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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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Patient leaflet information: friend or foe?

16 March, 2015

Every registered medication has an information insert in its package. This patient information leaflet (PIL) provides data on the product, which includes clinical pharmacology, recommended dose, mode of administration, how supplied, and a large section contains warnings and contraindications, adverse reactions, and precautions. With easy access of patients to information on drugs they use, mainly through the electronic media, it is very important that the text and contents of these patient leaflets are simple to understand and readable. Discussing the PIL with German patient focus groups resulted in agreements that (a) PILs contained too much risk information which was conveyed in a way that led to reduced patient compliance; (b) the current description of potential side-effects and drug interactions caused negative emotions which led to undesirable patient reactions; (c) PILs provoked certain behaviors in patients including accessing information from alternative sources or seeking support from professional and lay persons [1]. Also, most people thought that reliable information on efficacy and adverse effects of drugs should come from the treating physician, pharmacists being the second-line source. The forum suggested that, because current PILs convey risk information in a way that provoked feelings of fear and anxiety in the reader, regulators and producers of such written information should consider greater involvement of target patient groups at all stages of the production process.

Comment

How many of you read the patient information leaflets (PILs), the package inserts of the medications you prescribe? How many of you face the situation when your patient challenges you with questions based on the PIL or other external sources of information? Is it time to see how patients address the PIL and even criticize its format and contents? A study from the UK, while examining 48 PILs related to cardiovascular and diabetes medications found that only a few of the documents were fit specifically for the older population, either by failing to mention side-effects that could occur in the older generation, or by using small fonts and problematic phrasing [2].

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Short-term hormone therapy and ovarian cancer risk

23 February, 2015 

Many of us were exposed to the news in mid-February that a meta-analysis by Beral and colleagues [1] published inThe Lancet concluded that even a short-term use (< 5 years) of postmenopausal hormone therapy (HT) is associated with increased risk for ovarian cancer. Analyses used individual participant datasets from 52 epidemiological studies. The principal analyses involved the prospective studies (with last HT use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use.

During prospective follow-up, 12,110 postmenopausal women, 55% (6601) of whom had used HT, developed ovarian cancer. Among women last recorded as current users, risk was increased even with < 5 years of use (RR 1.43, 95% CI 1.31–1.56;p< 0.0001). Risk was significantly increased in women who had been recent HT users (any duration, but stopped < 5 years before diagnosis) (RR 1.23, 95% CI 1.09–1.37;p= 0.0006). Risk decreased the longer ago HT had last been used, although women who had used HT for at least 5 years (median duration 9 years) and then stopped were still at significantly increased risk more than 5 years (median time since last use 10 years) later (RR 1.10, 95% CI 1.01–1.20;p= 0.02). Combining current or recent use resulted in an RR of 1.37 (95% CI 1.29–1.46;p< 0.0001); this risk was similar in European and American prospective studies and for estrogen-only and estrogen–progestin preparations, but differed across the four main tumor types (heterogeneity,p< 0•0001), being definitely increased only for the two most common types, serous (RR 1.53, 95% CI 1.40–1.66;p< 0.0001) and endometrioid (RR 1.42, 95% CI 1.20–1.67;p< 0.0001). Age at initiation of HT had little effect. The increased risk may well be largely or wholly causal; if it is, women who use HT for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users.

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Vasomotor symptoms and fracture risk

9 February, 2015 

Vasomotor symptoms (VMS) are common, but whether VMS are associated with fracture incidence or bone mineral density (BMD) levels is unknown. The following data are derived from the Women's Health Initiative Clinical Trial participants (n= 23,573) aged 50–79 years not using menopausal hormone therapy, and 4867 participants of the BMD sub-study [1]. This was a prospective observational study with mean (standard deviation) follow-up of 8.2 (1.7) years (1993–2005). Baseline VMS, incident adjudicated fractures, and BMD (baseline, annual visits 1, 3, 6, and 9) were measured. The mean age of those with moderate/severe VMS was 60 years, and mean body mass index (BMI) was 30.7 kg/m2. After adjustment for baseline age, BMI, race/ethnicity, smoking, and education, the hazard ratio for hip fracture among women with baseline moderate/severe VMS (vs. no VMS) was 1.78 (95% confidence interval, CI 1.20–2.64;p= 0.01). There was no association between VMS and vertebral fracture. VMS severity was inversely associated with BMD during follow-up (p= 0.004 for femoral neck,p= 0.045 for lumbar spine). In repeated measures models, compared with women who reported no VMS, women with moderate/severe VMS had 0.015 g/cm2lower femoral neck BMD (95% CI -0.025 to -0.005) and 0.016 g/cm2lower lumbar spine BMD (95% CI -0.032 to -0.004).

