Use of dopamine agonists to target angiogenesis in women with endometriosis.

Endometriosis requires medical management during a woman's reproductive years. Most treatments aim to create a hypoestrogenic milieu, but for patients wishing to conceive, drugs that allow normal ovarian function are needed. Targeting angiogenesis, a hallmark of the disease, using dopamine agonists (DAs) is a promising strategy for endometriosis treatment. Herein, we review experimental and clinical data that investigate this concept. In experimental models of endometriosis, DAs (bromocriptine, cabergoline, quinagolide) downregulate proangiogenic and upregulate antiangiogenic pathways in inflammatory, endothelial and endometrial cells, blocking cellular proliferation and reducing lesion size. Impaired secretion of vascular endothelial growth factor (VEGF) and inactivation of its receptor type-2 are key events. VEGF inhibition also reduces nerve fiber density in lesions. In humans, quinagolide shows similar effects on lesions, and DAs reduce pain and endometrioma size. Moreover, a 20-fold downregulation of Serpin-1, the gene that encodes for plasminogen activator inhibitor 1 (PAI-1), has been observed after DAs treatment. Pentoxifylline, a PAI-1, increases pregnancy rates in women with endometriosis. Thus, the data support the use of DAs in the medical management of endometriosis to reduce lesion size and pain while maintaining ovulation. A combined approach of DAs and pentoxifylline is perhaps a smart way of targeting the disease from a completely different angle than current medical treatments.

Association of a dopamine beta-hydroxylase gene variant with depression in elderly women possibly reflecting noradrenergic dysfunction.

BACKGROUND: Depression has a multifactorial etiology which involves genetic factors and comorbid diseases. METHODS: A cross-sectional sample of 1371 elderly women (mean age=69.2 years) was examined. Detailed information on their health was obtained. Cognitive functions were assessed by the Short Blessed Test and the Animal Naming Task. A 19 bp insertion/deletion polymorphism in the dopamine beta-hydroxylase (DBH) gene, the apolipoprotein (APOE) epsilon2/epsilon3/epsilon4 variation and 5-HTTLPR in the serotonin transporter gene were genotyped. RESULTS: Depression was univariately associated with homozygosity for the DBH gene 19 bp deletion allele (odds ratio [OR]=1.96, 95% confidence intervals [95% CI]=1.17-3.29, p=0.01), family history of depression (OR=3.86, 95% CI=1.85-8.06, p=0.0003), a composite measure of cardiovascular diseases (OR=1.96, 95% CI=1.11-3.47, p=0.02), cognitive impairment assessed by the Short Blessed Test (OR=3.88, 95% CI=1.29-11.64, p=0.02) and performance on the Animal Naming Task (OR=0.74, 95% CI=0.59-0.93, p=0.01). The strength of the association of DBH genotype with depression essentially remained unchanged after correction for other variables in a multivariate model. This association may reflect noradrenaline dysfunction in the brain.

Enlarged waist combined with elevated triglycerides is a strong predictor of accelerated atherogenesis and related cardiovascular mortality in postmenopausal women.

BACKGROUND: Upward trends of obesity urge more effective identification of those at cardiovascular risk. A simple dichotomous indicator, enlarged waist (> or =88 cm) combined with elevated triglycerides (> or =1.45 mmol/L) (EWET), was shown to offer advantages in identifying individuals with atherogenic "lipid overaccumulation" compared with other indicators, including the metabolic syndrome defined by the National Cholesterol Education Program (MS-NCEP). Whether EWET offers superior disease and event prediction in postmenopausal women, however, remains unknown. METHODS AND RESULTS: A community-based sample of 557 women (48 to 76 years of age) were followed up for 8.5+/-0.3 years to assess the utility of EWET and MS-NCEP in estimating the risk of all-cause and cardiovascular mortality and the annual progression rate of aortic calcification. At baseline, 15.8% of women had EWET and 17.6% had MS-NCEP. All-cause mortality and cardiovascular mortality were increased in carriers of the dichotomous indicators (P<0.001). After adjustment for age, smoking, and LDL cholesterol, presence of EWET was associated with a 4.7-fold (95% CI, 2.2 to 9.8; P<0.001) increased risk and presence of MS-NCEP was associated with a 3.2-fold (95% CI, 1.5 to 6.5; P<0.001) increased risk for fatal cardiovascular events. Exclusion of women with prevalent diabetes did not change these trends; respective hazard ratios were 4.2 (95% CI, 1.9 to 9.3; P<0.001) and 2.5 (95% CI, 1.1 to 5.5; P<0.05). Among those who were discordant for EWET and MS-NCEP at baseline, those who had EWET alone (n=21) had a higher annual progression rate of aortic calcification compared with those who had MS-NCEP alone (n=31; P<0.05). CONCLUSIONS: The combined presence of EWET may be the best indicator of cardiovascular risk in postmenopausal women. Other components of the MS-NCEP add little medical value to screening in general practices.

