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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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Weight and breast cancer risk

11 December, 2017

Many studies link weight/body mass index (BMI) to breast cancer risk. However, BMI affects risk differently before and after menopause. Before menopause, being overweight or obese modestly decreases breast cancer risk whereas, after menopause, being overweight or obese increases breast cancer risk. Several recent studies have shed light on other relevant perspectives of this link. The Women's Health Initiative trial provided data on the potential association between the metabolic syndrome and breast cancer risk [1]. The evaluated parameters were: blood glucose, triglycerides, HDL cholesterol, blood pressure, waist circumference, and BMI. Women were then classified into six metabolic obesity phenotypes according to their BMI: 18.5 – < 25, 25 – < 30, > 30 kg/m2) and presence of the metabolic syndrome (> three of the following: waist circumference > 88 cm, triglycerides > 150 mg/dl, HDL cholesterol < 50 mg/dl, glucose > 100 mg/dl, and systolic/diastolic blood pressure > 130/85 mmHg or treatment for hypertension). The cohort included about 21,000 postmenopausal women and over 15 years of follow-up; 1176 cases of invasive breast cancer were diagnosed. Obesity, regardless of metabolic health, was associated with increased risk of breast cancer. Being obese and metabolically unhealthy were associated with the highest risk: HR 1.62, 95% CI 1.33–1.96. These associations were stronger in women who had never used hormone therapy. The investigators concluded that, beyond BMI, metabolic health should be considered a clinically relevant and modifiable risk factor for breast cancer.

What about weight changes? Does weight gain increase the risk? Contrarily, will weight loss help to lower the risk of breast cancer? The Nurses' Health Study demonstrated, in a huge cohort, that weight gain after the age of 18 years was unrelated to breast cancer incidence before menopause, but was positively associated with incidence after menopause [2]. This increased risk with weight gain was limited to women who never used postmenopausal hormones; among these women, the relative risk (RR) was 1.99 (95% CI 1.43–2.76) for weight gain of more than 20 kg vs. unchanged weight (p for trend < 0.001). Furthermore, the percentage of postmenopausal breast cancer accounted for by weight gain alone was approximately 16%. The Nurses' Health Study also presented data on the opposite case scenario, namely on weight loss and breast cancer risk [3]. Women who had never used postmenopausal hormones, lost 10.0 kg or more since menopause, and kept the weight off were at a lower risk than those who maintained weight (RR 0.43, 95% CI 0.21–0.86; p = 0.01 for weight loss trend).

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One-third of dementia may be preventable with lifestyle change

13 November, 2017

Dementia will become more common as our population ages. Globally, 15 million people were affected by dementia in 2015 and this number is expected to triple by 2050. Reduced exposure to dementia risk factors and increased exposure to protective factors create a 'cognitive buffer', reducing the progression to, or delaying the onset of, dementia.

It is thought that more than one-third of dementia cases may be preventable by modifying nine lifestyle factors. It has recently been suggested by the Lancet Commission on Dementia Prevention, Intervention and Care that, even if there is a genetic tendency for dementia, addressing these nine factors across the lifespan is associated with a reduced risk of dementia in later life [1]. There is no disease-modifying treatment for any common dementia, so delaying the onset of dementia would be of great benefit to the individual, their families and supporters, as well as the general community.

The potentially modifiable risk factors are:

  • not completing secondary education in early life (under 18 years old),
  • high blood pressure, obesity and hearing loss in midlife (age 45-65 years),
  • smoking, depression, physical inactivity, social isolation, and diabetes in later life (greater than 65 years).

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Dietary intervention targeting reduction of energy density

23 October 2017

Energy-dense foods are foods with a high proportion of energy relative to the food weight. Such foods are considered obesogenic. Hence, consumption of energy-dense foods, particularly those with a high content of unsaturated fats and sugar, predicts weight gain and greater waist circumference. This in turn increases the risk of obesity-related cancers such as breast, bowel, ovarian, endometrial, kidney, gallbladder, esophageal and pancreatic cancer.

Foods with a high dietary energy density (DED; kilocalories or kilojoules/gram of food or beverages consumed) may be associated with lower overall satiety (feeling of fullness), resulting in greater overall energy intake, whereas low energy-dense diets have been reported as resulting in weight loss and less hunger compared with dietary fat restriction in a year-long trial [1].

The association between energy-dense foods and the incidence of obesity-associated cancers has been further explored in an analysis of data from 92,295 postmenopausal women, aged between 50 and 79 years, who were enrolled in the Women’s Health Initiative (WHI) study in the US [2]. DED was defined as the amount of energy (calories or kilojoules) per gram of food. Each woman’s DED was assessed by self-reporting, using a food frequency questionnaire at baseline. The incidence of obesity-related cancer was self-reported at baseline and follow-up, and re-confirmed during the 14.6 ± 5.6 years of follow-up using medical records.

