Is estrogen plus progestin menopausal hormone therapy safe with respect to endometrial cancer risk?

Given the strong link between use of unopposed estrogens and development of endometrial cancers, estrogens are usually prescribed with a progestin, particularly for women with intact uteri. Some studies suggest that sequential use of progestins may increase risk; however, the moderating effects of usage patterns or patient characteristics, including body mass index (BMI), are unknown. We evaluated menopausal hormone use and incident endometrial cancer (n = 885) in 68,419 postmenopausal women with intact uteri enrolled in the National Institutes of Health‐American Association of Retired Persons Diet and Health study. Participants completed a risk factor questionnaire in 1996–1997 and were followed up through 2006. Hazard rate ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox regression. Among 19,131 women reporting exclusive estrogen plus progestin use, 176 developed endometrial cancer (RR = 0.88; 95% CI = 0.74–1.06). Long‐duration (≥10 years) sequential (<15 days progestin per month) estrogen plus progestin use was positively associated with risk (RR = 1.88; 95% CI = 1.36–2.60], whereas continuous (>25 days progestin per month) estrogen plus progestin use was associated with a decreased risk (RR = 0.64; 95% CI = 0.49–0.83). Increased risk for sequential estrogen plus progestin was seen only among thin‐to‐normal weight women (BMI < 25 kg/m²; RR = 2.53). Our findings support that specific categories of estrogen plus progestin use increases endometrial cancer risk, specifically long durations of sequential progestins, whereas decreased endometrial cancer risk was observed for users of short‐duration continuous progestins. Risks were highest among thin‐to‐normal weight women, presumably reflecting their lower endogenous estrogen levels, suggesting that menopausal hormones and obesity increase endometrial cancer through common etiologic pathways.     

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.     

Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women.

BACKGROUND: Because unopposed estrogen substantially increases endometrial carcinoma risk, estrogen plus progestin is one menopausal hormone therapy formulation for women who have not had a hysterectomy. However, endometrial carcinoma risks among estrogen plus progestin users and among former unopposed estrogen users are not firmly established. METHODS: We evaluated endometrial carcinoma risks associated with estrogen plus progestin and unopposed estrogen therapies in 30,379 postmenopausal Breast Cancer Detection Demonstration Project follow-up study participants. We ascertained hormone therapy use and other risk factors during telephone interviews and mailed questionnaires between 1979 and 1998. We identified 541 endometrial carcinomas via self-report, medical records, the National Death Index, and state cancer registries. Poisson regression generated time-dependent rate ratios (RR) and 95% confidence intervals (95% CI). RESULTS: Endometrial carcinoma was significantly associated with estrogen plus progestin only use (n = 68 cancers; RR, 2.6; 95% CI, 1.9-3.5), including both sequential (progestin <15 days per cycle; n = 32 cancers; RR, 3.0; 95% CI, 2.0-4.6) and continuous (progestin at least 15 days per cycle; n = 15 cancers; RR, 2.3; 95% CI, 1.3-4.0) regimens. The RR increased by 0.38 (95% CI, 0.20-0.64) per year of estrogen plus progestin use, and RRs increased with increasing duration of use for both regimens. The strong association with unopposed estrogen use declined after cessation but remained significantly elevated > or =10 years after last use (RR, 1.5; 95% CI, 1.0-2.1). CONCLUSIONS: Both estrogen plus progestin regimens significantly increased endometrial carcinoma risk in this study. Risks among unopposed estrogen users remained elevated long after last use. The prospect that all estrogen plus progestin regimens increase endometrial carcinoma risk deserves continued research.     

