A meta-analysis 3 used individual participant data from all eligible prospective studies about the type and timing of menopausal hormone therapy (HT). Every HT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use. Among current users, these excess risks were definite even during years 1-4 (oestrogen-progestagen RR 1.60, 95% CI 1.52 to 1.69; oestrogen-only RR 1.17, 1.10 to 1.26), and were twice as great during years 5-14 (oestrogen-progestagen RR 2.08, 2.02 to 2.15; oestrogen-only RR 1.33, 1.28 to 1.37). The oestrogen-progestagen risks during years 5-14 were greater with daily than with less frequent progestagen use (RR 2.30, 2.21 to 2.40 vs 1.93, 1.84 to 2.01; heterogeneity p<0.0001).
A Swedish prospective nationwide cohort study 4 included all women who received ≥1 HT prescription during the study period 2005-2012 (290 186 ever-users), group-level matched (1 : 3) to 870 165 never-users; respectively, 6376 (2.2%) and 18 754 (2.2%) developed breast cancer. Current use of oestrogen-only therapy was associated with a slight excess breast cancer risk [odds ratio (OR) 1.08 (1.02 to 1.14)] and oestrogen plus progestogen therapy was higher [OR = 1.77 (1.69 to 1.85)] and increased with higher age at initiation. The OR for current use was 1.12 (1.04 to 1.20) for estradiol, 0.76 (0.69 to 0.84) for estriol, 4.47 (2.67 to 7.48) for conjugated oestrogens, and 1.68 (1.51 to 1.87) for tibolone. Oral and cutaneous HT showed similar associations.
A cochrane review [Abstract] 2 included 22 studies involving 43 637 women. Nearly 70% of the data was derived from 2 studies (HERS 1998; WHI 1998). Oestrogen-only hormone therapy (HT) increased the risk of venous thromboembolism, stroke and gallbladder disease but reduced the risk of breast cancer and clinical fracture and did not increase the risk of coronary events at any follow-up time (table T1. Combined HT in women over 65 years of age increased risk of cardiovascular disease, stroke, venous thromboembolism, and breast cancer, and decreased incidence of fracture. (table T2. Data are insufficient for assessment of the risk of long-term HT use in perimenopausal women.
| Outcome: Follow-up: mean 7.1 years | Relative effect(95% CI) | Assumed risk - Placebo | Corresponding risk - Oestrogen-only hormone therapy (95% CI) | No. of participants(studies) Quality of evidence |
|---|---|---|---|---|
| Coronary events (MI or cardiac death) | RR 0.94(0.78 to 1.13) | 41 per 1000 | 38 per 1000(32 to 46) | 10 739(1) Moderate |
| Stroke | RR 1.33 (1.06 to 1.67) | 24 per 1000 | 32 per 1000(25 to 40) | 10 739(1) Moderate |
| Venous thromboembolism (DVT or PE) | RR 1.32 (1.00 to 1.74) | 16 per 1000 | 21 per 1000(16 to 28) | 10 739(1) Moderate |
| Breast cancer | RR 0.79 (0.61 to 1.01) | 25 per 1000 | 20 per 1000(15 to 25) | 10 739(1) Moderate |
| Gallbladder disease | RR 1.78(1.42 to 2.24) | 27 per 1000 | 47 per 1000(38 to 60) | 8 376(1) Moderate |
| All clinical fractures | RR 0.73 (0.65 to 0.80) | 141 per 1000 | 103 per 1000(92 to 113) | 10 739(1) Moderate |
| Outcome | Relative effect(95% CI) | Assumed risk - Placebo | Corresponding risk - Combined continuous hormone therapy (95% CI) | No. of participants(studies) Quality of evidence |
|---|---|---|---|---|
| Coronary events (MI or cardiac death) Follow-up: mean/median 1 year | RR 1.89 (1.15 to 3.10) | 2 per 1000 | 4 per 1000(3 to 7) | 20 993(2) Moderate |
| Stroke Follow-up: mean 3 years | RR 1.46(1.02 to 2.09) | 6 per 1000 | 8 per 1000(6 to 12) | 17 585(2) Moderate |
| Venous thromboembolism (DVT or PE) Follow-up: mean/median 1 year | RR 4.28 (2.49 to 7.34) | 2 per 1000 | 7 per 1000(4 to 11) | 20 993(2) Moderate |
| Breast cancer Follow-up: median 5.6 years | RR 1.27 (1.03 to 1.56) | 19 per 1000 | 24 per 1000(20 to 30) | 16 608(1) Moderate |
| Death from lung cancerFollow-up: median 8 years | RR 1.74(1.18 to 2.55) | 5 per 1,000 | 9 per 1000(6 to 13) | 16 608(1) Moderate |
| All clinical fractures Follow-up: mean 5.6 years | RR 0.78 (0.71 to 0.86) | 111 per 1000 | 87 per 1000(79 to 96) | 16 608(1) Moderate |
The Women's Health Initiative (WHI) conducted in 40 US clinical centers enrolled 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy 1. Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo. Estimated hazard ratios (HRs) (95% CIs) for CEE vs placebo for the major clinical outcomes were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22).
Primary/Secondary Keywords