Does Bioidentical Estradiol Increase the Risk of Blood Clots?

Should You Stop it Pre-Operatively? 

Can You Take It If You are High Risk for Clotting?

It is difficult to navigate the internet and journal articles when it comes to medicine.  The Practice of Medicine is an art.  It is not an exact science.  Everyone has different genetics and different detoxification systems, all playing into what kind of predisposition we have to specific diseases at certain ages. This being said, there is no “one size fits all” when it comes to Bioidentical Hormone Replacement Therapy (BHRT).  The use of BHRT using bioidentical hormones, versus HRT using synthetic hormones, became more popular after the Women’s Health Initiative results on HRT, but without great debate concerning the efficacy and safety of BHRT.

The use of HRT, synthetic hormones, has been shown to increase the risk of blood clots in women.  This thinking has been superimposed on BHRT.  Subsequently, physicians recommend women come off HRT and BHRT before surgery, but is this a safe thing to do?  Can women with a genetically increased risk of blood clotting take HRT or BHRT?

This blog reviews research on the risk of increased blood clotting when using HRT, or BHRT. It also points out how easily one can get confused in reading any research when it comes to estrogen!

Definition of Terms, Estrogen

In researching any subject, the first thing you need to know is a definition of terms.   In this case the term is ESTROGEN!  Unfortunately, current medical literature uses the term estrogen loosely to describe all estrogens, synthetic and bioidentical, making it difficult to interpret research and any major headline news when they use the word estrogen.  To which estrogen are they referring?

In the literature, “oral estrogen”, usually refers to synthetic estrogen such as Premarin or those in birth control pills, not bioidentical estradiol.  Therefore, when you see ‘oral estrogen’, know it is usually referring to synthetic estrogen unless otherwise stated.

The full name of the main natural estrogen made in women is ‘17 hydroxy beta estradiol’.  I am giving you this information, so you know these terms if they come up in your google search.  Estradiol converts into estriol and estrone which are also referred to as estrogens.  Ethinyl estradiol is synthetic estrogen often used in birth-control pills. Premarin is called an oral estrogen. You can see how quickly someone can get confused.

So, when a news headline says, “Estrogen causes blood clots in women”, your first question should be, “Which estrogen?”.  When your doctor says you should not use estrogen because of blood clots, your next question should be, “Which estrogen?”.  If they tell you any estrogen, or all estrogens act the same, find another doctor because they have not read the literature.

To increase confusion, the FDA requires all estrogens to be labeled with the same side effects, whether they are synthetic or bioidentical.  The FDA labeling of side effects comes from research on synthetic estrogen, not on bioidentical estrogen.  Synthetic and bioidentical estrogens have two completely different structures.

WHAT DOES THE RESEARCH SAY?

There are several excellent review articles concerning estrogen and blood clotting presented below.  I encourage you to plow through them.  The majority of research in the Unites States is on the use of synthetic hormones, whereas Europe has more research on bioidentical hormones.   Research in all countries agree, the delivery system of estradiol is of paramount importance in determining the risk of blood clots.  In other words, it may not be estrogen itself that causes blood clots whether it be synthetic or bioidentical, but the way in which it is introduced into the body!

 

Research Shows, the Delivery System of Hormones is Important in Risk of Blood Clots

Bioidentical estradiol can be delivered orally through capsules, as well as transdermally in the form of patches, gels, creams, injections, and pellets. Pellets and injections are absorbed below the skin surface. There are no transdermal delivery systems for synthetic estrogens given alone, other than Premarin cream.

The conclusions universally are:

Oral estrogens, (synthetic) increase the risk of blood clots 2-4 fold.  Oral estrogens combined with synthetic progestins (ie: birth-control pills) increase the risk of blood clotting more than oral estrogen alone.

However, transdermal delivery systems for bioidentical estradiol have been shown to NOT increase the normal risk of thromboembolism and may have the potential of decreasing the risk of blood clots as supported by the journal articles below. Transdermal bioidentical estradiol with oral or transdermal bioidentical progesterone do not increase the risk of blood clots.

