Testosterone treatment and risk of venous thromboembolism

Population based case-control study, The BMJ, November 2016

image of venous thromboembolism


To determine the risk of venous thromboembolism associated with use of testosterone treatment in men, focusing particularly on the timing of the risk.

Population based case-control study

370 general practices in UK primary care with linked hospital discharge diagnoses and in-hospital procedures and information on all cause mortality.

Testosterone treatment and risk of venous thromboembolism: population based case-control study, The BMJ 2016;355:i5968, 30 November 2016.

19 215 patients with confirmed venous thromboembolism (comprising deep venous thrombosis and pulmonary embolism) and 909 530 age matched controls from source population including more than 2.22 million men between January 2001 and May 2013.

Exposure of interest
Three mutually exclusive testosterone exposure groups were identified: current treatment, recent (but not current) treatment, and no treatment in the previous two years. Current treatment was subdivided into duration of more or less than six months.

Main outcome measure
Rate ratios of venous thromboembolism in association with current testosterone treatment compared with no treatment were estimated using conditional logistic regression and adjusted for comorbidities and all matching factors.

The adjusted rate ratio of venous thromboembolism was 1.25 (95% confidence interval 0.94 to 1.66) for current versus no testosterone treatment. In the first six months of testosterone treatment, the rate ratio of venous thromboembolism was 1.63 (1.12 to 2.37), corresponding to 10.0 (1.9 to 21.6) additional venous thromboembolisms above the base rate of 15.8 per 10 000 person years. The rate ratio after more than six months’ treatment was 1.00 (0.68 to 1.47), and after treatment cessation it was 0.68 (0.43 to 1.07). Increased rate ratios within the first six months of treatment were observed in all strata: the rate ratio was 1.52 (0.94 to 2.46) for patients with pathological hypogonadism and 1.88 (1.02 to 3.45) for those without it, and 1.41 (0.82 to 2.41) for those with a known risk factor for venous thromboembolism and 1.91 (1.13 to 3.23) for those without one.

Starting testosterone treatment was associated with an increased risk of venous thromboembolism, which peaked within six months and declined thereafter.

2 thoughts on “Testosterone treatment and risk of venous thromboembolism”

  1. “Cases were more often obese (body mass index ≥30: 27.0% v 20.6%) and had more comorbidities, notably polycythaemia, chronic pulmonary disease, congestive heart failure, myocardial infarction, and peripheral vascular disease than did the controls. Additionally, corticosteroids, non-steroidal anti-inflammatory drugs, and antiplatelets were used more frequently among cases than controls (table 1⇓).”

    On average, men who are given TRT tend to be sicker than age matched controls. This is hardly surprising, because chronic low testosterone damages your health! Furthermore, it’s very difficult to be placed on TRT in the UK, and you have to be severely hypogonadal before you have any chance of receiving treatment. What this means is that the people in their treatment group will have likely been suffering severe testosterone depletion for quite some time, and have problems with their health as a result. Those problems won’t necessarily immediately go away once treatment is commenced, so it wouldn’t be at all surprising to see an elevated risk of health problems vs controls for the first several months of treatment.

    Another thing is that the treatment they tend to use in the UK, Nebido, is pretty crappy from what I’ve heard. It’s an injection of long acting testosterone esters that (I think) is usually given at 3 month intervals. Even though the testosterone ester used (testosterone undecanoate) is supposed to have a long biological half life, they’ve nonetheless stretched out the injection intervals a very long way, and it leads to big swings in T levels. After each injection is administered, T is at supraphysiological levels for the first couple of weeks, which leads to very high rates of aromatization to estradiol (and probably downregulates androgen receptor expression too). As time goes by, T levels progressively fall, and near the due date for the next injection, they’ve fallen to the point where there’s a high likelihood of symptoms of hypogonadism re-emerging. This produces very poor results for the patient, who is likely to experience a lot of unpleasant side effects from estrogen excess for a couple of weeks after the injection, and then start experiencing depression, fatigue etc due to low T in the last couple of weeks before the next injection is due.

    Aside from giving the patient an unpleasant physical and emotional roller coaster ride, these big swing in hormone levels aren’t natural, and probably increase the likelihood of the patient experiencing adverse health events. So I wouldn’t read too much into this study, other than that HRT for both men and women in the UK has a great deal of room for improvement!

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