Aromatase (CYP19A1) gene variants, sex steroid levels, and late-life depression.

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.

Cardiac Diseases Following Childhood Cancer Treatment: Cohort Study.

BACKGROUND: Cardiac disease (CD) is one of the major side effects of childhood cancer therapy, but until now little has been known about the relationship between the heart radiation dose (HRD) received during childhood and the risk of CD. METHODS AND RESULTS: The cohort comprised 3162 5-year survivors of childhood cancer. Chemotherapy information was collected and HRD was estimated. There were 347 CDs in 234 patients, 156 of them were rated grade ≥3. Cox and Poisson regression models were used. The cumulative incidence of any type of CD at 40 years of age was 11.0% (95% confidence interval [CI], 9.5-12.7) and 7·4% (95% CI, 6.2-8.9) when only the CDs of grade ≥3 were considered. In comparison with patients who received no anthracycline and either no radiotherapy or an HRD<0·1Gy, the risk was multiplied by 18·4 (95% CI, 7.1-48.0) in patients who had received anthracycline and no radiotherapy or a HRD <0.1Gy, by 60.4 (95% CI, 22.4-163.0) in those who had received no anthracycline and an HRD≥30Gy, and 61.5 (95% CI, 19.6-192.8) in those who had received both anthracycline and an HRD≥30Gy. CONCLUSIONS: Survivors of childhood cancers treated with radiotherapy and anthracycline run a high dose-dependent risk of developing CD. CDs develop earlier in patients treated with anthracycline than in those treated without it.

Sex hormone-binding globulin and thrombin generation in women using hormonal contraception.

OBJECTIVES: We investigated the impact of serum sex hormone-binding globulin (SHBG) on thrombin generation (TG) in women according to hormonal contraception. PATIENTS AND METHODS: A cross-sectional study of SHBG and TG measured via calibrated automated thrombography was conducted in 150 healthy women, including 75 users of combined oral contraceptives (COC), 22 users of progestin-only contraceptives (POC) and 53 nonusers. RESULTS: COC but not POC-users had significantly higher SHBG levels compared with nonusers. In hormonal contraceptive users, SHBG was positively associated with both activated protein C (APC) resistance and baseline TG, and protein S and prothrombin were important mediators. CONCLUSION: These data provide further evidence that SHBG may be used as a biomarker in assessing prothrombotic profile of hormonal contraception.

Postmenopausal Hormone Therapy and Risk of Stroke: Impact of the Route of Estrogen Administration and Type of Progestogen.

BACKGROUND AND PURPOSE: The benefit/risk analysis of hormone therapy in postmenopausal women is not straightforward and depends on cardiovascular disease. Evidence supports the safety of transdermal estrogens and the importance of progestogens for thrombotic risk. However, the differential association of oral and transdermal estrogens with stroke remains poorly investigated. Furthermore, there are no data regarding the impact of progestogens. METHODS: We set up a nested case-control study of ischemic stroke (IS) within all French women aged 51 to 62 years between 2009 and 2011 without personal history of cardiovascular disease or contraindication to hormone therapy. Participants were identified using the French National Health Insurance database, which includes complete drug claims for the past 3 years and French National hospital data. We identified 3144 hospitalized IS cases who were matched for age and zip code to 12 158 controls. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Compared with nonusers, the adjusted ORs of IS were1.58 (95% CI, 1.01-2.49) in oral estrogen users and 0.83 (0.56-1.24) in transdermal estrogens users (P<0.01). There was no association of IS with use of progesterone (OR, 0.78; 95% CI, 0.49-1.26), pregnanes (OR, 1.00; 95% CI, 0.60-1.67), and nortestosterones (OR, 1.26; 95% CI, 0.62-2.58), whereas norpregnanes increased IS risk (OR, 2.25; 95% CI, 1.05-4.81). CONCLUSIONS: Both route of estrogen administration and progestogens were important determinants of IS. Our findings suggest that transdermal estrogens might be the safest option for short-term hormone therapy use.

A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential.

