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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 February 2017 onward are available to Members only when logged in. Selected articles are open to public.

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Better be divorced?

10 April, 2017

The title of this commentary is not a joke. Marital status seems to have a major impact on health. Traditionally, stability in intimate relations has positive effects on health and quality of life parameters, especially in old age. This assumption even translates into smaller insurance costs of married versus divorced persons. But recent data from the WHI observational study now challenges this accepted belief [1]. Among 79,094 postmenopausal women, transitions into marriage/marriage-like relationship after menopause were associated with greater increase in body mass index (BMI) and alcohol intake relative to remaining unmarried. Divorce/separation was associated with a reduction in BMI and waist circumference, changes that were accompanied by improvements in diet quality and physical activity, relative to women who remained married. The message coming from these results is that, contrary to earlier literature, in a cohort of well-educated, predominantly non-Hispanic white women, marital transitions after menopause are accompanied by modifiable health outcomes/behaviors that are more favorable for women experiencing divorce/separation than those entering a new marriage.

Comment

Marital status is a major parameter in every history-taking that health-care providers do. Thousands of articles have displayed all aspects of quality of life in health, as well as the potential impact on various disease situations adjusted to the marital status. Having a partner and intimate relations are considered as health promotors, while accordingly, marital disruption is perceived as a negative factor. For example, most studies on cardiovascular disease showed better outcomes for married persons, and men who were single generally had the poorest results [2]. Moreover, being married was associated with lower risk factors and better health status, even in the presence of many confounding effects. Physiological processes, such as cardiovascular reactivity, hormonal functionality, inflammatory manifestations and sleep patterns behave differently in the subsets of marital status, and so do many psychological variables [3, 4]. Even bone density was mentioned in this respect, as marriage before age 25 and marital disruptions seem deleterious to bone health in men, whereas marital quality was associated with better bone health in women [5].

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Sleep duration and health

24 April, 2017

A friend has just told me that sleep is a waste of time, because every minute being awake does count and should be used to enjoy life. Well, I guess he was wrong, since sleep is mandatory not only for relaxation, but also for the initiation of many active neuro-physiological processes which are vital. Extreme and prolonged deprivation of sleep may even eventually lead to death. The duration of sleep seems an important factor in maintaining optimal health. There is a consensus that a 7-hour night sleep should be recommended [1], whereas shorter or longer sleeps might be associated with a higher rate of health derangements and mortality risk [2]. Although there is probably no gender difference in the impact of sleep duration, herein are some clinical data related to women and menopause.

Cardiovascular disease: In the Women's Health Initiative observational study (n = 86,329; 50–79 years old, 10.3 years follow-up), shorter (5 h or less) and longer (10 h or more) sleep duration demonstrated significantly higher incident coronary heart disease (CHD) (25%) and cardiovascular disease (19%) in age- and race-adjusted models, but this was not significant in fully adjusted models [3]. Women with long sleep demonstrated the greatest risk of incident CHD compared to midrange sleep duration (hazard ratio =1.93, 95% CI 1.06–3.51) in fully adjusted models.

Hypertension: The Nurses' Health Study investigated the relationships between sleep duration and hypertension among women whose sleep durations were self-reported (n = 84,674) [4)]. The prevalence of hypertension was significantly higher among women who slept 5 h or less per night (odds ratio = 1.19, 95% CI 1.14–1.25) compared with 7 h, but further analysis showed that this association was only seen in those aged < 50 years.

Diabetes mellitus: A recent study used data from the China Kadoorie Biobank, coming from a rural county [5]. Sleep duration was shown to have a U-shaped association with diabetes in 33,677 women, in particular in postmenopausal women after adjustment for potential confounders. Compared with 7-h sleepers, odds ratios of sleep duration 5 h or less and 10 h or more for diabetes were 1.32 (95% CI 1.02–1.69) and 1.30 (95% CI 1.03–1.65), respectively.

