Venous thromboembolism

The reason testosterone-induced erythrocytosis is a safety concern is that erythrocytosis caused by polycythemia vera – a blood cancer in which the bone marrow produces an excessive amount of red blood cells - increases risk of thrombotic and cardiovascular events. However, no single testosterone therapy study has shown that testosterone-induced erythrocytosis is associated with thromboembolism. The studies showing that erythrocytosis increases risk of thromboembolism were done in populations with polycythemia vera. Nevertheless, hematocrit/erythrocytosis should be monitored regularly during testosterone therapy.

The AUA 2018 Guidelines state that patients should be informed that there is no definitive evidence linking testosterone therapy to a higher incidence of venothrombotic events. The Endocrine Society 2018 Guidelines point out “Case-control and pharmacoepidemiologic studies have not shown a consistent increase in the risk of venous thromboembolism with T treatment. However, there are too few T-associated venous thromboembolism events in RCTs to draw meaningful inferences.” The EAU 2017 Guidelines advise “treat men with hypogonadism and either pre-existing cardiovascular disease, venous thromboembolism or chronic cardiac failure who require testosterone treatment with caution by monitoring carefully with clinical assessment, haematocrit (not exceeding 0.54 or 54%) and testosterone levels maintained as best possible for age within the mid-normal healthy range.”

Cardiovascular disease

The first study showing that men with low testosterone have an increased risk of premature mortality, primarily cardiovascular mortality, was published in 2006. Since then, many studies have confirmed that low testosterone increases risk of death and that testosterone therapy reduces many risk factors for cardiovascular disease. A few flawed studies suggested the opposite, which in 2015 impelled the FDA to add a warning label to all testosterone products. However, the European Medicines Agency (EMA) performed its own review and declined to add a new cardiovascular warning.

Since FDA’s addition of a warning label in 2015, 23 studies (12 clinical trials, 11 observational studies) have been published as of July 2017. None of these studies reported increased MACE (major adverse cardiovascular events) in men receiving testosterone therapy. Men whose testosterone levels normalized with testosterone therapy had reduced risk of myocardial infarction and death compared to men whose testosterone levels failed to normalize (due to undertreatment) or non-treated men.

What do the guidelines say about cardiovascular risk?

AUA 2018 Guidelines

• Clinicians should inform testosterone deficient patients that low testosterone is a risk factor for cardiovascular disease. (Strong Recommendation; Evidence Level: Grade B)
• Prior to initiating treatment, clinicians should counsel patients that, at this time, it cannot be stated definitively whether testosterone therapy increases or decreases the risk of cardiovascular events (e.g., myocardial infarction, stroke, cardiovascular-related death, all-cause mortality). (Moderate Recommendation; Evidence Level: Grade B)
• Testosterone therapy should not be commenced for a period of three to six months in patients with a history of cardiovascular events. (Expert Opinion)

Endocrine 2018 Guidelines

• We recommend against testosterone therapy in men with…. heart failure, myocardial infarction or stroke within the last 6 months… (Low quality evidence)
• "…there is no conclusive evidence that testosterone therapy is associated with increased cardiovascular risk in hypogonadal men.”
• “Thus, there are insufficient data to establish a causal link between testosterone therapy and cardiovascular events.”

EAU 2017 Guidelines

• There is no substantive evidence that testosterone treatment, when replaced to the normal physiological range, is related to the development of major adverse cardiovascular events. LOE: 1a
• In hypogonadal men testosterone treatment has been demonstrated to have a positive impact on cardiovascular risks. LOE: 1b
• Treat men with hypogonadism and either pre-existing cardiovascular disease, venous thromboembolism or chronic cardiac failure who require testosterone treatment with caution by monitoring carefully with clinical assessment, haematocrit (not exceeding 0.54) and testosterone levels maintained as best possible for age within the mid-normal healthy range LOE: 1b Grade A

Prostate Cancer and BPH

FDA label states:

• Patients with BPH treated with androgens are at an increased risk for worsening of signs and symptoms of BPH.

