CLIMACTERIC 2014;17:211–212

Editorial

The ‘window of opportunity’ – should we be taking it? Nick Panay and Anna Fenton EDITORS-IN-CHIEF

If there is a window of opportunity with menopause, then why are we not taking it in every woman? What have we learnt from the Women’s Health Initiative (WHI)? That the age of initiation, dose, type and route of administration of HRT should all be taken into account when prescribing. So, when all these parameters are taken into account, does benefit truly outweigh risk for indefinite use of hormone replacement therapy (HRT)? If so, then why are we not advocating its use in all perimenopausal women to continue on an indefinite basis? We believe there is an urgent need for these issues to be discussed, investigated and resolved as outlined in this Editorial.

What has happened to prescribing and why? Prescribing of systemic HRT, whether for symptom relief or primary prevention, has fallen by 75% globally post-WHI due to media scares, strict regulatory advice and confusion in primary care. Even now in mid-2014 there is still little sign of recovery. Why is this? The following issues have been addressed in many commentaries and editorials: • Regulators still advocate the minimum effective dose of HRT for the shortest duration; • Education in menopause remains poor, despite clear guidelines from the menopause societies1; • The media continue to give mixed messages about safety and risk; • There are perceived conflicts of interest between pharma and menopause specialists; • All types of HRT are viewed as being the same in terms of benefit/risk ratio.

Why is there a need for primary prevention in the menopause? In our view, the main issue that remains unaddressed and which is perhaps taboo is the belief that menopause is natural and that the aging process is normal. The key question going forward is not whether menopause-related symptoms should

© 2014 International Menopause Society DOI: 10.3109/13697137.2014.917393

be treated but whether the deterioration of health and quality of life, which usually accompanies the aging process, should be proactively prevented? The aging population places a burden on the individual, their carers and society. We spend too much time treating disease rather than preventing it. The ‘silver tsunami’ is upon us and, unless we do something about it soon, our health-care systems will crumble under the weight of increasing obesity, diabetes, metabolic syndrome, cardiovascular disease, osteoporosis-related fractures and dementia. This is not to even mention the failure of most governments to deal with the huge burden of smoking and alcohol-related illness. Why should society and, specifically, menopausal women accept that health should inevitably decline before the individual passes away? Many women are now proactively seeking help for their symptoms, not prepared to put up with menopause-related problems. Many, having managed to ride out the scourge of hot flushes and sweats, have been beaten into submission by their relentless loss of vitality, sexuality, cognitive functioning and musculoskeletal symptoms which impair their ability to function normally on personal, social and professional levels. The medical systems in many countries are failing these women. Instead of preventively seeking to provide support and advice at such a crucial time of their lives about diet, exercise, smoking, alcohol, HRT and alternatives, they are being told that menopause is natural and, because HRT is ‘dangerous’, nothing can be done about their predicament.

What are the arguments for the use of HRT in primary prevention? The WHI studies were designed before the excellent animal studies by Clarkson and colleagues2 reported compelling evidence that there is a window of opportunity for cardiovascular benefit. Their findings and those of many observational trials were confirmed by the age-stratified data analysis from the WHI, particularly for estrogen-alone HRT, which showed a trend towards reduction of coronary heart disease risk and a significant reduction in mortality in the 50–59-year age group. Recent data from the DOPS3, in which women with

Editorial an average age of 50 were randomized to HRT or no treatment, showed a 50% reduction in the primary outcome composite measure of myocardial infarction, mortality and heart failure over a 16-year period (10 years randomized and 6 years observational) with no excess of stroke, venous thromboembolism and breast cancer. Publications from KEEPS and ELITE are expected to provide additional evidence for this window of opportunity. Many studies including WHI, DOPS and a large meta-analysis4,5 of randomized, controlled trials have all confirmed a window of opportunity for reducing mortality. Long-term cognitive benefits can result from early prescribing according to observational studies and meta-analyses6. HRT prescribed in younger women has also been shown to be cost-effective4. Conversely, delay in prescribing in younger menopausal and oophorectomized women leads to excess mortality due to the impact of the hypoestrogenic state on cardiovascular disease, osteoporosis and cognitive functioning7,8. The menopause societies advocate early prescribing as conferring a favorable benefit/risk ratio. Even the adverse breast cancer findings from the WHI study have now been criticized, questioning the ability of the data to prove a causal relationship9,10.

