Hormone therapy and health consecuences in post menopausal women

August 16, 2012
Hormone therapy decreases risk of osteoporosis in post menopausal women, but may increase breast cancer risk
Authors <> Marjoribanks J, Farquhar C, Roberts H, Lethaby A
Review Group <> Menstrual Disorders and Subfertility Group
Abstract <> 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).
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.
Implications <>
Implications for practice:
HT for women with menopausal symptoms Women who find menopausal symptoms intolerable and who are at low risk of cardiovascular disease, venous thrombo-embolism or breast cancer may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short term use. Current recommendations favour the use of low dose HT for relief of vasomotor syptoms among women within 10 years of their last period, taken for the shortest possible time required to achieve treatment goals, with doses individually tailored and reviewed regularly (NAMS 2010; RANZCOG 2011; Taylor 2011). Although none of the studies included in this review focused specifically on women in the age group most likely to require menopausal symptom relief, subgroup analyses in WHI 1998 suggested that among relatively healthy women in their 50s taking oestrogen-only or combined HT, the only significant risk was increased incidence of venous thrombo-embolism in those taking combined HT. The absolute risk of venous thrombo-embolism was low, at 0.5% overall for a woman taking HT for five years. For women in their 50s without a uterus, taking oestrogen-only HT for five to six years appears relatively safe and there may even be some health benefits; however, safety over longer term use is unknown. Additional risk factors such as a history of venous thrombosis or known increased risk of thrombo-embolic disease must also be considered when deciding whether likely symptom relief from HT outweighs potential harm. The risk of endometrial cancer for women with a uterus taking oestrogen-only HT is well documented. HT for other indications Hormone therapy may have a limited role in the treatment of osteoporosis for some women, but there is no evidence that any form of HT is beneficial for other clinical indications except menopausal symptom relief, nor is HT appropriate for the prevention of chronic disease. There is strong evidence that both oestrogen-only HT and combined therapy significantly increase the risk of stroke and gallbladder disease and that long term use of combined continuous therapy also increases the risk of coronary events, breast cancer, death from lung cancer and (in women aged over 65 years) dementia. HT for women with previous disease or smoking history HT is not recommended for use in women with cardiovascular disease (HERS 1998) or with a history of venous thrombosis (EVTET 2000) or breast cancer (Chlebowski 2004; Holmberg 2008; ICR 2001). The randomised evidence provides no specific contraindications for its use in women with a history of endometrial cancer (Barakat 2006) or ovarian cancer (Guidozzi 1999), though data are scanty. Women at high risk of lung cancer (current smokers or long term past smokers) should be aware that combined HT increases the risk of death from lung cancer.
Implications for research:
No studies have adequately assessed the safety of HT used for symptom relief for perimenopausal women, women aged under 50 years or women with temporary or permanent iatrogenic ovarian failure. Not enough is known about factors that may modulate the risks involved, such as clinical characteristics or biomarkers affecting individual women, different oestrogens and progestogens, different time-frames for the use of HT, and different doses and routes of administration (for example unopposed oestrogen and intrauterine progestogen). There is also a pressing need for reliable evidence on the efficacy and safety of alternatives to HT for the control of menopausal symptoms for those women who may wish to avoid using HT or for whom it is unsuitable.