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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 July 2015 onward are available to Members only when logged in. Selected articles are open to public.

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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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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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