pierre-yves.scarabin@inserm.fr The UK study by Vinogradova and colleagues provides further evidence that oral but not transdermal oestrogen is associated with increased risk of venous thromboembolism ...among women who use postmenopausal hormone therapy.1 Previous studies have shown this safety advantage of transdermal oestrogen, together with the important role of concomitant progestogens.23 Progesterone is the only natural progestogen, and synthetic progestogens are often called progestins. Surprisingly, the effect of progesterone on risk of venous thromboembolism is not discussed, despite strong evidence that progesterone has no effect on clotting factors4 and is resistant to activated protein C.5 Furthermore, an updated meta-analysis has recently shown that among users of transdermal oestrogen, progesterone was associated with the lowest risk of venous thromboembolism compared with other progestogens.6 Venous thromboembolism is one of the most frequent serious adverse effects of hormone therapy, so improving the risk-benefit profile of hormone therapy is an important challenge. 1 Vinogradova Y Coupland C Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases.
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.
Objective 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.Design Systematic review and meta-analysis.Data sources Medline.Studies reviewed Eight observational studies and nine randomised controlled trials.Inclusion criteria Studies on hormone replacement therapy that reported venous thromboembolism.Review measures Homogeneity between studies was analysed using χ2 and I2 statistics. Overall risk of venous thromboembolism was assessed from a fixed effects or random effects model.Results 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<0.05). No noticeable difference in the risk of venous thromboembolism was observed between unopposed oral oestrogen (2.2, 1.6 to 3.0) and opposed oral oestrogen (2.6, 2.0 to 3.2). Results from nine randomised controlled trials confirmed the increased risk of venous thromboembolism among women using oral oestrogen (2.1, 1.4 to 3.1). The combination of oral oestrogen and thrombogenic mutations or obesity further enhanced the risk of venous thromboembolism, whereas transdermal oestrogen did not seem to confer additional risk in women at high risk of venous thromboembolism.Conclusion Oral oestrogen increases the risk of venous thromboembolism, especially during the first year of treatment. Transdermal oestrogen may be safer with respect to thrombotic risk. More data are required to investigate differences in risk across the wide variety of hormone regimens, especially the different types of progestogens.
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.
Oral oestrogen-replacement therapy (ERT) activates blood coagulation and increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal ERT has little effect on haemostasis, ...but data assessing its effect on thrombotic process are scarce. We aimed to examine the effect of the route of oestrogen administration on VTE risk.
We did a multicentre hospital-based case-control study of postmenopausal women in France. During 1999–2002, we recruited 155 consecutive cases with a first documented episode of idiopathic VTE (92 with pulmonary embolisms and 63 with deep venous thrombosis), and 381 controls matched for centre, age, and time of recruitment.
Overall, 32 (21%) cases and 27 (7%) controls were current users of oral ERT, whereas 30 (19%) cases and 93 (24%) controls were current users of transdermal ERT. After adjustment for potential confounding variables, the odds ratio for VTE in current users of oral and transdermal ERT compared with non-users was 3·5 (95% CI 1·8–6·8) and 0·9 (0·5–1·6), respectively. Estimated risk for VTE in current users of oral ERT compared with transdermal ERT users was 4·0 (1·9–8·3).
Oral but not transdermal ERT is associated with risk of VTE in postmenopausal women. These data suggest that transdermal ERT might be safer than oral ERT with respect to thrombotic risk.
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.
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.
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.
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.
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).
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).
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.
PDF
