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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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Cognitive behavior therapy and hot flushes

9 December 2013

Mind and body go together, and psychosomatic interactions are very common, although not fully understood. Traditional medicine is perhaps a very good example for the healing potential of alternative therapies. Hot flushes, although believed to be derived from menopause-associated hormonal changes, may be influenced by a variety of emotional and psychological factors. Two recent studies have highlighted the role of cognitive behavior interventions on hot flushes [1, 2]. In the first study [1], a secondary analysis was performed of 140 women with problematic hot flushes/night sweats (HF/NS) who were recruited to the MENOS2 trial. Women suffered at least ten episodes per week for at least a month. Forty-eight women were randomly assigned to group cognitive behavior therapy (CBT), 47 were randomly assigned to self-help CBT, and 45 were randomly assigned to usual care. Self-report questionnaires were completed at baseline, 6 weeks post-randomization, and 26 weeks post-randomization. CBT was effective at reducing HF/NS problem-rating regardless of age, body mass index, menopause status, or psychological factors at baseline.

Fully reading the manual in the self-help CBT arm and completing most homework assignments in the group CBT arm were related to greater improvement in problem-rating at 6 weeks. The effect of CBT on HF/NS problem-rating was mediated by changes in cognitions (beliefs about coping/control of hot flushes, beliefs about night sweats and sleep) but not by changes in mood. The findings suggested that CBT works mainly by changing the cognitive appraisal of HF/NS. In the second study [2], CBT was provided through self-help CBT intervention (booklet and relaxation/paced breathing CD) during a 4-week period. Women (n = 47) also received one 'guiding' telephone call from a clinical psychologist 2 weeks into treatment to provide support and discuss individual treatment goals. Questionnaires were collected at baseline, 6 weeks (post-treatment) and 3 months (follow-up) after the end of the intervention. There was a significant reduction in HF/NS problem-rating following the intervention which was maintained at follow-up. Moreover, women reported less frequent HF/NS along with further improvements in sleep quality, mood and HF/NS beliefs and behaviors. Thus, self-help CBT for HF/NS proved effective in women unable to attend face-to-face sessions, or living at a distance, while using an additional, minimal telephone guidance.

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The value of repeat BMD testing in elderly people

25 November, 2013

Screening for osteoporosis with bone mineral density (BMD) is recommended for older adults; however, it is unclear whether repeating a BMD screening test improves fracture risk assessment. The aim of the study presented below was to determine whether changes in BMD after 4 years provide additional information on fracture risk beyond baseline BMD and to quantify the change in fracture risk classification by the FRAX model after a second BMD measure [1].

The cohort included 310 men and 492 women from the Framingham Osteoporosis Study with two measures of femoral neck BMD taken from 1987 through 1999. Participants were followed through 2009 or 12 years following the second BMD measure. Patients with a history of hip fracture were excluded. The mean age was 74.8 years. Less than one-quarter had normal basal BMD (T-score up to 1), a little more than one-half had osteopenia (T-score between 1 and 2.5), and almost one-quarter were osteoporotic. The mean (standard deviation, SD) BMD change was −0.6% per year (1.8%). Throughout a median follow-up of 9.6 years, 76 participants experienced an incident hip fracture and 113 participants experienced a major osteoporotic fracture. Annual percent BMD change per SD decrease was associated with risk of hip fracture (hazard ratio (HR) 1.43; 95% CI 1.16–1.78) and major osteoporotic fracture (HR 1.21; 95% CI 1.01–1.45) after adjusting for baseline BMD. At 10 years' follow-up, 1 SD decrease in annual percent BMD change compared with the mean BMD change was associated with 3.9 excess hip fractures per 100 persons. Using the net reclassification index, a second BMD measure increased the proportion of participants reclassified as at high risk of hip fracture by 3.9% (95% CI −2.2% to 9.9%), whereas it decreased the proportion classified as at low risk by −2.2% (95% CI −4.5% to 0.1%).

