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IMS Menopause Live

Commentaries from the IMS on recently published scientific papers that may be of interest. The latest articles from September 2018 onward are available to Members only when logged in. Selected articles are open to public.

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Vitamin D – are we overprescribing?

28 August 2017

There has been ongoing uncertainty as to what level of circulating 25-hydroxy-vitamin D (25OHVitD) indicates vitamin D insufficiency. Vitamin D deficiency has been designated as a 25OHVitD level less than 30 nmol/l and insufficiency as less than 75 nmol/l [1, 2]. Please note that many laboratories give their results in ng/ml, and thus 30 nmol/l is equivalent to 12 ng/ml, and 75 nmol/l is equivalent to 30 ng/ml.

This would lead one to the expectation that treatment of a person with vitamin D insufficiency would be associated with adverse biochemical and morphological bone effects. Two recent publications should make us question the proposed 25OHVitD cut-off for vitamin D insufficiency [3, 4]. Shah and colleagues studied 11,855 people being assessed for 25OHVitD levels at a commercial laboratory and 150 people attending the Austin Hospital Melbourne [4]. Through a series of statistical analyses, they identified a ‘breakpoint’ of 30 nmol/l of vitamin D below which serum calcium was significantly lower, and parathyroid hormone (PTH) and alkaline phosphatase levels significantly higher. Although 34% of those with a 25OHVitD below 30 nmol/l had secondary hyperparathyroidism, the majority of people with a 25OHVitD below this level were biochemically normal. There was no signal of any biochemical abnormality amongst those with a 25OHVitD level between 30 and 75 nmol/l that justified a person being classified as vitamin D-insufficient. They also found no association between 25OHVitD and bone remodelling markers, bone mineral density (BMD) or matrix mineralization density in the subset of 150 people in which these parameters were measured. However, few people in this group had a 25OHVitD level below 30 nmol/l and this substudy may have been underpowered.

Reid and colleagues have concurrently reported the findings of a study in which 452 adults (mean age 69 years and two-thirds male) were randomly allocated to 100,000 IU of vitamin D3/month or placebo for 2 years [3]. No significant treatment effect was seen for BMD in the lumbar spine, which was the primary outcome. Although hip BMD declined in both groups, this was attenuated by 0.5% in the treated group. A treatment effect at the lumbar spine and hip was seen for the subset of 46 people who had a 25OHVitD level of 30 nmol/l or less at baseline.

The use of vitamin D supplementation is widespread across the developed world. However, contrary to prevailing practice, these studies indicate no bone health benefits of such supplementation for otherwise healthy adults when the serum 25OHVitD level is above 30 nmol/l. These recent findings should cause us strongly to question the validity of untargeted vitamin D supplementation for community-dwelling adults.

Susan R. Davis

Chair of Women’s Health, Monash University, Melbourne, Australia

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Alcohol and disease risk with a spotlight on breast cancer: should women stop drinking?

21 August 2017

The Bible says that 'wine makes people happy'. Alcohol seems an inbred constituent of human nutrition, and so many studies have pin-pointed its various health benefits and risks. Usually, the bottom-line recommendation favors alcohol consumption, but limiting it to 'drink in moderation', in order to avoid the potential serious adverse outcomes of heavy and lasting drinking. A new report from the World Cancer Research Fund and the American Institute for Cancer Research addresses 'diet, nutrition, physical activity and breast cancer' [1]. The report states that there is strong evidence that consuming alcohol increases the risk for premenopausal and postmenopausal breast cancer. 

Comment

This has been known, of course, but interestingly, while reviewing the literature, it seems that no threshold has been detected. Dose-response meta-analysis showed that each 10 g of ethanol per day increase the risk of breast cancer by 5% in premenopausal women, and by 9% in postmenopausal women. To note, in the premenopause, only North American studies have demonstrated a statistically significant result, whereas European or Asian studies were in the same direction, but still non-significant. The bottom line of these data means that even just one drink per day, equivalent to 10 g of alcohol, already carries a higher risk for breast cancer. The recommendation was thus clear – 'it is best to avoid alcohol, but if alcohol is consumed, the amount should be limited'.

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Longevity in women and reproductive factors?

14 August 2017

In this ageing world, the field of the 'epidemiology of longevity' has been expanding rapidly in recent years. With a dramatic increase in survival rate to advanced old age over the past century, longevity can be described as an epidemic. Many studies have evaluated the impact of factors such as low socioeconomics in childhood, genetics, environmental, dietary and lifestyle (smoking and alcohol use), which negatively affect longevity. Although mortality rates for females are lower at each age than those of men, a close association between reproductive characteristics and longevity was recently documented. 