Estrogen receptor alpha and risk for cognitive impairment in postmenopausal women.

The estrogen receptor alpha (ESR1) gene has been implicated in the process of cognitive impairment in elderly women. In a paired case-control study, we tested whether two ESR1 gene polymorphisms (the XbaI and PvuII sites) are risk factors for cognitive impairment as measured by the six-item Orientation-Memory-Concentration test in postmenopausal Danish women. Hormone replacement therapy, age and executive cognitive ability were examined as covariates for ESR1 gene effects on cognitive impairment. The XbaI polymorphism showed a marginal effect on cognitive abilities (P=0.054) when adjusted for executive cognitive ability. Using a dominant genetic model for the X allele, we found an elevated risk (executive cognitive ability adjusted P=0.033) for cognitive impairment. Hormone replacement therapy also had a borderline effect on cognitive ability (P=0.049) and this effect was reflected in executive cognitive ability. These data support that the ESR1 gene variants affect cognitive functioning in postmenopausal women.

Peripheral adiposity exhibits an independent dominant antiatherogenic effect in elderly women.

BACKGROUND: Although several lines of evidence point to an atherogenic role of central fat mass (CFM), few data are available to address the specific role played by peripheral fat mass (PFM). METHODS AND RESULTS: This study was a cross-sectional analysis of 1356 women aged 60 to 85 years. Study variables were physical measures, CFM and PFM measured by DEXA, aortic calcification (AC) graded on lateral radiographs, lipid and glucose metabolites, blood pressure, and information on lifestyle factors and coronary disease. Peripheral fat mass showed independent negative correlation with both atherogenic metabolic risk factors and AC (P<0.001). The most severe insulin resistance-dyslipidemic syndrome and AC (score 5.10+/-0.76) was found in women with high central fat percentage (CF%, 21.7+/-0.2%) and low peripheral fat percentage (PF%, 18.3+/-0.2%, n=48). The least severe AC (score 2.45+/-0.31) was found in obese women with high CF% (21.6+/-0.1%) and high PF% (27.3+/-0.14%, n=112). The insulin resistance-dyslipidemic syndrome was also less severe compared with those with the same CF% but low PF%. The most favorable metabolic profile characterized women with low CF% (11.56+/-0.16%) and high PF% (26.86+/-0.33%, n=44). In women with a history of myocardial infarct (18.41+/-0.55%, n=45), CF% was significantly higher compared with women with no manifest coronary disease (16.48+/-0.12%, n=1210) without differences in PF%. CONCLUSIONS: In elderly women, localization of fat mass is apparently more important for atherosclerosis than obesity per se; although CFM is associated with atherogenic tendencies, PFM seems to exhibit an independent dominant antiatherogenic effect.

Novel associations between bioavailable estradiol and adipokines in elderly women with different phenotypes of obesity: implications for atherogenesis.

