Re: Testosterone treatment and risk of venous thromboembolism: population based case-control study
We read with interest the recent case-control study by Martinez et al, comparing rates of testosterone therapy between men with diagnoses of venous thromboembolism (VTE) and matched controls.1 The authors found significantly higher testosterone use among men with venous thromboembolism, largely driven by initial six months of use. These findings will add to the contentious topic of testosterone treatment – a therapy, which has ballooned in use over recent decades for “lifestyle purposes” despite considerable controversy about potential risks. With that said, we do have some comments about this study and its methods.
Most importantly, the authors mention the possibility of “differential identification”—that men using testosterone could have more opportunities to be diagnosed with venous thromboembolism but then state that this is “unlikely to be the case and is unlikely to alter the study findings.” We would argue that men pursuing testosterone therapy for lifestyle purposes could easily have increased opportunities for identification of venous thromboembolism. For example, men who seek out testosterone therapy may visit physicians more often, and may be more likely to seek out diagnostic tests or interventions for symptoms, which could be caused by venous thromboembolism. Perhaps controlling for number of physician visits would allow this to be addressed—a feasible statistical approach. Perhaps further exacerbating this, the study years encompass a period where a link between VTE and testosterone was suspected. Thus, conscientious physicians treating men using testosterone replacement could be more likely to order diagnostic tests or examinations that would identify blood clots.
Second, the authors point out that the rate ratio for men with pathological hypogonadism was not significant for VTE. It is only among those without hypogonadism that an elevated rate ratio was seen. It is not immediately clear why this would be the case, perhaps men with hypogonadism had more physiologic androgen levels while undergoing testosterone treatment? Without information on serum androgen levels it is difficult to say whether this is the case. Presumably the men in this study with and without encompass a wide range of hypogonadal and eugonadal states –information on serum androgen levels both pre and post treatment would help physicians counseling patients on whether to use these medications.
Regardless, professional guidelines agree that it is generally men with hypogonadism who should be receiving testosterone therapy.2 Fewer clinicians would argue that eugonadal men should be getting testosterone therapy –yet it is only among these men that increased rate ratios were seen.
Finally, there are well known limitations in using administrative data for identification of venous thromboembolism.3 4 The authors address this by using a previously validated tool for identifying venous thromboembolism, which appears to have good accuracy within the British database they employed.5 However, the accuracy for diagnoses of hypogonadism and for accurately capturing testosterone prescriptions is less clear. Given the common use of mail order and compounding pharmacies for testosterone replacement could some testosterone prescriptions have been missed from these data? Further, given the complexity involved in appropriately diagnosing hypogonadism, these pathological states could easily be over or under-diagnosed using administrative measures.
Ultimately, this study adds to the vigorous debate on the risks of testosterone therapy. There is no question that testosterone use probably exceeds what is medically necessary and may come with significance harms. However, we would argue that the above issues might limit the relevance of this study’s results for men with true hypogonadism, considering testosterone therapy. Ultimately, prospective, population-based cohorts of men using testosterone therapy will be vital for assessing the absolute and relative risk of VTE and may provide the key information for men deciding whether to start testosterone therapy.
1. Martinez C, Suissa S, Rietbrock S, et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. Bmj 2016;355:i5968.
2. Seftel AD, Kathrins M, Niederberger C. Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systematic Analysis. Mayo Clinic proceedings 2015;90(8):1104-15.
3. Lawson EH, Louie R, Zingmond DS, et al. A comparison of clinical registry versus administrative claims data for reporting of 30-day surgical complications. Annals of surgery 2012;256(6):973-81.
4. Lawson EH, Zingmond DS, Hall BL, et al. Comparison between clinical registry and medicare claims data on the classification of hospital quality of surgical care. Annals of surgery 2015;261(2):290-6.
