Can Testosterone Induce Blood Clots and Thrombosis? Interview with Dr Charles Glueck

[Nelson Vergel]

In my work collecting information for ExcelMale.com, I review abstracts daily on latest studies related to testosterone, men's health, nutrition, and more. I am always looking for studies that stand out and are no just repetitions of what we have seen before. Contrarian data to what I assume we know is what motivates me to read. In particular, I am looking for negative data and results in studies using testosterone. I have been using this hormone since 1993 to save my life and its quality and have not had any side effects. However, I know everyone is different and some people may have genetic or other variations that may make them susceptible to at least one side effect.

Good read:

What to do if you have a blood clot



The first time I read a paper than mentioned thrombosis risk in people on testosterone replacement (read abstract at the end of this article), my goal is to get in contact with the author. Dr Charles Glueck was kind to reply for my request for an interview to help me educate physicians and patients. He is a graduate from Harvard and Western Reserve Universities and has over 35 years of medical practice and have produced over 600 publications. He is currently the Medical Director of the Jewish Hospital Cholesterol Center. To say that he has credentials is an understatement.



I am impressed by his willingness to help anyone who may be concerned about this issue (he provides contact information below)

Here is the short interview:

Dr Glueck, Thank you so much for agreeing to educate my readers about your research.

Can you give give us a brief background of why you were interested in looking into thrombophilia and thrombosis in people on testosterone replacement therapy? Can you explain those terms to us?

Dr Glueck: As physicians who deal with deep venous thrombosis (DVT) and pulmonary embolus (PE), as well as blood clots in the eyes (central retinal vein and central retinal artery thrombosis), and ischemic stroke, and arterial blood clots, we realized that many of our referrals had started exogenous conventional testosterone therapy before sustaining their blood clots. Because we were very experienced with the diagnosis of thrombophilia and hypofibrinolysis, we hypothesized that the exogenous testosterone was interacting with underlying coagulation disorders producing the blood clots. We have now proven this in multiple publications.

In your best estimate or opinion, what is the incidence of this problem in men on testosterone replacement?

Dr Glueck: The incidence of DVT-PE or other clots in men on T therapy is not known, but our best estimates are that about 1-2% of men taking T will develop blood clots related to underlying inherited clotting abnormalities or to acquired thrombophilia (the antiphospholipid antibody syndrome). These men who landed in the hospital with dangerous and potentially lethal blood clots in the deep veins of the legs or in the lungs developed these clots within three months of starting testosterone therapy. None of them knew previously that they had an inherited clotting disorder that put them at greater risk for developing clots, nor did their providers test them before putting them on testosterone therapy.

You suggest that "thrombophilia should be ruled out before administration of exogeneous testosterone". How can that be done and are the tests commercially available or research tools? You used these tests in your study: factor V Leiden heterozygosity, high factors VIII and XI, high homocysteine, low antithrombin III, the lupus anticoagulant, high anticardiolipin antibody lgG, and the hypofibrinolytic 4G4G mutation of the PAI-l gene. Should all be performed? Would these tests be reimbursed by insurance and, if not, what do you think the retail value would be?

Dr Glueck: The 4 tests we would do include Factor V Leiden, Prothrombin gene, Factor VIII and Factor XI, all routinely available commercially at Lab Corp and Quest (big national labs), and at almost all regional labs as well. In our experience these tests are routinely covered by insurance. If not covered, I would estimate that the cost would be expensive, $800.

You also suggest a link between high estradiol with thrombophilia. Can you explain this finding? Would anastrozole or other E2 inhibitor improve outcome if used with TRT?


Dr Glueck: We have data to show that when T is aromatized in the body to estradiol (E2), the high E2 may be the agent which directly interacts with the underlying thrombophilia to produce the clots. We do not have enough data to know whether Arimidex used to lower E2 would be protective, but we know that Arimidex alone is prothrombotic in all of the thrombophilias and hence, probably not a good idea.

In your opinion, should all men on TRT be on low dose aspirin?

Dr Glueck: Low dose aspirin would have no effect on the clotting events seen in men on T who have underlying thrombophilia and I would not recommend it.

