Abstract
Polarised opinion on the menopause
The proposed guidance issued by NICE in November to add cognitive behavioural therapy to the treatments for vasomotor symptoms was not as warmly received as expected. In its announcement NICE indicated that CBT could be considered ‘alongside or as an alternative to’ HRT, but set out the proposal adjacent to new risk and benefit charts of HRT formulations. While some complained that symptoms would always be better managed by HRT than CBT, NICE stressed that its commitment was to individualised care - so the announcement itemised ‘the risks and benefits of different treatment options so people can work with their healthcare practitioner to agree what works best for their particular needs’.
The 2015 NICE menopause guidelines had in fact included CBT in their recommendations, but only to relieve low mood or anxiety linked to the menopause. Now, said NICE, new evidence showed that CBT could also reduce the frequency and severity of symptoms and the extent to which they proved bothersome. The review of new evidence - to answer NICE’s question of CBT’s efficacy in managing symptoms - included 14 RCTs mainly published since 2012 and several other studies comparing its effect with usual or no treatment. Generally, the quality of the evidence was rated ‘from very low to moderate’, although the review did surprisingly discern an ‘important benefit for some of the symptoms associated with the menopause’. The committee seemed persuaded that two of the hot flush rating scales applied ‘were valid and reliable measures’ and both showed an important benefit for CBT in reducing the frequency and distress or bother caused by symptoms - though this despite the still ‘variability of evidence’. Unfortunately, the committee passed on the best route of CBT delivery - face-to-face, online, guided or self-help.
Proposing this rather soft alternative for symptom relief drew an angry response from some quarters. MP Caroline Nokes, for example, chair of the Commons’ women and equalities committee, said that while there was ‘no one size fits all’ solution to the menopause ‘we cannot have a situation where the negatives around HRT are being emphasised over the very real positives’.
Of course, all this might just be seen as a spat, a stand-off reaction to yet another establishment proposal. But there does here seem a more existential question over the place of the menopause in women’s lives and how it should best be managed - and it’s one which seems now of polarised opinion in settling one’s position. On the one hand, ‘a normal life transition’, as NICE suggests, but on the other a debilitating phase which deservedly requires specialist intervention. Indeed, a recent debate in the journal Fertility and Sterility proposed that reproductive endocrinologists have the best knowledge of ovarian function among any medical specialty. ‘They should not relegate patients whose ovaries are at the end of their reproductive life span to the care of others with less knowledge,’ scoffed one author.(1) Right now, the larger debate - a natural or medicalised menopause with a range of treatments for symptoms - seems anchored by dogma and a somewhat loose grab at evidence in support.
The full revised guidance on the diagnosis and management of the menopause is expected to be published by NICE in May this year.
1. Berga SL, Merkison J, Schirmer A, et al. Should menopause care be part of the skill set of a reproductive endocrinology and infertility specialist? Fertil Steril 2023; DOI: 10.1016/j.fertnstert.2023.11.018
Stand by for the neurokinin antagonists
December’s UK approval of fezolinetant for the treatment of vasomotor symptoms brought a further flurry of interest in this neurokinin antagonist, a non-hormonal treatment said by the BMS in a statement to have the potential to revolutionise menopause management. Reports suggested that fezolinetant would be available via private prescription from mid-January, though not publicly until NICE has completed a clinical and cost appraisal likely to begin in July. Fezolinetant was approved by the FDA in May 2023, which in a press release explained its action as ‘blocking the activities of the NK3 receptor, which plays a role in the brain’s regulation of body temperature’.
The strongest evidence for fezolinetant’s efficacy comes from a series of phase 3 randomised trials, the first reported by The Lancet in April 2023 and performed in 97 centres in North America and Europe (including UK) over 12-52 weeks.(1) More than 2000 women aged 40-65 took part, randomised to placebo or one of two fezolinetant doses. When compared with the effect of placebo, both doses reduced symptoms significantly, and overall improvements in frequency and severity of symptoms were observed at four and 12 weeks. Results from a later study (known as DAYLIGHT) in 450 women and presented at a congress in December, similarly found a statistically significant reduction in vasomotor symptoms from baseline, now within 24 weeks. Commentaries so far suggest that the benefits of fezolinetant likely lie with those with contraindications to (or anxieties about) HRT for symptom relief. All subjects in the DAYLIGHT trial, for example, were ‘considered unsuitable for hormone therapy’.
