Abstract
Never too old …
There is no ambiguity about the title of this journal. ‘Postreproductive’ - like postmenopausal - is unequivocal, that natural conception is no longer possible and is now consigned to history. Like ‘dead’ or ‘pregnant’, you either are or you aren’t. Other more subjective terms, however, like ‘young’ or ‘middle-aged’, have no such certainty of definition, which is why one learned paper has now proposed that the perceived onset of ‘old’ age has changed over recent time.(1)
‘Middle-aged and older adults believe that old age begins later than did their peers one or two decades ago,’ conclude investigators from the German Ageing Survey after analysing data from more than 14,000 participants. Now, they add, at age 64 the average perceived onset of old age is at around 75 years. Longitudinal regression modelling found that this perceived onset of old age increased by about 1 year for every 4–5 years of actual ageing. The earliest-born participants in the study (born in 1911) reported an earlier perceived start of old age than those born later. Thus, when they were 65 years old they set the beginning of old age at age 71, while those born in 1956 said that old age begins at 74. There were gender differences to these observations: women, on average, said that old age started 2 years later than men – and that the difference in ‘old’ between men and women had increased over time.
Unlike old age, however, average menopausal age has remained remarkably consistent over time. Even an ever extending reproductive lifespan is now explained only by a younger age at menarche and not by older age at menopause. As the British endocrinologist Jean Ginsburg reminded her BMJ readers back in 1991, Aristotle in 350 BC had described menstrual cycles as drawing to an end in about the fortieth year, although they can last ‘even to the fiftieth year’.
Similarly, premature menopause, now more accurately described as ‘premature ovarian insufficiency’, is precisely defined by loss of ovarian activity before the age of 40, while loss of such function between the ages of 40 and 44 is precisely defined as ‘early menopause’. These definitions, incidentally, are clearly set out in the forthcoming collaborative guideline on Premature Ovarian Insufficiency now in development with ESHRE (and in collaboration with the International Menopause Society).(2) It seems likely that this updated guideline will be available later this year.
However, while POI and early menopause can be precisely defined, the prediction of menopausal age in individuals remains an inexact science. A new review in the journal Fertility & Sterility reports that anti-Mullerian hormone (AMH), FSH, menstrual cycle length, inhibins, antral follicle counts, ovarian volume and various sociodemographic indicators are all ‘undeniably correlated’ with age at menopause, but their precision in predicting the exact age of menopause remains inadequate.(3) Age, says the review, seems to have the best predictive power and all the others ‘are only adding in a very limited way to the prediction of menopause’.
Meanwhile, the investigators behind the notion of a postponed perception of old age suggest their findings may have implications for when and how people prepare for their own ageing, but they were unsure how this might play out - whether the trend towards postponing old age reflects more positive views on older people and ageing, or rather the opposite, a consideration that being old is an undesirable state.
1. Wettstein M, Park R, Kornadt AE, et al. Postponing old age: Evidence for historical change toward a later perceived onset of old age. Psych Aging 2024. DOI: 10.1037/pag0000812.
2. See https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Guidelines-in-development/POI_update
3. Laven JSE, Louwers YV. Can we predict menopause and premature ovarian insufficiency? Fertil Steril 2024. DOI: 10.1016/j.fertnstert.2024.02.029.
Polarised views on the menopause: The Lancet steps in
Britain, like the USA and Australia, is having a menopause moment, according to The Lancet. It’s a time when discussion about the menopause has spilt over from the clinic into politics, the workplace and the mass media. But, while recogising the wider awareness, The Lancet warns that the press and social media keyboard warriors latch on to ‘extreme negative experiences of menopause’, depicting it as an unfortunate and distressing experience, a critical downturn in women’s health, which can only be solved by hormone replacement treatment. So The Lancet’s answer to the media’s excesses? Why, a press release for the media denouncing ‘the overmedicalisaltion of the menopause’ and an odds-on favourite for a shock-horror headline.
In our March News & Views for this journal we noted a schism in menopause opinion, a split between recognising the menopause as a necessary phase of healthy female ageing or a more dramatic harbinger of mental and sexual decline, sleepless nights and restless days, remedied only by specialist support and HRT. The outgoing editor of the journal Climacteric described this dramatisation as ‘the second age of marketing the menopause’, urging readers to ‘avoid exaggeration and the mistakes of over-treatment and mistreatment seen in the mid twentieth century’.(1)
The Lancet’s comments came as the introduction to a four-part series on the menopause which similarly sought to steer readers away from any ‘overmedicalisation’ and towards ‘a new approach to how society views menopause and supports women as they age’.(2) The series comprised four papers - including reports on early menopause, mental health and management after cancer - whose red-line theme challenged the ‘over-simplified narrative’ of menopause as a health problem to be solved by replacing hormones. This narrative, the series argued, ‘is not based on evidence and deflects attention from the need for substantial societal shifts in how menopause, and midlife/older women in general, are viewed and treated around the world’. The series also noted how some groups - with early menopause or cancer treatment-induced menopause - often do not receive best dedicated care.