BACKGROUND: Peripheral adiposity confers protection against diabetes and atherosclerosis in elderly women. The underlying mechanisms, however, remain to be elucidated. METHODS AND RESULTS: On the basis on dual-energy X-ray absorptiometry measurements of central fat mass (CFM) and peripheral fat mass (PFM), we identified 290 elderly women with distinct forms of body fat distribution (lean, peripheral obesity, central obesity, or general obesity). Study parameters were plasma tumor necrosis factor-alpha, interleukin (IL)-6, adiponectin, estradiol, sex hormone-binding globulin, insulin resistance, and aortic calcification, graded on lateral radiography. In peripherally and generally obese women, plasma estradiol and insulin resistance were significantly lower, whereas sex hormone-binding globulin and adiponectin were significantly higher compared with centrally obese women independent of age, body mass index, total fat mass, and smoking habits (all P<0.05). After adjustment for these confounders, IL-6 in centrally obese women was comparable with that seen in generally obese (similar high CFM%) but significantly higher than in peripherally obese women and lean women (low CFM%). Atherosclerosis was less severe in generally obese (2.5+/-0.3) compared with centrally obese women (5.0+/-0.7, P=0.001). In multiple regression analysis, total fat mass, body fat distribution, insulin resistance, estradiol, current smoking, treated hyperlipidemia, and treated hypertension contributed independently to the variation of aortic calcification (R=0.55, SEE=3.60, P<0.001). CONCLUSIONS: Abundant presence of PFM in generally obese women is associated with increased plasma adiponectin and higher insulin sensitivity, which could explain the apparent protection against the atherogenic effects of IL-6 derived from CFM. Low peripheral exposure to estradiol appears to be a sine qua non of maintained adiponectin secretion from PFM.

Oral salmon calcitonin induced suppression of urinary collagen type II degradation in postmenopausal women: a new potential treatment of osteoarthritis.

OBJECTIVE: To assess the efficacy of 3 months of oral salmon calcitonin (sCT) on cartilage degradation as estimated by the changes in the urinary excretion of C-terminal telopeptide of collagen type II (CTX-II), and to investigate whether the response of oral sCT to urinary CTX-II depends on the baseline level of cartilage turnover. METHODS: This was a randomized, double blind, placebo-controlled clinical setting including 152 Danish postmenopausal women aged 55-85. The subjects received treatment with the different doses of sCT (0.15, 0.4, 1.0, or 2.5 mg) combined with Eligen technology-based carrier molecule (200 mg), or placebo for 3 months. The efficacy parameter was the changes in the 24-h excretion of urinary CTX-I/II corrected for creatinine excretion at month 3. RESULTS: sCT induced a significant dose-dependent decrease in 24-h urinary CTX-II excretion. Similar dose-dependent responses were found in 24-h urinary CTX-I. When stratifying the study population into tertiles of baseline urinary CTX-II, the present osteoarthritic symptoms and definite cases of osteoarthritis (OA) were significantly more frequent in women in the highest tertile of CTX-II (mean 391 +/- 18 ng/mmol). Women who received 1.0 mg of sCT and had the highest cartilage turnover presented the greatest decrease in urinary CTX-II after 3 months of treatment. CONCLUSION: In addition to its pronounced effect on bone resorption, this novel oral sCT formulation may also reduce cartilage degradation and thereby provide therapeutic benefit in terms of chondroprotection. Women with high cartilage turnover are more likely to benefit from oral sCT treatment.

Early postmenopausal hormone therapy may prevent cognitive impairment later in life.

OBJECTIVE: Estrogen deficiency has been implicated as a risk factor for cognitive impairment in elderly women, yet the role of hormone therapy (HT) to prevent this event remains controversial. The aim of this study was to investigate the impact of administration of HT for 2 to 3 years in the early postmenopausal years on the risk of cognitive impairment 5 to 15 years later. DESIGN: We followed a group of 343 women who had received HT in randomized, placebo-controlled trials and were reexamined 5, 11, or 15 years after completion of therapy. Of these women, 261 received either HT or placebo for 2 to 3 years during the trials with no further hormone treatment until follow-up, and the remaining 82 women reported either prolonged or current use of HT at reexamination. Outcome of the study was cognitive function assessed by the short Blessed test that includes tests of orientation, concentration, and memory function on a scale of 0 to 28 (score > or =6 indicates cognitive impairment). RESULTS: The mean age of participants at follow-up was 65 +/- 3 years. There was no difference in the mean cognitive scores between ever HT users and never users. For women who received 2 to 3 years of HT, the risk of cognitive impairment (cognitive score > or =6) was decreased by 64% (odds ratio [OR]: 0.36, 95% CI: 0.15-0.90; P = 0.03). A similar OR was found in long-term/current HT users. Adjustment for age, alcohol intake, current smoking, and education did not alter the results. CONCLUSION: The results of the present study suggest that previous short-term HT administered in the early phase of the menopause may provide a long-term protection against cognitive impairment.

