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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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Adverse long-term health outcomes associated with premature or early menopause

20 July, 2015 

Most women experience menopause between the ages of 45 and 55 years. However, 5% of women will go through menopause early, between the ages of 40 and 45 years, and 1% of women become menopausal prematurely, before the age of 40 years [1]. The causes of premature or early menopause are multiple and range from the most common, bilateral oophorectomy, to more rare causes such as genetic, autoimmune, or infectious etiologies. There are multiple adverse long-term health consequences associated with premature or early menopause, including increased risk of dementia, parkinsonism, glaucoma, depression, anxiety, osteoporosis, coronary heart disease, heart failure, sexual dysfunction, and early death. Replacing estrogen mitigates some of these risks, although it may not completely protect against the increased risk of parkinsonism, glaucoma, mood disorders, and sexual dysfunction [1].

Comment

The ovaries are both reproductive and endocrine organs. They secrete hormones both before menopause (primarily estrogen, progesterone, and testosterone) and after (primarily testosterone, androstenedione, and dehydroepiandrosterone). Ovarian hormones have important reproductive actions; however, they also have important endocrine actions mediated by receptors spread throughout most tissues and organs of the body [2]. Removal of the ovaries reduces the risk of ovarian (by 80–90%) and breast (by 50–60%) cancer; however, it increases the risk of all-cause mortality (28%), lung cancer (45%), coronary heart disease (33%), stroke (62%), cognitive impairment (60%), parkinsonism (80%), psychiatric symptoms (50–130%), osteoporosis and bone fractures (50%), and impaired sexual function (40–110%). The magnitude of the risk varies depending on the study referenced, the age at the time of oophorectomy, and the use of estrogen therapy after the surgery [2].

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Women at work: New horizons for menopause research

30 May, 2016

The relationship between menopause, paid employment and workplace environments is under the spotlight with the review of existing studies presented in our multi-authored paper [1]. 

We report that since 2000 there has been a growing number of studies which have systematically explored two interrelated concerns: whether, to what extent, and how menopausal symptoms influence women's work, including costs to employers; and the role of physical and psychosocial aspects of the workplace environment in aggravating or alleviating symptoms.

Work factors as well as menopause-related symptoms and disease affect working women. Work stress/overload, long/inflexible working hours, perceived job control, and gendered/aged-based workplace norms and stigmas, and anticipated supervisor/collegial responses, are key psychosocial factors that compound and complicate the impact of women's symptom experience. Vasomotor symptoms (VMS) are often reported as having a negative effect on women's productivity and experience at work. In some studies, the psychological and somatic symptoms accompanying VMS are more significant than the hot flashes per se.

Suggestions for employers are made which would support working women through menopause and the years that follow. Changes which could be made in the workplace are recommended, including health promotion programs.

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Effects of estradiol withdrawal on mood in women with past perimenopausal depression

29 June 2015

Peter Schmidt and his team have published some much needed research comparing the effects of the withdrawal of estrogen from women who have perimenopausal depression (PMD) with those who have continued the therapy [1]. After 3 weeks of open-label administration of transdermal estradiol (100 µg/day), participants were randomized to a parallel design to receive either estradiol (100 µg/day; 27 participants) or matched placebo skin patches (29 participants) for 3 additional weeks under double-blind conditions. The women completed the Center for Epidemiologic Studies-Depression Scale, the 17-item Hamilton Depression Rating Scale (completed by raters blinded to diagnosis and randomization status), and self-administered visual analog symptom ratings, and blood hormone levels were obtained at weekly clinic visits. The results showed that none of the 29 patients who received estradiol reported depressive symptoms but those who crossed over from estradiol to placebo experienced a significant increase in depressive symptoms. The conclusion was that, in women with a past history of PMD who had previous responded to hormone therapy, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that changes in estradiol can trigger an abnormal behavioral state in these susceptible women. Women with a history of PMD should be alert to the risk of recurrent depression when discontinuing hormone therapy and psychiatrists should be aware that there is more appropriate treatment than antidepressants and mood stabilizing drugs.

