Abstract
Sitting is the problem, not just lack of exercise
A report from the Women's Health Initiative Observational Study (WHI-OS) in 2002 found that low levels of recreational physical activity and a longer time spent sitting down were both associated with an increased risk of cardiovascular disease (CVD). 1 At the time, however, the independent and joint associations of sedentary time and physical activity with CVD events were not reported; since then, evidence has started to emerge that sedentary behaviour does indeed have independent effects on human metabolism, physical function and potentially on health outcomes.
Now, a 10-year follow-up of the same WHI-OS study has updated the original variables and examined the interrelationship of sitting time and physical activity – and the results do provide some idea of how these two separate components of “energy balance” exert their independent and joint effects on CVD risk in older women. 2
The results suggest that prolonged sitting time – independent of other physical activity – is indeed associated with a raised risk of CVD in postmenopausal women. So even those who exercise as ordained by current guidelines but flop back in the chair as soon as they're back from the yoga class may not be getting the best metabolic benefit from their activity. Sitting, warn the authors, is “a unique aspect of human behavior, [and] may not simply represent the extreme low end of the physical activity continuum”.
The WHI-OS was a prospective study of 71,018 women aged 50–79 years who were free of CVD at baseline assessment in 1993–1998. At that time and up to 2010, they also provided information on their sedentary as well as physically active behaviour in terms of hours per day. Results later showed that over a median follow-up period of 12.2 years, greater sitting time and decreased physical activity were both associated with an increased risk of heart disease and stroke.
Thus, sitting for 10 or more hours a day when compared to five or more hours a day was associated with an 18% increase in CVD risk (HR 1.18, 95% CI 1.09–1.29) in multivariable models which included physical activity. When women were “cross-classified” by sitting time and physical activity, CVD risk was found to be highest in the inactive women who also reported 10 or more hours a day sitting down. Results were similar for coronary heart disease and stroke when examined separately. Moreover, the associations between prolonged sitting and risk of CVD were stronger in overweight versus normal weight women and in women aged 70 years and older compared to younger women. The adjusted hazard ratio for CVD events for each hour per day sitting was 1.02 (95% CI 1.01–1.03).
The overall adjusted hazard ratios for CVD events (heart disease and stroke) according to physical activity level were 1.35 for inactive, 1.23 for low, 1.13 for medium and 1.00 for high. The highest risk was found in inactive women who also reported sitting at least 10 hours per day (HR 1.63, 95% CI 1.39–1.90). This risk was higher still when the subjects had a high (>25) BMI.
Speaking to the press, lead author Andrea Chomistek, from Harvard School of Public Health, explained that sitting was more harmful than almost every grade of exercise (which were defined as high, medium, low and inactive). The second-highest activity group, the women who were medium exercisers, were meeting physical-activity guidelines by getting, for example, two and a half hours a week of moderate activity. “But if they sat a lot,” said Chomistek, “they had an increased [CVD] risk.” Medium activity was defined as 8.4 to 20 metabolic equivalent task (MET)-hours per week.
She added that women who sat more tended to exercise less, and vice versa, but emphasised that sitting time and activity levels were independent of each other – “it's a common misconception that they are essentially opposites on the same spectrum,” she said.
Exercise, of course, remains the public health message from the study, but, with the numbers of elderly continuing to rise and a relatively high prevalence of physical inactivity in this age group, the investigators were somewhat sanguine about the resonance of the message. They propose that reducing sitting time among older women who are less active “could potentially” reduce the risk of heart disease and stroke, but concede that, for those who are unable or averse to exercise, the amount of time spent sitting may be more amenable to change than increasing levels of physical activity.
SERMs in the prevention of breast cancer
A large study involving more than 83,000 women, with 306,617 women-years of follow-up, has found that the selective estrogen receptor modulators (SERMs) reduce the incidence of invasive estrogen-receptor positive breast cancer both during and for at least five years after the completion of treatment. 1 The study was a meta-analysis of updated data from nine prevention trials comparing four SERMs – tamoxifen, raloxifene, arzoxifene and lasofoxifene with placebo, or in one study with tamoxifen. The primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10-year follow-up period.
Results showed a 38% reduction (HR 0·62, 95% CI 0·56–0·69) in breast cancer incidence; 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first five years of follow-up than in the second (42% versus 25%). No effect was noted for ER-negative breast cancers.
However, use of SERMs significantly increased the incidence of thromboembolic events (HR 1·73, 95% CI 1·47–2·05; p < 0·0001), but reduced the incidence of vertebral fractures (HR 0·66).
Commenting on the results in a press release, the study's principal investigator, Jack Cuzick from Queen Mary, University of London, said: “Despite their effectiveness, many women have opted not to take SERMs because of concerns about toxic effects. But our longer-term findings clearly show that the benefit-harm balance is now more favourable than previously calculated for short-term follow up. The benefits of these drugs continue well after treatment has stopped, whilst most of the side effects do not.”
However, Cuzick noted at the end of the report that “unfortunately, at the present time, none of these drugs are being actively marketed for breast cancer prevention, and approval by the US Food and Drug Administration or any other regulatory authority for this indication will probably not be sought for lasofoxifene or arzoxifene”.