The conclusion was that, in untreated men and women of mean age 75 years, a second BMD measure after 4 years did not meaningfully improve the prediction of hip or major osteoporotic fracture. Repeating a BMD measure within 4 years to improve fracture risk stratification may not be necessary in adults of this age untreated for osteoporosis.

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Breast cancer risk and pretreatment estrogen levels

18 November, 2013

The WHI database will probably provide an infinite number of publications. This time the focus of the analysis was to explore whether pretreatment levels of sex hormones modify the effect of estrogen + progestin (E+P) on breast cancer [1]. This was a nested case–control study within the WHI randomized clinical trial of E+P. The trial enrolled 16,608 postmenopausal women aged 50–79 years with an intact uterus and no breast cancer history. During a mean of 5.6 years of follow-up, 348 incident breast cancer case subjects were identified and matched with 348 control subjects. Case and control subjects had their sex hormone levels measured at baseline (estrogens, testosterone, progesterone and sex hormone binding globulin (SHBG)) and at year 1 (estrogens and SHBG) using sensitive assays. Statistically significant elevations in breast cancer risk were seen with greater pretreatment levels of total estradiol (p trend = 0.04), bioavailable estradiol (p trend = 0.03), estrone (p trend = 0.007), and estrone sulfate (p trend = 0.007). E+P increased all measured estrogens and SHGB at year 1 (all p < 0.001). The effect of E+P on breast cancer risk was strongest in women whose pretreatment levels of total estradiol, bioavailable estradiol and estrone were in the lowest quartiles. For example, the odds ratio for E+P relative to placebo was 2.47 (95% confidence interval (CI) 1.28–4.79) in the lowest total estradiol quartile, compared with 0.96 (95% CI 0.44–2.09) in the highest total estradiol quartile; p interaction = 0.04). The main conclusion was that women with lower pretreatment endogenous estrogen levels were at greater risk for breast cancer during E+P therapy compared with those with higher levels.

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HRT, body mass index and breast cancer risk

28 October, 2013

"In conclusion, there are now several studies showing no increase in the risk of breast cancer in obese women. This study is also consistent with a previous large one and both show that HRT does not increase breast cancer risk in women with low breast density."
Anne Gompel

Hou and colleagues have addressed the question of different levels of risk of breast cancer under hormone replacement therapy (HRT) according to race, body mass index (BMI) and breast density [1]. Using 1,642,824 screening mammograms, they analyzed 9300 breast cancer cases in postmenopausal women ≥ 45 years from the Breast Cancer Surveillance Consortium (BCSC), a longitudinal registry of mammography screening in the United States.

The aim was to investigate whether low- and high-risk groups could be identified. The BCSC was established in 1994 and collected participant characteristics (age group, mammographic breast density, race/ethnicity, BMI, HRT use, and diagnosis of cancer) at the time of each mammography screening examination. Breast density data were collected from the technician and radiologist at the time of mammography. Among the postmenopausal women, 44.4% reported being HRT users, 41.6% reported being HRT non-users, and the status of 14.0% was unknown.

Data on the duration of HRT use were not available and many data for risk factors were missing. Thus imputation (the process of replacing missing data with substituted values) was used to calculate the risks. The associations between HRT use and breast cancer risk were mostly positive in women aged 50 years and older, yet there was no statistically significant association for younger women aged 45–49 years.

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The breakfast dilemma

21 October, 2013

Keep your weight – don't miss breakfast

Here is the perception: skipping breakfast increases hunger throughout the day, making people overeat and seek out snacks to compensate for missing that first – and some would say most important – meal of the day. This belief is based on many studies and was not challenged until recently, when Brown and colleagues published their findings [1].

Basically, what the authors were pointing out was that sometimes science-related beliefs are presumed true even though insufficient evidence exists to support or refute them. They searched various sources of information in regard to the effect of eating breakfast on obesity, and focused on one meta-analysis and three systematic reviews, which included data from 92 relevant articles. They noted that there were only a few relevant randomized controlled trials, which gave a variety of results and were inconsistent in their conclusions.

