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Background and ObjectivesPrevious studies on the relationship between body mass index (BMI) and Parkinson disease (PD) provided inconsistent results, likely due to reverse causation explained by weight loss during the prodromal phase. We examined the association of BMI and abdominal adiposity with PD incidence using lagged analyses to address the potential for reverse causation and compared BMI trajectories in patients before diagnosis and matched controls.MethodsWe used data from the E3N cohort study of French women with a 29-year follow-up (1990–2018). BMI (kg/m2) was computed based on self-reported weight and height up to 11 times; up to 6 waist circumference (WC) and hip circumference measures were available. PD diagnoses were validated based on medical records and drug claim databases. Multivariable time-varying Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs according to BMI categories (underweight 2; normal = [18.5–25.0[ kg/m2; overweight = [25.0–30.0[ kg/m2; obese ≥30.0 kg/m2). Exposures were lagged by 5 years in main analyses; we used longer lags (10 and 20 years) in sensitivity analyses. We examined trajectories of BMI categories within a nested case-control study using multivariable generalized estimating equations multinomial logistic models.ResultsOf 96,702 women (baseline age = 40–65 years), 1,164 developed PD. PD incidence was lower (HR = 0.76, 95% CI = 0.59–0.98,p= 0.032) among women with obesity compared with those with normal BMI. There was a similar association in analyses using longer lag times (20 years, 598 cases, HR = 0.52, 95% CI = 0.30–0.88,p= 0.016). A similar pattern was seen for WC and waist-height ratio but not waist-hip ratio. Trajectories of BMI categories (1,196 patients and 23,876 controls) showed that obesity was less frequent in patients with PD before diagnosis than in controls, with a statistically significant difference 29 years before. In addition, the frequency of obesity decreased 5–10 years before diagnosis in patients.DiscussionIn this large cohort of women with a long follow-up, obesity was associated with a lower hazard of PD, even when measured 20 years before diagnosis, in agreement with Mendelian randomization studies. Our analyses underscore the importance of lagged analyses to account for reverse causation. These findings warrant further investigations to understand the mechanisms underlying this inverse association.

International audience; Background: Statins represent candidates for drug repurposing in Parkinson's disease (PD). Few studies examined the role of reverse causation, statin subgroups, and dose–response relations based on time-varying exposures. Objectives: We examined whether statin use is associated with PD incidence while attempting to overcome the limitations described previously, especially reverse causation. Method: We used data from the E3N cohort study of French women (follow-up, 2004–2018). Incident PD was ascertained using multiple sources and validated by experts. New statin users were identified through linked drug claims. We set up a nested case-control study to describe trajectories of statin prescriptions and medical consultations before diagnosis. We used time-varying multivariable Cox proportional hazards regression models to examine the statins–PD association. Exposure indexes included ever use, cumulative duration/dose, and mean daily dose and were lagged by 5 years to address reverse causation. Results: The case-control study (693 cases, 13,784 controls) showed differences in case-control trajectories, with changes in the 5 years before diagnosis in cases. Of 73,925 women (aged 54–79 years), 524 developed PD and 11,552 started using statins in lagged analyses. Ever use of any statin was not associated with PD (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.67–1.11). Alternatively, ever use of lipophilic statins was significantly associated with lower PD incidence (HR = 0.70, 95% CI = 0.51–0.98), with a dose–response relation for the mean daily dose (P-linear trend = 0.02). There was no association for hydrophilic statins. Conclusion: Use of lipophilic statins at least 5 years earlier was associated with reduced PD incidence in women, with a dose–response relation for the mean daily dose. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Despite experimental studies suggesting a disease-modifying role of oestrogens, results from epidemiological studies on the relation of reproductive characteristics and hormonal exposures with Parkinson disease in women are conflicting. We used the data from the E3N cohort study including 98 068 women aged 40–65 years in 1990 followed until 2018. Parkinson disease was ascertained using a validation process based on drug claim databases and medical records. Reproductive characteristics and hormonal exposures were self-reported (11 questionnaires). Associations of exposures with Parkinson disease incidence were investigated using time-varying Cox proportional hazards regression with a 5-year exposure lag and age as the timescale adjusted for confounders. We identified 1165 incident Parkinson disease cases during a mean follow-up of 22.0 years (incidence rate = 54.7 per 100 000 person-years). Parkinson disease incidence was higher in women with early (

International audience; Introduction: Migraine and combined hormonal contraceptives (CHCs) increase the risk of ischemic stroke in young women; however, the contribution of low-dose (

BACKGROUND/OBJECTIVES The associations of reproductive history and motor function are controversial. DESIGN Prospective cohort study with 10 years of follow-up. SETTING Three French cities between 1999 and 2011. PARTICIPANTS A total of 3043 community-dwelling women from the Three-City Dijon study population. MEASUREMENTS We examined the cross-sectional and longitudinal association of age at menopause, artificial menopause, and parity with walking speed (WS) using linear regression and linear mixed models, respectively. Cox proportional models were used to examine the association of characteristics of reproductive life with disability. RESULTS Mean baseline WS was 143.8 cm/s. Artificial menopause was associated with slower WS at baseline (β = -3.29; 95% confidence interval [CI] = -5.83 to -0.74; P = .01). Reproductive life characteristics had no effect on change in WS. Increasing age at menopause was associated with reduced disability risk (hazard ratio [HR] for 5-year increase = 0.92; 95% CI = 0.87-0.99; P = .02), while parity increased disability risk (HR for ≥3 vs 0 children = 1.53; 95% CI = 1.22-1.93; P

