Link between premature menopause and mortality risk

Women who experience premature ovarian insufficiency (POI) before the age of 40 are more likely to die early, but hormone therapy may lower this risk, according to research presented at the 2024 European Congress of Endocrinology (ECE), 11-14 May, 2024, Stockholm, Sweden. The long-term Finnish study is the largest to date on the links between premature menopause and mortality, and highlights the importance of evidence-based, appropriate hormone therapy for these patients. Around 1 per cent of women go through menopause before the age of 40 and are subsequently at a higher risk of long-term health problems such as cardiovascular disease. The cause is largely unknown, but can be brought on spontaneously or by some treatments such as chemotherapy or bilateral oophorectomy.

In this study, researchers from the University of Oulu and Oulu University Hospital, Finland, investigated 5,817 women who were diagnosed with spontaneous or surgical POI in Finland between 1988 and 2017. They compared these women with 22,859 women without POI and found that those who had experienced early menopause were more than twice as likely to die of any cause or of heart disease, and more than four times as likely to die of cancer. However, the risk of all-cause and cancer mortality was approximately halved in women who used hormone replacement therapy (HRT) for more than six months.

Previous studies have also shown that women with premature menopause have a higher risk of early death. However, this association has never been studied in women on such a large scale before, or for such a lengthy follow-up period (up to 30 years). “To our knowledge, this is the largest study performed on the linkage between POI and mortality risk,” said Ms Hilla Haapakoski, a PhD student at the University of Oulu, who led the study.

She added: “Our study is one of the first to explore both surgical and spontaneous POI in women’s all-cause, cardiovascular, and cancer-related mortality, and examine whether HRT for over six months may reduce mortality risk. Our findings suggest specific attention should be paid to the health of women with spontaneous POI to decrease excess mortality.”

The team will now assess whether women with premature menopause are more likely to have other illnesses or conditions, such as cancer or heart disease, and whether long-term use of HRT affects these conditions. “Various health risks of women with POI have not been well recognised and the use of HRT is often neglected. We hope to improve the health of these women by increasing awareness of the risks among healthcare professionals and the women themselves,” added Ms Haapakoski.

Fezolinetant safely reduces hot flushes in menopause for almost six months

Attendees at the ECE Congress 2024 heard that fezolinetant reduces the frequency and severity of hot flushes during menopause for 24 weeks without serious side-effects. Vasomotor symptoms (VMS) affect up to 80 per cent of women going through menopause and can severely impact many aspects of wellbeing.

Hormone replacement therapy (HRT) is not suitable for, or desired by, all women, and fezolinetant – which was recently approved in Ireland for VMS – acts directly on the thermo-regulatory pathway to alleviate these issues, and is a non-hormonal alternative for symptom management.

Previous late-stage clinical trials (SKYLIGHT 1 and SKYLIGHT 2) have shown that fezolinetant reduces both the frequency and severity of hot flushes in women with moderate or severe symptoms compared to placebo over 12 weeks. This phase 3b study, known as DAYLIGHT, investigated the effect of fezolinetant use over 24 weeks.

A total of 453 menopausal women aged 40-65 with moderate or severe hot flushes, who were unsuitable for HRT, were randomised to receive either fezolinetant or placebo. The primary endpoint was mean change in daily VMS frequency of moderate to severe episodes from baseline to week 24, while secondary endpoints included mean change in VMS severity and safety.

Women who took fezolinetant reported less frequent and severe hot flushes throughout the 24 weeks. They had consistently fewer hot flushes in the first week, with the strongest decrease during the first three days. The severity of their hot flushes was also reduced significantly by the drug in the first week from the second day. No safety issues were found for the 45mg fezolinetant dose over the 24 weeks.

“DAYLIGHT is the first study of fezolinetant to investigate placebo-controlled efficacy over 24 weeks,” said Prof Antonio Cano, INCLIVA Research Institute in Valencia, Spain, and senior author of the study. “Fezolinetant was effective and well tolerated for 24 weeks and the effect was observed as early as day one of treatment. While there are other NK (neurokinin-3) antagonists, none have shown a similar concurrence of efficacy and safety in clinical studies with a sufficiently high number of participants.

