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Objectives: The role of postmenopausal hormone therapy (HT) in the incidence of acute coronary syndrome (ACS) has been studied extensively, but less is known of the impact of HT on the mortality risk due to an ACS., Study Design and Main Outcome Measures: We extracted from a population-based ACS register, FINAMI, 7258 postmenopausal women with the first ACS. These data were combined with HT use data from the National Drug Reimbursement Register; 625 patients (9%) had used various HT regimens. The death risks due to ACS before admission to hospital, 2-28, or 29-365days after the incident ACS were compared between HT users and non-users with logistic regression analyses., Results: In all follow-up time points, the ACS death risks in HT ever-users were smaller compared to non-users. Of women with HT ever use, 42% died within one year as compared with 52% of non-users (OR 0.62, p<0.001). Most deaths (84%) occurred within 28days after the ACS, and in this group 36% of women with ever use of HT (OR 0.73, p=0.002) and 30% of women with ≥5year HT use (OR 0.54, p<0.001) died as compared to 43% of the non-users. Age ≤60 or >60 years at the HT initiation was accompanied with similar reductions in ACS mortality risk., Conclusions: Postmenopausal HT use is accompanied with reduced mortality risk after primary ACS., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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.

Data on the possible impact of postmenopausal hormone therapy (HT) on the incidence of rare primary fallopian tube carcinoma (PFTC) are scarce. Therefore, we conducted a nationwide case-control study analyzing the association between the use of different HTs and PFTC. All women aged 50 years or older with an incident PFTC (n = 360) during 1995-2007 were identified from the Finnish Cancer Registry. For each case of PFTC, ten age- and place of residence-matched controls were selected from the Finnish National Population Register, which also provided information on parity. Data on HT purchases were received from the Prescription Register, and data on hysterectomies and sterilizations from the National Care Register. Controls with a salpingectomy before the PFTC diagnosis of the respective case were excluded. The PFTC risk in relation to different HTs was estimated with a conditional logistic regression model, adjusted for parity, age at last delivery, hysterectomy and sterilization. The use for five years or more of estradiol combined with levonorgestrel-releasing-intrauterine system (odds ratio 2.84, 95% confidence interval 1.10-7.38) and sequential estradiol-progestin therapy (EPT; 3.37; 2.23-5.08) were both linked with increases in the risk of PFTC, while the risk with use of estradiol-only therapy or continuous EPT was not statistically significantly increased. The OR for the use of tibolone for one year or more was 1.56 (0.55-4.41). The use of HT is related to an increased risk of PFTC, particularly when a progestin component is intrauterine or systemic progestin is given in sequential manner., (© 2015 UICC.)

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.

Objective: The Women's Health Initiative (WHI) study clarified the indications and contraindications for postmenopausal hormone therapy (HT). We studied the impact of the WHI results on the risk of fatal stroke in HT users in Finland., Study Design: Retrospective analysis setting: Nationwide registers on postmenopausal HT use and causes of death between 1995 and 2009., Population: Women ≥40 years (n=290,272) using systemic estradiol-based postmenopausal HT., Methods: Follow-up started from the first HT purchase during the pre-WHI era (1995-2001) and post-WHI era (2002-2009)., Main Outcome Measures: Stroke deaths in HT users were compared with that in the age-matched background population and expressed as standardized mortality ratio (SMR) with 95% confidence intervals., Results: Overall, 311 HT users died due to stroke. The exposure to HT ≤1 year was associated with a similarly reduced 22% (0.67-0.91) risk of stroke death in the pre-WHI era and in the post-WHI era 27% (0.55-0.94). The risk reductions for HT exposure of 1-8 years in the pre-WHI era (47%, 0.42-0.65) did not differ from that in the post-WHI era (32%, 0.48-0.94). The discontinuation of HT was accompanied by a significant 33% (1.02-1.72) increase in stroke death risk in the pre-WHI era and a non-significant 32% (0.84-1.99) increase in the post-WHI era within the first post-treatment year, but no longer after 1-8 years., Conclusions: The change in prescribing policy after the WHI study did not affect the risk of fatal stroke in Finnish HT users., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess whether coronary heart disease mortality in Finnish hormone therapy (HT) users differed before and after 2002 when the Women's 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) Women's 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-Women's Health Initiative era. In the post-Women's 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-Women's Health Initiative era and 31% (1.31; 0.92-1.82; two per 10,000 extra deaths) in the post-Women's 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 Women's Health Initiative failed to affect coronary heart disease mortality of HT users in this nationwide study.

