NICE guidelines on the menopause
BMJ 2016; 352 doi: https://doi.org/10.1136/bmj.i191 (Published 18 January 2016) Cite this as: BMJ 2016;352:i191
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We read with interest the latest editorial by Professors Hickey and Banks regarding the ‘NICE guidelines on the Menopause’ [1] and their comments on the presentation of evidence underpinning the recommendations in this NICE guidance [2].
We dispute their allegation that ‘methodological deficiencies undermine its conclusions’. The development of the NICE Menopause guideline was based on a rigorous methodological approach involving complex meta-analysis called Network Meta-Analysis (NMA). This method was used to assess the relative effectiveness of different treatments (pharmacological and non-pharmacological) to relieve the frequency of vasomotor symptoms. This complex meta-analysis is methodologically superior to conventional meta-analysis as it allows the simultaneous comparison of different treatments to achieve an outcome for the population of interest (in this case, women in menopause). All the relevant peer-reviewed publications looking at pharmacological (such as HRT) and non-pharmacological interventions (such as relaxation) which met the review protocol set by the Guideline Committee were considered for inclusion. However, some references mentioned in the recent editorial did not meet the requirements of the protocol, considered different outcomes (sleep, quality of life) that were not prioritised for review during guideline development, or were published too late for inclusion. The Guideline Committee also considered evidence in a conventional meta-analysis for other outcomes commonly affecting women in menopause; mood and depression (not clinical depression), sexual difficulties and musculoskeletal symptoms, which are all domains of women’s quality of life. Although there were constraints of time and resources on the number of outcomes selected for review, the Committee considered that the selected outcomes were adequate for their decision-making.
In relation to the authors’ argument that ‘the guideline lacks appropriate and complex quantitative summary estimates of the risks and benefits from taking menopausal hormone therapy’, we strongly refute this. The evidence was synthesized separately for the different long term outcomes (including risks) that may be associated with HRT (CVD, stroke, breast cancer, osteoporosis, fractures) for two main reasons; firstly, because the baseline estimation of risk is different across these disorders, and secondly in order to communicate clearly the independent risks that may be associated with HRT for women who may place different importance on these diseases. This evidence was presented separately for randomized controlled trials (RCTs) and observational studies due to inherent methodological differences that impact on the confidence of risk estimates, as indicated by the Cochrane Handbook [3] and GRADE methodology [4]. Duration of HRT use was assessed separately during the guideline development, and disease risk associated with different durations of HRT use has been presented. The Guideline Committee recognised that communication needs may be different for women who are current or past users, or who had used HRT for different time intervals, and decided that this would the most appropriate method of presenting risks. In addition, the authors misread the presentation of evidence; the recommendations are based on the best available evidence (both RCT and observational data) and it is the RCT evidence that specifically includes women aged 50-59 at the time of enrolment in the RCT. The data describing the papers included in the meta-analyses and the Forest Plots are described fully in Appendices H-K (https://www.nice.org.uk/guidance/ng23/evidence/appendices-ik-559549264). The evidence statements synthesizing the results are described in the full guideline (https://www.nice.org.uk/guidance/ng23/evidence/full-guideline-559549261).
However, we agree with the authors that ‘the clinical challenge of HRT is balancing the benefits of symptomatic relief against the risks of disease’ as the new NICE menopause guideline presents the risks and benefits for HRT and recommends that an individualised approach should be adopted when different treatment options are discussed with women. The aim of the NICE guidance is to inform both healthcare professionals and their patients regarding the menopause, and to improve and standardise care across the UK, and we hope to achieve this in the future.
References
1. http://www.bmj.com/content/352/bmj.i191
2. National Institute for Health and Care Excellence. Menopause: diagnosis and management of menopause. (NICE guideline 23.) 2015. www.nice.org.uk/guidance/ng23.
3. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. http://handbook.cochrane.org/
4. Guyatt GH, Oxman AD, Vist GE, Zunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ2008;336:924-6.
Competing interests: No competing interests
NICE guidelines on the menopause
The editorial by Hickey and Banks on the NICE guidelines on the menopause [1] misrepresents important evidence, and it is biased. They concentrate on menopausal hormone therapy (MHT) which comprises only part of the guidelines, and they present views which appear largely based on findings from the Women’s Health Initiative (WHI) [2] and the Million Women Study [3].
