Drugs
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Articles| ABSTRACT |
Ten years ago, the Pennell Initiative brought together influential people from medicine and government to promote the mental and physical health of women through mid-life. Since then, the menopause has dropped below the political horizon, although the problems have not gone away. Menopause is a biological marker and should encourage us to assess and evaluate health risks for the post-reproductive phase. Where symptoms deriving from estrogen deficiency are troublesome, appropriate, individualised, informed decisions to choose and use HRT can be made with the backing of evidence to support safety and efficacy. Key words |
Following the first publication of the Women's Health Initiative (WHI) study in 2002,1 it has been suggested that menopause, having no impact on mortality, is not a significant concern. Newspaper headlines have resulted in HRT being perceived as dangerous. Women are less likely to report problems, but there is no evidence that these problems have gone away.
One of the consequences of the WHI study was the cessation of the WISDOM (Women's International Study of long Duration of Oestrogen after the Menopause) trial in October 2002. This had intended to be a 10-year trial of a combined HRT product containing 0.625mg conjugated equine estrogens (CEE) with either 5mg medroxyprogesterone acetate or 2.5mg versus placebo. Recruitment of 22,300 women had been planned from primary care in Australia, New Zealand and the UK.
At the time of cessation, 3,721 women had been randomised. They were aged 50-69 years and had to be postmenopausal at recruitment. Similar to the WHI, their average age at randomisation was 63 years, but unlike the WHI, symptomatic women were included in the trial.
WISDOM evaluated quality of life (QoL) using general and menopause-specific assessment tools. The data for the short duration of the trial have now been reported.2 This is helpful because an intervention used for symptom relief should produce a benefit that the woman can appreciate. The essential question is whether the HRT regimen works.
Trial results
Data were analysed for those women who had more than 40 weeks of trial medication and a final interview; 1,043 taking active treatment and 1,087 taking placebo. Using the Women's Health Questionnaire, significant improvements (all p = <0.001) were shown in the active treatment group in respect of vasomotor symptoms, sleep disturbance and sexual functioning.
Other instruments identified reduction in number of hot flushes, night sweats, aching joints and muscles, insomnia and vaginal dryness, but more breast tenderness and vaginal discharge. These were the most quoted reasons for discontinuation of the trial and probably relate to the fact that the study population were on average more than 10 years past mean menopausal age and the trial product was double the dose that would currently be advised in this age group. Depression was unaffected by HRT. It is no surprise to read that treatment benefits were greatest in those who had most symptoms at baseline. That this reflects clinical experience was ignored by WHI, which had reported no QoL benefit from HRT. Given the lack of baseline symptoms in the WHI population and the use of a non-specific QoL instrument, it can be argued that no benefit could have been expected.
Generalised aches and pains were shown to respond to HRT with benefit not restricted to those women who also had vasomotor symptoms. Independent benefit for insomnia, vaginal dryness and sexual function are also demonstrated.
Implications for quality of life
Using a time trade-off method to assess the value of QoL, it had been reported in 2004,3 that women rated the loss of QoL owing to menopausal symptoms very highly. It was then proposed that in severely affected women, HRT could be justified because the QoL benefit, in conjunction with benefits for bone and the endometrium, outweighed the loss deriving from cardiac disease, stroke, pulmonary embolism and breast cancer.
The WHI findings in respect of CHD have been adjudicated and reanalysed.4 Healthcare professionals are now able to advise women that there is no increase in cardiac risk if HRT is started close to menopause, when the symptoms are most troublesome. Thromboembolic risks are now better understood and while absolute risk is low for healthy, non-smoking women taking oral preparations, non-oral regimens may be safer for those with risk factors.5
Age-based reanalysis of the WHI study suggests an attributable breast cancer risk that is significant, but comparable to the risk from late menarche or two units of alcohol per day and less than that from obesity.
Women need to be informed of known risks, then allowed to make informed decisions. GPs are encouraged to practise evidence-based medicine and evidence is now available. The WISDOM paper reinforces the experience of clinical medicine and tells us that HRT relieves symptoms and improves QoL. This benefit is greatest for those most affected.
- Dr Sarah Gray is a GPSI in women's health in Truro, Cornwall
Competing interests: Dr Gray is chairwoman of the British Menopause Society education subcommittee
References
1. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomised controlled trial. JAMA 2002; 288: 321-33.
2. Welton AJ, Vickers MR, Kim J et al. Health related quality of life after combined hormone replacement therapy: randomised controlled trial. BMJ 2008; 337: a1190.
3. Minelli C, Abrams KR, Sutton AJ, Cooper NJ. Benefits and harms associated with hormone replacement therapy: clinical decision analysis. BMJ 2004; 328: 371-6.
4. Rossouw JE, Prentice RL, Manson JE et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297: 1465-77.
5. Canonico M, Plu-Bureau G, Lowe GDO, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and metanalysis. BMJ 2008; 336: 1227-31.
