Testosterone, Thrombophilia, and Thrombosis

[Michael Scally MD]

This is a very controversial statement for TRT: "Thrombophilia should be ruled out before administration of exogenous testosterone."

Testosterone, Thrombophilia, and Thrombosis

Glueck CJ, Richardson-Royer C, Schultz R, et al. Testosterone, Thrombophilia, and Thrombosis. Clin Appl Thromb Hemost. Testosterone, Thrombophilia, and Thrombosis

We describe thrombosis, deep venous thrombosis (DVT) pulmonary embolism (PE; n = 9) and hip-knee osteonecrosis (n = 5) that developed after testosterone therapy (median 11 months) in 14 previously healthy patients (13 men and 1 woman; 13 Caucasian and 1 African American), with no antecedent thrombosis and previously undiagnosed thrombophilia-hypofibrinolysis. Of the 14 patients, 3 were found to be factor V Leiden heterozygotes, 3 had high factor VIII, 3 had plasminogen activator inhibitor 1 4G4G homozygosity, 2 had high factor XI, 2 had high homocysteine, 1 had low antithrombin III, 1 had the lupus anticoagulant, 1 had high anticardiolipin antibody Immunoglobulin G, and 1 had no clotting abnormalities. In 4 men with thrombophilia, DVT-PE recurred when testosterone was continued despite therapeutic international normalized ratio on warfarin. In 60 men on testosterone, 20 (33%) had high estradiol (E2 >42.6 pg/mL). When exogenous testosterone is aromatized to E2, and E2-induced thrombophilia is superimposed on thrombophilia-hypofibrinolysis, thrombosis occurs. The DVT-PE and osteonecrosis after starting testosterone are associated with previously undiagnosed thrombophilia-hypofibrinolysis. Thrombophilia should be ruled out before administration of exogenous testosterone.

 

[beezil]

This is a very damning & controversial statement for TRT: "Thrombophilia should be ruled out before administration of exogenous testosterone."

Testosterone, Thrombophilia, and Thrombosis

Glueck CJ, Richardson-Royer C, Schultz R, et al. Testosterone, Thrombophilia, and Thrombosis. Clin Appl Thromb Hemost. Testosterone, Thrombophilia, and Thrombosis

We describe thrombosis, deep venous thrombosis (DVT) pulmonary embolism (PE; n = 9) and hip-knee osteonecrosis (n = 5) that developed after testosterone therapy (median 11 months) in 14 previously healthy patients (13 men and 1 woman; 13 Caucasian and 1 African American), with no antecedent thrombosis and previously undiagnosed thrombophilia-hypofibrinolysis. Of the 14 patients, 3 were found to be factor V Leiden heterozygotes, 3 had high factor VIII, 3 had plasminogen activator inhibitor 1 4G4G homozygosity, 2 had high factor XI, 2 had high homocysteine, 1 had low antithrombin III, 1 had the lupus anticoagulant, 1 had high anticardiolipin antibody Immunoglobulin G, and 1 had no clotting abnormalities. In 4 men with thrombophilia, DVT-PE recurred when testosterone was continued despite therapeutic international normalized ratio on warfarin. In 60 men on testosterone, 20 (33%) had high estradiol (E2 >42.6 pg/mL). When exogenous testosterone is aromatized to E2, and E2-induced thrombophilia is superimposed on thrombophilia-hypofibrinolysis, thrombosis occurs. The DVT-PE and osteonecrosis after starting testosterone are associated with previously undiagnosed thrombophilia-hypofibrinolysis. Thrombophilia should be ruled out before administration of exogenous testosterone.

What tests should be performed to rule out Thrombophilia?

 

[CensoredBoardsSuck]

What tests should be performed to rule out Thrombophilia?

It's expensive and time-consuming to rule out thrombophilia. I believe the current recommendation is testing should be performed only in patients who have a history of unexplained thromboembolism. It seems grossly excessive to recommend ruling out thrombophilia in EVERY patient before starting TRT.

 

[beezil]

It's expensive and time-consuming to rule out thrombophilia. I believe the current recommendation is testing should be performed only in patients who have a history of unexplained thromboembolism. It seems grossly excessive to recommend ruling out thrombophilia in EVERY patient before starting TRT.

thank you.

 

[biceps72]

this really isn't new.

Have MD test for platelet problems

Similarily look for irregular factor levels in vitamin K cascade (e.g. Leiden Factor V, factor VIII) and others.

genetic predisposition to clotting is not exactly rare.

Isn't the REAL problem with TRT and clotting is elevated E2????

REALLY

 

[Dr JIM]

Give me a break and "get a life" outside an academic institution where the mantra has been publish or perish.

The notion every TRT patient should have a preemptive formal evaluation for thrombophillia (an inheritable blood clotting disorder) is Ivory Tower dogma, utterly absurd and cost prohibitive. The Liden test alone is $113.00 at the lab I frequently use.

I suspect the full battery of lab tests used to determine if the patient is "at risk" because of a genetic clotting predisposition is somewhere between $500-$1K!

