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

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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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Role of breastfeeding in postmenopausal osteoporosis

09 January, 2017

Osteoporosis is a huge public health problem for menopausal women all over the world, both in developing and in developed countries. Roughly one in three menopausal women suffers from osteoporosis and one in two from osteopenia. Prevention is the main stay for osteoporosis. It is very important to study all aspects of a woman’s life that can lead to later development of postmenopausal osteoporosis.

Osteoporosis has been studied extensively in relationship to ethnicity, geographical variations and estrogen depletion in menopause. However, the negative relationship of lactation duration and effect of pregnancies with postmenopausal osteoporosis is still inconclusive. The definite role of hormone replacement therapy in the prevention of osteoporosis is now a resolved issue. In a study by Hwang and colleagues [1], a cross-sectional survey based on the Korea National Health and Nutrition Examination Survey (KNHANES) 2010 and 2011 data (n = 1222 postmenopausal women), showed that a duration of breastfeeding longer than 37 months was associated with higher prevalence of osteoporosis in postmenopause and more fractures of the lumbar spine. A duration of lactation longer than 37 months was associated with low bone mineral density (BMD) in the lumbar spine and hip; the number of spinal fractures was increased (37 or more months, odds ratio (OR) 3.292; 95% confidence interval (CI) 1.485–7.23). But, interestingly, the number of deliveries had no relationship with postmenopausal BMD. 

Comment

A woman’s life is a continuous cycle and various landmark changes have an effect on later development of postmenopausal problems; osteoporosis is one of these debilitating diseases, leading to poor quality of life and mortality.

Except for the above study by Huang [1], additional studies have looked into the role of lactation in women and later development of osteoporosis. Grimes and Wimalawansa believe that not only duration and frequency of lactation and return of normal menses, but also pre-pregnancy weight are related with postmenopausal osteoporosis [2]. The conclusion of the authors was that the importance of lactation and its effect on postmenopausal osteoporosis are very aptly considered as a public health problem needing new policy decisions, and so more work is required in this area.

Another interesting study was conducted in Jordan [3]. Multiple regression analysis at different bone sites revealed that there was a negative effect associated with the number of children (live births) and frequency of lactation but it was only evident at the femoral neck. In the final multivariable logistic regression model of variables that rendered significantly independent risk factors after adjustment for age and body mass index, it was found that ever-lactation, frequent lactation for four or more times, a lactation interval of 1–6 months, and clinical hyperthyroidism were significant protective factors. The authors concluded that, although osteoporosis is a large public health problem, in this study the number of pregnancies in their multiparous female population showed a negative impact on femoral neck BMD; no evidence of increased risk of osteoporosis among ever-pregnant women was noted.

Another analysis of data from the Korean KNHANES study [4] has reported that a significant increase (two- to three-fold) in the risk of osteoporosis is apparent in postmenopausal women with prolonged breast-feeding histories (24 or more months), particularly in those with inadequate serum vitamin D levels and calcium intake (>800 mg/day).

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Endocrine-disrupting chemicals – are they of concern and can we really reduce our exposure

15 December, 2016

There is increasing interest in chemicals called 'endocrine-disrupting chemicals'. These are chemicals, which may be natural or synthetic, that through exposure interfere with an organism's normal hormone balance. The actions of these chemicals are complex. Some have weak endocrine-like actions and others interfere with the pathways through which our hormones normally work, hence the term 'disrupters'. Endocrine disrupter chemicals include chemicals such as DDT and other pesticides, and plasticizers, such as bisphenol A (BPA) as well as phthalates and parabens.

The Endocrine Society guideline on this issue in 2009 [1] stated that 'The evidence for adverse reproductive outcomes (infertility, cancers, malformations) from exposure to endocrine-disrupting chemicals is strong, and there is mounting evidence for effects on other endocrine systems, including thyroid, neuroendocrine, obesity and metabolism, and insulin and glucose homeostasis.' The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals, 2015 [2] recognizes this to be an international problem and that more public awareness as to how to minimize personal exposure, plus more research in this area, is needed. Of considerable concern is that endocrine disrupters can cause epigenetic changes, such as DNA methylation which can be transmitted to offspring [2].