Hormone replacement therapy and cancer risk

The advantages and disadvantages of hormone replacement therapy (HRT) have been debated nearly as long as the treatment has been in use, especially the relationship between HRT and risk of cancer development. It is hoped that recently published studies will shed more light on this complex issue. Several large population studies suggest that there may be a small but increased risk of developing breast cancer in HRT users, especially in estrogen and progesterone users. This risk appears most pronounced after 5 years of HRT use. Endometrial cancer, which has long been associated with unopposed estrogen use, can be successfully prevented with the addition of progestins to the HRT regimen, provided it is given for at least 10 days each month. Estrogen replacement therapy has also been shown to significantly reduce the risk for colon cancer but not rectal cancers. Finally, a large prospective study has linked HRT with an increase in ovarian cancer mortality.     

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.     

Patterns of postmenopausal progestin use with estrogen in relation to endometrial cancer (United States)

Objective: To investigate the risk of endometrial cancer associated with various regimens of postmenopausal hormone therapy. Methods: Data from a population-based case–control study were analysed that included 591 women newly diagnosed with endometrial cancer, aged 40–79, and who were reported to Wisconsin's statewide tumor registry in 1991–1994. Similarly aged population controls (n = 2045) were randomly selected from lists of licensed drivers and Medicare beneficiaries. Information on hormone use and other factors was obtained through telephone interviews. Results: Ever use of estrogen–progestin hormones was associated with increased endometrial cancer compared to women who had never used hormones; the increase per year of use was 7% (95% confidence interval 1–13%). Both cyclic (<10 days per month) and continuous progestin used with estrogen were associated with comparable twofold increases in risk relative to non-users. There was no increased risk associated with progestin used for 10–21 days per month. Conclusions: Both continuous and cyclic progestin regimens are associated with a much lower risk of endometrial cancer than estrogen alone. However, many women using these regimens remain at significantly increased risk of endometrial cancer.     

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.     

Menopausal hormone therapy and risk of melanoma: Do estrogens and progestins have a different role?

The association between use of menopausal hormone therapy (HT) and occurrence of skin malignant melanoma (SMM) is controversial. We investigated the issue in a nationwide cohort of 684,696 Norwegian women, aged 45–79 years, followed from 2004 to 2008. The study was based on linkage between Norwegian population registries. Multivariable Poisson regression models were used to estimate the effect of HT use, different HT types, routes of administration and doses of estrogen and progestin on the risk of SMM. During the median follow‐up of 4.8 years, 178,307 (26%) women used HT, and 1,476 incident SMM cases were identified. Current use of HT was associated with increased risk of SMM (rate ratios (RR) = 1.19; 95% confidence interval (CI) 1.03–1.37). Plain estrogen therapy was associated with an increased risk of SMM (RR 1.45; 95% CI 1.21–1.73), both for oral (RR 1.45; 95% CI 1.09–1.93) and vaginal (RR 1.44; 95% CI 1.14–1.84) formulations, while combined estrogen and progestin therapy (EPT) was not (RR 0.91; 95% CI 0.70–1.19). We performed a dose–response analysis of estrogen and progestin in women using tablets, and found that use of estrogens was associated with increased risk (RR 1.24; 95% CI 1.00–1.53 per 1 mg/day) and use of progestins with decreased risk (RR 0.71; 95% CI 0.57–0.89 per 10 mg/month) of SMM. In conclusion, estrogens were associated with increased risk of SMM, while combinations of estrogens and progestins were not. Our results suggest that estrogens and progestins might affect the risk of SMM in opposite ways.     

Estrogen-progestin replacement therapy and breast cancer risk: the Women's Health Study (United States)

Objective: While there is substantial evidence that unopposed estrogen use increases the risk of breast cancer, there are limited data from epidemiologic studies on the impact of estrogen–progestin combinations. We therefore examined estrogen–progestin replacement therapy and breast cancer risk in the Women's Health Study. Methods: We investigated postmenopausal hormone (PMH) use among 17,835 apparently healthy postmenopausal women aged 45 years, and followed them prospectively for an average of 5.9 years. Breast cancer occurred in 411 women. Results: The multivariate relative risks of all breast cancer associated with never use of PMH, use of estrogen replacement therapy (ERT), and use of estrogen–progestin replacement therapy (HRT) were 1.00 (referent), 0.96 (95% CI 0.65–1.42), and 1.37 (95% CI 1.05–1.78). The increase in risk among users of HRT was largely limited to those women who had used estrogen–progestin replacement therapy for five years or more, and to those women who were on continuous rather than cyclic progestin combinations. Higher doses of estrogen, but not progestin, were associated with increased breast cancer risk, compared with lower doses. Conclusions: These prospective data suggest that use of estrogen–progestin replacement therapy imparts an increased risk of breast cancer in comparison with never use of PMH.     

