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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., (Copyright © 2011 UICC.)

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.)

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., (Copyright © 2011 UICC.)

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.