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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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What if?

14 April, 2014

In a recent publication, under the section heading 'Personal Perspectives', Dr James Simon considers hypothetical comparisons between oral conjugated equine estrogens (CEE) and transdermal estradiol and between oral medroxyprogesterone acetate (MPA) and oral micronized progesterone for their effects on four primary outcomes of the Women's Health Initiative (WHI) [1]: cardiovascular disease risk, cerebrovascular disease risk, venous thromboembolism risk, and breast cancer risk. Although the discussion in this article focused on transdermal estradiol delivered through patches, gels, or lotions, it could be broadened to include all forms of non-oral estrogen administration. After a brief review of the WHI and a survey of the relevant literature in which the safety of these various hormone therapies was assessed or compared, the author used statistical methods to ascertain the attributable risk of venous thromboembolism for transdermal estradiol versus oral hormone therapy and imputed those risks into the WHI primary outcomes.

Comment

This is not a regular comment for Menopause Live, but rather an appraisal. Although medicine is not accurate as mathematics is, it cannot be based on a 'what if' situation, since the treating physician makes decisions after considering both the individual clinical facts and personal experience. Still, the 'what if' issue here is not purely fiction, but an attempt to extrapolate results from studies in women using transdermal estradiol and progesterone to the WHI arena, where CEE and MPA were the only study medications. The manuscript is built in a very logical way, first bringing the up-to-date information on all available aspects of the WHI study results, then discussing the four risk domains mentioned earlier in regard to current knowledge on the potential relevant adverse effects of non-oral estradiol and progesterone, and finally bringing the author's conclusions. The main message, which is not innovative, but well phrased and referenced, is that 'postmenopausal hormones' should not be regarded as a single entity, and therefore the WHI results should not be the sole basis for guidelines and recommendations.

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HRT, acute pancreatitis and cholecystectomy

10 March, 2014

The potential association of postmenopausal hormone use and the occurrence of acute pancreatitis was investigated in a prospective study involving 31,494 postmenopausal women (aged 48–8 years) from the population-based Swedish Mammography Cohort [1]. Participants completed a baseline questionnaire in 1997 assessing their use of hormone replacement therapy (HRT). The cohort was linked to the hospital-based Swedish National Patient Register to determine hospital admissions for acute pancreatitis through 2010. Over a total follow-up of 389,456 person-years, 237 cases of incident acute pancreatitis were identified. The age-standardized incidence rates per 100,000 person-years were 71 cases among women who had ever used HRT and 52 cases among women who had never used such hormones. Among ever-users of HRT, the multivariable-adjusted relative risk (RR) of acute pancreatitis was 1.57 (95% confidence interval (CI) 1.20–2.05) compared with never-users. The risk did not differ by current or past use, but it seemed to be higher among women who used systemic therapy (RR = 1.92, 95% CI 1.38–2.66) and among those with duration of therapy of more than 10 years (RR = 1.87, 95% CI 1.11–3.17).

Comment

So let's be realistic. Should this information change our perceptions on the risk of HRT? Does it have any innovative clinical significance? On the one hand, it is a large-scale study, with a long follow-up period. On the other hand, data on hormone use was self-reported and did not include important information on specific hormonal preparations, dose and route of administration of HRT [1]. By the end of the day, there were 19 additional events of acute pancreatitis among 100,000 person-years, or only about two additional cases among 10,000 women per year of use. This seems to be a tiny risk that may not be accounted for when benefit–risk balance of HRT is discussed. Furthermore, no data were presented for the exact definition and severity of acute pancreatitis, i.e. whether a mild course of abdominal pain with elevation of liver enzymes/amylase serum levels, or a serious disease necessitating surgical procedures, or even a fatal outcome, etc. Nevertheless, the authors concluded that 'Physicians should consider this potential increase in risk when prescribing such therapy.'