Are you planning to do any further studies on this troubling issue?

Dr. Gluek: We are working hard to better understand this troubling issue. If any of your readers have had DVT-PE or other clots while taking exogenous T, or during hCG or clomid therapy to raise T, we would be glad to help them out with expert consultative advice free of charge. Have them contact us by email ([email protected]) or by phone (513-924-8250) fax (513-924-8273) and we will advise them on what blood samples to have drawn, and how to deal with their problem. All of their information will, of course, be entirely private and totally confidential. We will also be glad to work with their doctors in their local communities.

Thank you so much for your time and I will be contacting you in a few months to see if you have any updated data for us.


____________________________________________

ClincAppl Thromb Hemost. 2014 Jan;20(1):22-30. Epub 2013 Apr 23.


Testosterone, thrombophilia, and thrombosis.

Glueck CJ, Richardson-Royer C, Schultz R, Burger T, Labitue F, Riaz MK, Padda J, Bowe D, Goldenberg N, Wang P.


Abstract

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.

Click here for part 2:

Article: Second Interview with Dr Charles Glueck About Testosterone and DVT

 

[Marco N Cognito]

Thanks to Nelson's efforts above, for those of us that have any incidence of familial or acquired incidence of blood clots or/and that have a prior history (as I do), we now have a thread on this topic to post ongoing concerns and updates for all to benefit from.

I will be contacting Dr. Glueck with my concerns and report back in hopes I can ascertain some type of more aggressively-managed protocol for those of us at risk or who suspect risk while commencing TRT. Warfarin (coumadin) is only one type of anticoagulant, acting as a Vit K antagonist, blocking its action, and aspirin (and prescription anticoagulants like Plavix) only works to prevent platelet aggregation, however, there are other anticoagulants that work upon the clotting cascade entirely differently that as far as I know were not used in his research. These would be the older ones, i.e. Lovenox, heparin, and the much newer direct thrombin inhibitors like Xarelto, Eliquis and Pradaxa.

As far as AIs to control E2, I am at a loss as to what will not affect the clotting cascade in some way; they all do. Perhaps natural AIs are thew only safe ones. In my case, I have the opposite issue, as my E2 is almost non-existent. Yet another argument in favor of TRT.

Also – it would be interesting to see if having therapeutic phlebotomies would have prevented clots in those subject.

In opposition to Glueck's work is this 1990 study which states that AAS is NOT thrombogenic: http://www.nejm.org/doi/full/10.1056/NEJM199002153220716

In the meantime, here is my own doc's take, given my past history of clots:
"I did not see any mortality data, just recurrent DVT with the T treatment. We have a large volume of data showing decreased mortality from all causes with testosterone replacement therapy vs no treatment for low T patients, let alone the subjective improvement in the quality of life. Also, even though ONE patient had DVT with a normal E2 level, most had high levels of E2.

You would have to balance risk vs benefits for your particular case with an increased risk for thrombosis, although the case numbers appear to be very small. Really, there is no right or wrong avenue to take. Risks treating as well as risks for not treating, you need to decide which are more important for you. It appears by % and numbers that reducing MI's by T treatment could outweigh the risk of thrombosis by case numbers and %, but you ultimately need to decide what scares you more."

Some further data:

1) There have been 10 cases with major gene thrombophilia FULLY ANTICOAGULATED (with warfarin) who had second or even third thrombotic events when exogenous T therapy was continued.

2) There is one case in which Arimidex by itself caused thrombosis in a V Leiden heterozygote.

Glueck's actual studies:

This is not a black and white issue and there are many offsetting factors like elevated Lp(a) which may have a link between thrombosis and atherosclerosis, interfering with plasminogen function in the fibrinolytic cascade. Exogenous T acts as a fibrinolytic and is use as a protocol to lower Lp(a) in men.

With the aggressive marketing of global TRT clinics, I expect we will see an incidence of thrombotic events increasing as more men commence TRT. This will greatly increase the necessity to overcome the hurdle as to what prophylactic measures can be taken to prevent future episodes, some of which can be fatal in the event a DVT causes PE.