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.     

Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort

Most epidemiological studies have shown an increase in breast cancer risk related to hormone replacement therapy (HRT) use. A recent large cohort study showed effects of similar magnitude for different types of progestogens and for different routes of administration of estrogens evaluated. Further investigation of these issues is of importance. We assessed the risk of breast cancer associated with HRT use in 54,548 postmenopausal women who had never taken any HRT 1 year before entering the E3N-EPIC cohort study (mean age at inclusion: 52.8 years); 948 primary invasive breast cancers were diagnosed during follow-up (mean duration: 5.8 years). Data were analyzed using multivariate Cox proportional hazards models. In this cohort where the mean duration of HRT use was 2.8 years, an increased risk in HRT users compared to nonusers was found (relative risk (RR) 1.2 [95% confidence interval 1.1-1.4]). The RR was 1.1 [0.8-1.6] for estrogens used alone and 1.3 [1.1-1.5] when used in combination with oral progestogens. The risk was significantly greater (p <0.001) with HRT containing synthetic progestins than with HRT containing micronized progesterone, the RRs being 1.4 [1.2-1.7] and 0.9 [0.7-1.2], respectively. When combined with synthetic progestins, both oral and transdermal/percutaneous estrogens use were associated with a significantly increased risk; for transdermal/percutaneous estrogens, this was the case even when exposure was less than 2 years. Our results suggest that, when combined with synthetic progestins, even short-term use of estrogens may increase breast cancer risk. Micronized progesterone may be preferred to synthetic progestins in short-term HRT. This finding needs further investigation.     

Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe

Epidemiologic studies have shown an increased risk of breast cancer following hormone replacement therapy (HRT). The aim of this study was to investigate whether different treatment regimens or the androgenecity of progestins influence the risk of breast cancer differently. The Danish Nurse Cohort was established in 1993, where all female nurses aged 45 years and above received a mailed questionnaire (n = 23,178). A total of 19,898 women returned the questionnaire (86%). The questionnaire included information on HRT types and regimens, reproductive history and lifestyle-related factors. Breast cancer cases were ascertained using nationwide registries. The follow-up ended on 31 December 1999. Women with former cancer diagnoses, women with missing information on HRT, surgical menopause, premenopausal, as well as hysterectomized women were excluded, leaving 10,874 for analyses. Statistical analyses were performed using Cox proportional hazards model. A total of 244 women developed breast cancer during follow-up. After adjustment for confounding factors, an increased risk of breast cancer was found for the current use of estrogen only (RR = 1.96; 95% CI = 1.16-3.35), for the combined use of estrogen and progestin (RR = 2.70; 95% CI = 1.96-3.73) and for current users of tibolone (RR = 4.27; 95% CI = 1.74-10.51) compared to the never use of HRT. In current users of combined HRT with testosterone-like progestins, the continuous combined regimens were associated with a statistically significant higher risk of breast cancer than the cyclical combined regimens (RR = 4.16, 95% CI = 2.56-6.75, and RR = 1.94, 95% CI = 1.26-3.00, respectively). An increased risk of breast cancer was noted with longer durations of use for the continuous combined regimens (p for trend = 0.048). The European traditional HRT regimens were associated with an increased risk of breast cancer. The highest risk was found for the use of continuous combined estrogen and progestin.     

