Primary screening for increased fracture risk by the FRAX® questionnaire-uptake rates in relation to invitation method.

The aim of the study was to evaluate the feasibility and most efficient way of offering middle-aged Swedish women a primary fracture screening program via a questionnaire. Two out of five invited women returned the FRAX questionnaire and those contacted directly by mail were most prone to respond. PURPOSE: Osteoporosis and its associated fractures are increasing, and this study aims to explore ways to identify women at an increased risk of fracture using the FRAX® algorithm. METHODS: Three thousand middle-aged women were invited and presented a questionnaire distributed by three different methods-by mail, at routine mammography, or internet-based. RESULTS: In total, 1120 (37.3%) women responded to the questionnaire and agreed to participate. The response rates for the mail, mammography, and internet-based groups were 39.1%, 35.7%, and 25.2% respectively. Women in the mammography group weighed more, were slightly older than the other women, and also had a higher BMI than women from the mail and internet-based groups. No difference was observed between the groups regarding previous fracture, family history for fracture, current smoking, glucocorticoid use, and alcohol usage. The mammography group had a higher median (interquartile range) major osteoporotic FRAX® score (10.0% (7.8-17.0)) than the mail group (9.7% (7.1-15.0); p = 0.005) and the internet-based group (8.7% (6.7-14.0); p = 0.001). CONCLUSIONS: Two out of five early postmenopausal women returned the questionnaire and women contacted directly by mail were more prone to respond. Out of the participants, 26.6% had a 10-year fracture risk score ≥ 15% according to the FRAX® algorithm.

EMAS position statement: The ten point guide to the integral management of menopausal health.

With increased longevity and more women becoming centenarians, management of the menopause and postreproductive health is of growing importance as it has the potential to help promote health over several decades. Women have individual needs and the approach needs to be personalised. The position statement provides a short integral guide for all those involved in menopausal health. It covers diagnosis, screening for diseases in later life, treatment and follow-up.

Associations between cadmium exposure and circulating levels of sex hormones in postmenopausal women.

Recent epidemiological as well as in vivo and in vitro studies collectively suggest that the metalloestrogen cadmium (Cd) could be a potential risk factor for hormone-related cancers in particularly breast cancer. Assessment of the association between Cd exposure and levels of endogenous sex hormones is of pivotal importance, as increased levels of such have been associated with a higher risk of breast cancer in postmenopausal women. The present study investigated the perceived relationship (multivariable-adjusted linear regression analyses) between Cd exposure [blood Cd (B-Cd) and urinary Cd (U-Cd)], and serum levels of androstenedione, testosterone, estradiol, and sex-hormone binding globulin (SHBG), in 438 postmenopausal Swedish women without hormone replacement therapy (HRT). A significant positive association between B-Cd (median 3.4 nmol/L) and serum testosterone levels, as well as a significant inverse association between B-Cd and serum estradiol levels and with the estradiol/testosterone ratio were encountered. However, U-Cd (median 0.69 nmol/mmol creatinine) was inversely associated with serum estradiol levels only. Our data may suggest that Cd interferes with the levels of testosterone and estradiol in postmenopausal women, which might have implications for breast cancer risk.

Use of proton pump inhibitors (PPI) and history of earlier fracture are independent risk factors for fracture in postmenopausal women. The WHILA study.

Postmenopausal women in the Western world are highly burdened by osteoporotic fractures. The aim of this study is to investigate risk factors at baseline for fracture in 6416 postmenopausal women during long-term follow-up. At baseline, all women completed a questionnaire regarding background factors, diseases, current use of medications and reproductive and contraceptive history, a physical examination and laboratory analyses. Fracture occurrence after inclusion in the study was recorded with the help of official registries. All significant variables in univariate logistic regression with a decreased or increased risk for fracture were analysed in a multivariate logistic regression. Increased fracture risk was observed in women currently using proton pump inhibitors (PPI), odds ratio (OR) 2.53 (95% confidence interval (CI)) 1.28-4.99, and women having had a fracture after the age of 40, but before inclusion in the study, OR 1.70 (95% CI 1.24-2.32). A protective effect against fractures was observed in women with a positive family history of diabetes OR 0.66 (95% CI 0.44-0.98). A significant interaction was observed between fracture risk, use of PPI and HT status (p=0.014) and women with HT had an increased fracture risk with use of PPI (OR 3.37 (95% CI 1.96-5.80)) compared to women without HT (OR 1.13 (95% CI 0.57-2.24)). In conclusion, usage of PPIs was associated with a doubled risk for fracture in postmenopausal women. Women with previous fractures using PPI should be considered for prophylactic treatment reducing fracture risk.

