Association of Serum Sex Hormones with Hemostatic Factors in Women On and Off Hormone Therapy: The Multiethnic Study of Atherosclerosis

Abstract

Background: Hormone therapy (HT) is associated with increased risk of both venous and arterial thrombosis, which are multifactorial in origin. Objectives: Our objectives were twofold: first, we sought to examine associations between endogenous serum sex hormone levels and biomarkers of thrombosis and/or coagulation in postmenopausal hormone nonusers. Second, we separately studied the associations between serum sex hormone levels and biomarkers of thrombosis and/or coagulation in postmenopausal hormone users considering the fact that pattern of circulating hormones is different in women taking exogenous hormones. Patients/Methods: We performed a cross-sectional analysis of postmenopausal women enrolled in a large multiethnic community-based cohort study, The Multiethnic Study of Atherosclerosis. We hypothesized that higher levels of estrogen-related sex hormones would be associated with biomarkers of thrombosis, suggesting mechanisms for differences in thrombotic risk from HT. Women (n = 2878) were included if they were postmenopausal and had thrombotic biomarkers (homocysteine, fibrinogen, C-reactive protein [CRP], factor VIII, and d-dimer) and sex hormone levels (total testosterone [T], bioavailable testosterone, sex hormone binding globulin [SHBG], estradiol [E2], and dehydroepiandrosterone [DHEA]) measured. A smaller random sample of 491 women also had von Willebrand factor (vWF), plasminogen activator inhibitor (PAI-1), and tissue factor pathway inhibitor (TFPI) levels measured. Results and Conclusions: We found that elevated levels of estradiol and SHBG in HT users were associated with elevated levels of CRP and lower levels of TFPI, both of which may be related to a prothrombotic milieu in HT users. HT nonusers had far more prothrombotic associations between elevated serum sex hormone levels and thrombotic biomarkers when compared with HT users.

Hemostasis in elderly patients with human immunodeficiency virus (HIV) infection—Cross-sectional study

“…It is suggested that PI may influence coagulation changes detected in menopause.The interaction of ART, in the case of PI, competing with female hepatic hormones in the use of P53 and estrogen deprivation with early menopause of these patients, are poorly studied topics, especially in the area of hemostasis [68]. Evidence of pre-thrombotic status was also reported in a multiethnic study that found an association between female sex hormones and changes in hemostatic variablesin general population [33]. Although hemostatic variables may also be related to early menopause, Bull et al pointed to difficulties in discriminating which factors trigger early menopause in HIV + women [69].…”

“…They affect lymphocytes and monocytes, increase inflammatory proteins and, when activated by the inflammatory response, express in their cytoplasmic membranes the Tissue Factor (TF), initiating coagulation [22][23][24][25][26].Studies started before and after ART, when compared to others in the geriatric area, confirm the common pre-thrombotic state among the two groups [27,28]. This pre-thrombotic state is usually associated with comorbidities and severity of infection [29], making the association a risk factor for mortality and for the survival rate of these patients not yet the same as the general population [10,24,[30][31][32][33].…”

Sex-related differences in oxidative stress and neurodegeneration

“…Although hormone manipulations were not examined in the TARCC cohort, estrogen hormone replacement can decrease homocysteine levels in post-menopausal women [69–72]. Interestingly, estrogen hormone replacement therapy in post-menopausal women is associated with decreased testosterone, along with the expected increased estradiol [71, 73, 74]. Generally, menopause is associated with the loss of estrogen, but testosterone levels are maintained [75–78].…”

Prospective Study of Endogenous Hormones and Incidence of Venous Thromboembolism: The Atherosclerosis Risk in Communities Study

“…In women, high endogenous SHBG was associated with higher D-dimer, vWF and factor VIII, 14 all of which are risk factors for VTE. 4,[17][18][19] High SHBG was also associated with lower PAI-1 and tPA antigen, possibly reflective of increased fibrinolytic activity, but also with lower factor VIIc.…”

“…The relationship between endogenous testosterone and haemostasis is less clear in women (who have low testosterone concentrations); one study reported higher endogenous testosterone was associated with higher PAI-1 and tissue plasminogen activator (tPA) antigen, 10 possibly reflective of hypofibrinolysis. 11 High endogenous DHEAS is associated with a variety of biomarkers that may not be specifically relevant to the aetiology of VTE, including lower thrombin generation, 12 higher fibrinogen 13,14 and higher tPA antigen and PAI-1 10 in women and lower fibrinogen in men. 7 Nevertheless, DHEAS levels decline substantially with age in women and men 15 and may represent an inverse marker of mortality risk.…”