HRT and blood clots: how route, age, and health history change the risk

Blood clots are one of the best-documented risks of hormone therapy. They are also one of the risks that depends most on how you take it. Here is what the research measured, who is more likely to be affected, and the warning signs worth knowing whether or not you ever take hormones.

What a venous blood clot is

Doctors group two related problems under the name venous thromboembolism, or VTE. A deep vein thrombosis (DVT) is a blood clot that forms in a vein deep inside the body, mainly in the large veins of the lower leg and thigh ^[8]. A pulmonary embolism (PE) is a blockage of an artery in the lungs ^[9].

The CDC lists higher estrogen levels among the factors that raise clot risk, along with older age, family history, limited movement, and certain chronic illnesses ^[7]. MedlinePlus lists taking estrogen as a risk factor for both DVT and PE ^{[8, 9]}. That is why the type of hormone therapy, the route, and your own health history all matter.

What the WHI found with pills

The Women's Health Initiative (WHI) tested oral conjugated equine estrogens, with or without the progestin medroxyprogesterone acetate, against placebo ^{[2, 3]}.

In the combination trial, 16,608 women aged 50 to 79 were followed for 5.6 years ^[2]. Clots in the legs or lungs occurred at a rate of 3.5 per 1,000 women per year on hormones, versus 1.7 per 1,000 on placebo, about double ^[2].

In the estrogen-alone trial, 10,739 women who had had a hysterectomy were followed for an average of 7.1 years ^[3]. The rate was 3.0 per 1,000 women per year on estrogen versus 2.2 on placebo ^[3]. That overall increase was smaller and fell just short of statistical significance, though deep vein clots on their own were significantly higher ^[3]. The risk was highest in the first 2 years, and it was lower than with the combination ^[3].

Age changes the absolute numbers. Updated FDA labeling reports that among women aged 50 to 59 in the WHI combination trial, there were 6 extra pulmonary emboli and 10 extra deep vein clots per 10,000 women per year compared with placebo ^[6]. Across all ages, 50 to 79, the figures were 9 and 12 ^[6].

Pill vs patch: why the route matters

When you swallow estrogen, it passes through the liver first. Non-oral routes, like a patch or a cream, bypass that first pass ^[1]. The Menopause Society notes that this may offer advantages, but that trials have not been designed to show whether non-oral routes lower clot risk ^[1]. What we have instead are large observational studies, and they point the same way.

• UK, 2019: Researchers compared 80,396 women aged 40 to 79 who had a clot with 391,494 women who did not ^[4]. Oral hormone therapy was linked to higher clot risk, while transdermal therapy was not ^[4].
• Within pills: oral estradiol was linked to lower risk than conjugated equine estrogens, and conjugated estrogens with medroxyprogesterone acetate carried the highest risk ^[4].
• France, 2007: In the ESTHER study of women aged 45 to 70, current oral estrogen use was linked to about 4 times the odds of a clot, while transdermal estrogen was not linked to higher odds ^[5].

The Menopause Society agrees that transdermal hormone therapy has not been associated with clot risk in observational studies, and that a systematic review suggests less risk than with oral therapy, but it stresses that randomized trials comparing the routes are lacking ^[1]. Observational studies show links, not proof of cause, so these results are a strong signal rather than a guarantee.

Dose may matter too. Lower doses of oral estrogen may carry less clot risk than higher doses, although comparative trial data are lacking ^[1].

Does the progestogen matter?

It may. In the ESTHER study, micronized progesterone was not linked to higher clot risk, while one group of synthetic progestins, the norpregnane derivatives, was linked to about 4 times the odds ^[5]. The Menopause Society says micronized progesterone may be less likely to promote clots than other progestins ^[1]. In the WHI, the clot increase was significantly greater with estrogen plus medroxyprogesterone acetate than with estrogen alone ^[3].

For more on how progesterone is used and what it can feel like, see progesterone side effects.