Comment

Although this seems quite strange, but as Crandall and colleagues state and a PubMed search verifies, the associations between VMS and fracture risk have not been frequently investigated. Previous studies examined the potential relationship of VMS and BMD, and indeed most found that women with more severe VMS had lower BMD values. Gast and colleagues analyzed data from a population-based sample of 5,600 women, aged 46–57 years and free from bone diseases, who participated in the first cross-sectional part of the Eindhoven Perimenopausal Osteoporosis Study between 1994 and 1995 [2]. They rated the degree of menopausal symptoms and correlated it with spine BMD results, and demonstrated that, after multivariate adjustments for age, BMI, menopause status, smoking, education, exercise, and hormone use, women with the highest frequency of symptoms had a 0.022 g/cm (95% CI -0.03 to -0.01) lower BMD compared with asymptomatic women. Women who reported having the highest frequency of night sweats had a 0.011 g/cm (95% CI -0.02 to -0.001) lower BMD compared with women with no symptoms of night sweats. Interestingly, the same investigators were able to establish similar associations with coronary artery disease: women with menopausal night sweats had a significantly moderately increased risk which could not be totally explained by the levels of cardiovascular risk factors: multivariable-adjusted hazard ratio 1.33 (95% CI 1.05–1.69), attenuated but not eliminated after correction for BMI, blood pressure, and total cholesterol (hazard ratio 1.25; 95% CI 0.99–1.58) [3]. However, symptoms of flushing were not associated with risk of coronary artery disease.

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DHEA given to healthy postmenopausal women

19 January, 2015

Blood levels of dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS) and androgens, such as testosterone, fall with age. Over the last two decades, there have been many clinical trials performed replacing these sex hormones, hoping to improve symptoms such as general well-being, energy, and sex drive. DHEAS is the most abundant steroid in serum; however, no receptor for DHEA has yet been found. It can be interconverted into estrogenic and androgenic metabolites in those tissues that have the appropriate enzyme systems.

Elraiyah and colleagues performed a systematic review and meta-analysis [1] of studies where DHEA was given orally. They identified 23 randomized, controlled trials which enrolled a total of 1188 women. They found that DHEA replacement did not improve sexual desire (or any other measure of sexuality), nor did it have an effect on metabolic markers such as lipids, fasting glucose, weight (or bone mineral density).

Comment

This important meta-analysis confirms the work of others such as Davis [2] that DHEA replacement given to postmenopausal women appears to have no benefit. Despite these reviews, many women around the world are taking DHEA, often compounded and via a number of delivery systems (oral, troche, creams) for dubious reasons.

In contrast to these data, there may be a role for giving low doses of DHEA vaginally [3,4]. The vagina has all the enzyme systems necessary to convert DHEA into estrogens and androgens. Labrie and colleagues have shown that daily DHEA 6.5 mg given vaginally, estrogenizes the vagina and clinically improves menopause-induced vaginal atrophy. Furthermore, using mass spectrometry, they showed that vaginal DHEA did not change serum estrogenic or androgenic metabolites. In other words, vaginal low-dose DHEA improves vaginal atrophy without any systemic effects. Davis points out that, for the average woman, twice weekly vaginal estrogen is probably more convenient [3].

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Anti-aging therapies and hormone replacement

12 January, 2015

A new article reviews the effects of age-related hormone decline on the aging process and age-related diseases such as sarcopenia and falls, osteoporosis, cognitive decline, mood disorders, cardiovascular health and sexual activity [1]. Information on the efficiency and safety of hormone replacement protocols in aging patients is provided as well. Anti-aging therapies are a huge business world-wide, and this reflects a human desire to fight nature and prolong longevity. During the last 20 years, a multitude of anti-aging practices have appeared, aiming at retarding or even stopping and reversing the effects of aging on the human body. One of the cornerstones of anti-aging is hormone replacement. Women live one-third of their lives in a state of sex hormone deficiency, whereas men are also subject to age-related testosterone decline, but andropause remains frequently under-diagnosed and under-treated. Due to the decline of hormone production from the gonads in both sexes, the importance of dehydroepiandrosterone (DHEA) in steroid hormone production increases with age. However, DHEA levels also decrease with age. Also, the age-associated decrease in growth hormone may be so important that insulin growth factor-1 levels found in elderly individuals are sometimes as low as those encountered in adult patients with established deficiency. Skin aging, as well as decreases in lean body mass, bone mineral density, sexual desire and erectile function, intellectual activity and mood have all been related to this decrease of hormone production with age. Great disparities exist between recommendations from scientific societies and the actual use of hormone supplements in aging and elderly patients.