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Prevention of Alzheimer's disease

16 October 2017

The prevalence of Alzheimer's disease (AD) is constantly increasing to very alarming figures, and this already has a huge impact on society in terms of needed medical and nursing services as well as the associated financial burden. Herein, I bring a very condensed bullet-type summary published in Medscape by the author of a paper, just published in the Journal of the American Geriatric Society [1]. First, the major risk factors, which are not modifiable, are age and female gender, and the presence of the apolipoprotein E ε4 allele. Still many risk factors may be modified and thus should be considered as worthy targets in the prevention of AD. These include optimal management of diabetes mellitus and insulin resistance, obesity, metabolic syndrome, hypertension, hypercholesterolemia, cerebrovascular disease, depression, psychological and physiologic stress, traumatic brain injury, sleep-disordered breathing, smoking, alcohol abuse, high blood pressure, renal disease, alcohol and tobacco use, high cholesterol, coronary heart disease, sedentary lifestyle, and diet. These potentially modifiable risk factors, when combined, account for more than 50% of AD risk, based on observational studies. To note, many of these risk factors do not appear to affect amyloid or tau proteins.

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New insights on current osteoporosis risk assessment

9 October 2017

Once upon a time, not too many years ago, osteoporosis was defined as having a history of low-trauma, major site fracture. Then came the high technology era and DXA machines were introduced all over the world. By testing large populations, sex-, ethnic-, age- and weight-adjusted bone density (BMD) averages were calculated, which allowed new definitions of osteoporosis (by T-score), and comparison of the individual values with the adjusted average values in their community (Z-score). Still, because most people who fracture do not have osteoporosis and most people with osteoporosis do not break their bones, a more sophisticated method to measure the risk for fractures seemed reasonable. Furthermore, new medications to prevent fractures have been developed and commercialized, adding a substantial financial burden to health budgets, thus putting cost-effectiveness as a top priority issue. As a result, it became evident that prescribing therapies must be based on accurate prediction of individual risk for future major osteoporosis-related fractures. Incorporation of various risk factors for osteoporosis or for fractures led to the creation of screening tools, with or without BMD data, which claimed to have higher predictive values [1]. FRAX® is probably the most recognized risk assessment tool, as it also takes into consideration the local situation, based on data raised in the particular country or region.

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No increased death toll for long-term MHT

25 September 2017

The saga of the Women's Health Initiative (WHI) seems to have come to a turning point with a declaration that should vibrate now throughout the whole world. A new release of data from the WHI study has concluded that 'Among postmenopausal women, hormone therapy with CEE [conjugated equine estrogen] plus MPA [medroxyprogesterone acetate] for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years' [1]. Amazing as it is, the safety concerns that were attributed in the past to menopausal hormone therapy (MHT) need to be re-considered and to be put in their right perspective. It is not necessary to present again the main features of the CEE + MPA and the CEE-alone randomized studies.

The main issues discussed by the WHI investigators included the following:

  • The present report is based on mortality follow-up through December 2014 and includes 7489 deaths (1088 occurred during the intervention phase and 6401 occurred post-intervention; 4083 additional deaths had occurred since the last report). For the CEE + MPA trial, the median post-intervention follow-up was 12.5 years and the cumulative follow-up was 18 years; for the CEE-alone trial, the median post-intervention follow-up was 10.8 years and the cumulative follow-up was 18 years.
  • During the intervention phase, all-cause mortality in the pooled cohort was 4.0% with hormone therapy vs. 4.0% with placebo. Compared with placebo, women randomized to receive CEE + MPA had a hazard ratio (HR) of 0.97 (95% confidence interval (CI) 0.82–1.16) and women randomized to receive CEE alone had a HR of 1.04 (95% CI 0.89–1.22). During the post-intervention period, the HR for all-cause mortality was 1.04 (95% CI 0.97–1.10) for CEE + MPA and 0.92 (95% CI 0.85–0.99) for CEE alone.
  • The HRs for all-cause mortality tended to differ by age during the intervention and cumulative follow-up phases. Comparison of women aged 50–59 years with those aged 70–79 years showed that the risk was significantly lower for the younger age group, as ratios of nominal HRs for all-cause mortality in the pooled cohort were 0.61 (95% CI 0.43–0.87) during the intervention phase and 0.87 (95% CI 0.76–1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. Although younger women tended to have lower HRs than older women for mortality due to cardiovascular disease (CVD), cancer, and other (non-CVD, non-cancer) causes during the intervention phases of the two trials, only the latter outcome in the CEE-alone trial showed a statistically significant trend with age (p for trend by age = 0.002). During cumulative follow-up, trends in cause-specific mortality across age groups were not statistically significantly different.

In the Discussion section, the investigators had several important comments as well. They claimed that no other randomized clinical trial of hormone therapy has been large enough to assess a potentially modifying effect of age on all-cause mortality. They noted that observational studies, which primarily include women who initiate hormone therapy in early menopause, have generally demonstrated lower mortality among women using hormone therapy compared with non-users. HRs in most large cohort studies have ranged from 0.40 to 0.80. Regarding cause-specific mortality, the most marked risk reductions reported in observational studies have been for coronary or CVD deaths. Total cancer mortality did not differ significantly between intervention and placebo groups in either trial despite the increased incidence of breast cancer with CEE + MPA. However, a significant reduction in breast cancer was seen with CEE. Divergent findings for CEE alone and CEE + MPA for breast cancer point to an adverse effect of progestin on the breast epithelium, but progestins have been linked to favorable effects on the endometrium, and a decreased risk of endometrial cancer became apparent with long-term follow-up of the CEE + MPA trial. Last, but not least, it was mentioned that only one dose, formulation and route of administration in each trial were assessed; thus, results cannot necessarily be generalized to other hormone preparations.