As for the observational evidence, there was a clear association between breakfast omission and excess weight on the one hand, but this association did not show causation on the other hand. Several methodological flaws were detected in the database as well, such as biased interpretation of one’s own results, improper use of causal language in describing the results, or misleadingly citing others’ results.

To summarize, Brown and colleagues suggested that careful analysis of the data dictates caution, since the belief in the association between eating breakfast and better management of obesity exceeds the strength of scientific evidence.

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Oncology in midlife and beyond

To mark World Menopause Day on 18th October, the International Menopause Society has published a major review of cancer during and after the menopause, and asks women and their doctors to take appropriate precautions to minimise cancer risk.

Full Paper

Gompel A, Baber RJ, de Villiers TJ, Huang KE, Santen RJ, Shah D, Villaseca P, Shapiro S. Oncology in midlife and beyond. Climacteric. 2013 Oct;16(5):522-35. doi: 10.3109/13697137.2013.823539. Epub 2013 Aug 9.

pdfOncology in midlife and beyond - (personal use only)298.78 KB

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Menopausal hormone therapy and prevention of chronic diseases:

IMS members react to the recent JAMA paper

15 October, 2013

Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. A total of 27,347 postmenopausal women aged 50–79 years were enrolled at 40 US centers to the Women's Health Initiative trial [1]. Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/day) plus medroxyprogesterone acetate (MPA; 2.5 mg/day) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/day) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE + MPA trial and 7.2 years in the CEE-alone trial with 13 years of cumulative follow-up until September 30, 2010. During the CEE + MPA intervention phase, the numbers of coronary heart disease (CHD) cases were 196 for CEE + MPA vs. 159 for placebo (hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.95–1.45) and 206 vs. 155, respectively, for invasive breast cancer (HR 1.24; 95% CI 1.01–1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥ 65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated post-intervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE + MPA vs. 323 for placebo; HR 1.28; 95% CI 1.11–1.48). The risks and benefits were more balanced during the CEE-alone intervention with 204 CHD cases for CEE-alone vs. 222 cases for placebo (HR 0.94; 95% CI 0.78–1.14) and 104 vs. 135, respectively, for invasive breast cancer (HR 0.79; 95% CI 0.61–1.02); cumulatively, there were 168 vs. 216, respectively, cases of breast cancer diagnosed (HR 0.79; 95% CI 0.65–0.97). Results for other outcomes were similar to CEE + MPA. Neither regimen affected all-cause mortality. For CEE-alone, younger women (aged 50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index. Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE + MPA ranged from 12 excess cases for ages of 50–59 years to 38 for ages of 70–79 years; for women taking CEE-alone, from 19 fewer cases for ages of 50–59 years to 51 excess cases for ages of 70–79 years. Quality-of-life outcomes had mixed results in both trials. In conclusion, findings from the intervention and extended post-intervention follow-up of the two WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.


Comment I

There are several key points to the newest WHI manuscript [1], the largest compendium of WHI data published in one place to date. Importantly, the WHI investigators issue the following warning on page 1354 under 'Statistical Analysis': 'The p values do not adjust for multiple outcomes, sequential monitoring, or multiple subgroup comparisons due to the large number of tests conducted; therefore, the p values should be interpreted cautiously.' As Figures 2 and 4 show, even in the absence of the foregoing appropriate adjustments, almost no adverse outcomes are statistically significant, and, as the original publications from the WHI have shown for breast cancer, stroke and all of the other adverse outcomes, that, when adjusted for multiple outcomes and sequential monitoring according to the a-prioridefined statistic, all of these outcomes are not statistically significantly different between hormone therapy (HT) and placebo in both the CEE + MPA and CEE trials [2, 3]. The one exception is the venous thromboembolic event outcome in the CEE + MPA trial. In other words, all of the adverse outcomes from the WHI HT trials are not statistically significantly different between HT and placebo (except for the one exception noted previously) when analyzed across all women randomized to these trials (average age 64 years and average time from menopause > 10 years). Further, this newest WHI publication again validates that not only are all of the adverse outcomes non-significant, but they are similar to the types and magnitude of adverse events reported with other commonly used medications, that is, rare (< 1/1000 additional events per year of therapy) [2, 3].

