Increased risk of recurrent venous thromboembolism during hormone replacement therapy--results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET)

Recent observational studies suggest a 2-4 fold increased risk of venous thromboembolism (VTE) in women taking hormone replacement therapy (HRT). The present study was started before publication of these studies, and the aim was to determine if HRT alters the risk of VTE in high risk women. The study was a randomized. double-blind, and placebo-controlled clinical trial with a double-triangular sequential design. Females with previously verified VTE were randomized to 2 mg estradiol plus 1 mg norethisterone acetate, 1 tablet daily (n = 71) or placebo (n = 69). The primary outcome was recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE). Between 1996 and 1998 a total of 140 women were included. The study was terminated prematurely based on the results of circumstantial evidence emerging during the trial. Eight women in the HRT group and one woman in the placebo group developed VTE. The incidence of VTE was 10.7% in the HRT group and 2.3% in the placebo group. In the HRT group, all events happened within 261 days after inclusion. The sequential design did not stop the study, but strongly indicated a difference between the two groups. Our data strongly suggests that women who have previously suffered a VTE have an increased risk of recurrence on HRT. This treatment should therefore be avoided in this patient group if possible. The results also support those of recent epidemiological studies, which also indicate increased risk of VTE in non-selected female populations during HRT.     

The dexamethasone suppression test and the diagnosis of depression in adults with severe and profound developmental disabilities

The dexamethasone suppression test (DST) was administered to 40 adults with severe and profound mental retardation. All participants were free from known conditions which may have given misleading results from cortisol assay. Of nine participants who showed symptoms possibly indicating depression the DST results concurred in two cases (i.e. there were two true-positives). However there were four or five (depending on criteria adopted) false-positive DST results. There did not appear to be a consistent behavioural profile for positive DST responders. With sensitivity to possible depression estimated at 22%, and a diagnostic confidence of <35%, these data do not support recommendations that the DST is useful for assisting in diagnosis of depression in this population.     

Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein--a cross-sectional population survey

The effects of hormone replacement therapy (HRT) on thrombosis risk, thrombotic variables, and the inflammatory marker C-reactive protein (CRP) may vary by route of administration (oral versus transdermal). We studied the relationships of 14 thrombotic variables (previously related to cardiovascular risk) and CRP to menopausal status and to use of HRT subtypes in a cross-sectional study of 975 women aged 40-59 years. Our study confirmed previously-reported associations between thrombotic variables and menopausal status. Oral HRT use was associated with increased plasma levels of Factor IX, activated protein C (APC) resistance, and CRP; and with decreased levels of tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor (PAI) activity. Factor VII levels were higher in women taking unopposed oral oestrogen HRT. The foregoing associations were not observed in users of transdermal HRT; hence they may be consequences of the "first-pass" effect of oral oestrogens on hepatic protein synthesis. We conclude that different effects of oral and transdermal HRT on thrombotic and inflammatory variables may be relevant to their relative thrombotic risk; and suggest that this hypothesis should be tested in prospective, randomised studies.     

Combined biological tests for suicide prediction

Disturbances in serotonin neuroregulation and in hypothalamic-pituitary-adrenal axis activity are both likely, and possibly independent, factors in the genesis of suicidal behavior. This analysis considers whether clinically accessible measures of these two disturbances have additive value in the estimation of risk for suicide. Seventy-four inpatients with RDC major or schizoaffective depressive disorders entered a prospective follow-up study from 1978-1981, underwent a dexamethasone suppression test (DST) and had fasting serum cholesterol levels available in the medical record. As reported earlier, patients who had had an abnormal DST result were significantly more likely to commit suicide during follow-up. Serum cholesterol concentrations did not differ by DST result and low cholesterol values were associated with subsequent suicide when age was included as a covariate. These results indicate that, with the use of age-appropriate thresholds, serum cholesterol concentrations may be combined with DST results to provide a clinically useful estimate of suicide risk.     

The dexamethasone suppression test in borderlines: is it useful?

The relationship between borderline personality disorders (BPD) and major depressive disorder (MDD) continues to be controversial. A reliable biological marker for depressed BPD patients would not only support the diagnosis but could also help in predicting treatment outcome. A large sample of psychiatric patients was screened and data on the Dexamethasone Suppression Test (DST) were obtained for 67 patients who met the criteria for BPD by scoring 7 or greater on the Diagnostic Interview for Borderlines. The DST was positive in 23.9% of the cases. Fifty cases of BPD also met the Research Diagnostic Criteria for MDD. The DST was positive in 26.0%. Of the 50 patients with MDD, 34 also met the criteria for endogenous depression. Only 17.6% of this subgroup had positive results on the DST. The low sensitivity and specificity of the DST for depression in BPD patients suggests that the DST is not a useful test in differentiating BPD patients with MDD from those without MDD. The possible reasons for the DST not being useful in this population are discussed. These findings raises further questions about the nature of the depression suffered by BPD patients.     

