ≥20 years earlier remained at reduced risk (OR = 0.7) compared with non-users. The negative association with COC use was apparent regardless of the presence or level of several other risk factors for endometrial cancer, including age, menopausal status, parity, obesity, ever-use of menopausal estrogens, smoking history, or history of infertility. The magnitude of the negative association observed in COC users, however, was considerably diminished in women with no full-term births and in women who subsequently used replacement estrogens for 3 or more years. These results provide new evidence that the protective effect of COC use lasts for 20 or more years after use is discontinued, and highlight several sub-groups of users in whom the level of protection is attenuated by the presence of other risk factors for this disease.     

Exogenous estrogens and development of breast and endometrial cancer

The risk of breast cancer and endometrial cancer in 1483 menopausal and postmenopausal women who had received estrogen therapy for other than contraceptive use was examined. The incidence and mortality rates of the study cohort (cohort A) were compared with the age-specific cancer incidence and mortality rates of the female populations of Ontario (cohort B) and of Saskatchewan (cohort C). A significant difference was found in each of the two comparisons between the observed and expected survival curves for breast cancer incidence and breast cancer mortality. However, the incidence rate of endometrial cancer in the study cohort (cohort A) did not differ significantly from the rates of the reference populations (cohorts B and C). The results suggest that the women in the study may have received some protective effect against breast cancer by taking estrogens, but the estrogens did not protect them against endometrial cancer and may indeed have predisposed them to this cancer.     

A population‐based cohort study on the use of hormone treatment and endometrial cancer in southern Sweden

Our aim was to determine the risk of endometrial cancer associated with long‐term use of combined hormone therapy (HT) and low‐potency estrogens. In this prospective population‐based cohort, 40,000 women aged 25–64 years, without prior cancer or hysterectomy, were included. The women answered 2 questionnaires at a 10‐year interval regarding HT use and personal details. Women were followed up for an average of 15.5 years through the National Cancer and Causes of Death Registry, representing 236,611 women years. Among the 17,822 postmenopausal women included, 166 cases of endometrial cancer were diagnosed. Only use of combined HT was related to a decreased risk of endometrial cancer (OR 0.3, 95% CI 0.1–0.8), the protective effect was found after 2 years, and increased with extended duration of use. “Only use” of low‐potency estrogens increased the risk of endometrial cancer almost to the same extent as use of high‐potency estrogens (OR 2.0, 95% CI 1.1–3.6 vs. OR 2.5, 95% CI 1.3–4.8), the increased risk was confined to non‐obese women in both groups. The risk was significantly increased for oral but not for local low‐potency estrogen users (OR 2.1, 95% CI 1.1–3.6 vs. OR 1.5, 95% CI 0.4–6.2, respectively). In long‐term estrogen users the risk was highest during the first 2 years, dropping slightly thereafter. Since low‐potency estrogen use increases the risk of endometrial cancer almost as much as high‐potency estrogen use, they should only be given if medically indicated. © 2009 UICC     

Hormone replacement therapy and endometrial cancer

Postmenopausal hormone replacement therapy (HRT) using unopposed estrogens significantly increases endometrial cancer risk and should not be used in non-hysterectomized women. Even low-potency estrogens (oral estriol) or low-dose unopposed estrogens significantly enhance the risk to develop endometrial cancer. This risk is markedly reduced, when in addition to estrogens, progestins are administered for at least 10 days (better 14 days) per month. In some studies, a normalization of endometrial cancer risk to that of women receiving no HRT was only found when a continuous combined estrogen/progestin replacement was used. The use of progestins for less than 10 days per month and long-cycle regimens, where a progestin is added only every 3 months cannot be recommended. For women needing HRT, estrogen dose should be selected as low as possible and reassessment of the need of HRT should be performed annually.     