They state that women should be informed about alternatives to, and the risks of MHT, but mention nothing of the risks of alternatives, some of which are considerable [4]. They criticise NICE for a lack of quantitative summary evidence, but themselves refer only to the MHRA safety update [5] which is 9 years out of date. They are critical of the focus on risk estimates in the 50-59 year age group, the age at which MHT is most commonly initiated, and they claim, incorrectly, that the relative risks of diseases related to MHT do not vary by age of initiation. Below age 60, but not above, the risk of coronary heart disease (CHD), by far the most important outcome, is significantly reduced [6,7]. They state that the symptomatic benefits of MHT should be balanced against the risks of diseases resulting from MHT, but ignore the benefits of disease prevention (CHD, osteoporosis). They claim that current users of MHT are at increased risk of venous thromboembolism, stroke, breast cancer, and potentially, ovarian cancer. However, the vascular risks are dependent on the type of MHT (dose, route of administration), whilst the cancer risks are highly contentious. In the estrogen plus progestogen arm of WHI trials an increased risk of invasive breast cancer was not statistically significant when appropriately adjusted for confounding variables [8], and it was significantly reduced with follow-up among women treated with estrogen alone [9]. They state that the drop in MHT use following the initial publication from the WHI [2] was accompanied by substantial declines in breast cancer incidence. Declines were not present in all populations, in some the decline preceded the drop in MHT use, in some there was no decline at all, and in some there was a rise in incidence [10]. For ovarian cancer the strong likelihood is that the purported association was spurious [9,11]. They quote recommendations from drug regulatory agencies that do not support the use of MHT for long term health. Those recommendations are out of date and are in urgent need of revision. They then cite risk estimates, once again out of date, stating that MHT use for 5 years results in an excess of life-threatening diseases. Astonishingly, no mention is made of the reductions in cardiovascular deaths [12], breast cancer mortality [13] and all-cause mortality [14] associated with MHT use.
The editorial denigrates MHT use, and fails to review the actual NICE guidelines.
References
1. Hickey M, Banks E. NICE guidelines on the menopause. BMJ 2016;352:i191.
2. Rossouw, JE, Anderson, GL, Prentice, RL et al. 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 randomized controlled trial. JAMA 2002;288:321-33.
3. Million Women Study Collaborators. Breast cancer and hormone replacement
therapy in the Million Women Study. Lancet 2003;362:419-27.
4. Coupland C, Hill T, Morriss R, Arthur A, Moore M, Hippisley-Cox J. Antidepressant use and risk of suicide and attempted suicide or self harm in people aged 20 to 64: cohort study using a primary care database. BMJ 2015;350:h517.
5. Medicines and Healthcare Products Regulatory Authority. Hormone replacement therapy: safety update. MHRA, 2007.
6. Salpeter SR, Walsh JME, Greyber E, Salpeter EE. Coronary heart disease events
associated with hormone therapy in younger and older women. J Gen Intern Med 2006;21:363-366.
7. Boardman HMP, Hartley L, Eisinga A, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev 2015;DOI:10.1002/14651858.CD002229.pub4.
8. Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen plus progestin. Maturitas 2006;55:103-15.
9. Manson JE , Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the interventions and postintervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 2013;310:1353-68.
10. Shapiro S, Farmer RDT, Stevenson JC, Burger HG, Mueck AO, Gompel A. Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies. Part 5. Secular trends. J Fam Plan Reprod Health Care 2013;39:80-88.
11. Shapiro S, Stevenson JC, Mueck AO, Baber R. Misrepresentation of the risk of ovarian cancer among women using menopausal hormones. Spurious findings in a meta-analysis. Maturitas 2015;81:323-26.
12. Tuomikosko P, Lyytinen H, Korhonen P, et al. Coronary heart disease mortality and hormone therapy before and after the Women’s Health Initiative. Obstet Gynecol 2014;124:947-53.
13. Chen W, Pettiti DB, Geiger AM. Mortality following development of breast cancer while using oestrogen or oestrogen plus progestin: a computer record-linkage study. B J Cancer 2005;93:392-98.
14. Salpeter SR, Cheng J, Thabane L, Buckley NS, Salpeter EE. Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women. Am J Med 2009;122:1016-22.
John C Stevenson 1, Samuel Shapiro 2.
1 National Heart & Lung Institute, Imperial College London, Royal Brompton Hospital, London UK
2 Department of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa
Correspondence: j.stevenson@imperial.ac.uk
Competing interests: John Stevenson and Samuel Shapiro presently consult, or in the past have consulted, with manufacturers of MHT products, and they have received research grants from manufacturers of MHT products.