5. Martinez C, Cohen AT, Bamber L, et al. Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost 2014;112(2):255-63.
Competing interests:
No competing interests
13 December 2016
Alexander P Cole
Resident Physician
Maxine Sun, Quoc-Dien Trinh
Division of Urological Surgery, Center for Surgery and Public Health, Brigham and Women's Hospital, Harvard Medical School
Rapid Response:
Re: Testosterone treatment and risk of venous thromboembolism: population based case-control study
We read with interest the recent case-control study by Martinez et al, comparing rates of testosterone therapy between men with diagnoses of venous thromboembolism (VTE) and matched controls.1 The authors found significantly higher testosterone use among men with venous thromboembolism, largely driven by initial six months of use. These findings will add to the contentious topic of testosterone treatment – a therapy, which has ballooned in use over recent decades for “lifestyle purposes” despite considerable controversy about potential risks. With that said, we do have some comments about this study and its methods.
Most importantly, the authors mention the possibility of “differential identification”—that men using testosterone could have more opportunities to be diagnosed with venous thromboembolism but then state that this is “unlikely to be the case and is unlikely to alter the study findings.” We would argue that men pursuing testosterone therapy for lifestyle purposes could easily have increased opportunities for identification of venous thromboembolism. For example, men who seek out testosterone therapy may visit physicians more often, and may be more likely to seek out diagnostic tests or interventions for symptoms, which could be caused by venous thromboembolism. Perhaps controlling for number of physician visits would allow this to be addressed—a feasible statistical approach. Perhaps further exacerbating this, the study years encompass a period where a link between VTE and testosterone was suspected. Thus, conscientious physicians treating men using testosterone replacement could be more likely to order diagnostic tests or examinations that would identify blood clots.
Second, the authors point out that the rate ratio for men with pathological hypogonadism was not significant for VTE. It is only among those without hypogonadism that an elevated rate ratio was seen. It is not immediately clear why this would be the case, perhaps men with hypogonadism had more physiologic androgen levels while undergoing testosterone treatment? Without information on serum androgen levels it is difficult to say whether this is the case. Presumably the men in this study with and without encompass a wide range of hypogonadal and eugonadal states –information on serum androgen levels both pre and post treatment would help physicians counseling patients on whether to use these medications.
Regardless, professional guidelines agree that it is generally men with hypogonadism who should be receiving testosterone therapy.2 Fewer clinicians would argue that eugonadal men should be getting testosterone therapy –yet it is only among these men that increased rate ratios were seen.
Finally, there are well known limitations in using administrative data for identification of venous thromboembolism.3 4 The authors address this by using a previously validated tool for identifying venous thromboembolism, which appears to have good accuracy within the British database they employed.5 However, the accuracy for diagnoses of hypogonadism and for accurately capturing testosterone prescriptions is less clear. Given the common use of mail order and compounding pharmacies for testosterone replacement could some testosterone prescriptions have been missed from these data? Further, given the complexity involved in appropriately diagnosing hypogonadism, these pathological states could easily be over or under-diagnosed using administrative measures.
Ultimately, this study adds to the vigorous debate on the risks of testosterone therapy. There is no question that testosterone use probably exceeds what is medically necessary and may come with significance harms. However, we would argue that the above issues might limit the relevance of this study’s results for men with true hypogonadism, considering testosterone therapy. Ultimately, prospective, population-based cohorts of men using testosterone therapy will be vital for assessing the absolute and relative risk of VTE and may provide the key information for men deciding whether to start testosterone therapy.
1. Martinez C, Suissa S, Rietbrock S, et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. Bmj 2016;355:i5968.
2. Seftel AD, Kathrins M, Niederberger C. Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systematic Analysis. Mayo Clinic proceedings 2015;90(8):1104-15.
3. Lawson EH, Louie R, Zingmond DS, et al. A comparison of clinical registry versus administrative claims data for reporting of 30-day surgical complications. Annals of surgery 2012;256(6):973-81.
4. Lawson EH, Zingmond DS, Hall BL, et al. Comparison between clinical registry and medicare claims data on the classification of hospital quality of surgical care. Annals of surgery 2015;261(2):290-6.
5. Martinez C, Cohen AT, Bamber L, et al. Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost 2014;112(2):255-63.
Competing interests: No competing interests