Key messages
• The effects of hormone therapy on women’s long-term health differ depending on whether they take combined hormone therapy (both oestrogen and progestogen) or oestrogen alone.
• We suggest using caution when considering the results of this review, given the evolution in the doses and methods for taking hormone therapy over time. Findings summarised here come from studies that gave hormone therapy as tablets taken by mouth.
• Future studies could explore the long-term effects of hormone therapy in women who are under 50 years, or whose ovaries have stopped working because of medical treatment.
What are menopause and perimenopause?
Menopause occurs naturally (usually between 44 and 55 years) when the ovaries stop releasing eggs and reduce (almost stop) hormone production. Menopause is diagnosed when these changes lead to 12 consecutive months without a menstrual period. Menopause also occurs after surgery to remove both ovaries, and does not require this 12-month timeframe.
Perimenopause is the transitional phase before menopause, when hormone levels decline and periods become irregular. It may last several years and causes symptoms like hot flushes, night sweats and mood changes.
Lower hormone levels may affect women's heart, blood vessels and bones, increasing the risk of high cholesterol, weight and fat changes, high blood pressure, diabetes, heart disease, stroke, osteoporosis and reduced strength or mobility.
What is hormone therapy?
Hormone therapy uses oestrogen, with or without another hormone called progestogen, to relieve menopause symptoms. Women without a womb (uterus) can take oestrogen alone, while those with a womb need both (oestrogen and progestogen) to protect against cancer of the womb lining (endometrial cancer).
Oestrogen may be given orally or through the skin (transdermally), and progestogen may be given orally, through the vagina (transvaginally) or by using an intrauterine device (T-shaped device inside the womb). Combined hormone therapy can be taken daily or cyclically (oestrogen is given daily and progestogen is given for part of the month, producing withdrawal vaginal bleeds).
What did we want to find out?
We wanted to find out if long-term use of hormone therapy affects women’s health in the long term.
What did we do?
We searched for studies that compared menopausal women taking hormone therapy for at least one year to those taking an inactive 'dummy' medicine (placebo). We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 24 studies involving 45,660 participants. Most data came from two large, high-quality studies conducted during the 1990s and reported in the early 2000s. The results presented below are drawn from one of those studies. We present full results in the main review.
Combined continuous hormone therapy compared to placebo
Based on evidence from one study in 16,608 women that measured outcomes at roughly 5.5 years of follow-up, combined continuous hormone therapy probably:
• made little or no difference to the risk of having a heart attack or developing lung cancer;
• increased the chance of developing breast cancer (from about 19 to 24 women in every 1000);
• reduced the risk of bone fractures (from about 111 to 87 women in every 1000).
Combined continuous hormone therapy may have increased the chances of having:
• a stroke (from about 13 to 18 women in every 1000);
• a blood clot in a vein (from about 10 to 20 women in every 1000);
• gallbladder disease requiring surgery (from about 16 to 27 women in every 1000).
Oestrogen-only therapy compared to placebo
Based on evidence from one study in 10,739 women who had undergone a hysterectomy (surgery to remove the womb) that measured outcomes at 7 years of follow-up, oestrogen-only hormone therapy probably:
• made little or no difference to the risk of having a heart attack, a blood clot in a vein, or developing breast cancer;
• reduced the chance of having a bone fracture (from about 141 to 103 women in every 1000);
• increased the chance of having a stroke (from about 24 to 32 women in every 1000) and gallbladder disease requiring surgery (from about 27 to 47 women in every 1000).
Oestrogen-only hormone therapy may have made little or no difference to the risk of developing lung cancer.
We did not have enough data to assess the risk of long-term hormone therapy use in women younger than 50 years.
What are the limitations of the evidence?
Only about 30% of the women were 50 to 59 years old at baseline, the age group most likely to consider hormone therapy for hot flushes and night sweats. In addition, hormone therapy has changed over time, with new ways to take it, different hormone types, and updated doses. The study providing most of the data gave women hormone therapy in pill form, which may have different risks to the types currently used in clinical practice.
How current is this evidence?
The evidence is current to September 2024.
อ่านบทคัดย่อฉบับเต็ม
Hormone therapy is widely provided to control menopausal symptoms and has 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.
วัตถุประสงค์
To assess the long-term effects of prolonged use (at least one year) of hormone therapy on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures and cognition in perimenopausal and postmenopausal women.
