Menopause in the 21st century: the need for research and development

Introduction: what are the key issues?

Controversy continues to surround the management of menopause. Following release of the recent National Institute of Health and Care Excellence (NICE) UK menopause guidelines¹, which met with general acclaim, there was once again criticism that risks of breast cancer with HRT had been downplayed. The declarations of interest of the guideline development committee were in the public arena and had already been scrutinized as per NICE policy, yet these were still sensationalized by a few epidemiologists and a minority of the media. There is still confusion amongst some physicians and the public as to the precise balance of benefits and risks of hormone therapy and alternatives. Recent guidelines¹, recommendations² and consensus statements are important and are helpful to health-care professionals managing menopause; however, their usefulness is restricted by the available data. There is still therefore a pressing need for more research to clarify areas of controversy and to develop menopause products which maximize benefits and minimize risks.

Meta-analysis of old data: is there still a need?

The Core Outcome Measures in Effectiveness Trials (COMET) and the Core Outcomes in Women's Health (CROWN)³ initiatives have called for consistency of outcome measures to facilitate meta-analysis of study data. The problem with menopause studies performed thus far is that primary and secondary outcome measures have been too diverse. For instance, where vasomotor symptoms are concerned, some studies have measured severity of flushes and others have measured frequency. With regards to assessment of long-term benefit and risk, most randomized studies have not been of a sufficient size or duration and have had to report on surrogate markers rather than major outcomes, e.g. intima media thickness and calcium scores rather than cardiovascular events, or bone density rather than fracture data. Study design has been variable and in many cases flawed, e.g. the older age groups using relatively high doses of HRT in the Women’s Health Initiative trials. In view of this inconsistency, further meta-analysis of existing data is unlikely to be of value.

New data acquisition: what is realistic, what is not?

This leaves us with the prospect of having to invest huge sums of money to perform a definitive, large, prospective, long-term, randomized trial, which is unlikely to happen⁴. An alternative solution would be to perform a series of smaller studies but with consistent design and outcome measures; this would facilitate meta-analysis, thereby enhancing the validity of results. High-quality, prospective, observational data will also continue to provide interesting results in large populations over long durations; these are of greatest value where confounding variables can be adequately controlled. The global expansion of registries, such as those in Finland⁵, will provide even more valuable data and facilitate the analysis of differences according to ethnicity. Good-quality global registries of less common menopause-related conditions such as premature ovarian insufficiency, e.g. https://poiregistry.net⁶, will also facilitate the collection and analysis of data where etiology and management remain uncertain.

Priority research areas

There is a pressing need for research in a number of menopause-related areas. Given the controversy regarding malignancy and HRT, there needs to be clarification of the precise risk of breast and ovarian cancer with long-term HRT usage. There is still debate regarding the possibility of primary prevention of cardiovascular disease and dementia. Larger studies are needed based on the principles of KEEPS⁷ and ELITE⁸, but looking at major outcomes, evaluating the optimum estrogen dose, timing, duration delivery route and mechanism of action. In women using combined therapy, how much difference does the type of progestogen or progesterone make from the breast and cardiovascular perspectives? The route of estrogen and type of progestogen/progesterone also modulate risk of venous thromboembolism; this should be studied further.

New product development

Following the publication of the WHI study, development of new menopause products came to a grinding halt. New products such as conjugated estrogens/bazedoxifene have been developed to avoid the side-effects and risks of progestogens altogether. There is still some question as to the prothrombotic risk although data thus far seem reassuring. Another area of interest is whether this combination may actually have a protective effect on breast cancer risk. Research and development of further body-similar or body-identical estrogen and progesterone would be of interest. Ongoing research into the development of newer types of estrogen such as estetrol may also be a further positive step towards maximizing benefits whilst minimizing risks.

Further research into established non-hormonal menopause therapies such as acupuncture, homeopathy and cognitive behavioral therapy would be welcome; studies thus far have been too small and poorly controlled. Complementary therapies such as isoflavones are possible options, but once again, large-scale, long-term randomized, controlled trials looking into benefits and risks are absent. Should we now be focusing our research efforts on further development of 'perfect' selective estrogen or progesterone receptor modulators (SERMs/SPRMs)? Development of the perfect SERM with estrogenic benefits and no side-effects may be the future solution. Newer SERMs such as ospemifene are beneficial for the urogenital system but still do not address the problem of vasomotor symptoms.

Perhaps the way forward for vasomotor symptoms will be through neuromodulation; for example, neurokinin B receptor antagonists are currently being studied to see whether they are fully effective for vasomotor symptoms. These products would be particularly welcome for women with hormone-sensitive malignancies such as breast cancer. There is also a neglected need for androgenic products which are licensed for female usage for those women with sexual desire and arousal disorders.

Conclusions

As the global population continues to age, the impact of menopause on quality of life and long-term health will become increasingly felt. This will have implications not only for individual women but for society as a whole through the economic impact of lost work days and productivity. Epidemiologists who are quick to criticize hormone therapy do not provide alternative solutions for women who suffer from life-altering severe symptoms and fail to provide effective preventive strategies for the problems of aging. Menopausal health cannot be achieved through lifestyle measures alone, although these are the building blocks. There is a pressing need to continue research into understanding the impact of the long-term hypoestrogenic state (especially in premature ovarian insufficiency) now that menopause is a midlife point. The pressing questions are worth repeating: why some women are affected so much more severely than others, how can we prevent this and how can hormone therapy and alternative products be used to optimize quality of life and long-term health?