There have in the past been initiatives to introduce non-hormonal interventions to treat vasomotor symptoms. Several RCTs have reported studies with SSRIs, though with inconsistent results. One placebo controlled trial - of low-dose estradiol and venlafaxine - found that both interventions were effective, improving quality of life in women with symptoms.(2) However, only the SSRI paroxetine is approved (and only in the USA) for treating vasomotor symptoms. In its approval statement the FDA, in listing the contraindications to HRT, stressed that fezolinetant is not a hormone, but ‘targets the neural activity which causes hot flashes during menopause’.
While fezolinetant has been described as the first in its class of neurokinin receptor antagonists, there are others apparently waiting in the wings. Elinzanetant, a dual neurokinin (N1 and N3) antagonist, has already shown strong signals for efficacy in phase 2, with the first phase 3 results (from the OASIS trials programme) buoyantly announced by the manufacturer in January. As with the new GLP-1 agonists for weight loss, manufacturers seem to be expecting blockbuster returns, with speculative revenue predictions already touching the billions.
1. Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet 2023; 401: P1091-1102. DOI: 10.1016/S0140-6736(23)00085-5
2. Caan B, LaCroix AZ, Joffe H, et al. Effects of estrogen and venlafaxine on menopause-related quality of life in healthy postmenopausal women with hot flashes: a placebo-controlled randomized trial. Menopause 2015; 22: 607-615. DOI: 10.1097/GME.0000000000000364.
Government under fire for poor support of Fracture Liaison Services
The Royal Osteoporosis Society has stepped up its agitation for more Fracture Liaison Services, taking aim at the government for an apparent string of U-turns and broken promises, and now teaming up with the Sunday Express newspaper for a ‘Better Bones’ campaign. The latter is calling for everyone over 50 to be covered by a quality Fracture Liaison Service, described by the ROS as the ‘gold standard for systematically identifying, assessing and treating anyone who breaks a bone after age 50’, with osteoporosis risk evaluation and better access to DXA scanning. Most are located in hospitals, though some in primary care centres.
The ROS’s moan with the government began last summer when MP Maria Caulfield, Minister for Women, promised to ‘explore ways to establish more Fracture Liaison Services’ and to add more details ‘later in the year’. However, according to the ROS, nothing further was said about the pledge until a minister in a House of Lords debate on osteoporosis said that a package to improve Fracture Liaison Services would be announced in the chancellor’s autumn statement. But according to the ROS that very promise ‘was retracted the next day’, and the chancellor’s autumn statement made no mention whatsoever of fracture services. Hence the accusations of false promises and U-turns, and this hard-hitting government-directed campaign from the ROS (including full-page newspaper adverts). ‘If the Government had honoured its promise,’ said the ROS, ‘we could have prevented 74,000 fractures over the next five years, including 31,000 life-threatening hip fractures.’
The latest priorities of the Women’s Health Strategy for England, marking the outset of its second year, were announced in January by the Health Secretary and, yes, by Maria Caulfield, to include ‘menstrual problems and menopause, maternity care and birth trauma support’, but once again no mention of fractures or Fracture Liaison Services. So far, it seems, the best the government can do in its move against falls and fractures is advice to ‘walk like a penguin’, with helpful how-to diagrams supplied by the NHS.
Meanwhile, Fracture Liaison Services remain patchily available throughout England and Wales (51% of NHS Trusts), although with 100% coverage in Scotland and Northern Ireland. ‘This postcode lottery,’ said the ROS, ‘is leading to a revolving door of fractures in hospitals, as thousands suffer preventable hip and spinal fractures which could have been avoided with therapy.’
Don’t skip breakfast, Rishi
While the Mediterranean diet with its emphasis on fruits, vegetables, olive oil and fish remains the world’s number one diet as ranked by the influential US News & World Report, other dietary plans are increasingly marked by timing as well as by the quality and quantity of food intake. Intermittent fasting, for example, has now become one of the most popular weight reduction initiatives around, with several time-restricted eating plans available, from 5:2, 16:8 to OMAD (one meal a day). Even Prime Minister Rishi Sunak confessed to 36 hours fasting at the start of each week, surely not for weight loss.
Now, a huge prospective cohort study from France, known as NutriNet-Santé and including 80% mid-life women among its 100,000+ subjects, has found that delayed first and last meals of the day are associated with an increased risk of cardiovascular disease.(1) Results showed having a later breakfast (later than 9am compared to earlier than 8am) and last meal of the day (later than 9pm compared to earlier than 8pm) was associated with a higher risk of coronary heart disease, cardiovascular and cerbrovascular outcomes, especially among women. ‘Our results,’ write the authors, ‘suggest a potential benefit of adopting earlier eating timing patterns, and coupling a longer nighttime fasting period with an early last meal, rather than breakfast skipping, in CVD prevention.’ Behind the results, they explain, lies the daily eating/fasting cycle as a ‘dominant synchroniser of circadian rhythms’ in peripheral organs, including mainly the liver, but also the heart and cardiometabolic functions. They add that ‘chrononutrition has emerged as a new field in nutritional sciences to unravel the relationship between timing of food intake, circadian rhythms and health’.
