Long term hormone therapy for perimenopausal and postmenopausal women

Cochrane Database Syst Rev. 2012 Jul 11;(7):CD004143. doi: 10.1002/14651858.CD004143.pub4.


Background: Hormone therapy (HT) is widely used for controlling menopausal symptoms and has also been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005.

Objectives: To assess the effects of long term HT on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, cognition and quality of life in perimenopausal and postmenopausal women, both during HT use and after cessation of HT use.

Search methods: We searched the following databases to February 2012: Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO.

Selection criteria: We included randomised double-blind studies of HT versus placebo, taken for at least one year by perimenopausal or postmenopausal women. HT included oestrogens, with or without progestogens, via oral, transdermal, subcutaneous or intranasal routes.

Data collection and analysis: Two authors independently assessed study quality and extracted data. We calculated risk ratios (RRS) for dichotomous data and mean differences (MDs) for continuous data, with 95% confidence intervals (CIs). Where findings were statistically significant, we calculated the absolute risk (AR) in the intervention group (the overall risk of an event in women taking HT).

Main results: Twenty-three studies involving 42,830 women were included. Seventy per cent of the data were derived from two studies (WHI 1998 and HERS 1998). Most participants were postmenopausal American women with at least some degree of co-morbidity, and the mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women. In relatively healthy postmenopausal women (that is generally fit, without overt disease) combined continuous HT significantly increased the risk of a coronary event (after one year's use: AR 4 per 1000, 95% CI 3 to 7), venous thrombo-embolism (after one year's use: AR 7 per 1000, 95% CI 4 to 11), stroke (after three years' use: AR 18 per 1000, 95% CI 14 to 23), breast cancer (after 5.6 years' use: AR 23 per 1000, 95% CI 19 to 29), gallbladder disease (after 5.6 years' use: AR 27 per 1000, 95% CI 21 to 34) and death from lung cancer (after 5.6 years' use plus 2.4 years' additional follow-up: AR 9 per 1000, 95% CI 6 to 13). Oestrogen-only HT significantly increased the risk of venous thrombo-embolism (after one to two years' use: AR 5 per 1000, 95% CI 2 to 10; after 7 years' use: AR 21 per 1000, 95% CI 16 to 28), stroke (after 7 years' use: AR 32 per 1000, 95% CI 25 to 40) and gallbladder disease (after seven years' use: AR 45 per 1000, 95% CI 36 to 57) but did not significantly increase the risk of breast cancer. Among women aged over 65 years who were relatively healthy and taking continuous combined HT, there was a statistically significant increase in the incidence of dementia (after 4 years' use: AR 18 per 1000, 95% CI 11 to 30). Among women with cardiovascular disease, long term use of combined continuous HT significantly increased the risk of venous thrombo-embolism (at one year: AR 9 per 1000, 95% CI 3 to 29). Women taking HT had a significantly decreased incidence of fractures with long term use (after 5.6 years of combined HT: AR 86 per 1000, 95% CI 79 to 84; after 7.1 years' use of oestrogen-only HT: AR 102 per 1000, 95% CI 91 to 112). Risk of fracture was the only outcome for which there was strong evidence of clinical benefit from HT. There was no strong evidence that HT has a clinically meaningful impact on the incidence of colorectal cancer.One trial analysed subgroups of 2839 relatively healthy 50 to 59 year old women taking combined continuous HT and 1637 taking oestrogen-only HT versus similar-sized placebo groups. The only significantly increased risk reported was for venous thrombo-embolism in women taking combined continuous HT: their absolute risk remained low, at less than 1/500. However, other differences in risk cannot be excluded as this study was not designed to have the power to detect differences between groups of women within 10 years of the menopause.

Authors' conclusions: HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia, nor for preventing deterioration of cognitive function in postmenopausal women. Although HT is considered effective for the prevention of postmenopausal osteoporosis, it is generally recommended as an option only for women at significant risk, for whom non-oestrogen therapies are unsuitable. There are insufficient data to assess the risk of long term HT use in perimenopausal women or postmenopausal women younger than 50 years of age.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Aged
  • Cardiovascular Diseases / chemically induced
  • Cardiovascular Diseases / mortality
  • Estrogen Replacement Therapy / adverse effects*
  • Estrogen Replacement Therapy / methods
  • Estrogens / adverse effects*
  • Estrogens / therapeutic use
  • Female
  • Hot Flashes / drug therapy
  • Humans
  • Middle Aged
  • Neoplasms / chemically induced
  • Neoplasms / mortality
  • Perimenopause*
  • Postmenopause*
  • Progesterone / adverse effects*
  • Progesterone / therapeutic use
  • Randomized Controlled Trials as Topic
  • Venous Thromboembolism / chemically induced


  • Estrogens
  • Progesterone