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

[Kushman42]

That is very interesting information.

 

[JPB]

Age 58, I am not on TRT. My therapy for hormones the last several years consisted of Clomid and growth hormone peptides. Approx. 1 year ago I had injured my leg and subsequently developed a clot (popliteal vein). I was put on Xarelto, three months later the clot was gone and I got off the Xarelto. I had got off the Clomid when clot was diagnosed. When the clot cleared at some point I resumed Clomid and growth peptides. This past week I rapidly developed symptoms in the same spot and was diagnosed again with a DVT in the popliteal vein and was started on Eliquis, since I did not want the Xarelto again. Will be talking to my doc about more detailed testing. At this point I am blaming things on the original injury and the Clomid. I'm not telling my doc about the Clomid since he told me to stay off it. But I do think the estrogens it produces are probably partly at blame. Hopefully can get the tests recommended by Dr. Glueck to help figure this out.

 

[easternpromise]

Looking at studies post 2014 shows no correlation between trt use and thrombosis. Texas study in 2015, u.s. chest physicians study, etc etc. I feel like one study showing it's true is not enough to warrant such anxiety and fear. Technically there are more studies showing no correlation then there are showing correlation. Reminds me of the studies on weather trt induces heart attacks, there were one or two which led to fear in the media, later those studies were shown to be inconclusive.

 

[Nelson Vergel]

I agree with you, easternpromise.

 

[easternpromise]

I agree with you, easternpromise.

I enjoy reading all the debate and the studies. I'm fascinated by medical science, and how much work it takes to conclusively correlate something. I think in some cases it may be impossible

 

[vood13]

I agree with you, easternpromise.

So, would it make sense that my trt doc suggests stopping TRT based on having FVL, but, with NO thrombosis event ever occurring?

 

[Nelson Vergel]

Aging (Albany NY). 2018 May 2;10(5):902-929. doi: 10.18632/aging.101438.

Testosterone and dihydrotestosterone reduce platelet activation and reactivity in older men and women.

Karolczak K1, Konieczna L2, Kostka T3, Witas PJ1, Soltysik B3, Baczek T2, Watala C1.

Author information
1
Department of Haemostatic Disorders, Medical University, Lodz, Poland.
2
Department of Pharmaceutical Chemistry, Medical University of Gdansk, Gdansk, Poland.
3
Department of Geriatrics, Healthy Ageing Research Centre (HARC), Medical University, Lodz, Poland.

Abstract

The cardiovascular effects of testosterone and dihydrotestosterone are generally attributed to their modulatory action on lipid and glucose metabolism. However, no ex vivo studies suggest that circulating androgen levels influence the activation and reactivity of blood platelets - one of the main components of the haemostasis system directly involved in atherosclerosis. The levels of testosterone, dihydrotestosterone and oestradiol in plasma from men and women aged from 60 to 65 years were measured by LC-MS; the aim was to identify any potential relationships between sex steroid levels and the markers of platelet activation (surface membrane expression of GPII/IIIa complex and P-selectin) and platelet reactivity in response to arachidonate, collagen or ADP, monitored with whole blood aggregometry and flow cytometry. The results of the ex vivo part of the study indicate that the concentrations of testosterone and its reduced form, dihydrotestosterone are significantly negatively associated with platelet activation and reactivity. These observations were confirmed in an in vitro model: testosterone and dihydrotestosterone significantly inhibited platelet aggregation triggered by arachidonate or collagen. Our findings indicate that testosterone and dihydrotestosterone are significant haemostatic steroids with inhibitory action on blood platelets in older people.

 

[Nelson Vergel]

More from Glueck

J Investig Med. 2018 Apr;66(4):733-738. doi: 10.1136/jim-2017-000637. Epub 2017 Dec 15.


Thromboembolism peaking 3 months after starting testosterone therapy: testosterone-thrombophilia interactions.

Glueck CJ1, Goldenberg N1, Wang P1.