 

[Marco N Cognito]

It's one thing to read it and be concerned; it's another to read advice directed specifically at you:

"Exogenous testosterone would be, to my assessment, absolutely contraindicated in you, given your history, without or without concomitant anticoagulation."

All my hopes of any progress commencing TRT and relishing in its benefits now crushed. But should I be surprised after reading his research in which it clearly states TRT is off limits, especially for those with ANY history of clots?

So am I faced with no quality of life, no ability just to avoid these #%^& clots? If I do TRT, it will be like playing Russian roulette because you really won't know if or when you will clot until the clot is already in place - or be already dead from a pulmonary embolism (when the clot has broken off). What alternatives do I have? Natural T boosters don't work. SARMs?

I sent Dr. G a follow-up email suggestion that NOT being on TRT (of SOME kind) is not an option.

I can't be the only one faced with this dilemma.

Other takeaways from him:
1) ALL of the anti-estrogens (i.e. Arimidex) are reported to be thrombogenic (induce clots).
2) The putative risk of low T and MI (heart attack) is way overweighed by increased MI, CVD (cardiovascular disease),and all cause mortality.
3) Several studies have shown that endogenous (natural) T throughout its distribution (particularly on the high end) is NOT associated with thrombotic events.

List of labs necessary to evaluate possible thrombophilia - via LabCorp:

1. Methylenetetrahydrofolate Reductase (MTHFR) Thermolabile Variant, DNA Analysis
2. Protein C Activity
3. Protein S, Functional
4. Alpha-2-Antiplasmin
5. Fibrinogen Activity
6. HOMOCYSTEINE, PLASMA
7. Factor II, DNA Analysis (G20210A)
8. Apo E Genotyping: Cardio Risk
9. PAI-1 GENE POLYMORPHISM
10. Prothrombin Antibodies, IgG
11. Prothrombin Antibodies, IgM
12. Antiphosphatidylserine IgM
13. Antiphosphatidylserine IgA
14. Antiphosphatidylserine IgG
15. Anticardiolipin Ab,IgM,Qn
16. Anticardiolipin Ab,IgA,Qn
17. Beta-2 Glycoprotein I Ab, IgG
18. Beta-2 Glycoprotein I Ab, IgA
19. Beta-2 Glycoprotein I Ab, IgM
20. CBC w/ differential
21. Factor V Leiden (FVL) mutation
22. von Willebrand Factor (vWF) Ag
23. Disseminated Intravascular Coagulation (DIC) Profile, Comprehensive Plus [A2-antiplasmin; antithrombin activity; D-dimer; factor V activity; factor VIII activity; fibrinogen antigen; international normalized ratio (INR); plasminogen; platelet count; prolonged activated partial thromboplastin time (aPTT); prothrombin time (PT)]
24. Intrinsic Pathway Coagulation Factor Profile [Factor VIII activity; factor IX activity; factor XI activity; factor XII activity]
25. Extrinsic Pathway Coagulation Factor Profile [Factor II activity; factor V activity; factor VII activity; factor X activity]
26. Lupus Anticoagulant Comprehensive
27. Paroxysmal Nocturnal Hemoglobinuria (PNH)
28. Leukemia/Lymphoma Immunophenotyping Profile

Has anyone from this forum contacted Dr. Glueck about their own concerns with respect to clotting up while on TRT??

If so, please reply.

We need to come up with some solutions to this!

 

[indydaddy]

I have been on TRT since 1993, since my own testicles stopped all production of testosterone at age 45.

I had a DVT (deep venous thrombosis) when I had a PICC line for antibiotics in 2007. Same vein as the line so likely caused by the line. Treated with Coumadin for 6 months and the clot resolved. I have remained on TRT continuously since 1993. 3 years ago I added Arimidex due to high estrogen levels.

I have never had another DVT. I have had to have 3 coronary stents placed due to artery stenosis since 2000, but I have a horrible familial history of coronary artery disease. So I don't know if my CAD can be blamed on the TRT?

