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By James Thomas PA-C Education
Key Points:
  • Testosterone therapy can increase the number of RBCs (red blood cells), but the increase has not been proven to increase the risk of clots.
  • It is theoretically plausible that elevated RBC’s may increase the risk of cardiovascular events (including blood clots) – as a result, regular monitoring of hematocrit during TRT is important.
  • Testosterone injections typically have the largest effect on RBC’s, as a result other forms of TRT (topical creams) should be considered if your natural RBC level (hematocrit) is high.
  • Elevations in hematocrit can be counterbalanced by blood donation or changing the dosing schedule.
  • The overwhelming majority of studies have have failed to show in increased risk of developing blood clots while using TRT.
  • The American Urological Association (AUA) also assures us that there is no evidence of increased clot risk with testosterone optimization therapy.
DOES TESTOSTERONE REPLACEMENT THERAPY INCREASE THE RISK OF BLOOD CLOTS?
THE SHORT ANSWER:

No, the majority of the scientific evidence has shown that a well-managed testosterone replacement program does not increase the risk of blood clots.  However, there have been studies that have shown an increased risk in individuals with an underlying genetic clotting disorder (such as Factor V Leiden).  This is why it is important for your clinician and you to know your family medical history.  In addition, testosterone increases the number of red blood cells and can theoretically thicken the blood.  Some think that this thickening could predispose patients to clots, but this has never been proven by a single study.  Below I will review how the concern over blood clots developed and the important studies that have been done in this area.

 

THERE has been cONCERN that TESTOSTERONE could increase THE RISK OF BLOOD CLOTS.  Here’s why?

 

1. TESTOSTERONE INCREASES THE NUMBER OF RED BLOOD CELLS:
Testosterone plays a role in the signaling process for the body to produce red blood cells (RBC’s).  Red blood cells are responsible for carrying oxygen to our cells. The majority of men who start testosterone replacement therapy (TRT), will see an increase in the number of RBC’s.  The more RBC’s we have, the more viscous (thicker) the blood becomes.  In “theory”, some believe that thicker blood will have a more difficult time moving through blood vessels and predispose a patient to a clot.  However, this has never been shown to be the case in practice. There are no studies that have shown an increased risk of clots attributable to a higher number of RBC’s.  In addition, if the testosterone is dosed properly the RBC number should no exceed the normal range.
2. PEOPLE WITH POLYCYTHEMIA HAVE A HIGHER RISK OF CLOTS:

Many equate the increase in RBC’s from testosterone supplementation to another medical condition called polycythemia.  Polycythemia Vera is an abnormality of the bone marrow (the factory that produces all of our different types of blood cells – red cells, white cell and platelets).  People with polycythemia produce too many RBC’s.  They also produce too many white blood cells and platelets.  As you may know, the platelets are partly responsible for the clotting ability of our blood.  When there are too many platelets, the risk of blood clots increases.  Many clinicians incorrectly believe that testosterone therapy causes polycythemia.  This is simply not true.  Testosterone only increases the number of RBC’s (the medical term is erythrocytosis).  It does not increase the number of platelets and it does not cause polycythemia.

3. CLOTS WERE REPORTED WHEN MEN WITH CLOTTING DISORDERS TOOK TESTOSTERONE:

A few studies have shown increased blood clots when men with underlying clotting disorders took testosterone.  The clots typically developed within the first 3-6 months of testosterone therapy.  The CDC estimates that approximately 5-8% of the population has at least one genetic risk factor for a clotting disorder.  These facts highlight how important it is to obtain a thorough family medical history before starting testosterone therapy.  In my opinion, if there is concern for a possible clotting disorder the patient should be screened before starting TRT.

4. THE FDA REQUIRES A BLOOD CLOT WARNING ON TESTOSTERONE PRODUCTS:

In 2014 the FDA issued a warning that testosterone products could carry a risk of blood clots.  It is important to note that the warning was not in response to any particular study that showed an increased risk.  The was in response to several “post market” reports the FDA received.  What this means, is that several doctors wrote to the FDA to report that their patients suffered a blood clot possibly due to testosterone therapy.  The majority of the reported clots were shown to be in individuals with existing clotting disorders.  Before these reports were issued, there was no evidence that TRT carried an increased risk of clots.  The FDA functions to regulate pharmaceuticals and their job is to warn patients about potential adverse effects of medications.  In this case, the FDA would not be doing their job if they did not respond to these reported cases, even though the majority of studies have failed to show an increased risk.

So, is THE CONCERN WARRANTED?

Now that you understand the history, is this concern justified?  Below are the key areas of research that have failed to show a link between testosterone and an increased risk of clots.

Research has shown that MEN WITH NATURALLY HIGH TESTOSTERONE DO NOT HAVE AN INCREASED RISK OF CLOTS.