Moreover although the frequency of VTE is dependent upon route, dose and duration of therapy, KNOWN "risk factors" (erythrocytosis in particular) also play a critical role in the overwhelming majority of patients whom develop thromboembolism.

The suggestion physicians should be attempting to locate zebras amongst horses is ludicrous.

 

[steroidsfax]

Its unfortunate that a quick and easy test doesn't exist for this yet.

It has long beem a concern of mine that, considering the rapid advancement in the number of men on TRT in recent years will lead to new, previously unforeseen issues, such as this. I understand we have been using testosterone for a long time, but I feel having increased the number of patients as dramatically as has happened recently will almost certainly lead to some revelations.

Which ultimately is a good thing, I just worry about further demonization.

 

[steroidsfax]

The suggestion physicians should be attempting to locate zebras amongst horses is ludicrous.

I think we would both agree that physicians do actually have both a moral, and professional obligation to spot zebras amongst horses, before prescribing potentially life threatening drugs. Right?

What I mean is, there would be some kind of thorough interview performed, where you would ask about familial health, and history in an effort to discover if the patient is at risk for any issues known to arise with a given therapy, right?

 

[idmd]

I think we would both agree that physicians do actually have both a moral, and professional obligation to spot zebras amongst horses, before prescribing potentially life threatening drugs. Right?

What I mean is, there would be some kind of thorough interview performed, where you would ask about familial health, and history in an effort to discover if the patient is at risk for any issues known to arise with a given therapy, right?

The problem with your thought process is it assumes a medical history is capable of uncovering all zebras and its not. While I do think a thorough med hx is essential and often not utilized as well as it could in this day of 5 min consults there are many conditions where the diagnosis is made with additional tests AFTER excluding all the horses as the problem.

With limited health care dollars to spend I'll go with the obvious (horse) and be "right" 99% of the time over the less obvious (zebra) to be right 1% of the time.

 

[Charles J. Glueck MD]

screen for major thrombophilias before giving exogenous testosterone

If the prevalence of major gene thrombophilias in the general population of Caucasians is ~20%, then a signficant percentage of the population is at risk for thrombotic events when given exogenous testosterone, usually deep venous thrombosis-pulmonary embolus-osteonecrosis. The cost of hospitalization (and who can adequately estimate cost of premature death) for these disorders is usually $50,000 +. Assuming that there are 10 hospitalizations per year for DVT-PE-osteonecrosis, total cost ~$500,000, which would pay for 1,000 screenings of men before testosterone, for Factor V Leiden, Prothrombin gene, Factors VIII and XI, and homocysteine. As physicians, above all, we are taught to do no harm. Screening before giving testosterone is not only ethical, but probably cost-effective in preventing otherwise serious morbidity and mortality.

 

[Michael Scally MD]

Re: screen for major thrombophilias before giving exogenous testosterone

If the prevalence of major gene thrombophilias in the general population of Caucasians is ~20%, then a signficant percentage of the population is at risk for thrombotic events when given exogenous testosterone, usually deep venous thrombosis-pulmonary embolus-osteonecrosis. The cost of hospitalization (and who can adequately estimate cost of premature death) for these disorders is usually $50,000 +. Assuming that there are 10 hospitalizations per year for DVT-PE-osteonecrosis, total cost ~$500,000, which would pay for 1,000 screenings of men before testosterone, for Factor V Leiden, Prothrombin gene, Factors VIII and XI, and homocysteine. As physicians, above all, we are taught to do no harm. Screening before giving testosterone is not only ethical, but probably cost-effective in preventing otherwise serious morbidity and mortality.

Welcome.

As you are more than aware, this is a very controversial stance. Even more so when one considers the number (millions) of men on TRT. Are these the screening tests recommended: Factor V Leiden, Prothrombin gene, Factors VIII and XI, and homocysteine.

As a point of clarification, are you stating TRT can be used in someone who screens positive? If so, what would be the monitoring? If not, how is the hypogonadism to be treated, particularly if in the face of overt signs (osteoporotic fracture)? Thanks.

 

[Millard]

In 60 men on testosterone, 20 (33%) had high estradiol (E2 >42.6 pg/mL). When exogenous testosterone is aromatized to E2, and E2-induced thrombophilia is superimposed on thrombophilia-hypofibrinolysis, thrombosis occurs.

Isn't the REAL problem with TRT and clotting is elevated E2????

a signficant percentage of the population is at risk for thrombotic events when given exogenous testosterone, usually deep venous thrombosis-pulmonary embolus-osteonecrosis. .

How does management of E2 levels while on TRT play into this equation?

 

[Jockmuscletank]

Where can anyone order these tests?

Nelson Vergel
Author
Testosterone: A Man's Guide

 

[Dr JIM]

20% prevalence of hereditary thrombophilia, in the general population? Closer estimates of effected patients with proven thrombosis would suggest the prevelance of strictly defined TP, lies somewhere between 1-5% and it's occurrence often depends upon the site of the VTE.

More specifically for "asymptomatic controls", the estimates lie somewhere between 5-10% compared to 20-30% of those hospitalized for VTE.