How a mother's age at menopause predicts her daughter's ovarian reserve
A curious study from Denmark has shown that a woman's age at menopause is associated with the ovarian reserve of her daughter at any given age. 1 The finding thus adds a little biology to the epidemiological truth that the menopausal age of mothers and daughters is inheritably linked: that an early maternal menopause is related to an advanced depletion of the ovarian reserve and that late maternal menopause is related to a delayed depletion.
Ovarian reserve has become a hot topic in reproductive medicine over the past decade, measured principally by two markers supposedly indicative of the number of functional follicles remaining in the ovary. However, while ovarian reserve – as measured by anti-Mullerian hormone (AMH) or antral follicle count (AFC) – has proved useful in predicting how women will respond to ovarian stimulation for IVF, its ability to predict pregnancy has been less evident.
Nevertheless, studies do consistently show that female “fertility” is broadly linked to ovarian reserve – that is, that the age-related decline in fertility which all women experience is accompanied by (and reflected in) a decline in AMH levels and AFC. The decline in fertility and in ovarian reserve is thus a decline in loose parallel, with each stage along the way fixed by years. Thus, a woman whose menopause begins with evident symptoms at the age of 45 will probably have started her age-related decline in fertility some 20 years earlier – and it's for this reason that fertility clinics are more disposed to think of ovarian age than chronological age in the fertility status of their patients.
AMH has already been proposed as a predictive marker for menopausal age. 2 But this Danish study is, apparently, the first to demonstrate a significant association between age at maternal menopause and serum AMH levels in daughters. The study comprised 527 subjects from a prospective cohort of 20–40-year-old healthcare workers (at Copenhagen University Hospital) whose mothers' age at natural menopause was known. Ovarian status was assessed by serum AMH analyses and transvaginal ovarian sonography, while data on reproductive history, including age at maternal menopause, were obtained via questionnaire. Covariate analysis was adjusted for BMI, use of oral contraceptives, smoking habits and prenatal smoking exposure.
The analysis found a significant effect of the mother's menopausal age on both serum AMH levels and AFC in the daughters. Median serum AMH concentration declined by 8.6% per year in the group with early maternal menopausal age (≤45 years), by 6.8% per year in the group with normal maternal menopausal age (46–54 years) and by 4.2% per year in the group with late maternal menopausal age (≥55 years). Comparable declines in AFC were also found.
So what do the results mean? The study appears to show that the age band of maternal menopause is related to the rate of decline in markers of ovarian reserve, with a greater rate of decline found in subjects whose mothers had an early menopause. However, the investigators would not go so far as to say that maternal age at menopause is a direct predictor of menopausal age in the offspring – or their chance of pregnancy.
“Nevertheless,” they write, “from a biological point of view, it may be reasonable to assume that a low ovarian reserve may have a long-term effect that will shorten the reproductive life span. We therefore assume that markers such as ‘maternal age at menopause’ in combination with AMH or AFC, and chronological age may represent a more complete picture when evaluating the ovarian reserve of the individual.”
Fat distribution in postmenopausal women
While most women will know from experience that they carry any excess fat on their hips and thighs (and men on their stomachs), they will be less aware that after the menopause their fat distribution starts to resemble that of men. Estrogen – as with so many physiological processes in women – has long been linked to this pattern of fat storage, but the underlying cellular mechanism has not been fully explained.
Now a small study from the Mayo Clinic in the US suggests that certain proteins and enzymes which correspond with fat storage are more active in post than in premenopausal women and tend to store more fat than before the menopause. 1
The study measured adipose tissue fatty acid (FA) storage and FA storage factors in 12 premenopausal and 11 postmenopausal women matched for age and body composition. It was found that the postmenopausal women had lower postprandial FA oxidation, greater meal FA and direct free FA storage than the premenopausal women, which included a two-fold greater meal FA storage in the femoral depot, suggesting, said the authors, that the propensity for subcutaneous adipose tissue FA storage is increased in postmenopausal women, mainly from changes in adipocyte FA storage factors. And the explanation for these differences in adipocyte fatty acid storage factors is thought to be “female sex steroids, most likely estrogen.” Falling levels of estrogen, they add, “have important effects on adipose tissue FA storage and FA oxidation that could promote fat gain in postmenopausal women.”
Use of strontium ranelate restricted in treatment of osteoporosis
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a restriction in the use of strontium ranelate for the treatment of osteoporosis. 1 The move follows an analysis of pooled data from randomised studies in around 7500 postmenopausal women with osteoporosis. The results showed an increase in the risk of myocardial infarction as compared with placebo (1.7% versus 1.1%), with a relative risk of 1.6 (95% CI, 1.07–2.38). No increased risk in mortality was observed.
The CHMP thus recommended that strontium ranelate (available as Protelos or Osseor) should only be used to treat severe osteoporosis in postmenopausal women at high risk of fracture and severe osteoporosis in men at increased risk of fracture. Additional measures, including restrictions in patients with heart or circulatory problems, were also recommended to minimise the heart risks of these medicines.
According to the EMA, the opinion will now be sent to the European Commission for a legally binding decision.