News and views

Premature surgical menopause raises cardiovascular risk

While age at menopause and type of menopause (natural or surgical) are known to contribute to an associated risk of cardiovascular disease, the extent of that association and how it varies interdependently are unclear. An earlier age at menopause and premature menopause have each been linked to an increased risk of CVD, while bilateral oophorectomy is similarly known to increase that risk. Now, an Australian study which pooled data from ten observational studies has sought to quantify the variation in CVD risk according to type of menopause and determine the extent which their effects interact with age at menopause and HRT use. The ten studies were part of the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE) consortium and provided pooled individual data from more than 200,000 postmenopausal women.¹

Analysis of the timing and type of menopause in these women firstly showed that those with a surgical menopause were at a 22% overall higher risk of a cardiovascular event than those whose menopause was natural (defined as absence of menstruation over a period of 12 months). However, when the participants were stratified according to age that same risk was attenuated such that a surgical menopause before age 39 was associated with an even higher relative risk of CVD than natural menopause at the same age. When age at menopause was analysed as a continuous variable, each one-year decrease was associated with an increased risk of incident CVD of 3% in the natural menopause group, and 5% in the surgical menopause group.

The association between surgical menopause and incident CVD was only evident in non-users of HRT. So women who had had a surgical menopause at an earlier age and also took HRT had a lower risk of incident CVD than those not taking HRT. This same effect of HRT was not evident in those with a natural menopause.

The authors cite ‘several possible reasons’ why a surgical menopause should have such a greater impact on CVD risk than natural menopause. First, the indications for hysterectomy – which may often be accompanied by bilateral oophorectomy – may include benign diseases such as fibroids or endometriosis, which have their own metabolic associations raising the risk of CVD. And second, the authors propose, endogenous estrogen levels – ‘protective against heart disease’ – in surgical menopause may suffer a more acute decline than found in natural menopause, and this ‘may have a severe impact on the vascular system’.

Significantly, this raised CVD risk in women with a surgical menopause before the age of 45 was lower in those taking HRT than in those who were not. These findings would seem to support the recommendations of the British Menopause Society and other associations that HRT should be encouraged in women with an early surgical menopause or premature ovarian insufficiency, at least until the general age of natural menopause.

The authors add other public health implications, notably that bilateral oophorectomy alongside hysterectomy ‘should be undertaken with great caution’, especially in younger subjects. And with that in mind, the timing of menopause should be considered an important factor in mid-life health assessment, particularly in considering the risks of CVD, which, according to WHO, remains the leading cause of older-age female mortality in the developed world.

Last year, extending the length of prematurity in natural or surgical menopause even further, a seven-year median follow-up study from the UK Biobank of almost 150,000 subjects found that those who were menopausal before the age of 40 were similarly at a small but significant increased risk for a composite of cardiovascular diseases.² This CVD endpoint occurred in 3.9% of the women with no premature menopause, in 6.0% of those with a premature natural menopause, and in 7.6% of those with a premature surgical menopause.

References

Zhu D, Chung H-F, Dobson AJ, et al. Type of menopause, age of menopause and variations in the risk of incident cardiovascular disease: pooled analysis of individual data from 10 international studies. Hum Reprod 2020; doi:10.1093/humrep/deaa124.

BMA calls for better recognition of menopause by employers

Responses from more than 2000 working-doctor members of the British Medical Association suggests that many are ‘suffering in silence’ from symptoms of the menopause because they are afraid of their colleagues’ reactions.¹ Employers, says the BMA, ‘should be establishing a culture where those experiencing symptoms can speak openly and get access for the particular support they need’.

With age at menopause defined between 45 and 55 years, the BMA estimated that some 30,000 women doctors within this age range are currently registered to practice in the UK, and the survey – from albeit a modest response – found that a significant number have reduced their hours, left management roles or intend to leave medicine altogether. Such difficulties may be especially so in those experiencing the menopause at an early age.

The BMA’s response is for employers to take a more proactive approach to normalising the menopause, to enable more flexible working hours, improve room ventilation, and encourage an inclusive culture.

Among the survey’s findings

*93% of survey respondents had experienced symptoms as a result of the menopause

*90% said that these symptoms had had an impact on their working lives, with 38% saying that the impact was significant

*36% of respondents had made changes to their working lives as a result of menopause and 9% intended to make changes

The most common adjustment that respondents had made, wanted to make, or planned to make was a reduction in their working hours. However, there was a strong theme of reluctance to ask about working hours because of understaffing.

