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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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Lupus erythematosus, rheumatoid arthritis and menopause

8 April, 2013:

Understanding the impact of menopause and age-related androgen decline on the onset and course of autoimmune diseases, as well as the potential for hormonal interventions, is critically important [1]. In women, the course of systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA) with onset after the age of menopause differs from that with onset before menopause. Early age at menopause is associated with increased disease risk and, after menopause, disease course changes in SLE and RA. This article summarizes what is known about the relationship between reproductive aging and autoimmune diseases in men and women, and highlights areas for further investigation.

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Genetic profiling of fracture risk

25 March, 2013:

A few decades ago, this might have been considered science fiction. But the ability to screen the entire human genome has become an important aid in the individualization of management of severe diseases. So far, gene profiling is mainly used in the hemato-oncology field and, to a lesser extent, in the area of chronic inflammatory diseases. A new review has shed light on both the research and clinical implications of genetic profiling as a means to identify individuals with high fracture risk [1]. To note, the tools already available in the market focus on people already afflicted with some serious disease, in which case gene profiling helps to decide on the best therapeutic approach. However, in regard to osteoporotic fractures, the idea is to detect future risk early and to implement primary prevention strategies accordingly. At the moment, bone mineral density (BMD) is the best predictor of fracture risk, and the initiation of anti-fracture therapies is based primarily on BMD results. However, several additional parameters (clinical, laboratory, personal and family history) should be part of decision-making as well. The FRAX score, adapted for each country, represents an approach better to identify individuals at higher risk for fractures. Early intervention according to predictive models has proved to have a beneficial effect in this respect [2]: in a fairly large study using the FRAX model, women lying at the 75th percentile of fracture probability (10-year probability, 24% at baseline) demonstrated a 27% reduction in fracture risk as a result of bisphosphonate therapy, whereas, in those with a fracture probability of 30% (90th percentile), the fracture risk reduction was 38%.

Nevertheless, the existing predictive models have not considered genetic variants in the prediction. Genome-wide association studies conducted in the past decade have identified several genetic variants relevant to fracture risk. These genetic variants are common in frequency but have very modest effect sizes. All genetic variants identified so far when considered in a multivariate model explain < 5% of variance in BMD and fracture susceptibility. It is thus assumed that additional genes should be sought, and perhaps some of these will demonstrate a higher impact on risk prediction. Empirical and simulation studies have shown that the usefulness of a single genetic variant for fracture risk assessment is very limited, but a profile of 50 genetic variants, each with an odds ratio ranging from 1.02 to 1.15, could improve the accuracy of fracture prediction beyond that obtained by use of existing clinical risk factors.

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SERMs, vulvovaginal atrophy and breast cancer

18 February, 2013:

A recent review [1] was intriguing, since it brought again to our attention the search for a desired molecule which should have optimal dual characteristics: inducing estrogen-like effects on menopause-related symptoms on the one hand, but avoiding the potentially serious adverse effects of postmenopausal hormone therapy on the other hand. Here is an Abstract of this review:

Vulvovaginal atrophy (VVA) in postmenopausal breast cancer patients has a significant impact on quality of life. While the etiology of VVA is primarily related to low estrogen levels seen in menopause, women with breast cancer have an added risk of VVA induced by a combination of chemotherapy, hormonal therapy, and menopause. Ospemifene is a new, non-hormonal selective estrogen receptor modulator (SERM) triphenylethylene derivative that is effective in treating VVA in postmenopausal women. Although other SERMs have antagonistic effects on the vagina, ospemifene exerts an estrogen-like effect on the vaginal epithelium. The review focuses on data demonstrating the antiestrogenic activity of ospemifene in several unique breast cancer animal models, and the implications for utilizing ospemifene in patients with breast cancer suffering from VVA.

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When and how often should we measure bone mineral density?

14 January, 2013:

In a study published last year, Margaret Gourlay and colleagues attempted to propose strategies for screening intervals of bone mineral density (BMD) testing [1]. Since then, the paper has been discussed in the correspondence section of the journal [2–5]. The authors analyzed data of 4957 women, 67 years of age or older, recruited in 1986 in the USA, who did not have osteoporosis at baseline, and who were followed longitudinally for up to 15 years within the Study of Osteoporotic Fractures (SOF) [6]. For this analysis, 49% of the total study population were excluded because they either already had osteoporosis, as defined by the World Health Organization (25%) [7] or treatment for osteoporosis or incomplete BMD data. BMD was measured by DXA at the femoral neck and total hip.

The primary outcome was to determine the BMD testing interval in these women, defined as the estimated time for 10% of the subjects to make the transition to osteoporosis from normal bone density or osteopenia at baseline, before a hip or clinical vertebral fracture occurred and before treatment for osteoporosis was initiated. The participants were stratified into four groups according to the T-score range (lowest T-score at femoral neck or total hip): normal BMD (T-score ≥ 1.00), mild osteopenia (T-score −1.01 to −1.49), moderate osteopenia (T-score −1.50 to −1.99), and advanced osteopenia (T-score −2.00 to −2.49). Sixty-two percent of women with advanced, 21% with moderate, and less than 5% with mild osteopenia, and not even 1% with normal BMD made the transition to osteoporosis.

Referring to calculations with parametric cumulative incidence models, the authors conclude that osteoporosis would develop in less than 10% of older women during rescreening intervals of approximately 1 year for women with advanced osteopenia, 5 years for women with moderate osteopenia, and 15 years for women with normal bone density or mild osteopenia, and, thus, they propose such interval testing for each group.

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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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