Safety and efficacy of a novel salmon calcitonin (sCT) technology-based oral formulation in healthy postmenopausal women: acute and 3-month effects on biomarkers of bone turnover.

UNLABELLED: Oral administration of calcitonin could improve compliance to long-term treatment. Efficacy and safety of a novel oral formulation was assessed on 277 postmenopausal women. The results show (1) effective enteral absorption, (2) marked inhibition of bone resorption with minimal alteration of formation, and (3) reproducibility of responses over 3 months. INTRODUCTION: We have recently introduced an Eligen technology-based oral formulation of salmon calcitonin (sCT) that effectively delivers the hormone to the circulation. The efficacy and safety during longer-term administration, however, has not been investigated in the target population. MATERIALS AND METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging clinical trial including 277 healthy postmenopausal women 55-85 years of age. Women received treatment with either daily (0.15, 0.4, 1.0, or 2.5 mg) or intermittent doses (1.0 mg, every other day) of sCT combined with the delivery agent (8-[N-2-hydroxi-5-chloro-benzoyl]-amino-caprylic acid, 200 mg) or placebo for 3 months. All participants received 1,000 mg calcium plus 400 IU vitamin D daily throughout the study. Efficacy parameters were the acute and/or pre-dose changes in serum and urinary C-terminal telopeptide of type I collagen (CTx), N-mid osteocalcin (OC), bone-specific alkaline phosphatase (BSALP), calcium, and parathyroid hormone (PTH) measured by established immunoassays. RESULTS: After the first dose, sCT evoked dose-dependent decreases in serum CTx (-60.8% to -81.8% from baseline) compared with placebo, reaching nadirs 2-3 h after drug intake, after which, gradual increases were observed. The simultaneous acute changes in OC were statistically nonsignificant. Area under the curve (AUC) of serum CTx responses at months 1 and 3 showed strong correlation with those at baseline (both r = 0.78, p < 0.001). At month 3, the placebo-corrected changes in the pre-dose value of serum and urinary CTx were significant only in the 1.0-mg dose group (-18.9% and -20.5%, respectively, p < 0.05). The placebo-corrected change in OC was -8.6 (p = 0.09), whereas the change in BSALP was -7.3 (p = 0.02). The oral formulation was well tolerated, with mild to moderate gastrointestinal and skin manifestations apparent mainly in the high-dose groups. CONCLUSION: The results of this 3-month trial show that the novel Eligen technology-based oral formulation of sCT has potential to become a safe and effective treatment for postmenopausal bone loss. Future trials are needed to assess the impact of long-term administration on changes in BMD and fracture risk.

Alendronate has a residual effect on bone mass in postmenopausal Danish women up to 7 years after treatment withdrawal.

Alendronate has been shown to reduce bone turnover and increase bone mass. However, little is known about the duration of the effect on bone after treatment withdrawal. The aim of this study was to investigate the long-term effects on bone mineral density (BMD) and bone turnover of various alendronate regimens after treatment withdrawal. In this study, we followed 203 postmenopausal women who previously participated in two alendronate randomized placebo-controlled trials. Daily oral treatment with various doses of alendronate (2.5-20 mg) were given for 2, 4, or 6 yr followed by no treatment for 7, 5, or 3 yr, respectively. Bone mineral density of the lumbar spine, hip, and forearm was measured by dual-energy x-ray absorptiometry. Biochemical markers of bone turnover were induced serum C-terminal telopeptides of type I collagen (CTX) and osteocalcin. Women who received alendronate (2.5-10 mg per day) for 2 yr had a 3.8% higher BMD compared to those receiving placebo when assessed 7 yr after withdrawal. The residual effect was proportionally larger in women who had received treatment for 4 (5.9%, P=0.02) or 6 yr (8.6%, P=0.002), respectively. However, the largest residual effect was found in women treated with alendronate 20 mg per day for 2 yr (9.7%, P=0.01 vs. placebo). The rate of bone loss after alendronate withdrawal was comparable to the bone loss observed in the placebo group. Bone markers tended to reverse back to normal levels, but were still affected even several years after withdrawal of treatment. This study has demonstrated that the efficacy of alendronate in preventing bone loss was proportional to the duration of treatment. The rate of bone loss after withdrawal of alendronate corresponded to the normal postmenopausal rate of bone loss. A residual effect on BMD was found up to 7 yr after treatment withdrawal.