Comment

Before getting into the heart of the matter, one must define several key parameters. Brüssow gives the accepted definitions of health, aging and healthy aging [2]. Health, according to the 1948 WHO definition, is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity. Aging is a progressive decline in structure and function of the body, or regression of physiological function accompanied by advancement of age. The definition in the Nurses' Health Study for successful aging was as follows: being free from 11 major chronic diseases (such as cancer, cardiovascular, pulmonary, renal, Parkinson’s disease), no cognitive impairment, no physical disabilities, no mental health limitations [3]. The pivotal physiological change throughout the perimenopause is the decline in estrogen and progesterone production, whereas an abrupt, substantial decrease in all sex hormone levels follows castration. This creates a significant deficiency state to which the body must adapt. The associated metabolic alterations may therefore be regarded as induced by the menopause but, in fact, in most cases the effects of aging itself are the main underlying factors. Nevertheless, it has always been tempting to believe that treating menopausal women with estrogen replacement will change the hormonal milieu, correct the deprivation state and reverse not only the menopause-related but also the age-related physiological processes. This is very logical, but does this work in real life?

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Hormone therapy and depression in perimenopausal and postmenopausal women

8 December 2014

A recent review written by three Finnish psychiatrists supports the use of estrogens, perhaps together with antidepressants, for depression and anxiety in perimenopausal women [1]. Depressive symptoms are experienced by 15–50% of women during the menopausal transition and up to 30% of perimenopausal depression is severe enough to be regarded as a depressive disorder. This problem, described as 'reproductive depression' [2] occurs with fluctuations of gonadal hormones in the form of premenstrual depression, postnatal depression and climacteric depression. In the menopausal age group, the depression, anxiety and loss of self-confidence are at their worst in the 2–3 years of the transition period before the cessation of periods. Toffol and colleagues, in their review of the literature, have come to the conclusion that hormone therapy may contribute to the alleviation of menopause-related depressive symptoms. They claim that the administration can be followed across time and should be specifically individualized. In cases of more severe depressive disorders, a combination of antidepressants and hormone therapy should be considered. This view has also been proposed by others [3,4].

Comment

The perimenopause is usually accompanied by more-or-less-impairing climacteric symptoms of hot flushes, palpitations and tachycardia as well as some degree of psychological symptoms of sleep impairment, anxiety, panic attacks and depressive symptoms. The proportion of perimenopausal women suffering depressive symptoms ranges between 15% and 50%. It is possible that the fluctuations in estrogen levels and their eventual fall increase the risk in women who are vulnerable. These are particularly women who have had a premorbid history of psychiatric problems, particularly anxiety and depression related to reproductive events such as menstruation, post pregnancy and the contraceptive pill.

The cause of this hormone-responsive depression is unclear but, in our present state of knowledge, it is certain that gonadal hormones produce many effects on the central nervous system. In the adult brain, estrogen and progestogen receptors are widely expressed in different regions. Estrogen receptors are present not only in the hypothalamus but also in the hippocampus, amygdala, cerebellum, pituitary, cerebral cortex and glial cells. The mechanism is even more complex in that there are different types of estrogen receptors which are expressed in different brain regions and in different cells within the same brain region and even in the same cell in the same region. Therefore, the final effects induced by estrogens change depending on the type of receptor to which they bind. Target genes include those responsible for neurotransmitters, serotonin and GABA. The role of progesterone is even more complicated as it is involved in the control of opioidergic, sertoninergic and cholinergic systems with anxiolytic effects.

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Postmenopausal hormone therapy and blood pressure revisited

17 November, 2014

The effects of hormone therapy (HT) on mean and visit-to-visit variability (VVV) of blood pressure in postmenopausal women were recorded in the Women's Health Initiative (WHI) randomized controlled trials [1]. Blood pressure was measured at baseline and annually in the two WHI HT trials, in which 10,739 and 16, 608 postmenopausal women were randomized to conjugated equine estrogens (CEE, 0.625  mg/day) or placebo, and CEE plus medroxyprogesterone acetate (MPA, 2.5  mg/day) or placebo, respectively. At the first annual visit (year 1), the mean systolic blood pressure was 1.04  mmHg (95% confidence interval (CI) 0.58–1.50) and 1.35  mmHg (95% CI 0.99–1.72) higher in the CEE and CEE + MPA arms, respectively, compared with the mean systolic blood pressure in women taking the corresponding placebos. These effects remained stable after year 1. CEE also increased the VVV of systolic blood pressure (ratio of VVV in CEE vs. placebo, 1.03; p  <  0.001), whereas CEE + MPA did not (ratio of VVV in CEE + MPA vs. placebo, 1.01; p  =  0.20). After accounting for study drug adherence, the effects of CEE and CEE + MPA on mean systolic blood pressure increased at year 1, and the differences in the CEE and CEE + MPA arms vs. placebos also continued to increase after year 1. Further, both CEE and CEE + MPA significantly increased the VVV of systolic blood pressure (ratio of VVV in CEE vs. placebo, 1.04; p  <  0.001; ratio of VVV in CEE + MPA vs. placebo, 1.05; p  <  0.001).