Thrombin, the major enzyme of the hemostatic system, is involved in biological processes associated with several human diseases. The capacity of a given individual to generate thrombin, called the thrombin generation potential (TGP), can be robustly measured in plasma and was shown to associate with thrombotic disorders. To investigate the genetic architecture underlying the interindividual TGP variability, we conducted a genome-wide association study in 2 discovery samples (N = 1967) phenotyped for 3 TGP biomarkers, the endogenous thrombin potential, the peak height, and the lag time, and replicated the main findings in 2 independent studies (N = 1254). We identified the ORM1 gene, coding for orosomucoid, as a novel locus associated with lag time variability, reflecting the initiation process of thrombin generation with a combined P value of P = 7.1 × 10(-15) for the lead single nucleotide polymorphism (SNP) (rs150611042). This SNP was also observed to associate with ORM1 expression in monocytes (P = 8.7 × 10(-10)) and macrophages (P = 3.2 × 10(-3)). In vitro functional experiments further demonstrated that supplementing normal plasma with increasing orosomucoid concentrations was associated with impaired thrombin generation. These results pave the way for novel mechanistic pathways and therapeutic perspectives in the etiology of thrombin-related disorders.

Low testosterone and the risk of dementia in elderly men: Impact of age and education.

OBJECTIVE: The objective of this study was to examine the association of plasma estradiol and testosterone with risk for dementia in elderly men. METHODS: Within the population based Three-City study, including 3650 men age 65 years and older, a case-cohort design was set up after 4-years of follow-up. Baseline plasma levels of total 17-ß estradiol (Total-E2), total testosterone (total-T) and bioavailable testosterone (bio-T) were measured for all cases of incident dementia (n=105) and for a random sample of the cohort (n=413). Cox regression models were used to estimate multivariate steroid sex hormone-associated hazard ratios (HR) and 95% confidence intervals of dementia. RESULTS: There was a reverse J-shaped relationship between total-T and risk for dementia (P=.007). Compared with the median tertile, the HRs associated with total-T in the lower and upper tertile were increased (HR, 2.33; P=.026; HR, 1.9, P=.126; respectively). Low bio-T was associated with a greater risk for dementia (HR for one standard deviation of decreasing log(bio-T), 1.29; 95% confidence interval, 1.03-1.62). An interaction was found between bio-T and age (P<.0001), and bio-T and education (P=.044). Risk for dementia associated with low bio-T was greater in older men (80 years or older) than in younger men (younger than 80 years; HR, 3.11; P=.011 vs. HR, 1.07, P=.715, respectively) and in men with high level of education compared with those with low level of education (HR, 2.32; P=.0002 vs. HR, 0.95; P=.790, respectively). No significant association was found between Total-E2 and dementia. CONCLUSIONS: Low levels of testosterone are associated with a risk for dementia in elderly men. The association between low bio-T and dementia may be more relevant to men 80 years or older and men with a high level of education.

Estrogen receptor polymorphisms and incident dementia: the prospective 3C study.

BACKGROUND: Genetic variation in the estrogen receptor (ESR) may be associated with the incidence of Alzheimer's disease (AD), but this association could be modified by genetic and environmental factors. METHODS: The association between five ESR α (ESR1) and ß (ESR2) polymorphisms with 7-year dementia incidence was examined among 6959 older men and women from the Three City Study using multivariate-adjusted Cox regression models with delayed entry. Gender, the apolipoprotein E (APOE) ε4 allele, and hormone treatment were considered as potential effect modifiers of this association. RESULTS: Among women, the CC genotype of ESR1rs2234693 was specifically associated with a small increased risk of AD (adjusted hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.03-2.28, P = .03). However, women with this genotype had a substantially increased risk of AD associated with the APOE ε4 allele (adjusted HR: 3.24, 95% CI: 1.81-5.79 for women rs2234693 CC; compared with HR: 1.87, 95% CI: 1.37-2.56 for all women). There was also evidence of a nominally significant interaction between the ESR1 and ESR2 polymorphisms on the risk of all dementias (P = .04). Hormone treatment did not modify these associations, and there were no significant associations in men. CONCLUSIONS: Although there was only weak support for a gender-specific association between the common ESR1rs2234693 polymorphism and AD, this polymorphism may act as an effect modifier, modifying the association between an ESR2 polymorphism and dementia, as well as the risk of AD associated with the APOE ε4 allele.