Two to three years of hormone replacement treatment in healthy women have long-term preventive effects on bone mass and osteoporotic fractures: the PERF study.

Hormone replacement therapy (HRT) is often prescribed for a few years to suppress menopausal symptoms. Although its long-term use of HRT for the primary prevention of osteoporosis is not currently recommended, the long-term skeletal benefits of the limited therapy are of great interest. To determine whether administration of HRT for 2-3 years in the early postmenopausal years provides long-term benefits, such as prevention of bone loss and osteoporotic fractures, we studied a group of 347 healthy postmenopausal women with normal bone mass who had earlier completed one of four placebo-controlled HRT trials and who were reexamined 5, 11, or 15 years after stopping HRT. Of these women, 263 received either HRT or placebo for 2-3 years with no further bone-sparing treatment until follow-up, and the remaining 84 women reported either prolonged or current use of HRT at reexamination. Bone mineral density (BMD) at the spine (L1-L4) and bone mineral content (BMC) in the forearm were measured at baseline, the end of the trials, and follow-up. At follow-up, we assessed the radiological presence of vertebral fracture and collected information on the new incidence of nonvertebral fractures. Compared with that of the placebo-treated women, the BMD and BMC of HRT-treated women continued to show significantly higher values (>5%) even many years after stopping HRT. After stopping treatment, the rate of bone loss returned to normal postmenopausal rates. The preservation of bone mass in the HRT group was accompanied by a significantly reduced risk of all osteoporotic fractures as compared with the placebo group [OR = 0.48 (95% CI, 0.26-0.88)]. 'Fast losers' on placebo had more than a 4-fold higher risk of fractures than had the women on limited HRT with a normal rate of bone loss after withdrawal. In conclusion, limited HRT administered in the early postmenopausal years offers long-lasting benefits for the prevention of postmenopausal bone loss and osteoporotic fracture.

Changes in bone density and turnover after alendronate or estrogen withdrawal.

OBJECTIVE: To compare bone mineral density (BMD) and bone turnover changes after therapy withdrawal in postmenopausal women treated with alendronate or estrogen-progestin. DESIGN: In this randomized, blinded, multinational, placebo-controlled trial, 1,609 healthy postmenopausal women ages 45 to 59 years were assigned to receive alendronate, placebo, or open-label estrogen-progestin (conjugated equine estrogens plus medroxyprogesterone acetate or a cyclic regimen of 17 beta-estradiol, norethisterone acetate and estradiol). Of the original women, one third after year 2 and one third after year 4 were switched from alendronate to placebo, while remaining blinded to treatment assignment. The women taking estrogen-progestin in years 1 to 4 were followed off therapy in years 5 and 6. BMD at the lumbar spine and hip and biochemical markers of bone turnover were measured. RESULTS: The treatment groups described in the current report represent 860 women at baseline; 481 women entered year 5, and 430 completed 6 years. BMD steadily decreased in the placebo group during all 6 years. In contrast, spine and hip BMD increased during the first 4 years in the groups receiving daily continuous alendronate 5 mg and estrogen-progestin. During years 5 and 6, BMD decreased at the lumbar spine -2.42% (95% CI = -4.10, -0.74) and total hip -1.09% (-2.60, 0.41) in the group previously treated with alendronate 5 mg for 4 years. In comparison, large BMD decreases were observed at the spine [-7.69% (-8.96, -6.41)] and total hip [-5.16% (-6.30, -4.01)] among women who had received estrogen-progestin for 4 years. CONCLUSION: Alendronate produces greater residual skeletal effects than estrogen-progestin after therapy discontinuation.

Cognitive performance in elderly women: significance of the 19bp insertion/deletion polymorphism in the 5' flank of the dopamine beta-hydroxylase gene, educational level, body fat measures, serum triglyceride, alcohol consumption and age.