CSF 5-HIAA and DST non-suppression — Orthogonal biologic risk factors for suicide in male mood disorder inpatients

Two biomarkers of suicide risk; non-suppression in the dexamethasone suppression test (DST) and low 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) have been reported to be predictors of suicide in mood disorders. The interrelation of the two systems seems to be different in suicide attempters compared with depressed inpatients who have not made a suicide attempt, indicating that the two biomarkers may be seen as independent. This investigation examined the interrelation of low CSF 5-HIAA and DST non-suppression in suicide victims with mood disorder. Fifty-eight mood disorder inpatients not receiving any treatment with antidepressants underwent lumbar puncture and the DST. Plasma cortisol levels at 8:00 a.m., 4:00 p.m. and 11:00 p.m. were analysed in relation to CSF 5-HIAA. All patients were followed up for causes of death and suicides were verified with death certificates. During follow-up (mean 21 years), 11 (19%) patients had committed suicide. In male suicide victims (n = 6), the serum cortisol level at 4:00 p.m. showed a significant positive correlation with CSF 5-HIAA. Low CSF 5-HIAA predicted all early suicides (within 1 year), whereas all males who committed suicide after 1 year were DST non-suppressors. In female suicide victims (n = 5), the post-DST serum cortisol did not correlate with CSF 5-HIAA. Low CSF 5-HIAA and DST non-suppression are orthogonal biologic risk factors for suicide in male mood disorder inpatients. CSF 5-HIAA is associated with short-term suicide risk; dysregulation of the hypothalamic-pituitary-adrenal axis seems to be a long-term suicide predictor.     

Hyperactivity of the hypothalamic-pituitary-adrenal axis and mortality in major depressive disorder

Convergent evidence indicates that HPA-axis hyperactivity is a risk factor for suicide in major depressive disorder, and seven independent reports have shown that patients with abnormal dexamethasone suppression test (DST) results have significantly higher rates of eventual suicide. The identification of interactions between DST results and other clinical predictors would enhance risk assessment, but modest sample sizes have limited such analyses in earlier cohorts. Subjects with major depressive disorder who participated in research protocols at the University of Michigan between 1980 and 1991, who had fully structured diagnostic interviews, and who underwent a 1-mg DST while actively depressed were screened with the National Death Index for a mean (S.D.) follow-up period of 18.0 (5.5) years. Of 334 subjects, 69 (20.7%) were identified as having died. Of these, 13 (18.8%) had died by suicide and 32 (46.4%) from cardiovascular causes. Baseline DST results did not significantly predict death from suicide or from cardiovascular disease for the sample as a whole. Significant relationships between DST results and later suicide did exist for inpatients, for patients with manifest suicidality and, in particular, for inpatients with manifest suicidality. Because nearly all previous reports of DST results and suicide described depressed inpatients, it is possible that the DST is a useful predictor only within this population.     

Changes in ischemic stroke occurrence following daylight saving time transitions

BackgroundCircadian rhythm disruption has been associated with increased risk of ischemic stroke (IS). Daylight saving time (DST) transitions disrupt circadian rhythms and shifts the pattern of diurnal variation in stroke onset, but effects on the incidence of IS are unknown.MethodsEffects of 2004–2013 DST transitions on IS hospitalizations and in-hospital mortality were studied nationwide in Finland. Hospitalizations during the week following DST transition (study group, n = 3033) were compared to expected hospitalizations (control group, n = 11,801), calculated as the mean occurrence during two weeks prior to and two weeks after the index week.ResultsHospitalizations for IS increased during the first two days (Relative Risk 1.08; CI 1.01–1.15, P = 0.020) after transition, but difference was diluted when observing the whole week (RR 1.03; 0.99–1.06; P = 0.069). Weekday-specific increase was observed on the second day (Monday; RR 1.09; CI 1.00–1.90; P = 0.023) and fifth day (Thursday; RR 1.11; CI 1.01–1.21; P = 0.016) after transition. Women were more susceptible than men to temporal changes during the week after DST transitions. Advanced age (>65 years) (RR 1.20; CI 1.04–1.38; P = 0.020) was associated with increased risk during the first two days, and malignancy (RR 1.25; CI 1.00–1.56; P = 0.047) during the week after DST transition.ConclusionsDST transitions appear to be associated with an increase in IS hospitalizations during the first two days after transitions but not during the entire following week. Susceptibility to effects of DST transitions on occurrence of ischemic stroke may be modulated by gender, age and malignant comorbidities.     

