Heli Lyytinen

Breast cancer risk in postmenopausal women using estradiol-progestogen therapy.

OBJECTIVE: To estimate the risk for breast cancer in Finnish women using postmenopausal estradiol (E2)–progestogen therapy. METHODS: All Finnish women over 50 years using E2–progestogen therapy for at least 6 months in 1994–2005 (N=221,551) were identified from the national medical reimbursement register and followed up for breast cancer incidence (n=6,211 cases) through the Finnish Cancer Registry to the end of 2005. The risk for breast cancer in E2–progestogen therapy users was compared with that in the general population. RESULTS: The standardized incidence ratio for all types of breast cancer was not elevated within the first 3 years of use, but it rose to 1.31 (95% confidence interval 1.20–1.42) for the use from 3–5 years and to 2.07 (1.84–2.30) with 10 or more years of use. Exposure to sequential progestogen for 5 years or more was accompanied with a lower risk elevation (1.78, 1.64–1.90) than exposure to continuous use (2.44, 2.17–2.72). Oral and transdermal use of E2–progestogen therapy was associated with comparable risk elevations for breast cancer. The use of norethisterone acetate was accompanied with a higher risk after 5 years of use (2.03, 1.88–2.18) than that of medroxyprogesterone acetate (1.64, 1.49–1.79). The risk of lobular breast cancer increased sooner than that for ductal cancer and was detectable for E2–progestogen therapy use less than 3 years (1.35, 1.18–1.53). There was no excess risk of breast cancer with distant metastases among E2–progestogen therapy users. CONCLUSION: The use of E2–progestogen therapy is associated with an increased risk for breast cancer after 3 years of use. The risk is lower for sequential than for continuous use, but comparable for oral and transdermal use. The risk elevation may not be uniform for all progestogens. LEVEL OF EVIDENCE: II

Breast Cancer Risk in Postmenopausal Women Using Estrogen-Only Therapy

OBJECTIVE: To evaluate whether the risk of estrogen-only therapy on breast cancer varies by dose, constituent, and route of administration. METHODS: All Finnish women older than age 50 years using oral or transdermal estradiol (n=84,729), oral estriol (n=7,941), or vaginal estrogens (n=18,314) for at least 6 months during 1994–2001 were identified from the national medical reimbursement register. They were followed for breast cancer with the aid of the Finnish Cancer Registry to the end of 2002. RESULTS: Altogether, 2,171 women with breast cancer were identified. The standardized incidence ratio of breast cancer with systemic estradiol for less than 5 years was 0.93 (95% confidence interval 0.80–1.04), and for estradiol use for 5 years or more, 1.44 (1.29–1.59). Oral and transdermal estradiol was accompanied by a similar risk of breast cancer. The risk was most prominent with the dose greater than 1.9 mg/d orally; whereas the risk associated with transdermal route was not dose-dependent. The standardized incidence ratio for the lobular type of breast cancer (1.58) was slightly higher than that for the ductal type (1.36). The use of estradiol was associated with both localized breast cancer (1.45; 1.26–1.66) and cancer spread to regional nodes (1.35; 1.09–1.65). The incidence of carcinoma in situ (n=32) was increased (2.43; 1.66–3.42) among estradiol users. CONCLUSION: Estradiol for 5 years or more, either orally or transdermally, means 2–3 extra cases of breast cancer per 1,000 women who are followed for 10 years. Oral estradiol use for less than 5 years, oral estriol, or vaginal estrogens were not associated with a risk of breast cancer. LEVEL OF EVIDENCE: II-2

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.

Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality.

Objective:Data on the health benefits and risks of postmenopausal hormone therapy (HT) are derived mainly from the use of conjugated equine estrogens. Estradiol-based regimens may have a different risk-benefit profile. We evaluated the risk of death caused by coronary heart disease (CHD), stroke, or any disease among users of estradiol-based HT regimens in a nationwide study in Finland. Methods:A total of 489,105 women who used HT from 1994 to 2009 (3.3 million HT exposure years), as indicated in the nationwide reimbursement register and the national Cause of Death Register, were followed. A total of 28,734 HT users died during follow-up; among the deaths, 3,843 were caused by CHD and 2,464 were caused by stroke. Mortality risk in HT users with varying duration of exposure (⩽1 y, >1 to 3 y, >3 to 5 y, >5 to 10 y, or >10 y) was compared with that in an age-matched background population. Results:Risk of CHD death was significantly reduced by 18% to 54% in HT users and was positively related to HT exposure time. Risk of stroke death was also reduced by 18% to 39%, but this reduction was not clearly related to HT exposure time. Risk of all-cause mortality was reduced in HT users by 12% to 38%, almost in linear relationship with duration of exposure. All these risk reductions were comparable in women initiating HT before age 60 years and women initiating HT at age 60 years or older. Conclusions:In absolute terms, the risk reductions mean 19 fewer CHD deaths and 7 fewer stroke deaths per 1,000 women using any HT for at least 10 years.