Risk of endometrial cancer following cessation of menopausal hormone use (Washington, United States)

While there are a number of benefits to the health of postmenopausal women from use of unopposed estrogens, the increased risk of endometrial cancer related to these hormones has led many women to use combined estrogen-progestogen therapy instead, or not to use hormones at all. Most women who take hormones do so only in the early portion of their postmenopausal years, so the risk of endometrial cancer following cessation of use might bear heavily on the overal risk/benefit evaluation. We analyzed data from a case-control study of women in western Washington (United States) to assess the magnitude of excess risk of endometrial cancer following discontinuation of estrogen use. Cases (n=661) consisted of women aged 45 to 74 diagnosed between 1985 and 1991 who resided in one of three counties in Washington State. Controls (n=865) were identified by random-digit dialing. Subjects were interviewed in-person to ascertain current and prior hormone use. The analysis was restricted to women who had not received combined estrogen-progestin therapy. Among women who had used unopposed estrogens at some time, risk of endometrial cancer declined as time since last use increased. Nonetheless, even among women who used these hormones for just a few years, the risk remained elevated by 30 to 70 percent almost a decade after cessation. These results, combined with those of most (but not all) other studies of this issue, suggest that a woman who has discontinued unopposed estrogen therapy may retain a small increased risk of endometrial cancer for a long period of time.Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, the Department of Epidemiology, University of Washington Department of Biostatistics University of Washington, Seattle, WA. Department of Epidemiology, University of Washington, Seattle, WA 98195, USA. This research was supported by US National Cancer Institute contracts R01 CA47749 and R35 CA39779.     

Recency,duration, and progestin content of oral contraceptives in relation to the incidence of endometrial cancer (Washington,USA)

Women who have used combined oral contraceptives (COC) have a reduced risk of endometrial cancer relative to that of women who have never used oral contraceptives, but it is unclear whether the size of the reduction is influenced by the progestin content of the preparation. We analyzed data from two population-based case-control studies of endometrial cancer to investigate this question. Among women aged 40 to 59 years who were residents of King or Pierce Counties, Washington (United States), incident cases who were diagnosed during 1975–77 or 1985–87 were identified. Personal interviews were conducted with 316 such women and their responses compared with those of 501 controls who were selected by household surveys or random-digit dialing. A reduced risk of endometrial cancer associated with COC use was present only among users of five or more years' duration, and even then only in women who were not long-term users of unopposed postmenopausal estrogens. Among these women, the relative risk (RR) of endometrial cancer did not differ according to the progestin potency of the COC used: it was equally low for women who had used a COC with low progestin content (RR=0.2, 95 percent confidence interval [CI]=0.1–0.8) as for women who had used a COC with high progestin content (RR=0.3, CI=0.1–0.9). Our results argue that, if the reduced risk of endometrial cancer in long-term users of COCs is due to the progestins contained in these preparations, that amount of progestin in most COCs exceeds the threshold amount needed to produce this beneficial effect.This project was supported by Grant 5R35CA39779 and Contract NO1-CN-05230 from the US National Cancer Institute.     

Risk of endometrial cancer following estrogen replacement with and without progestins.

BACKGROUND: Unopposed estrogen replacement therapy (i.e., estrogen without progestins) increases the risk of endometrial cancer. In this study, we examined the endometrial cancer risk associated with combined estrogen-progestin regimens currently in use, since the safety profiles of these regimens have not been clearly defined. METHODS: We conducted a nationwide population-based, case-control study in Sweden of postmenopausal women aged 50-74 years. We collected information on use of hormone replacement from 709 case patients with incident endometrial cancer and from 3368 control subjects. We used unconditional logistic regression to calculate odds ratios (ORs) as estimates of relative risks. All individual comparisons were made with women who never used the respective hormone replacement regimens. RESULTS: Treatment with estrogens alone was associated with a marked duration- and dose-dependent increase in the relative risk of endometrial cancer. Five or more years of treatment had an OR of 6.2 for estradiol (95% confidence interval [CI] = 3.1-12.6) and of 6.6 for conjugated estrogens (95% CI = 3.6-12.0). Following combined estrogen-progestin use, the association was considerably weaker than that for estrogen alone; the OR was 1.6 (95% CI = 1.1-2.4) after 5 or more years of use. This increase in risk was confined to women with cyclic use of progestins, i.e., fewer than 16 days per cycle (most commonly 10 days per cycle [OR = 2.9; 95% CI = 1.8-4.6 for 5 or more years of use]), whereas continuous progestin use along with estrogens was associated with a reduced risk (OR = 0.2; 95% CI = 0.1-0.8 for 5 or more years of use). CONCLUSION: The risk of developing endometrial cancer is increased after long-term use of estrogens without progestins and with cyclically added progestins. Continuously added progestins may be needed to minimize the endometrial cancer risk associated with estrogen replacement therapy.     