The second important fact to realize from this newest WHI publication is that Figures 5 and 6 show that all outcomes are reduced with CEE relative to placebo in women who are 50–59 years old when randomized. Pulmonary embolism and hip fracture, which show three additional events per 10,000 women per year of therapy, are the only exceptions to the consistent reduction in outcomes. As such, the data in these figures do not support the conclusion of the manuscript that HT should not be used for chronic disease prevention. Some may argue that these are subgroup analyses and therefore should be ignored. However, if this is the case, then no statement concerning chronic disease prevention can be made based on the WHI data except for women over all ages, the majority of whom are well beyond the age in which HT is initiated. Women require HT and HT is initiated predominantly in women < 60 years of age, typically in the perimenopause or early menopause, when the data support clear benefit relative to risk, as shown in a recent 10-year randomized trial of such women [4]. In other words, the WHI has no relevance to clinical practice as presented across the entire cohort of women; its importance is in showing a reduction of coronary heart disease, breast cancer, stroke and, most importantly, total mortality by 30% with CEE as well as CEE + MPA therapy in women who were initiated on such therapy when < 60 years of age. Based on the WHI data, it has recently been estimated that 50,000–90,000 women over the last decade have needlessly died by avoiding the use of HT [5]. This estimate appears to be consistent with the inexplicable worsening mortality rate of women in the United States relative to men from 1992 to 1996 (pre-WHI) relative to 2002–2006 (post-WHI) [6].

It must be emphasized that WHI data cannot inform about chronic disease prevention since benefits and risks of HT when initiated in a 70–80-year-old women cannot be assumed to equate to the benefits and risks of women 20–30 years after initiating HT at 50–60 years of age. The contrary, however, is that which follows known preventive therapy logic in which risk is reduced initially and is followed by reduction in adverse events, such as bone fracture prevention. There is absolutely no evidence to indicate that HT operates differently from this well-known paradigm of chronic disease prevention. The fact that '…the risk reductions dissipated post-intervention', as stated on page 1366 of the newest WHI manuscript, clearly indicates that chronic disease prevention will only be appreciated with continuous HT, as seen with the prevention of bone fractures.

Howard N. Hodis
Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, USA

Comment II

The recent updated report of the WHI study (follow-up of 13 years) did not add anything of importance to help practitioners who care for postmenopausal women [1]. It must be emphasized again that the methodology followed by the WHI study does not in any way reflect what is meant by good clinical practice. This is their capital error. Let it not be forgotten that all enrolled patients were treated with the same medication and dosage irrespective of their age and tolerance. Furthermore, the estrogen (CEE) and the progestogen (MPA) used were not the best choices since they may cause important side-effects that are rare with 17β-estradiol and natural progesterone, as mostly used in Europe. Past observational studies and the recent KEEPS study, much closer to good clinical practice, did not support most of the conclusions of the WHI investigators. The only important observation is that the good candidates for hormone therapy are women younger than 60 years of age or within 10 years after the menopause. There is nowadays a general consensus that CEE + MPA should not be first-choice medications and that the more one mimics physiology the better, i.e. 17β-estradiol and progesterone itself, or dydrogesterone. The parenteral route for the administration of estradiol seems to be safer. WHI investigators, with their unbalanced conclusions, have already caused much damage to women who have been deprived of appropriate and needed hormone therapy and thus of the resulting preventive effects at the level of the cardiovascular system and bones.

Manuel Neves-e-Castro
Lisbon, Portugal


1. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative Randomized Trials. JAMA 2013;310:1353-68. 

2. Hodis HN, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. 1. Comparison of therapeutic efficacy. J Am Geriatr Soc 2013;61:1005-10.

3. Hodis HN, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. 2. Comparative risks. J Am Geriatr Soc 2013;61:1011-18.

