Differential associations of oral estradiol and conjugated equine estrogen with hemostatic biomarkers

Blondon, Marc; Vlieg, Astrid van Hylckama; Wiggins, Kerri L.; Harrington, Laura B.; McKnight, Barbara; Rice, Kenneth; Rosendaal, F. R.; Heckbert, Susan R.; Psaty, Bruce M.; Smith, Nicholas L.

doi:10.1111/jth.12560

Cited by 29 publications

(22 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We had limited power to analyze data by HT type, however most associations were similar by study. Studies suggest a lower risk of VT with estradiol or transdermal treatment than oral conjugated equine estrogens and we could not address this. To conserve power, we did not exclude women with pre‐baseline self‐reported VT, but we did adjust for this.…”

Section: Discussionmentioning

confidence: 97%

Biomarkers, menopausal hormone therapy and risk of venous thrombosis: The Women's Health Initiative

Cushman

Larson

Rosendaal

et al. 2018

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

Essentials Venous thrombosis is the most common vascular complication of menopausal hormone use.We studied biomarkers to predict thrombosis with hormones in the Women's Health Initiative.Lower proteins C and S, and higher D‐dimer were related to thrombosis risk.The 25% of women with high D‐dimer had a six‐times greater risk of thrombosis with hormones. BackgroundOral menopausal hormone therapy causes venous thrombosis but whether biomarkers of thrombosis risk can identify women at risk is unknown.MethodsWe completed a nested case control study in the two Women's Health Initiative hormone trials; 27 347 women aged 50‐79 were randomized to hormone therapy (conjugated equine estrogen with or without medroxyprogesterone acetate) or placebo. With 4 years follow‐up, biomarkers were measured using stored baseline samples prior to starting treatment, and one‐year later, in 215 women who developed thrombosis and 867 controls.ResultsOverall, lower protein C and free protein S, and higher D‐dimer, prothrombin fragment 1.2 and plasmin‐antiplasmin complex were associated with risk of future thrombosis with odds ratios ranging from 1.9 to 3.2. Compared to women with normal biomarkers assigned to placebo, the risk of thrombosis with hormone therapy was increased among women with abnormal biomarkers, especially elevated D‐dimer, elevated plasmin‐antiplasmin, and low free protein S; the largest association was for D‐dimer: odds ratio 6.0 (95% CI 3.6‐9.8). Differences in associations by hormone use were not significant on the multiplicative scale. Considering a multi‐marker score of eight biomarkers, women with three or more abnormal biomarkers had 15.5‐fold increased odds of VT (95% CI 6.8‐35.1). One‐year changes in biomarkers were not robustly associated with subsequent thrombosis risk.ConclusionAbnormal levels of biomarkers of thrombosis risk identified women at increased risk of future venous thrombosis with oral menopausal hormone therapy. Findings support the potential for clinical use of D‐dimer testing in advance of hormone therapy prescription.

show abstract

Section: Discussionmentioning

confidence: 97%

Biomarkers, menopausal hormone therapy and risk of venous thrombosis: The Women's Health Initiative

Cushman

Larson

Rosendaal

et al. 2018

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

show abstract

“…Reanalysis of the WHI indicated an enhanced risk of stroke in association with oestrogen-only (HR 1.47 [95% CI 0.92–2.35]) and combined CEEs (HR 1.12 [95% CI 0.76–1.64]) when initiated >10 years after the onset of menopause. Our finding that CEEs, but not oestradiol, were associated with an increased stroke risk in some analyses may reflect thrombotic effects exerted by CEEs [ 36 , 37 ]. In all of the aforementioned studies addressing the timing of HT initiation, women could not be precisely allocated into early and late HT initiation groups; allocation was based on age rather than detailed information on timing [ 10 , 13 , 14 ].…”

Section: Discussionmentioning

confidence: 99%

Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies

et al. 2017

View full text Add to dashboard Cite

BackgroundRecent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT.Methods and findingsData on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987–2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI −0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0–5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, −4.41 years; 95% CI −7.14 to −1.68) and haemorrhagic stroke-free (first PD, −9.51 years; 95% CI −12.77 to −6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, −1.97 years; 95% CI −3.81 to −0.13), but not with a shorter stroke-free period (fifth PD, −1.21 years; 95% CI −3....

show abstract

“…Studies using animal models have demonstrated that treatment with oral CEE improves arterial function (Ceravolo et al, 2013) and, therefore, may be beneficial to the cardiovascular system. However, transdermal estrogen (Speroff, 2010) and oral CEE (Peeyananjarassri and Baber, 2005) have also been associated with increased risk of venous thrombosis (Hu and Grodstein, 2002;Blondon et al, 2014;Smith et al, 2014), suggesting that CEE may display opposing effects in arteries and veins.…”

Section: Introductionmentioning

confidence: 99%

Treatment with Standard and Low Dose of Conjugated Equine Estrogen Differentially Modulates Estrogen Receptor Expression and Response to Angiotensin II in Mesenteric Venular Bed of Surgically Postmenopausal Hypertensive Rats

Araujo

Costa

Echem

et al. 2017

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Standard hormone therapy for menopausal women [conjugated equine estrogen (CEE) 0.625 mg] has been associated with increased risk of venous thrombosis. Regimens containing a lower CEE dose (0.30 mg) have been used clinically to decrease side effects of supraphysiologic doses of estrogen. In this study, we determined the effects of standard (SD) and low dose (LD) of CEE on venular function in ovariectomized (OVX) spontaneously hypertensive rats (SHR). Contractions by angiotensin-II (Ang-II 10 M) in perfused mesenteric venular bed were markedly increased in OVX (21.5 ± 1.3 mmHg) compared with Sham (14.7 ± 1.1 mm Hg, < 0.05). CEE-SD did not modify Ang-II responses in OVX, whereas CEE-LD restored Ang-II contraction to Sham levels. Endothelial nitric oxide synthase (eNOS) inhibition by L-NAME increased Ang-II contractions in Sham and CEE-LD and was without effect in venules of OVX SHR and CEE-SD. In OVX there was decreased NO generation in association with diminished eNOS phosphorylation and increased O generation in the venular wall. CEE-LD reverted the deleterious effects of ovariectomy. Although CEE-SD augmented eNOS phosphorylation in OVX, it was unable to increase NO levels, probably owing to its inability to reduce O Distinct effects by CEE-SD and CEE-LD parallel the differential modulation of Ang-II and estrogen receptors. Compared with Sham, CEE-LD increases Ang II receptor type 2, whereas CEE-SD modified ER expression in the venous bed. Interestingly, both CEE doses increased G protein-coupled estrogen receptor in OVX. Our data suggest that estrogen dose is an important factor for venous function. Although CEE-LD reversed deleterious effects of OVX, CEE-SD showed null effects despite its ability to increase eNOS activity.

show abstract

Differential associations of oral estradiol and conjugated equine estrogen with hemostatic biomarkers

Cited by 29 publications

References 43 publications

Biomarkers, menopausal hormone therapy and risk of venous thrombosis: The Women's Health Initiative

Biomarkers, menopausal hormone therapy and risk of venous thrombosis: The Women's Health Initiative

Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies

Treatment with Standard and Low Dose of Conjugated Equine Estrogen Differentially Modulates Estrogen Receptor Expression and Response to Angiotensin II in Mesenteric Venular Bed of Surgically Postmenopausal Hypertensive Rats

Contact Info

Product

Resources

About