BACKGROUND: Genetic and environmental factors influence cognitive aging. The gene encoding dopamine beta-hydroxylase (DBH) could be one such factor since this hydroxylase converts dopamine to norepinephrine both of which are involved in cognition regulation. OBJECTIVE: To assess the effect of the 19bp insertion/deletion polymorphism in the 5' flank of the DBH gene on cognitive performance in elderly women relative to other factors of cognitive aging. METHODS: We examined a cross-sectional sample of 1371 postmenopausal women. Cognitive abilities were assessed by the 6-item orientation-memory-concentration test. The 19bp insertion/deletion polymorphism of the DBH gene was genotyped and apolipoprotein E (APOE) epsilon4 allele status was determined. In addition blood pressure, body fat mass and blood lipids were measured. Information was also obtained by personal interviews. Data were analyzed by regression analysis. RESULTS: Cognition was univariately associated with DBH genotype (p = 0.04). A univariate association of borderline significance was observed for APOE epsilon4 allele status (p = 0.07). Exclusion of women with severe cognition impairment did not alter the strength of the association with the DBH gene polymorphism markedly (p = 0.06) but obliterated the weak association between APOE epsilon4 allele status and cognition. The association of the DBH gene polymorphism with cognition persisted after adjustment for other variables (p = 0.03). CONCLUSIONS: The 19bp insertion/deletion polymorphism of the DBH gene influences cognition in elderly women and might have a stronger effect than APOE epsilon4 allele status on mild cognitive impairment. Both genetic polymorphisms had a significantly smaller impact on cognition than age, education, alcohol consumption and body fat measures.

The long-term predictive value of bone mineral density measurements for fracture risk is independent of the site of measurement and the age at diagnosis: results from the Prospective Epidemiological Risk Factors study.

Although the utility of bone mass measurements has been the subjects of extensive investigations, the number of studies comparing the predictive value of bone mass measurement at different skeletal sites in the same cohort with a large number of clinically verified endpoints is limited. Furthermore, scant information is available on how age at the time of diagnosis influence the risk of future fractures posed by low bone mineral density (BMD). We have followed 5,564 Danish postmenopausal women for a mean period of 7.3 years. Bone mineral content (BMC) at the forearm and BMD at the spine and hip were assessed at baseline. Vertebral fractures were assessed on digitalized images of lateral X-rays of the thoracic and lumbar spine, whereas non-vertebral fractures were self-reported. At follow-up, 17.6% of the women revealed an incidental vertebral fracture and 14.2% reported a new non-vertebral fracture. The absolute risk per 1,000 person-years of osteoporotic fracture increased significantly with decreasing bone mass at all three skeletal sites (P<0.001). Osteoporotic BMD (T-score < or =-2.5) had similar predictive values of fractures regardless of the skeletal site of measurement. Furthermore, the absolute risk of osteoporotic fractures increased significantly with increasing age at the same level of bone mass. Interestingly, the relative risk (RR) of vertebral fracture accompanying 1 SD decrease in spine BMD was similar across different age groups: <55 years (RR:2.1, 95% CI 1.3-3.3), 55-64 years (RR:2.3, 95%CI 1.7-3.2), 65-74 years (RR:2.0; 95%CI 1.5-2.6). Furthermore, women with any prior osteoporotic fracture had a 2.4-fold (95% CI 2.01-2.75, P<0.001) increased risk of a new vertebral fracture. Both age and prior fracture are strong predictors of future fractures. The long-term predictive value of bone mass measurement is independent of the site of measurement and the age at diagnosis.

Associations between aortic calcification and components of body composition in elderly men.

OBJECTIVE: To investigate associations among body composition, cardiovascular risk factors, and atherosclerosis in middle-aged and elderly men for the identification of potential pathogenic links. RESEARCH METHODS AND PROCEDURES: The study included 168 white men 44 to 86 years old. Severity of aortic calcification (AC) was graded on lateral radiographs, and body fat and lean mass were measured by DXA. Information on demographic and lifestyle characteristics also was gathered. RESULTS: A strong and independent inverse association was found between AC and peripheral lean mass (PLM), even after adjusting for age and BMI (p < 0.05). Independently of the influence of PLM, AC was directly correlated with truncal fat mass (p < 0.05). Furthermore, AC was inversely associated with tertiles of the free androgen index (p < 0.05). In a multiple regression model, age and serum cholesterol (p < 0.01) contributed directly, and truncal fat mass tended also to contribute directly (p = 0.09), whereas PLM contributed borderline inversely (p = 0.06) to the variation of AC (R = 0.635, p < 0.0001). DISCUSSION: Severity of AC is strongly dependent on age and further modulated by an array of traditional cardiovascular risk factors. Sarcopenia and truncal fat mass are reciprocal correlates of atherosclerosis of borderline statistical significance in multivariate models. To clarify whether sarcopenia is an atherogenic risk factor or rather a parallel consequence of low-grade inflammation also promoting atherogenic trends, further longitudinal studies in larger sample sizes of men and women are needed.