Serial dexamethasone suppression tests in psychiatric illness: Part III. The influence of intervening variables

The effects of different intervening variables on dexamethasone suppression test (DST) results were evaluated in depressed, schizophrenic, and manic patients. There was a significant correlation between age and DST results in major depression. Some "isolated peaks" of DST nonsuppression were explained by low dexamethasone serum levels. In schizophrenic and manic patients, the dexamethasone concentrations increased to above the normal range during the study period. A significant negative correlation between dexamethasone concentrations and DST results was found in schizophrenia and mania, but not in depression. Dexamethasone levels were generally higher in men than in women. Weight loss and hospital admission affected the DST in individual cases, whereas length of episode and drug withdrawal did not. Thus, the intervening variables accounted for some of the abnormal DST results, but other factors such as severity of illness, nonspecific stress, or possibly depression itself emerged as the main causes of abnormal DST results.     

Hormone replacement therapy with estradiol and risk of venous thromboembolism--a population-based case-control study.

Recent epidemiological studies on hormone replacement therapy (HRT) containing mainly conjugated equine estrogens indicate increased risk for venous thromboembolism (VTE). The purpose of the present epidemiological study was to evaluate the effect of HRT containing natural estrogens, i.e., estradiol, on the risk of VTE. HRT formulations containing estradiol are commonly used in Scandinavia. The study was a population-based case-control study. Cases were consecutive females, aged 44-70 years, discharged from Ullev?l University Hospital with the diagnosis of deep venous thrombosis or pulmonary embolism during 1990-1996. Fifty-one women with cancer-associated thrombosis were excluded from the study. Controls were randomly collected from the same source population and matched by age. The material comprised 176 cases and 352 controls, i.e., 2 controls for each case. Only formulations containing estradiol were used. The frequency of HRT use was 28% (50/176) in cases and 26% (93/352) in controls. The estimated matched crude odds ratio with 95% confidence interval was 1.13 (0.71-1.78), which indicates no significant association of overall use of HRT and VTE. The estimated adjusted odds ratio was 1.22 (0.76-1.94) performing multi-confounder adjustment using the conditional logistic model and adjusting for hypertension, coronary heart disease, diabetes mellitus, smoking habit, BMI, and the presence of previous VTE. Stratification for time of exposure indicated an increased risk of VTE during the first year of use with a crude odds ratio of 3.54 (1.54-8.2). This effect was reduced by extended use to a crude odds ratio of 0.66 (0.39-1.10) after the first year of use. We conclude that use of HRT containing estradiol was associated with a threefold increased risk of VTE, but this increased risk was restricted to the first year of use.     

Pharmacological modulation of cortisol secretion and dexamethasone suppression in Alzheimer's disease

We have investigated the dexamethasone suppression of cortisol release in a group of 28 patients with senile dementia of the Alzheimer type (SDAT) after stimulation by physostigmine and clonidine, as compared with basal conditions. All patients but one had previously been evaluated with a depression symptom checklist and had submitted to a standard Dexamethasone Suppression Test (DST). SDAT patients showed normal baseline cortisol values measured at 4:00 PM. DST was reproducible, but nonsuppression did not appear to be a feature of the disease, nor of the dementia syndrome, although a majority of the most demented patients were found to be nonsuppressors. Physostigmine stimulated cortisol secretion in 20 of 24 cases, irrespective of the severity of dementia. Clonidine induced a secretion in 12 of 15 cases, but this was less than that observed after cholinergic stimulation. Physostigmine made cortisol release significantly less sensitive to the suppressive effect of dexamethasone than clonidine in SDAT. This double response should be tested as a possible predictor of a cholinergic therapeutic effect.     