One of the four reports also questioned the increasingly common assumption that the menopause is causatively associated with poor mental health problems.(3) However, a review of 12 studies as part of the series did not confirm this. Two of the 12 studies reported increased depressive symptoms, but three found no such increase and the remaining seven reported mixed results. After reviewing these studies and others, the series’ experts concluded there is no robust evidence that the risk of anxiety, bipolar disorder, psychosis or suicide increases for all women over the menopause transition.
The series acknowledges that hormone therapy is the most effective treatment for hot flushes and night sweats, adding that ‘treating hot flushes may also improve sleep and mood’ but noting that evidence ‘is lacking’ on the benefit of HRT on other symptoms associated with menopause and ageing in women.
There is also an obligatory warning about the intrusion of money into menopause management. These commercial interests, adds the report, ‘have strongly influenced media messaging’ about menopause in which the small but serious risks of HRT are often downplayed or ignored. The series thus argues that women should have access to accurate and evidence-based information in a form they can understand - and created without undue commercial influence.
The Lancet called for a ‘new approach’ to viewing the menopause and, right on cue, the International Menopause Society responded in search of a ‘well balanced narrative of the menopause momentum’.(4) The response was quicky into its stride, addressing The Lancet series within five paragraphs and recognising the pros and cons of its arguments - that attributing many symptoms to the menopause can be misleading but that under-treatment may have undeserving health effects. So the schism persists. Indeed, as the editorial says, ‘the claim being proffered by some medical and social media influencers that there is insufficient prescribing of MHT, and that it should routinely be offered to women, not only to manage distressing symptoms but also to prevent non-communicable diseases represents the other extreme of the polarized views’. In the end, the editorial comes down on the side of evidence-based information and education, an ’empowerment’ which neither over-sensationalises nor underplays this phase in women’s lives. But the editorial shares one consistent opinion with The Lancet - that there remains ‘poor access to education, inadequate resources, cultural and religious influences, and governments not prioritizing women’s health care’.
1. Baber R. Marketing the menopause. Climacteric 2023; 26: 171–172. DOI: 10.1080/13697137.2023.2196885.
2. Hickey M, LaCroix AZ, Doust J, et al. An empowerment model for managing menopause. Lancet 2024; 403: 943–957. DOI: 10.1016/S0140-6736(23)02799-X.
3. Brown L, Hunter MS, Chen R, et al. Promoting good mental health over the menopause transition. Lancet 2024; 403: 969–983. DOI: 10.1016/S0140-6736(23)02801-5.
4. Nappi RE, Panay N, Davies SR. In search of a well-balanced narrative of the menopause momentum. Climacteric 2024. DOI: 10.1080/13697137.2024.2339129.
Unscheduled bleeding in women on HRT
A new guideline published in this journal on unscheduled bleeding in women taking HRT has been developed by the British Menopause Society and other groups (including the RCOG) in response to a ‘significant increase’ in women presenting with unscheduled bleeding.(1) The comprehensive guide comprises five sections - on assessment, risk factors for endometrial cancer, when to investigate, how to investigate and adjusting the HRT regime to reduce bleeding. Each section has been summarised with key messages. Notably, the guideline notes ‘major’ risk factors for endometrial cancer as a BMI ≥ 40 and evidence of hereditary conditions such as Lynch or Cowden syndrome. Minor risk factors include BMI30-39, diabetes and polycystic ovarian syndrome (PCOS). The guideline stresses the importance of progestogen for reducing the risk of endometrial cancer: a monthly progestogen dose in proportion to the estrogen dose in women with a uterus, or a minimum of 10 days norethisterone (NET) or MPA or 12 days micronised progesterone per month for those using sequential HRTs. The guidance recommends offering all women a 52 mg levonorgestrel IUD, which ‘reduces episodes of unscheduled bleeding when compared to all other preparations’. Oral preparations provide higher rates of amenorrhoea than transdermal preparations and could be offered if there are no risk factors for thrombosis.
Lest we forget …
It is 22 years since the Women’s Health Initiative changed the perception of hormone therapy for the menopause, and now the same investigators (well, many of them) are back in the same journal with a review and conclusions drawn from a generation of claim and counter claim.(1). While the original two trials - of combined and unopposed HRT - created the headlines, there were two others, to assess the effects of calcium plus vitamin D supplementation (on bone health), and low-fat dietary modification.(2,3,4,5)
Of the two less publicised latter trials, calcium and vitamin D supplementation did not significantly reduce the rate of hip or other fractures in postmenopausal women. However, the review does now propose that supplementation remains appropriate for those who do not reach the recommended dietary intakes of these nutrients through food. Similarly, The WHI’s low-fat dietary intervention study was associated with a small loss of weight but did not significantly reduce the incidence of breast or colorectal cancer, although a reduced risk of breast cancer mortality was observed during long-term follow-up.
