Safety, tolerability, and pharmacokinetics of single- and multiple-ascending doses of olamkicept: Results from randomized, placebo-controlled, first-in-human phase I trials.

Olamkicept selectively inhibits the cytokine interleukin-6 (IL-6) trans-signaling pathway without blocking the classic pathway and is a promising immunoregulatory therapy for inflammatory bowel disease (IBD). These first-in-human, randomized, placebo-controlled, single- (SAD) and multiple-ascending dose (MAD) trials evaluated olamkicept safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics. Doses tested in the SAD trial included seven single intravenous doses (0.75, 7.5, 75, 150, 300, 600, and 750 mg) and one subcutaneous (SC) dose (60 mg) given to healthy subjects (N = 64), and three intravenous doses (75 mg, 300 mg, and 750 mg) given to patients with Crohn's disease (CD; N = 24). Doses tested in the MAD trial included multiple intravenous doses (75, 300, and 600 mg once weekly for 4 weeks) given to healthy subjects (N = 24). No severe or serious treatment-emergent adverse events (TEAEs) were recorded. The most common TEAEs were headache, nasopharyngitis, and myalgia in the SAD trial, and diarrhea, headache, and cough in the MAD trial. Infusion-related reactions occurred in one and two subjects in the SAD and MAD trial, respectively, leading to treatment discontinuation in the MAD trial. Olamkicept showed dose-independent pharmacokinetics after single and multiple administrations, and there was no major difference in systemic exposure between healthy subjects and patients with CD. Complete target engagement (inhibition of phosphorylation of signal transducer and activator of transcription-3) was achieved in blood around or above olamkicept serum concentrations of 1-5 µg/mL. Overall, these results suggest that olamkicept is safe and well-tolerated in healthy subjects and patients with CD after single intravenous/SC and multiple intravenous administrations.

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.

Lack of association of the serotonin transporter gene promoter region polymorphism, 5-HTTLPR, including rs25531 with cigarette smoking and alcohol consumption.

We addressed the question whether 5-HTTLPR, a variable number of tandem repeats located in the 5' end of the serotonin transporter gene, is associated with smoking or alcohol consumption. Samples of DNA from 1,365 elderly women with a mean age of 69.2 years were genotyped for this polymorphism using a procedure, which allowed the simultaneous determination of variation in the number of repeat units and single nucleotide changes, including the A > G variation at rs25531 for discrimination between the L(A) and L(G) alleles. Qualitative and quantitative information on the women's current and previous consumption of cigarettes and alcohol were obtained using a questionnaire. Genotypes were classified according to allele size, that is, S and L with 14 and 16 repeat units, respectively, and on a functional basis by amalgamation of the L(G) and S alleles. Data were subjected to regression analyses. These analyses revealed P values for associations between 5-HTTLPR genotype and alcohol and cigarette consumption in the range from 0.15 to 0.92. On adjustment for age and educational level, significance for the associations of 5-HTTLPR with the smoking and alcohol consumption measures was not reached. We conclude that 5-HTTLPR is not an important determinant of smoking behavior and alcohol consumption in elderly women.

Modulatory effect of farnesyl pyrophosphate synthase (FDPS) rs2297480 polymorphism on the response to long-term amino-bisphosphonate treatment in postmenopausal osteoporosis.

INTRODUCTION: Polymorphisms of genes encoding enzymes of the mevalonate pathway could modulate the response to amino-bisphosphonate treatment in postmenopausal osteoporosis. RESEARCH DESIGN AND METHODS: A characterisation of 234 Danish osteoporotic postmenopausal women (as part of the Prospective Epidemiological Risk Factors study (PERF)), treated for at least 2 years with amino-bisphosphonates, with respect to the adenosine/cytosine (A/C) rs2297480 farnesyl pyrophosphate synthase (FDPS) gene polymorphism, was carried out by PCR-based enzymatic digestion and quantitative PCR allelic discrimination on genomic DNA extracted from blood leukocytes. The association between these polymorphism genotypes and the response of spine and femur bone mineral density (BMD) and of biochemical bone biomarkers to treatment with amino-bisphosphonates was statistically examined. RESULTS: FDPS polymorphism did not show any relationship to baseline spinal and femoral BMD in Danish postmenopausal women. BMD response to treatment with amino-bisphosphonates was similar in the AA and the AC genotypes, while the CC genotype showed a lower BMD response to 2-year-treatment with amino-bisphosphonates at all examined skeletal sites (p=0.60 at the spine and p=0.59 at the femur). Interestingly, after 2 years of treatment the response of urinary Cross-laps to amino-bisphosphonates treatment was significantly (p<0.05) lower in the CC genotype when compared to both the AC and AA genotypes. Even the response of serum osteocalcin was lower in the CC genotype, but without reaching a statistical significance (p=0.65). CONCLUSIONS: Danish postmenopausal women with osteoporosis bearing the homozygous CC genotype for rs2297480 FDPS polymorphism showed a decreased response of bone turnover markers to amino-bisphosphonate therapy, when compared to the heterozygous AC and to the homozygous AA genotypes. Further investigation on larger and different populations, together with polymorphism functional studies are required to confirm these data.

Multiple genetic loci for bone mineral density and fractures.