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Type 2 diabetes, menopause and HRT revisited

18 September 2017

Several recent publications have raised again the complex association between menopause, glucose handling and insulin status, type 2 diabetes and hormone replacement (HRT/MHT). Interestingly, a cohort of 3639 postmenopausal women from Rotterdam, followed for 9.2 years, revealed a clear statistical correlation between the age at natural menopause and the future risk of becoming diabetic [1]. Hazard ratios (HRs) for type 2 diabetes were 3.7 (95% CI 1.8–7.5), 2.4 (1.3–4.3) and 1.60 (1.0–2.8) for women with premature (< 40 years), early (40–44 years) and normal menopause (45–55 years), respectively, relative to those with later menopause (ptrend < 0.001). The HR for type 2 diabetes per 1 year older at menopause was 0.96 (0.94–0.98). The investigators concluded that early onset of natural menopause is an independent marker for type 2 diabetes in postmenopausal women. These findings certainly raise again the discussion over the relevance of the hormonal changes around the menopause vis-a-vis the metabolic pathways involved in glucose metabolism and the development of insulin resistance and type 2 diabetes. It also puts forward the potential consequences of HRT in this respect.

The 2017 position statement on the menopause that was issued by the American Association of Clinical Endocrinologists and the American College of Endocrinology includes a section on type 2 diabetes [2]. The main points were:

(1) Women without diabetes at baseline: spontaneous menopause has not been associated with an increased risk of diabetes; evidence from observational trials suggested a neutral or slightly beneficial effect of estrogen on glucose metabolism; in randomized controlled clinical trials, including HERS (women with known cardiovascular disease), blood glucose levels did not rise over time in estrogen-treated women, and fewer women with impaired fasting glucose at study onset progressed to overt diabetes. In younger, non-diabetic women in the shorter KEEPS trial, no effect of conjugated estrogen was seen, while transdermal estrogen-treated subjects showed a modest reduction in blood sugar. In the WHI, there was a 21% reduction in diabetes incidence over time in women treated with estrogen/progesterone therapy, but this effect was limited to the age group 50–69 years old; in the estrogen-only arm of the WHI, the incidence of diabetes in treated women was 12% less than in controls at all age groups.

(2) Women with diabetes at baseline: in observational studies, treatment with HRT has resulted in either neutral or beneficial effects on glucose levels in patients with pre-existent type 2 diabetes.

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Vaginal laser therapy in gynecology practice: a real new option but keep an eye on the scientific data

11 September 2017

The word 'LASER' is an acronym for 'Light Amplification by Stimulated Emission of Radiation'. Laser light energy has been widely used for different medical and surgical indications. Different light sources are available for the laser practitioner. In the last years, a number of publications have appeared and vaginal laser has gained interest as a treatment for genitourinary syndrome of menopause (GSM) and as an option for stress urinary incontinence (SUI) [1-10].

The carbon dioxide (CO2) laser is the first-generation laser for GSM treatment. In 2011, Gaspar and colleagues [1] first demonstrated that vaginal fractional CO2 laser treatment induced a significant improvement in clinical and histological signs of vaginal atrophy. Subsequently, in a pivotal paper, Salvatore and colleagues [2] reported a 12-week study where symptoms were analyzed before and after three sessions (one per month) of fractionated CO2 laser, using a specific, registered technology. This paper opened a new era for non-hormonal treatment of GSM. Other studies confirmed these data, showing morphological changes in vaginal tissues, and the alleviation of the symptoms of dryness and dyspareunia [3], with an improvement in sexual gratification.

In the same years, there were studies of the thermal effects of a non-ablative 2940 nm Erbium:YAG laser, using precisely controlled, sequentially packaged bursts of long pulses (SMOOTH® mode vaginal erbium laser, VEL). The SMOOTH mode is registered and allows the use of full beam and patterned handpieces to deliver Er:YAG laser energy with different fluences to the vaginal tissue. VEL increases the tissue temperature up to the optimal range, but does not exceed the threshold for ablation or tissue damage, leading to significant improvement in GSM [4-7].

Both the microablative fractional CO2 laser and the non-ablative VEL have been repeatedly reported in observational studies to be effective for GSM treatment: vaginal dryness improves in 80–90% of women and dyspareunia in all (100.0%) sexually active women, with clinical changes similar to those induced by local estrogen administration. In addition, VEL treatment induces a deep collagen remodelling and synthesis [3], leading to a reinforcement to correct mild to moderate SUI [8-10]. VEL was reported to improve SUI as well as vaginal prolapse, by assessing the impact on the Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF), the PAD test, the post-void residual urine volume and Q-tip angulation [8-10]. After VEL treatment, a reduction of four to six points in the ICIQ-UI score has been reported, with a success in 70–80% of patients [8-10].

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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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