Hormone therapy is the most effective treatment available for the symptoms of menopause. Although a number of clinical trials have shown that it is not without significant drawbacks, substantially increased risks with short duration of use are unlikely for healthy women in early menopause.
Most women experience menopause between 40 and 58 years of age. Apart from cessation of periods, the commonest symptoms are hot flushes, night sweats, vaginal dryness and sleep disturbance. Hormone therapy (HT) is the most effective treatment for symptoms and a Cochrane review of randomised trials showed a 75 per cent reduction in flushes (18 fewer per week) with hormones compared with a 50 per cent reduction with placebo.1
Long-term HT for peri- and postmenopausal women
A Cochrane review looked at multiple outcomes and followed the usual Cochrane methodology.2 It included 23 randomised double-blind trials of hormone therapy. Nearly all the statistically significant findings came from the two biggest studies, The Heart and Estrogen/progestin Replacement Study (HERS) and the Women’s Health Initiative study (WHI).
Death from lung cancer
This outcome came mainly from the post-hoc analysis of the combined arm of WHI. After a mean follow-up of eight years, including 2.4 years’ follow-up post-intervention when women had stopped taking hormones, women in the intervention group were significantly more likely to die of non small cell lung cancer (RR 1.91:CI 1.24 – 2.95) than women in the placebo arm. This is thought to be due to stimulation of the growth of pre-existing cancers. The finding was independent of smoking status and was not found in the oestrogen-only arm of WHI.
Death from breast cancer
No statistically significant difference was found between HT and placebo for this outcome at 5.6 years. When combined hormones were stopped and after a total of 11 years of follow up there were more deaths from breast cancer in the HT group than in the placebo group. This was of borderline statistical significance (RR 1.98: CI 1.00 -3.95).
Also at this time, after 11 years of follow up, there was significantly more deaths from all causes occurring after a breast cancer diagnosis in the combined HT group than in the placebo group (HR 1.57: CI 1.01 -2.48).
Pooled data from three studies showed an increased risk of myocardial infarction at one year (RR 1.89: CI 1.15-3.10) and at three years of use (RR1.45: CI 1.07 – 1.98) for combined HT. No other trials found any difference and at five years of use; the WHI study found no difference between groups. There was no increase with oestrogen only.
Stroke and transient ischaemic attack
Pooled data from two studies showed an increased risk of ischaemic stroke at three years with combined HT over placebo (RR 1.46: CI 1.02-2.09). At seven years follow up, the oestrogen-only arm of WHI also showed an increased risk of ischaemic stroke (RR1.35: CI 1.08 – 1.70) that became apparent after four years of use. No studies showed any increase in risk for transient ischaemic attack.
An increased risk of venous thrombo-embolism with oestrogen-only HT was found in pooled data from two studies with a statistically significant increase in risk at one year (RR 4.28). WHI data also showed an increased risk for oestrogen alone over placebo with a RR 2.22 at two years (CI 1.12 – 4.39) and this diminished with time so that at the end of the seven-year study the risk was RR1.32 (CI 1.00- 1.74). In the combined HT arm of WHI, women taking hormones were also at a significantly higher risk of a thrombo-embolic event than women taking placebo at one year: RR 3.59 (CI 1.95 – 6.61) and at two years: RR 2.98 (CI 1.88 – 4.71) with the risk again diminishing over time.
The oestrogen-only arm of WHI found a decrease in breast cancer with hormone use. This decrease became statistically significant when pooled with the data from the Women’s International Study of long Duration Oestrogen after Menopause (WISDOM) study.3 For the WHI study this non-significant trend for lower breast cancer rates in the HT group continued in the extended follow-up period and the overall cumulative breast cancer incidence over the entire 10.7 years of follow up showed a significantly lower rate in the HT group (RR 0.78:CI 0.63 -0.96). The decreased risk was for early stage disease and ductal carcinoma.
Subgroup analysis showed that the reduction in breast cancer was statistically significant only for those women who had no prior hormone use before study entry and only applied to women who had started oestrogen more than five years after menopause. For those women who had started at the time of menopause there was no advantage. This so-called gap time concept, the time from menopause to first use of hormones, remains controversial. Unlike the gap time hypothesis of potential decrease in cardiovascular disease if oestrogen is started early, the possible decrease in breast cancer may only be if oestrogen is started late.4
An increase in breast cancer diagnosis was found in the WHI study after taking combined HT for five or more years (RR 1.26:CI 1.02 to 1.56). For combined HT, breast cancer rates were initially lower; the suggestion being that combined HT may stimulate breast cancer growth, but delay diagnosis possibly by hindering mammographic detection. Subgroup analysis showed that women who had previously used combined HT, before joining WHI, had an increase in risk earlier, after three years of hormone study use.
Although the breast cancer risk decreased after hormones were stopped, the rate of invasive breast cancer was still significantly higher in the combined HT arm at a mean of 11 years of follow up (RR 1.25:CI 1.08 – 1.45). Breast cancers diagnosed in the HT group were of similar histology and stage to those in controls, but more likely to be node positive.
No study showed an increase in risk of endometrial cancer with combined HT. Endometrial cancer is a well-documented adverse effect of unopposed oestrogen and in studies where oestrogen-only HT was used in women with a uterus, close monitoring showed that they were more likely to develop atypical endometrial hyperplasia.
