A case‐control study on hormone therapy as a risk factor for breast cancer in Finland: Intrauterine system carries a risk as well

The purpose of this study was to evaluate the association between postmenopausal hormone therapy (HT) and the risk for breast cancer in recently postmenopausal Finnish women. All Finnish women with first invasive breast cancer diagnosed between the ages of 50 and 62 years during 1995–2007 (n = 9,956) were identified from the Finnish Cancer Registry. For each case, 3 controls of the same age were retrieved from the Finnish Population Register. The cases and controls were linked to the national medical reimbursement register to assess the use of HT. The odds ratios (ORs) and 95% confidence intervals (CIs) for breast cancer were calculated with conditional logistic regression analysis, adjusting for parity, age at the first birth and health care district. Estradiol‐only therapy (991 users with breast cancer, n) or oral progestagen (n = 138) was not accompanied by an increased risk. Estradiol‐progestagen therapy (EPT) (n = 1,731) was associated with an elevated risk in the whole series (OR 1.36; 95% CI 1.27–1.46). The risk became detectable in less than 3 years of use. Continuous EPT use tended to be associated with a higher risk for breast cancer than the sequential EPT use. The use of tibolone (n = 80) (1.36; 1.15–1.96), a levonorgestrel‐releasing intrauterine system (LNG–IUS) alone (n = 154) (1.45; 1.97–1.77) or as a complement to estradiol (n = 137) (2.15; 1.72–2.68) was also associated with an increased risk. The association between HT use and the risk for breast cancer shows a large variation between various forms of HT, and also the use of LNG‐IUS may carry a risk.     

Endometrial cancer associated with various forms of postmenopausal hormone therapy: a case control study

This study evaluates the effect of different modes of estradiol-progestagen therapy (EPT) regimens on the postmenopausal endometrial cancer risk in Finland. Women diagnosed with endometrial cancer in 1995-2007 at the age of 50-80 years were identified from the Finnish Cancer Registry (N = 7,261). For each case, three age-matched controls were retrieved from the Finnish Population Register. The use of EPT since 1994 was ascertained from the national Medical Reimbursement Register. Odds ratios (ORs) for different EPT regimens were calculated with conditional logistic regression analysis, adjusted for parity and ages at the deliveries. For use of <5 years, the OR for sequential EPT was 0.67 (95% confidence interval 0.52-0.86), for continuous EPT 0.45 (0.27-0.73), and for estradiol plus levonorgestrel-releasing intrauterine device system (LNG-IUS) 0.39 (0.17-0.88). A decreased risk persisted for the use of continuous EPT and estradiol plus LNG-IUS of up to 10 years. The use of long-cycle EPT showed a tendency toward an elevated risk both for exposure of <5 years (1.40; 0.82-2.38) and for estimated use of >5 years (1.63; 1.12-2.38). For an estimated exposure of >10 years, the risk for endometrial cancer was elevated for both users of long-cycle EPT (2.95; 2.40-3.62) and sequential EPT (1.38; 1.15-1.66). Norethisterone acetate and medroxyprogesterone acetate as parts of EPT did not differ in their endometrial cancer risk. The use of tibolone showed no endometrial risk. The use of sequential and long-cycle EPT is associated with an increased risk of endometrial cancer, whereas the use of continuous EPT or estradiol plus LNG-IUS shows a decreased risk.     

Do the dose or route of administration of norethisterone acetate as a part of hormone therapy play a role in risk of breast cancer: National‐wide case‐control study from Finland

We examined the associations between various doses and routes of administration of norethisterone acetate (NETA) in estrogen–progestagen therapy (EPT) and the risk of breast cancer in Finland. All Finnish women with first invasive breast cancer diagnosed between the ages of 50–62 during 1995–2007 (n = 9,956) were identified from the Finnish Cancer Registry. For each case, 3 controls of the same age were retrieved from the Finnish Population Register. The use of estradiol+NETA‐therapy by the cases and controls was traced from the national Medical Reimbursement Registry. The data were analyzed with multivariate conditional logistic regression, adjusting for parity, age at the first birth, and health care district. The continuous mode of NETA use tended to be associated with a higher rate ratio for breast cancer than the sequential use. The use of continuous “low” dose (NETA 0.5 mg + estradiol 1.0 mg) was associated with an increased rate ratio of breast cancer already in less than 3 years of use (odds ratio 1.94; 95% confidence interval 1.39–2.70) while a risk elevation for “high” dose (NETA 1.0 mg + estradiol 2.0 mg) was seen after 3 years use (1.71; 1.51–2.54). Oral and transdermal use of NETA were accompanied with comparable risks for breast cancer. In conclusion, the dose or route of administration of NETA in EPT do not modify the risks for breast cancer.     