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Low dose aspirin for cardiovascular disease prevention

17 February, 2014

Once in a while the question whether or not low-dose aspirin should be recommended for primary prevention of cardiovascular disease is put on the table, analyzed and debated, but still there is no clear-cut recommendation. Patrono has recently provided another overview on this topic [1]. Low-dose aspirin has been shown to be effective in preventing about one-fifth of atherothrombotic vascular complications (non-fatal myocardial infarction, non-fatal stroke, or vascular death) in a meta-analysis of 16 secondary prevention trials in patients with previous myocardial infarction, stroke, or transient cerebral ischemia. This corresponds to an absolute reduction of about 10-20 per 1000 patients in the yearly incidence of non-fatal events, and to a smaller, but still definite, reduction in vascular death. Against this benefit, the absolute increase in major extracranial bleeding complications (mostly, gastrointestinal) is 20- to 50-fold smaller, depending on age and sex. Hence, for secondary prevention, the benefits of antiplatelet therapy substantially exceed the risks. For primary prevention, the balance between vascular events avoided and major bleeds caused by aspirin is substantially uncertain because the risks without aspirin, and hence the absolute benefits of antiplatelet prophylaxis, are at least an order of magnitude lower than in secondary prevention. For many people without pre-existing vascular disease, the cardiovascular benefits of adding long-term aspirin to other, safer, forms of primary prevention (e.g. statins and antihypertensive drugs) are likely to be of similar magnitude as the hazards [2].

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Long-term consequences of LNG-IUS vs hysterectomy for menorrhagia

10 February, 2014

Heliövaara-Peippo and colleagues have recently reported on a randomized controlled trial in five Finnish university hospitals to compare the effect of treatment with a levonorgestrel-releasing intrauterine system (LNG-IUS) and the effect of hysterectomy in women with menorrhagia (n = 221) [1]. The studied population that fulfilled the inclusion criteria, initially aged 35–49 years, was monitored for 10 years and the endpoints were health-related quality of life (HRQoL), psychosocial well-being, and cost-effectiveness.

Instruments to measure quality of life and psychosocial well-being were used periodically, including the five-dimensional EuroQoL, the 36-item RAND Health Survey, the Spielberger 20-Item State-Trait Anxiety Inventory, the Beck Depression Inventory and the McCoy Sex Scale. Direct and indirect costs, sick-leave days and out-of-pockets costs were calculated from the time of randomization up to the 10-year follow-up control. There have been several previous publications concerning this trial, including the 12-month and the 5-year follow-up results.

HRQoL and psychosocial well-being were improved during the initial 5 years but diminished between 5 and 10 years; the improved HRQOL returned close to the baseline level without any significant difference between the LNG-IUS-treated and hysterectomy-treated groups. The overall costs in the LNG-IUS group ($ 3423/patient) were lower than in the surgery group ($ 4937/patient), despite the fact that 55 women (46%) assigned to the LNG-IUS group subsequently underwent surgery: 24 (44%) during the first year, 26 (47%) between 12 months and 5 years and five (9%) between 5 and 10 years. The main reasons for hysterectomy were bleeding problems during the first 5 years and fibroids and bleeding problems in the five hysterectomies performed between 5 and 10 years.

At the 10-year follow-up, 44 women had a LNG-IUS in situ; of these 40 women (91%) reported amenorrhea or oligomenorrhea, two hypomenorrhea, one normal menstrual bleeding and one irregular bleeding. In 18 women, the LNG-IUS was removed but hysterectomy was not performed; of these 18 women, 12 women reported amenorrhea or oligomenorrhea, three normal menstrual bleeding, two irregular bleeding, and one woman submitted to thermoablation after reported hypomenorrhea.

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Exercise, breast size and cancer risk