Endogenous oestradiol as a positive correlate of plasma fibrinogen among older postmenopausal women: a population-based study (the Three-City cohort study).

BACKGROUND: Plasma fibrinogen is a strong predictor of ischaemic arterial disease in women. Sex steroid hormones including hormone therapy may play an important role in the development of cardiovascular disease. However, whether endogenous sex steroid hormones influence the plasma fibrinogen concentrations among postmenopausal women remains unclear. OBJECTIVES: To investigate the association of plasma fibrinogen levels with endogenous sex steroid hormones and sex hormone binding globulin (SHBG) among postmenopausal women. METHODS: We used data from the French prospective Three-City cohort study that included 9294 noninstitutionalized men and women over 65 years of age. Total 17ß-oestradiol (E2, pg/ml), total testosterone (T, ng/ml), SHBG (nm) and fibrinogen (g/l) were measured in stored plasmas in a subcohort of 602 randomly selected postmenopausal women who used neither hormone medication nor anticoagulation therapy. Multivariate linear regression models were used to estimate the regression coefficients assessed in fibrinogen unit by 1 SD increase in log-distribution of sex steroid hormones and SHBG. RESULTS: E2 but neither T nor SHBG was positively associated with plasma fibrinogen levels (ß = 0·148, P < 0·001). Adjustment for cardiovascular risk factors including diabetes made no substantial change to the results (ß = 0·145, P < 0·001). The association of fibrinogen with E2 was stronger among women with body mass index over 25 kg/m(2) compared with those with normal weight (ß = 0·156, P < 0·001 and ß = 0·092, P = 0·02, respectively, P for interaction = 0·04). CONCLUSION: E2 emerges as a positive and independent correlate of plasma fibrinogen among postmenopausal women, especially in subjects who are overweight. These findings suggest a deleterious effect of endogenous oestrogens on cardiovascular risk profile among postmenopausal women.

Increased thrombin generation is associated with acute ischemic stroke but not with coronary heart disease in the elderly: the Three-City cohort study.

OBJECTIVE: A high thrombin generation level has been associated with the risk of venous thrombosis. Whether changes in this biomarker are relevant to arterial disease remains unknown. We investigated the association of thrombin generation with coronary heart disease (CHD) and acute ischemic stroke (AIS) in the elderly. METHODS AND RESULTS: We used data from the Three-City study, a prospective cohort including 9294 subjects aged >65 years. After 4 years of follow-up, a case-cohort study was established. Using the calibrated automated thrombography method, endogenous thrombin potential and peak height were measured in plasma samples of all CHD and AIS cases and a random sample of 1177 controls. We did not find any significant association between thrombin generation and CHD. In multivariate analyses, high levels of endogenous thrombin potential and peak height were associated with an increased risk of AIS (hazard ratio=1.16 [95% CI, 0.90 to 1.50] and 1.31 [95% CI, 1.01 to 1.69] for a 1 SD increase, respectively). Data also suggested that these associations might be more important in women (hazard ratio=1.55 [95% CI, 1.05 to 2.33] and 1.71 [95% CI, 1.11 to 2.63], respectively) than in men (P for interaction=0.04 and 0.08, respectively). CONCLUSION: Thrombin generation emerges as an independent predictor of AIS, particularly in women. Hypercoagulability may have an important role in the pathogenesis of AIS.

Effectiveness of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on total and cardiovascular mortality and morbidity in primary prevention: A nationwide study based on French Health Insurance Data (SNDS).