Several reproductive factors, such as the age at first birth, parity and age of menopause, have been found to be associated with women's longevity. The recent prospective (WHI) study, in a large multi-ethnic cohort of postmenopausal women, examined 20,248 women from 40 clinical centers (aged 50–79 years, mean age at baseline 74.6 years); 10,909 (54%) of these women survived to age 90 years [1]. The odds of longevity were significantly higher in women with later age at first childbirth (adjusted odds ratio 1.11; 95% confidence interval 1.02–1.21 for age 25 years or older vs. younger than 25 years; p for trend = 0.04). Among parous women, the relationship between parity and longevity was significant among White but not Black women, while women with two to four term pregnancies compared with one term pregnancy had higher odds of longevity. This long-term, follow-up study reported that a rising number of pregnancies were associated with higher likelihood of longevity in the participants who survived to the age of 90 years. It was pointed that this was independent of demographic characteristics, socioeconomic position, lifestyle behaviors, reproductive factors and health-related factors. Despite these strengths, the authors pointed at a limitation of the study: women included in this study were on average aged 75 years at enrolment and may have had a higher likelihood of achieving longevity as they had already survived to their seventies. Also, with respect to historical events, participants may have had different experiences that may have influenced their life expectancy. So, because of potential selection bias, this cannot be applicable to the general population of childbearing women.

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Pharmacogenomics in personalized medicine: menopause perspectives

31 July 2017

Pharmacogenomics is the study of how genes affect a person's response to drugs. This relatively new field combines pharmacology and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person's genetic make-up [1]. Many drugs that are currently available are 'one size fits all', but they don't work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side-effects. Pharmacogenomics aims to develop rational means to optimize drug therapy, with respect to the patient's genotype, and to ensure maximum efficacy with minimal adverse effects.

Personalized management of menopausal symptoms and other menopause-related disorders should be based, among other variables, on pharmacogenomics. One main example is hormone therapy (HT), as nicely discussed in the Editorial by Moyer and colleagues [2]. Typically, dosing is targeted toward symptom relief, but there is significant variability in the doses required for symptom relief among women. In addition, if therapy is needed not only for symptoms but also for prevention of chronic diseases of old age, such as osteoporosis or cardiovascular diseases, then the effective doses might be different. Pharmacogenomic approaches may help identify women with different estrogen-dose requirements based on identification of genetic variants in enzymes involved in hormone/drug metabolism and impacting hormone/drug targets. The Kronos study provided data on the impact of genetic variations on the development of atherosclerosis in healthy, recently menopausal women receiving HT [3].

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FRAX®

24 July 2017

Since its launch in 2008, the web-based fracture risk assessment tool FRAX® [1] has been evaluated thoroughly in additional validation studies and widely published in meta-analyses and clinical review papers. Furthermore, its predictive and discriminative powers have been compared with other osteoporotic fracture risk prediction tools [2]. Two recent papers elucidate different aspects of the tool, one assessing its diagnostic accuracy in women and men from five different non-US populations [3], the other one calculating the time to 'clinically relevant' risk scores in US postmenopausal women [4], and both using the 10-year intervention thresholds of 20% for major osteoporotic fractures (MOF) and 3% for hip fractures (HF), as suggested by the National Osteoporosis Foundation (NOF) [5].

In the first paper, a systematic review and meta-analysis of seven studies from New Zealand, Canada, the USA, France and Poland, which tested FRAX® in populations other than the derivation cohorts, the tool 'performed better in identifying patients who will not have a MOF or HF within 10 years, than those who will. A substantial number of patients who developed fractures, especially MOF within 10 years of follow-up, were missed by the baseline FRAX® assessment', as stated by the authors in their conclusion.

For MOF prediction, the mean sensitivity, specificity, and diagnostic odds ratio (DOR) along with their 95% confidence intervals (CI) were 10.25% (3.76–25.06%), 97.02% (91.17–99.03%) and 3.71 (2.73–5.05); for HF prediction 45.70% (24.88–68.13%), 84.70% (76.41–90.44%) and 4.66 (2.39–9.08), respectively, the latter one being less precise because of its larger confidence region.

FRAX® is freely available and easy to use, not least because of its condensed and time-saving features. But this is at the expense of its sensitivity. Tools with a larger number of clinical risk factors, e.g. QFracture®, may be more sensitive but less feasible [2]. Lowering the intervention threshold may also improve sensitivity but increase over-treatment [6].

The second paper estimates the timing of occurring ‘clinically relevant’ scores, i.e. treatment-level FRAX® scores, according to 2014 National Osteoporosis Foundation guidelines [5], and screening-level FRAX® scores, according to 2011 US Preventive Services Task Force (USPSTF) guidelines [7], in postmenopausal women of the Women’s Health Initiative (WHI) cohort.