“A safe and effective non-hormonal molecule may be available for the very high number of menopausal women who suffer from VMS and improve their overall health, quality of life, and work performance. However, these symptoms vary in prevalence or intensity depending on ethnicity – for example, VMS are more frequent and severe in black women – so more clinical data are needed in different populations or geographical areas in the world.”

Arm fat may indicate risk of spinal fracture

Measuring the total fat mass of the arms could potentially predict those over 50 who are at increased risk of spinal fracture, according to research presented at the ECE Congress 2024. Osteoporosis is a common disease among older people, but is also one of the most underdiagnosed and untreated medical conditions in the world. The findings may help identify high-risk individuals with a very simple and inexpensive method.

To date, the relationship between body composition and bone health is still unclear. Therefore, to further understanding in the area, researchers from the National and Kapodistrian University of Athens, Greece, analysed 14 men and 101 women without osteoporosis.

The sample had an average age of 62 and demonstrated that total fat mass is negatively associated with trabecular bone score (TBS). Moreover, total lean mass was positively associated with TBS. Visceral fat, in particular, was associated with lower quality trabecular bone.

The researchers then looked at the distribution of subcutaneous body fat and discovered that individuals with higher fat mass in the arms were more likely to have lower bone quality and strength in the spine.

“Surprisingly, we identified, for the first time, that the body composition of the arms – in particular, the fat mass of the arms – is negatively associated with the bone quality and strength of the vertebrae,” said senior author Prof Eva Kassi, Professor of Endocrinology/Biochemistry, National and Kapodistrian University of Athens, Medical School, Athens, Greece.

“This could mean that the arm’s subcutaneous fat, which can be easily estimated even by the simple and inexpensive skin-fold calliper method, may emerge as a useful index of bone quality of the spine, possibly predicting the vertebrae fracture risk.

“It should be noted that visceral fat, which we found to be strongly correlated with low bone quality, is the hormonally more active component of the total body fat. It produces molecules called adipocytokines that provoke a low-grade inflammation, so the increased inflammatory status plausibly poses a negative impact on bone quality.” 

Prof Kassi also acknowledged that larger studies are needed to confirm the link between arm fat and spinal fracture risk, and that research is still ongoing. “Although our results remain robust after controlling for age and weight, we will now increase the number of participants and expand the age range by including younger adults between the ages of 30 and 50 years old, as well as more men.

“Moreover, using the loss of arm fat mass as a marker, we will try to determine the most effective physical exercise routine that not only targets the visceral fat, but also focuses on the upper part of the body so that these higher-risk adults lose arm fat and achieve a favourable effect on vertebrae bone quality.”

Blood sugar levels at gestational diabetes diagnosis correlate with level of risk

The level of glucose above diagnostic threshold at the time of gestational diabetes (GD) diagnosis is associated with worse neonatal outcomes and abnormal maternal glucose homeostasis, but not with obstetric outcomes, according to data presented at the ECE 2024 Congress.

GD affects around 20 million pregnancies worldwide and poses a range of health risks for both mothers and their babies. The higher the blood sugar level in pregnant women when first diagnosed, the higher the risk of complications, attendees heard.

Researchers from the Tâmega e Sousa Hospital Centre, Portugal, conducted a retrospective study based on the national register of GD. A total of 6,927 women aged between 30-37 with live-born singleton pregnancies were included and analysed between 2012 and 2017.

The researchers found that for every 5mg/L increase in their blood sugar levels, there was a 9 per cent higher risk of hypoglycaemia and a 6 per cent higher risk of large birth weight in newborns, as well as a 31 per cent higher risk of post-partum maternal hyperglycaemia. The findings suggest that high-risk women with GD should be classified further to limit these complications for both mothers and newborns.

“While it is not surprising that high glucose levels are associated with these adverse outcomes in mothers and newborns, our study shows for the first time how much increase in risk there is with 5mg/dL of increase in the mother’s blood glucose levels when first diagnosed with GD,” said study co-lead Dr Catarina Cidade-Rodrigues.

“The magnitude of elevated risk can be calculated with our measurements and, in practice, could be used to identify and stratify women at higher risk of developing these complications. We now want to evaluate if there is a benefit in further stratifying these high-risk women with GD, who will need to be more closely monitored and to whom pharmacological interventions can be carried out appropriately. This may help reduce complications during labour and in newborns and prevent future diabetes in these women.”