I know my quality of life is greatly enhanced from the TRT as I well recall how miserable life was when I had no testosterone in my body. You have to weigh the risk vs. the benefits. When my T was low, not only did I have no libido but I was severely depressed, constantly fatigued, suffered from constant panic attacks and anxiety to the point my life was miserable. With my first injection of T, I was a changed man and none of those symptoms have ever reoccurred. To me it is not even a question as whether to continue the TRT. When my Cardiologist demanded I stop the TRT in 2000, following my first stent, I plainly told him I would rather be dead than live without testosterone. He has never brought the subject up again. 14 years later, I certainly don't regret my decision to continue the TRT.

With a history of DVT, if you are just looking to jack up your testosterone even though your natural level is normal or near-normal, then I say it is contraindicated. If your endogenous testosterone is low and it is drastically affecting your quality of life, then you have to decide if the benefits outweigh the risks? I would rather live a shorter happy life than live a long miserable life.

 

[Kevin Moseley]

IWhen my T was low, not only did I have no libido but I was severely depressed, constantly fatigued, suffered from constant panic attacks and anxiety to the point my life was miserable.

Wow. That describes me to a T. I have my first injection tomorrow.

With my first injection of T, I was a changed man and none of those symptoms have ever reoccurred.

I am hoping I will be saying that in the not too distant future.

I would rather live a shorter happy life than live a long miserable life.

Ditto.

 

[Marco N Cognito]

We have not been able to determine an exact cause of the clots in either case, although I do show +/+ (homozygous) for the MTHFR C667T gene mutation, but homocysteine was normal (7.0), and am +/- (heterozygous) for PAI-1 gene mutation.
All of the other genetic tests known to cause thrombosis resulted in negatives (Lupus Anticogulant, Anticardiolipin antibodies, Antiphospholipid antibodies, Leukemia, Lymphoma, Factor XI, APOE E mutation, protein C, S, prothrombin 20210A, PNH, Factor V Leiden). I was also not on any testosterone replacement during the time of the clots nor when these labs were drawn:

Following are my ultrasound reports from my two separate thromboses which occurred in 2012, one in each leg (they both cleared within a couple weeks with no further incidence or symptoms; I was on warfarin for the first one for 4 mos. and then stopped).

Non-Occlusive DVT:
https://app.box.com/s/icyio8g4qqs1a0t513pn
Occlusive superficial VT:
https://app.box.com/s/pwcbckxc9v5x89olzz4m

The factors that are showing increased elevation since the two 2012 episodes are:
d-dimer: 1.2 in Nov. '12; 0.80 in Sept. '13; 0.50 in Nov. '13 - ref range: 0.0 − 0.4ug FEU/mL
Factor XII: 197 in July '13; 180 in Sep. '13 - ref range: 50 − 150%
Factor V: 141 in Sept. '13; 113 in Nov. '13 - ref range: 60 − 140%
Factor VIII: 171 in Nov. '12; 191 in Sept. '13; 122 in Nov '13 - ref range: 50 − 150%
Factor XII: 197 in July '13; 180 in Sept. '13 - ref range: 50 − 150%
von Willebrand Factor: 206 in Sept. '13; 169 in Nov. '13 - ref range: 50 − 150%

When I asked my hematologist's opinion on these out of range levels, his answer was that there are "not clinically significant." His answer is based on his opinion that it's unnecessary to anticoagulate in the absence of a DVT.

My HCT (43.30) and HGB (13.70) are normal and I have the APO E 3/3 genotype.
My Lp(a) level recently increased also: 124 on Nov. '13 (I have read that Lp(a) can be thrombogenic itself)
My estradiol is currently very low: 5.0 on Nov. '13 (I could actually use some testosterone!)
During the period in which my thromboses occurred my estradiol was the following:
March, '12: <11.80
Nov. '12: 10.0

Dr. Glueck's advice was the following:
"Current practice suggests that any one with two thrombotic events, irrespective of etiology, should be anticoagulated for life. Of the clotting tests which look significant to me, there are two Factor VIII levels which would be high by our lab standards, and the von Willebrand's factor, which is just another way of measuring Factor VIII was also high. There is also a controversy in the literature whether MTHFR C677T homozygosity with normal homocysteine levels might be thrombophilic."