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Urine proteomics: a non-invasive diagnostic tool

22 June 2015: 

As a clinician, I was not aware of the growing interest in analyzing urine proteomics. The routine urine analysis includes urine protein levels but, in fact, in almost all cases we are interested in the urine albumin as a marker of kidney disease (nephropathy of all sorts, mainly diabetic). A full screen of urinary proteins and peptides (the urine proteome) is not available for routine clinical work. The reason for this has been two-fold: lack of data to establish the value of the test, and technical issues related to preparing the samples for the best and most accurate analysis. However, many recent studies show that characteristic changes in healthy elderly people's urine proteomes appear to reflect certain physiological processes associated with metabolic changes and the aging process [1]. Furthermore, documenting the urine proteome may facilitate earlier detection of disease, improve assessment of prognosis and allow closer monitoring of response to therapy [2]. So, which of the urinary proteins may serve as biomarkers of specific diseases?

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Suspected underutilization of hormone therapy in women 40–44 years

18 May, 2015:

The average age of menopause in women in the Western world is 51 years. Women who experience menopause between the ages of 40 and 45 years have what has been called 'early menopause', which is reported to occur in approximately 5% of women [1, 2]. These women, with a premature decrease of estrogen production, seem to have an increased risk of overall mortality and morbidity [2–5]. However, to our knowledge, only a few studies have been published on the benefits from long-term hormone therapy (HT) in this population [4,6].

According to the standard recommendations, HT should be given to women at premature or early menopause and should be continued at least to age 51–52 years, the average age of menopause in Shuster's study population (Mayo Clinic Olmsted County, Minnesota) [2].

In Sweden, the use of HT in 47–56-year-old women was approximately 6% (data from the Swedish Prescribed Drug Registry 2010–2012), which we consider to be an underutilization of HT when considering the prevalence of symptoms in this age group. We also suspected that the underutilization would be even more pronounced in women aged 40–44 years.

The aim was to determine the number of current and new HT users and the duration of HT use in Swedish women aged 40–44 years with probable early menopause during a 5-year period (July 2005–December 2011).

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To be or not to be in sexual desire: the androgen dilemma

11 May, 2015:

There is a biological plausibility for the association between sexual desire and androgens. Indeed, according to epidemiological and clinical studies, they both decline with age. However, any attempt to link directly low sexual desire with circulating low androgens (total testosterone, free testosterone) or androgen precursors (androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)) has failed to identify a lower limit that can be used to diagnose women with sexual dysfunction related to androgen deficiency [1]. A Danish cross-sectional study by Wåhlin-Jacobsen and colleagues [2] has recently reported that sexual desire, measured by the total score in the sexual desire domain of the Female Sexual Function Index (FSFI), correlated overall with free testosterone and androstenedione in a cohort of 560 healthy women aged 19–65 years. Moreover, the androstenedione : total testosterone ratio, an indirect marker of the activity of 17β-hydroxysteroid dehydrogenase, was overall correlated with women's sexual desire in women not using systemic hormonal contraception (HC) or postmenopausal hormone therapy (HT), indicating that the speed of transformation of androstenedione to testosterone is important. When the study population was stratified into three age groups depending on the intake of HC and HT, the authors demonstrated that, in women aged 25–44 years with no use of HC, sexual desire correlated with total testosterone, free testosterone, androstenedione, and DHEAS, whereas, in women aged 45–65 years, only androstenedione correlated with sexual desire. The primary androgen metabolite androsterone glucuronide did not show a correlation with sexual desire.

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For how long should osteoporosis treatment continue?

21 April, 2015

The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis was examined by Black and colleagues in a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT) [1]. The first extension study (EXT1) with zoledronic acid 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), a decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers compared with discontinuation after 3 years, but left the optimal duration of treatment uncertain.

To investigate the longer-term efficacy and safety of zoledronic acid, a second extension (EXT2) was conducted to 9 years, in which 190 women, out of 451 women on zoledronic acid for 6 years in EXT1, were randomized to either zoledronic acid (Z9) (n = 95) or placebo (Z6P3) (n = 95) for three additional years. The primary endpoint was the change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Secondary endpoints included fractures, bone turnover markers, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% CI -0.37% to 1.93%; p = 0.183). Bone turnover markers showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest that almost all patients who have received six annual infusions of zoledronic acid can stop medication for up to 3 years with apparent maintenance of benefits.

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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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