Of course, 2000 responses from a probable pool of 30,000 is no doubt a tiny representation of what is a far greater social problem, and one which has been aired many times before. Indeed, the European Menopause and Andropause Society (EMAS) has developed its own specific recommendations (not unlike those of the BMA) and the professional group for occupational medicine has also produced guidance.2,3 What they share is a recognition that the symptoms of the menopause may well affect employees and that both employers and the working environments should be sensitive to this.

Above all, as the BMA and other trade unions have noted over the years, the menopause can be for the employee a sensitive, difficult and stressful time, and for the employer a more formal matter of health and well-being, and one which needs particularly careful handling.

References

https://www.bma.org.uk/media/2913/bma-challenging-the-culture-on-menopause-for-working-doctors-report-aug-2020.pdf.

20-year WHI follow-up finds breast cancer protection persists in hysterectomised CEE subjects

Long-term follow-up of the two original trials of the Women’s Health Initiative has shown that the protective effects of unopposed estrogen when given to hysterectomised women was significantly associated with lower breast cancer incidence and lower breast cancer mortality.¹ However, prior randomised use of combined therapy, which in the WHI trials was conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA), in women with an intact uterus remained significantly associated with a higher breast cancer incidence than in those given placebo – though with no significant difference in breast cancer mortality. In a statement the WHI said ‘that after more than 20 years of median follow-up, the protective effects of estrogen-alone therapy continued to endure’.

The statement also noted that these effects were evident even ‘despite many years having passed since the withdrawal of hormone treatment’. The study investigators, many of whom were veterans of those two original trials, attributed the somewhat anomalous but lasting findings ‘to altered cellular processes in breast tissue’ affecting apoptosis.

The updated incidence rates in hysterectomised women given unopposed estrogen reflected a lower risk of breast cancer against placebo of 0.30% vs 0.37% (HR 0.78) and breast cancer mortality of 0.031% vs 0.046 (HR 0.60). Prior randomised use of CEE plus MPA in women with an intact uterus remained significantly associated with higher risk of breast cancer (0.45% vs 0.36%; HR 1.28), though with no significant difference in breast cancer mortality.

As an editorial accompanying the report suggests, the publication and promotion of the 2002 WHI reports ‘complicated the narrative’ of hormone therapy’s relative benefits and potential harms for the next 20 years. Although the trials had been planned to test the cardioprotective effect of HRT, the first headlines when the combined trial was stopped in July 2002 – as flagged by JAMA in its press release (‘Hormone therapy study stopped due to increased breast cancer risk’) – was solely about breast cancer, not the study’s primary outcome. However, the story took another turn just two years later when the estrogen-alone trial was also stopped (for an adverse effect on stroke); this time CEE use was found to result in a slight decrease in coronary heart disease, an almost statistically significant reduction in breast cancer, and an increase in stroke similar to that seen in the CCE/MPA trial.^3,4 In the meantime, in 2003, the Million Women Study had published its results to a fanfare of publicity, showing an increased incidence of breast cancer associated with combined and unopposed therapies, particularly the former. Regulatory agencies heeded the warnings, and all forms of HRT were relegated to danger status. Moreover, as the incidence of breast cancer began to fall over the next few years, that decline was intuitively attributed to the moratorium on HRT use. However, that non-significant benefit of estrogen alone in the initial WHI trial did become significant at later follow-up (HR 0.77), and set a pattern now apparently evident in the latest WHI report.^6,7 The findings from this 2013 follow-up – that ‘women with hysterectomy seeking relief of climacteric symptoms may be given reassurance regarding breast cancer influence of oestrogen’ – would appear to be maintained in this latest 20-year follow-up.

The WHI report was included in an updated consensus statement on HRT after a diagnosis of breast cancer for the British Menopause Society and RCOG published in this issue of the journal. Overall, the statement notes that findings from the two latest publications, the WHI update and the meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer published last year, ‘concur with previous evidence’, notably that the risk of a breast cancer diagnosis is greater with combined than with unopposed therapy.⁸ However, the Collaborative Group’s re-analysis, much of whose core data came from the widely criticised Million Women Study, found unopposed estrogen associated with an increased risk of breast cancer, in contrast to the WHI findings of several follow-up studies, where a decreased risk was consistently reported with unopposed CEE.

Overall, the consensus reaffirms former advice – as evident in BMS and other published statements – that decisions about HRT ‘should be made on an individualised basis after discussing the benefits and risks with each patient’. But in women with a low underlying risk of breast cancer (‘most of the population’), ‘the benefits of HRT for up to 5 years’ use for symptom relief will exceed potential harm’. Moreover, as the WHI follow-ups make clear, ‘unopposed oestrogen is associated with no, or little change in risk but this may be influenced by age at initiation’, although ‘combined HRT can be associated with an increased risk, which appears duration dependent’.