Exploring past mistakes, misinformation, and the importance of a holistic approach in menopause

For decades menopausal women were deprived of hormone replacement therapy (HRT) due to a study we now know to have produced scientifically flawed breast cancer results, leading to a fear of breast cancer among HRT prescribers and women. In addition, women feel unsupported and lacking in information and education on menopause, leading them to feel unprepared to deal with this transition.

Menopause is more than a collection of symptoms, it can impact not only the physical, but the psychosocial, family, and workplace. Menopause also has significant adverse economic implications for women, their workplace, and government. This report seeks to highlight the flaws of the misleading study, the importance of formal education for women, families, and healthcare professionals, menopause stigma, the financial impact of menopause, and how we can help demarginalise menopausal women.

Menopause

Menopause is the permanent cessation of menses for 12 months with no other medical cause. Perimenopause is the lead-up to menopause, where menses may be irregular and the onset of menopausal symptoms due to oestrogen reduction occur.

The depletion of oestrogen can lead to women experiencing varying symptoms including hot flushes; night sweats; lethargy; sleep disturbance; depression; cognition impairment; decreased sex drive; joint and muscle pain; and genitourinary issues including vaginal dryness, dyspareunia, and recurrent urinary tract infections.

Approximately 85 per cent of menopausal women experience at least one menopausal symptom during their lifetime, with 42 per cent expressing that symptoms were worse than expected. Blumel et al (2000) found that menopause, irrespective of age or demographics, negatively impacts quality-of-life.

The flawed evidence

The Women’s Health Initiative Report (WHI) 2002 misled decades of women due to exacerbated claims linking HRT usage to breast cancer. This study was subsequently found to be flawed in its methodology due to several factors. For instance, they used an older population of menopausal women which many experts deem inappropriate for HRT treatment – the average age being 63.2 years, and as we know, breast cancer risk increases with age. The average body mass index of participants was 28.5, also a known risk factor for breast cancer.

The HRT used in the trial was conjugated equine oestrogen with medroxyprogesterone acetate, which would not be the safer body identical HRT used today, and therefore, cannot be compared. The confidence interval was not adjusted for clinical variables. An adjusted confidence interval allows for results to be generalised for the population, while an unadjusted effect size can provide an overestimation of the population effect size. Confidence intervals provide measure of the certainty of a result, telling us if we can apply the findings to the general population.

The WHI study, by its own admission, states the breast cancer arm of the research “almost reached statistical significance”, and as we know, ‘almost’ is not a scientific term. If they had used adjusted confidence intervals, as would have been best practice at the time, the results would have clearly demonstrated they did not reach statistical significance.

A long-term WHI follow up in 2020 found no increase in breast cancer within the oestrogen-only (HRT for hysterectomised women without endometriosis) arm of the study, and a slight increase in the oestrogen and progesterone arm (HRT for women with uterus), but no increase in breast cancer mortality.

Despite this, HRT-related fear of breast cancer still exists today among both women and healthcare professionals. Bacon (2017) states, “a clear understanding of the physiology of the menopausal transition, clinical symptoms, and physical changes is essential for individualised patient management, maximising benefits, and minimising risks for the present and the future.”

Gaps in menopause care

Apart from the specific fear of breast cancer risk and HRT, in general, knowledge and treatment of menopause is not always well understood by clinicians. Lin et al (2020) demonstrated that menopause training gaps led to half of the healthcare professionals studied not being aware of contraindications to prescribing menopausal hormonal treatment (MHT).

A recent UK study (2022) revealed that 30 per cent of women who approached GPs regarding menopausal symptoms experienced delayed diagnosis, and only 40 per cent were offered HRT, which is considered first-line treatment for menopausal symptoms in patients with no contra-indications.

The recent paper in The Lancet (2024) perpetuated this fear of HRT, stating that menopause was “over medicalised”. They go on to say, “menopause is a natural phase of life that they transition as part of biological ageing”. The office for national statistics UK state that just over 100 years ago, women were spending a mere two years in menopause, as the average age of menopause in 1921 was 57 years with the lifespan then being 59 years.