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.     

Do breast cancer risk factors modify the association between hormone therapy and mammographic breast density? (United States)

Objective To evaluate whether the association between hormone therapy (HT) and breast density differs by levels of breast cancer risk factors. Methods We evaluated 80,867 screening mammograms from 39,296 postmenopausal women from Washington State. We estimated odds ratios and 95% confidence intervals for dense breasts (Breast Imaging Reporting and Data System categories 3 “heterogeneously dense” and 4 “extremely dense”) compared to fatty breasts (categories 1 “almost entirely fat” and 2 “scattered fibroglandular”) among HT users compared to never users. We separately examined former HT use and current HT use by type (estrogen plus progestin therapy (EPT) and estrogen-only therapy (ET)). We stratified the associations by age, BMI, race, family history, and reproductive and menopausal factors. Results Current EPT users had a 98% (1.87–2.09) greater odds of having dense breasts and current ET users had a 71% (1.56–1.87) greater odds compared to never users. Current HT users were more likely to have dense breasts if they were older, had more children, or younger at first birth compared to never users; these associations were stronger among EPT users than ET users. Conclusions HT, particularly EPT, may reduce protective effects of older age, parity, and younger age at first birth on mammographic density.     

Parity, tubal sterilization, hysterectomy and risk of primary fallopian tube carcinoma in Finland, 1975-2004

We studied the possible relationship among parity, female sterilization, hysterectomy and the risk of primary fallopian tube carcinoma (PFTC) in a case-control study in Finland in cases occurring between 1975 and 2004. A total of 573 PFTC cases were identified from the Finnish Cancer Registry, and 10 age-matched controls per case were randomly selected from the Finnish Central Population Registry. In multivariate analysis (including 189 PFTC cases and 1764 controls) parity was protective: the odds ratio (OR) for 1-2 deliveries was 0.63 (95% CI 0.44-0.91) and for > or =3 deliveries, 0.32 (95% CI 0.19-0.52). The OR for sterilization was 0.74 (95% CI 0.42-1.30) and for hysterectomy 1.27 (95% CI 0.73-2.21). Our findings suggest a possible hormonal background as regards the development of PFTC.     

An overview of menopausal oestrogen-progestin hormone therapy and breast cancer risk

Results from the Women's Health Initiative (WHI) trial support findings from observational studies that oestrogen-progestin therapy (EPT) use is associated with an increase in breast cancer risk. We conducted a meta-analysis using EPT-specific results from the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) pooled analysis and studies published since that report to obtain an overview of EPT use and breast cancer risk. We also assessed risk by histologic subtype of breast cancer, by schedule of the progestin component of EPT, and by recency of use. We estimate that overall, EPT results in a 7.6% increase in breast cancer risk per year of use. The risk was statistically significantly lower in US studies than in European studies - 5.2 vs 7.9%. There was a significantly higher risk for continuous-combined than for sequential EPT use in Scandinavian studies where much higher total doses of progestin were used in continuous-combined than in sequential EPT. We observed no overall difference in risk for lobular vs ductal carcinoma but did observe a slightly higher risk for current vs past EPT use.     

Does hormone therapy counter the beneficial effects of physical activity on breast cancer risk in postmenopausal women?

Studies consistently demonstrate that physical activity is inversely associated with postmenopausal breast cancer. Whether this association is stronger among non-hormone users or former users of menopausal hormone therapy (HT) is of interest given the marked decline in HT use since 2002. The Women's Contraceptive and Reproductive Experiences Study, a population-based case-control study of invasive breast cancer, recruited white women and black women ages 35-64 years and collected histories of lifetime recreational physical activity and HT use including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT). Among postmenopausal women (1,908 cases, 2,013 control participants), breast cancer risk declined with increasing levels of lifetime physical activity among never HT users; among short-term HT users (fewer than 5 years); and among current ET users; P (trend) values ranged from 0.004 to 0.016. In contrast, physical activity had no significant association with risk among long-term and past HT users and among current EPT users. No statistical evidence of heterogeneity was demonstrated for duration or currency of HT use. Breast cancer risk decreases with increasing lifetime physical activity levels among postmenopausal women who have not used HT, have used HT for less than 5 years, or are current ET users, yet this study was unable to demonstrate statistically that HT use modifies the relationship between physical activity and breast cancer. With profound changes in HT use occurring since 2002, it will be important in future studies to learn whether or not any association between physical activity and breast cancer among former HT users is a function of time since last HT use.     

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.     