Cytochrome P450 1B1 and catechol-O-methyltransferase polymorphisms and endometrial cancer susceptibility

Estrogen production and metabolism play critical roles in the development and pathogenesis of endometrial carcinoma. Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are two key enzymes in the estrogen metabolism pathway that result in the hydroxylation and conjugation of estradiol, respectively. We evaluated the association between the CYP1B1 Leu432Val and CYP1B1 Asn453Ser polymorphisms and the COMT Val158Met polymorphism and invasive endometrial cancer risk in a case-control study nested within the Nurses' Health Study (n = 222 cases, 666 controls). We also evaluated whether body mass index (BMI), postmenopausal hormone (PMH) use and cigarette smoking modified the associations of the CYP1B1 and COMT genotypes and endometrial cancer risk. Conditional logistic regression was used to calculate the adjusted odds ratios (OR) and 95% confidence intervals (CI) to quantify the risk of endometrial cancer among subjects who had at least one variant allele compared with subjects who were homozygous for the wild-type allele. Carriers of the CYP1B1 Ser allele had a statistically significant decreased risk of endometrial cancer (OR = 0.62; 95% CI, 0.42-0.91); there was no significant association between the CYP1B1 Val allele and endometrial cancer risk (OR = 1.10; 95% CI, 0.75-1.59). Compared with the COMT Val/Val wildtype genotype, the adjusted OR of endometrial cancer for women with the COMT Val/Met or COMT Met/Met genotype was 0.96 (95% CI, 0.65-1.43). We did not observe any effect modification by BMI, PMH use and cigarette smoking for the CYP1B1 and COMT genotypes. Our data suggest, that the CYP1B1 Ser allele may decrease endometrial cancer risk by altering the production of catechol estrogens. However, further studies are warranted to elucidate the role of CYP1B1 in endometrial cancer.     

Alcoholism and risk for endometrial cancer.

Endogenous estrogens increase the risk of endometrial cancer and are also elevated among women with high alcoholic intake. It is incompletely known, however, whether alcohol intake in general and alcohol abuse in particular increases risk for endometrial cancer. We thus analyzed prospectively the risk for endometrial cancer among 36,856 women hospitalized with alcoholism between 1965 and 1994 through linkages between several national Swedish registers. Compared with the general population, women who were alcoholics had an overall 24% lower risk of developing endometrial cancer, a finding challenging our a priori hypothesis. However, among women below the age of 50 years at follow-up, the mean age of menopause among Swedish women, the risk was 70% higher, whereas the risk among women aged 50 years or more at follow-up was 40% lower compared with the general population. Hence, the effect of alcoholism on endometrial cancer appears to be age dependent.     

The epidemiology of endometrial cancer in young women

A case-control study was conducted in Los Angeles County, California, of 127 endometrial cancer cases aged 45 years or less at diagnosis, to investigate the role of fertility, obesity and exogenous oestrogens in the development of the disease in young women. Use of sequential oral contraceptive (SOCs) or oestrogen replacement therapy (ERT) for greater than or equal to 2 years was strongly associated with increased risk of endometrial cancer. After excluding these cases, since the SOC or ERT use was probably the cause of their disease, we were left with 110 case-control pairs for further study. Among these remaining case-control pairs increasing parity was strongly associated with decreased risk (relative risk of 0.12 for women of parity 3 compared to nulliparous women, P less than 0.001). Current weight was associated with increased risk (relative risk of 17.7 for women weighing greater than or equal to 190 lbs compared to women weighing less than 130 lbs, P less than 0.001). Combination oral contraceptive (COC) use was associated with a decreased risk, which decreased with duration of COC use (relative risk of approximately 0.28 at 5 years of use, P less than 0.001), but the estimate of the protective effect was reduced and became statistically non-significant when allowance was made for weight and parity. The protective effect of COC use was only clearly evident in women who had less than 3 live-births and weighed less than 170 lbs. These results provide further support for the "unopposed" oestrogen hypothesis of the aetiology of endometrial cancer.     