Alcohol use and early mortality in Swedish middle-aged women: Nine-year follow-up of the Women's Health in Lund Area study.

AIMS: The majority of prospective studies on alcohol use and mortality risk indicate that non-drinkers are at increased risk of death compared to moderate drinkers. This article investigates the association between middle-aged women's alcohol use and mortality, controlling for socio-demographic and health variables. An association between alcohol use and hospital in-patient care is also analysed. METHODS: Baseline data were collected during 1995-2000 in a population-based cohort of 6917 women aged 50-59 years living in southern Sweden, the Women's Health in Lund Area (WHILA). After 9 years, a register follow-up was performed from the National cause-of-death register and the Swedish hospital discharge register. Cox proportional hazards regression were used to analyse differences in survival. RESULTS: During the observation period, 201 (2.9%) women died. In a crude model, non-drinkers had a significantly increased risk for death. When including socio-demographic predictors in the model, there was a strong indication that non-drinkers were at increased risk for death compared to moderate drinkers. Adding health predictors, not drinking alcohol was no longer a risk factor for death. Further, analyses of in-patient care indicate that non-drinkers had poorer health during their entire adult life. CONCLUSIONS: This study underlines the importance of including health status at base-line when prospectively studying the association between alcohol use and mortality, otherwise moderate alcohol consumption may appear more beneficial than is the case.

Low androstenedione/sex hormone binding globulin ratio increases fracture risk in postmenopausal women. The Women's Health in the Lund Area study.

The Women's Health in the Lund Area (WHILA) project (n=6917) is a cohort study that started in 1995 and includes a postal questionnaire, physical examination, bone density measurement and blood laboratory analyses. Fracture data have been added, and in this report fracture risk and its association with sex hormones was analysed in postmenopausal women without current hormone therapy (HT). A total of 409 women (median age 56.8 years) with 489 fractures were identified from the postmenopausal women without HT during a median follow-up time of 8.4 years. Lower serum levels of androstenedione (p<0.001), testosterone (p=0.008), androstenedione/sex hormone binding globulin (SHBG) ratio (p<0.001), testosterone/SHBG ratio (p=0.003) and higher levels of SHBG (p=0.005) were observed in women with fractures compared to no fracture. No difference in oestradiol levels was observed. Androstenedione and androstenedione/SHBG ratio were further divided into percentiles. Increased fracture risk was found in postmenopausal women with androstenedione in 5th percentile compared to 11-89th percentile HR 1.51 (95% CI 1.02-2.24). The androstenedione/SHBG ratio (11-89th percentile as reference) showed increased fracture risk in women with low ratio 5th percentile HR 1.75 (95% CI 1.20-2.54) and decreased fracture risk with high ratio 95th percentile HR 0.52 (95% CI 0.28-0.98). An increased fracture risk during follow-up was encountered in postmenopausal women with low serum androstenedione and androstenedione/SHBG ratio at baseline and a decreased fracture risk with high androstenedione/SHBG ratio. This study suggests that postmenopausal osteoporosis is influenced by lower levels of androgens.

Hormone therapy and coronary heart disease risk by vasomotor menopausal symptoms.