Ovarian cancer incidence was reported only in the combined HT arm, with no statistically significant difference over placebo after 5.6 mean years of use. However, a systematic review of mainly observational studies suggests that both long-term use of oestrogen-only and combined therapy may be associated with an increased risk of ovarian cancer.
Three studies comparing oestrogen-only HT with placebo for the outcome of gallbladder disease requiring surgery showed a statistically significant increase in risk in the HT group (RR1.75:CI 1.40 -2.19). Four studies comparing combined continuous HT with placebo also showed significantly increased risk in the HT group (RR 1.55: CI 1.29 -1.86).
Results for cognitive outcomes come from the WHI studies. In the Women’s Health Initiative Memory Study (WHIMS), neither combined HT nor oestrogen only conferred any benefit in global cognitive function for women over the age of 65. The short-duration Women’s Health Initiative Study of Cognitive Aging (WHISCA) study found, for all participants, a rise in mean scores used to measure global cognitive function, attributed to the learning effect of repeated administration of cognitive tests. However, a marked decrease in these scores occurred more frequently in the hormone treatment group, reaching statistical significance for combined HT.
Similarly, for the outcome of probable dementia there was a negative trend in both active treatment groups which reached statistical significance in the combined HT group. Evidence of increased risk in this group began to appear as early as one year after randomisation and persisted over five years of follow up. The overall risk of dementia in women taking combined HT was twice that of women in the corresponding placebo group. The investigators noted however that the absolute risk of dementia remained relatively small, at 45 per 10 000 postmenopausal women aged over 65 years who took combined HT for one year.
These findings were in contrast to earlier observational research and the investigators suggested that this might be due to the healthy user bias in observational studies; though it remains possible that there may be a critical period, such as menopause, during which HT needs to be initiated in order to protect cognitive function at a later age. However, previous users of HT in WHI, who had started hormones at a younger age, did not have higher scores.
Quality of life
There was no clinically meaningful quality-of-life benefit found in WHI, though these findings may not be applicable to women taking HT specifically for severe hot flushes that affect their quality of life.
At one year in the oestrogen-only arm of WHI there was a slightly greater improvement in sleep disturbance over the placebo group, which was statistically significant. However, the mean benefit – 0.4 points on a 20 point scale – may not be clinically significant. Moreover, a subgroup of women who were measured at three years reported no statistically significant benefit for any quality-of-life-related outcomes.
At one year, in the combined arm of WHI there was a difference in quality of life change scores for two out of eight categories in the RAND 36 survey: these two categories were improvement in physical functioning and decrease in role limitations owing to physical problems. However, these were not apparent during follow up at three years.
WHI found a decreased risk of hip fracture for both oestrogen alone (RR 0.64: CI 0.45 to 0.93) and combined HT (RR 0.68: CI 0.48 to 0.97).This reduction became statistically significant only after five years of use. WHI also showed a decreased risk of vertebral fracture in both arms of the study, again after five years of use. In WHI, reduction in fracture risk with HT was no greater for women who had a higher risk of fracture.
The combined HT arm of WHI also found a reduced risk of colorectal cancer compared to placebo after five years of use, which was offset by the finding that the cancers tended to be more advanced and with greater likelihood of lymphatic or metastatic involvement.
Health benefits and risks after stopping HT
The combined HT arm of WHI reported health outcomes at a mean of 2.4 years’ extended follow up after the hormones were stopped. Over the course of follow up, the risk of coronary events, stroke and venous thromboembolism decreased in the group that had been randomised to combined HT and reached a level comparable with the placebo group. Similarly, the benefit for fracture and colorectal cancer had disappeared. As discussed previously, there was an increase in non clear cell lung cancer and some continued excess of breast cancer risk.
The oestrogen-only arm reported health outcomes at a mean of 3.9 years’ extended follow-up after hormones were stopped. The increases in risk of stroke and venous thromboembolism rapidly disappeared as did the reduced risk of hip fracture in this group. As noted above, the lower incidence of breast cancer persisted and became statistically significant with extended follow-up to 10.7 years. WHI was not powered for sub-group analysis in the 50–59 year age group, but owing to the extended follow-up period the lower hazard ratios for myocardial infarction and coronary heart disease became statistically significant as did the lower breast cancer risk. The authors point out that an important caveat is that study participants took unopposed oestrogen for a median duration of less than six years and that the results cannot be extrapolated to longer or shorter treatment durations.
Current recommendations favour the use of low-dose HT for relief of vasomotor symptoms taken for the shortest possible time required to achieve treatment goals.5 Not all countries have low-dose packaged combinations and, for women with a uterus, individual prescribing of oestrogen and progestogen may be needed.6 Individualised risk assessment will determine those women with high background risk of disease.7 The primary aim of the WHI study was to see if the use of HT decreased heart disease and it was not designed or powered to determine the risks of use for symptoms in early menopause. However, subgroup analysis in the 50–59 year age group, showed only a small number of adverse events with combined HT. Healthy women have a low absolute risk of adverse events, whether they use short-term hormone treatment during early menopause or not. 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 a longer term use is unknown.