What are the arguments against the use of HRT in primary prevention? A number of problems remain with HRT that are still unresolved. Despite individualized tailor-made regimens using the best evidence-based principles, women often experience physical and psychological adverse effects which limit continuation of therapy. Questions remain about the possibility of HRT provoking major adverse events, particularly in older age-group women. There is still a debate as to whether use of HRT into old age is essential to achieve cardiovascular and

Panay and Fenton cognitive benefits, or risky in terms of breast cancer, thromboembolism and stroke. KEEPS, ELITE and DOPS should still be regarded as pilot studies. Although data emerging from these studies have been reassuring, as discussed in our previous Editorial, there is a need for the definitive global randomized trial in women close to the menopause transition. This would need to be of a large enough magnitude and duration to fully explore the benefit/risk balance for major adverse events with optimal HRT regimens, given current evidence11.

The way forward All women entering the menopause should have the opportunity to make genuinely well-informed choices about their lifestyle and possible preventive interventions such as HRT. Menopausal women are currently being neglected for fear that proactive management of the menopause will open the flood gates, resulting in the need for massive expenditure. We believe that an increase in short-term investment in our aging population will lead to long-term savings. Not only will women continue to enjoy a high-standard quality of life, they will not be a burden to the health-care system and will also be able to continue contributing productively to society. Although the data that HRT could be used in prevention of long-term disease are compelling, for the moment HRT is still indicated primarily for symptom relief, as per the guidelines from the menopause societies. However, we believe that health departments are neglecting their duty of care to menopausal women if they do not invest in the prevention of menopause-related problems. This includes the funding of HRT research to determine whether it should be a vital component of the primary prevention program for all menopausal women. The time has come to definitively investigate the ‘window of opportunity’ for the sake of menopausal women and society as a whole.

References 1. de Villiers TJ, Pines A, Panay N, et al. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric 2013;16:316–37 2. Williams JK, Anthony MS, Honoré EK, et al. Regression of atherosclerosis in female monkeys. Arterioscler Thromb Vasc Biol 1995;15:827–36 3. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomized trial. BMJ 2012; 345:e6409 4. Hodis HN, Mack WJ. A ‘window of opportunity’: the reduction of coronary heart disease and total mortality with menopausal therapies is age- and time-dependent. Brain Res 2011;1379: 244–52 5. Salpeter SR, Walsh JM, Greyber E., Ormiston TM, Salpeter EE. Mortality associated with HRT in younger and older women: a meta-analysis. J Gen Intern Med 2004;19: 791–804

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6. Whitmer RA, Quesenberry CP, Zhou J, Yaffe K. Timing of hormone therapy and dementia: the critical window theory revisited. Ann Neurol 2011;69:163–9 7. Rocca WA, Grossardt BR, Shuster LT. Oophorectomy, menopause, estrogen treatment, and cognitive aging: clinical evidence for a window of opportunity. Brain Res 2011;1379:188–98 8. Sarrel PM, Njike VY, Vinante V, Katz DL. The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50 to 59 years. Am J Public Health 2013;103:1583–8 9. Shapiro S, De Villiers TJ, Pines A, et al. Risks and benefits of hormone therapy: has medical dogma now been overturned? Climacteric 2014;17:215–22 10. Shapiro S, de Villiers TJ, Pines A, et al. Re: Estrogen plus progestin and breast cancer incidence and mortality in the Women’s Health Initiative observational study. J Natl Cancer Inst 2014; 106:djt372 11. Panay N, Fenton A. Has the time for the definitive, randomized, placebo-controlled HRT trial arrived? Climacteric 2011;14:195–6

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The 'window of opportunity'--should we be taking it?

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