Hormone Replacement Therapy and the Risk of Blood Clots

by | Jul 6, 2014 | Articles, Conditions, Hormone Replacement, Women's Health

Many women are denied hormone replacement therapy (HRT) due to a fear of blood clot formation, particularly if they have had a blood clot in the past or already have a known risk factor.  The risk of a blood clot in a large vein (thrombosis) is increased with the administration of 1) estrogens given by the oral route, 2) conjugated estrogens, and 3) numerous progestins.  The risk of blood clots is not increased with non-oral administration (sub-lingual or topical) of bioidentical estrogens or progesterone.  Let’s look carefully at the evidence for each of the above statements.

1) Orally administered estrogens increase risk of blood clotting.

This is because the hormone is absorbed from the gut directly into the hepatic circulation, meaning it first gets processed by the liver prior to being circulated throughout the body.  This is called first pass metabolism.  The result is that the liver is hit with a sudden blast of hormone that it is required to process – this is not the normal physiologic routine, in which hormones are secreted into the blood stream, distributed into the body tissues, and finally processed by the liver.  First pass metabolism of hormones is not natural and one result is that the liver makes more chemicals of inflammation and there is an increase in the factors that encourage blood clotting.

The risk of blood clots is highest with oral estrogens, highest in the first year of use, highest when other risk factors are present and highest when progestins are also used (more on that below). Trans-dermal (topical) estrogens do not appear to increase the risk of blood clots:

Postmenopausal hormone replacement therapy and venous thromboembolism.

Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk.

A 2001 study showed oral estrogen causes mixed results as to risk factors for heart disease, and again causes an increased risk for blood clot. Trans-dermal estrogen had no effect on the risk for clots:

Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women.

Known risk factors for blood clots such as obesity, age, and genetic mutations (e.g. Factor V Leiden) are worsened with oral estrogen and progestins, but again topical administration does not carry this risk.

Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration.

We have many patients taking sublingual HRT in which the HRT tablet dissolves under their tongue and enters the bloodstream directly, thus bypassing the first pass metabolism as well.  Arguably, trace amounts of hormones may be swallowed but I suspect it is negligible.

2) Conjugated estrogens increase the risk of blood clots.

Conjugated means bound to another chemical. Conjugated (e.g. Premarin, Cenestin) and Esterified (e.g. Menest) estrogens are similar in that they are bound to another chemical, usually a sodium salt. Many drugs used for hormone replacement are simply slight modifications to our native hormones, with a variety of chemicals simply attached to make a similar (but different) molecule. The end result is a drug that sometimes acts like the native hormone – sometimes not.   And… there are sometimes unexpected side effects not seen with the native hormone.

Conjugated estrogens increase risk of blood clots, whereas esterified estrogens do not:

Conjugated equine estrogen, esterified estrogen, prothrombotic variants, and the risk of venous thrombosis in postmenopausal women.

Our suggestion is to take neither conjugated or esterified estrogens since bioidentical estrogens are widely available.

3) Progestins are chemicals that stimulate progesterone receptors.

As with conjugated estrogens, progestins are not identical to our native progesterone, and may stimulate lots of other receptors. For example, many progestins will also stimulate estrogen or testosterone receptors, and some even stimulate aldosterone (an adrenal gland hormone) receptors. Many of them, namely medroxy-progesterone (MPA) or Provera, will cause a significant increase in the factors that encourage blood to clot.  Progesterone does not increase risk of blood clotting.

More results from the Women’s Health Initiative, showing increased risk of blood clots and stroke with oral estrogen and especially with MPA:

Estrogen plus progestin and risk of venous thrombosis.

Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial.

MPA increases risk of blood clots, progesterone does NOT:

Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study.

Finally, a 2008 review in the journal “Maturitas” that nicely summarizes the correct method for HRT – non-oral estrogen and bioidentical progesterone – which minimizes the risks while conferring the benefits of HRT:

Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review.


Scott Rollins, MD, is Board Certified with the American Board of Family Practice and the American Board of Anti-Aging and Regenerative Medicine.  He specializes in bioidentical hormone replacement for men and women, thyroid and adrenal disorders, fibromyalgia and other complex medical conditions.  He is founder and medical director of the Integrative Medicine Center of Western Colorado (www.imcwc.com) and Bellezza Laser Aesthetics (www.bellezzalaser.com).   Call (970) 245-6911 for an appointment or more information.


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