20 January 2014

At first glance, the new study by Williams [1] seemed, well, just another study showing how important physical activity is. Indeed, exercise reduces morbidity and mortality in a large list of diseases including cardiovascular, respiratory and oncological diseases. Clicking the key words 'breast cancer' and 'exercise' in PubMed yields about 2000 hits. So what's the point in commenting on this study? I guess it is because I liked its different way of looking at the issue. But first things first, and here are the core methods and findings [1]. Cox proportional hazard analyses were made of baseline pre-diagnosis MET-hours/week vs. breast cancer mortality adjusted for follow-up age, race, baseline menopause, and estrogen and oral contraceptive use in 79,124 women (32,872 walkers, 46,252 runners) from the National Walkers' and Runners' Health Studies. Women were categorized into three groups according to their level of exercise: below (< 7.5 metabolic equivalent h/week, MET-h/week), at (7.5–12.5 MET-h/week), or above (≥ 12.5 MET-h/week) recommended levels. Despite the large number of participants, only 111 women (57 walkers, 54 runners) died from breast cancer during the 11-year follow-up. The decline in mortality in women who exercised ≥ 7.5 MET-h/week was not different for walking and running (p  =  0.34), so running and walking energy expenditures were combined. The risk for breast cancer mortality was 41.5% lower for ≥ 7.5 vs. < 7.5 MET-h/week (hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.38–0.92, p =  0.02), which persisted when adjusted for body mass index (BMI) (HR 0.58, 95% CI 0.37–0.96, p  =  0.03). Other than age and menopause, baseline bra cup size was the strongest predictor of breast cancer mortality, i.e. 57.9% risk increase per cup size when adjusted for MET-h/week and the other covariates (HR 1.58, 95% CI 1.27–1.97, p < 0.0001), and 70.4% greater when further adjusted for BMI (HR 1.70, 95% CI 1.34–2.2, p  =  0.0005). Breast cancer mortality was 4.0-fold greater for C-cup, and 4.7-fold greater for ≥ D-cup vs. A-cup when adjusted for BMI and other covariates. Adjustment for cup size and BMI did not eliminate the association between breast cancer mortality and ≥ 7.5 MET-h/week walked or run (HR 0.61, 95% CI 0.39–1.00, p  =  0.05). The final conclusions were that breast cancer mortality decreased in association with both meeting the exercise recommendations and smaller breast volume.

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Metformin treatment and evolution of endometrial cancer

13 January 2014

Ko and colleagues have recently reported that metformin may improve survival in women with endometrial cancer [1]. They retrospectively studied 1495 women who were diagnosed between 2005 and 2010 at two tertiary US academic institutions. Median follow-up was 33 months. Demographic, pathological, clinical and follow-up data were obtained from medical records. Body mass index (BMI) and data on use of metformin, insulin, sulfonamide and thiazolidinedione at the time of cancer diagnosis were obtained. Information on recurrence and death were recorded from clinical and/or electronic data and/or from the Social Security Death Index. Causes of death were not available for all patients. A total of 363 women (24%) had diabetes mellitus, of whom 55% used metformin (n = 200). Some metformin-treated women were also using other treatments, including 34% on sulfonylureas, 18% on thiazolidinediones, 15% on insulin, and 7% on other anti-diabetics. Metformin users were younger (median 62.2 vs. 64.8 years) and heavier (median (interquartiles] BMI = 38 [33–34] vs. 36 [31–42] kg/m2; p = 0.004) than non-metformin-users. Pathologic findings were similar by stage and grade in both groups, although histology was significantly different between groups (despite this, 75% in both groups were endometrioid endometrial carcinomas).

Recurrence-free survival (RFS; %) was decreased more while overall survival was increased more in metformin users than in non-metformin users: non-metformin users had a 1.7% worse RFS (adjusted value 1.8%) and were 2.0 (adjusted value 2.3) times more likely to die as compared with metformin users. Time to recurrence was not significantly different between the groups.

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Do women really take their osteoporosis therapy?

16 December, 2013

This was a retrospective observational cohort study using 2005–2009 data from a large, commercially insured population [1]. Inclusion criteria were women aged > 55 years initiating osteoporosis therapy, having a > 12-month (baseline) period with no claims for osteoporosis therapy preceding initiation, and > 24 months follow-up after therapy initiation. Discontinuation was defined as a gap of 60 days in prescription claims. Re-initiation was defined as a prescription claim for the same or different osteoporosis therapy following the therapy gap. Of the 92,839 patients, 45%, 58%, and 70% discontinued therapy at 6, 12, and 24 months, respectively, following initiation. Of the discontinuers, 46% re-initiated therapy, with the majority doing so within 6 months of discontinuation. Women were less likely to re-initiate therapy if they were older (p = 0.0001) or were hospitalized during baseline (p = 0.0007). Women who discontinued treatment early (< 6 months) following initiation were less likely to re-initiate (p = 0.0001) and remained on therapy for shorter periods following re-initiation. Depending on the available observation time, the median time on therapy following re-initiation was 58–193 days.

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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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