Now, with the average age of menopause being 51 and average life expectancy 82 years, women are spending approximately one-third of their lives in menopause. Science and medicine have increased the lifespan of women, should we not embrace the innovations to improve quality-of-life? Do women really need to suffer? Could the same not be said for other presentations that are now more prevalent due to the ageing population, hypertension, diabetes, cardiovascular disease?

Menopause: The reality

A survey of 1,132 women carried out in Ireland in 2020 revealed that 80 per cent were unprepared for menopause. Around 79 per cent of the women surveyed felt that information and support surrounding menopause was poor and almost half did not feel confident discussing menopause with their GP. This indicates that menopause is not ‘over-medicalised’, with many women left to navigate menopause alone without medical support, interventions, or treatment.

Irish comedian Anne Gildea refers to menopause as an “all-inclusive condition – you don’t have to have it to suffer from it”. Menopause impacts all aspects of life, including friendships, social life, work, and family. A British Menopause Society study found that over one-third of women felt less outgoing socially and not as good company, with almost a quarter feeling isolated.

A 2022 UK survey found that 80 per cent of respondents felt peri/menopause put pressure/tension on their relationships with partners and children. A further seven-out-of-10 women attributed menopause as the reason for marital breakdown. To quote my own research on the impact of menopause education; a meta-analysis revealed statistically significant improvements in both quality-of-life and symptom control following menopause education in symptomatic menopausal women.

Interestingly, a recent study found educating partners to also be effective, increasing knowledge of menopause and leading to increases in relationship satisfaction.

Menopause can be associated with feelings of embarrassment, shame, and stigma. This may be in part due to the lack of public/traditional conversations about menopause. Rarely are menopausal women mentioned in TV or movies, and when they are, it is the stereotypical presentations, dripping with sweat or throwing a temper tantrum.

An Ofcom survey (2018) supported this feeling of under-representation, finding that men appeared on screen much more frequently than women in the BBC programmes, with a ratio of 62:38 male-to-female. Another finding was that women who did appear on screen in peak time BBC programmes were much more likely to be under 55 years old. This could make the women who are experiencing menopause feel invisible and they may not recognise symptoms as being related to menopause.

With regards to menopause in the workplace, the European Menopause and Androgen Society (2020) reported there were 657 million women aged between 45-to-59 years globally, with almost half contributing to the workforce.

An Irish survey (2020) found that 40 per cent of menopausal women thought about giving up work, with 12 per cent leaving their job. Half stated it had some effect on their performance, while 30 per cent said that menopause affected work a lot.

A significant 86 per cent of women were not happy telling their manager the real reason for missing work. At least 39 per cent missed work days due to menopausal symptoms, with 22 per cent missing more than three days. Vodafone (2021) found similar impacts with their female workers in a study of over 4,000 menopausal women, which are outlined in Figure 1.

FIGURE 1: Findings from the Vodaphone 2021 survey

The House of Commons Women and Equalities Committee (2022) also carried out a report on menopause and the workplace and found nearly 900,000 UK women left their jobs due to menopausal symptoms, many in senior roles and at the peak of their careers. This can lead to ripple effects on company productivity and gender-related pay and pension gaps. The committee found this to be detrimental to the economy and to society. With these findings, it is imperative we do better to support and protect this marginalised cohort.

The Irish Menopause, a support group for women, say that the cost of HRT is a major barrier to women taking up the treatment. They estimate that standard HRT prescriptions cost between €30 and €70 a month, and that women have halted treatment because they cannot afford the cost. This is despite the Government removal of VAT from HRT products to improve accessibility, leading to an approximate saving of €6-to-€16 depending on the HRT product prescribed.

Comparing this to the Working Group Report on Access to Free Contraception (2019) which stated that only 3 per cent of respondents cited affordability as being an issue regarding contraception, this free access programme was implemented in 2022. The working group found, based on General Medical Services data, the most likely cost range for the introduction of a State-funded contraceptive scheme for 17-to-24 year-olds would be in the region of €18-to-€22 million.

The working group cited the economic rationale for universal contraception was to potentially reduce the future financial burden associated with unplanned or crisis pregnancies (including terminations). This programme has now been extended to those aged up to 35, as of July 2024.