He further suggested Xarelto would be more efficient in preventing clots than the older anticoagulants.

 

[Marco N Cognito]

I have been on TRT since 1993, since my own testicles stopped all production of testosterone at age 45.

I had a DVT (deep venous thrombosis) when I had a PICC line for antibiotics in 2007. Same vein as the line so likely caused by the line. Treated with Coumadin for 6 months and the clot resolved. I have remained on TRT continuously since 1993. 3 years ago I added Arimidex due to high estrogen levels.

I have never had another DVT. I have had to have 3 coronary stents placed due to artery stenosis since 2000, but I have a horrible familial history of coronary artery disease. So I don't know if my CAD can be blamed on the TRT?

I know my quality of life is greatly enhanced from the TRT as I well recall how miserable life was when I had no testosterone in my body. You have to weigh the risk vs. the benefits. When my T was low, not only did I have no libido but I was severely depressed, constantly fatigued, suffered from constant panic attacks and anxiety to the point my life was miserable. With my first injection of T, I was a changed man and none of those symptoms have ever reoccurred. To me it is not even a question as whether to continue the TRT. When my Cardiologist demanded I stop the TRT in 2000, following my first stent, I plainly told him I would rather be dead than live without testosterone. He has never brought the subject up again. 14 years later, I certainly don't regret my decision to continue the TRT.

With a history of DVT, if you are just looking to jack up your testosterone even though your natural level is normal or near-normal, then I say it is contraindicated. If your endogenous testosterone is low and it is drastically affecting your quality of life, then you have to decide if the benefits outweigh the risks? I would rather live a shorter happy life than live a long miserable life.

Good points, although in my case, my clots are idiopathic (unknown cause at this point) which means they could be either familial or acquired. Although my last total T is low normal (mid 400s), my free T (the one that matters) is in the dumps @ 5.3 (ref rand 7.2-46.0ng/dL). I have a scrip waiting for me, but have been holding off because of this concern. My use of T would not be just to boost levels, but to enhance the quality of life in many ways.


He seems to be very set in his ways with respect to TRT:

"There are 3 recent trials (cf vigen, JAMA 2014, Finkle 2014, Basaria 2011) which show that compared to no testosterone, testosterone supplementation is associated with a highly significant increase in all cause mortality and CVD mortality. There is no recent data to indicate that even in hypogonadal men, T therapy reduces morbidity and mortality, only that it increases it."

I think many of us would disagree.

 

[Nelson Vergel]

A case report just published by Glueck

Blood Coagulation & Fibrinolysis:
April 2014 - Volume 25 - Issue 3 - p 286-288
doi: 10.1097/MBC.0000000000000047
Case Reports

Testosterone, anastrozole, factor V Leiden heterozygosity and osteonecrosis of the jaws, Ramesh S.; Glueck, Charles J.




Our specific aim is to describe the development of thrombotic osteonecrosis of the jaws after testosterone diagnosed factor V Leiden heterozygosity. Before the diagnosis of V Leiden heterozygosity, he was given testosterone gel, 50mg/day, and on testosterone, serum testosterone (963ng/dl) and estradiol were high (50pg/ml). Anastrozole was started, and testosterone was continued. Six months later, osteonecrosis of the jaws was diagnosed. Exogenous testosterone is aromatized to estradiol and estradiol-induced thrombophilia, when superimposed on underlying familial thrombophilia, as in this case, may lead to thrombosis and osteonecrosis. We recommend that before giving testosterone, at a minimum, screening for the factor V Leiden and G20210A mutations, and factor VIII and XI activity be carried out, to avoid unanticipated thrombosis.

 

[Marco N Cognito]

A case report just published by Glueck

Blood Coagulation & Fibrinolysis:
April 2014 - Volume 25 - Issue 3 - p 286-288
doi: 10.1097/MBC.0000000000000047
Case Reports

Testosterone, anastrozole, factor V Leiden heterozygosity and osteonecrosis of the jaws

Pandit, Ramesh S.; Glueck, Charles J.






