Menopausal hormone therapy: the route matters for clot risk

Design

Nationwide nested case-control study (observational)

Population

Danish women aged 50 to 69, 2003 to 2021, without prior thrombosis or cancer

Primary outcome

First venous thromboembolism, ischaemic stroke or myocardial infarction

Effect

Oral oestrogen VTE hazard ratio 1.6 (95% CI 1.5-1.8); transdermal not associated with increased risk

This Danish nested case-control study used national registries to compare current users of menopausal hormone therapy with non-users among women aged 50 to 69, covering nearly 40,000 thrombotic events.

Oral oestrogen therapy, alone or with progestin, was associated with higher rates of venous thromboembolism (hazard ratio 1.6), ischaemic stroke (1.3) and myocardial infarction (1.2). The absolute increases were small, with numbers needed to harm over a year of around 1,000 for venous thromboembolism and higher for the arterial events. High-dose oral oestradiol above 1 mg daily for more than five years carried the steepest arterial risks. Transdermal therapy was not associated with increased thrombotic rates, bar one signal for myocardial infarction with combined cyclic patches.

The message aligns with existing guidance and sharpens it: where thrombotic risk is a concern, transdermal oestrogen is the safer route, and the oral-route risk holds across doses for venous thromboembolism.

• Nationwide Danish registry study of women aged 50 to 69, nearly 40,000 thrombotic events.
• Oral oestrogen was associated with higher venous thromboembolism (hazard ratio 1.6), stroke (1.3) and myocardial infarction (1.2).
• Absolute risk was small: about one extra venous thromboembolism per 1,000 women per year of oral use.
• High-dose oral oestradiol above 1 mg daily for over five years carried the highest arterial risk.
• Transdermal therapy showed no overall increase in thrombotic events.

Why it matters

It gives a concrete, route-based reason to choose a preparation rather than treating all hormone therapy as equally risky.

Don't overread it

This is observational, so it shows association, not cause; women prescribed transdermal therapy may differ systematically from oral users.

The statistics, in plain English

A hazard ratio of 1.6 for venous thromboembolism means about 60% higher relative risk, but the absolute increase is roughly 0.09% per year, which is why the number needed to harm is around 1,000. Small relative risks on a low baseline stay small in absolute terms.

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