The headlines, of course, were reserved for the two HRT trials and especially the first, of combined HRT and its effects on long-term health. The dramatic JAMA press release (‘Hormone therapy study stopped due to increased breast cancer risk’) was followed immediately by a similarly headlined release from the National Heart, Lung and Blood Institute, the trial’s sponsors, and a flurry of earnest statements from investigators saying that trial subjects had been told to stop their treatment. Shock and terror, indeed. By the year’s end the US news agency Associated Press had dubbed it the ‘top medical story of 2002’, describing the fall-out - in the words of WHI investigator JoAnn Manson - as ‘the most dramatic sea change in clinical medicine that I have ever seen’. And certainly, the story was bursting with drama, even in the very wording of that first press release: ‘a major study . . . stopped because of health safety concerns . . . increased breast cancer risk . . . 16,608 menopausal women . . . stop prescribing estrogen plus progestin . . . treatment not beneficial overall’. Breast cancer was the story, even though the investigators themselves made clear that ‘the primary outcome for the trial . . . [was] coronary heart disease’. But still, this looked like the axe for long-term HRT.
Now, 22 years later the WHI investigators repeat their mantra that their results ‘do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases’. However, they acknowledge that HRT ‘is appropriate to treat bothersome vasomotor symptoms among women in early menopause without contraindications’. They also acknowledge a factor hiding in full view in the 2002 report, that women in both HRT trials under the age of 60 ‘had a more favorable benefit-risk ratio than women aged 60 to 69 years or 70 to 79 years’. They explain that this was primarily because of lower absolute risks in younger women, a fact well known at the time of the study, but also because of lower hazard ratios found in younger than in older women (especially in the estrogen-alone trial).
It was not until 2007 with results from a secondary analysis of HRT’s effects on cardiovascular disease that the age factor would be fully described.(6) That report proposed that women who began HRT within the first 10 years following the menopause actually reduced their risk of coronary heart disease (HR 0.76). Those who started 10–19 and more than 20 years after slightly increased their risk (HR 1.10 and 1.28 respectively) - which meant that for every 10,000 women taking HRT within 10 years of the menopause there would be six fewer coronary deaths per year than in non-users. The data also showed that hormone users aged 50–59 had a 30% lower risk of all-cause mortality than those given placebo. Thus, with a continuing recognition of HRT’s unequivocal effect on climacteric symptoms, the concept of a window of prescribing opportunity began to materialise, which would largely shape the regulatory and public position of HRT today.
As required by most journals today (though not in 2002), authors are asked to define their study’s limitations, which in this case could well have been a long list. But here we find only an acknowledgement that hormone formulations other than the combination selected for the trial (CEE plus MPA) ’may have yielded different results’. No mention of the misguided emphasis on breast cancer, no mention of the U-turn on CHD, no mention of the 16,000+ women recruited with a mean age of 63.3 years, with many in their 70 s.
Nevertheless, and despite the dramatic rhetoric of the original announcements, the reviewers today take a more moderate line, reflecting the measured position of most guidelines: that ‘individualized patient care and shared decision-making should be implemented, taking into account patient preferences, severity of symptoms, and cardiometabolic and general health status’.
And commenting on the review, first author JoAnn Manson told a US medical news website: ‘The WHI findings really should never be used as a reason to deny the use of hormone therapy to women who are presenting with bothersome vasomotor or other menopausal symptoms and seeking treatment, especially when they are in early menopause and free of contraindications . . . On the other hand . . . the bar is set very high for using medications for prevention purposes, and the risk needs to be extremely low.’
1. Manson JE, Crandall CJ, Rossouw JE, et al. The Women’s Health Initiative randomized trials and clinical practice: A review. JAMA 2024. DOI: 10.1001/jama.2024.6542.
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: 321–333. DOI: 10.1001/jama.288.3.321.
3. The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative Randomized Controlled Trial. JAMA 2004; 291: 1701–1712. DOI: 10.1001/jama.291.14.1701.
4. Jackson RD, LaCroix AZ, Gass M, et al. Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354: 669–683. DOI: 10.1056/NEJMoa055218.
5. Howard BV, Manson JE, Stefanick ML, et al. Low-fat dietary pattern and weight change over 7 years: the Women’s Health Initiative dietary modification trial. JAMA 2006; 295: 39–49. DOI: 10.1001/jama.295.1.39.
6. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297: 1465–1477. DOI: 10.1001/jama.297.13.1465.