Cognitive impairment in elderly women: the relative importance of selected genes, lifestyle factors, and comorbidities.

BACKGROUND: A variety of factors contribute to the development of cognitive impairment in elderly people. Previous studies have focused upon a single or a few risk factors. In this study we assessed and compared the significance of a wide variety of potential risk factors for cognitive impairment in postmenopausal women. METHODS: A total of 208 pairs of elderly women (mean age = 73.2 years) were examined in a cross-sectional case-control study. Each pair consisted of a case (with impaired cognition) and a control subject matched by age and educational status. Cognitive functions were determined using a modified version of the Blessed test. Participants were also subjected to a general clinical examination and they were interviewed to collect information on lifestyle practices and comorbid disorders. Genotypes for the apolipoprotein E (APOE) epsilon4, catechol-O-methyltransferase (COMT) Val/Met, and brain-derived neurotropic growth factor (BDNF) Val/Met polymorphisms were determined. Data were analyzed by conditional logistic regression. RESULTS: We identified a set of risk factors for age-related cognitive impairment. A statistical model for assessment of the importance of these factors was constructed. The factors in this model were physical exercise (odds ratio [OR] = 0.50, 95% confidence interval [CI] = 0.32-0.78), regular alcohol consumption (OR = 0.49, 95% CI = 0.29-0.83), metabolic syndrome (OR = 2.83, 95% CI = 1.26-6.39), depression (OR = 3.24, 95% CI = 1.28-8.22), and the APOE epsilon4 allele (OR = 1.76, 95% CI = 1.09-2.83). Also COMT genotype was present as a risk factor in the statistical model (p = 0.08). CONCLUSIONS: Lifestyle risk factors, comorbid disorders, and genetic factors contribute to development of age-related cognitive impairment. The two former groups of risk factors appear to be particular important in this respect.

Effective doses of ibandronate do not influence the 3-year progression of aortic calcification in elderly osteoporotic women.

Animal experiments revealed conflicting results as to the impact of bisphosphonate treatment on atherosclerosis and related vascular calcification. The effect of long-term treatment with clinical doses of bisphosphonates on aortic calcification (AC) in an "at-risk" population of osteoporotic elderly women has not been assessed systematically. In the present analysis including 474 women (55-80 years) participating in two 3-year randomized, placebo-controlled clinical trials, we assessed the simultaneous impact of ibandronate given either orally (2.5 mg daily or 20 mg intermittently) or intravenously (0.5 mg or 1.0 mg IV every 3 months) on bone mass and AC. All women received calcium and vitamin D supplements. Bone mineral density (BMD) was measured at the lumbar spine and the total hip using dual-energy X-ray absorptiometry (DXA). Calcified deposits of the lumbar aorta (L1-L4) were visualized on lateral radiographs and severity was graded by a validated scoring system. Measurements were performed at baseline and at years 1, 2, and 3. At baseline, there was a significant inverse correlation between the severity of AC and BMD at the hip (r=-0.151, P=0.003), but not at the lumbar spine. The two oral doses and the 1.0 mg IV dose evoked statistically significant increases in both hip and spine BMD compared with placebo, whereas the effect of 0.5 mg was significant only at the hip (P<0.05). No differences in the yearly rate of progression or the 3-year change in AC was observed between the different intervention groups. Furthermore, there were no statistically significant correlations between the 3-year change in BMD and the simultaneous change in AC. These findings thus suggest that 3-year treatment with effective doses of ibandronate does not pose any cardiovascular risk in terms of altering vascular calcification.