Cancer: The WHI observational study showed that deviation from the ideal 7-h night sleep increases the risk for colorectal cancer [6]. There were 851 incident cases with an average 11.3 years of follow-up. Compared with 7 h of sleep, the hazard ratios were 1.36 (95% CI 1.06–1.74) and 1.47 (95% CI 1.10–1.96) for short (5 h or less) and long (9 h or more) sleep duration. The Nurses' Health Study experience was summarized as 'no convincing evidence for an association between sleep duration and the incidence of breast cancer' [7]. In few other studies, results were mixed, either a small reduced risk or a small increased risk for women who deviated from the optimal sleep duration.

Cognition: Both the Nurses' Health and WHI studies demonstrated an adverse impact of shorter or longer sleep durations on cognitive function [8]. Also, women whose sleep duration changed by 2 h or more per day over time had worse cognition than women with no change in sleep duration.

To note, despite statistically significant associations between sleep duration and many health aspects, the excessive risks are relatively small or modest, when converted into absolute numbers. Still, sleep is needed for maintaining our normal physiology, and keeping the recommended schedule of a 7-h sleep duration per night will probably promote better health.

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Langer's insights on the WHI study: unbiased evaluation and behind the scene facts

27 March, 2017

I urge everyone carefully to read Robert Langer's article in the April issue of Climacteric [1]. Members can download the paper from the IMS website. Langer was one of the chief investigators of the WHI project, both clinician and epidemiologist, who was able to bring not only his unbiased view on the clinical data, but also some important anecdotes related to behind-the-scene administrative issues. Below are the main points that I found most significant, as quoted from the article.

1. 'The WHI set out to test whether (contemporary in 1993) HRT prevents CHD, fractures, and bowel cancer, in women well beyond menopause who are at greater risk of those diseases than the younger women represented in the prior studies. Enrollment was restricted within age groups so that no more than 10% of women would be 50–54 years old, and no more than 20% would be between 55 and 59 years old. Fully 70% of WHI women were to be 60–79 years old.'

2. 'The initial results paper was written by a small group from the coordinating center and program office and submitted to the journal without informing or consulting the clinical site principal investigators. . . . On June 27th, the entire investigator group consisting of the principal investigators for the 40 clinical sites, the coordinating center team, and the NIH program staff gathered for the semi-annual meeting in Chicago. After minor preliminaries, the investigator group was stunned by the announcement that the Data Safety and Monitoring Committee (DSMB) had recommended stopping the CEE + ‏MPA trial and that the Director had accepted their recommendation. Minutes later the group was shocked by the distribution of a typeset copy of the primary results paper soon to be published in JAMA. This was the first time that the vast majority of principal investigators had seen the paper. . . . Concerns were raised about the propriety of producing a paper on behalf of the entire study group in this manner. More importantly, concerns were raised about the tone, the analyses conducted and reported, and the interpretation of the results in the paper. After some discussion, it was agreed that the concerned investigators could quickly provide edits addressing the tone and interpretation. . . . Edits were produced in the brief time remaining before lunch and taken to JAMA. The courier returned shortly with the message that the journal issue had already been printed.'

3. 'The NIH press release announcing the stopping of the study began with the headline "NHLBI Stops Trial of Estrogen Plus Progestin Due to Increased Breast Cancer Risk, Lack of Overall Benefit". The draft press release was distributed to the investigator group after lunch on June 27th, following on the news that the journal was already printed and the paper could not be edited. There was heated discussion about the wording of the press release. But, in the end, the wording favored by the program office prevailed. That headline, pandering to women's greatest fear – the fear of breast cancer – ensured that word of the study would spread like wildfire. And it ensured that the conversation would be driven much more by emotion and politics than by science.'

4. 'Contrary to the usual procedure in clinical trials . . . , no covariate adjusted analyses were reported. . . . The only significant findings in the 'adjusted' results were for a reduction in total fracture and an increase in VTE. The nominal results were significant for benefits in colorectal cancer, hip fracture and total fracture, and significant for adverse outcomes in CHD, stroke and VTE. Even the nominal results were not statistically significant for breast cancer; although the hazard ratio (HR) was 1.26, the 95% confidence interval (CI) (1.0–1.59) included 1.0. The 'adjusted' 95% confidence interval for breast cancer was 0.83–1.92. Nonetheless, incredibly, the paper included the statistically unsupported statement 'The WHI is the first randomized controlled trial to confirm that combined estrogen plus progestin does increase the risk of incident breast cancer and to quantify the degree of risk'.'