Hormone replacement therapy and cognitive performance in postmenopausal women--a review by cognitive domain

Laboratory, animal and neuroimaging evidences suggest that hormone replacement therapy (HRT) may be beneficial to human cognition. This systematic review includes 26 studies on the association between HRT and cognition and 17 studies on HRT and risk of dementia. It was hypothesised that HRT would have a positive association with cognitive speed and verbal memory and possibly visual memory but not with executive functioning, and would be associated with a decreased risk of dementia. Evidence for HRT's neuroenhancing and neuroprotective properties was also evaluated. There was significant statistical and clinical heterogeneity among studies precluding meta-analysis. Results showed no consistent relationship between HRT and performance in any cognitive domain. Cross-sectional studies tended to report more positive results than longitudinal studies and randomised-controlled trials, particularly in the areas of verbal memory and executive functioning. HRT was associated with decreased risk of dementia in observational studies, but with increased risk in one randomised-controlled trial. Cognitive improvement or maintenance are not secondary benefits of HRT.     

The dexamethasone suppression test and suicide prediction

OBJECTIVE: Despite the substantial risks of eventual suicide associated with major depressive disorder, clinicians lack robust predictors with which to quantify these risks. This study compared the validity of demographic and historical risk factors with that of the dexamethasone suppression test (DST), a clinically practical measure of hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. METHOD: Seventy-eight inpatients with Research Diagnostic Criteria major depressive disorder or schizoaffective disorder, depressed type, entered a long-term follow-up study between 1978 and 1981, and, in addition, underwent a 1-mg DST. The number of suicides in this group during a 15-year follow-up period was determined, and the predictive validity of four demographic and historical risk factors reported in the literature to be consistently predictive of suicide in depressed patients was compared to the predictive validity of the DST results. RESULTS: Thirty-two of the 78 patients had abnormal DST results. Survival analyses showed that the estimated risk for eventual suicide in this group was 26.8%, compared to only 2.9% among patients who had normal DST results. None of the demographic and historical risk factors examined in the study significantly distinguished those who later committed suicide from those who did not. CONCLUSIONS: In efforts to predict and prevent suicidal behavior in patients with major depressive disorder, HPA-axis hyperactivity, as reflected in DST results, may provide a tool that is considerably more powerful than the clinical predictors currently in use. Research on the pathophysiology of suicidal behavior in major depressive disorder should emphasize the HPA axis and its interplay with the serotonin system.     

Hormonal replacement therapy. Benefits and risks

A woman lives an average of between 25 to 30 years since the beginning of menopause. This period of life is characterized for the appearance of chronic diseases. Estrogens are effective in controlling vasomotor symptoms and also over the loss of bone mineral density, therefore lowering the risk of fractures in about 25-30%. The use of unopposed estrogens (without progesterone) raises 8 to 10 times the risk of endometrial and 2 to 3 times the risk of deep venous thrombosis as well. Until now, no raise was seen in breast cancer in short treatments (less than 5 years) especially if they are not opposed with progesterone. The recent publication of the surprising data of the trial Women's Health Initiative demonstrates a significative but small increase in the risk of breast cancer associated with the use of combined estrogen/progestin therapy proportional to the duration of the treatment. The reduction of the plasmatic levels of low density lipoproteins associated with the use of Hormonal Replacement Therapy (HRT), has not been linked to evident cardiovascular protection. There is a higher cardiovascular risk with the use of HRT in the first year of the treatment. No clear benefit of HRT has been associated to treatment of Alzheimer disease, and is still under investigation its role in the prevention of the disease. Conclusions: 1) A careful analysis of advantages and risks of HRT must be done before its use. 2) The treatment must be instituted on an individual basis and should be discussed with each patient.     

Clinical investigations into antidepressive mechanisms. II. Dexamethasone suppression test predicts response to nomifensine or amitriptyline

This prospective study investigates the possibility of a central noradrenergic-cholinergic imbalance in subgroups of depressed inpatients using the dexamethasone suppression test (DST) as one peripheral indicator. The DST was performed in 43 depressed inpatients. Subsequently, a group (n = 20) of DST suppressors (DST-) and a group (n = 23) of DST nonsuppressors (DST+) were treated under double blind conditions with either nomifensine (NOM) a noradrenaline potentiating drug, or amitriptyline (AMI) a noradrenaline potentiating and strong anticholinergic compound. DST+ depressives responded favorably to AMI, but not to NOM. Conversely, DST- depressives responded favorably to NOM but less well to AMI. Together with other biochemical findings this data suggests: 1) a hypofunction of the noradrenergic system in DST- patients who may, from a clinical point of view, usually show minor or 'neurotic' depressions; 2) a hypofunction of the noradrenergic and a hyperfunction of the cholinergic system in DST+ patients who may present a more severe or 'endogenous' depression. These data suggest a biochemical heterogeneity of depression and offer an aid for a more specific antidepressive drug therapy.     