Several studies have examined whether men with high natural testosterone levels have an increased risk of blood clots.  The most important of these was the Tromoso Study.  They followed 1,350 men over 10 years.  The researchers concluded that endogenous (natural) testosterone levels were not associated with and increased risk of blood clots.  Similar results were seen in studies by Holmegard et al. and Mumoli et al.

The fact that naturally high testosterone levels do not increase the risk of clots makes logical sense.  Men’s testosterone levels typically peak in their mid to late 20s.  If high testosterone levels caused an increase in clots, then we would expect to see a higher incidence of clots in men during there 20s.  However, this is not the case.  Clots are typically higher in men over the age of 65 (when testosterone levels are typically lower) and very rare in younger men.

Three LARGE STUDIES FAILED TO FIND A CONNECTION BETWEEN TRT AND CLOTS.

Many studies have examined whether there is an increased risk of blood clots with testosterone replacement therapy (TRT).  Two large studies in particular looked a very large set of men on testosterone.  One study did not find a link while the other reported an increased risk.  Here is a review of the two studies as well as a 3rd study that combined both studies:

1. RISK OF VTE IN MEN RECEIVING TESTOSTERONE THERAPY

This study examined 30,572 men over the age of 40.  The researchers compared the rate of clots in men on testosterone therapy with men who were not on testosterone.  The researchers found that testosterone therapy did not increase the rate of VTE (medical term for blood clots) in these men.  This is one of the the largest studies to date that has examined the issue of clots and testosterone therapy.  While the results showed no link between TRT and blood clots, the following study brought those findings into question.

2. TESTOSTERONE TREATMENT & RISK OF VENOUS THROMBOEMBOLISM

In contrast to the previous study the researchers in this study reported an increased risk of clots with TRT.  This large study compared 19,215 men with confirmed blood clots and compared them with 909,530 patients who did not have clots.  They then examined whether men who received TRT were at a higher risk of developing a clot compared to men who did not.  The researchers found that on the whole, testosterone therapy did not increase the risk of blood clots.

However, when the researchers limited the timeframe to men who started TRT within first 6 months, they reported a higher incidence of clots.  To say this another way, men who started TRT had a higher incidence of clots in the first 6 months than men who were no on TRT.  After 6 month of TRT therapy, there was no difference in the risk of clots.

THE RESULTS WEREN’T AS SIGNIFICANT AS THEY MAY SEEM:
While the results of this study may seem worrisome, we have to take them with a grain of salt.  The study reported a rate increase of 10 additional clots (in the first 6 months) per 10,000 person years.  This means that if you were a physician with 1,000 men on testosterone therapy, every year you would see one additional man develop a clot compared to men not on TRT.  The rate of VTE (blood clots) in the general population is about 1-2 per 1,000 people.  So in our practice of 1,000 men on TRT, we would expect to see about 2 or 3 men with a clot instead of 1 or 2.
THE TWO STUDIES WERE COMBINED to show no increased risk.
I understand this sounds confusing and statistical methods often are. Luckily, some researchers decided to clear up the confusion by combining the results of the two studies in something called a meta-analysis.  Here is what they found:
3. TESTOSTERONE TREATMENT AND CV AND VTE RISK: WHAT IS NEW?
This study combined the results of the two previous studies in hopes of giving us a more definitive answer.  The researchers performed something called a meta-analysis.  This type of analysis is statistical approach to combine the results of multiple studies.  It is often used to resolve uncertainties when studies disagree.  When the researchers combined the two studies they found that testosterone therapy is not associated with an increased risk of VTE (blood clot).  They also found that there was no increased risk, when the study was limited to the first 6 months of testosterone therapy.
NO LINK BETWEEN INCREASED RED BLOOD CELLS AND CLOTS

It is well known that testosterone therapy (especially injections) can increase the number of red blood cells (RBCs) in the blood stream.  In theory, the increase could cause blood to become thicker.  The thicker blood may have a more difficult time moving through blood vessels.  One of the first things doctors are taught is that when blood becomes stagnant, there is an increased risk of developing a clot.  So in theory, the increase in RBCs from testosterone could increase the risk of developing a clot.  However, this has never been shown to be the case in any study.  We know there are several other conditions (lung disease, living at altitude, smoking) that increase the number of RBCs.  None of these conditions have ever been shown to increase the risk of clots.

MULTIPLE OTHER STUDIES HAVE SHOWN NO increased risk:

Previously, we reviewed two large studies and a meta-analysis that failed to show a consistent association between TRT and clot risk.  Several other studies have also shown no conclusive link between the two.  Below I have listed the numerous other studies performed in this area to date.  I also provide you with a brief summary of their findings (in quotations).

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