Cochrane Review (CD004143) - long‐term hormone therapy for perimenopausal and postmenopausal women

Hormone therapy for postmenopausal women (long-term effects)

Overview

• updated Cochrane systematic review evaluating the long-term clinical effects (minimum 1 year of use) of prolonged hormone therapy (HT) on major health outcomes in peri- and postmenopausal women
• search updated to September 2024; includes 24 RCTs (45,660 participants), with ~70% of data derived from the WHI (1998) and HERS (1998) trials
• mean age across most trials was >60 years (only ~30% were aged 50–59 years at baseline)

Combined continuous HT vs. placebo (intact uterus) data based on oral conjugated equine oestrogen (CEE) plus medroxyprogesterone acetate (MPA) at mean follow-up of 5.6 years:

• breast cancer:
  • increased risk (RR 1.27, 95% CI 1.03 to 1.56; moderate-certainty evidence)
• venous thromboembolism (VTE):
  • increased risk (RR 2.03, 95% CI 1.55 to 6.64; low-certainty evidence)
• stroke:
  • increased risk (RR 1.39, 95% CI 1.09 to 2.09; low-certainty evidence)
• gallbladder disease (requiring surgery):
  • increased risk (RR 1.64, 95% CI 1.30 to 2.06; low-certainty evidence)
• clinical fractures:
  • reduced risk across all clinical fractures (RR 0.78, 95% CI 0.71 to 0.86; moderate-certainty evidence)
• coronary events:
  • little to no difference in risk (RR 1.17, 95% CI 0.95 to 1.44; moderate-certainty evidence)
• lung cancer:
  • little to no difference in risk (RR 1.06, 95% CI 0.77 to 1.46; moderate-certainty evidence)

Oestrogen-only HT vs. placebo (prior hysterectomy) data based on oral conjugated equine oestrogen (CEE) at mean follow-up of 7 years:

• stroke:
  • increased risk (RR 1.33, 95% CI 1.06 to 1.67; moderate-certainty evidence)
• gallbladder disease (requiring surgery):
  • increased risk (RR 1.78, 95% CI 1.42 to 2.24; moderate-certainty evidence)
• clinical fractures:
  • reduced risk across all clinical fractures (RR 0.73, 95% CI 0.65 to 0.80; moderate-certainty evidence)
• breast cancer:
  • little to no difference in risk (RR 0.79, 95% CI 0.61 to 1.01; moderate-certainty evidence)
• coronary events:
  • little to no difference in risk (RR 0.94, 95% CI 0.78 to 1.13; moderate-certainty evidence)
• VTE:
  • little to no difference in risk (RR 1.32, 95% CI 1.00 to 1.74; moderate-certainty evidence)
• lung cancer:
  • little to no difference in risk (RR 1.04, 95% CI 0.73 to 1.48; low-certainty evidence)

Clinical application and limitations

• study demographic vs typical UK practice:
  • main limitation is that only ~30% of participants were aged 50–59 years, which represents the age group most likely to initiate HT for vasomotor symptoms
• formulation applicability:
  • outcomes reflect oral CEE preparations (with or without MPA); caution is advised when extrapolating these findings to modern UK prescribing practice, which frequently utilizes transdermal oestradiol and body-identical progestogens (e.g. micronised progesterone)

Reference:

1. Bofill Rodriguez M, Yong LN, Mirkov S, Bekos C, Lethaby A, Farquhar C. Long‐term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database of Systematic Reviews 2026, Issue 9. Art. No.: CD004143.