Dr Khera points out that no single study has shown this. In fact, most data suggest potentially the opposite.

What do the guidelines say about Prostate Cancer and BPH?

AUA 2018 Guidelines

• Clinicians should inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer. (Strong Recommendation; Evidence Level: Grade B)
• Patients with testosterone deficiency and a history of prostate cancer should be informed that there is inadequate evidence to quantify the risk-benefit ratio of testosterone therapy (Expert Opinion)

Endocrine Society 2018 Guidelines

We recommend against testosterone therapy in men with…. prostate cancer, a palpable prostate nodule or induration, a prostate-specific antigen level >4 ng/mL, a prostate-specific antigen level >3 ng/mL combined with a high risk of prostate cancer (without further urological evaluation)… severe lower urinary tract symptoms,… (Low quality evidence)

EAU 2017 Guidelines

• Randomized controlled trials support the hypothesis that testosterone treatment does not result in changes in prostatic histology. LOE: 1b
• Recent studies indicate that testosterone treatment does not increase the risk of prostate cancer, but long-term follow-up data are not yet available. LOE: 3
• Testosterone treatment is clearly contraindicated in men with advanced prostate cancer

Testosterone therapy in men with a history of prostate cancer

In a 2013 study, Pastuszak et al. published a report of 103 hypogonadal men previously treated with radical prostatectomy that underwent testosterone treatment. Twenty six (25%) men in the study had high-risk disease. The cohort was compared with 49 controls who did not receive testosterone. A statistically significant increase in PSA was noted in the treatment group during the median 27.5-mo follow up period while no increase was detected in the no-treatment group. Despite this PSA increase, however, there were actually more true prostate cancer recurrences in the control group;
4 biochemical recurrence in TTh group (15.3%) and 8 biochemical recurrences in control (non-TTh group) (53.3%).

In laboratory experiments, Denmeade and colleagues found that prostate cancer cells that are not killed by castration can paradoxically be killed if they get the opposite treatment: high levels of testosterone. “Based on this, we performed a small pilot clinical trial, in which we learned that men with metastatic castrate-resistant prostate cancer could tolerate high doses of testosterone without worsening of side effects or disease.” Quality of life improved for these men, and some men had “significant therapeutic responses lasting up to a year or more,” Denmeade says. These results were so promising that Denmeade is planning another clinical study “to test whether rapid alteration between low and high levels of testosterone would produce a beneficial response in men with prostate cancer. We believe that rapid cycling between high and low levels does not allow time for the prostate cancer cells to adapt to the ever-changing environment.” This observation led to the development of bipolar androgen therapy (BAT), which has shown promising results in several studies.

Dr Khera presents results from his own experiments showing that adding testosterone to prostate cancer cells that are in an environment of low testosterone concentrations make them grow. However, as the testosterone concentration increases, the growth of prostate cancer cells gets suppressed. Dr Khera explains that castrate testosterone levels and eugonadal testosterone levels seem to be protective, but that the hypogonadal range is dangerous.

Testosterone and BPH / LUTS

In contrast to widespread belief, studies show that men on testosterone therapy experience an improvement in BPH / LUTS. Some of these studies also included men with severe LUTS at baseline. At worse, there was no change in LUTS.

Dr Khera believes this may be thanks to an anti-inflammatory effect of testosterone therapy. Long-term data from Haider et al. suggest that LUTS may temporarily get worse during the first 3 months of testosterone therapy, but then markedly improves with continued non-interrupted testosterone therapy.

Conclusion

• There are no convincing data to support that testosterone therapy increases the risk of prostate cancer, BPH, venous thromboembolism or cardiovascular events.
• Testosterone therapy has been shown to improve BPH and LUTS.
• Testosterone therapy has been used to treat men with metastatic prostate cancer.
• Low testosterone has been associated with an increased cardiovascular risk.