BACKGROUND Sex differences in psychiatric disorders are common and could involve sex steroids. Aromatase, the product of the CYP19A1 gene, is the key enzyme in the conversion of androgen to estrogen. Whether CYP19A1 variants could be associated with depression differently in men and women has not been examined. METHODS This population-based study included 405 men and 602 women aged ≥65 years. A clinical level of depression (DEP) was defined as having a score ≥16 on the Center for Epidemiology Studies Depression scale or a diagnosis of current major depression based on the Mini-International Neuropsychiatric Interview and according to DSM-IV criteria. Seven single-nucleotide polymorphisms (SNPs) spanning the CYP19A1 gene were genotyped and circulating levels of estradiol and testosterone were determined. Multivariable analyses were adjusted for age, body mass index, ischemic pathologies, cognitive impairment, and anxiety. RESULTS Five SNPs were associated with DEP in women specifically and this varied according to a history of major depression (p-values .01 to .0005). Three SNPs were associated with an increased risk of late-life DEP in women without a history of major depression, while two SNPs were associated with a decreased DEP risk in women with a history of major depression and were also associated with higher estradiol levels. CONCLUSIONS Variants of the CYP19A1 gene appear to be susceptibility factors for late-life depression in a sex-specific manner. The polymorphisms decreasing the risk of recurrent depression in postmenopausal women also influence estradiol levels.

Background Previous studies have shown conflicting results regarding the influence of cardiovascular risk-factors on venous thromboembolism. This study aimed to determine if these risk-factors, i.e. physical activity, smoking, hypertension, dyslipidaemia, and diabetes, were associated with the risk of venous thromboembolism, and to determine if these associations were confounded by BMI. Methods We used data from the E3N cohort study, a French prospective population-based study initiated in 1990, consisting of 98,995 women born between 1925 and 1950. From the women in the study we included those who did not have prevalent arterial disease or venous thromboembolism at baseline; thus 91,707 women were included in the study. Venous thromboembolism cases were self-reported during follow-up, and verified via specific mailings to medical practitioners or via drug reimbursements for anti-thrombotic medications. Hypertension, diabetes and dyslipidaemia were self-reported validated against drug reimbursements or specific questionnaires. Physical activity, and smoking were based on self-reports. Cox-models, adjusted for BMI and other potential risk-factors were used to determine hazard ratios for incident venous thromboembolism. Results During 1,897,960 person-years (PY), 1, 649 first incident episodes of thrombosis were identified at an incidence rate of 0.9 per 1000 PY. This included 505 cases of pulmonary embolism and 1144 cases of deep vein thrombosis with no evidence of pulmonary embolism. Hypertension, dyslipidaemia, diabetes, smoking and physical activity were not associated with the overall risk of thrombosis after adjustment for BMI. Conclusions Traditional cardiovascular risk factors were not associated with the risk of venous thromboembolism after adjustment for BMI. Hypertension, dyslipidaemia and diabetes may not be risk-factors for venous thromboembolism.

CONTEXT: Although endogenous estradiol, generally considered as the female hormone, has been little investigated in men, it could play a role in men's health, mortality in particular. The influence of estrogen receptors (ER) genetic polymorphisms on this relationship has never been studied. DESIGN AND PARTICIPANTS: The Three-City cohort study included (1999-2001) 3650 men >/=65 years who were followed for mortality over 12 years. At baseline, total estradiol (tE2) was measured and ER genotyped in a random subsample of 472 men without hormonal treatment. Free estradiol (fE2) was estimated using Vermeulen and Sodergard algorithms. MAIN OUTCOME: Mortality data were obtained from death certificates. We used inverse probability weighted Cox models to examine the association of estradiol with all-cause and cause-specific mortality and its interaction with ER genetic polymorphisms. RESULTS: 183 men died over the follow-up (cardiovascular disease (CVD), n=44; cancer, n=57; other causes, n=82). After adjustment, there was a quadratic relationship of all-cause mortality with tE2 and fE2 (p-quadratic=0.04 and 0.05, respectively), with higher mortality for the top and bottom tertiles compared to the middle one. These associations were stronger for CVD mortality (p-quadratic=0.01 and 0.02 for tE2 and fE2, respectively) and disappeared for cancer mortality. There was no evidence of an interaction of estradiol with any ER polymorphisms on all-cause mortality. CONCLUSION: In elderly men, we showed a nonlinear association of tE2 and fE2 with all-cause mortality. These quadratic relationships were stronger for CVD mortality and did not exist for cancer mortality. ER genetic polymorphisms did not modify this association. This article is protected by copyright. All rights reserved.

ObjectiveTo examine the relation of age with male-to-female (M/F) ratios and incidence rates of motor neuron disease (MND) in a French nationwide study and meta-analysis of incidence studies.MethodsWe used data from the French National Health Insurance databases. Patients with incident MND (2010–2014) were identified based on drug claims (riluzole), hospitalization records, death records, and long-term chronic disease benefits. We estimated age-specific M/F incidence ratios using Poisson regression. Poisson, Gompertz, and multistep models were used to model the relation between age and incidence. We performed a meta-analysis (n = 28 studies) and used meta-regression to examine the relation of age with incidence rates and ratios.ResultsIn France, we identified 10,848 patients with incident MND (6,021 men, 4,827 women). Incidence was higher in men than in women in all age groups. M/F ratios were significantly different across age groups and followed a quadratic trend (p < 0.001). Between 20 and 49 years, the average M/F ratio was 2.26 (95% confidence interval [CI] = 1.96–2.62); it was 1.41 (95% CI = 1.35–1.47) between 50 and 84 years, and 1.88 (95% CI = 1.64–2.17) after 85 years. Incidence was lower in women than men at younger ages, but increased more steeply in women than men. Similar patterns were observed in the meta-analysis of incidence studies, especially in 19 higher-quality studies.ConclusionThe relation between age and M/F incidence ratios of MND follows a quadratic U-shaped pattern with an abrupt drop after the fifth decade. The change in M/F ratios before and after menopause suggests that reproductive/hormonal protective factors have a role in women and should prompt further studies to explore this hypothesis.