Oral contraceptive and IUD use and endometrial cancer: a population-based case-control study in Shanghai, China

Oral contraceptive (OC) and intrauterine device (IUD) use have been shown to be protective factors for endometrial cancer in several epidemiological studies; however, few studies have been conducted in Chinese populations. We evaluated the association between OC and IUD use and endometrial cancer risk in a population-based case-control study among Chinese women in Shanghai, China. The study included 1,204 newly diagnosed endometrial cancer cases and 1,212 age frequency-matched healthy controls. Logistic regression models were used to estimate adjusted odds ratios (OR) and their 95% confidence intervals (95% CI). In our study population, 18.5% cases and 24.9% controls reported having ever used OCs with an OR of 0.75 (95% CI, 0.60-0.93), after adjusting for known risk or protective factors for endometrial cancer. The risk of endometrial cancer decreased with long-term use of OCs with the OR for more than 72 months of use being 0.50 (95% CI, 0.30-0.85). The effect of OC use remained 25 or more years after cessation of use; the associated OR was 0.57 (95% CI = 0.42-0.78) as compared to nonusers. Similarly, fewer cases than controls had ever used IUD, with the multivariable adjusted OR being 0.53 (95% CI = 0.43-0.65). A reduction in risk was observed regardless the duration of use or age at first and last use. These results suggest that OC and IUD use may confer long-term protection against endometrial cancer.     

Menopausal estrogen use and risk of breast cancer

To assess the relationship of menopausal estrogens to breast cancer risk, the authors conducted a case-control study among 881 cases and 863 controls identified through the Breast Cancer Detection Demonstration Project (BCDDP). Use of estrogens was associated with a relative risk (RR) of 1.24 (95% C.I. 1.0-1.5), with higher risks observed among users of high-dose preparations. Hormone effects predominated among women who received them following bilateral oophorectomy (RR = 1.54), obliterating the protective effect normally associated with the operation. In this group, risk increased with years of estrogen use, reaching risks of 2-3 for users of ten or more years. High risks were also observed among oophorectomized women who used hormones in the presence of other risk factors, including nulliparity, family history of breast cancer, and benign breast disease. These results suggest a possible, although complex, relationship between estrogen use and risk of breast cancer.     

Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy—long-term follow-up of a Swedish cohort

We analyzed cancer incidence and mortality in a cohort of 22,597 Swedish women who were prescribed replacement hormones. After 13 years of follow-up in national registries, 2,330 incident cancer cases and 848 cancer deaths were observed. Overall, our results were reassuring since incidence rate ratios (SIRs) for 16 cancer sites and mortality ratios (SMRs) for all 10 examined sites were at, or lower than, unity. However, we found that exposure to an estrogen-progestin combined brand was associated with an increasing relative risk of breast cancer with follow-up time, the SIR reaching 1.4 (95% CI 1.1–1.8) after 10 years of follow-up. The relative risk of endometrial cancer was substantially increased, with the highest SIR of 5.0 (95% CI 1.6–5.9) in women prescribed estrogens alone, whereas those given an estrogen-progestin combination showed no elevation in risk. The risk estimates for liver and biliary tract cancers and for colon cancer were reduced by about 40%, notably in women prescribed the estradiol-progestin compound. Further detailed analyses revealed no evidence of adverse or protective effects on the risk of ovarian, uterine cervical, vulvar/vaginal, rectal, pancreatic, renal, lung, thyroid and other endocrine cancers, brain tumors, malignant melanoma or other skin cancers. Hormone replacement therapy was not associated with an increase in mortality for any cancer site, at this time of follow-up. For breast and endometrial cancers, SMRs were below baseline but tended to increase with follow-up time. We conclude that hormone replacement increases the endometrial-cancer risk after unopposed estrogens and the breast-cancer risk—notably after estrogen-progestin combined therapy—and tentatively suggest that it exerts a protective effect against colon and liver cancer risks. © 1996 Wiley-Liss, Inc.     

