Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis

Postmenopausal hormone therapy (HT) is a modifiable risk factor for venous thromboembolism (VTE). While the route of estrogen administration is now well recognized as an important determinant of VTE risk, there is also increasing evidence that progestogens may modulate the estrogen-related VTE risk. This review updates previous meta-analyses of VTE risk in HT users, focusing on the route of estrogen administration, hormonal regimen and progestogen type. Among women using estrogen-only preparations, oral but not transdermal preparations increased VTE risk (relative risk (RR) 1.48, 95% confidence interval (CI) 1.39-1.58; RR 0.97, 95% CI 0.87-1.09, respectively). In women using opposed estrogen, results were highly heterogeneous due to important differences between the molecules of progestogen. In transdermal estrogen users, there was no change in VTE risk in women using micronized progesterone (RR 0.93, 95% CI 0.65-1.33), whereas norpregnane derivatives were associated with increased VTE risk (RR 2.42, 95% CI 1.84-3.18). Among women using opposed oral estrogen, there was higher VTE risk in women using medroxyprogesterone acetate (RR 2.77, 95% CI 2.33-3.30) than in those using other progestins. These clinical findings, together with consistent biological data, emphasize the safety advantage of transdermal estrogen combined with progesterone and support the current evidence-based recommendations on HT, especially in women at high VTE risk.