Specifically, each additional hour delaying the time of breakfast was associated with a small higher risk for overall CVD (HR 1.06) with the association stronger in women than in men. Each additional hour in delaying the time of the last meal, however, was associated with far greater increased risk for cerebrovascular disease - a last meal after 9pm was associated with a 28% higher risk than before 8pm (HR 1.28). The results were calculated after a median follow-up of 7.2 years.
This is not the first study to suggest that regularly skipping breakfast and eating late at night might have a negative effect on cardiometabolic health. There have been many studies, but not all consistent in their findings. However, a 2020 meta-analysis did find a benefit from regular timely meals, even advising in its conclusion that ‘eating breakfast regularly may promote cardiovascular health and decrease all cause mortality’.(2)
1. Palomar-Cros A, Andreeva VA, Fezeu LK, et al. Dietary circadian rhythms and cardiovascular disease risk in the prospective NutriNet-Santé cohort. Nat Commun 2023; 14: 7899. DOI: 10.1038/s41467-023-43444-3
2. Chen H, Zhang B, Ge Y, et al. Association between skipping breakfast and risk of cardiovascular disease and all cause mortality: A meta-analysis. Association between skipping breakfast and risk of cardiovascular disease and all cause mortality: a meta-analysis. Clin Nutr 2020; 39: 2982–2988. DOI: 10.1016/j.clnu.2020.02.004
Statins found to lower the VTE risk of HRT
The NICE menopause guidelines of 2015 listed deep vein thrombosis and venous thromboembolism as risks associated with menopausal hormone therapy - and to a greater extent with oral than with transdermal preparations. Indeed, a review of HRT in women with a history of thrombosis, published in this journal last year, noted that transdermal therapy ‘is not associated with an increased risk of thrombosis’, linking the risk to the combination of hormones and route of administration.(1) Now, a new case-control study has suggested that statins may be associated with a reduced risk of VTE in women taking HRT - and that HRT may not be contraindicated in women taking statins.(2)
The study was based on more than 220,000 women aged 50 to 64 identified from a large US insurance database, with filled prescriptions for estrogens, progestogens and statins recorded in the 12 months prior to analysis. Cases of VTE were similarly recorded and matched to controls (10:1) by age. Statin exposure was defined as 90 or more days of continuous use prior to and including the index date.
Almost 9% of the entire sample had used HRT, and 16% statins. First, from adjusted models results showed women with any recent HRT exposure had indeed a far greater risk of VTE than those with no recent HRT use (OR 1.51); however, that risk fell substantially in those taking statins. Women taking HRT with concurrent statins had 18% lower odds of VTE than those taking HRT without statins (OR 0.82) - and there was even greater risk reduction with higher intensity statins. A similar case-control study based on a UK GP practice database found a comparable risk reduction for VTE in women taking HRT and statins.(3)
The apparent benefit, which, say the authors, must be confirmed in larger trials, is not surprising, given the effect of statins on some cardiovascular conditions. The landmark JUPITER trial, for example, was stopped early by its monitoring board back in 2008 because of a 44% reduction in all vascular events, a 54% reduction in myocardial infarction and a 48% reduction in stroke in healthy men and women taking statins.(4)
The challenging scenario from this latest and earlier studies is the co-prescription of HRT and statins, especially in those who might have been at greater risk of VTE, in the expectation that statins might mitigate their excess risk. From these latest results, a transdermal formulation and a lower dose also seem essential to help lower the risk.
1. Morris G, Talaulikar V. Hormone replacement therapy in women with history of thrombosis or a thrombophilia. J Post Reprod Health 2023; 29: 33-41. DOI: 10.1177/20533691221148036
2. Davis JW, Weller SC, Porterfield L, et al. Statin use and the risk of venous thromboembolism in women taking hormone therapy. JAMA Network Open 2023; 6(12): e2348213. DOI: 10.1001/jamanetworkopen.2023.48213
3. Fournier J, Duijnhoven RG, Renoux C, et al. Concurrent use of statins and hormone therapy and risk of venous thromboembolism in postmenopausal women. Menopause 2014; 21: 1023-1026. | DOI: 10.1097/GME.0000000000000279
4. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195–2207. DOI: 10.1056/NEJMoa0807646