The Seanad Éireann in 2023 recognised the range of physical and psychological symptoms of menopause, with HRT not only being associated with symptom reduction, but also the long-term cardiovascular and bone health benefits, which have long-term financial impacts on the health service. Green Party Senator Pauline O’Reilly stated the cost of making HRT freely available to every woman would be €10-to-€20 million per year, including those already receiving the HRT with a medical card.

Given the impact HRT (where clinically indicated) has on those suffering with menopausal symptoms and the long-term health benefits such as a reduction in cardiovascular disease and osteoporotic fractures, which would reduce future financial burden on the Government, did we really do enough in just removing VAT from HRT?

Solutions

From September 2020, menopause education has been added to the secondary school curriculum in the UK. As multiple studies have shown, women have limited education and no formal menopause education in Ireland, therefore, I suggest menopause education strategies start at school and extend beyond using a multifaceted approach, social media, apps, public health campaigns, and workplace education to deliver menopause education going forward.

The Irish College of GPs launched a free menopause theory course in 2023. There is an urgent need for more menopause education directed at all healthcare professionals at both an undergraduate and post-graduate level. Menopause is complex; therefore, education needs to consider not only symptom management, but also the psychological impact on the individual, their personal, social, family, and working life.

While media coverage of menopause has increased in recent years, it seems to be more of a documentary/interview/podcast approach. Hollywood actresses have for years discussed the impact of getting older on getting roles, with younger actresses being favoured. It is time we see women aged 45-plus being fairly represented in TV shows and movies, addressing the transition of menopause without the focus being the stereotypical presentation to reduce stigma.

Employers can do several things to ensure employee retention during menopause transition. Menopause champions are non-medical educated employees who provide support to those approaching or going through menopause.

Simple inexpensive adjustments could be actioned, such as access to cold drinking water, having sanitary products in the toilets, desk fans/offer to move nearer a window, a place to go if feeling overwhelmed, flexible working, and breathable uniforms. These implementations make women feel visible and understood. The provision of menopause education/training for staff and managers can create a workplace culture that supports those going through menopause.

With regards to cost implication of HRT (if needed), we look again at our neighbours. Northern Ireland, Scotland, and Wales all provide free HRT, with England having introduced a HRT PPC (prescription pre-payment certificate) in 2023, which means that all eligible HRT prescriptions will be capped at £19.30 for a full 12 months of treatment. Could a working group be set up to find a more impactful way to address the cost impact of HRT?

Conclusion

Menopause is not a disease, it is a transition; however, for some this time can be psychologically and physically difficult. We need to appreciate there is not a one-size-fits-all approach to menopause and treatment. Be it medical or otherwise, any approach needs be tailored to the individual. Women live up to a third of their lives in menopause, therefore, menopause education for healthcare professionals, patients, and families, along with the assessment and treatment/management of menopausal transition to increase quality-of-life in menopausal women, should be of great public-health interest.

References on request

The Menopause Hub has launched the first Irish app to support women during menopause. The innovation offers the latest information and research about the hormonal changes endured by women in their 40s and 50s. It can also be used to monitor menopausal and perimenopausal symptoms and receive medication reminders. Menopause Hub CEO and founder Loretta Dignam, who was instrumental in developing the app, said the data gathered by it can also be used by researchers to investigate future treatments.

“Combining the latest technology with up-to-date data about female health will not only improve outcomes for women today, but will also improve the range and impact of menopause treatments available to future generations,” said Ms Dignam.

“There is a myriad of menopausal symptoms, which women in their 40s and 50s experience in varying degrees, including insomnia, hot flushes, anxiety, depression, and brain fog, to name but a few. Every woman’s menopause will be vastly different. Some will sail through it, while others will struggle to such an extent that they feel they have to give up their careers or their long-term relationships break down. It is, therefore, vital that we gather as much clinical data as we can to help medical researchers develop future treatments.

For far too long, the impact menopause was having on women’s lives was ignored. But women are now demanding – and deserve – more help with symptoms.” The app was co-designed by women going through menopause alongside a range of clinical experts, and developed by medical technology company Zendra Health, which is helping over 80 healthcare services and organisations across the US, UK, and Ireland digitalise their care pathways.

The Menopause Hub App will be available to download in March 2024.