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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 November 2016 onward are available to Members only when logged in. Selected articles are open to public.

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Coronary events in the WHI trial and the metabolic syndrome

24 December, 2012:

A recent manuscript describes a nested case–control study of incident coronary heart disease (CHD) events during the first 4 years of follow-up in the Women's Health Initiative hormone therapy trials (estrogen plus progestin therapy, EPT and estrogen therapy, ET) [1]. There were 359 incident cases of CHD during follow-up. After the exclusion of women with cardiovascular disease (n = 90), diabetes, or hypertension at baseline (n = 103), 166 CHD cases were matched to 524 controls on age, randomization date, and hysterectomy status. Metabolic syndrome (MetS) classification required at least three of five Adult Treatment Panel III criteria. The main outcome measure was the odds for CHD with hormone therapy use versus placebo by MetS status. MetS modified the risk of CHD events with hormone therapy. In the pooled analysis, risk was increased with hormone therapy versus placebo in women with MetS (odds ratio (OR) 2.26; 95% confidence interval (CI) 1.26–4.07), whereas women without MetS were not found to have an increased risk for a CHD event with hormone therapy (OR 0.97; 95% CI 0.58–1.61; p for interaction = 0.03). Results of the EPT and ET trials, when examined separately, were similar. The constellation of MetS variables was more predictive of risk from hormone therapy than MetS components assessed individually. When women with diabetes or hypertension were included in the analysis, statistically significant effect modification was not detected. In conclusion, MetS at baseline in women without prior cardiovascular disease, diabetes, or hypertension at baseline identifies women who are more likely to have had adverse coronary outcomes on hormone therapy. CHD risk stratification is recommended before initiating hormone therapy.

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Weight gain during the menopause transition: which comes first, the chicken or the egg?

17 December, 2012:

Study data were drawn from the Study of Women Across the Nation (SWAN) database to address the question of whether or not weight gain preceded or followed the hormonal changes associated with the menopause transition [1]. The cohort consisted of 1528 women with a mean age of 46 years who had baseline measurements of waist circumference, body mass index (BMI), and serum follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), testosterone, and estradiol drawn at baseline and at 3, 6, and 9 years after entry. The outcome measure of weight gain or waist circumference versus hormone levels was assessed in the following manner. The dynamic sequential relationships between hormones and waist circumference were examined using structural equation modeling. Specifically, these equations examined the following three longitudinal relationships: (1) the association of current hormone values and waist circumference with their respective future values; (2) the associations of current waist circumference with future hormone values; and (3) the associations of current hormone values with future waist circumference. The results indicate that the changes in adiposity and waist circumference occur during and following the menopause transition. Current waist circumference predicted future decreases in FSH and SHBG and the increase in serum testosterone. Waist circumference predicted future estradiol levels, while current estradiol levels were associated with future weight gain. Both relationships were dependent upon the changing estradiol levels but the former result was greater than the latter [1].

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DXA vs. QUS to predict fracture risk

19 November, 2012:

A total of 2341 postmenopausal women were recruited in five centers in Italy during 2006 and 2007 for quantitative ultrasound (QUS) measurement at the phalanges during a screening program for osteoporosis [1]. Two ultrasound parameters were collected: amplitude-dependent speed of sound (AD-SoS) and ultrasound bone profile index (UBPI). Women were then re-contacted in 2010 (n = 2211) and were asked about fracture occurrence during the period since previous QUS measurement. The mean age of the recruited women was 60.9 ± 10.0 years, the mean age at menopause was 49.3 ± 4.4 years, and the mean body mass index (BMI) was 26.5 ± 4.6 kg/m2. A total number of 108 new major osteoporotic fractures occurred during the 3-year period, of which 23 were hip fractures and 51 were vertebral fractures. The relative risk (RR) per standard deviation (SD) decrease for major fractures was 1.77 (95% confidence interval (CI) 1.59–1.97) for AD-SoS and 2.06 (95% CI 1.78–2.37) for UBPI. When corrected for age, BMI, and age at menopause, the RRs were still significant and equal to 1.44 (95% CI 1.26–1.65) for AD-SoS and 1.67 (95% CI 1.39–2.00) for UBPI. The RR for vertebral fractures was 1.63 (95% CI 1.41–1.88) for AD-SoS and 1.73 (95% CI 1.44–2.08) for UBPI. The RR for hip fractures was 1.92 (95% CI 1.55–2.37) for AD-SoS and 2.68 (95% CI 1.86–3.86) for UBPI. Thus, this study showed that ultrasound parameters AD-SoS and UBPI were able to significantly predict future major fractures in a prospective cohort of more than 2000 postmenopausal women.

