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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.

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.

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.