Following the publication of this article [1], the authors noticed that they incorrectly reported the Absolute risk of ischemic stroke in women aged 20 to 44 years in relation to the use of hormonal contraception and migraine status due to a miscalculation. They apologize for this misreported result.

Background : Use of antidepressants is seen to be a risk factor for type 2 diabetes, even though the underlying mechanisms remain unclear. We examined whether antidepressant use was associated with change in fasting plasma glucose, glycated haemoglobin (HbA1c), β-cell function (HOMA2-%B) and insulin sensitivity (HOMA2-%S) over time. Methods : Participants in the French D.E.S.I.R. cohort study included over 4700 men (48.1%) and women, free of diabetes, aged 30–65 years at baseline in 1994–96 (D.E.S.I.R. 0), who were followed for 9 years at 3-yearly intervals (D.E.S.I.R. 3, 1997–99; 6, 2000–02; 9, 2003–05). Antidepressant use, fasting plasma glucose, HbA1c, HOMA2-%B and HOMA2-%S were assessed concurrently at four medical examinations. Linear mixed models were used to examine the cross-sectional and longitudinal associations of time-dependent antidepressant use with changes in these four biological parameters. Results : Mean fasting plasma glucose and HbA1c increased whereas HOMA2-%B and HOMA2-%S decreased over the follow-up. In a fully adjusted model, there were no differences in: mean fasting plasma glucose ( β = 0.01 mmol/l, P = 0.702); HbA1c ( β = 0.01 %, P = 0.738); HOMA2-%B ( β = 0.00, P = 0.812); or HOMA2-%S ( β =−0.01, P = 0.791) at baseline (1994–96) between antidepressant users and non-users. The interaction term with time also suggested no differences in the annual change in: fasting plasma glucose ( β = 0.00 mmol/l, P = 0.322); HbA1c ( β = 0.00 %, P = 0.496); HOMA2-%B ( β = 0.00, P = 0.609); or HOMA2-%S ( β = 0.00, P = 0.332) between antidepressant users and non-users. Similar associations were observed in analyses of type and cumulative use of antidepressants over follow-up. Conclusion : Our longitudinal data show that use of antidepressants is not associated with altered glucose metabolism, suggesting that the association between antidepressant use and diabetes reported by previous studies may not be causal. Detection bias or clinical ascertainment bias may account for much of this apparent association.

The benefit of ideal cardiovascular health (CVH) on health-related outcomes in middle-aged patients is firmly established. In the growing elderly population, the high prevalence of comorbidities and medications for chronic diseases may offset such benefit.This study analyzed the association of ideal CVH with mortality, incident coronary heart disease, and stroke events in elderly individuals from the community.Between 1999 and 2001, 9,294 men and women, noninstitutionalized and aged 65 years and over were examined, and thereafter followed up for the occurrence of vascular events and mortality within the Three-City Study. Hazard ratios (HRs) were estimated by Cox proportional hazard model and compared subjects with 3 to 4 and subjects with 5 to 7 ideal metrics with those with 0 to 2 ideal metrics, respectively.The mean age was 73.8 ± 5.3 years, and 36.7% were men. Only 5% of the participants had ≥5 metrics at the ideal level. After a median follow-up of 10.9 years and 8.6 years, respectively 1,987 deaths and 680 adjudicated coronary heart disease or stroke events had occurred. In multivariate analysis, the risk of mortality and of vascular events decreased across the categories of ideal metrics. In particular, in subjects with ≥5 metrics at the ideal level (compared with those with ≤2), there was a 29% (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.55 to 0.90) decreased risk of all-cause mortality and 67% (HR: 0.33; 95% CI: 0.19 to 0.57) for coronary heart disease and stroke combined (p for trend 0.001).Even in the elderly, higher CVH status is highly beneficial regarding mortality and vascular event risks.

To assess whether AF is a risk factor for cognitive dysfunction we used prospective data on AF, repeat cognitive scores, and dementia incidence in adults followed over 45 to 85 years.Data are drawn from the Whitehall II study, N = 10 308 at study recruitment in 1985. A battery of cognitive tests was administered four times (1997-2013) to 7428 participants (414 cases of AF), aged 45-69 years in 1997. Compared with AF-free participants, those with longer exposure to AF (5, 10, or 15 years) experienced faster cognitive decline after adjustment for sociodemographic, behavioural, and chronic diseases (P for trend = 0.01). Incident stroke or coronary heart disease individually did not explain the excess cognitive decline; however, this relationship was impacted when considering them together (P for trend 0.09). Analysis of incident dementia (N = 274/9302 without AF; N = 50/912 with AF) showed AF was associated with higher risk of dementia in Cox regression adjusted for sociodemographic factors, health behaviours and chronic diseases [hazard ratio (HR): 1.87; 95% confidence interval (CI): 1.37, 2.55]. Multistate models showed AF to increase risk of dementia in those free of stroke (HR: 1.67; 95% CI: 1.17, 2.38) but not those free of stroke and coronary heart disease (HR: 1.29; 95% CI: 0.74, 2.24) over the follow-up.In adults aged 45-85 years AF is associated with accelerated cognitive decline and higher risk of dementia even at ages when AF incidence is low. At least in part, this was explained by incident cardiovascular disease in patients with AF.