วิธีการสืบค้น
We used the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, three other databases and two trial registers, together with reference checking, citation searching and contact with study authors to identify the studies included in the review. The latest search date was 26 September 2024.
เกณฑ์การคัดเลือก
We included randomised, double-blind trials in which peri- or postmenopausal women took hormone therapy or placebo for at least one year. We included various oestrogen formulations, with or without progestogens. We focused on studies assessing hormone therapy's effects on long-term clinical outcomes, including death, coronary events and cancer. Hormone therapy's efficacy in managing menopausal symptoms was beyond the scope of this review, and is assessed in other Cochrane reviews.
การรวบรวมและวิเคราะห์ข้อมูล
Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE.
ผลการวิจัย
We included 24 studies – with two newly added in this update – involving 45,660 participants. We derived nearly 70% of the data from two well-conducted studies: the Heart and Estrogen/progestin Replacement Study (HERS 1998) and the large, multi-component Women's Health Initiative research programme, which included two hormone therapy arms (WHI 1998). Across all the studies, most participants were postmenopausal American women with one or more comorbidities. The mean participant age in most studies was over 60 years. Only one included study focused on perimenopausal women.
We present full results for all included studies with available data in the main review. The results presented below are drawn from WHI 1998, in which the combined hormone therapy arm and the oestrogen-only arm were run concurrently, with women assigned to the appropriate trial based on their uterus status.
One study with 16,608 postmenopausal women with an intact uterus compared combined continuous hormone therapy (conjugated equine oestrogen and medroxyprogesterone acetate) to placebo, and measured outcomes at an average of 5.6 years of follow-up. Based on this study, combined continuous hormone therapy probably makes little to no difference to the risk of a coronary event (RR 1.17, 95% CI 0.95 to 1.44; moderate-certainty evidence). It may increase the risk of stroke (RR 1.39, 95% CI 1.09 to 2.09; low-certainty evidence) and venous thromboembolism (RR 2.03, 95% CI 1.55 to 6.64; low-certainty evidence). Compared to placebo, combined continuous hormone therapy probably increases the risk of breast cancer (RR 1.27, 95% CI 1.03 to 1.56; moderate-certainty evidence) and probably makes little to no difference to the risk of lung cancer (RR 1.06, 95% CI 0.77 to 1.46; moderate-certainty evidence). It may increase gallbladder disease requiring surgery (RR 1.64, 95% CI 1.30 to 2.06; 14,203 participants; low-certainty evidence), and probably reduces the risk of all clinical fractures (RR 0.78, 95% CI 0.71 to 0.86; moderate-certainty evidence).
One study including 10,739 postmenopausal women who had undergone a hysterectomy compared oestrogen-only (conjugated equine oestrogen) hormone therapy to placebo, and measured outcomes at an average of seven years' follow-up. Based on this study, oestrogen-only hormone therapy probably makes little to no difference to the risk of coronary events (RR 0.94, 95% CI 0.78 to 1.13), venous thromboembolism (RR 1.32, 95% CI 1.00 to 1.74) and breast cancer (RR 0.79, 95% CI 0.61 to 1.01), all with moderate-certainty evidence. It may make little to no difference to the risk of lung cancer (RR 1.04, 95% CI 0.73 to 1.48; low-certainty evidence). Oestrogen-only hormone therapy probably increases the risk of stroke (RR 1.33, 95% CI 1.06 to 1.67) and gallbladder disease requiring surgery (RR 1.78, 95% CI 1.42 to 2.24), and probably reduces the risk of all clinical fractures (RR 0.73, 95% CI 0.65 to 0.80), all with moderate-certainty evidence.
We judged most included studies to have a low risk of bias for most domains. The overall certainty of evidence for the main comparisons was moderate. The main limitation was that only about 30% of women were 50 to 59 years old at baseline, the age group most likely to consider hormone therapy for vasomotor symptoms.
ข้อสรุปของผู้วิจัย
Long-term follow-up of women using hormone therapy suggests that the risk profiles vary between combined hormone therapy and oestrogen-only therapy.
Oestrogen-only hormone therapy probably makes little to no difference to coronary events, and probably increases the risk of stroke and gallbladder disease. It probably makes little to no difference in the risk of breast cancer, and probably reduces the risk of all fractures. Combined hormone therapy may increase the risk of thromboembolism and probably increases the risk of breast cancer.
These results should be interpreted with caution as they are based on one study using oral hormone therapy, which may not represent the risks of the hormone therapy currently used in clinical practice.
