Exogenous estrogens used in the combined oral contraceptive pill have long been recognised as causative factors in the pathogenesis of venous thromboembolism (VTE). Hormone replacement therapy (HRT), either sequential or continuous combined, also exposes women to exogenous estrogen but in the past was not considered to be associated with VTE. The difference between these preparations was attributed to ‘physiological’ doses of natural estrogens in HRT which contrasted with the ‘pharmacological’ doses of synthetic estrogens of high potency in the pill.
However, case–control studies and prospective randomised trials have shown a modest increase in the relative risk of VTE in women on estrogen containing HRT. In particular, the Women’s Health Initiative study in the USA assessed the major health benefit of oral HRT (0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate daily) in a randomised placebo-controlled clinical trial with more than 8000 women in each arm and confirmed an increase in risk of pulmonary embolism (hazard ratio 2.13, 95% CI 1.39–3.25).
On available evidence, however, a substantial risk of VTE may only relate to oral and not transdermal preparations. Thus, the risk of VTE and the type of preparation must be considered in women starting or continuing HRT. This guideline reviews the evidence and provides guidance to clinicians.