There is increasing evidence of a role of vascular risk factors and disease in decline of physical function. Lifetime estrogen exposure is associated with cardiovascular disease among postmenopausal women. Whether reproductive history is related to motor decline remains poorly investigated. Analyses are based on elderly women from the Three-City Study followed over 10y. We examined the cross-sectional and longitudinal associations of age at menopause, oophorectomy, and parity with gait speed (GS, cm/s) and disability. One-year older age at menopause was associated with faster baseline GS (beta: 0.21; 95% CI: 0.01;0.42) and lower disability hazard over the follow-up (HR=0.98; 95%CI:0.97;0.99). Oophorectomy was associated with slower baseline GS (beta:-5.07; 95%CI:-9.07;-1.07). There was no association of parity with GS and disability. Higher endogenous estrogen exposure during reproductive life may be protective for motor function in the elderly. These results are consistent with the hypothesis of a cardiovascular component of motor function.

The route of estrogen administration is an important determinant of the risk of the first venous thromboembolism (VTE) event in postmenopausal women using hormone therapy (HT). However, the impact of transdermal estrogens on VTE recurrence risk has not been investigated. The aim of our study was to assess the impact of HT by route of estrogen administration on the risk of recurrent VTE.A total of 1,023 consecutive postmenopausal women aged 45 to 70 years with a confirmed first VTE were recruited from an outpatient clinic of a hemostasis hospital unit between January 2000 and December 2008 and were followed for an average of 79 months after discontinuation of anticoagulation therapy.Recurrent VTE occurred in 77 women (1.1% per year). During the follow-up, 130 women used HT (12.7%), including 103 transdermal estrogen users (10.0%) and 10 oral estrogen users (1.0%). After adjustment for potential confounders, there was no significant association between recurrent VTE and use of transdermal estrogens (hazard ratio, 1.0; 95% CI, 0.4-2.4), with the nonusers as a reference group. In contrast, women using oral estrogens had an increased risk of recurrent VTE (hazard ratio, 6.4; 95% CI, 1.5-27.3). Consistently, no subgroup of women had evidence of a risk of recurrent VTE with transdermal HT that significantly differed from that observed for all women.Oral but not transdermal estrogens are associated with a higher risk of recurrent VTE among postmenopausal women. This result provides further epidemiological evidence that transdermal estrogens may be safe with respect to VTE risk.

Context: The association between combined oral contraceptives (OC) and the risk of myocardial infarction (MI) has been intensively studied, and conclusions are controversial. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular diseases is poorly investigated and remains unclear. Objective: We carried out a meta-analysis based on EMBASE- and MEDLINE-referenced literature corresponding to OC marketed since 1960. Methods: Eligible articles published in English language describing OC or POC use and MI outcome were reviewed, and relevant ones were extracted. All types of POC and route of administration were considered. Results: Six case-control studies were identified. The combined odds ratio showed no increase in the MI risk with POC use (odds ratio = 1.07; 95% confidence interval, 0.62–1.84). This result was similar according to the route of administration, including implant, injectable, and oral POC. Conclusion: Data from observational studies suggest no increase in risk of MI with POC use. However, these results are based on limited data. Further investigations are needed, especially among women at high MI risk.

Introduction Hormone therapy (HT) is the most effective treatment to counteract menopauserelated symptoms. Because venous thromboembolism (VTE) is the main harmful effect of HT among young postmenopausal women, reducing VTE risk appears to be a relevant strategy to improve the benefit/risk profile of HT among postmenopausal women. Methods This article is a review of recent findings regarding the VTE risk among women using HT. Results Recent data confirmed the safety of the transdermal route of estrogens administration in postmenopausal women requiring treatment. In addition, epidemiological data showed that use of concomitant progestins could increase VTE risk compared with progesterone use. Finally, results of a meta-analysis showed that the VTE risk increased with doses of oral estrogens. Conclusion The route of estrogen administration, the type of concomitant progestogens and the dose of estrogens are three important determinants of the thrombotic risk among postmenopausal women using HT.

Venous thromboembolism (VTE) is a main harmful effect of oral estrogen therapy among postmenopausal women. Transdermal estrogens may be safer but early results need to be confirmed. This review provides a summary of the most recent findings regarding the VTE risk among oral versus transdermal estrogens users.Since 2008, we identified five relevant observational studies. Among them, two large cohort studies confirmed that oral but not transdermal estrogens were associated with VTE risk among postmenopausal women. In an updated meta-analysis of current data, pooled risk ratios for VTE were 1.9 [95% confidence interval (CI) 1.3-2.3] and 1.0 (95% CI 0.9-1.1) among oral and transdermal estrogens users, respectively. In addition, one recent cohort study showed that transdermal estrogens did not confer an excess risk of recurrent VTE among postmenopausal women with a history of VTE. The difference in VTE risk between oral and transdermal estrogen users is supported by biological data. Whereas oral estrogens can increase thrombin generation and induce a resistance to activated protein C, transdermal estrogens have minimal effects on hemostatic variables.Transdermal estrogens may improve substantially the benefit/risk ratio of postmenopausal hormone therapy and should be considered as a safer option, especially for women at high risk for VTE.