Physical activity and risk of endometrial cancer: the European prospective investigation into cancer and nutrition

The etiologic role of physical activity in endometrial cancer risk remains unclear given the few epidemiologic studies that have been conducted. To investigate this relation more fully, an analysis was undertaken in the European prospective investigation into cancer and nutrition (EPIC). During an average 6.6 years of follow-up, 689 incident endometrial cancer cases were identified from an analytic cohort within EPIC of 253,023 women. Cox proportional hazards models were used to estimate the associations between type of activity (total, occupational, household, recreational) and endometrial cancer risk. For total activity, women in the highest compared with the lowest quartile of activity had a risk of 0.88 (95% confidence interval (95% CI=0.61-1.27). No clear associations between each type of activity and endometrial cancer risk were found for the total study population combined. Associations were more evident in the stratified results, with premenopausal women who were active versus inactive experiencing a risk of 0.66 (95% CI=0.38-1.14) overall. Among premenopausal women, for household and recreational activities the risk estimates in the highest as compared with the lowest quartiles were, respectively, 0.48 (95% CI=0.23-0.99) and 0.78 (95% CI=0.44-1.39). No effect modification by body mass index, hormone replacement therapy, oral contraceptive use or energy intake was found. This study provides no evidence of a protective effect of increased physical activity in endometrial cancer risk in all women but some support for a benefit among premenopausal women. The relative risk reductions are most apparent for household activities.     

Endometrial cancer risk in estrogen users after switching to estrogen–progestin therapy

Objective It is unknown whether postmenopausal unopposed estrogen users are better off, in terms of endometrial cancer risk, switching to a combined estrogen–progestin regimen or stopping hormone use altogether. Methods We analyzed data from a series of three population-based case–control studies in western Washington state during 1985–1999, comparing proportions of “switchers” and “stoppers” in cases and controls. We also assessed whether the risk of endometrial cancer in either group of former unopposed estrogen users returned to that of never users. Results After multivariate adjustment using unconditional logistic regression, women who switched to a combined regimen with a progestin added for at least ten days/month (37 cases, 47 controls) had half the risk of endometrial cancer of women who stopped hormone use altogether (86 cases, 78 controls) (adjusted odds ratio = 0.5, 95% confidence interval: 0.3–1.1). Most subgroups of former users, whether they switched or stopped, had some increased risk of endometrial cancer compared to never users. Conclusions Results from this study suggest that unopposed estrogen users may reduce their risk of endometrial cancer more by switching to a combined regimen with progestin added for at least ten days/month than by stopping hormone use altogether.     

A case-control study of breast cancer and hormonal contraception in Costa Rica

By 1981, 11% of married women in Costa Rica ages 20-49 years had used depot-medroxyprogesterone acetate (DMPA) and 58% had used oral contraceptives (OCs). Since 1977, the Costa Rican Ministry of Health has maintained a nationwide cancer registry. These circumstances provided an opportunity for a population-based, case-control study of DMPA, OCs, and breast cancer in Costa Rica. Cases were 171 women ages 25-58 years with breast cancer diagnosed between 1982 and 1984; controls were 826 women randomly chosen during a nationwide household survey. Cases and controls were interviewed with the use of a standard questionnaire covering their reproductive and contraceptive histories. Logistic regression methods were used to adjust for confounding factors. While few cases or controls had ever used DMPA, DMPA users had an elevated relative risk (RR) estimate of breast cancer of 2.6 (95% confidence limits = 1.4-4.7) compared with never users. However, no dose-response relationship was found; even the group of women who had used DMPA for less than 1 year had an elevated RR estimate (RR = 2.3; 95% confidence limits = 1.0-5.1). In contrast, OC users had no elevation in RR compared with never users (RR = 1.2; 95% confidence limits = 0.8-1.8). The results of the DMPA analysis are inconclusive. Before decisions are made on whether to continue providing this effective contraceptive method, other ongoing studies will need to confirm of refute these findings.     