Comparison of quantitative ultrasound of the phalanges with conventional bone densitometry in healthy postmenopausal women.

The objective of this study was to evaluate the utility of the quantitative ultrasound (QUS) technique for the identification of subjects with spine fracture or low bone mineral density (BMD) previously determined by dual energy X-ray absorptiometry (DEXA). QUS of the phalanges in 1,350 postmenopausal women (60-83 years old) was compared with DEXA measurements of four skeletal sites (lumbar spine, total hip, femoral neck, and distal radius) of the same subjects. The contribution of body mass index (BMI) was also assessed. Amplitude dependent speed of sound (AD-SoS), ultrasound bone profile index (UBPI), and BMD of all anatomical regions, except for the spine, decreased significantly with increasing age quartiles. QUS parameters correlated weakly but significantly with BMD ( r =0.21-0.31, p <0.01). After adjustment for BMI, the association between QUS parameters and BMD remained unchanged. UBPI was found to be independent of BMI. All techniques and all sites were able to significantly discriminate fractured from non-fractured subjects by receiver operating characteristic (ROC) analysis (area under the curve [AUC]> or =0.60, p <0.0001). AD-SoS and UBPI showed similar fracture discrimination ability of spine, distal radius and total body BMD in terms of odds ratios, but BMD of the total hip and femoral neck showed the best performance in discriminating fractured from non-fractured subjects. In conclusion, QUS assessment of the phalanges correlates moderately with BMD of all skeletal sites and is able to effectively discriminate fractured from non-fractured subjects.

The implications of body fat mass and fat distribution for cognitive function in elderly women.

OBJECTIVE: To investigate how body fat mass, an established source of endogenous estrogen after menopause, influences cognitive impairment in elderly women. RESEARCH METHODS AND PROCEDURES: Study participants were 5607 generally healthy postmenopausal women with mean age of 63.8 years at baseline followed for an average of 7.3 years. Cognitive function assessed at follow-up using the short Blessed test was related to baseline body weight, the yearly change in weight, and follow-up measures of body fat depots assessed by DXA. Cognitive function was also related to various surrogates of lifetime estrogen exposure. RESULTS: Women with the worst cognitive performance (score >or= 9) at follow-up were the ones who lost the most body weight and revealed the lowest central fat mass (CFM). The association of weight loss with worse cognitive performance was apparent across all age groups except for those more than 80 years old. In the multivariate logistic model, the risk of cognitive impairment was 18% lower in women in the second quartile of CFM (p = 0.14), 32% lower in the third (p = 0.01), and 48% lower in the fourth (p < 0.001) compared with those in the first quartile. CFM showed significant correlation with the simultaneously measured serum estradiol (r = 0.25; p < 0.001). Cognitive score showed an inverse linear relationship with the duration of reproductive period and bone mineral density assessed at follow-up. DISCUSSION: These findings argue for a protective association of body fat mass with cognitive impairment in elderly women. This association seems to involve a more prominent exposure to endogenous estrogens.

Central and peripheral fat mass have contrasting effect on the progression of aortic calcification in postmenopausal women.

AIM: To investigate the long-term effects of central fat mass (CFM) and peripheral fat mass (PFM) on atherogenic risk profile and the progression of aortic calcification (AC) in postmenopausal women. METHODS AND RESULTS: Participants were 316 women aged 50-76 years, who were followed for 7.7 years. CFM and PFM were measured at baseline by DXA and related to follow-up measures of atherogenic metabolites, blood pressure, and the progression of AC assessed on lateral radiographs. CFM and PFM independently of each other exhibited contrasting influence on follow-up measures of atherogenic risk factors and the progression of AC. In a multiple regression model, the negative contribution of PFM (P<0.05), but not the adverse contribution of CFM, was independent of confounders. When comparing different extreme forms of obesity, women with central obesity showed the greatest (2.36+/-0.60, n=11), whereas those with peripheral obesity the smallest changes in AC (0.50+/-0.34, n=10) over the study period. Women with general obesity also tended to show less progression of AC compared with women with central obesity (1.23+/-0.42, n=21). CONCLUSIONS: This study provides direct support for the independent anti-atherogenic influence of PFM and calls on further research to define the adipocyte-derived factors involved in this favourable effect.