International audience; To assess the risk of venous thromboembolism in women using hormone replacement therapy by study design, characteristics of the therapy and venous thromboembolism, and clinical background. Systematic review and meta-analysis. Medline. Eight observational studies and nine randomised controlled trials. Studies on hormone replacement therapy that reported venous thromboembolism. REVIEW MEASURES: Homogeneity between studies was analysed using chi(2) and I(2) statistics. Overall risk of venous thromboembolism was assessed from a fixed effects or random effects model. Meta-analysis of observational studies showed that oral oestrogen but not transdermal oestrogen increased the risk of venous thromboembolism. Compared with non-users of oestrogen, the odds ratio of first time venous thromboembolism in current users of oral oestrogen was 2.5 (95% confidence interval 1.9 to 3.4) and in current users of transdermal oestrogen was 1.2 (0.9 to 1.7). Past users of oral oestrogen had a similar risk of venous thromboembolism to never users. The risk of venous thromboembolism in women using oral oestrogen was higher in the first year of treatment (4.0, 2.9 to 5.7) compared with treatment for more than one year (2.1, 1.3 to 3.8; P

Despite a decrease in the use of postmenopausal hormone therapy (HT) over the last decade, many women are still prescribed this treatment, as it remains the most effective means of counteracting climacteric symptoms. Its use declined when it was shown that HT increases the risk of breast cancer, stroke and venous thromboembolism (VTE). Nevertheless, that benefit/risk ratio was established among women using oral estrogens alone or combined with a specific progestogen and it cannot necessarily be extrapolated to other HTs. Oral estrogens increase the risk of VTE especially during the first year of treatment and past users revert to a similar risk as women who have never used them. There is now growing evidence that VTE risk among HT users strongly depends on the route of administration. Indeed, transdermal estrogens, unlike oral estrogens, are not associated with an increased VTE risk and biological data support this difference between oral and transdermal estrogens. In addition, transdermal estrogens may not confer additional risk in women at high risk of VTE. Significant differences in thrombotic risk between HT preparations also relate to the concomitant progestogen. Studies have consistently shown that VTE risk is higher among users of combined estrogens plus progestogens than among users of estrogens alone. With respect to the different pharmacological classes of progestogens, two observational studies found that norpregnane derivatives are associated with an increased VTE risk, whereas micronized progesterone may be safe with respect to thrombotic risk. In conclusion, transdermal estrogens alone or combined with micronized progesterone may represent the safest alternative for women who require HT.

Objectifs L’association entre la testosterone et la mortalite chez les hommes reste controversee. De plus, l’influence du syndrome metabolique (SM), par ailleurs associe au risque de deces au cours du vieillissement, est mal connue. Nous examinerons les associations entre la testosterone totale (TT) et la mortalite apres 12 ans de suivi, ainsi que l’influence du SM, chez les hommes de la cohorte des Trois Cites (3C). Methodes L’etude 3C a inclus 3650 hommes âges entre 1999 et 2001 dans trois villes francaises. Le dosage de TT a l’inclusion a ete realise chez 443 sujets ; parmi eux, 166 decedaient apres 12 ans de suivi. Les hazard ratios (HR) du risque de mortalite et leurs intervalles de confiance a 95 % (IC a 95 %) ont ete estimes a l’aide de modeles de Cox. Resultats Apres ajustement sur les facteurs de risque, une relation en J a ete mise en evidence entre la TT et le risque de mortalite (p Conclusions Nos resultats mettent en evidence un lien complexe entre les niveaux de TT et la mortalite chez les hommes. De plus, cette relation semble etre modulee par la presence du SM.

International audience; Postmenopausal hormone therapy (HT), which consists of exogenous estrogens with or without combined progestogens, remains the most effective treatment of climacteric symptoms. Depending on its characteristics, it may nevertheless increase the risk of venous thromboembolism, and its effects on hemostasis have been studied for several decades. The aim of this review was to summarize current knowledge on the effects of HT on hemostasis, taking into account the route of estrogen administration, the daily dose and chemical structure of estrogens, and the pharmacologic class of progestogens. Data from randomized controlled trials that included a control group (either placebo or no treatment) were selected, and analysis was conducted on different generations of biomarkers. Overall, studies showed a hemostasis imbalance among oral estrogen users with a decrease in coagulation inhibitors and an increase in markers of activation coagulation, leading to global enhanced thrombin generation. By contrast, transdermal estrogen use was associated with less change in hemostasis variables and did not activate coagulation and fibrinolysis. No clear difference in HT effects on hemostasis was highlighted between daily doses of estrogens, between estrogen compounds, and between pharmacologic classes of progestogens. Changes in hemostasis are in accordance with clinical results showing an increased thrombotic risk with oral--but not transdermal--estrogen use.

International audience; In older postmenopausal women, high levels of endogenous estrogen have been related to adverse health outcomes including ischemic arterial disease (IAD). Whether estrogen receptor-α (ESR1) and -β (ESR2) polymorphisms modulate the effects of estrogens on IAD has not been investigated. In the Three-City prospective cohort study among subjects older than 65 years, we used a case-cohort design in which plasma levels of total and bioavailable 17β-estradiol were measured. After exclusion of postmenopausal women using hormone therapy, a random subcohort of 533 women and 105 incident cases of first IAD events over 4 years of follow-up were analyzed. Five common polymorphisms of ESR1 and ESR2 were genotyped. Hazard ratios (HRs) of IAD for a 1-SD increase in hormones levels by the genotypes were estimated from Cox models after adjustment for cardiovascular risk factors and a correction for multiple testing. We also investigated the role of hemostasis and inflammation as potential mediators. Neither estrogens nor IAD risk was significantly associated with estrogen receptor polymorphisms. Overall, IAD risk increased with total estradiol [HR1.40, 95% confidence interval (CI) 1.11-1.77]. Stratified analysis by genotypes showed that total estradiol was positively related to IAD risk in women with ESR1 rs9340799-AA genotype but not in women with the AG/GG genotype (HR 1.62, 95% CI 1.22-2.17 and HR 1.03, 95% CI 0.81-1.30, respectively; P for interaction