Endometrial cancer and menopausal hormone therapy in the National Institutes of Health-AARP Diet and Health Study cohort

BACKGROUND: Menopausal hormone therapy formulations for women without hysterectomy have included estrogen plus progestin for years, but endometrial cancer risks associated with the use of sequential and continuous estrogen-plus-progestin regimens remain unclear. METHODS: The National Institutes of Health-AARP Diet and Health Study included 73,211 women who were ages 50 years to 71 years at baseline and who completed 2 questionnaires (1995-1996 and 1996-1997). Linkage to state cancer registries and mortality indices identified 433 incident endometrial cancers through 2000. Using proportional hazards regression, the authors estimated relative risks (RRs) and 95% confidence intervals (95% CIs) relative to never-use of hormone therapy. RESULTS: In 51,312 women who never used hormones or only used estrogen-plus-progestin regimens at doses consistent with current practice, neither sequential estrogen plus progestin (daily estrogen plus progestin for 10-14 days per cycle: RR, 0.74; 95% CI, 0.39-1.40) nor continuous estrogen plus progestin (daily estrogen plus progestin for >/=20 days per cycle: RR, 0.80; 95% CI, 0.55-1.15) had any statistically significant association with endometrial cancer. Long durations (>/=5 years) of sequential regimen use (RR, 0.79; 95% CI, 0.38-1.66) and of continuous regimen use (RR, 0.85; 95% CI, 0.53-1.36) were not associated with endometrial cancer. CONCLUSIONS: Confirmation that these estrogen-plus-progestin regimens neither increase nor decrease the risk of endometrial cancer could influence menopausal symptom management for women who are considering estrogen-plus-progestin therapy.     

Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin

BACKGROUND: Hormone replacement therapy (HRT) given as unopposed estrogen replacement therapy (ERT) gained widespread popularity in the United States in the 1960s and 1970s. Recent prescribing practices have favored combination HRT (CHRT), i.e., adding a progestin to estrogen for the entire monthly cycle (continuous combined replacement therapy [CCRT]) or a part of the cycle (sequential estrogen plus progestin therapy [SEPRT]). Few data exist on the association between CHRT and breast cancer risk. We determined the effects of CHRT on a woman's risk of developing breast cancer in a population-based, case-control study. METHODS: Case subjects included those with incident breast cancers diagnosed over 4(1/2) years in Los Angeles County, CA, in the late 1980s and 1990s. Control subjects were neighborhood residents who were individually matched to case subjects on age and race. Case subjects and control subjects were interviewed in person to collect information on known breast cancer risk factors as well as on HRT use. Information on 1897 postmenopausal case subjects and on 1637 postmenopausal control subjects aged 55-72 years who had not undergone a simple hysterectomy was analyzed. Breast cancer risks associated with the various types of HRT were estimated as odds ratios (ORs) after adjusting simultaneously for the different forms of HRT and for known risk factors of breast cancer. All P values are two-sided. RESULTS: HRT was associated with a 10% higher breast cancer risk for each 5 years of use (OR(5) = 1.10; 95% confidence interval [CI] = 1.02-1.18). Risk was substantially higher for CHRT use (OR(5) = 1.24; 95% CI = 1.07-1.45) than for ERT use (OR(5) = 1. 06; 95% CI = 0.97-1.15). Risk estimates were higher for SEPRT (OR(5) = 1.38; 95% CI = 1.13-1.68) than for CCRT (OR(5) = 1.09; 95% CI = 0. 88-1.35), but this difference was not statistically significant. CONCLUSIONS: This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. These findings have important implications for the risk-benefit equation for HRT in women using CHRT.     