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Management of aromatase inhibitor-associated bone loss in postmenopausal women

17 July, 2017

Several guidelines have been reported for bone-directed treatment in women with early breast cancer for averting fractures, particularly during aromatase inhibitor (AI) therapy. A systematic literature review identified both several fracture-related risk factors as well as recent advances in the management of aromatase inhibitor-associated bone loss (AIBL). Although the FRAX algorithm includes fracture risk factors in addition to bone mineral density (BMD), it does not seem to adequately address the effects of AIBL. Several antiresorptive agents can prevent and treat AIBL. However, concerns regarding compliance and long-term safety remain. Overall, the evidence for fracture prevention is strongest for denosumab 60 mg s.c. every 6 months. Additionally, recent studies as well as an individual patient data meta-analysis of all available randomized trial data support additional anticancer benefits from adjuvant bisphosphonate treatment in postmenopausal women, with a 34% relative risk reduction in bone metastasis and 17% relative risk decrease in breast cancer mortality that needs to be taken into account when advising on management of AIBL.

A Joint Position Statement of the International Osteoporosis Foundation, the Cancer and Bone Society, the European Calcified Tissue Society, the International Expert Group for AIBL, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, the International Society for Geriatric Oncology and the International Menopause Society recently provided a treatment algorithm [1]. In all patients initiating AI treatment, fracture risk should be assessed and recommendation with regard to exercise and calcium/vitamin D supplementation given. Bone-directed therapy should be given to all patients with a T-score <−2.0 or with a T-score of < –1.5 SD with one additional risk factor, or with two or more risk factors (without BMD) for the duration of AI treatment. Patients with a T-score > −1.5 SD and no risk factors should be managed based on BMD loss during the first year and the local guidelines for postmenopausal osteoporosis. Compliance should be regularly assessed as well as BMD on treatment after 12–24 months. Furthermore, because of the decreased incidence of bone recurrence and breast cancer-specific mortality, adjuvant bisphosphonates are recommended for all postmenopausal women at significant risk of disease recurrence.

Comment

The use of adjuvant endocrine therapy in women with hormone-sensitive breast cancer is divided, usually by menopausal status, between the selective estrogen receptor modulator tamoxifen and the newer class of drugs known as aromatase inhibitors. The latter are indicated in postmenopausal women only. A Cochrane systematic review [2] found that disease-free survival and overall survival were improved with AI monotherapy compared to tamoxifen. Sequenced therapy with AI to tamoxifen (or vice versa) improved disease-free survival compared to tamoxifen but not overall survival. Fractures were more frequently associated with AI use. Thromboembolic disease and endometrial cancer were more frequently associated with tamoxifen use. AIs have largely replaced tamoxifen in adjuvant treatment of postmenopausal hormone receptor-positive breast cancers.

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Breast density, breast cancer risk, and hormone therapy

10 July, 2017

The radiographic appearance of the breast on mammography varies among women. Fat appears dark on a mammogram, whereas connective and epithelial tissues are radiologically dense and appear white. This is the basis for determining the mammographic density, and the relative percentage of dense versus lucent breast areas (percent mammographic density, PMD). It has been well established that parameters of breast density correlate with breast cancer risk, with a four- to six-fold-fold gradient in risk between women with 75% or more PMD compared with those with 10% or less [1]. A systematic meta-analysis of data for more than 14,000 cases and 226,000 non-cases from 42 studies found that greater PMD was consistently associated with an increased risk of breast cancer [2]. No differences were observed by age/menopausal status at mammography or by ethnicity. For PMD using pre-diagnostic mammograms, combined relative risks of incident breast cancer in the general population were 1.79 (95% CI 1.48–2.16), 2.11 (95% CI 1.70–2.63), 2.92 (95% CI 2.49–3.42), and 4.64 (95% CI 3.64–5.91) for categories 5–24%, 25–49%, 50–74%, and greater than or equal to 75% relative to less than 5%. While this generalized notion is actually 'old news', there might be, in fact, some deviations from the core principle, which relate to the exact parameter evaluated, the characteristics of the cohort and the technique of density measurement. Some studies picked breast density as the main tested parameter, whereas others used PMD, or changes over time in density or in PMD. As an example, in a study of 6710 women aged 40–49 at intermediate familial risk of breast cancer (average lifetime risk of 23%), the absolute density, but not percent density, was a significant risk factor for breast cancer after adjusting for area of non-dense tissue (OR per 10 cm2 = 1.07, 95% CI 1.00–1.15, p = 0.04) [3]. The effect was stronger in premenopausal women, who made up the majority of the study population. Absolute density remained a significant predictor of breast cancer risk after adjusting for age at menarche, age at first live birth, parity, past or present hormone replacement therapy, and the Tyrer-Cuzick 10-year relative risk estimate of breast cancer. Eng and colleagues drew attention to the potential impact of the mammography technique on the measured density [4]. They pointed out that there is currently no validated estimation method for full-field digital mammography, while differences in the obtained results may occur if various techniques are compared.