Synergism between non-O blood group and oral estrogen in the risk of venous thromboembolism among postmenopausal women: The ESTHER Study

Contexte Les estrogenes oraux induisent une hypercoagulabilite mais le lien entre l’estradiol plasmatique et l’hemostase est peu connu. De plus, le role des hormones sexuelles endogenes dans le developpement de l’atherothrombose chez les femmes menopausees est incertain. Objectif Etudier les interrelations entre hormones sexuelles endogenes, hemostase et incidence a 10 ans des evenements cardiovasculaires chez les femmes menopausees. Methodes Les parametres de l’hemostase (fibrinogene, facteur Willebrand, generation de thrombine in vitro, D-Dimeres), l’estradiol, la testosterone et la SHBG plasmatique ont ete mesures dans un echantillon aleatoire de 623 femmes participant a l’etude de cohorte prospective des Trois-Cites (3C), âgees de plus de 65 ans et ne prenant aucun traitement hormonal. Apres 10 annees de suivi, 69 evenements cardiovasculaires majeurs sont survenus. Les hazard ratios (HR ; intervalle de confiance a 95 %) associes a une variation d’un ecart-type de chaque predicteur ont ete estimes par des modeles de Cox multivaries prenant en compte les facteurs de risque cardiovasculaires traditionnels. Resultats Le risque cardiovasculaire augmentait significativement avec l’estradiol (HR = 1,49 ; 1,10–2,02 ; p = 0,01), le fibrinogene (HR = 1,34 ; 1,05–1,70 ; p = 0,02), le facteur Willebrand (HR = 1,56 ; 1,19–1,05 ; p p = 0,02) et n’etait pas modifie par la SHBG. L’impact de l’estradiol sur le risque cardiovasculaire s’expliquait en partie par une augmentation du fibrinogene et de la generation de thrombine. Conclusion Les hormones sexuelles et certains parametres de l’hemostase apparaissent comme des predicteurs a long terme du risque cardiovasculaire chez les femmes menopausees apres 65 ans. Une hypercoagulabilite pourrait jouer un role mediateur dans l’effet de l’estradiol sur l’atherothrombose.

International audience; This study aims to investigate venous thromboembolism (VTE) risk in relation to age at menopause, age at menarche, parity, bilateral oophorectomy, and time since menopause, as well as any interaction with randomized hormone therapy (HT) assignment, among postmenopausal women. Using pooled data from the Women's Health Initiative HT clinical trials including 27,035 postmenopausal women aged 50 to 79 years who had no history of VTE, we assessed the risk of VTE in relation to age at menopause, age at menarche, parity, bilateral oophorectomy, and time since menopause by Cox proportional hazards models. Linear trends, quadratic relationships, and interactions of reproductive life characteristics with HT on VTE risk were systematically tested. During follow-up, 426 women reported a first VTE, including 294 non-procedure-related events. No apparent interaction of reproductive life characteristics with HT assignment on VTE risk was detected, and there was not a significant association between VTE and age at menarche, age at menopause, parity, oophorectomy, or time since menopause. However, analyses restricted to non-procedure-related VTE showed a U-shaped relationship between age at menopause and thrombotic risk that persisted after multivariable analysis (P < 0.01). Compared with women aged 40 to 49 years at menopause, those who had early menopause (age 55 y) had a significantly increased VTE risk (hazard ratio [95% CI]: 1.8 [1.2-2.7] and 1.5 [1.0-2.4], respectively). Reproductive life characteristics have little association with VTE and do not seem to influence the effect of HT on thrombotic risk among postmenopausal women. Nevertheless, early and late onset of menopause might be newly identified risk factors for non-procedure-related VTE.

The cardiovascular safety of widely used combined hormonal contraceptives is still debated. Newer generations of oral formulations as well as non-oral contraceptives (transdermal and vaginal) have been recently evaluated in the context of cardiovascular disease. This review provides a summary of the association between combined oral contraceptives (COCs) and arterial diseases, with an emphasis on new formulations of hormonal contraceptives, as well as routes of administration. A systematic search of the Medline database was performed to find all relevant articles which included women who had widely use third generation pills, and the development of new progestins. Eligible articles published in English and reporting risk of arterial events (myocardial infarction [MI] and stroke) among users of hormonal contraceptives were reviewed. A quantitative assessment was made from included studies. Overall, current use of oral combined contraceptives increased the risk of MI and ischemic stroke (pooled OR: 1.7; 95% confidence interval [95% CI]: 1.2-2.3 and OR: 1.8; 95% CI: 1.2-2.8, respectively), but this was not associated with the risk of hemorrhagic stroke (OR: 1.1; 95% CI: 0.7-1.9). The increase in ischemic arterial disease was higher among first generation pill users compared with second or third generation pill users. In contrast, risk of ischemic arterial disease among current users of second or third generation pill was similar (p = 0.23 for MI risk and 0.99 for ischemic stroke). In conclusion, newer generation formulations of COCs, as well as the non-oral hormonal contraceptive, do not seem to be safer than second generation hormonal contraceptives.