OBJECTIVES: We examined whether the association between hormone therapy (HT) use and coronary heart disease (CHD) risk differed between women with and without vasomotor symptoms (VMS). STUDY DESIGN: We used data from a Dutch (EPOS) and Swedish (WHILA) population-based sample of 8865 women, aged 46-64 years, and free of CHD, stroke, venous thrombosis/pulmonary embolism or cancer at baseline. Data on HT use, VMS and potential confounders were collected by questionnaires. MAIN OUTCOME MEASURES: CHD endpoints, obtained via registries. RESULTS: 252 CHD cases occurred during 10.3 years of follow-up. Neither for women with nor for women without flushing or (night) sweats ever HT use was associated with CHD risk, compared with never HT use. Among women with intense VMS, ever HT use borderline significantly decreased CHD risk compared with never HT use (HR 0.48 [95% CI 0.20-1.03]). Among women without intense VMS, ever HT use was associated with a borderline significant increased CHD risk (HR 1.28 [95% CI 0.96-1.70]; P for interaction=0.02). However, after multivariate adjustment, as compared to never HT use, ever HT use was not associated with risk of CHD among women with or without intense VMS. CONCLUSIONS: In both groups of women with and without VMS, HT use does not seem to be associated with the risk of CHD. Hence, our findings do not support the view that HT use increases the CHD risk among women with an indication, i.e. VMS, but this needs to be confirmed in specifically designed studies.

Retinol may counteract the negative effect of cadmium on bone.

Cadmium and high vitamin A intake are both proposed risk factors for low bone mineral density (BMD), but potential interactions have not been studied. Within the Women's Health in the Lund Area, a population-based study in southern Sweden, we measured retinol in serum among 606 women aged 54-64 y. Data on BMD were measured by DXA at the distal forearm. Parathyroid hormone (PTH), bone alkaline phosphatase (bALP), and osteocalcin in serum and deoxypyridinoline (DPD) and cadmium in urine were available. Associations were evaluated using multivariable-adjusted linear regression analysis. Serum retinol concentrations (median, 1.9; range, 0.97-4.3 µmol/L) were inversely associated with the bone formation markers bALP and osteocalcin (P ≤ 0.04) and with PTH (P = 0.07) and tended to be positively associated with BMD (P = 0.08) but not with the bone resorption marker DPD, indicating different effects on bone compared to urinary cadmium (median, 0.66; range, 0.12-3.6 nmol/mmol creatinine). Women with serum retinol less than the median and cadmium greater than the median had lower BMD than those with retinol greater than the median and cadmium less than the median (P = 0.016 among all women and P = 0.010 among never-smokers). Our findings suggest that adequate vitamin A status may counteract the adverse association between cadmium and BMD.

Serum estradiol does not differentiate stress, mixed and urge incontinent women around menopause. A report from the Women's Health in the Lund Area (WHILA) study.

OBJECTIVE: To outline serum estradiol levels in perimenopausal women with stress, mixed or urge incontinence. We believe the majority of urgency symptoms in perimenopausal women to be caused by a pelvic floor dysfunction and a hypermobility of the bladder neck. If this is the case, there would be no difference in estradiol levels between the groups. SETTING: University hospital. In the observational Women's Health in the Lund Area study, a subset of 400/2221 women reporting urinary incontinence completed a detailed questionnaire regarding lower urinary tract symptoms and had their serum steroid hormone levels measured. Statistical analyses were made by Chi-square test, nonparametrical tests, ANOVA, multi- and univariate logistic regression analysis. RESULTS: Stress incontinence was reported by 196, mixed incontinence by 153 and urge incontinence by 43 women; in 369, serumestradiol values were available. Serum estradiol did not differ significantly between stress incontinent (median 49.5 pmo/l, range 2.63-875.4), urge incontinent (median 31.6 pmol/l, range 2.63-460.7) or mixed incontinent women (median 35.5 pmol/l, range 2.63-787.9, p=0.62). Logistic regression analysis correcting for age, parity, hormonal status, smoking, hysterectomy and BMI also failed to show any difference in estradiol levels between the groups (p=0.41-0.58). CONCLUSION: No significant differences in serum estradiol levels between stress, mixed or urge incontinent perimenopausal women could be demonstrated.

Vasomotor menopausal symptoms are associated with increased risk of coronary heart disease.