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Cognitive aging in midlife women: is it real?

20 March, 2017

Cognitive aging has become an important issue because of increased life expectancy in women. Cognitive complaints are common during midlife, as part of the climacteric syndrome. By using data from a longitudinal observational study in 2124 participants from the Study of Women's Health Across the Nation, Karlamangla and colleagues [1] attempted to demonstrate that cognitive aging is present in midlife women, irrespective of menopausal transition and its associated symptoms. Moreover, their study design tried to avoid the so-called practice effects deriving from the ability to learn from repeat testing in younger women. Average age at baseline (third cognition testing visit) was 54 years and the majority of the women were postmenopausal, with half the cohort being 2 or more years beyond the final menstrual period. There were 7185 cognition assessments (processing speed, verbal episodic memory [immediate and delayed], and working memory) with median follow-up time of 6.5 years. By adjusting for practice effects, retention, menopause symptoms (depressive, anxiety, vasomotor, and sleep disturbance), and covariates, they found a mean decline in cognitive speed of 0.28 per year (95% confidence interval, CI 0.20–0.36) or of 4.9% in 10 years, and a mean decline in verbal episodic memory (delayed testing) of 0.02 per year (95% CI 0.00–0.03) or of 2% in 10 years.

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New information technologies in medical practice

13 March, 2017

New information technologies have entered medical practice. The role of the internet has frequently been investigated regarding advantages and disadvantages. In August, Medscape surveyed 1423 health-care providers, including 847 physicians, and 1103 patients to assess their attitudes toward new emerging technologies in medicine [1]. Here are the most important results of this survey. Further reading can be found in references [2-8].

Smartphones

Smartphone apps to monitor blood glucose levels or cardiac irregularities have already arrived and are in use by many patients. When patients and physicians were asked whether they support taking this technology one step further – using technologies to self-diagnose non-life-threatening medical conditions, twice as many patients as physicians said they did. But half of the respondents agreed that all final diagnoses should be made by a qualified health professional.

Access to physicians' notes

Physicians and patients disagree widely on how much access patients should have to physicians' notes. Twice as many patients as physicians felt they should have access to lab results as soon as they are available, regardless of whether they might cause patients to worry or panic. Physicians wanted to have more control over how and when lab results were released. More than seven of ten physicians felt that they should review all lab results before providing patients with access to the results. Patients with cancer, in particular, exemplify the risks of immediate access to lab results. Patients may be able to see results of such tests as tumor markers – a potentially high-anxiety experience – before their physician has been able to put the results in context.

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Risk of recurrent venous thromboembolism in hormone therapy users

20 February, 2017

One of the main issues discussed in relation to postmenopausal hormone therapy (HT) is the risk for venous thromboembolic (VTE) events. In fact, this safety aspect of HT use is probably the only significant one in healthy women younger than 60 or during the first decade of use. A history of VTE usually deters physicians from prescribing HT as these women have anyway a higher risk for recurrent VTE in the future. Is this true also for women who were already using HT when the index VTE occurred?

Kiconco and colleagues investigated the outcomes in women whose initial VTE event was hormone-related and compared them to women whose initial event had no obvious cause [1]. Their cohort utilized the Clinical Practice Research Datalink linked to Hospital Episode Statistics data from England. The investigators selected 4170 women aged between 15 and 64 years who were diagnosed with a first VTE event between 1997 and 2011, and treated for a while with anticoagulants, which were then discontinued. The median follow-up time after stopping anticoagulation was around 2 years. Recurrent VTE events were higher in non-users than in users of hormones (15.3% vs. 9.5%; 51 cases per 1000 vs. 37 cases per 1000). Further to the significant difference in the absolute number of events in each subgroup, hormone users had 29% lower recurrence risk than non-users (adjusted HR = 0.71; 95% CI 0.58–0.88), a relationship which existed both in women aged 15–44 years (predominantly oral contraceptive users) and those aged 45–64 years (predominantly HT users). The conclusion was that having a hormone-associated VTE was associated with a lower recurrence risk than that related to unprovoked VTE after cessation of both the hormone-containing preparation and the subsequent anticoagulation. Furthermore, if this is the case, then prolonged anticoagulation may be unjustified in such women.