Age-related variation in the relationship between menopausal hormone therapy and the risk of dying from breast cancer

Multiple past studies have reported a reduced risk of breast cancer-related mortality (BCM) in relation to pre-diagnostic use of hormone therapy (HT); however, the extent to which this reduction is due to heightened screening or tumor biology is unknown. Using a population-based cohort of 1,911 post-menopausal women diagnosed with invasive breast cancer at ages 45–79 from 1993 to 1999, we investigated the extent to which the reduced risk in BCM observed in relation to HT might be explained by screening patterns or tumor features. Estrogen–progestin therapy (EPT) use was associated with a decreased risk of BCM (after adjustment for age, study, mammography, stage, and treatment), but only among older women (ever use: ≥65 years: HR = 0.45 [95% CI 0.26–0.80]; <65 years: HR = 1.03 [95% CI 0.60–1.79]). Estrogen-alone therapy (ET) use was not associated with risk of BCM (ever use: ≥65 years: HR = 0.76 [95% CI 0.51–1.12]; <65 years: HR = 1.20 [95% CI 0.71–2.02]). HT users had a much greater frequency of mammography (P value <0.001). EPT use was associated with tumor characteristics related to improved prognosis in older women after adjustment for screening, including an inverse association with poorly differentiated tumors (OR = 0.57 [95% CI 0.38–0.85]) and an association with lobular tumors (OR = 1.68 [95% CI 1.07–2.65]). Beyond the influence of EPT use on screening uptake, these data indicate that the improved survival associated with pre-diagnostic EPT use may be due in part to the development of more favorable tumor characteristics.     

Postmenopausal hormone therapy and breast cancer risk: the Multiethnic Cohort

Epidemiological studies indicate that menopausal estrogen-progestin therapy (EPT) use is associated with an increase in breast cancer risk. Further data are needed on whether this association varies by specific prognostic factors and ethnicity. We conducted a cohort study among 55,371 African-American, Native Hawaiian, Japanese-American, Latina and White postmenopausal women aged 45-75 years old in the Multiethnic Cohort Study (MEC). A total of 1,615 incident invasive breast cancer cases were identified over an average of 7.3 years. Adjusted relative risks (RRs) were computed for the various forms of hormone therapy (HT). Assuming current users continued HT use to the end of follow-up, current EPT use was associated with a 29% increased risk of breast cancer per 5 years of use (95% confidence interval (CI) = 23-35%), and current estrogen therapy (ET) use with a 10% increase in risk per 5 years of use (95% CI = 5-16%). These figures increased to only a very small extent when we adjusted for the estimated 3% of such women who stop HT use per year of follow-up. EPT and ET use were associated with greater risk among leaner women, but the increase in risk with EPT use was still very evident in women with BMI > or =30 kg/m(2). Current EPT use was associated with increased risk for ER+/PR+, ER+/PR- and ER-/PR- tumors. There was little difference in risk by stage of disease or histologic subtype. The increase with EPT use was clearly seen in all 5 ethnic groups; and the increase with ET in 4 of the 5 groups.     

Menopausal hormone therapy and risk of epithelial ovarian cancer.

Substantial increase in the use of menopausal hormone therapy (HT) throughout the 1990s, followed by widespread discontinuation after the 2002 publication of the Women's Health Initiative findings, has resulted in large numbers of former HT users among U.S. women. However, few studies have examined whether ovarian cancer risk varies according to recency and duration of specific HT regimens. We assessed risk of epithelial ovarian cancer among users of unopposed estrogen (ET) and combined estrogen/progestogen (EPT). In a population-based study in Washington state, 812 women with ovarian cancer diagnosed in 2002 to 2005 and 1,313 controls were interviewed in person about the use of HT and other characteristics. Women who used a single form of therapy (ET or EPT) were compared with women who never used HT using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CIs). Risk was increased among current or recent (within the last 3 years) users of ET with > or = 5 years of use (ORs, 95% CIs: 1.6, 1.1-2.5 and 1.8, 0.8-3.7, respectively). Little increase in risk was noted among long-term ET users who discontinued use in the more distant past (OR, 1.2; 95% CI, 0.6-2.6). No increase in risk was noted among women who used only EPT, regardless of duration. Compared with women who never used HT, current users of EPT had an OR of 1.1 (95% CI, 0.8-1.5), and risk declined with increasing time since stopping; the OR was 0.7 (95% CI, 0.4-1.0) among women who had discontinued EPT within the last 3 years and 0.5 (95% CI, 0.3-0.7) among women who stopped at an earlier point. Long-term ET may be associated with an increased ovarian cancer risk that wanes after use ceases. We did not observe an increased risk with EPT, and with increasing time after stopping, a reduction in risk became increasingly evident. The progestogen component of HT may confer a risk reduction that is masked by an opposing effect of estrogen until, among former users, estrogenic influences have diminished. These findings, if replicated, may have implications both for public health and development of chemoprevention strategies.     