 

The Consensus: Transdermal Estradiol Does Not Increase Blood Clots 

A review article published in 2009, compared the efficacy and safety of BHRT vs HRT in the current literature.  In regards to clotting, the authors concluded,

“Transdermal estradiol, when given with or without oral progesterone, has no detrimental effects on coagulation and no observed increased risk for venous thromboembolism (VTE).

This result is in contrast to an increased risk for VTE with CEE (Premarin), with or without synthetic progestin, which significantly increases the risk for VTE…”

 

Estrogen and Decreased Plaque Formation

As an aside, but quite interesting and thought provoking, the above referenced article discusses a 1997 study showing a 50% reduction in atherosclerotic plaque formation in monkeys with induced menopause treated with CEE (Premarin) combined with bioidentical progesterone given in their food.  A 1990 study on monkeys also shows a 50% reduction in atherosclerotic plaque formation with bioidentical estradiol pellets and cyclical oral bioidentical progesterone.

These well-done studies imply estrogen is a potent inhibitor of coronary artery disease.  The authors also found atherosclerotic lesions were independent of cholesterol level, lipoprotein fractionation, apoprotein A-1 and B concentrations!  Another blog will follow addressing this.  However, it opens one’s thinking to the possibility, Premarin orally with food or transdermal estradiol either combined with progesterone may actually be good to decrease thrombogenic activity in blood vessels and treatment of coronary artery disease.

 

Transdermal Estradiol Safe to Use

In an editorial in the British Journal of General Practice 2019, ‘The dangers of compounded bioidentical hormone replacement therapy’, the author states:

“Transdermal estrogen is the preferred route of administration because, in contrast with oral estrogen, estrogen as a patch or gel is not associated with an increased risk of venous thromboembolism. It can be safely given to women who have a history of migraines, gallbladder disease, diabetes, or who are obese…in addition there is no increased risk of breast cancer for the first 5 years of taking estrogen with micronized progesterone.”

In a journal review and studies from France in 2007, Canonico et al compared the risk for VTE in 271 cases of women with confirmed VTE for the first time and 610 matched controls with no VTE in a blinded RCT (randomized control trial).  A history of thrombophilia, women at high risk for thrombosis, were excluded.  BHRT or HRT use was documented.  Bioidentical estradiol was used orally and transdermally.  This is an instance when they use the term oral estrogen they were referring to oral bioidentical estradiol as was stated in the article.  The authors found:

“Our data confirm that oral but not transdermal estradiol increases VTE risk among postmenopausal women.,,,,, we have previously reported that transdermal estrogen combined with micronized progesterone (bioidentical)  had little or no effect on blood coagulation activation as shown by the absence of significant variation in plasma concentration of prothrombin fragment 1+2…..

In addition, 4 randomized controlled trials have shown oral but not transdermal estrogen, both combined with micronized progesterone, induced an activated protein C resistance…..(meaning increased clotting)

There is now a strong body of biologic evidence suggesting a lower risk of VTE, among users of transdermal estradiol therapy.”

This means, even in those with an inherited activated protein C anomaly predisposing one to an increased risk of blood clots, transdermal estradiol did not affect clotting factors and therefore did not increase risk of blood clots. This is huge. And with larger studies they may see a decreased risk of blood clots in healthy post-menopausal women using transdermal estradiol.

From the American College of Obstetricians and Gynecologists, ACOG,

A journal article entitled ‘Postmenopausal Estrogen Therapy Route of Administration and Risk of Venous Thromboembolism.’yr?

This was an excellent article, and I highly recommend reading it. There are 7 studies to support their statement:

“Studies that compared oral and transdermal ET (estrogen therapy) have demonstrated transdermal administered estrogen has little or no effect in elevating prothrombotic substances and may have beneficial effects on proinflammatory markers, including C-reactive protein, prothrombin activation peptide, and antithrombin activity. Also, in contrast to oral ET, transdermal ET also may have a suppressive effect on tissue plasminogen activator antigen and plasminogen activator inhibitor activity”   This means transdermal ET may decrease the incidence of blood clots in this disease state.