The dexamethasone suppression test and response to somatic treatment: a review

The dexamethasone suppression test (DST) has been primarily investigated as an aid in diagnosing endogenous depression; yet, its major clinical use has been as a predictor of treatment response. It is commonly held that 1) an abnormal DST predicts response to somatic (and not psychologic) therapies, 2) an abnormal DST predicts response to noradrenergic antidepressants, and 3) a normal DST predicts response to serotonergic agents. The DST predicted response to somatic therapies in only 6 of 16 published studies. No single methodologic factor, such as population variables, DST technique, or study design, can explain the marked discrepancy in study results. Only two of seven studies examining the DST and response to neurotransmitter-specific antidepressant groups found a positive relationship. The evidence that the DST predicts response to noradrenergic agents is weak. The DST does not predict acute response to somatic treatment in general or response to specific antidepressants. The selection of the appropriate treatment for depressed patients is still best made using clinical criteria.     

The effects of hormone replacement therapy on thrombin generation, fibrinolysis inhibition, and resistance to activated protein C: prospective cohort study and review of literature

Recent studies have found that hormone replacement therapy (HRT) is associated with a two- to fourfold increased risk of venous thromboembolism, but the thrombogenic mechanism of HRT remains unclear. To investigate whether HRT use induces a procoagulant state, we undertook a prospective cohort study in postmenopausal women to investigate the effects of 3 months of treatment with oral HRT (conjugated equine estrogen 0.625 mg daily and medroxyprogesterone 2.5 mg daily) on markers of thrombin generation (prothrombin fragment 1+2, thrombin-antithrombin complexes), fibrinolytic potential (plasminogen activator inhibitor-1 (PAI-1) activity), and activated protein C (APC) resistance. In addition, we reviewed the literature for studies investigating the effects of HRT on markers of thrombin generation and fibrinolytic potential. In 12 patients who received HRT for a mean of 3.8 months, there was no significant effect of HRT on levels of F1+2, thrombin-antithrombin complexes, or the APC ratio. HRT use had the greatest effect on PAI-1 activity (mean difference = -3.75 UI/mL; 95% confidence interval: - 8.9, 1.1) compared to other coagulation parameters, but this did not attain statistical significance (p = 0.12). In the literature review, the effects of HRT on markers of thrombin generation were inconsistent across studies. There was a consistent pattern of increased fibrinolytic potential with HRT use associated with one marker (PAI-1), but not with another marker (tissue plasminogen activator antigen). We conclude that there is a lack of consistent evidence that the increased risk of venous thromboembolism associated with HRT use is due to a procoagulant state related to increased thrombin generation, decreased fibrinolytic potential, or acquired APC resistance.     

The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism--results from a randomized, double-blind, clinical trial

In a recent randomized, double-blind, placebo-controlled trial of women with a history of venous thromboembolism (VTE), we found that hormone replacement therapy (HRT) was associated with an early excess risk of recurrent thrombosis. The aims of the present study were to characterize the effects of HRT on coagulation in these women to elucidate the mechanism(s) by which HRT increases the risk of thrombosis. The study comprised 140 women who were randomized to receive continuous treatment for 24 months with once daily 2 mg 17-beta-estradiol plus 1 mg norethisterone acetate (n = 71) or placebo (n = 69). HRT caused significant increases in prothrombin fragments 1+2, thrombin-antithrombin complex, and D-Dimer after 3 months, but these changes were less pronounced on prolonged treatment. The increases in markers of activated coagulation was higher in those women who subsequently developed recurrent thrombosis, but was similar in carriers and non-carriers of the factor V Leiden mutation. HRT had no effects on fibrinogen and factor VIII. Activated factor VII, but not factor VII antigen, decreased significantly on HRT as compared with placebo. The coagulation inhibitors antithrombin, protein C, and TFPI, but not protein S, all showed significant sustained decreases in the HRT group as compared with placebo. Antithrombin and protein C decreased by 8-12% on HRT, whereas TFPI activity decreased by 12-17% and TFPI free antigen by 29-30%. In multivariate analysis, only TFPI activity was a significant predictor for the increased activation of coagulation. We conclude that HRT was associated with early activation of coagulation, which corroborates the finding of an early risk of recurrent VTE. This activation may in part be explained by reduction in circulating anticoagulants.