Since the early 1960s, it has been well documented that combined hormonal contraceptives increase the risk of cardiovascular disease. Newer generation of oral formulations, as well as non-oral contraceptives (transdermal and vaginal), have been recently studied for thrombotic risk. This review provides a summary of the association between hormonal contraceptives and venous thromboembolism with emphasis on new formulations of hormonal contraceptives as well as route of administration. A systematic search of Medline database was done for all relevant articles which included women having used third generation pills, and the development of new progestins. Eligible articles published in English and reporting the risk of venous thromboembolism (VTE) (pulmonary embolism or deep venous thrombosis) among users of hormonal contraceptives were reviewed. A quantitative assessment was made from included studies. Current use of drospirenone or cyproterone oral combined contraceptives increased the risk of VTE compared with second generation pills (pooled OR: 1.7; 95% confidence interval [95% CI]: 1.4–2.2 and OR: 1.8; 95% CI: 1.4–2.3, respectively). In the context of contraceptive use, non-oral route of ethinyl-estradiol administration seems to be more thrombogenic than oral route. In contrast, low doses of both oral progestin contraceptives and intrauterine levonorgestrel could be safe with respect to VTE risk. In conclusion, newer generation formulations of hormonal contraceptives, as well as the non-oral hormonal contraceptive, seem to be more thrombogenic than second generation hormonal contraceptives.

Objectifs Si le lien entre la testosterone et la mortalite chez les hommes a ete etudie, il existe a ce jour peu de donnees sur l’association entre l’estradiol (E2) et le risque de deces. Par ailleurs, l’influence de polymorphismes genetiques (SNP) des recepteurs aux estrogenes (ER) sur cette relation n’a jamais ete investiguee. Nous examinerons le lien entre l’E2 et la mortalite en considerant le statut genetique des ER chez les hommes de la cohorte des trois cites (3 C). Methodes L’etude 3 C a recrute 3650 hommes âges entre 1999 et 2001 dans trois villes francaises. Sur un sous-echantillon de 473 sujets dont 183 sont decedes apres 12 ans de suivi, nous avons dose l’E2 et recherche 5 SNPs des ER. Les Hazard ratios (HR) du risque de mortalite et leurs intervalles de confiance a 95 % (IC a 95 %) ont ete estimes a l’aide de modeles de Cox. Resultats Apres ajustement, une relation quadratique a ete mise en evidence entre l’E2 et le risque de mortalite (p = 0,004). Compares aux sujets du deuxieme quartile (51,0–68,6 nmol/L), ceux presentant des taux bas et des taux eleves avaient un risque significativement augmente de mortalite (HR = 1,55 ; IC a 95 % : 1,00–2,43 et HR = 1,83 ; IC a 95 % : 1,18–2,84 respectivement). Neanmoins, aucune interaction entre l’E2 et les SNP sur le risque de mortalite n’a ete detectee. Conclusions Nos resultats mettent en evidence un risque de mortalite plus eleve chez les hommes presentant des valeurs extremes d’E2. Cette association ne semble pas etre modulee par le statut genetique des ER.

Background Despite evidence that estrogens may be involved in atherothrombosis, the role of endogenous sex steroid hormones in ischemic arterial disease among postmenopausal women remains uncertain. Methods and Results In the Three‐City prospective cohort study of subjects (n=9294) >65 years of age, we investigated the association of total 17β‐estradiol, bioavailable 17β‐estradiol, and total testosterone with the 4‐year incidence of ischemic arterial disease among postmenopausal women who did not use any hormone therapy. We designed a case–cohort study including a random sample of 537 subjects and 106 incident cases of first cardiovascular events. Weighted Cox proportional‐hazards models with age as the time scale were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for ischemic arterial disease by a 1–standard deviation increase in sex steroid hormones. In univariate analysis, HR of ischemic arterial disease was positively and significantly associated with both total and bioavailable estradiol levels. These associations remained significant after adjustment for traditional cardiovascular risk factors, including body mass index, diabetes, hypercholesterolemia, hypertension, and smoking status (HR: 1.42, 95% CI: 1.12–1.79, P P P =0.01; and adjusted HR: 1.50, 95% CI: 1.11–2.04, P P =0.08; and HR: 1.32, 95% CI: 0.94–1.84, P =0.11, respectively). By contrast, no significant association was found between total testosterone and ischemic arterial disease in both univariate and adjusted analyses. Conclusions High plasma level of endogenous estradiol emerges as a new predictor of ischemic arterial disease in older postmenopausal women. ( J Am Heart Assoc . 2012;1:e001388 doi : 10.1161/JAHA.112.001388 .)

International audience; Hormone therapy (HT) increases venous thromboembolism (VTE) risk among postmenopausal women. Data on the influence of steroids receptors polymorphisms on this association remain scarce. Since progesterone receptor (hPR) is expressed in human veins and specific progestogens increase VTE risk, we investigated the impact of the functional +331G/A hPR polymorphism on the association of VTE with HT. Using the data of the ESTHER study, we showed that ORs for VTE in current users of progesterone or progestins were not significantly different by hPR+331G/A genotype status. hPR polymorphism appears not to have a significant effect on VTE risk related to HT.

