The past decade has seen marked fluctuations in opinions concerning the merits and risks of postmenopausal hormone replacement therapy (HRT). In July 2002, menopause management faced a major turning point when the first data from the Women’s Health Initiative (WHI) trial were released (JAMA 2002;288:321-333). This study was categorized as a primary prevention trial for coronary heart disease (CHD).
However, the mean age at recruitment was 63 years, when menopausal symptoms have usually finished and HRT is rarely started, but this important difference from common clinical practice was not acknowledged at that time. Instead, WHI investigators concluded that HRT was not cardioprotective and that its risk/benefit ratio did not favor the use of postmenopausal hormones for prevention of chronic diseases. As a result, there was dramatic change in prescription habits following recommendations to reserve HRT for symptomatic women and to limit its use to the ‘shortest duration needed’ and to ‘the lowest effective dosage’. The results of the WHI changed the perception of the risk/benefit of HRT.
During the ten years which followed the publication of the WHI results, additional outcomes from subsequent analysis and new studies have kept alive the scientific debate: the increased risk for breast/uterine cancer and cardio-vascular disease found in the WHI have been increasingly viewed with scepticism and the focus of the research is now on other unresolved issues:
Critical window for starting HRT and treatment duration
Based on more than 40 observational studies on HRT, the total relative risk for CHD was 40-50% lower among current or previous users of HRTcompared to those who never had used it (p < 0.001). The key differences between the design of the WHI and the following observational studies on HRT were the timing of the initiation and the duration of HRT therapy and time since menopause. HRT administered around menopause, when there are still vascular estrogen receptors responsive to exogenous HRT, appears to reduce progression of atherosclerotic plaque. However, if HRT is administered many years after menopause, it is not beneficial and may sometimes disrupt established plaque with adverse effects.
The optimal treatment’s duration
The latest data on HRT do not warrant the fear and ultra-conservative approach adopted in 2002. Longer-term therapy is appropriate for women with long-term symptoms who are aware of the potential risks for their regimen in their personal circumstances. Individualised regimens can reduce the incidence of adverse outcomes.
HRT can be offered to informed women for as long as they have debilitating symptoms but the data are not yet strong enough to advocate it for chronic disease prevention (except perhaps for osteoporosis prevention near menopause with the option of other effective fracture prevention treatments at a later age). However, some women have continuing symptoms even into their seventh decade and they should not be denied HRT if their therapy and risks are individualized, understood, and not exaggerated.
The best formulations for minimizing breast/uterine cancer risks
Although the risks of HRT have been inflated by the popular press, there are potential side effects and risks that must be individualized and reduced by tailoring the therapy. Emerging data suggests fewer side effects with:
- lower HRT doses
- minimal use of systemic progestogens
- use of non-oral routes in some women and the use of HRT in symptomatic women from near menopause
HRT remains the most effective therapy for vasomotor symptoms and urogenital atrophy. By 2030, an estimated 47 million women will be undergoing menopause each year. Quality of life is an important end point in women’s health research. We should not forget that a woman’s prolonged life expectancy has resulted in an extended postmenopausal lifetime, which could be longer than the woman’s entire reproductive age.
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