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) both inhibit the renin-angiotensin system (RAS) but have different sites of action. Whether clinically meaningful differences exist is still debated. The authors set up a population-based nationwide retrospective cohort study with at least 5 years of follow-up based on the comprehensive French Health Insurance Database linked to the French hospital discharge database. Patients aged 50 or above, identified as ARB or ACE inhibitor new users in 2009 (at least one delivery during the year and no such delivery in 2008) were eligible. Exclusion criteria included history of cancer, cardiovascular disease, or chronic renal insufficiency. Main outcome measure was overall mortality. Secondary outcomes were cardiovascular deaths, major cardiovascular events, and major or other cardiovascular events. Out of 407 815 eligible patients, 233 682 (57%) were ARB users; two-third had no previous exposure to antihypertensive drug. Based on propensity-score based Cox model, ARB new user group had a better overall (HR: .878, 95%CI, .854 to .902), and cardiovascular (HR: .841, 95%CI, .800 to .84) survival and had a lower risk for major cardiovascular events (HR: .886, 95%CI, .868 to .905). Statistically significant quantitative interactions were detected with diabetes. Considering subgroup analyses, ARBs had a better survival than ACE inhibitors in nondiabetic patients.

Oestrogen receptor polymorphisms and late-life depression.

BACKGROUND: Evidence suggests a role for oestrogen in depression but the involvement of oestrogen receptor polymorphisms remains unknown. AIMS: To determine the association between oestrogen receptor polymorphisms and late-life depression and the modifying effect of hormone treatment. METHOD: Depression was assessed using the Mini-International Neuropsychiatric Interview, according to DSM-IV criteria and the Centre for Epidemiologic Studies - Depression Scale. The association between oestrogen receptor α and ß (ER-α and ER-ß) polymorphisms with severe depression was examined in 6017 community-dwelling elderly people using multivariate logistic regression. RESULTS: In women, the ER-α rs2234693 and rs9340799 polymorphisms were significantly associated with the risk of late-life depression. The A allele of ER-ß rs1256049 increased the risk of depression, but only for non-current users of hormone treatment. In men, only the ER-ß rs4986938 polymorphism showed a weak association with depression risk. CONCLUSIONS: Oestrogen receptor polymorphisms are associated with severe late-life depression risk in women only.

Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study.

OBJECTIVE: Oral estrogen therapy increases venous thromboembolism risk among postmenopausal women. Although recent data showed transdermal estrogens may be safe with respect to thrombotic risk, the impact of the route of estrogen administration and concomitant progestogens is not fully established. METHODS AND RESULTS: We used data from the E3N French prospective cohort of women born between 1925 and 1950 and biennially followed by questionnaires from 1990. Study population consisted of 80 308 postmenopausal women (average follow-up: 10.1 years) including 549 documented idiopathic first venous thromboembolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional models. Compared to never-users, past-users of hormone therapy had no increased thrombotic risk (HR=1.1; 95% CI: 0.8 to 1.5). Oral not transdermal estrogens were associated with increased thrombotic risk (HR=1.7; 95% CI: 1.1 to 2.8 and HR=1.1; 95% CI: 0.8 to 1.8; homogeneity: P=0.01). The thrombotic risk significantly differed by concomitant progestogens type (homogeneity: P<0.01): there was no significant association with progesterone, pregnanes, and nortestosterones (HR=0.9; 95% CI: 0.6 to 1.5, HR=1.3; 95% CI: 0.9 to 2.0 and HR=1.4; 95% CI: 0.7 to 2.4). However, norpregnanes were associated with increased thrombotic risk (HR=1.8; 95% CI: 1.2 to 2.7). CONCLUSIONS: In this large study, we found that route of estrogen administration and concomitant progestogens type are 2 important determinants of thrombotic risk among postmenopausal women using hormone therapy. Transdermal estrogens alone or combined with progesterone might be safe with respect to thrombotic risk.

Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Progestogen-only contraceptives and the risk of stroke: a meta-analysis.