Comment

It is well documented that elevated blood pressure in women is an important risk factor for cardiovascular disease and therefore its control may have a substantial impact on women's health [2,3]. Shimbo and colleagues [1] concluded that, in the particular clinical set-up of the WHI trial (women at a mean age of 62 years using CEE or CEE + MPA at conventional doses), mean and VVV of systolic blood pressure were increased. Thus, these results actually support the WHI-related notion that HT may have a detrimental effect on coronary artery disease. Although the exact mechanisms that may explain how HT influences blood pressure are not fully understood, several possibilities have been suggested [4]. HT has an effect on vascular tone, cardiac function, the immune system, the kidneys and other organs. Of particular interest is the modulation of the renin–angiotensin pathway by estrogen.

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KEEPS results: a true frustration?

10 November, 2014

One of the main arguments against extrapolation of the Women's Health Initiative (WHI) study data to the whole postmenopausal population was that it actually focused on the 60+ year-old women who were treatment-naïve until then [1], whereas in real life most hormone users are 45–55 years old at initiation of therapy. The Kronos Early Estrogen Prevention Study (KEEPS) was designed to provide information on the effects of hormone therapy (HT) in recently menopausal women. Results from KEEPS are now published in the literature [2]. The main aim of KEEPS was to assess atherosclerosis progression and cardiovascular risk factors after HT initiation. The study enrolled 727 healthy menopausal women aged 42–58 years (mean 52.7 years), between 6 and 36 months from last menses, without prior cardiovascular disease events, who had a coronary artery calcium (CAC) score less than 50 Agatston units and had not received estrogen or lipid-lowering therapy for at least 90 days. Study medications included oral conjugated equine estrogens (o-CEE), 0.45 mg/day, or transdermal 17β-estradiol (t-E2), 50 μg/day, each with 200 mg of oral progesterone for 12 days per month, or placebo for 48 months.

The primary endpoint was annual change in carotid artery intima-media thickness (CIMT). Secondary endpoints included changes in markers of cardiovascular disease risk. Of 727 randomly assigned women, 89.3% had at least one follow-up CIMT and 79.8% had CIMT at 48 months. Mean CIMT increases of 0.007 mm/year were similar across groups. The percentages of participants in whom the CAC score increased did not differ significantly across groups. No changes in blood pressure were observed with o-CEE or t-E2. Low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol levels improved and levels of C-reactive protein and sex hormone binding globulin but not interleukin-6 increased with o-CEE. Insulin resistance decreased with t-E2. Serious adverse events did not differ by treatment. Power to compare clinical events was insufficient. Thus 4 years of early HT did not affect progression of atherosclerosis despite improving some markers of cardiovascular disease risk.

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Body image and depression

06 October, 2014:

With aging, women's bodies undergo changes that can affect body image perception, yet little is known about body image in midlife. In a subset of the SWAN cohort from Chicago, the associations between body image and depressive symptoms were investigated [1]. Body image was measured using the Stunkard Adult Female Figure Rating Scale, and a clinically significant level of depressive symptoms was defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score of ≥ 16 (total n = 405; depression n = 63 (15.6%)). Differences between perceived actual, perceived ideal and actual body size and responses to questions concerning weight satisfaction and attractiveness were examined using logistic regression for associations with a CES-D score of ≥ 16. Women with body image dissatisfaction (odds ratio, OR = 1.91; p = 0.04) or who perceived themselves as 'unattractive' (OR 7.74; p < 0.01) had higher odds of CES-D of ≥ 16. There was no significant difference by race, and results were not confounded by body mass index. To conclude, midlife women with poor body image may be more likely to have clinically significant levels of depressive symptoms.

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Prevalence of urinary incontinence according to hysterectomy status in the WHI observational study

29 September, 2014: 

Urinary incontinence (UI) is a common and frequently overlooked problem in aging women [1,2]. Leaking urine limits daily and working activities, social interaction and sexual intimacy, and therefore severely disrupts quality of life [3]. The relationship between menopause, aging and hysterectomy is complex and still unresolved. While it is clinically appreciated that all these factors have some impact on the frequency and severity of urinary incontinence, epidemiologic evidence is contradictory and a clear demonstration of how these factors interact in favoring incontinence is not available.

Removal of the uterus is one of the most frequent surgical procedures performed in women, and appropriate counseling related to future risks, particularly that of UI or pelvic organ prolapse (POP), is currently based on feeble evidence.

The Women’s Health Initiative Observational Study (WHI OS) has explored this issue, assessing prevalence, at baseline and after a 3-year time interval, of different forms of UI in 92,093 postmenopausal women between 50 and 80 years (53,569 with the uterus in place, 38,524 hysterectomized) [4]. This is the largest cohort of women in which information on UI has ever been gathered.

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