International audience; Hormone therapy increases the risk of venous thromboembolism (VTE) among postmenopausal women. This effect may be modulated by the expression of cytochromes P450 3A5 (CYP3A5) and 1A2 (CYP1A2) which are involved in the hepatic metabolism of estrogens. The objective was to investigate the impact of CYP3A5 and CYP1A2 genetic polymorphisms on the association of VTE with hormone therapy. We conducted a case-control study. This study was conducted in eight French hospital centers and in the general population. CYP3A5 and CYP1A2 genotypes were evaluated among 195 cases with a first documented episode of idiopathic VTE and 533 controls matched for center, age, and admission date. The outcome measure was hormone therapy by route of estrogen administration. Overall, oral but not transdermal estrogen increased VTE risk [odds ratio (OR) = 4.5, 95% confidence interval (CI) = 2.6-7.6, and OR = 1.2, 95% CI = 0.8-1.8, respectively]. The allele frequency of CYP3A5*1 was 9 and 10% among cases and controls (OR = 1.0; 95% CI = 0.6-1.5) and that of CYP1A2*1F was 72 and 71% among cases and controls (OR = 1.5; 95% CI = 0.8-2.8). Compared with nonusers, OR for VTE in users of oral estrogen was 3.8 (95% CI = 2.1-6.7) among patients without CYP3A5*1 allele and 30.0 (95% CI = 4.4-202.9) among patients with this allele (test for interaction P = 0.04). By contrast, there was no significant interaction between CYP3A5*1 allele and transdermal estrogen on VTE risk. There is no interaction between CYP1A2 genetic polymorphism and hormone therapy on VTE risk. Women with CYP3A5*1 allele using oral estrogen can define a subgroup at high VTE risk. Additional data are needed to assess the relevance of this genetic biomarker in the medical management of menopause.

We thank Drs Micheletti and Chevallier for their interest in our report.1 First, we believe that odds ratios (ORs) and 95% confidence intervals (CIs) estimated from logistic regressions provide adequate information about significance and the size and direction of the effect of norpregnane derivatives. Because elevation in venous thromboembolism (VTE) risk is substantial (OR: 4) and significantly different from 1 (with the 95% CI not crossing 1), our results suggest a thrombogenic effect of norpregnanes, and the probability value ( P

International audience; EPIC-Heart is the cardiovascular component of the European Prospective Investigation into Cancer and Nutrition (EPIC), a multi-centre prospective cohort study investigating the relationship between nutrition and major chronic disease outcomes. Its objective is to advance understanding about the separate and combined influences of lifestyle (especially dietary), environmental, metabolic and genetic factors in the development of cardiovascular diseases by making best possible use of the unusually informative database and biological samples in EPIC. Between 1992 and 2000, 519,978 participants (366,521 women and 153,457 men, mostly aged 35-70 years) in 23 centres in 10 European countries commenced follow-up for cause- specific mortality, cancer incidence and major cardiovascular morbidity. Dietary information was collected with quantitative questionnaires or semi-quantitative food frequency questionnaires, including a 24-h dietary recall sub-study to help calibrate the dietary measurements. Information was collected on physical activity, tobacco smoking, alcohol consumption, occupational history, socio-economic status, and history of previous illnesses. Anthropometric measurements and blood pressure recordings were made in the majority of participants. Blood samples were taken from 385,747 individuals, from which plasma, serum, red cells, and buffy coat fractions were separated and aliquoted for long-term storage. By 2004, an estimated 10,000 incident fatal and non-fatal coronary and stroke events had been recorded. The first cycle of EPIC-Heart analyses will assess associations of coronary mortality with several prominent dietary hypotheses and with established cardiovascular risk factors. Subsequent analyses will extend this approach to non-fatal cardiovascular outcomes and to further dietary, biochemical and genetic factors.

The temperature dependence of the frequencies and linewidths of the Raman-active longitudinal optical (LO) phonons in GaAs and AlAs have been measured. The low-temperature lifetime of the LO phonon in AlAs is found to be 9.7 ps, very close to the corresponding GaAs value of 9.5 ps. This contradicts early theoretical predictions. The agreement between theory and experiment can be restored when the accidental degeneracy between the AlAs LO phonon frequency and a feature in the two-phonon density of states is taken into account.

Contexte Des travaux recents ont suggere que des concentrations elevees d’estrogenes endogenes augmentaient le risque de maladies arterielles ischemiques chez les femmes menopausees. Cette association pourrait etre modulee par des polymorphismes genetiques identifies dans les recepteurs des estrogenes (ER). Methodes Dans l’etude cas-cohorte des Trois Cites, les taux plasmatiques du 17β-estradiol et 5 polymorphismes ER ont ete analyses chez des femmes menopausees de plus de 65 ans sans traitement hormonal. Cette etude comprenait un echantillon aleatoire de 533 sujets et 105 cas incidents de maladies arterielles ischemiques survenus apres quatre annees de surveillance. Un modele de Cox ajuste sur les facteurs de risque cardiovasculaire a permis d’estimer les hazard ratios (HR) de maladies arterielles ischemiques associes a un ecart-type d’estradiol en fonction des genotypes ER. Le role mediateur de l’hemostase et de l’inflammation a ete egalement analyse. Resultats Les genotypes ER n’etaient associes significativement ni au risque arteriel ischemique, ni a l’estradiol. Globalement, le risque arteriel ischemique augmentait significativement avec l’estradiol (HR : 1,40, IC95 % : 1,11–1,77). En stratifiant par genotype, cette association etait retrouvee chez les femmes porteuses de rs9340799 -AA mais pas chez celles avec rs9340799 -AG/GG (HR : 1,62, IC95 % : 1,22–2,17 ; HR : 1,03, IC95 % : 0,81–1,30, respectivement, interaction p rs9340799 -AA (HR : 1,41, IC95 % : 1,06–1,90). Conclusion Le genotype ESR1 - rs9340799 peut moduler l’augmentation du risque arteriel ischemique liee aux estrogenes endogenes chez les femmes menopausees âgees. Cet effet pourrait etre en partie explique par une hypercoagulabilite.