Again, the last statement raises the question of whether transdermal estradiol therapy is actually beneficial in reducing the risk of blood clots in post-menopausal women leading us to wonder if women should be placed prophylactically on transdermal estradiol for this health benefit.

 

Should you Stop BHRT or HRT for Surgery?

By extrapolating the above data to surgical patients, keeping in mind the increased risk of blood clotting pre- and peri-operatively due to reactive vasoconstriction during surgery, there should be no increased risk of blood clots with the use of transdermal estradiol and/or oral progesterone, and it may have potential to lessen the risk!

In fact, in the British Journal of Anesthesia, 2001, the authors stated:

“there is no evidence base for any of the current recommendations concerning pre-and perioperative management of women using HRT…. Although there is clear evidence from RCTs (randomized clinical trials) that use of HRT is associated with a small increase in relative risk of venous thromboembolism, there is no such evidence to demonstrate any increased risk of peri‐operative venous thromboembolism in HRT users.

Current advice (based on limited evidence and expert opinion rather than on the results of RCTs) is that HRT use should be regarded as one of the risk factors for venous thromboembolism to be considered when assessing patients pre‐operatively. There is no evidence to support stopping HRT pre‐operatively. Use of mechanical or pharmacological methods of thromboprophylaxis is recommended for women taking HRT; the choice of thromboprophylaxis will depend upon the number of risk factors for venous thromboembolism.”

The literature is sparce in the use of HRT and BHRT peri-operatively, but it is currently being reassessed in gender affirming surgical cases in which patients are getting higher than normal synthetic estrogen doses.  The surgery itself carries a low risk of thromboembolic events and yet patients are being told to stop their hormones 2-6 weeks peri-operatively inducing many physiological and psychological problems.  The consideration is to use transdermal estradiol and not stop estrogen for the surgery. These studies may finally shed light on the use of HRT and BHRT peri-operatively.

 

Factor V Leiden. Prothrombin and Blood Clotting with Estrogen Use

Lastly, a literature review in 2022 concerning hormone replacement therapy in women with a history of thrombosis or a genetic thrombophilia (protein C, protein S, Factor V Leiden, Prothrombin), states:

“A multicenter case-control study into the risk of VTE in women using oral HRT with thrombophilia found that the presence of Factor V Leiden increased the risk 3.4 times. In their analysis, the presence of a prothrombotic gene mutation and oral HRT resulted in a significantly increased risk of thrombosis compared to untreated women. Their analysis also demonstrated that the use of transdermal HRT did not increase the risk of VTE above non-users with the same thrombophilic mutation. 

Prothrombin G20210 A is the second most common inherited thrombophilia with approximately 2% of the population as heterozygous carriers. A study assessing the risk of HRT and FVL or prothrombin gene mutation found that the presence of the prothrombin mutation was associated with a 4.8-fold increased VTE risk when using oral HRT. In contrast, transdermal HRT was associated with the same risk of VTE for women with the prothrombin gene mutation as non-users. “

Hence, women predisposed to thrombophilia can use transdermal estradiol without increased risk of clotting.

Summary:

Conclusion and recommendations from the above literature:

1. The use of oral synthetic estrogens commonly used in birth control pills and HRT for postmenopausal women increase the risk of blood clots.
2. The use of oral bioidentical estrogen in menopausal women is controversial, some research showing an increase in blood clots and some not.
3. The use of transdermal estradiol does not increase the risk of blood clots at any age.
4. The use of transdermal estradiol with inherited thrombophilia does not increase the risk of blood clots.
5. The use of transdermal estradiol peri-operatively has not been studied, but research consensus is, in healthy individuals it may be better to continue BHRT and even possibly HRT than stop hormone replacement therapy peri-operatively.
6. Another blog will follow reviewing research of the use of oral and transdermal estradiol to decrease plaque formation in coronary arteries

Have an awesome day!   Dr. D