Comment

Quantitative ultrasound of the bone provides information not only about bone density but also on architecture and elasticity. It is a radiation-free technique, relatively inexpensive and easily transportable. Measurements at the fingers take only a few minutes. Theoretically, it seems to be the ideal modality for assessing bone strength, yet dual-energy X-ray absorptiometry (DXA), a much more expensive and time-consuming examination, is the gold standard recommended by health authorities and guidelines and is an important component of the FRAX risk assessment tool [2,3]. There could be several reasons for the existing inferiority of QUS versus the traditional DXA measurement. QUS examinations could be performed in several sites, which raises the question whether measurements at various peripheral sites (heel, finger, wrist) are similar in regard to their predictive values for vertebral and hip fractures. Other arguments relate to the accuracy of QUS when tested head-to-head with DXA, and to the efficacy of QUS, both as a screening tool and for monitoring the consequences of treatment, as compared to DXA.

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HRT to prevent chronic conditions

29 October, 2012:

The United States Prevention Services Task Force (USPTF) has updated its 2005 recommendations on the use of postmenopausal hormones as a strategy to prevent chronic conditions in healthy women [1]. The USPSTF commissioned a review of the literature to update evidence about the benefits and harms of using menopausal hormone therapy to prevent chronic conditions, as well as whether the benefits and harms of hormone therapy differ by population subgroups defined by age, the presence of comorbid medical conditions, and the type, dose, and method of hormonal delivery.

This recommendation applies to postmenopausal women who are considering hormone therapy for the primary prevention of chronic medical conditions. It does not apply to women who are considering hormone therapy for the management of menopausal symptoms, such as hot flushes or vaginal dryness. It also does not apply to women younger than 50 years who have had surgical menopause.

The USPSTF recommends against the use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women. The USPSTF recommends against the use of estrogen for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy. Recommendations are based on the evidence of both the benefits and harms of the service and an assessment of the balance.

The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision-making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.

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Post-oophorectomy estrogen use and breast cancer risk

23 October, 2012:

An article by Nichols and colleagues [1] provides a detailed analysis of data collected from 10,449 women with invasive breast cancer compared to 11,787 age-matched controls without breast cancer to determine whether the use of estrogen therapy following a bilateral oophorectomy prior to reaching a natural menopause had any influence on the development of breast cancer. In pooled data from the Collaborative Breast Cancer Studies population-based, case–control studies collected between 1992 and 2007, the use of estrogen prescribed for women, following total abdominal hysterectomy with bilateral salpingo-oophorectomy, was analyzed for subsequent development of breast cancer. Case participants were compared with age-matched control cohorts obtained by identifying women in a register of licensed drivers or from a list of Medicare beneficiaries.

A very confusing picture emerges from the results.

1. All women who had their ovaries removed before the age of 40 years were found to have a decreased risk of developing breast cancer – a 24% reduction following estrogen use and 30% reduction when no hormone was used.

2. Women over the age of 45 years when their ovaries were removed were found to have no reduction in the risk of breast cancer if they used estrogen therapy (but no increased risk).

3. Those women who began estrogen therapy within 5 years of bilateral oophorectomy had a 22% increased risk of breast cancer, whereas those who delayed estrogen use for 5 or more years had a 54% reduction in the risk of breast cancer.

4. Among current estrogen users, those women taking the hormone for less than 10 years had a 32% increased risk of breast cancer, whereas those using estrogen for longer than 10 years had no significant increase in breast cancer.

5. Among current users of estrogen therapy, those who were younger when beginning therapy had a decreased risk of breast cancer while there was an overall increase in breast cancer for older women on estrogen.

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The safety of postmenopausal testosterone therapy

16 October, 2012:

Testosterone therapy has been used in postmenopausal women for many years. However, it remains a contentious issue and few products are designed specifically for use in women. There are many potential benefits of testosterone replacement. Improvements in sexual function, mood, cognition, bone density and quality of life have all been demonstrated and testosterone has even been shown to improve outcomes in women with congestive cardiac failure [1-3]. Despite these potential benefits, many regulatory authorities remain unconvinced by the currently available safety data, particularly concerning the breast and cardiovascular systems. A recently published review [4] looks at the most recent data on postmenopausal testosterone therapy, focusing particularly on the effects of testosterone on breast, endometrium and cardiovascular health.

There are many inherent difficulties with studying the effects of testosterone in women and subsequently many of the available data have methodological flaws. For instance, concerns exist about the limitations of the different testosterone assays. There is also doubt whether systemic testosterone levels represent the true effect in the breast and cardiovascular system due to local tissue intracrinology. Variations in menopausal status, use of concomitant hormone therapy and the testosterone fraction used for analysis can limit comparisons between studies. Furthermore, many studies fail to adjust for estradiol, sex hormone binding globulin or body mass index, all of which can have a profound effect on risk factors.