OBJECTIVE: Emerging evidence suggests that women with vasomotor menopausal symptoms (VMS) may have an adverse cardiovascular disease (CVD) risk profile. We investigated whether VMS are related to an increased risk of future coronary heart disease (CHD) and whether possible associations can be explained by CVD risk factors. METHODS: Data used were from a Dutch and Swedish population-based sample of 10,787 women enrolled between 1995 and 2000, aged 46 to 64 years, and free of CVD at baseline. Data on VMS were collected by questionnaires. Body mass index and blood pressure were measured in all women, and total cholesterol levels were measured in a subgroup of the population. Multivariable Cox regression models were used to analyze the data. RESULTS: After a mean ± SD follow-up period of 10.3 ± 2.1 years, 303 women were diagnosed with CHD. Symptoms of flushing were not associated with risk of CHD. However, the presence of night sweats was associated with a significantly modest increased risk of CHD, with a multivariable-adjusted hazard ratio of 1.33 (95% CI, 1.05-1.69). This association was attenuated but not eliminated after correction for body mass index, blood pressure, and total cholesterol (hazard ratio, 1.25; 95% CI, 0.99-1.58). CONCLUSIONS: Women with menopausal symptoms of night sweats have a significantly moderately increased risk of CHD, which cannot be totally explained by the levels of CVD risk factors.

Menstrual cycle characteristics and risk of coronary heart disease and type 2 diabetes.

In a prospective cohort study, we observed that women with a history of irregular cycles have a 28% increased coronary heart disease risk and tended to have a higher type 2 diabetes risk as compared with women who had a regular cycle length of 27 to 29 days. This association could not be explained by metabolic risk factors or altered hormone levels.

Vasomotor symptoms, estradiol levels and cardiovascular risk profile in women.

OBJECTIVES: We investigated whether menopausal vasomotor symptoms (VMS) are related to an adverse cardiovascular risk profile. Furthermore, we examined the association between estradiol levels and VMS, and whether an association between VMS and cardiovascular risk factors can be explained by estradiol levels. STUDY DESIGN: We used data from a Swedish population-based sample of 5857 women, aged 50-64 years. Data on VMS and potential confounders were collected by questionnaires. MAIN OUTCOME MEASURES: Body mass index (BMI), waist hip ratio (WHR), glucose, blood pressure, lipid profile and estradiol levels were measured. RESULTS: Symptoms of flushing/sweats were reported by 55% and sweats by 31% of all women. Estradiol concentrations were significantly lower in women with VMS. After multivariate adjustment, women with symptoms of sweats had a statistically significantly higher BMI, waist hip ratio, total cholesterol level, LDL level, triglycerides level, glucose level, systolic and diastolic blood pressure. These patterns did not change after correction for estradiol. The associations between flushing/sweats combined and cardiovascular risk factors were less pronounced. CONCLUSIONS: Women with VMS have a less favorable cardiovascular risk profile. Although estradiol levels were significantly lower among women with VMS, the increased cardiovascular risk profile cannot be explained by circulating estradiol levels.

A prospective observational study of the effects of treatment with extended-release tolterodine on health-related quality of life of patients suffering overactive bladder syndrome in Sweden.

OBJECTIVE: Overactive bladder (OAB) is a chronic condition that has a profound impact on health-related quality of life (HRQoL). This study measured changes in bother of OAB symptoms and self-perceived HRQoL over 6 months in patients treated with extended-release (ER) tolterodine in a naturalistic setting. MATERIAL AND METHODS: This was a prospective, single-cohort observational study of patients diagnosed with OAB, naïve to antimuscarinic treatment and prescribed tolterodine ER for the first time. Patients were asked to complete the Overactive Bladder Questionnaire (OAB-q) containing a symptom bother scale (0-100) and an HRQoL scale (0-100), which measures coping, social interaction, concern and sleep, at baseline and after 3 and 6 months. RESULTS: In total, 235 patients (211 women and 24 men), with a mean age of 61 years (30-87), were recruited. The numbers of patients who completed the OAB-q were 220 and 169 at 3 and 6 months, respectively. The mean reductions in the symptom bother score from baseline were 19.6 and 19.3 at 3 and 6 months, respectively. Significant improvement (p < 0.0001) was seen in all HRQoL subscale scores. The proportion of responders who met the minimally important difference (change in the score of 10 or more units between baseline and 6 months) was 64% for the symptom bother score and 34-60% for the total HRQoL and subscale scores. CONCLUSIONS: OAB patients beginning treatment with tolterodine ER reported clinically significant improvement in OAB symptoms and self-perceived HRQoL over the 6 months of this observational study. The rate of discontinuation from treatment was 49%.