4. SchierbeckLL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012;345:e6409.

5. Sarrel PM, Njike VY, Vinante V, et al. The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50–59 years. Am J Public Health 2013;103:1583-8

6. Kindig DA, Cheng ER. Even as mortality fell in most US counties, female mortality nonetheless rose in 42.8% of counties from 1992 to 2006. Health Affairs 2013;32:451-8.

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Antihypertensives and breast cancer risk

23 September, 2013

Another potential 'bomb' exploded recently, with the online publication of a study which showed that common therapies for controlling blood pressure may have an effect on the risk for breast cancer [1]. The study, which was observational and retrospective, was based on interviews with breast cancer patients and comparable healthy controls in Seattle, USA. Women were asked whether they used antihypertensive medications and, if they did, what type, when, and for how long. The cohort included 880 women with invasive ductal breast cancer, 1027 women with invasive lobular breast cancer, and 856 women with no cancer who served as controls. Results showed that those currently taking calcium-channel blockers for more than 10 years had about 2.5 times the risk for breast cancer (both ductal and lobular) compared to healthy women, whereas the use of angiotensin II antagonists was associated with a non-significant decrease in risk, and diuretics or beta-blockers were neutral in this respect. Shorter periods of use were not associated with a change in breast cancer risk.

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Controlling caloric intake and energy expenditure

May not be enough to keep weight stable

16 September, 2013

Whenever one talks about the need to keep optimal weight in order to reduce cardiovascular risk and other health hazards, one will always quote the mantra – eat healthy and stay fit, which means keeping the desired balance between caloric intake and energy expenditure. The standard equation says that 7000 kcal equal 1 kg of fat, so, if the energy balance over a period of time points is (-)7000 kcal, this negative figure should also be expressed while standing on the scale, which should show 1 kg reduction in weight. All guidelines and recommendations are based on this formulation, and the scenario of failure to maintain or reduce weight despite keeping the instructions is attributed solely to poor adherence to the intervention program. Now it seems that there may be other explanations. A study published recently in Science examined mice that were put in a system that could accurately measure both their caloric intake and energy expenditure [1]. Two groups were compared: normal mice and those with deletion of melanocortin 2 receptor accessory protein 2 (MRAP2), which are known to develop severe obesity at a young age. Even when fed the same amount of chow, null mice gained more weight than did wild-type mice. Only when the amount of food intake in null mice was further restricted to 10% (females) and 13% (males) less than that of wild-type mice was there equivalent weight gain. This was the case while mice were young but, at later stages of their life, the null mice demonstrated overt hyperphagia and associated weight gain.

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Changes in bone resorption during the menopause transition

26 August 2013

Sowers and colleagues have investigated potential associations between changes in bone resorption during the menopause transition and reproductive hormones, body mass index (BMI) and ethnicity [1]. Urinary type I collagen N-telopeptide (NTX), estradiol, and follicle stimulating hormone (FSH) levels were measured annually for up to 8 years spanning the menopause transition in 918 African-American, Chinese, Japanese, or Caucasian women. Urinary NTX began to increase sharply about 2 years before the final menstrual period (FMP), reaching its peak level about 1–1.5 years after the FMP. NTX levels declined modestly from 2–6 years after the FMP but remained about 20% higher than before the menopause transition. The sharp rise in FSH occurred in conjunction with a sharp decline in estradiol and shortly after FSH levels began to increase rapidly. The mean increase in urinary NTX across the menopause transition was greatest in women with BMI < 25 kg/m2 and smallest in women with BMI > 30 kg/m2. Increases in NTX were greatest in Japanese women and smallest in African-Americans. These differences were attenuated, but not eliminated, when analyses were adjusted for covariates, particularly BMI. During the menopause transition, a decline in ovarian function beginning about 2 years before the FMP is followed by an increase in bone resorption and subsequently by bone loss. The magnitude of the increase in bone resorption is inversely associated with BMI. Ethnic differences in changes in bone resorption are attenuated, but not eliminated, by adjustment for BMI. Ethnic differences in BMI, and corresponding ethnic differences in bone resorption, appear to account for much of the ethnic variation in perimenopausal bone loss.

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