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Misclassification rates in breast histopathology biopsies: how can they be lowered?

13 February, 2017

Because misclassification of breast biopsies is relatively common, and no prior study had analyzed strategies for reducing error, the recent Elmore study is timely [1]. Here, 12 different strategies for acquiring second opinions were compared in order to help define which strategies worked best to reduce misclassification errors. The authors systematically tested whether and which pathology classification affected the best strategic choice for: invasive breast cancer, ductal carcinoma in situ (DCIS), atypia, proliferative without atypia, or benign without atypia. Also analyzed was the influence of the perceived case difficulty, the pathologists’ clinical volumes, and local institutional policy.

The test sample consisted of a set of 240 histopathology slides (one per case) that had previously undergone expert consensus to form a reference diagnosis. A total of 115 pathologists were assigned to one of four groups of 60 slides distributed according to the range of outcomes usually found. Each pathologist independently interpreted all 60 slides from one of the four sets of 60 breast biopsy specimens. The key findings were: (1) Over-interpretation of benign cases without atypia was cut in half (12.9% to 6.0%) by second opinions when initial diagnosis of atypia, DCIS and invasive cancer always included a second opinion; (2) atypia cases had the highest misclassification rate after a single interpretation (52.2%) which remained at more than 34% in every second opinion strategy tested; (3) excluding invasive breast cancer slides, the misclassification rates decreased (p < 0.001) from 24.7% to 18% when all of these received a second opinion; (4) high-volume pathologists (> nine cases per week) consistently delivered fewer misclassifications; (5) accuracy of diagnosis improved by the second opinion regardless of the pathologists’ confidence in their experience or diagnosis.

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Asthma, menopause and HRT

30 January, 2017

Asthma is basically an inflammatory disease, sometimes associated with allergy. Several publications have addressed recently the potential association between menopause and asthma. The latest study examined the possibility that there is a link between menopause and new-onset asthma [1]: the Respiratory Health in Northern Europe study provided questionnaire data pertaining to respiratory and reproductive health at baseline (1999–2001) and follow-up (2010–2012). The study cohort included women aged 45–65 years at follow-up, without asthma at baseline, and not using exogenous hormones (n = 2322). Menopausal status was defined as non-menopausal, transitional, early postmenopausal, and late postmenopausal. Associations with asthma (defined by the use of asthma medication, having asthma attacks, or both) and respiratory symptoms scores were analyzed by using logistic (asthma) and negative binomial (respiratory symptoms) regressions, adjusting for age, body mass index, physical activity, smoking, education, and study center. The odds (OR) of new-onset asthma were increased in women who were transitional (OR 2.4; 95% CI 1.09–5.30), early postmenopausal (OR 2.1; 95% CI 1.06–4.20), and late postmenopausal (OR 3.4; 95% CI 1.31–9.05) at follow-up compared with non-menopausal women. The risk of respiratory symptoms increased in early postmenopausal and late postmenopausal women as well.

Comment

Epidemiological data show that asthma prevalence, severity, exacerbation rate, hospitalizations and mortality are higher among women than men overall [2]. The transition from childhood to adulthood is characterized by a higher odds ratio of persistence of wheezing and asthma worsening in females. A growing body of clinical and experimental evidence indicates that female sex hormones, particularly estrogen, have significant effects on normal airway function. These effects are very complex and are exerted at several levels, directly on airway reactivity or indirectly through regulation of the immune and inflammatory responses in the lung. Asthma presents as a heterogeneous disease: in typical Th2-type allergic asthma, interleukin (IL)-4 and IL-13 predominate, driving IgE production and recruitment of eosinophils into the lungs. Chronic Th2-inflammation in the lung results in structural changes and activation of multiple immune cell types, leading to a deterioration of lung function over time. Most immune cells express estrogen receptors (ER alpha and beta, or the membrane-bound G-protein-coupled ER) to varying degrees and can respond to the hormone. Together these receptors have demonstrated the capacity to regulate a spectrum of immune functions. Kesselman and Heller reviewed the current understanding of estrogen signaling in allergic inflammation and discussed how this signaling may contribute to sex differences in asthma and allergy [3].