The women's health in the Lund area (WHILA) study--an overview.

The Women's Health in the Lund Area (WHILA) study invited all women (n=10,766) living in the Lund area of Southern Sweden by 1995, who were born between 1935 and 1945. The health screening program included a postal validated questionnaire concerning medical history, drug treatment, family history of diabetes and hypertension, menopausal status, smoking and alcohol habits, education, household, and working status, physical activity, quality of life as well as subjective physical and mental symptoms. The screening consisted of a routine physical examination with standardized blood pressure measurements, bone densitometry and an extended laboratory examination. A link with the mammography registry was established. Based on menopausal status, the population was divided in three subgroups; premenopausal (PM), postmenopausal with hormone replacement therapy (PMT), and postmenopausal without hormone replacement therapy (PM0). Menopause was defined as a bleed-free interval of at least 12 months. Of 10,766 women, 6917 (64.2%) had complete data sets. A number of observational analyses were carried out based on the screening data at baseline, to be followed by long-term follow-up analyses based on national register linkages that are currently being started.

Exposure to p,p'-DDE: a risk factor for type 2 diabetes.

BACKGROUND: Persistent organic pollutants (POPs), such as PCBs, DDT and dioxins have in several cross-sectional studies shown strong associations with type 2 diabetes mellitus. Reversed causality can however not be excluded. The aim of this case-control study was to evaluate whether POPs concentration is a risk factor for type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: A case-control study was performed within a well-defined cohort of women, age 50-59 years, from the Southern part of Sweden. Biomarkers for POP exposure, 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE) were analyzed in stored serum samples, which were collected at the baseline examination when the cohort was established. For 107 out of the 371 cases, serum samples were stored at least three years before their type 2 diabetes was diagnosed. In this data set, CB-153 and p,p'-DDE were not associated with an increased risk to develop type 2 diabetes. However, when only the cases (n = 39) that were diagnosed more than six years after the baseline examination and their controls were studied, the women in the highest exposed quartile showed an increased risk to develop type 2 diabetes (OR of 1.6 [95% 0.61, 4.0] for CB-153 and 5.5 [95% CI 1.2, 25] for p,p'-DDE). CONCLUSIONS/SIGNIFICANCE: The results from the present case-control study, including a follow-up design, confirms that p,p'-DDE exposure can be a risk factor for type 2 diabetes.

The relation between urinary incontinence and steroid hormone levels in perimenopausal women. A report from the Women's Health in the Lund Area (WHILA) study.

OBJECTIVE: To outline possible associations between urinary incontinence (UI) and serum levels of steroid hormones in middle-aged women. DESIGN AND SETTING: Community-based observational study. SAMPLE: All women aged 50-59 living in the Lund area by December 1995 were invited to a screening procedure. Sixty-four percent (n = 6,917) attended the screening that included physical and laboratory examinations and questionnaires. METHODS: Serum levels of cortisol, testosterone, androstendione, SHBG (sex hormone-binding globulin), and estradiol were analyzed and the 2,221 (32%) women who reported urinary leakage causing a social or hygienic problem were compared to those who denied incontinence. MAIN OUTCOME MEASURE: Possible differences in serum levels of steroid hormones in continent and incontinent women. RESULTS: There were no significant differences between continent and incontinent women regarding serum levels of cortisol, testosterone, androstendione, or testosterone + androstendione combined. Serum estradiol adjusted for body mass index, parity, smoking, and hysterectomy was significantly higher in incontinent women (87.1 +/- 138.4 pmol/l vs. 78.0 +/- 118.5 pmol/l, p = 0.005), whereas the ratio estradiol/SHBG was not. These differences persisted when the group of women not on hormonal treatment was analyzed. CONCLUSIONS: UI in middle-aged women seems related to higher serum estradiol levels. This corroborates with studies showing a higher incidence and/or prevalence of UI in women on hormone therapy. No association between UI and serum levels of cortisol, testosterone, or androstendione was found.

Nonhormonal drug use and its relation to androgens in perimenopausal women: a population-based study of Swedish women. The Women's Health in the Lund Area Study.