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A new look at hormone therapy and dementia

26 June 2017

Mikkola and colleagues examined the association between use of hormone therapy (HT) and death from Alzheimer’s disease (AD) or vascular dementia (VaD) in a sample of 489,105 Finnish women who had documented use of systemic HT on a nationwide drug reimbursement register [1]. A nationwide Finnish death register indicated that 1057 of those women died of AD and 581 died of VaD. Findings revealed that, compared to population averages, women who used HT for at least 5 years had a 15–19% reduced risk of death from AD, and use of HT for any period of time was associated with a 37–39% reduced risk of death from VaD. No reduction in AD was observed among women who used HT for less than 5 years, nor did age at initiation (< 60 years versus > 60 years) influence risk of AD or VaD.

Comment

Concern about the risks of dementia with HT stems primarily from the Women’s Health Initiative Memory Study (WHIMS), which showed a doubling of the risk of all-cause dementia with conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) [2]. These findings were observed in a sample of women aged 65 years and older, and questions regarding the generalizability of those findings to younger women and to other formulations of HT have been the topic of much debate. A definitive answer to those questions is unlikely to be determined, as it is not feasible to conduct a long-term, large-scale, randomized, controlled trial of HT for primary prevention of dementia among early postmenopausal women. For that reason, we must rely on observational studies to guide understanding of HT and dementia.

Observational studies of HT and dementia risk focus primarily on AD, the most common form of dementia, and less on VaD, the second most common form of dementia. Meta-analyses of HT and AD risk generally provide support for the view that HT lowers AD risk [3,4]. However, observational studies, particularly those in the United States, are difficult to interpret because of the healthy-user bias, the tendency for women who use HT to be healthier and better educated than those who do not use HT, and the tendency to rely on self-report of HT exposure (not optimal for a memory study!). Additionally, the most common form of HT used in those studies is CEE with or without MPA and little is known about estradiol, which is used widely outside of the United States.

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HRT and cardiovascular disease

12 June 2017

Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women [1]. Hormone replacement therapy (HRT) has been shown to reduce future risk of cardiovascular disease when taken within 10 years of the menopause. Avoiding HRT in menopausal women can actually be detrimental to their health. Some experts are now recommending that HRT should be considered as part of a general prevention strategy for women at the onset of the menopause [2]. However, some doctors and nurses feel very apprehensive about this as they are confused about the association of HRT with cardiovascular disease (CVD).

The negative publicity regarding the misinterpretation in the media of the Women’s Health Initiative (WHI) study has led to many women and health-care professionals still being concerned and anxious about the potential risks of HRT [3], in particular regarding HRT and cardiovascular disease (CVD). A large proportion of doctors are still informing women that HRT is associated with a greater risk of CVD and are refusing to prescribe HRT for women who would actually benefit from taking it. Many women with hypertension are still being told to stop taking their HRT. This misperception is resulting in large numbers of women needlessly enduring menopause symptoms and also increasing their future risk of osteoporosis, cardiovascular disease and diabetes by not taking HRT.

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Neurokinin-3 receptor antagonist to treat hot flushes

8 May, 2017

Hot flushes, which are among the most frequent symptoms of menopause, are considered to be the result of the changes in the sex hormone milieu and tissue exposure at midlife and beyond. However, modern medicine tries also to tie physiological processes with the individual gene profile. This was also done in regard to vasomotor symptoms (VMS) in the WHI study, in search of potential associations between VMS and certain genetic variations and single nucleotide polymorphisms (SNPs). After adjustment for bilateral oophorectomy, age, smoking, alcohol intake, physical activity, population structure, body mass index, education, income, and menopausal hormone therapy use, 14 SNPs were associated with increased odds of VMS at a p value threshold < 5 × 10-8 [1]. These 14 SNPs are located within the same region of chromosome 4, the gene which encodes tachykinin receptor 3 (TACR3), and neurokinin B (NKB), a member of the tachykinin family of peptides, preferentially binds to NK3R. NKB mRNA-expressing neurons are located predominantly in the infundibular nucleus and the anterior hypothalamic area. In humans, NKB neurons co-localize with the gonadotropin releasing hormone tract in the infundibular stalk, and the NKB pathway is implicated in pubertal development and hypogonadatropic hypogonadism. Another study showed that the expression of tachykinins and their receptors in the mouse uterus are tightly and differentially regulated by ovarian steroids [2]. Estrogen effects are mainly mediated by estrogen receptor alpha, supporting an essential role for this estrogen receptor in the regulation of the tachykinergic system in the mouse uterus. Furthermore, menopause and/or oophorectomy are associated with changes in NKB gene expression: in the human infundibular nucleus it increases after menopause, and in monkeys and rats ovariectomy induces similar increases in NKB gene expression that are reversed by estradiol therapy [3].

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