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Evidence summaries

Menopausal Hormone Therapy and Breast Cancer

Menopausal hormone therapy increases the risk of breast cancer. The risk appears to be greater with oestrogen-progestagen than oestrogen-only preparations. Level of evidence: "A"

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.

Oestrogen-only hormone therapy compared with placebo for postmenopausal women

Outcome: Follow-up: mean 7.1 yearsRelative effect(95% CI)Assumed risk - PlaceboCorresponding 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 100038 per 1000(32 to 46)10 739(1) Moderate
StrokeRR 1.33 (1.06 to 1.67)24 per 100032 per 1000(25 to 40)10 739(1) Moderate
Venous thromboembolism (DVT or PE)RR 1.32 (1.00 to 1.74)16 per 100021 per 1000(16 to 28)10 739(1) Moderate
Breast cancerRR 0.79 (0.61 to 1.01)25 per 100020 per 1000(15 to 25)10 739(1) Moderate
Gallbladder diseaseRR 1.78(1.42 to 2.24)27 per 100047 per 1000(38 to 60)8 376(1) Moderate
All clinical fracturesRR 0.73 (0.65 to 0.80)141 per 1000103 per 1000(92 to 113)10 739(1) Moderate

Combined continuous HT (moderate-dose oestrogen) - CEE 0.625 mg + MPA 2.5 mg

OutcomeRelative effect(95% CI)Assumed risk - PlaceboCorresponding 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 yearRR 1.89 (1.15 to 3.10)2 per 10004 per 1000(3 to 7)20 993(2) Moderate
Stroke Follow-up: mean 3 yearsRR 1.46(1.02 to 2.09)6 per 10008 per 1000(6 to 12)17 585(2) Moderate
Venous thromboembolism (DVT or PE) Follow-up: mean/median 1 yearRR 4.28 (2.49 to 7.34)2 per 10007 per 1000(4 to 11)20 993(2) Moderate
Breast cancer Follow-up: median 5.6 yearsRR 1.27 (1.03 to 1.56)19 per 100024 per 1000(20 to 30)16 608(1) Moderate
Death from lung cancerFollow-up: median 8 yearsRR 1.74(1.18 to 2.55)5 per 1,0009 per 1000(6 to 13)16 608(1) Moderate
All clinical fractures Follow-up: mean 5.6 yearsRR 0.78 (0.71 to 0.86)111 per 100087 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).

    References

    • Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O'Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S, Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004 Apr 14;291(14):1701-12. [PubMed]
    • Marjoribanks J, Farquhar C, Roberts H et al. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2017;(1):CD004143. [PubMed]
    • Collaborative Group on Hormonal Factors in Breast Cancer.. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019;394(10204):1159-1168. [PubMed]
    • Brusselaers N, Tamimi RM, Konings P et al. Different menopausal hormone regimens and risk of breast cancer. Ann Oncol 2018;29(8):1771-1776.[PubMed]

Primary/Secondary Keywords