OBJECTIVE: To outline the prevalence of nonhormonal drug use in middle-aged women and to assess plausible associations between serum androgen levels and variables associated to health such as drug use and planned visits to healthcare units. METHODS: This was a population-based study of women aged 50 to 59 years (n = 6,893). Women were divided into three groups according to their menopause status: premenopausal (PM), postmenopausal without hormone therapy (PM0), and postmenopausal with hormone therapy (PMT). Data regarding current drug use and healthcare visits were collected from a questionnaire. RESULTS: The overall prevalence of nonhormonal drug use was 36.4% in all women. In the PM, PM0, and PMT groups, these percentages were 28.3%, 35.3%, and 39.3%, respectively, and the differences between them were statistically significant (P < 0.01). In all women, the most common medication used was for cardiovascular conditions (12.0%), followed by those for asthma (4.0%) and pain (3.7%). The number of drugs used by all women and women in the PM0 and the PMT groups were negatively associated with the serum levels of androstenedione (P < 0.05). In the postmenopausal groups, the number of visits to healthcare units was negatively associated to the levels of serum testosterone and androstenedione (P < 0.05). CONCLUSIONS: Hormone therapy in postmenopausal women seems to be associated with increased use of nonhormonal pharmacotherapy, rendering higher prevalence of such drugs in middle-aged women. Postmenopausal women with lower serum testosterone and a higher number of office visits used medications for cardiovascular problems and depression more than other medications. Whether this is an effect related to the hormone therapy itself or to experiencing more perimenopausal symptoms in this group of women is still unclear.

Prevalence of symptoms in relation to androgen concentrations in women using estrogen plus progestogen and women using estrogen alone.

OBJECTIVE: Women using estrogen plus progestogen therapy sometimes report difficult to describe symptoms, eg, changes in libido, mood, and memory, that may be related to decreased androgens. To evaluate the prevalence of such symptoms and relate these symptoms to androgen levels in women using estrogen plus progestogen therapy, data from the Women's Health in the Lund Area Study were analyzed. DESIGN: A total of 2,816 women using estrogen plus progestogen therapy were asked to complete a questionnaire consisting of questions concerning sexual well-being and different aspects of quality of life. Serum concentrations of testosterone, androstendione, sex hormone-binding globulin, and estradiol were measured. RESULTS: A total of 2,048 questionnaires were eligible for evaluation. Almost 40% of the women reported decreased libido. Approximately 70% were satisfied with their current sex life. Eight percent reported that intercourse was unpleasant because of vaginal dryness. No evident associations were found between libido and serum hormone concentrations. The most positive effects of estrogen plus progestogen therapy concerning memory and urinary tract and vaginal complaints were found in women with the highest and/or moderate testosterone levels (P < 0.05). CONCLUSIONS: We found no strong association between symptoms related to sexual well-being or quality of life and androgen concentrations in this study. Estrogen plus progestogen therapy did not seem to affect symptoms that might be related to low levels of androgens in the group of climacteric women whom we studied.

Vasomotor symptoms are associated with a lower bone mineral density.

OBJECTIVE: The severity of vasomotor symptoms has been hypothesized to be linked to a lower bone mineral density (BMD). We examined whether women with vasomotor symptoms are different from women without symptoms with regard to BMD. METHODS: We used data from a population-based sample of 5,600 women, aged 46 to 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. Questionnaires at baseline were used to collect data on vasomotor symptoms and potential confounders. At baseline, BMD of the lumbar spine was measured using dual energy x-ray absorptiometry. Linear regression analysis was used to analyze the data. RESULTS: Flushing was reported by 39% of all women, and night sweats, by 38% of all women. The average BMD was 1.01 +/- 0.14 g/cm and decreased with increasing frequency of flushing (P for trend < 0.0001) and night sweats (P for trend = 0.03). After multivariate adjustments for age, body mass index, 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. CONCLUSIONS: Our findings show that vasomotor symptoms are associated with reduced bone density. It could be hypothesized that women with vasomotor symptoms might be more susceptible to the beneficial effects of estrogens, possibly by neutralizing the effect of estrogen fluctuations. Further research is needed to extend these findings to other estrogen-sensitive end organs.