Abstract



Our specific aim is to describe the development of thrombotic osteonecrosis of the jaws after testosterone&#8211;anastrozole therapy in a 55-year-old white man subsequently found to have previously undiagnosed factor V Leiden heterozygosity. Before the diagnosis of V Leiden heterozygosity, he was given testosterone gel, 50&#8202;mg/day, and on testosterone, serum testosterone (963&#8202;ng/dl) and estradiol were high (50&#8202;pg/ml). Anastrozole was started, and testosterone was continued. Six months later, osteonecrosis of the jaws was diagnosed. Exogenous testosterone is aromatized to estradiol and estradiol-induced thrombophilia, when superimposed on underlying familial thrombophilia, as in this case, may lead to thrombosis and osteonecrosis. We recommend that before giving testosterone, at a minimum, screening for the factor V Leiden and G20210A mutations, and factor VIII and XI activity be carried out, to avoid unanticipated thrombosis.

Thanks for the update, Nelson.

Through my exhaustive testing, I have determined I have familial high Factor VIII which predisposes me to clots regardless of T or not. It seems even clearer now that the blame for thrombotic events for those with acquired or genetic thrombophilia can be put squarely on elevated E2. In this case, even Arimidex did not stop the damage already done. And the problem is that Arimidex itself, according to Glueck, is thrombogenic. This goes for all prescription AIs. There needs to be a potent enough non-thrombogenic AI that will work safely to counter this conversion. For now, the only AIs that I can think of that will not put men at risk would be OTC. Calcium-d-glucarate may hold promise, but there is no research to prove this.

 

[Dr. John Crisler]

"1-2% of men taking T will develop blood clots related to underlying inherited clotting abnormalities or to acquired thrombophilia (the antiphospholipid antibody syndrome)."

I have not seen a single case of this in a dozen years of prescribing TRT, including use of anastrazole, on a daily basis.

One patient has suffered a heart attack, a Type II diabetic who once weighed 350lbs (now a svelt 185#).

 

[Nelson Vergel]

Yes, I agree. 1-2 percent incidence is so low that it does not justify spending money for those expensive genetic tests unless the man had a thrombotic event in the past.

 

[Marco N Cognito]

This is a tough call, IMO. Even the though the risk is minute, it's still a risk and I think should be ruled out before just jumping on TRT and finding out after the fact when it may be too late.

 

[Marco N Cognito]

"1-2% of men taking T will develop blood clots related to underlying inherited clotting abnormalities or to acquired thrombophilia (the antiphospholipid antibody syndrome)."

I have not seen a single case of this in a dozen years of prescribing TRT, including use of anastrazole, on a daily basis.

One patient has suffered a heart attack, a Type II diabetic who once weighed 350lbs (now a svelt 185#).

That's good to know. What would be your thoughts or approach as to how TRT could be safely implemented, if at all, in one that is clearly hypogonadal and could benefit but has a history of thrombosis and likely familial thrombophilia? I know of two guys, one with Factor V Leiden and a prothrombin defect, and the other, with elevated Factor VIII, both on TRT for years and no problems, as they are careful to watch their E2, HGB, HCT from getting out of hand, and get phlebs as needed.

 

[Dr. John Crisler]

How much faith do we have in the 1-2% incidence claim?

IF there is going to be an issue, he says it will show up in the first 3 months.

This sure does warrant an additional two questions on Medical History (personal and Family Medical History).

 

[Dr. John Crisler]

That's good to know. What would be your thoughts or approach as to how TRT could be safely implemented, if at all, in one that is clearly hypogonadal and could benefit but has a history of thrombosis and likely familial thrombophilia? I know of two guys, one with Factor V Leiden and a prothrombin defect, and the other, with elevated Factor VIII, both on TRT for years and no problems, as they are careful to watch their E2, HGB, HCT from getting out of hand, and get phlebs as needed.

I always have monitored the CBC.

 

[Marco N Cognito]

I always have monitored the CBC.

As for E2 management, the problem is that, according to Glueck, all of the prescription AIs are as thrombogenic as exo T which on one hand will help control E2 (his warning of >42), but on the other, could also predispose to DVT/PE. The only solution I can think of would be a OTC E2 blocker like calcium-d-glucarate.