Unfortunately many literature estimates grossly overestimate the idiopathic nature of TP since patients with known "circumstantial clinical risk factors" (those which predispose patients to VTE ) were not excluded in most studies. (What that implies is the majority of patients with a VTE predisposition could have been detected on a clinical basis alone and by definition do NOT have TP)

It is also well known the majority of patients with TP never acquire a VTE and never would excluding the development of an acquired RF such as; CHF, blunt extremity trauma, immobilization, surgery, cancer, etc.

Interestingly these are all well established RF for VTE and, some are, on a comparative basis more so than TRT, yet at present no screening is done in those patients. Should they all be placed on Wairfin or heparin to abate the oncoming clot, I think not.

Whether TRT is the sentinal event responsible for a patients VTE, probably has more to do with the "degree" of a patients deficiency and or the magnitude of the inciting event.

Finally if the TP battery of lab tests (about $1000.00) fails to alter therapy obviously their acquisition will only serve to increase the cost of health care, which is astronomical at present. For myself, a simple "TRT increases the chances of blood clots sir", is more than sufficient.

Best Regards
JIM

 

[Charles J. Glueck MD]

What tests should be performed to rule out Thrombophilia?

Factor V Leiden, G20210A Prothrombin, both PCR tests
Factors VIII, XI, homocysteine (serologic tests)

 

[techlogik]

If a quick questionnaire and conversation with a patients tells you there is no family history of strokes/heart attacks, blood disorders etc...I don't know why, except to CYA, you would run any of these test before administering Test.

Then again, most people's health is very poor in general compared to others. So a general precaution might dictate running tests, just to rule out the 20%...which is still no guarantee they won't drop over and die anyway.

 

[Michael Scally MD]

Glueck CJ, Bowe D, Valdez A, Wang P. Thrombosis in three postmenopausal women receiving testosterone therapy for low libido. Womens Health (Lond Engl) 2013;9(4):405-10. http://www.futuremedicine.com/doi/abs/10.2217/whe.13.31 (An Error Occurred Setting Your User Cookie)

Our hypothesis was that thrombosis occurring in postmenopausal women given testosterone (T) or testosterone-estradiol (TE) to improve libido was associated with a prothrombotic interaction between T or TE with underlying inherited procoagulants.

In three previously healthy, postmenopausal, Caucasian women with no antecedent thrombosis and previously undiagnosed G20210A prothrombin gene heterozygosity, hyperhomocysteinemia and 4G4G homozygosity of the PAI-1 gene, we describe central retinal vein thrombosis and osteonecrosis that developed at 16 days, 2 months and 11 months in the three cases, respectively, after T or TE therapy was started.

Exogenous T or TE in postmenopausal women may be associated with thrombosis, speculatively when it is superimposed on underlying procoagulants. This small observational case series can serve as a starting point for a larger observational study with greater detail on patient history, serum T and estradiol levels, and detailed PCR and serologic assessment of thrombophilia and hypofibrinolysis.

 

[Michael Scally MD]

Glueck CJ, Richardson-Royer C, Schultz R, et al. Testosterone Therapy, Thrombophilia-Hypofibrinolysis, and Hospitalization for Deep Venous Thrombosis-Pulmonary Embolus: An Exploratory, Hypothesis-Generating Study. Clin Appl Thromb Hemost. Testosterone Therapy, Thrombophilia–Hypofibrinolysis, and Hospitalization for Deep Venous Thrombosis-Pulmonary Embolus: An Exploratory, Hypothesis-Generating Study

In our study of 596 men hospitalized in the last 3 years for deep venous thrombosis-pulmonary emboli (DVT-PE), we determined the prevalence of exogenous testosterone (T) use with subsequent development of DVT-PE. Of the 596 men, 110 were now dead, 97 had cancer thought to cause DVT-PE, 250 could not be contacted, leaving 139, of whom 7 had taken T before and at the time of their admissions, 1.2% of the total cohort, a conservative estimate of the prevalence of T-associated DVT-PE. In all, 5 of the 7 DVT-PE events occurred within 3 months of initiation of T, with mean and median intervals between initiation of T and hospitalization with DVT-PE 6.7 and 2 months. Of the 7 men treated with exogenous T, all 5 men who had evaluation of thrombophilia-hypofibrinolysis were found to have previously undiagnosed familial or acquired thrombophilia or hypofibrinolysis, suggesting a thrombotic interaction between exogenous T and thrombophilia-hypofibrinolysis.

 

[zkt]

Lets up the ante and consider those on anticoagulant therapy.
Should I be worried?

 

[biceps72]

Lets up the ante and consider those on anticoagulant therapy.
Should I be worried?

Good question! One of my fishing buddies is being treated for A-fib with warfarin (and other drugs) but is also taking Test-C shots twice weekly. He runs total test between 500-650 an E2 generally less than 45. His MD told him to maintain his INR between 2-3 and no sweat?

Does this seem reasonable? He is 72 and in pretty good shape for the most part. He has lived with this medication protocol for 9 years.