Abstract

We assessed time of thrombotic events (venous thromboembolism (VTE)) after starting testosterone therapy (TT) in 21 men who sustained 23 VTE. The density of thrombotic events was greatest at 3 months after starting TT, with a rapid decline in events by 10 months. The 21 cases with VTE on TT differed from 110 patient controls with unprovoked VTE, not taking TT (VTE-no TT) for Factor V Leiden heterozygosity (FVL) (33 per cent vs 13 per cent, P=0.037), for high lipoprotein (a) (Lp(a)) (55 per cent vs 17 per cent, P=0.012), and for the lupus anticoagulant (33 per cent vs 4 per cent, P=0.003). These differences between cases and VTE-no TT controls were independent of age and gender. TT can interact with underlying thrombophilia-hypofibrinolysis promoting VTE. We suggest that TT should not be started in subjects with known thrombophilia. Coagulation screening, particularly for the FVL , Lp(a), and the lupus anticoagulant should be considered before starting TT, to identify men at high VTE risk who have an adverse risk/benefit ratio for TT.



KEYWORDS:
pulmonary embolism; testosterone; thromboembolism; thrombophilia; thrombosis

 

[Marco N Cognito]

More from Glueck

J Investig Med. 2018 Apr;66(4):733-738. doi: 10.1136/jim-2017-000637. Epub 2017 Dec 15.


Thromboembolism peaking 3 months after starting testosterone therapy: testosterone-thrombophilia interactions.

Glueck CJ1, Goldenberg N1, Wang P1.

Abstract

We assessed time of thrombotic events (venous thromboembolism (VTE)) after starting testosterone therapy (TT) in 21 men who sustained 23 VTE. The density of thrombotic events was greatest at 3 months after starting TT, with a rapid decline in events by 10 months. The 21 cases with VTE on TT differed from 110 patient controls with unprovoked VTE, not taking TT (VTE-no TT) for Factor V Leiden heterozygosity (FVL) (33 per cent vs 13 per cent, P=0.037), for high lipoprotein (a) (Lp(a)) (55 per cent vs 17 per cent, P=0.012), and for the lupus anticoagulant (33 per cent vs 4 per cent, P=0.003). These differences between cases and VTE-no TT controls were independent of age and gender. TT can interact with underlying thrombophilia-hypofibrinolysis promoting VTE. We suggest that TT should not be started in subjects with known thrombophilia. Coagulation screening, particularly for the FVL , Lp(a), and the lupus anticoagulant should be considered before starting TT, to identify men at high VTE risk who have an adverse risk/benefit ratio for TT.



KEYWORDS:
pulmonary embolism; testosterone; thromboembolism; thrombophilia; thrombosis

I can't believe that after 5 years, his assessments remain a one-way ticket to another dead end: staying hypogonadal which is no better option. Also, T reduces Lp(a): Testosterone-induced suppression of lipoprotein(a) in normal men; relation to basal lipoprotein(a) level. - PubMed - NCBI
To the contrary:
https://www.sciencedirect.com/science/article/pii/S0090429518312007

 

[Nelson Vergel]

Testosterone replacement therapy and the risk of venous thromboembolism: A systematic review and meta-analysis of randomized controlled trials - PubMed

Our systematic review suggests that TRT is not associated with an increased risk of VTE. However, estimates were accompanied by a wide 95% CIs, and a clinically important increased risk cannot be ruled out.

pubmed.ncbi.nlm.nih.gov

 

[Nelson Vergel]

Testosterone therapy increases the anticoagulant potential in men with opioid-induced hypogonadism: a randomized, placebo-controlled study

INTRODUCTION
Hypogonadism is prevalent during opioid treatment and low testosterone concentrations are associated with cardiovascular disease. The effect of testosterone replacement therapy (TRT) on the coagulation system in men with hypogonadism is not clarified. We investigate effects of TRT on the tissue factor (TF) and contact activation pathways of coagulation in opioid treated men.


MATERIALS AND METHODS
Double-blinded, placebo-controlled study in 37 men with total testosterone < 12 nmol/l randomized to 24 weeks of testosterone injections (n = 17) or placebo (n = 20). Variables of the coagulation system were analysed at baseline and after 24 weeks. Measurements included the TF pathway (endogenous thrombin potential (ETP), peak thrombin), the contact activation pathway (endogenous kallikrein potential (EKP), peak kallikrein), coagulation factors (FVII, FX, prothrombin, FXII), and inhibitors (tissue factor pathway inhibitor (TFPI), protein C, protein S, antithrombin, C1 esterase inhibitor (C1inh)). Between-group differences at 24 weeks were determined with analysis of covariance. Within-group changes in TRT and placebo were analysed with paired t-test.