Risk factors for endometrial cancer at different ages

The importance of the major risk factors for endometrial cancer in women of different ages was evaluated with the use of data from a hospital-based case-control study conducted in Milan, Italy, on 283 women with endometrial cancer and 566 age-matched controls. Current weight was related strongly to the risk of endometrial cancer both in younger (premenopausal) and in older women (with risk estimates for the heaviest categories of 20.3 and 7.7, respectively), thus confirming that obesity is the major cause of endometrial cancer in Northern Italy. Endometrial cancer risk appeared to be approximately proportional to the second power of body mass index. Early menarche and nulliparity were associated with an increased risk of endometrial cancer in premenopausal women, the point estimate for nulliparity rising to 35.1 (with lower confidence limit of 10.2) after adjustment for marital status. However, no association with these factors was evident in postmenopausal women. Combination oral contraceptives were used by 2 cases and 19 controls only [relative risk (RR) = 0.2, with 95% confidence interval = 0.1-0.8]. The use of noncontraceptive estrogens was associated with an elevated risk, which was greater in perimenopausal women (RR = 5.1 for greater than 2 yr of use), and decreased progressively with increasing time after menopause. Late menopause was also related to endometrial cancer. However, the risk estimates for late menopause apparently were more elevated in older women (greater than or equal to 65 yr) than in perimenopausal women. Most of the risk factors identified (excluding late menopause) apparently act on one of the later stages of the process of carcinogenesis, because the excess risk drops after cessation of exposure.     

Intra-uterine contraception and the risk of endometrial cancer

Despite the increasing world-wide popularity of contraceptive intra-uterine devices (IUDs), their potential long-term effects on the risk of developing endometrial carcinoma have been poorly studied. This paper reports on the relationship between intra-uterine contraception and endometrial cancer by analyzing epidemiological data from a large, multicenter, population-based, case-control study of epithelial endometrial cancer. Cases were 437 women, 20 to 54 years of age, with histologically confirmed epithelial endometrial cancer ascertained through 6 population-based cancer registries in the United States. Controls were 3200 women selected at random from the populations of these areas. The age- and parity-adjusted odds ratio (OR) for the association between ever having used intra-uterine contraception and endometrial cancer was 0.51 (95% confidence interval (Cl) 0.3–0.8). Although the protective effect increased with duration of use, a dose-response relationship among users was not statistically demonstrable. The association did not vary significantly with age at first or last IUD use or with time elapsed since first or last IUD use. Years of education significantly modified the effect of intra-uterine contraception. Thus, intra-uterine contraception appeared to be strongly protective for women with at least 13 years of education (OR = 0.29, 95% Cl, 0.15–0.6). It is proposed that intra-uterine contraception exerts its protective effect through local structural and biochemical changes in the endome-trium that may alter endometrial sensitivity and response to circulating estrogen and progesterone.     

Risks of breast and endometrial cancer after estrogen and estrogen–progestin replacement

Objective: We studied the risk of breast and endometrial cancer in a cohort of 11,231 Swedish women prescribed different replacement hormone regimens.Methods: All 10,472 women at risk of developing breast cancer and 8,438 women at risk of endometrial cancer were followed up from the time of the questionnaire in 1987–88 through 1993, by record-linkages to the National Swedish Cancer Registry. Using data from a questionnaire we analyzed the relationships between hormone exposures and cancer risk, with non-compliers and users of less than 1 year as a reference group.Results: For breast cancer, women reporting use of estrogens combined with progestins had evidence of an increased risk relative to women denying intake or taking hormones for less than 1 year; relative risk (RR) = 1.4 (95% confidence interval 0.9–2.3) after 1–6 years of intake, and RR=1.7 (95% CI 1.1–2.6) after more than 6 years. This excess risk seemed confined to recent exposure. We found no association with intake of estrogens alone using non-compliers and short-term takers as the reference group. The risk of invasive endometrial cancer was increased four-fold in women using medium-potency estrogens alone for 6 years or longer, RR = 4.2 (95% CI 2.5–8.4). Women on such long-term progestin-combined treatment had a lower, non-significant, excess risk (RR = 1.4; 95% CI 0.6–3.3).Conclusions: We conclude that long-term recent use of estrogen–progestin combined replacement therapy may increase the risk of breast cancer. Exposure to estrogen alone substantially elevates the risk of endometrial cancer, an increase that can be reduced or perhaps avoided by adding progestins.