Relation of regimens of combined hormone replacement therapy to lobular,ductal, and other histologic types of breast carcinoma

BACKGROUND: The incidence of invasive lobular carcinoma has been increasing among postmenopausal women in some parts of the United States. Part of this may be due to changes in classification over time. However, the use of combined (estrogen and progestin) hormone replacement therapy (CHRT) also has increased during the last decade and may account in part for the increase in invasive lobular breast carcinoma. METHODS: A large, multicenter case-control study of Caucasian and African-American women who were diagnosed at age < 65 years with their first invasive breast tumor from July 1, 1994 through April 30, 1998 was conducted. In-person interviews were conducted with 1749 postmenopausal patients, and their responses were compared with the responses of 1953 postmenopausal control women identified through random-digit dialing who met the study criteria of being postmenopausal at the time of diagnosis. Polytomous logistic regression was used to calculate the odds ratio (OR) as an estimate of the relative risk and to compute the 95% confidence interval (95%CI) associated with the use of various regimens of hormone replacement therapy (HRT) among women diagnosed with ductal breast carcinoma, lobular (or mixed lobular and ductal) breast carcinoma, and a grouping of other histologic types of breast carcinoma. RESULTS: Ever use of unopposed estrogen therapy (ERT) was not associated with an increase in the risk of any histologic type of breast carcinoma. The risk of invasive lobular breast carcinoma and the risk of breast carcinoma of the grouping of other histologies increased among women currently using CHRT (OR, 2.2; 95%CI, 1.4-3.3; and OR, 1.9; 95%CI, 1.0-3.4, respectively). The risk increase was greater for the mixed lobular-ductal type than for the pure lobular type of breast carcinoma, although the difference was not statistically significant. There was some indication that >or= 5 years of continuous CHRT (>or= 25 days per month of progestin) was associated with a higher risk of lobular breast carcinoma (OR, 2.5; 95%CI, 1.4-4.3) compared with sequential CHRT (< 25 days per month of progestin; OR, 1.5; 95%CI, 0.8-2.6). Current use of continuous CHRT was only moderately associated with risk of ductal breast carcinoma. CONCLUSIONS: Postmenopausal women who take CHRT appear to be at an increased risk of lobular breast carcinoma. Data from this study suggest that neither ERT use nor CHRT substantially increase the risk of ductal breast carcinoma among women age < 65 years.     

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.     

Reducing cancer risk in women through lifestyle-mediated changes in hormone levels

The major hormone-associated cancers of women, viz. breast, endometrium, and ovary, account for some 40% of all female cancers in the U. S. Variable expression of estrogens and progestins account for major differences in the incidence of breast and endometrial cancer. Identified differences in premenopausal ovarian hormone expression and the known effects of post-menopausal weight on estrogen metabolism now permit an essentially complete hormonal explanation of the epidemiology of endometrial cancer. Recent confirmation of decreased ovarian steroid levels in certain Oriental women now permits a hormonal explanation of the four- to sixfold differences in breast cancer rates between Japanese and U.S. women, and a complete hormonal explanation of the epidemiology of breast cancer is almost at hand. A delay of 2 years in the age at menarche plus a low postmenopausal weight are predicted to lead to a more than 50% lifelong reduction in both breast cancer and endometrial cancer. A 2-year delay in menarche is predicted to lead to an 18% reduction in ovarian cancer. The lifestyle basis of variable premenopausal ovarian hormone expression is poorly understood and should be the focus of a major research effort. Profound effects on estrogen and progestin expression and on cancer rates are obtained from use of hormonal contraceptives and menopausal hormone replacement therapy; it appears possible to use this knowledge to construct a LHRHA-plus-estrogen contraceptive regimen that should produce a major lifelong reduction in current U.S. breast cancer rates (32% reduction from 5 years use; 55% from 10 years use). The proposed regimen should also cause a major lifelong reduction in ovarian cancer rates (40% reduction from 5 years use; 66% from 10 years use). Addition of a progestin-containing IUCD to such a regimen should also cause a major lifelong reduction in endometrial cancer rates (55% reduction from 5 years use; 82% reduction from 10 years use).     