References

Chlebowski RT, Anderson GL, Aragaki AR, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women's Health Initiative randomized clinical trials. JAMA 2020; 324: 369–380.

Natural conception rates still ‘clinically relevant’ in women in their forties having fertility treatment

Global fertility rates, as a complex modelling study forecast in a recent Lancet report, are set to decline throughout this century, a trend explained by better access to contraception and the improved education of girls and women.¹ The study estimated that by the close of this century 183 of 195 countries will have total fertility rates below the replacement level of 2.1 births per woman, with population expected to halve in many countries.

While such trends are more immediately evident in declining birth rates in many European countries, notably in younger couples deferring their first pregnancies, it may be not so surprising that the latest data from the UK’s Office for National Statistics (for 2018) finds the number of women aged 45 and over giving birth at the highest level since records began 80 years ago. The absolute numbers are not high – from 1619 births a decade ago to 2366 in 2018 – but they do suggest that pregnancy may well be an ambition for some women in their later forties.

Most of the advice on pregnancy in this age group rests on data derived from IVF registries, which clearly show that live birth rates decline quite markedly after the female partner’s age of 35, and continue this decline thereafter. Thus, according to the latest figures from the Human Fertilisation & Embryology Authority (HFEA), IVF birth rates in patients under the age of 35 and using their own eggs were 31% per embryo transferred, but below 5% for those aged 43 and older. It’s for this reason that most of the women seeking fertility treatment in their forties rely on egg donation for their pregnancies; the evidence is unequivocal that it’s the age of the egg which matters, not the age of the uterus.

A new systematic review of natural fertility in ‘infertile’ women over 35 and starting treatment confirms the age-related decline, but nevertheless finds that natural conception rates in these women are ‘still clinically relevant’ and cannot be discounted, even in those well into their forties.³ The 4000+ subjects in the review had taken their first steps of treatment and were then followed-up via their clinics to determine fertility outcomes. Some, as ever, did become pregnant naturally during their treatment programme. And a calculation by the authors was able to determine this natural conception rate according to age, and duration and type of ‘infertility’. Thus, for a 35-year-old woman with two years of primary unexplained infertility, the predicted probability of natural conception leading to ongoing pregnancy or live birth was 0.15 after six months and 0.24 after 12 months. For a 42-year-old woman, this decreased to 0.08 after six months and 0.13 after 12 months.

The authors note that presently ‘older women’ account for a substantial proportion of assisted reproduction treatments, with some registries showing more than 60% over the age of 35. With such results in mind, however, the authors conclude that these women attending fertility services ‘should be encouraged to pursue natural conception’ while waiting for the start of treatment and during treatment, ‘and not give up on their fertility even after treatment fails’.

References

Vollset SE, Goren E, Yuan C-W, et al. Fertility, mortality, migration, and population scenarios for 195 countries and territories from 2017 to 2100: a forecasting analysis for the Global Burden of Disease Study. Lancet 2020; doi.org/10.1016/S0140-6736(20)30677

Early menopause in women exposed to ‘forever chemicals’

Per- and polyfluoroalkyl substances, better known as PFAS, are a large family of multiple synthetic chemicals whose strong chemical bonds lend themselves to durability. They’re found in everyday products, especially packaging – hence their more familiar name of ‘forever chemicals’. Studies show that PFAS are now present as contaminants throughout many environments, with measurable concentrations also found in many people. Moves are thus afoot to control their use and seek alternatives.

So it should be no surprise that PFAS, like other well known endocrine disrupting chemicals, have now been linked to the menopause and its onset in an analysis of data from more than 1100 women in the Study of Women's Health Across the Nation (SWAN).¹ The study found that women with high serum levels of PFAS were likely to reach the menopause two years earlier than those with low levels – 50.8 years vs 52.8 years. Women were classified into four clusters based on their overall PFAS concentrations: low, low–medium, medium–high, and high. Compared with the low cluster, the high cluster had a significant hazard ratio of 1.63, equivalent to a 2.0 years earlier median time to natural menopause. The public health impact, said one investigator, was in the adverse health outcomes associated with an earlier menopause.

A press release on the study from the Endocrine Society in the USA noted that PFAS were present in such everyday products as non-stick cookware, waterproof rain gear, microwave bags, and firefighting foam, and further proposed that household water for an estimated one-in-three Americans was contaminated with PFAS. This was not the first such press release, nor the first such study, but the whole catalogue of perfluorocarbons (PFCs) seem to have adverse effects in both female and male reproduction.

Reference

Ding N, Harlow SD, Randolph JF, et al. Associations of Perfluoroalkyl Substances with Incident Natural Menopause: The Study of Women’s Health Across the Nation. J Clin Endocrinol Metab 2020; 105: dgaa303.