BACKGROUND: Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture. METHODS: We performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively). RESULTS: Sequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2x10(-7) to 2.0x10(-21)). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-kappaB ligand gene (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-kappaB gene (RANK), and loci at 2p16 and 11p11. CONCLUSIONS: We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis.

Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes.

We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.

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.

Estrogen receptor alpha and beta polymorphisms: is there an association with bone mineral density, plasma lipids, and response to postmenopausal hormone therapy?

OBJECTIVE AND DESIGN: A cross-sectional segregation analysis of polymorphisms in the estrogen receptor (ER) genes (Pvull and Xbal in ERalpha, and Alul in ERAbeta with bone mineral density in the lumbar spine and forearm and with lipid profile was performed in 1098 postmenopausal women. Additionally, in a subpopulation of 280 women, who completed 1 year of treatment with estrogen plus progestin, the association between genotypes and the response to treatment in both plasma lipids and bone was investigated. In another untreated subpopulation of 443 women, genotype influence on the prevalence of vertebral fractures and on annual rate of bone loss during a mean follow-up period of 11 years was estimated. RESULTS: Baseline plasma lipids, bone mineral density, annual rate of bone loss and prevalence of spinal fractures were not significantly associated with polymorphisms in the ERbeta gene. The ERA polymorphism was significantly associated with bone loss from the distal forearm (P = 0.04) but not with bone loss from the spine. After 1 year of treatment with hormone therapy there was also a significant association between the ERbeta polymorphism and the response in total cholesterol (P = 0.02); while the ERalpha gene polymorphisms did not significantly influence the response to hormone therapy. CONCLUSIONS: In a large white population of postmenopausal women, ERalpha gene polymorphisms were not associated with bone mineral density or lipid profile at baseline or after hormone therapy. Conversely, the ERbeta genotype appeared to segregate with bone loss from the forearm and to modulate the decrease in total cholesterol during hormone therapy.

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.

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.

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.

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.

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.

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.

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.

Pulsed estrogen therapy in prevention of postmenopausal osteoporosis. A 2-year randomized, double blind, placebo-controlled study.

The aim of this study was to evaluate the efficacy of pulsed estrogen therapy (intranasal 17beta-estradiol) in the prevention of postmenopausal bone loss. A total of 386 women (40-65 years old), less than 5 years past menopause, were randomized to intranasal placebo, 17beta-estradiol 150 micro g, or 300 micro g daily for 2 years. Women with an intact uterus received micronised progesterone 200 mg per day, 14 days of each 28-day cycle. Women randomised to placebo-treatment received placebo progesterone. The primary endpoints were changes in BMD at the spine (L2-L4) and femoral neck. Secondary endpoints were changes in bone turnover markers: serum osteocalcin (sOC) as a marker of bone formation and urinary C-terminal telopeptides (uCTX) as a marker of bone resorption. BMD increased at all measured sites in women receiving active treatment in a dose-related manner, the difference compared to placebo being 5.2% and 6.7% at the spine, and 3.2% and 4.7 % at the hip, respectively, with 150 microg and 300 microg ( P<0.001). On the other hand, a decrease versus baseline of -3.2% and -3.3% at the spine and hip, respectively, was observed in women receiving placebo ( P<0.001). In the patients with at least one risk factor for osteoporotic fracture, the difference between placebo and 150 microg or 300 micro g was even higher at the spine (5.4% and 7.4%, respectively), and at the femoral neck (4.0% and 5.2%, respectively). Correspondingly, uCTX decreased from baseline by 39% and 46 %, and sOC by 22% and 27%, in the 150 micro g group and 300 micro g group (all P<0.001 versus placebo). A strong correlation was found between variations of bone turnover markers after 1 year and BMD after 2 years, emphasizing that bone markers can predict BMD response during hormonal treatment. Acceptability and general tolerance were good. This study demonstrates that pulsed estrogen therapy at the dose of 150 microg and 300-microg per day prevents bone loss in a dose-dependant manner at each site studied, and normalizes bone turnover markers to premenopausal levels.

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.

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.

Serum placental protein 14: a novel marker of selective oestrogen receptor modulator action on the postmenopausal endometrium.

The primary objective of this study was to investigate whether changes in the serum level of an endometrial secretory protein, placental protein 14 (PP14), can reflect endometrial adverse events induced by selective oestrogen receptor modulators (SERMs). A randomized, double-blind, placebo-controlled trial was used. Participants were healthy postmenopausal women aged 45-65 years, who received either various doses of raloxifene (30, 60 or 150 mg day-1) or levormeloxifene (1.25, 5, 10 or 20 mg day-1) or placebo for 12 months. Serum PP14 and endometrial thickness (ET) were monitored by radio-immunoassay and transvaginal ultrasonography, respectively. In the levormeloxifene trial, endometrial status at 12 months was assessed by hysteroscopy. Raloxifene induced only slight increases in serum PP14 and ET. Levormeloxifene, however, induced marked increases in both study parameters at all the does tested. The 6 month changes in PP14 showed a positive correlation with both the 6 and 12 month changes in ET (P < 0.001). Marked stromal oedema, pseudocysticity with or without hypervascularity and endometrial proliferation were seen on hysteroscopy in those showing the largest increases in serum PP14. These results suggest that the PP14 assay used on a group basis may provide useful information on the endometrial effects of SERMs administered in a given dose range, and thereby could assist future clinical trials aiming to find the optimal dose range of new SERMs.