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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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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.


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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Cigarette smoking and age of menopause

23 July, 2012:

A recent 21-year follow-up prospective study was designed to analyze the association between smoking and the onset of menopause at an earlier age in a large cohort of middle-aged women after adjustment for a number of potential confounders [1]. The main outcomes were age of menopause measured at the 21-year follow-up, smoking and menopausal status. This study was based on 3545 women who provided data on their menopausal status at the 21-year follow-up of the study and prospective as well as concurrent data on smoking. In univariate analysis, tobacco smoking during the reproductive life course, socioeconomic status and gravidity were significantly associated with earlier age of menopause. In multivariate analyses, women who smoked cigarettes were more prone to develop earlier menopause than non-smokers. Compared to current smokers, risk of early menopause was significantly lower in those women who were former smokers. In summary, data from this study suggest that the impact of smoking is independent of other covariates associated with both smoking and age of menopause. These findings raise the possibility that effective programs for smoking cessation may lead to a later age of menopause and reduce the risk of adverse health consequences of early menopause.

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Long-term effects of the Women’s Health Initiative in the USA

16 July, 2012:

To study long-term prescriptions of hormone therapy (HT) in postmenopausal women, during a decade after the Women's Health Initiative (WHI), Steinkellner and colleagues [1] used a national pharmacy database from 2000 to 2009. Women who were 50 years and older at the start of the calendar year with continuous pharmacy benefits during the entire 12-month period were included in the study population for that year. The yearly study population varied from a low of 3,579,838 in 2000 to a high of 9,712,325 in 2009. The prevalence of HT use in each year's study population dropped from 21.6% in the year 2000 to 8.8% in the year 2009. The sharpest decline occurred between 2001 and 2003 and then it remained relatively stable. Analysis of different age groups showed a maximum fall in the decade 65–74 years old.

In the year 2000, oral HT accounted for 19% of this 21.6% and then it went down to a prevalence of 4.8% in 2009. Transdermal estrogen, not very popular in the US, remained stable throughout this period of time – around 4%, and vaginal formulations increased from an annual incidence of 0.9% in the year 2000 to 1.7% in 2009.

High and standard doses showed a prevalence of 16.6% in 2000 and then declined very fast in 2003 and continued to run low till 2009 with a share of 2.4%. Low-dose preparations remained constant in the range of 2.3–2.5% during the study period.

At the beginning of this survey, the prevalence of women prescribed by GP/IM/FP (Family Practice/Internal Medicine/General Practice) was 9.9% and gynecologists contributed another 8.8%. At the end of the decade, the gynecologists became the main prescribers of HT, with a prevalence of 5.3%, whereas GP/IM/FP accounted for only 2.9%.

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Mood, menopause and hysterectomy

9 July, 2012:

In a recent study by Gibson and colleagues, depression and anxiety symptoms were assessed in 1970 women followed up annually since premenopause for up to 10 years in a sub-study of the SWAN (Study of Women's Health Across the Nation) cohort, with the objective of examining whether mood symptoms were influenced negatively by hysterectomy, with or without bilateral oophorectomy, relative to natural menopause [1]. Women were recruited in a community-based setting, which is one of SWAN's specifications together with its multiethnic commitment [2]. They were 42–52 years of age, premenopausal, had an intact uterus and at least one ovary at baseline, as well as one or more menstrual cycles in the 3 months before. Symptoms were measured with the 'Center for Epidemiological Studies Depression Index' along with the evaluation of four anxiety items. In line with multivariate analyses, piece-wise hierarchical growth models were used to relate natural menopause, hysterectomy with ovarian conservation, and hysterectomy with bilateral oophorectomy to trajectories of mood symptoms before and after the final menstrual period or surgery.

Around 90% of the women reached natural menopause by the tenth annual visit, whereas 5.2% (n = 101) reported hysterectomy with bilateral oophorectomy and 3.9% (n = 76) hysterectomy with ovarian conservation. Depressive symptoms declined before the final menstrual period or surgery (regardless of whether the ovaries were conserved) and continued to decline afterwards. There was no significant difference in the mean rate of change in depressive symptoms relative to natural menopause. Both depressive and anxiety symptoms generally improved over the course of the menopausal transition for all women.