Who is at higher risk

The WHI looked at how combination hormones interacted with other risk factors ^[2]. Compared with women aged 50 to 59 on placebo:

• Age: women in their 60s on hormones had about 4 times the risk, and women in their 70s about 7 times ^[2].
• Weight: compared with normal-weight women on placebo, overweight women on hormones had about 4 times the risk, and women with obesity on hormones nearly 6 times ^[2].
• Factor V Leiden: women with this inherited clotting variant who took hormones had nearly 7 times the risk of women without it on placebo ^[2].

Timing matters too. The Menopause Society says women who start hormone therapy after 60, or more than 10 to 20 years after menopause, have higher absolute risks of clots than women who start in early menopause ^[1]. It also advises that personal and family risk of clots be considered before starting ^[1].

When hormones are off the table

FDA labeling for an approved estradiol and progesterone capsule lists these contraindications related to clots ^[6]:

• A current deep vein thrombosis or pulmonary embolism, or a history of one ^[6]
• A current or past stroke or heart attack ^[6]
• A known clotting disorder, such as protein C, protein S, or antithrombin deficiency ^[6]

The Menopause Society likewise lists a past clot, or a personal history or inherited high risk of clotting, among contraindications for oral and transdermal hormone therapy ^[1]. If any of these apply to you, your clinician can talk with you about non-hormone options.

Surgery and long periods without moving

The same label advises stopping estrogen plus progestogen at least 4 to 6 weeks before surgery of a type linked to higher clot risk, when feasible, and during long periods of immobilization ^[6]. MedlinePlus notes that clot risk also rises after surgery and during long bed rest ^[9]. If you have an operation coming up, tell both your surgeon and your hormone prescriber well ahead of time.

The CDC advises moving around as soon as possible after being confined to bed, such as after surgery ^[7].

Warning signs of a blood clot

About half of people with a DVT have no symptoms at all ^[7]. When symptoms do appear, they show up in the affected arm or leg ^{[7, 8]}:

• Swelling ^{[7, 8]}
• Pain or tenderness ^{[7, 8]}
• Skin that feels warm ^{[7, 8]}
• Redness or discoloration ^{[7, 8]}

A pulmonary embolism can happen without any DVT symptoms first ^[7]. Its signs include ^{[7, 9]}:

• Trouble breathing, or shortness of breath that comes on suddenly ^{[7, 9]}
• Chest pain that often gets worse with a deep breath or a cough ^{[7, 9]}
• A fast or irregular heartbeat ^{[7, 9]}
• Coughing up blood ^{[7, 9]}
• Lightheadedness, dizziness, or fainting ^{[7, 9]}

If you have symptoms of a pulmonary embolism, call 911 or go to the emergency room ^[9]. For a swollen, painful leg or arm, contact a clinician right away. FDA labeling says to stop hormone therapy immediately if a clot is suspected ^[6].

Keeping the risk in perspective

Clots are one risk among several, and they sit beside real benefits. Hormone therapy remains the most effective treatment for hot flashes and night sweats ^[1]. For healthy women under 60 or within 10 years of menopause, The Menopause Society finds the benefit-risk ratio favorable for treating bothersome symptoms, and describes the added risks of clots, breast cancer, and stroke as rare in that group ^[1]. For the full picture, read is HRT safe? and our guide to the estradiol patch.

Talking it through with WarriorBabe Health

A WarriorBabe Health clinician asks about past clots, clotting disorders, and family history before deciding whether hormone therapy fits. Options include an estradiol patch, estradiol cream, oral estradiol, and a progesterone capsule for women with a uterus. Compare them on our hormone treatments page.

Our hormone products are compounded by a licensed pharmacy. Compounded drugs are not FDA-approved, which means the FDA does not review their safety, effectiveness, or quality before they are marketed ^[10]. The studies in this article looked at approved products, so ask your clinician how they apply to you.

Curious whether hormone therapy might be an option? Take the 2-minute quiz. A licensed clinician makes the final call on whether any prescription is appropriate.

This article is for general information. It is not medical advice and does not replace a visit with a licensed clinician who knows your history. Do not start, stop or change a medication without talking to your clinician. If you think you are having a medical emergency, call 911.