Menopause Live - IMS Updates

Date of release: 19 August, 2013

Age at menopause, reproductive history and VTE risk

Recently, Canonico and colleagues published an analysis from the Women's Health Initiative (WHI) hormone therapy (HT) clinical trial (both estrogen and estrogen + progestin) of venous thromboembolism (VTE) risk and markers of reproductive life related to lifetime endogenous estrogen exposure [1]. These markers included ages at menarche and menopause, number of term pregnancies (parity), bilateral oophorectomy, or time since menopause. Interactions of HT with these characteristics on VTE risk were also evaluated. Postmenopausal women without a history of VTE at baseline (n = 27,035) were included in the analysis; the mean follow-up was 6.2 years.
There was no interaction between the individual markers and treatment assignment on the risk of a first VTE event found in the analysis. A pooled analysis of first VTE event by individual markers also did not find significant associations. However, pooled analyses restricted to first non-procedure-related VTE event found a significant interaction (p < 0.01) for age at menopause (a U-shaped relationship). Relative to women having their menopause in their forties, those with early menopause (age < 40 years) or late menopause (age > 55 years) were at significantly greater risk for VTE. Analyses for deep vein thrombosis but not for pulmonary embolism and age at menopause yielded similar results.


In the Heart and Estrogen/progestin Replacement Study (HERS), 2763 postmenopausal women with coronary artery disease but without a history of previous VTE were randomized to conjugated estrogen 0.625 mg/medroxyprogesterone acetate 2.5 mg or placebo. The women were 44–79 years of age (mean 67 years) and were followed for an average of 4.1 years in the clinical trial. Age greater than 52 years at last menstrual period was independently predictive of VTE in multivariate analysis (p < 0.001) [2].
In the Estrogen and venous THromboEmbolism Risk (ESTHER) study, a hospital-based case-control study of 191 postmenopausal women with a first episode of idiopathic VTE and 417 age-matched controls, compared to women with menopause occurring between ages 46 and 54 years, women with menopause at age ≥ 55 years had significantly increased VTE risk and women with menopause ≤ 45 had decreased risk in adjusted analyses [3]. Parity was also related to VTE risk: compared to women with two or fewer children, women with more than two children were at significantly greater risk of VTE.
In the Iowa Women’s Health Study cohort of 40,377 women, those aged 65 years or older, followed for nearly 20 years, showed a 'modest' decreased risk for incident VTE with increasing age at menopause, compared to women with menopause at age < 45 years. Parity was not related to VTE risk [4]. The Longitudinal Investigation of Thromboembolism Etiology study pooled two population-based cohort studies (the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study) and included 8236 postmenopausal women in the analyses. There was no significant association with the incidence of VTE and age at menopause or parity [5].
Oral and, to a lesser extent, transdermal hormone therapy (HT) has been associated with an increased risk of VTE. Although the absolute risk of VTE in postmenopausal women is low, the risk increases with increasing age. Lifetime endogenous estrogen exposure and the risk of VTE have been evaluated in a number of studies with varying results. Although some studies suggested that increased parity was associated with increased VTE risk, the majority did not. A number of studies (though not all) did suggest that increased age at menopause was related to increased VTE risk. However, the study by Canonico and colleagues may be the first to suggest that menopause occurring prior to age 40 is associated with an increased VTE risk compared with menopause occurring between ages 40 and 49. This finding should be considered cautiously as it has not been confirmed by other studies evaluating age at menopause and VTE risk and is a post hoc analysis from the WHI in which many analyses were done, making it likely that some result could occur by chance alone.

James H. Pickar

Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, USA


  1. Canonico M, Plu-Bureau G, OSullivan MJ, et al. Age at menopause, reproductive history, and venous thromboembolism risk among postmenopausal women: the Womens Health Initiative hormone therapy clinical trials. Menopause 2013;21. Epub ahead of print

  2. Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. Ann Intern Med 2000;132:689-96.

  3. Simon T, De Jonage-Canonico MBY, Oger E, et al. Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism. J Thromb Haemostasis 2006;4:71-6.

  4. Lutsey PL, Virnig BA, Durham SB, et al. Correlates and consequences of venous thromboembolism: the Iowa Womens Health Study. Am J Public Health 2010;100:1506-13.

  5. Ohira T, Folsom, AR, Cushman M, et al. Reproductive history, hormone replacement, and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology. Br J Haematol 2010;149:606-12.