Hormone therapies and venous thromboembolism: where are we now?

Deep vein thrombosis is a common disease, with an incidence of one to three per 1000 individuals per year [1]. Numerous risk factors are known, which can be divided into genetic and acquired [2]. One of the most well-known acquired risk factors is the use of female hormones, i.e. oral contraceptive use or the use of hormone replacement therapy. Apart from the use of hormones orally, other routes of administration are also available, e.g. intrauterine devices, injectables, subcutaneous implants, or skin patches. While most research regarding the risk of venous thrombosis has been conducted on oral hormone use, an increasing number of studies are focusing on the thrombotic effect of these alternative routes of administration. Here, we will review the current knowledge on the risk of venous thrombosis associated with premenopausal hormone use for contraception and with postmenopausal hormone replacement therapy. The impact of hormone use for women who have an increased risk for venous thrombosis will be discussed. These include carriers of thrombophilia, women with a positive family history of venous thrombosis, and women who have experienced venous thrombosis. Oral contraceptives Combined oral contraceptives (containing an estrogen and a progestagen) were first approved in the USA in 1960. It is estimated that more than 100 million women worldwide use an oral contraceptive [3]. Soon after their introduction, it became apparent that the use of these female hormones was associated with an increased risk of thrombosis. The first report of an increased risk of venous thrombosis associated with oral contraceptive use appeared in 1961 [4]. Subsequently, numerous reports have been published on the increase in thrombotic risk, indicating a two-fold to six-fold increased risk of deep vein thrombosis associated with current oral contraceptive use [5–11]. Most currently available oral contraceptives are combined preparations containing both an estrogen (i.e. ethinylestradiol [EE2]) and a progestagen. Numerous types of oral contraceptives are available, containing different doses of estrogen and different types of progestagen. The first available preparations contained a high dose of the estrogen EE2. However, after the reported increased thrombotic risk associated with combined oral contraceptive use was attributed to the amount of estrogen in the contraceptive pill, the dose of estrogen was reduced stepwise. The initial lowering of the estrogen dose from >5 0l gt o 30lg was indeed shown to be associated with a clear decrease in the risk of venous thrombosis [12,13]. In two recently published studies, it was shown that a further decrease in the estrogen dose to 20 lg led to an additional lowering of the risk of venous thrombosis [10,11]. In the MEGA study, a large case–control study, we showed that, after adjustment for type of progestagen, oral contraceptives containing 20 l go f estrogen were associated with a slightly decreased risk of venous thrombosis as compared with oral contraceptives containing 30 lg of estrogen (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.5–1.2) [10]. The study by Lidegaard et al. [11] also showed that a reduction in estrogen dose from 30 or 40 to 20 lg was associated with an 18% reduction in the risk of venous thrombosis [11].