Competing interests: John Stevenson and Samuel Shapiro presently consult, or in the past have consulted, with manufacturers of MHT products, and they have received research grants from manufacturers of MHT products.
Hickey and Banks write that women and their healthcare providers should have confidence that most women will manage their symptoms at the menopause without pharmacotherapy.1 Exogenous hormones or antidepressants should be avoided but instead, it is very important that biochemical causes of warning steroid-withdrawal symptoms are diagnosed. Ignorance is no longer bliss as most women a history of using hormonal and/or menopausal progestogens and oestrogens.
Hormone use causes nutritional deficiencies, especially of zinc and magnesium and B vitamins which impairs serotonin and noradrenaline metabolic pathways.2,3 Progestogens and oestrogens raise copper levels and lower copper stores which results in lowered superoxide dismutase activities. Vascular over reactivity, including headaches and migraines, relates to increased development of endometrial arterioles.4 Oestrogens lower monoamine oxidase levels whereas progesterone raises levels before menstruation when premenstrual tension can occur or continually when progestogens are taken increasing the risk of depression.5
Both progestogens and environmental toxins can induce potentially carcinogenic DNA adducts. Doctors practicing Ecological Medicine employ the best available scientific tests to diagnose and treat their patients - such as DNA adducts in genomic DNA from leucocytes.6 Structurally similar progestogens form DNA adducts in primary cultures of human hepatocytes signifying a genotoxic risk.7,8 DNA adducts also involve cadmium from tobacco smoke, chlorine from tap water, nickel from stainless steel and exhaust gases, disinfectants, pesticides and malondialdehyde from endogenous oxidation. Nickel has a high affinity for hormone-binding sites. The risk of cancer is increased if DNA adducts block the multiple tumour suppressor gene.
1.Hickey M, Banks E.Nice guidelines on the menopause. BMJ 2016;352:i191.2 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity, and mineral imbalance .J Nutr Environ Med 1998;8:105-116.
3 Grant ECG. The influence of hormones on headache and mood in women Hemicrania 1975:3,4 :2-10.
4 Grant ECG. Relation of arterioles in the endometrium to headaches from oral contraceptives. Lancet 1965;1:1143-.44.
5 Grant ECG, Pryse Davies J. Effect of oral contraceptives on depressive mood changes and on endometrial monoamine oxidase and phosphatases. Br Med J 1968;3:777-80
6 Howard JM. The detection of DNA adducts (risk factors for DNA damage. A method for genomic DNA, the results and some effects of nutritional intervention, J Nutr Environ Med 2002;12:19-31.
7 Werner S1, Kunz S, Beckurts T, Heidecke CD, Wolff T, Schwarz LR. Formation of DNA adducts by cyproterone acetate and some structural analogues in primary cultures of human hepatocytes. Mutat Res 1997 Dec 12;395(2-3):179-87.
8 Hemminki, K. DNA adducts, mutations and cancer. Carcinogenesis,1993; 14,2007–2012.
Competing interests: No competing interests
Re: NICE guidelines on the menopause
The current combined evidence from conventional and from network meta-analysis of randomised controlled trial (RCT) data is that menopausal hormone therapy (MHT) is effective for the relief of vasomotor symptoms.1,2 We noted this in our editorial, and are in agreement with the NICE guidelines on this matter; hence we are unsure why it has been considered a point of contention by Sarri et al (BMJ Rapid Response, 15 February 2016).
We also agree that women differ in their priorities and information needs and that it is important to provide summary evidence on the risks and benefits of MHT according to each outcome separately. However, we would argue that an overall assessment of the whether MHT is likely to be harmful or beneficial for health in terms of serious, potentially life-threatening conditions is also important information for many women and their health professionals. We remain concerned that the NICE guidelines do not present women and their health professionals with appropriate and useful summary estimates on the risks of MHT for serious disease. In particular:
(i) The restriction of RCT data to those from women aged 50-59 at trial entry is inappropriate. We can reassure Sarri et al that we did not misunderstand them on this point. It is a statistical principle that, where effects in study subgroups, such as age, do not differ significantly, the relative risks from the study as a whole should be assumed to apply to these subgroups.3-5 The relative risks for the relationship of MHT to cardiovascular disease and global health outcomes from RCT do not differ significantly by age6; hence the RCT relative risks for all age groups combined should be considered to apply to each age group. The only exception to this is breast cancer, where the effects of MHT on the relative risk are greater the closer to menopause6 i.e. in younger age groups. Hence, using the relative risk estimates across all age groups would be conservative. Restricting data to women aged 50-59 at trial entry has the effect of excluding a large proportion of the relevant RCT data on MHT (see NICE guidelines, Appendix G), inappropriately increasing uncertainty and reducing statistical power to detect MHT risks and benefits.