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Menopause and work

23 Janaury 2017

Menopause is a normal life event for women and so it is not an illness or a medical condition. This often means that the symptoms of the menopause are too often under recognized, undervalued and not taken seriously. The psychological symptoms associated with the menopause such as loss of self-confidence, low self-esteem, anxiety and depressive symptoms are the ones that often affect women the most.

On average, women spend nearly one-third of their life being postmenopausal. The retirement age is increasing and elderly people are far more active, both physically and mentally, than they were in the past. Symptoms of the menopause last far longer than most women anticipate; the average length of time is 4 years and many women still have some symptoms for longer than 10 years.

Around 3.5 million women aged between 15 and 65 years are currently in employment in the UK. The employment rate for women in the UK has actually increased in the past few decades and women now represent nearly a half of the UK labor force. This means that many more women are being affected by symptoms of their menopause, often to the detriment of their families, work and life in general. Clearly, the symptoms vary between women with around 25% of women suffering severe symptoms. Not only can this have a significant impact on the individuals, but also on their work colleagues.

As many women still do not recognize that it is the menopause (or perimenopause) causing their symptoms, they will not talk about it and, more importantly, they will not ask for help. In addition, if their colleagues do not know enough about the menopause, then it potentially makes it very hard for women to talk about symptoms they are experiencing at work.

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Cosmetics and women's health

16 January, 2017

Cosmetics. Everyone uses them, women and men alike. Cosmetics include many different materials with various roles that determine the activity, texture, color and smell of the final product. People are not aware of the fact that, unlike medications, cosmetics are not tested as rigorously by the regulatory authorities and the included chemicals may be harmful. The external placement and targets for use should not distract us from investigating potential systemic ill-effects. For example, ingredients in cosmetics may have an effect on a variety of hormonal pathways. A recent review, which analyzed possible associations with age at menopause, concluded that there is lack of data on the relevant risk outcomes of cosmetic use [1].

Comment

A review of the ingredients in the best-selling and top-rated products of the top beauty brands in the world, as well as a review of highlighted chemicals by non-profit environmental organizations, revealed 11 chemicals and chemical families of concern: butylated hydroxyanisole/butylated hydroxytoluene, coal tar dyes, diethanolamine, formaldehyde-releasing preservatives, parabens, phthalates, 1,4-dioxane, polycyclic aromatic hydrocarbons, siloxanes, talc/asbestos, and triclosan [1]. A previous review pointed at the same problematic chemicals and expressed concerns that, despite laboratory and animal incriminating findings, studies in humans have rarely been done and therefore there is no clear proof for harm [2]. Of interest, parabens exhibit very weak estrogenic activity in vitro and in vivo, but evidence of paraben-induced developmental and reproductive toxicity in vivo lacks consistency and physiological coherence. Evidence attempting to link paraben exposure with human breast cancer is non-existent. Still, a study from Japan demonstrated a negative association between estrogen-equivalent total paraben (odds ratio 0.73, 95% confidence interval 0.56–0.96) and butyl paraben concentrations (odds ratio 0.83, 95% confidence interval 0.70–0.99) and menstrual cycle length [3]. Phthalates (plasticizers) are industrial contaminants which are endocrine disruptors and may affect reproductive health and pregnancy [4]. Phthalates are almost ubiquitous in personal care products such as perfumes, cosmetics, moisturizer, nail polish, liquid soaps, and hair spray. These chemicals are sometimes added intentionally as a solvent and a fixative. In fact, examination of 47 branded perfumes showed untoward exposure to phthalates through the skin in almost all of them [5]. Another aspect related to cosmetics is environmental contamination. A survey identified ten potential harmful chemicals: polydimethylsiloxane, butylated hydroxylanisole (BHA), butylated hydroxytoluene, triclosan, nano titanium dioxide, nano zinc oxide, butylparaben, diethyl phthalate, octinoxate methoxycinnamate and benzophenone [6]. Skin care products had the highest quantities of chemicals of concern, with titanium dioxide and zinc oxide nanomaterials being dominant potential contaminants.

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