One thing everyone who takes oral oestrogens, whether for contraception, menopausal HRT or gender-affirming HRT, gets told by their doctor is that oral oestrogen raises the risk of blood clots - called a thromboembolism in the medical world. However we’re never really told what the risk actually is. If the rate without the medication is 1 in 100,000 per year and the increase in risk is 10% - to 1.1 in 100,000 of people on the medication - then perhaps it’s not a problem? But if increase is to 50 in 100,000 - a 500% increase if I can do maths today - then that might be more concerning.

So let’s dig in to the literature again!

Summary (for the TL;DR)

Yes oestrogen HRT increases the rate of blood clots, but dose doesn’t make much difference when using bio-identical 17β-estradiol. The difference in risk of using pills, patches gels or injections is still not clearly understood. The rates reported are not adequately controlled for dose form, oestrogen type, and additional risk factors.

Synthetic oestrogen such as ethinyl estradiol have a much higher risk than bio-identical 17β-estradiol.

Overall the risk of HRT containing bio-identical 17β-estradiol is higher that the general population, but still a very low risk.

Does oestrogen itself increase blood clots?

While a study showing a correlation between oestrogen levels during pregnancy and blood clots has previously been widely circulated, a more modern study¹ shows that in the absence of oestrogen-containing medications sex hormone levels have no significant impact on rates of blood clots. Oestrogen levels during pregnancy are an order of magnitude higher than would be achieved by any form of medication.

So no, oestrogen levels are not the cause of blood clots, at least when in the normal physiological range.

The story is different with oestrogen-containing medications

Does HRT increase the rate of blood clots?

In short, yes.

The main clots that have been studied are venous thromboembolisms - VTE - which are clots that form in veins, generally in your arms and legs. We’re often told it depends on the dose level and route of administration - pills, transdermal patch/gel, injection or implant - with pills being the worst.

Fortunately there have been two studies performed on this recently! They are both meta-analyses, which means their authors haven’t done a direct study, but have identified previous good studies and combined their results. In particular they’ve found studies that not only recorded the rate of VTE, but also the type of oestrogens used, the dose, route of administration, and any other hormone medication used alongside. So many papers just say “transgender HRT has this rate of VTE” with no detail of what form, dose, or administration route is being used! This makes my job easier.

I’m only going to refer to one of the papers here, because it cites the other. I’ll link to both.

Publication: Managing the risk of venous thromboembolism in transgender adults undergoing hormone therapy ²

The paper I’m going to cite identified 13 studies that had observed the rate of VTE and also noted the form of oestrogen and dose used. I’m going to be a bit naughty and do a pull-quote from the results before discussing it more, to set the stage a bit

Finally, even if the risk from exogenous estrogen use remains significant statistically, the absolute clinical risk remains low.

In plain English - even if HRT causes an increase in blood clots which can be measured, it’s still a very low rate.

In depth

This analysis found that the synthetic oestrogen ethinyl estradiol causes a much larger increase in the rate of VTE than bio-identical estradiol. Synthetic progestins - such as cyproterone acetate - were also found to have a larger effect on VTE rate than estradiol valerate in any form.

The paper also says that:

Data suggest a positive correlation between estrogen use and VTE. A recent review³ found the overall incidence rate to be 2.3 events per 1,000 patient-years.

which cites the other paper - but there’s another point made. VTEs are associated with other health conditions and behaviours. Smoking tobacco is well known to increase the rate of blood clots, as are having high blood pressure, hypertension, undergoing surgery, and being HIV positive. Additionally acute stress and other mental health conditions are correlated with blood clot rates. From the paper:

Only one study to date demonstrates an occurrence of VTE in the absence of risk factors beyond hormone therapy.

That study⁴ followed 676 trans women over 8 years on predominantly oral oestrogen, and only had one incidence of VTE.

Their conclusion?

Firstly, avoid ethinyl estradiol containing medications. They have a significantly higher risk of blood clots

Secondly,

Although there seems to be clear evidence that transdermal estrogens dosed up to 0.1 mg/day or below are a lower risk for VTE than other forms of estrogen, it is unclear whether this is related to the delivery method or a dose effect.

0.1mg/day is a low transdermal dose. The current PATHA guidelines go up to 0.2mg/day, which has similar risks to oral estradiol valerate.

Risk mitigation is an important part of the care of transgender patients due to the many risks associated with not providing hormone therapy (ie, poor mental health) and the potential risks associated with hormone therapy. Further study of the relationship between estrogen and the risk of VTE will serve to inform the safest possible care for transgender patients

So as always, the conclusion is there’s not enough data to draw a solid conclusion, but treatment should be based on risk mitigation and acknowledge that focussing on risk minimisation may have worse outcomes for the patient.

So where are we?

Women not on any form of oestrogen medication have a VTE rate of around 4.2 per 10,000 person-years. With a rate of 2.3 per 1,000 patient-years according to that study that’s a large difference, but the analysis included use of synthetic hormones that are known to have far higher risk. They also noted that only one study identified a blood clot occurring without other know risk factors present - that paper gave a rate of 7.8 per 10,000 person-years.

Unlike menopausal HRT, the risks associated with different delivery mechanisms is not as clear-cut.

So yes, you will have a higher risk of blood clots on any form of estrogen and you should try to manage it through other factors you can control, such as not smoking and monitoring your health.