BACKGROUND AND PURPOSE: The association between combined oral contraceptives (OC) use and increased risk of stroke has been reported. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular disease remains unclear. METHODS: A meta-analysis based on EMBASE and MEDLINE referenced literature corresponding to OCs marketed since 1960 was carried out. Eligible articles assessing the risk of stroke in relation to OC or POC were reviewed, and relevant studies were extracted. All types of POC and routes of administration were taken into account in the meta-analysis. RESULTS: Six case-control studies were identified. The combined odd ratio (OR) showed no increase in the risk of stroke among POC users (OR=0.96; 95% confidence interval: 0.70 to 1.31). This result was similar according to the route of administration (either implant or injectable or oral POC). CONCLUSIONS: Data from observational studies show that POC use is not associated with an increased risk of stroke. However, these results are based on limited data. Further investigations are needed in women with risk factors of stroke.

Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study.

BACKGROUND: Oral estrogen therapy increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal estrogen may be safer. However, currently available data have limited the ability to investigate the wide variety of types of progestogen. METHODS AND RESULTS: We performed a multicenter case-control study of VTE among postmenopausal women 45 to 70 years of age between 1999 and 2005 in France. We recruited 271 consecutive cases with a first documented episode of idiopathic VTE (208 hospital cases, 63 outpatient cases) and 610 controls (426 hospital controls, 184 community controls) matched for center, age, and admission date. After adjustment for potential confounding factors, odds ratios (ORs) for VTE in current users of oral and transdermal estrogen compared with nonusers were 4.2 (95% CI, 1.5 to 11.6) and 0.9 (95% CI, 0.4 to 2.1), respectively. There was no significant association of VTE with micronized progesterone and pregnane derivatives (OR, 0.7; 95% CI, 0.3 to 1.9 and OR, 0.9; 95% CI, 0.4 to 2.3, respectively). In contrast, norpregnane derivatives were associated with a 4-fold-increased VTE risk (OR, 3.9; 95% CI, 1.5 to 10.0). CONCLUSIONS: Oral but not transdermal estrogen is associated with an increased VTE risk. In addition, our data suggest that norpregnane derivatives may be thrombogenic, whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk. If confirmed, these findings could benefit women in the management of their menopausal symptoms with respect to the VTE risk associated with oral estrogen and use of progestogens.

Synergism between oral estrogen therapy and cytochrome P450 3A5*1 allele on the risk of venous thromboembolism among postmenopausal women.

CONTEXT: 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. OBJECTIVE: The objective was to investigate the impact of CYP3A5 and CYP1A2 genetic polymorphisms on the association of VTE with hormone therapy. DESIGN: We conducted a case-control study. SETTING: This study was conducted in eight French hospital centers and in the general population. PATIENTS: 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. OUTCOME MEASURE: The outcome measure was hormone therapy by route of estrogen administration. RESULTS: 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. CONCLUSIONS: 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.

Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the role of radiation dose received to the circle of Willis (WC) during radiation therapy (RT) and of potential dose-response modifiers on the risk of stroke after treatment of childhood cancer. METHODS: We evaluated the risk factors for stroke in a cohort of 3172 5-year survivors of childhood cancer who were followed up for a median time of 26 years. Radiation doses to the WC and brain structures were estimated for each of the 2202 children who received RT. RESULTS: Fifty-four patients experienced a confirmed stroke; 39 were ischemic. Patients not receiving RT had a stroke risk similar to that of the general population, whereas those who received RT had an 8.5-fold increased risk (95% confidence interval [CI]: 6.3-11.0). The excess of incidence of stroke increased yearly. The dose of radiation to the WC, rather than to other brain structures, was found to be the best predictor of stroke. The relative risk was 15.7 (95% CI: 4.9-50.2) for doses of 40 Gy or more. At 45 years of age, the cumulative stroke incidence was 11.3% (95% CI: 7.1%-17.7%) in patients who received 10 Gy or more to the WC, compared with 1% expected from general population data. Radiation doses received to the heart and neck also increased the risk. Surgery for childhood brain cancer was linked to hemorrhagic strokes in these patients. CONCLUSION: The WC should be considered as a major organ at risk during RT for childhood brain cancers. The incidence of radiation-induced ischemic stroke strongly increases with long-term follow-up.