RESULTS
Between-group differences at 24 weeks were observed for ETP (p = 0.036), FVII (p = 0.044), FX (p = 0.015), prothrombin (p = 0.003), protein C (p = 0.004), and protein S (p = 0.038). Within the TRT group, ETP, peak thrombin, FVII, FX, prothrombin, TFPI, protein C, FXII, and C1inh decreased and protein S increased (all p < 0.05). Within the placebo group, coagulation outcomes were unchanged.


CONCLUSION
TRT affects the coagulation system in an anticoagulant direction through suppressed TF pathway in men with opioid-induced hypogonadism.

Source: Testosterone therapy increases the anticoagulant potential in men with opioid-induced hypogonadism: a randomized, placebo-controlled study - PubMed

 

[J2048b]

I do believe the good doc has since retired? If so who took over for him? Last i heard it was his daughter, perhaps?

I tried emailing him but never received a reply….

 

[Nelson Vergel]

I do believe the good doc has since retired? If so who took over for him? Last i heard it was his daughter, perhaps?

I did not know. Some believe he created an irrational fear that made the FDA add a black box warning on every testosterone product package insert.

 

[Nelson Vergel]

According to the provided web search results, the FDA has issued multiple black box warnings for testosterone products. Here are the details on when each warning was added:

1. Cardiovascular Risk: The FDA issued a safety communication about the cardiovascular risk associated with testosterone products on March 3, 2015. [1]
2. Abuse and Dependence: The FDA approved class-wide labeling changes for all prescription testosterone products, adding a new warning and updating the abuse and dependence information on October 25, 2016. [2]
3. Prostate Cancer: None of the provided search results mentioned a black box warning specifically related to prostate cancer for testosterone products.
4. Blood Clots: In response to studies showing the risk of blood clots, stroke, heart attack, and death associated with testosterone therapy, Public Citizen filed a petition to the FDA on February 25, 2014, demanding the agency immediately require a black-box warning for cardiovascular risks on all testosterone therapy drugs. However, it is not clear from the provided search results whether the FDA ever issued a black box warning specifically related to blood clots for testosterone products. [3, 4]
5. Children's Risk: The FDA ordered a black box warning for the risk that testosterone gel products pose to children inadvertently exposed to those products by adults on May 7, 2009. [5]

 

[J2048b]

I did not know. Some believe he created an irrational fear that made the FDA add a black box warning on every testosterone product package insert.

So i have some questions in regards to that statement and the doc

Do u believe he did this? If he did why??

So Now im confused… was he saying u have less risk of blood clots and cardiovascular risks on testosterone OR was he saying its highly likely it can lead to these issues??

 

[Nelson Vergel]

TO YOUR GOOD HEALTH: Men with factor V Leiden can still receive testosterone therapy

DEAR DR. ROACH: I have factor V Leiden, but I have been wanting to do testosterone replacement therapy. I have heard that testosterone causes blood clots. Obviously, with FVL, that

www.mycouriertribune.com

 

[RustyBear]

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

View attachment 538
View attachment 539
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.

View attachment 537

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

Detailed interview and well article, thank you Nelson and the good. Doctor. 41 yrs immune compromised an 33 yrs on HRT, you have to know your labs, and limits. You eat the American diet of ooee-gooee, drippy sugary, and smear Androgel all over yourself but go to the gym, in long run you may look on the surface like the muscle bear of the year; but one sunny day, there's this strange pain and your breathing is all screwed up.
You have to set limits in lifestyle, it's not the end of world to skip 5 days of HRT or even more, till your labs and heart rate are normal all day long, and not just one measurement rising out of bed. As for the ooyee gooyee sugary salty American diet, you don't need a double blind gazillion dollar NIH study, just Miranda around your local Wal-Mart and take in the sights the heifers and blood clots are everywhere.