It is difficult to give a definitive overview on the long-term safety of postmenopausal testosterone therapy because of the limitations discussed thus far and the absence of gold standard data [4]. Older studies using oral testosterone have shown an adverse effect on lipid metabolism, body composition and surrogate markers for cardiovascular disease. There has been a recent move to the use of transdermal preparations with a very different metabolic profile. Transdermal testosterone does not appear to affect cardiovascular risk factors such as body mass, blood pressure or lipid metabolism and low-dose subcutaneous therapy appears to have a beneficial effect on endothelial function [5]. However, robust data on cardiovascular risks are lacking; there are no sufficiently powered long-term, randomized, controlled trials (RCTs) investigating cardiac events with physiological transdermal replacement.

Similarly with breast cancer, there are no RCTs with exogenous testosterone investigating the risk of breast cancer as a primary outcome, so definitive conclusions cannot be drawn. Observational studies investigating the risk of breast cancer have shown conflicting results; although the majority have shown no increase in risk, two older trials investigating the effects of oral testosterone did show a small risk. Randomized, controlled trial data have shown no effect from transdermal testosterone on surrogate risk markers such as breast cell proliferation and mammographic density.

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Kronos Early Estrogen Prevention Study (KEEPS)

8 October, 2012:

The preliminary results of the Kronos Early Estrogen Prevention Study (KEEPS) were presented at the NAMS meeting last week and immediately brought to the public attention through the media. KEEPS was a 4-year randomized, double-blinded, placebo-controlled clinical trial of low-dose oral or transdermal (skin patch) estrogen and cyclic monthly progesterone in healthy women aged 42–58 years (mean age 52 years) who were within 3 years after menopause at randomization. A total of 727 women were randomized into the following three arms, along with cyclical micronized progesterone (Prometrium®): oral arm, conjugated equine estrogen (CEE) given as Premarin®, 0.45 mg/day (a lower dose than the 0.625 mg/day used in the Women's Health Initiative (WHI) trial); transdermal arm, estradiol given by Climara® patch, 50 μg/day; and a placebo arm.

 

Improvements in hot flushes, night sweats, mood, sexual function, and bone density were observed with hormone therapy (HT) vs. placebo. Oral CEE, but not transdermal estradiol, was associated with an increase in HDL cholesterol. The oral CEE group had a decrease in LDL cholesterol, but also an increase in triglyceride levels. Transdermal estradiol had neutral effects on these biomarkers. Transdermal estradiol appeared to improve insulin sensitivity, calculated from glucose and insulin levels as HOMA-IR. Neither oral CEE nor transdermal estradiol significantly affected systolic or diastolic blood pressure, in contrast to the higher dose of CEE in the WHI, which increased blood pressure levels. During 48 months of treatment with either type of HT vs. placebo, there were no apparent effects, either beneficial or deleterious, on atherosclerosis progression assessed by carotid ultrasound and a non-significant trend toward less accumulation of coronary artery calcium. No significant differences in adverse events (breast cancer, endometrial cancer, myocardial infarction, transient ischemic attack, stroke, or venous thromboembolic disease) were found among groups. However, the absolute numbers of such events were extremely small in all three treatment groups, making definitive conclusions impossible.

In conclusion, KEEPS found many favorable effects of HT in newly menopausal women. The results provide reassurance for women who are recently menopausal and taking HT for short-term treatment of menopausal symptoms. KEEPS also highlights the need for individualized decision-making about HT, given that oral CEE and transdermal estradiol may have different profiles of effects and different women have different symptom profiles and priorities for treatment.

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Dietary intervention, weight change and vasomotor symptoms

 

10 September, 2012:

A recent paper by Kroenke and colleagues discussed the dietary intervention component of the Women's Health Initiative [1]. The intervention was a reduction in fat intake whilst increasing that of fruit, vegetables and whole grains. The outcome was the impact of this, whether accompanied by weight loss or not, on vasomotor symptoms (VMS) in postmenopausal women. A total of 17,500 postmenopausal women aged 50–79 years were recruited into this arm, none of whom were meant to be taking menopausal hormone replacement therapy (HRT). The study found that there was a significant weight loss in the dietary intervention arm that was associated with elimination of symptoms among women who had vasomotor symptoms at baseline (odds ratio (OR) 1.14; 95% confidence interval (CI) 1.01–1.28), who lost more than 10 lbs (OR 1.23; 95% CI 1.05–1.46) or lost 10% or more of their baseline body weight (OR 1.56; 95% CI 1.21–2.02) between baseline and year 1. These groups were significantly more likely to cease having VMS, compared with those who maintained weight. Finally, women who lost substantial weight as a part of the intervention group (OR 1.89; 95% CI 1.39–2.57), but not as part of the control group (OR 1.40; 95% CI 0.92–2.13), were significantly more likely to stop having VMS. Large weight loss (> 22 lbs), but not dietary changes, was related to the elimination of moderate/severe VMS. The conclusion to the study was that weight loss, as part of healthy diet modification, may help eliminate vasomotor symptoms amongst postmenopausal women.