Endometrial Cancer in Postmenopausal Women Using Estradiol-Progestin Therapy

OBJECTIVE: To estimate the risk of endometrial cancer in all Finnish postmenopausal women using various forms of estradiol–progestin therapy. METHODS: All Finnish women (aged more than 50 years) who had used estradiol–progestin therapy in 1994–2006 for at least 6 months (n=224,015) were identified from the national medical Reimbursement Registry and linked to the Finnish Cancer Registry. A total of 1,364 type I and 38 type II endometrial cancers were recorded by the end of 2006. The incidence of endometrial cancer in estradiol–progestin therapy users was compared with that in the general population in this cohort study. RESULTS: The use of a continuous estradiol–progestin therapy regimen for 3 years or more was associated with a 76% reduction of the risk for type 1 cancer (95% confidence interval [CI] 6–60%). In contrast, the use of a sequential estradiol–progestin therapy regimen for at least 5 years was accompanied with a 69% elevation (95% CI 43–96%) if the progestin was added monthly, and with a significantly higher, 276% risk elevation (95% CI 190–379%) if progestin was added at 3-month intervals. Sequential regimens containing norethisterone acetate, medroxyprogesterone acetate or dydrogesterone administered orally showed no significant differences in the endometrial safety. Oral and transdermal norethisterone acetate were associated with similar risk elevations. Women using a monthly sequential estradiol–progestin regimen tended to be diagnosed with endometrial cancer in an earlier stage than the background population. CONCLUSION: Use of a continuous rather than a sequential estradiol–progestin regimen decreases the risk of endometrial cancer, whereas the route of administration or type of progestin does not differ in terms of endometrial cancer risk. LEVEL OF EVIDENCE: II

Increased Cardiovascular Mortality Risk in Women Discontinuing Postmenopausal Hormone Therapy

CONTEXT Current guidelines recommend annual discontinuation of postmenopausal hormone therapy (HT) to evaluate whether a woman could manage without the treatment. The impact of HT on cardiovascular health has been widely studied, but it is not known how the withdrawal of HT affects cardiovascular risk. OBJECTIVE We evaluated the risk of cardiac or stroke death after the discontinuation of HT. Design, Patients, Interventions, and Main Outcome Measures: Altogether 332 202 Finnish women discontinuing HT between 1994 and 2009 (data from National Reimbursement register) were followed up from the discontinuation date to death due to cardiac cause (n = 3177) or stroke (n = 1952), or to the end of 2009. The deaths, retrieved from the national Cause of Death Register, were compared with the expected number of deaths in the age-standardized background population. In a subanalysis we also compared HT stoppers with HT users. RESULTS Within the first posttreatment year, the risk of cardiac death was significantly elevated (standardized mortality ratio; 95% confidence interval 1.26; 1.16-1.37), whereas follow-up for longer than 1 year was accompanied with a reduction (0.75; 0.72-0.78). The risk of stroke death in the first posttreatment year was increased (1.63; 1.47-1.79), but follow-up for longer than 1 year was accompanied with a reduced risk (0.89; 0.85-0.94). The cardiac (2.30; 2.12-2.50) and stroke (2.52; 2.28-2.77) death risk elevations were even higher when compared with HT users. In women who discontinued HT at age younger than 60 years, but not in women aged 60 years or older, the cardiac mortality risk was elevated (1.94; 1.51-2.48). CONCLUSIONS Increased cardiovascular death risks question the safety of annual HT discontinuation practice to evaluate whether a woman could manage without HT.

A Nationwide Cohort Study on the Incidence of Meningioma in Women Using Postmenopausal Hormone Therapy in Finland

The authors conducted a nationwide cohort study to evaluate the association between postmenopausal hormone therapy and meningioma incidence in Finland. All women who had used hormone therapy at least for 6 months at the age of 50 years or older during 1994-2009 were included. Women who had used postmenopausal hormone therapy were identified from the medical reimbursement register of the Social Insurance Institution (131,480 estradiol users and 131,248 estradiol-progestin users), and meningioma cases were identified from the Finnish Cancer Registry. During the average 9 years of follow-up, 289 estradiol users and 196 estradiol-progestin users were diagnosed with meningioma. Ever use of estradiol-only therapy was associated with an increased risk of meningioma (standardized incidence ratio = 1.29, 95% confidence interval: 1.15, 1.44). Among women who had been using estradiol-only therapy for at least 3 years, the incidence of meningioma was 1.40-fold higher (95% confidence interval: 1.18, 1.64; P < 0.001) than in the background population. In contrast, this risk was not increased in users of combination therapy (standardized incidence ratio = 0.93, 95% confidence interval: 0.80, 1.06). There was no difference in risk between continuous and sequential use of hormone therapy. Estradiol-only therapy was accompanied with a slightly increased risk of meningioma.