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HRT, dry eyes and other ocular manifestations

28 November, 2016

From time to time, we have to remind ourselves and the health-care providers that estrogen and the other sex steroids are actually involved in all the body organs, and that their physiological effects are not limited to fertility, treatment of menopausal symptoms, or cardiovascular and bone protection. Menopause Live has addressed in the past the effects of estrogen on other tissues and bodily functions, such as the skin, the voice or hearing. This time, I put the eye and sight into this context. A small, but double-blind, placebo-controlled study (n = 40, age 63.9 ± 5.1 years, 13.2 ± 6.3 years postmenopause) investigated the outcomes of estrogen, testosterone or their combination in hysterectomized women with dry eyes [1]. The results demonstrated estrogen-related worsening in dryness intensity after 8 weeks of estradiol gel 1 mg/g as compared to placebo; 1% testosterone cream showed a neutral effect, but a combination of the two hormones led to a significant increase in tear secretion.

Comment

Dry eye syndrome, also known as keratoconjunctivitis sicca, is a common condition which is the result of low production of tears or too quick evaporation. Symptoms include irritation, redness, discharge, easily fatigued eyes and blurred vision. This can result from meibomian gland dysfunction, allergies, autoimmune disorders, pregnancy, local surgery, smoking, conjunctival infections and other etiologies. Among relevant medications that may cause dry eyes are anti-depressants, which are frequently prescribed in midlife and beyond. Postmenopausal hormone replacement (HRT) has been mentioned in this framework as well. However, there seems to be some controversy in regard to the impact of HRT on dry eyes.

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Recent studies on natural alternatives to hormone therapy

21 November, 2016

Have you noticed the increased number of publications on natural remedies for menopause symptoms in good-quality journals? The reason for these studies, in my view, is not only the alleged problematic benefit–risk balance of hormone therapy (HT) or other approved medications, but the higher awareness of women to achieve better quality of life during midlife and beyond. This may be more prominent in developing countries where traditional medicine is popular, but is certainly valid in the Western world too. The willingness of Editors of journals with a medium to high impact factor to accept such papers, provided that these meet the quality standards of the aforementioned journals, gives a tail wind to this trend. Here are a few such examples.

A randomized controlled trial (RCT) in 82 postmenopausal women compared Pueraria mirifica gel to a conjugated estrogen cream [1]. Pueraria mirifica is a widely used, herbal female hormone supplement derived from a plant found in the wild in certain regions in Thailand. Use for 12 weeks showed that Pueraria mirifica was efficacious and safe for the treatment of vulvovaginal atrophy. Yet, conjugated estrogen cream was found to be more beneficial in improving signs of vaginal atrophy and restoring vaginal epithelium at 6 and 12 weeks.

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Smell identification, cognition and hormone therapy

14 November, 2016

Failure to identify odors may be an early sign of cognitive impairment. A recent study included persons aged 65 years or older without dementia (males and females, n = 1037) [1]. They were asked to identify 40 different odors, and their success rate was scored. Also, a brain MRI and a battery of cognitive tests were performed. Follow-up at 2 and 4 years in 757 participants showed that low baseline scores correlated with cognitive decline and the appearance of Alzheimer's disease. MRI hippocampal volume did not show predictive utility in this cohort. The investigators suggested that the inexpensive smell test could be useful as a predictor of future cognitive impairment.

Comment

The above study by Devanand and colleagues is one of several similar ones showing that low performance in smell testing correlated with a higher risk of cognitive impairment [1]. In a recent study among 1430 cognitively normal participants (mean age 79.5 ± 5.3 years, 49.4% men, mean 3.5 years of follow-up), there were 250 incident cases of minimal cognitive impairment (MCI). An association between decreasing olfactory identification, as measured by a decrease in the number of correct responses in Brief Smell Identification Test score, and an increased risk of MCI was established [2]. The same was demonstrated in patients with Parkinson's disease: worse baseline olfaction was associated with long-term cognitive decline [3]. Interestingly, even a simple test, using a container of 14 g of peanut butter, which was opened and moved up 1 cm at a time during the participant's exhale-until-odor detection, while measuring the distance between the subject's nostril and container, appeared to be a sensitive and specific test for probable Alzheimer's disease [4]. A nice overview on the influence of age on the olfactory system and pathways mentioned that the magnitude of olfactory deficits, which occur in neurodegenerative and neurodevelopmental diseases, appears to be associated with the relative damage to the basal cholinergic system [5]. Perhaps the link between cognition and olfactory function involves the apolipoprotein E É›4 allele (ApoE) that has been associated with increased cognitive and olfactory deficits [6].

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