Postmenopausal hormone therapy (HT) associates with an increased risk of ovarian cancer, but its' influence on tumor histology is not as well known. Therefore, we evaluated the effect of various types of HT on the risk of epithelial ovarian cancer by histological subtype. All Finnish women diagnosed with ovarian cancer (n = 3,958) aged over 50 during 1995-2007 were identified from the Finnish Cancer Registry. For each case, three controls, matched for age and place of residence, were recruited from the Finnish National Population Register, which also provided data on parity and ages at deliveries. After exclusion of controls with oophorectomy, 11,325 controls remained. The prescription register provided HT use from age 50. Odds ratios (OR) for different HTs were estimated by conditional logistic regression: adjusted for parity, ages at deliveries and hysterectomy. Estradiol-only therapy use for 5 years or more associated with an increased risk (OR 1.45; 95% confidence interval 1.20-1.75) of a serous subtype, but with a decreased risk of mucinous subtype (0.35; 0.19-0.67). Use of sequential estradiol-progestin therapy (EPT) for 5 years or more associated with an increase in overall ovarian cancer risk (1.35; 1.20-1.63) and with an increase in the endometrioid subtype (1.88; 1.24-2.86) particularly. Continuous EPT, estradiol + levonorgestrel-releasing intrauterine system or tibolone had no effect on overall ovarian cancer risk. In conclusion, only sequential EPT use for 5 years or more associates with an increased risk of overall ovarian cancer. Furthermore, HT regimens differ significantly in their association with various histological types of ovarian cancer., (© 2013 UICC.)

Objective: Primary fallopian tube carcinoma (PFTC) is a rare malignancy and only sparse data exist on its possible association with postmenopausal hormone therapy (HT). We therefore studied this association in a nationwide cohort of Finnish HT users., Methods: All women> 50 years using systemic estradiol-only therapy (ET) (n=117,820 hysterectomized women) or estradiol-progestin therapy (EPT) (n=247,781 nonhysterectomized women) for ≥ 6 months during 1994-2008 were identified from the national medical reimbursement register. The incidence of PFTC in HT users was compared to that in the comparable background population (standardized incidence ratio, SIR, with 95% confidence interval, CI)., Results: A total of 160 cases of PFTC were encountered in users of ET (n=34) or EPT (n=126). The use of EPT ≥ 5 years was accompanied by an increased risk for PFTC (SIR 2.15; 95% CI 1.66-2.72). The SIR increased further to 3.36 (95% CI 2.02-5.24) when EPT use lasted ≥ 10 years. The EPT-related risk for PFTC was restricted to the sequential EPT and it was not seen for continuous EPT. Two leading progestins in EPT, norethisterone acetate and medroxyprogesterone acetate, associated with comparable risk elevations. ET use was not associated with the risk for PFTC., Conclusions: The long-term, sequential use of EPT associates with an increased risk for PFTC. In absolute terms, 4 additional cases of PFTC would be detected in 10-year follow-up of 10,000 women who have used EPT for at least 5 years., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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.

Objective: Insufficient data exist on the effect of postmenopausal hormone therapy as the risk factor for uterine sarcomas. We therefore evaluated the association of estradiol-progestin therapy (EPT) with the risk of uterine sarcoma in nation-wide cohort study., Methods: All Finnish women (>50 years of age) who had used EPT during the years 1994-2008 for at least 6 months (n=243,857) were identified from the national Medical Reimbursement Registry. Their incidence of uterine stromal and leiomyosarcoma among the EPT users was compared to that in the background population with the aid of the Finnish Cancer Registry., Results: A total of 76 uterine sarcomas were encountered in the EPT cohort; 45 (59%) were leiomyosarcomas, 24 (32%) stromal sarcomas and 7 (9%) other sarcomas. The exposure to EPT for less than 5 years did not associate with significant rises in the sarcoma risk but longer exposure was accompanied with significant risk elevations for all uterine sarcomas: the standardized incidence ratio (SIR) for 5-10 years of use was 2.0, 95% confidence interval (CI) 1.4-2.9 and for ≥10 years of use 3.0 (1.3-5.9): the SIRs were highest for leiomyosarcoma. The sequential and continuous uses of progestin were associated with similar increased SIRs for uterine sarcoma., Conclusions: The use of EPT for 5 years or more is associated with an increased risk for uterine sarcomas. This turns to an absolute excess risk of 2-3 extra uterine sarcoma cases per 10,000 long-time EPT users followed for 10 years., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Breast cancer is a heterogenous disease and hormonal factors are involved. Since national differences exist in the use of postmenopausal hormone therapy (HT) and other risk factors, associations between HT and breast cancer should be studied nationally. In Finland, estrogen-progestin therapy is associated with higher breast cancer risk than estrogen-only therapy. Also tibolone and levonorgestrel releasing intauterine device combined with estrogen are accompanied with an increased risk of breast cancer. Hormone therapy possibly promotes the growth of the existing undetectable cancer.

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.

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.

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.

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.

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. [ABSTRACT FROM AUTHOR]