 

Women were randomized to a diet with 20% of energy derived from fat and five servings of fruit and vegetables daily as well as six of whole grain. They were, in addition, given an intensive behavioral modification program to assist them in achieving this diet. The control group received a copy of a publication 'Dietary guidelines for Americans' but had no direct contact with the nutrition interventionists. Although weight loss was not a primary end to the diet modification, 21% of the intervention group and 7% of the controls lost weight. Weight change was assessed looking at absolute values as well as a percentage change in weight to allow categorization. VMS were reported using a questionnaire assessing hot flush and night sweat occurrence and severity in the previous 4 weeks that was scored from none (0) to severe (3). A score of 1 indicated that there was no interference with the usual activities, 2 that they interfered somewhat, and 3, interfered a lot. Covariates such as demographic factors, years since hysterectomy and depressive symptoms were taken into account.

A total of 6104 women had VMS at baseline and were examined separately; 26% of women reported hot flushes at baseline with only 1% being severe, i.e. 61 women. These women, not surprisingly, were younger and more recently menopausal as one would expect and the VMS were more likely to occur in African-American women, those who were less educated, smoked and with depressive symptoms as well as lower alcohol intake. No comment was made on whether the women had taken HRT in the past or not. The intervention led to an improvement in symptoms, although it is very difficult to take account of natural history since it is known that the women with symptoms were younger and some would be expected to improve anyway. Not all VMS, particularly in older women, respond well to hormone intervention.

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Treatment failure in osteoporosis

29 August, 2012:

The treatment goal in osteoporosis is to reduce fracture risk. But how do we estimate if this has been achieved in an individual patient? In other words, how do we know that a certain therapy is effective or not? A very respectable working group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF) was convened to define outcome variables that may assist clinicians in decision-making [1]. In the face of limited evidence, failure of treatment may be inferred when two or more incident fractures have occurred during treatment, when serial measurements of bone remodeling markers are not suppressed by antiresorptive therapy, and where bone mineral density continues to decrease. The provision of pragmatic criteria to define failure to respond to treatment provides an unmet clinical need and may stimulate research into an important issue.

Comment

What is treatment failure in osteoporosis? For most of us, it would be a decrease in bone density despite therapy; for others, a new fracture means failure. But is it so simple and clear? First, we must ensure that our patient was compliant, because adherence to therapy has a direct association with fracture risk reduction and increase in bone mineral density (BMD) [2]. Second, how can we determine that a certain fracture was osteoporosis-related? The IOF document states that 'Fractures of the hand, skull, digits, feet and ankle are not considered as fragility fractures' [1]. Healthy bones will break if the trauma is forceful enough. Contrarily, hip and vertebral fractures that occur with minimal or no trauma, especially in the elderly population, are usually categorized as related to osteoporosis. Third, we have to be sure that the reason for our patient's non-response to therapy is not the result of suffering from secondary osteoporosis that needs an assessment of potential endocrinological, gastroenterological or many other conditions that may cause some derangements of bone metabolism.

On average, one should expect a reduction of around 40–60% in fracture risk for the spine and hip/femur areas in a cohort that uses an effective treatment. Thus, the mere occurrence of a fracture during the course of treatment cannot be taken automatically as proof of treatment failure. We must also remember that bone strength is determined by many factors. No therapy so far can guarantee complete prevention of future fractures.

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Memory symptoms during the menopausal transition

13 August, 2012:

Memory complaints are relatively common during midlife. Depending on how the question is asked, more than half of midlife women will endorse problems with memory, and many will indicate that poor memory carries over to their daily function [1-4]. A major concern of patients and their physicians is that forgetfulness, poor concentration, or simply just fuzzy thinking might portend more serious cognitive impairment in the years to come. Among midlife women, a related question is whether their memory symptoms are caused by hormonal fluctuations or hormonal loss associated with the menopausal transition and postmenopause.

In the July issue of Menopause, Weber and her colleagues [4] report findings on 75 midlife women. They examined the relation between memory complaints and cognitive performance on a comprehensive battery of neuropsychological tests, and the relation with serum estradiol levels. These women, who were aged 40–60 years, were asked to rate their memory with the 64-item Memory Function Questionnaire (MFQ). Their answers were analyzed according to total score as well as factors related to Frequency of Forgetting, Seriousness of Forgetting, Retrospective Functioning (current memory relative to past memory), and Mnemonics Usage. Self-rated mood was assessed with the Beck Depression Inventory.

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