Testostérone plasmatique et risque cardiovasculaire chez les hommes après 65 ans

Le déclin des hormones sexuelles avec l'âge a été mis en cause dans le développement de nombreuses maladies. Chez les hommes, la baisse de la testostérone circulante est un prédicteur de la mortalité toutes causes mais son impact sur le risque cardiovasculaire est incertain. A partir de l étude de cohorte des Trois Cités (3C), réalisée en France dans la population générale, j'ai étudié le rôle de la testostérone plasmatique dans la survenue des évènements artériels ischémiques chez les hommes de plus de 65 ans.J'ai montré, dans une première partie, que des taux diminués de testostérone étaient associés à des facteurs de risque cardiovasculaire. J'ai notamment confirmé le rôle central de la masse grasse et du diabète comme déterminants des androgènes. De plus, j'ai mis en évidence une association inverse entre la testostérone et l épaisseur intima-media (EIM) des artères carotidiennes. J'ai montré que cette relation dépendait du statut inflammatoire systémique avec des variations significatives de l'EIM observées uniquement chez les hommes ayant des niveaux élevés de protéine C-réactive. En revanche, aucune association significative n'a pu être détectée entre les androgènes et la présence de plaques d'athérome.Dans une seconde partie, j'ai mis en évidence une relation originale en forme de J entre la testostérone et le risque de maladies artérielles ischémiques. Les hommes ayant des taux élevés ou diminués de testostérone présentaient un risque accru d évènements artériels et cette relation ne dépendait pas des principaux facteurs de risque cardiovasculaire. Des résultats similaires étaient observés pour les cardiopathies ischémiques et les accidents vasculaires cérébraux ischémiques.Ces résultats suggèrent que des taux moyens de testostérone totale circulante (4-5 ng/mL) protègent des maladies artérielles ischémiques. Ce rôle modulateur des androgènes pourrait être lié à un processus de vieillissement précoce non spécifique.The age-related decline in sex hormones has been involved in the development of many diseases. In men, low endogenous testosterone levels predict mortality due to all causes. However, the role of testosterone in the development of cardiovascular disease remains uncertain. In the french Three-City population-based cohort study, I assessed the association of plasma sex hormones with the incidence of ischemic arterial disease in men aged over 65 years.First, I showed that low testosterone levels were associated with cardiovascular risk factors. I confirmed a leading role of obesity and diabetes as determinants of androgens. I also found an inverse association between testosterone and carotid intima-media thickness (IMT). I highlighted that, this relationship was mediated through systemic inflammation as significant changes in IMT were observed only in men with high C-reactive protein levels. However, no significant association was detected between androgens and the presence of carotid plaques.Second, I found an original J-shaped association between testosterone and risk of ischemic arterial disease. Men with elevated or decreased testosterone levels had higher risk of arterial events and this association was independent of major cardiovascular risk factors. Similar results were observed for ischemic heart disease and ischemic stroke.Overall, these results suggest that intermediate testosterone levels (4-5 ng/mL) could protect against cardiovascular events. Androgens could also be involved in general ageing process.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Hormone Treatment, Estrogen Receptor Polymorphisms and Mortality: A Prospective Cohort Study

International audienceBACKGROUND: The association between hormone treatment (HT) and mortality remains controversial. This study aimed to determine whether the risk of mortality associated with HT use varies depending on the specific characteristics of treatment and genetic variability in terms of the estrogen receptor. METHODOLOGY/PRINCIPAL FINDINGS: A prospective, population-based study of 5135 women aged 65 years and older who were recruited from three cities in France and followed over six years. Detailed information related to HT use was obtained and five estrogen receptor polymorphisms were genotyped. The total follow-up was 25,436 person-years and during this time 352 women died. Cancer (36.4%) and cardiovascular disease (19.3%) were the major causes of death. Cox proportional hazards models adjusted for age, education, centre, living situation, comorbidity, depression, physical and mental incapacities, indicated no significant association between HT and mortality, regardless of the type or duration of treatment, or the age at initiation. However, the association between HT and all-cause or cancer-related mortality varied across women, with significant interactions identified with three estrogen receptor polymorphisms (p-values = 0.004 to 0.03) in adjusted analyses. Women carrying the C allele of ESR1 rs2234693 had a decreased risk of all-cause mortality with HT (HR: 0.42, 95% CI: 0.18-0.97), while in stark contrast, those homozygous for the T allele had a significantly increased risk of cancer-related mortality (HR: 3.18, 95% CI: 1.23-8.20). The findings were similar for ESR1 rs9340799 and ESR2 rs1271572. CONCLUSIONS/SIGNIFICANCE: The risk of mortality was not associated with HT duration, type or age at initiation. It was however not equal across all women, with some women appearing genetically more vulnerable to the effects of HT in terms of their estrogen receptor genotype. These findings, if confirmed in another independent study, may help explain the differential susceptibility of women to the beneficial or adverse effects of HT