Coronary Heart Disease Mortality and Hormone Therapy Before and After the Women's Health Initiative

OBJECTIVE: To assess whether coronary heart disease mortality in Finnish hormone therapy (HT) users differed before and after 2002 when the Womens Health Initiative study was published. METHODS: The risks of coronary heart disease death in HT users in relation to the age-matched background population were compared between the pre– (1995–2001) and post– (2002–2009) Womens Health Initiative eras. We used a nationwide register on HT (ie, estradiol with or without progestin) reimbursement and linked them to causes of death in 290,272 women aged 40 years or older. RESULTS: Exposure to HT for 1 year or less was accompanied by a 29% reduction (0.71; 0.63–0.80; three per 10,000 fewer deaths) and an exposure of 1–8 years with a 43% reduction (0.57; 0.48–0.66; three per 10,000 fewer deaths) in the risk of coronary heart disease death in the pre–Womens Health Initiative era. In the post–Womens Health Initiative era, HT use of 1 year or less was associated with an 18% reduction (0.82; 0.76–1.00; one per 10,000 fewer deaths) and an exposure of 1–8 years with a 54% reduction (0.46; 0.32–0.64; two per 10,000 fewer deaths) in coronary heart disease mortality. Discontinuation of HT was associated with an increased risk of cardiac death of 42% (1.42; 1.17–1.71; seven per 10,000 extra deaths) in the pre–Womens Health Initiative era and 31% (1.31; 0.92–1.82; two per 10,000 extra deaths) in the post–Womens Health Initiative era during the first posttreatment year. This risk increase vanished in further follow-up during both eras. CONCLUSION: Changes in HT use after the Womens Health Initiative failed to affect coronary heart disease mortality of HT users in this nationwide study. LEVEL OF EVIDENCE: II

Vaginal estradiol use and the risk for cardiovascular mortality

STUDY QUESTION Does the use of post-menopausal vaginal estradiol (VE) affect the mortality risk for coronary heart disease (CHD) and stroke. SUMMARY ANSWER The use of VE reduces the risk for cardiovascular mortality. WHAT IS KNOWN ALREADY A growing number of women use VE for post-menopausal genitourinary symptoms. Although this therapy is intended to have only local effects, estrogen is absorbed into the blood circulation and thus VE use may also have systemic effects. STUDY DESIGN, SIZE, DURATION We studied a nationwide cohort in Finland 1994-2009 during which post-menopausal women (n = 195 756) initiated the use of VE (age [mean ± SD] 65.7 ± 10.9 years). Follow-up data gathered 1.4 million women-years and we assessed the mortality risk due to CHD (n= 9656) or stroke (n = 4294). PARTICIPANTS/MATERIALS, SETTING, METHODS The mortality risk in VE users was compared with that in the age-matched background population (standardized mortality ratio; [SMR]; 95% confidence interval) and related to various durations of exposure to VE (1 to ≤3, >3 to ≤5, >5 to ≤10 and >10 years). MAIN RESULTS AND THE ROLE OF CHANCE The use of VE was accompanied by decreases in the risk for CHD and stroke death. The risk reduction for CHD death was highest for >3 to ≤5 years exposure (SMR 0.64; 0.57-0.70) and for stroke for >5 to ≤10 years exposure (SMR 0.64; 0.57-0.72). The risk reductions for both CHD and stroke mortality were detected in all age groups with the highest risk reduction being in women aged 50-59 years (SMR 0.43; 0.19-0.88 and SMR 0.21; 0.06-0.58, respectively). LIMITATIONS, REASONS FOR CAUTION Our series lack a placebo arm and thus, may harbor a healthy woman bias. Moreover, data on clinical variables such as weight, smoking, blood pressure and family background were unobtainable for this study. Women using both VE and systemic hormone therapy (HT) were included in the comparator background population. This should not cause any significant error because the proportion of women using VE or other HT was modest (<10% in age-matched population) and because the use of systemic HT also reduces death risks in the same population. Our data cannot be directly applied for local regimens containing conjugated equine estrogens, because they are absorbed differently and may show effects that differ from those of estradiol. WIDER IMPLICATIONS OF THE FINDINGS In 1000 women using VE for up to 10 years, a maximum of 24 fewer CHD deaths and 18 fewer stroke deaths is likely to occur. STUDY FUNDING/COMPETING INTERESTS This work was supported by unrestricted grants from the Päivikki and Sakari Sohlberg Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, Finska Läkaresällskapet, the Orion Farmos Research Foundation, the Paavo Nurmi Foundation and a special governmental grant for health sciences research. The funding sources had no role in the study design, data handling or manuscript preparation. EPID Research is a company that performs financially supported studies for several pharmaceutical companies. Dr Korhonen, Dr Hoti and MSc Vattulainen, employed by Epid Research, report financial activities from several other pharmaceutical companies outside the submitted work. Dr Mikkola has been a speaker and/or received consulting fees from Mylan and Novo Nordisk. Dr Tuomikoski has been a speaker and/or received consulting fees from Orion and Mylan. The remaining authors report no conflict of interest.