Prospective Study of Exogenous Hormones and Risk of Pulmonary Embolism in Women

Department of Nutrition , Harvard University, Cambridge, Massachusetts, United States
Obstetrical and Gynecological Survey (Impact Factor: 1.86). 04/1997; 52(5):295-296. DOI: 10.1016/S0140-6736(96)07308-4


Current use of oral contraceptives (OCs) is a well-recognised risk factor for venous thrombosis and consequent pulmonary embolism (PE). Little is known about residual effects of past OC use. Furthermore, few epidemiological studies have assessed the relation between postmenopausal use of hormones and thrombotic disease.

In this prospective study information was obtained through questionnaires sent every 2 years (1976–92) to 112 593 women aged 30–55 in 1976. We excluded women with previously diagnosed cardiovascular disease or cancer in 1976 and at the beginning of each subsequent 2-year follow-up period.

From self-reports and medical records, we documented 123 cases of primary PE (no identified antecedent cancer, trauma, surgery, or immobilisation). Current users of postmenopausal hormones had an increased risk of primary PE (relative risk adjusted for multiple risk factors 2·1 [95% CI 1·2–3·8]). However, past use showed no relation to PE (1·3 [0·7–2·4]). In current users of OCs the risk of primary PE was about twice that in non-users (2·2 [0·8–5·9]), but this finding was based on only five cases who were current OC users. Users of OCs in the past had no increase in risk of PE (0·8 [0·5–1·2]). These relations were consistent irrespective of cigarette-smoking status.

Primary PE was uncommon in this cohort. The risk was increased by current though not past use of postmenopausal hormones or OCs.

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    • "Although previous hospital-based studies reported that late menopause and a history of having more than two children were associated with increased risk of VTE (Grady, et al 2000) (Simon, et al 2006) (Samama 2000), in this population-based prospective study, there were no associations of parity or late menopause with incidence of VTE. On the other hand, women currently using hormone replacement had an increased risk of VTE, consistent with previous studies (Grodstein, et al 1996) (Grady, et al 2000) (Cushman, et al 2004a). Therefore, effects of estrogen exposure on incidence of VTE differ between endogenous production and exogenous administration. "
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    ABSTRACT: Numerous studies have established that hormone replacement therapy increases the risk of venous thromboembolism (VTE), but an association of endogenous oestrogen exposure with the incidence of VTE is not fully established. Using a prospective design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, we studied the 12-year risk of VTE in relation to hormone replacement therapy use, age at menopause, parity number, and type of menopause in 8236 post-menopausal women. There were no significant associations of age at menopause, parity number, or type of menopause with incidence of VTE. Women currently using hormone replacement had a 1.6-times higher multivariate-adjusted rate ratio (RR) of VTE compared with those without hormone use in the time-dependent model (RR=1.60, 95% confidence interval [CI], 1.06-2.36; Population attributable fraction=6.7%, 95%CI, 1.0-10.3). When we excluded women with 1-year or more duration of hormone therapy at baseline, the association was stronger (RR=2.02, 95%CI, 1.31-3.12). The multivariate-adjusted RRs of VTE for current users tended to be higher in those with idiopathic VTE (RR=2.40, 95%CI, 1.40-4.12) than those with secondary VTE (RR=1.08, 95%CI, 0.63-1.85). Hormone replacement therapy is associated with increased risk of VTE, but reproductive history markers of endogenous oestrogen exposure were not associated with VTE.
    Full-text · Article · Mar 2010 · British Journal of Haematology
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    • "The risk of VTE is probably higher during the first year of use [4] [5], higher on oral than transdermal therapy [9], and possibly higher for users of combined estrogen–progesterone HT than treatment with estrogen alone [10]. Epidemiological studies have failed to detect significant differences in risk of VTE between different estrogen doses [6] [7] [8], but these studies have not been powered to detect such differences. However, some studies have suggested a reduction in risk of arterial diseases at lower doses [11,12]. "
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    ABSTRACT: Hormone therapy (HT) is associated with a modest, but significantly increased risk for arterial and venous thromboembolism. We have compared the effects of estrogen, tibolone, and raloxifene on relevant markers of coagulation activation and investigated whether there is a dose-response relationship of oral HT. Randomized, open-label, comparative study of 202 healthy women who were assigned to receive treatment for 12 weeks with either low-dose hormone therapy containing 1 mg 17beta-estradiol + 0.5 mg norethisterone acetate (NETA) (n=50), conventional-dose HT containing 2 mg 17beta-estradiol and 1 mg NETA (n=50), 2.5 mg tibolone (n=51), or 60 mg raloxifene (n=51). The groups were comparable with regard to demographic characteristics and laboratory variables at baseline. D-dimer increased markedly in the conventional-dose HT group, but remained unchanged in the low-dose HT group. Tibolone was associated with a medium increase, whereas raloxifene was associated with a decrease in D-dimer levels. Changes in prothrombin fragment 1 + 2 showed a similar pattern for all four groups, whereas no significant differences in changes of thrombin-antithrombin complex were observed. Our data suggest that low-dose HT is associated with less activation of coagulation than conventional-dose HT. This finding may be of clinical importance since randomized clinical trials showing increased risk of thrombosis have utilized conventional-dose HT.
    Full-text · Article · Nov 2006 · Maturitas
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    • "However, since 1996, a large number of observational studies consistently found a significant two to fourfold increased relative risk of VTE in current HRT users compared with nonusers (Daly et al, 1996; Grodstein et al, 1996; Jick et al, 1996; Perez Gutthann et al, 1997; Varas-Lorenzo et al, 1998; Hoibraaten et al, 1999). Most studies found the highest risk during the first year of use, with OR ranging from 2 to 7 (Daly et al, 1996; Grodstein et al, 1996; Perez Gutthann et al, 1997; Varas-Lorenzo et al, 1998; Hoibraaten et al, 1999). There is no consistent evidence of a difference in the thrombotic risk of unopposed and combined oestrogen/progestin therapy. "
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    ABSTRACT: During their lifetimes, women face several unique situations with an increased risk of venous thromboembolism (VTE). Doctors in a variety of specialties must advise women on the risks of oral contraceptives (OC), hormone replacement or pregnancy. Modern 'low dose' OC are associated with a three to sixfold increased relative risk of VTE. Hormone replacement and selective oestrogen receptor modulators confer a similar two to fourfold increase in thrombotic risk. However, because the baseline incidence of thrombosis is higher in older postmenopausal women, the absolute risk is higher than in younger OC users. The risk of venous thrombosis is six to 10-fold higher during pregnancy than in non-pregnant women of similar age. Thrombophilic disorders increase the thrombotic risk of OC, hormone replacement and pregnancy, especially in women with homozygous or combined defects. This review focuses on recent data estimating the thrombotic risk of hormonal therapies and pregnancy in women with and without other thrombotic risk factors.
    Preview · Article · Sep 2004 · British Journal of Haematology
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