(ii) The guidelines use observational data to estimate the effects of MHT on coronary heart disease and stroke, despite the acknowledged major issues in their interpretation; and
(iii) Whilst it is clear that pre-defined protocols were followed closely, the relative risk and absolute risk summaries presented do not appear to include all relevant studies and do not apply the data in a way that maximises its usefulness to women and their health professionals. For example, the data on cohort studies estimating the relationship of current versus ever use of combined MHT to breast cancer risk appear to be only from three studies – excluding the vast majority of relevant studies, for a range of reasons which mostly appear to relate to the age or menopausal status of women included (see NICE guidelines, Appendices G and J).
As well as excluding much relevant data, the NICE data synthesis, designed to inform clinicians and consumers on the relationship of MHT use to the absolute risk of disease, do not apply the best of what is known about the relative risk and relationships with duration of use to the background absolute risks. If data from observational studies have been shown to be unreliable, as is the case for MHT and coronary heart disease and stroke, then RCT data should be emphasised. Where there is clear evidence that risk varies according to MHT type, then data on risk for each of these types should be presented separately. However, where they do not differ, data should be combined to maximise statistical reliability.7 Whether or not the relative risks vary by duration of use should be taken into account, based on the summary of the best evidence. All of these data should then be brought together and applied to data on the background risk of the particular outcome, for different durations of use.7
For example, the MHRA summary of the relationship of current MHT use to stroke (the most recent independent and comprehensive quantitative assessment of the evidence) from RCTs shows a 25% increase in risk (95%CI 10-43%), consistent for oestrogen-only (RR1.27, 95%CI 1.05 to 1.53) and combined oestrogen-progestogen MHT (RR1.24, 95%CI 1.03 to 1.50, p(heterogeneity between MHT types)=0.9) preparations.7 No clear variation in the relative risk according to duration of use has been established.8 Hence, the best current evidence on the relationship of MHT to stroke for different durations of use is obtained by applying the summary relative risk to the background risk of stroke for women of different age groups. The MHRA estimates that 5 years of MHT use among 1000 women will lead to 1 extra stroke in women aged 50-59 and 3 extra strokes in women aged 60-69; corresponding figures for 10 years of use are 2 and 5.7
In contrast, the NICE guidelines present separate absolute risk estimates for randomised and observational studies on oestrogen-only, combined and unspecified MHT exposure, leading to six estimates for current use alone. More importantly, despite Sarri et al’s statement that “disease risk associated with different durations of HRT use has been presented“, the estimates for absolute risk according to duration (<5y and 5-10y) are virtually all listed as “no data available”; for stroke, only one of 12 potential estimates is provided, from observational data.1 It is clinically unhelpful that around 70% of the 40 MHT duration/disease categories in the guideline as a whole are listed as “no data available” and only 1 of these 40 categories has an estimate from RCT evidence.1 The table relating to stroke below illustrates this point.
In summary, we congratulate the authors of the NICE guidelines on menopause for their focus on individualised care, but re-emphasise that the best available data on overall risks are also key to informed decision making by women and their health care providers.
1. National Institute for Health and Care Excellence (NICE). Menopause: diagnosis and management of menopause. (NICE guideline 23.) 2015. www.nice.org.uk/guidance/ng23.
2. MacLennan A, Broadbent J, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestagen therapy versus placebo for hot flushes. Cochrane Database of Systematic Reviews 2004;Issue 4:Art. No.: CD002978. DOI:10.1002/14651858.CD002978.pub2.
3. Yusuf S, Wittes J, Probstfield J, Tyroler H. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991;266(1):93-8.
4. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer 1976;34:585-612.
5. Cuzick J. Forest plots and the interpretation of subgroups. Lancet 2005;365:1308.
6. Prentice RL, Manson, J.E., Langer, R.D., Anderson, G.L., Pettinger, M., Jackson, R.D., Johnson, K.C., Kuller, L.H., Lane, D.S., Wactawski-Wende, J., Brzyski, R., Allison, M., Ockene, J., Sarto, G., Rossouw, J.E. Benefits and risks of postmenopausal hormone therapy when initiated soon after then menopause. . Am J Epidemiol 2009;170:12-23.
7. UK Public Assessment Report. Hormone-replacement therapy: safety update. . MHRA, 2007. http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con20...
8. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33.
Competing interests: No competing interests