 

[Dr. John Crisler]

As for E2 management, the problem is that, according to Glueck, all of the prescription AIs are as thrombogenic as exo T which on one hand will help control E2 (his warning of >42), but on the other, could also predispose to DVT/PE. The only solution I can think of would be a OTC E2 blocker like calcium-d-glucarate.

Have they been shown to be so in adult males? Or is he extrapolating?

All these years, hundreds of patients, and not a single event while on Arimidex.

 

[Marco N Cognito]

Have they been shown to be so in adult males? Or is he extrapolating?

All these years, hundreds of patients, and not a single event while on Arimidex.

Here are the main takeaways I gleaned from Glueck's emails:

1. On the basis of our published data, when a patient has a major gene familial thrombophilia like V Leiden or Prothrombin gene heterozygosity, or familial high Factors VIII or XI, or acquired thrombophilia (lupus anticoagulant, anti phospholipid antibody syndrome), exogenous testosterone appears to be contraindicated absolutely, irrespective of the E2 level, although most events occurr when E2 is >42.6.

2. We have 10 cases with major gene thrombophilia fully anticoagulated with warfarin who had second or even third thrombotic events when exogenous T therapy was continued.

3. We have one case (not yet published but soon in Blood Coag Fibrinolysis) where arimidex by itself caused thrombosis in a V Leiden heterozygote.

4. All of the anti-estrogens are reported to be thrombogenic. Tamoxifen is the most thrombogenic, but all of the others are clearly thrombogenic, but only confer about half of the thrombogenic risk of tamoxifen.

5. Clomid and hCG are known to increase thrombotic events, both in men and women.

6. Several studies (Svartbarg, Tromso) have shown that endogenous T throughout its distribution (particularly on the high end) is NOT associated with thrombotic events.

7. T increases platelet aggregation and increases viscosity. As T is aromatized to E2 , E2 then increases resistance to activated protein C and increases clotting. In patients with hypogonadotrophic hypogonadism, plasminogen activator inhibitor is low, and is modestly increased by TT

8. In our cases with thrombosis, NONE of them had high rbc hct hgb; the thrombogenic effects of TRT in our research are theorized to be predominantly E2-mediated and is entirely independent of the added risk of polycythemia.

 

[Nelson Vergel]

More great information about testosterone replacement, HCG, testicular function, estradiol, anastrozole, exercise, nutrition and supplements:

 

[Nelson Vergel]

To to Dr Glueck's research, the FDA added this warning to testosterone package insert labels:

FDA adding general warning to testosterone products about potential for venous blood clots


[06/19/2014] The U.S. Food and Drug Administration (FDA) is requiring manufacturers to include a general warning in the drug labeling of all approved testosterone products about the risk of blood clots in the veins. Blood clots in the veins, also known as venous thromboembolism (VTE), include deep vein thrombosis (DVT) and pulmonary embolism (PE). The risk of venous blood clots is already included in the labeling of testosterone products as a possible consequence of polycythemia, an abnormal increase in the number of red blood cells that sometimes occurs with testosterone treatment. Because there have been postmarket reports of venous blood clots unrelated to polycythemia, FDA is requiring a change to drug labeling of all testosterone products to provide a more general warning regarding venous blood clots and to ensure this risk is described consistently in the labeling of all approved testosterone products.

Because these clots occur in the veins, this new warning is not related to FDA's ongoing evaluation of the possible risk of stroke, heart attack, and death in patients taking testosterone products. We are currently evaluating the potential risk of these cardiovascular events, which are related to blood clots in the arteries and are described in the (link removed)
Testosterone products are FDA-approved for use in men who lack or have low testosterone levels in conjunction with an associated medical condition. Examples of these conditions include failure of the testicles to produce testosterone for reasons such as genetic problems or chemotherapy.

FDA asks health care professionals and consumers to report any adverse reactions to the FDA's MedWatch Safety Information and Adverse Event Reporting program:
Complete and submit the report online at MedWatch Voluntary Reporting Form

Download and complete the form, then submit it via fax to 1-800-FDA-0178