Impact des estrogènes et de leurs récepteurs sur le risque eschémique chez les femmes ménopausées : une approche cas-cohorte

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocSudocFranceF

Hormone therapy and risk of venous thromboembolism among postmenopausal women

International audienceVenous thromboembolism, either deep vein thrombosis or pulmonary embolism, is a serious side-effect of postmenopausal hormone therapy. Current use of oral estrogens increases the risk of venous thromboembolism, especially during the first year of treatment, but past users of hormone therapy have a similar risk as never-users. Among women at high risk for venous thromboembolism (for example, thrombogenic mutations, obesity), oral estrogens use further enhances the thrombotic risk. Recent studies have shown that transdermal estrogens might be safe with respect to thrombotic risk. The difference in thrombotic risk between oral and transdermal estrogens may be partially explained by changes in hemostasis. Few data are currently available regarding the impact of progestogens on venous thromboembolism risk, but norpregnane derivatives might be thrombogenic. Individual assessment of the benefit-risk ratio is needed before initiating treatment and oral estrogens should be avoided among women at high risk for venous thromboembolism

La maladie veineuse thromboembolique (étude des facteurs de risque de récidive)

A partir des données de deux études de cohortes hospitalières françaises (MEVE etFARIVE), nous nous sommes intéressés aux facteurs de risque de récidive de maladieveineuse thromboembolique (MVTE).Nous avons confirmé un excès de risque de récidive de MVTE chez les hommescomparés aux femmes et montré que cette relation dépendait en partie de l âge, de lamutation du FV Leiden et de la prise d'hormones au premier événement. Une analyse enfonction du sexe a mis en évidence que l âge, l obésité et des niveaux élevés de D-dimèresaugmentaient significativement le risque de récidive de MVTE chez les femmes. Par ailleurs,contrairement aux estrogènes oraux, les estrogènes transdermiques seuls ou combinés à laprogestérone micronisée n'exposaient pas les femmes ménopausées à un risque accru derécidive de MVTE. Chez les hommes, la mutation du facteur V Leiden, un antécédent familialde maladie artérielle et un premier événement idiopathique étaient des facteurs de risqueindépendants de récidive.L'identification de profils de risque différents en fonction du sexe pourrait permettreune meilleure stratification du risque de récidive de MVTE. Ces résultats devraientcontribuer à améliorer la prise en charge de la maladie par une évaluation individuelle de ladurée optimale du traitement anticoagulant. De plus, une bonne sécurité d emploi desestrogènes transdermiques seuls ou combinés à la progestérone micronisée ouvre desperspectives cliniques intéressantes dans le traitement des troubles sévères de laménopause chez des patientes avec un antécédent personnel de MVTE.MotsBased on data from two French hospital cohort studies, we investigated the riskfactors for recurrent venous thromboembolism (VTE).We confirmed the higher risk of recurrent VTE among men compared with womenand we suggested that this relation depended on age, Factor V Leiden mutation andhormone-related first event. A sex-specific analysis showed that advancing age, obesity andelevated D-dimer significantly increased the risk of recurrent VTE in women. Moreover, oralbut not transdermal estrogens, were associated with a higher risk of recurrent VTE amongpostmenopausal women. In men, factor V Leiden mutation, family history of arterial diseaseand an idiopathic first event were independent risk factors for VTE recurrence.The identification of sex-specific risk factors provides a new insight to riskstratification for VTE recurrence. These results could improve the prevention of this diseaseby an individual assessment of the optimal duration of anticoagulation therapy. In addition,our results provide first evidence supporting the safety of transdermal estrogens alone orcombined with micronized progesterone with respect to VTE recurrence risk. These datacould have important clinical implications for women with personal history of VTE whorequire hormone therapy for severe postmenopausal symptoms.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Letter to the Editor: "Transdermal vs Oral Estrogen Therapy and Venous Thromboembolism: Upgrade the Level of Evidence" by

International audienceScarabin PY, et meta-analysis by Mohammed et al (1) confirms the safety advantage of transdermal vs oral estrogens with respect to the risk of venous thromboembolism (VTE). Surprisingly, the quality of evidence is described as very low (see Table 4 in the report). We believe that this quality rating based on “the observational nature of the studies and inconsistency of results” is not appropriate..

[Deep venous thrombosis: epidemiology, acquired risk factors].

International audienceDeep vein thrombosis is a frequent disease with an annual incidence reaching 5 per thousand among subjects over 75 years. Major acquired risk factors for venous thrombosis include surgery, neoplasm, reduced mobility or paresis, and a previous episode of deep vein thrombosis. Among women, hormonal status (pregnancy, oral contraceptive, hormone replacement therapy) is responsible for the majority of all venous thrombotic events. The impact of other factors is controversial: obesity, tobacco use and varicose veins. Venous thrombosis is a multifactorial disease and analysis of the interactions between acquired and inherited risk factors is an extremely interesting field of investigation