Hormone therapy (HT) was concurrently associated with lower levels of depressive and anxiety symptoms, while antidepressant use increased anxiety scores. HT was used at some point of the study by the majority of participants and was particularly common among women with hysterectomy and oophorectomy; but exclusion of HT users, as stated by the authors, did not affect the trajectories of changes in depressive or anxiety symptoms.

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Testosterone concentrations in ovarian insufficiency: a review

25 June 2012

An important and to date not clearly resolved question in clinical reproductive medicine has been whether premature loss of ovarian function (e.g. primary ovarian insufficiency (POI) below the age of 40 years) and iatrogenic premature loss of ovarian function (as a result of surgery, gonadotoxic chemotherapy or pelvic irradiation) result in a significant decrease in circulating testosterone concentrations and hence might merit testosterone treatment. Many published studies have included small sample sizes and/or non-uniform control groups. Janse and colleagues [1] have undertaken a systematic review and meta-analysis of the literature and conclude that testosterone levels are lower, though the magnitude of the difference is relatively small. They reviewed 206 articles on POI and 1358 on iatrogenic menopause, of which nine and 17, respectively, were selected for final analysis. In both groups, there was evidence of a lower testosterone concentration than in controls. Weighted mean differences were -0.38 nmol/l (95% confidence interval (CI) -0.55 to -0.22) and -0.29 nmol/l (95% CI -0.39 to -0.18), respectively. The mean differences represented a range of 1–49% lower (average 25%) in POI and a range of 11% higher to 77% lower (average 22% lower) for iatrogenic menopause. A sensitivity analysis of the three highest-quality studies in each group did not change the data substantially. The significance of such relatively small differences and their clinical importance are unclear.

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The relationship of mammographic density and age

11 June 2012:

Chemoprevention of breast cancer has the potential of a bright future in menopausal medicine. However, before chemoprevention can be implemented effectively, better methods for the reliable prediction of breast cancer are needed. Three major strategies for early prediction or risk assessment of breast cancer have been established. Next to the algorithm of epidemiological factors, as given by the Gail criteria, rank the assessment of the endocrine environment, mainly the circulating sex steroids, and mammographic density of the breast. The latter has been shown to provide an independent prediction of the breast cancer risk, although the link between enhanced mammographic density and the cellular and molecular pathways leading to breast cancer has not yet been elucidated.


Checka and co-workers [1] now present a retrospective analysis of a large cohort of more than 7000 women, in which the relationship between mammographic density, as given by the BI-RADS density categories, and age is analyzed. BI-RADS is the acronym for Breast Imaging-Reporting and Data System and was defined and published by the American College of Radiology. The BI-RADS assessment system consists of seven categories, but only those ranking from 1 to 4 can be used for the prediction of breast cancer risk, as they classify mammographic density differences from negative to suspicious. The median age of the cohort was 57 years. There was a significant inverse relationship between age and breast density (p g biopsy.

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Simple ovarian cysts in postmenopausal women: scope of conservative management

21 May 2012:


The prevalence of simple ovarian cysts in postmenopausal women may range from 3% to 15%. Simple cysts are usually followed conservatively, but concern about progression to malignancy may lead to surgical exploration, which in most cases would likely be for benign conditions. A recent retrospective study from the USA [1] evaluated 619 patients with 743 simple ovarian cysts; 305 patients (49.27%) were lost in follow-up. Therefore, 314 patients (50.73%) with 378 cysts were followed further by ultrasound study. In all, 175 (46.30%) of the 378 cysts that could be followed further had spontaneous resolution and 166 cysts (43.91%) persisted unchanged over the follow-up period. Thirty cysts (7.94%) turned into complex cysts and four cysts (1.06%) significantly increased in size. One cyst significantly decreased in size, although it did not resolve. Only one patient developed papillary serous carcinoma (high grade) of the ovary. This occurred 3 years after her last ultrasound for simple cyst surveillance. Thus, simple ovarian cysts during the menopause can be followed conservatively because their risk for malignant transformation is low. The majority of these cysts either resolve spontaneously or persist unaltered on follow-up.

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