The effect of estrogen vs. combined estrogen-progestogen therapy on the risk of colorectal cancer

Studies suggest that estrogen therapy (ET) and combined estrogen-progestogen therapy (EPT) may have different associations with colorectal cancer (CRC) risk, but data are conflicting. Prior meta-analyses did not distinguish between ET and EPT. We conducted a meta-analysis to summarize the relative risks (RR) of CRC due to ET versus EPT among peri- or postmenopausal women. From a total of 2,661 articles, four randomized controlled trials, eight cohort and eight case-control studies were included. Variables assessed included study characteristics, duration and recency of menopausal hormone therapy (HT) use, method of assessment of HT use, outcome definition and its ascertainment method. RRs were synthesized by random-effects models. We found that EPT ever use was associated with a decreased risk of CRC (RR 0.74, 95% CI 0.68-0.81), and so was ET ever use (RR 0.79, 95% CI 0.69-0.91). While current use of ET was associated with a significantly reduced risk of CRC (RR 0.70, 95% CI 0.57-0.85), former use was not (RR 0.86, 95%CI 0.67-1.11). Recency did not significantly modify the association between EPT and CRC risk. EPT former use was associated with a lower RR of CRC compared to ET former use (p = 0.008) but no such difference was observed between EPT and ET current use (p = 0.12). Overall, we found consistent evidence supporting the association between EPT and CRC risk reduction, regardless of recency. While literature for the association between ET and CRC risk is heterogeneous, our analyses suggest only current use of ET is associated with a decreased CRC risk.     

Postmenopausal estradiol-progestagen therapy and risk for uterine cervical cancer

The aim of this study was to evaluate the association of postmenopausal estradiol-progestagen therapy (EPT) with the risk for precancerous lesions, squamous cell carcinoma and adenocarcinoma of the uterine cervix. All Finnish women who had used EPT in 1994-2008 for at least 6 months (n = 243,857) at the age of 50 years or more were identified from the national Medical Reimbursement Registry and linked to the Finnish Cancer Registry. The incidence of cervical precancerous or cancerous lesions among EPT users was compared to that in the background population. There were 210 EPT users with squamous lesions (178 with precancerous and 32 with cancer) and 79 EPT users with glandular lesions (14 precancerous and 65 adenocarcinomas). The ever use of EPT did not associate with the incidence of precancerous lesions, but the risk for squamous cell carcinoma decreased (standardized incidence ratio 0.41; 95% confidence interval 0.28-0.58) and that for adenocarcinoma increased (1.31; 1.01-1.67). After the use of EPT for 5 years, the risk for squamous cell carcinoma decreased (0.34; 0.16-0.65), and the risk for adenocarcinomas increased (1.83; 1.24-2.59). The prolonged use of EPT is associated with the occurrence of cervical malignancies. If the association would be a causal one, the use for 5+ years among 10,000 women followed for 10 years would mean about two to three fewer cases of cervical squamous cell carcinoma but about two extra cases with adenocarcinoma.     

Menopausal hormone therapy and breast cancer risk: Impact of different treatments. The European Prospective Investigation into Cancer and Nutrition

Menopausal hormone therapy (MHT) is characterized by use of different constituents, regimens and routes of administration. We investigated the association between the use of different types of MHT and breast cancer risk in the EPIC cohort study. The analysis is based on data from 133,744 postmenopausal women. Approximately 133,744 postmenopausal women contributed to this analysis. Information on MHT was derived from country‐specific self‐administered questionnaires with a single baseline assessment. Incident breast cancers were identified through population cancer registries or by active follow‐up (mean: 8.6 yr). Overall relative risks (RR) and 95% confidence interval (CI) were derived from country‐specific Cox proportional hazard models estimates. A total of 4312 primary breast cancers were diagnosed during 1,153,747 person‐years of follow‐up. Compared with MHT never users, breast cancer risk was higher among current users of estrogen only (RR: 1.42, 95% CI 1.23–1.64) and higher still among current users of combined MHT (RR: 1.77, 95% CI 1.40–2.24; p = 0.02 for combined vs. estrogen‐only). Continuous combined regimens conferred a 43% (95% CI: 19–72%) greater risk compared with sequential regimens. There was no significant difference between progesterone and testosterone derivatives in sequential regimens. There was no significant variation in risk linked to the estrogenic component of MHT, neither for oral vs. cutaneous administration nor for estradiol compounds vs. conjugated equine estrogens. Estrogen‐only and combined MHT uses were associated with increased breast cancer risk. Continuous combined preparations were associated with the highest risk. Further studies are needed to disentangle the effects of the regimen and the progestin component.