Hormone replacement therapy and the risk of breast cancer. Nested case-control study in a cohort of Swedish women attending mammography screening

There is concern that hormone replacement therapy (HRT) increases the risk of breast cancer. We undertook a case-control study of this risk relationship within a cohort of 40- to 74-year-old women in Uppsala County, Sweden, who participated in mammography screening. Incident cases of breast cancer were ascertained during 5 years of follow-up. In all, 435 cases (87% invasive, 13% in situ cancers) were detected, 313 through screening and 122 through clinical diagnosis. As controls, 1,740 women were selected randomly. Information on risk factors and use of HRT was obtained through interviews before the start of follow-up. Multivariate analyses revealed an increased risk among users of any type of HRT for more than 10 years, the odds ratio (OR) being 2.1 (95% confidence interval [CI] 1.1–4.0), as well as when restricting analyses to cases diagnosed through mammography screening. After stratification for compound type, risk estimates were apparently higher among women reporting estradiol–progestin combined treatment vs. estradiol or conjugated estrogens alone, with ORs for more than 10 years of intake being 2.4 (95% CI 0.7–8.6) and 1.3 (95% CI 0.5–3.7), respectively. Analyses through a model including both compound type and length of hormone intake confirmed a significant excess risk linked to treatment for more than 10 years, OR = 2.6 (95% CI 1.3–5.1). Our results indicate a moderately increased risk of breast cancer after many years of HRT and, hypothetically, a further enhancement of the risk with added progestins. Int. J. Cancer 72:758–761, 1997. © 1997 Wiley-Liss, Inc.     

Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women

BACKGROUND: Estrogen replacement therapy (ERT), which is mainly used to relieve climacteric symptoms, increases a woman's risk for uterine endometrial cancer and epithelial ovarian cancer (EOC). Estrogens are often combined with progestins in hormone replacement therapy (HRT) to reduce the risk of uterine endometrial cancer. Data on the association between HRT including progestins and EOC risk are limited. This nationwide case-control study examined EOC risk in relation to HRT regimens with sequentially added progestins (HRTsp) and continuously added progestins (HRTcp). METHODS: Between 1993 and 1995, we enrolled 655 histologically verified incident case patients with EOC and 3899 randomly selected population controls, all 50-74 years of age. Data on HRT use were collected through mailed questionnaires. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by the use of unconditional logistic regression. RESULTS: Risks of EOC were elevated among ever users as compared with never users of both ERT (OR = 1.43, 95% CI = 1.02 to 2.00) and HRTsp (OR = 1.54, 95% CI = 1.15 to 2.05); risks were elevated for serous, mucinous, and endometrioid subtypes. For all EOC types combined, the greatest risk increases were seen with hormone use exceeding 10 years. Ever use of HRTcp was not associated with increased EOC risk relative to HRTcp never use (OR = 1.02, 95% CI = 0.73 to 1.43). The risk of EOC was elevated among HRTsp ever users as compared with HRTcp ever users (OR = 1.78, 95% CI = 1.05 to 3.01). ORs for EOC after ever use of low-potency estrogens were 1.18 (95% CI = 0.89 to 1.55) for oral and 1.33 (95% CI = 1.03 to 1.72) for vaginal applications, but no relationship was seen between EOC risk and duration of use. CONCLUSION: Ever users of ERT and HRTsp but not HRTcp may be at increased risk of EOC.     

Hormone replacement therapy and breast cancer]

An evaluation of the role of estrogen and progesterone in hormone replacement therapy (HRT) as a cause and promotor of breast cancer should begin with a study of the effect of these hormones on normal breast tissue. Cyclic alterations in the histologic changes of the breast in relation to menstruation have been confirmed in some papers. However, the histological influence on the breast of the use of exogenous estrogen and progestin in postmenopausal women remains very controversial. There has been little consistency with regard to the relative risk of HRT and breast cancer in many epidemiological studies. However, the Collaborative. Group on Hormonal Factors in Breast Cancer has brought together and reanalyzed about 90% of the international epidemiological evidence on the relation between risk of breast cancer and use of HRT. These analyses revealed that the risk of breast cancer in HRT users was significantly increased. However, whether HRT affects mortality from breast cancer is unknown.