Postmenopausal Estrogen Therapy Route of Administration and Risk of Venous Thromboembolism

The purpose of this Committee Opinion is to review evidence on the safety of postmenopausal estrogen therapy. Noting that the gynecologist may prescribe either synthetic progestins or natural progesterone in conjunction with estrogen, this Committee Opinion will address estrogen-related risks only. The absolute risk of venous thromboembolism is age dependent. The incidence is estimated to be approximately 54/100,000 per year in women in their 40s, increasing to 62–122/100,000 per year in women in their 50s, and is approximately 300–400/100,000 per year in women aged 70–80 years. For women in their 80s, the estimated annual risk is approximately 700/100,000 1 2 3 4. Combination estrogen plus progestin hormone therapy (HT) or estrogen therapy (ET) for the management of menopausal symptoms and related disorders is associated with an increased risk of venous thromboembolism. Commonly, a relative increase in risk of twofold to fivefold is cited for HT users 5 6 7 8 9. There is adequate evidence in the medical literature that natural progesterone is not associated with an increased risk of venous thromboembolism 10. Conversely, there is evidence that by comparison, synthetic progestins (eg, medroxyprogesterone acetate) do increase the risk of venous thromboembolism 10 11 12. The use of estrogen alone has been associated with a 1.2–1.5-fold relative risk compared with that of nonusers 13 14 15 16 17 18.

The relative risk of venous thromboembolism in women who take ET seems to be even greater if the treated population has preexisting risk factors for venous thromboembolism, such as obesity, immobilization, and fracture. As observed in the Heart and Estrogen/progestin Replacement Study, increased age and underlying coronary vascular disease are also risk factors for venous thromboembolism 16. Women with prothrombotic mutations, such as Leiden factor V, G20210A prothrombin mutation, protein C and protein S deficiencies, and other congenital thrombophilic disorders, are also especially at risk, as are women with acquired thrombophilic conditions 17. A number of substances, such as factor VII, factor VIIIc, factor IX, protein C, and C-reactive protein, are linked to an increased risk of venous thromboembolism 16 17.

In most investigations of the relationship of venous thromboembolism and menopausal HT, the route of hormone administration has been primarily oral. It has been proposed that orally administered estrogen may exert a prothrombotic effect through the hepatic induction of some of these substances 18 19 20 21 22 23. The prothrombotic effect is possibly related to high concentrations of estrogen in the liver due to the “first-pass” effect. Studies that compared oral and transdermal ET have demonstrated that transdermally administered estrogen has little or no effect in elevating prothrombotic substances and may have beneficial effects on proinflammatory markers, including C-reactive protein, prothrombin activation peptide, and antithrombin activity. Also, in contrast to oral ET, transdermal ET also may have a suppressive effect on tissue plasminogen activator antigen and plasminogen activator inhibitor activity 23 24 25 26 27 28 29.

The Estrogen and Thromboembolism Risk study, a multicenter case–control study of thromboembolism among postmenopausal women aged 45–70 years, demonstrated an odds ratio for venous thromboembolism in users of oral and transdermal estrogen to be 4.2 (95% CI, 1.5–11.6) and 0.9 (95% CI,0.4–2.1), respectively, when compared with nonusers 10. Transdermal estrogen had no increased risk compared with nonusers. Similar results were reported elsewhere 30 31 32 33 34 35 and of particular importance, in women who were stratified for weight 36 and the presence of prothrombotic mutations 37.

Several nonoral delivery systems presently are available for the administration of estradiol. These include transdermal estradiol patches, ethanolic estradiol-containing gels and sprays, and the vaginal (ring) delivery system. Topical vaginal creams and tablets prescribed for treatment of local urogenital atrophic changes have low levels of systemic absorption but have no detectable effect on coagulation proteins or incidence of venous thromboembolism. Both transdermal (patches or gels) and vaginal (ring) delivery bypass the gastrointestinal conversion of estradiol to estrone with less increase of triglyceride levels, clotting factors, and globulins 38. The vaginal ring containing estradiol acetate for systemic treatment, shown to be effective in the management of vasomotor symptoms, is not associated with an increased risk of venous thromboembolism 38 39 40. The practicing gynecologist should be aware that other less mainstream estrogen delivery methods, including transbuccal lozenges and troches, are widely used throughout the United States. These alternatives, which are meant to dissolve in the mouth and bypass the enterohepatic circulation, are available as single agents or in combination with other hormones and are fashioned by compounding pharmacies. Data on the safety and efficacy of compounded troches and lozenges are limited. Although widely prescribed, these less mainstream estrogen delivery methods have not been subjected to significant scientific scrutiny.