Safety of testosterone therapy: There's no boogeyman in the closet

Description

Dr. Pastuszak addresses the question “Is testosterone therapy safe?” by discussing the three primary controversies in the field; cardiovascular risk, prostate cancer and benign prostatic hyperplasia (BPH).

Testosterone, mortality and cardiovascular risk

Numerous studies have examined the relationship between testosterone and mortality. A study published in the Archives of Internal Medicine in 2006 assessed the impact of testosterone levels on survival rates.1 858 male veterans >40 years old without diagnosed prostate cancer were categorized based on serum testosterone levels and followed for up to 8 years.

Low testosterone was defined as total testosterone level of less than 250 ng/dL (<8.7 nmol/L) or a free testosterone level of less than 0.75 ng/dL (<0.03 nmol/L). The prevalence of low, equivocal and normal low testosterone levels was 19%, 28% and 53%, respectively. Mortality in men with normal testosterone levels was 20.1% vs 24.6% (95% CI, 19.2%-30.0%) in men with equivocal testosterone levels, and 34.9% (95% CI, 28.5%-41.4%) in men with low testosterone levels.1 Even after adjusting for age, medical morbidity, and other clinical covariates, low testosterone levels were associated with a nearly 2-fold increased mortality risk (hazard ratio = 1.88).1

Over the past decade, a growing number of large studies have demonstrated an INCREASED RISK of mortality – both cardiovascular mortality and all-cause mortality - in men with LOW TESTOSTERONE.

A large review of all published research between 1940 - 2014 examining the relationship between endogenous testosterone, testosterone therapy and cardiovascular disease identified over 200 studies.2 Only 4 studies suggested increased cardiovascular risk in association with testosterone; 2 retrospective prescription analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies reported a beneficial effect of normal testosterone levels on cardiovascular risk and mortality. Low testosterone levels were found to be associated with incident coronary artery disease, severity of coronary artery disease and mortality.2 Regarding testosterone therapy, data clearly show that testosterone therapy reduces obesity, fat mass, and waist circumference, and improves glycemic control. Two retrospective studies showed that men on testosterone therapy had reduced mortality by half compared to men not given testosterone therapy. Several randomised controlled trials in men with coronary artery disease or heart failure reported improved heart function in men who received testosterone therapy compared to men who received placebo. The largest meta-analysis to date showed no increase in cardiovascular risks in men who received testosterone therapy, and even a reduced cardiovascular risk among those with metabolic disease. In summary, there is no convincing evidence of increased cardiovascular risks with testosterone therapy.2 To the contrary, there appears to be a strong beneficial relationship between normal testosterone levels and cardiovascular health that has not yet been widely appreciated.2

Despite the overall finding that low testosterone is more detrimental to health than normal testosterone, in 2015 the American FDA added a section to drug labels under the warnings and precautions, stating “Patients should be informed of the possible increased cardiovascular risk when deciding whether to use or continue to use testosterone therapy”. Importantly, the European Medicines Agency (equivalent to FDA) declined to add a cardiovascular warning to testosterone products.

One may wonder, how could testosterone possibly contribute to an increased cardiovascular risk? While there are no hard and fast explanations yet, several potential mechanisms have been proposed. These include increased neutrophil migration platelet activation through the thromboxane A2 receptor and erythropoiesis. However, despite these plausible mechanisms, still no increase in cardiovascular risk. It may be that testosterone’s beneficial effects override any purported negative effects, so that overall the good weighs down the bad.

Since the FDA label change in 2015, several new studies that examined the relation between testosterone and cardiovascular risk have been published.3 A review of 23 new studies concluded that there is no new evidence supporting the proposition that testosterone therapy increases cardiovascular risk. To the contrary, men on testosterone therapy had a reduced risk of myocardial infarction and death when compared with men with low testosterone levels.3 This review also pointed out that testosterone therapy confers significant benefits to men with hypogonadism, regardless of underlying cause of the hypogonadism.3

Further support for a reduced cardiovascular risk comes from a study that investigated the association between testosterone levels and blood levels of cardiovascular risk biomarkers.4 Men with low testosterone levels had elevated levels of cardiovascular risk markers, consistent with a potential increased risk of cardiovascular disease.

A notable study examined stroke risk in hypogonadal men with type 2 diabetes who were treated with testosterone therapy for 5 years after they had already had an ischemic stroke.5 As expected, there were improvements in symptoms and biochemical variables. However, most remarkably, there was no increased risk of repeat stroke or all-cause mortality in the testosterone therapy group. In fact, increased risk of stroke and mortality was only observed in the group that had discontinued testosterone therapy.

In answering the questions:

  • Does low testosterone increase mortality risk?
    • Yes!
  • Does giving testosterone to men with hypogonadism increase cardiovascular risk?
    • Doesn’t look that way based on the available (and growing) evidence.
  • Does normalization of testosterone levels decrease cardiovascular risk?
    • This also looks promising, with more and more studies showing a decreased cardiovascular risk with normalization of testosterone levels.

In summary, testosterone therapy can probably be used safely in men, with low concern for cardiovascular risk. Rather, we can expect a reduced cardiovascular risk in men on testosterone therapy.

Prostate cancer

Should we be concerned about giving men with prostate cancer, or with a history of prostate cancer that’s been treated, testosterone?

The FDA thinks that we need to be careful. In fact, the testosterone package insert states that testosterone therapy is contraindicated in men with known or suspected prostate cancer. But what do the research data show?

Men with low testosterone who have prostate cancer suffer from hypogonadism like (or in some cases more than) men with low testosterone without prostate cancer. Therefore, the historical fear that testosterone can stimulate prostate cancer cell growth needs to get addressed.

The origin of the concern for testosterone contributing to prostate cancer growth was a report published in 1941, when Huggins and Hodges reported that reducing testosterone to castrate levels caused regression of prostate cancer and that administration of testosterone caused progression of prostate cancer. However, this work was essentially based on the results from a single patient, and today would not likely be accepted as more than a case report. Nevertheless, this work did set the foundation for the androgen-dependent model of prostate cancer growth. But it begs the question of whether testosterone administration results in prostate cancer growth under all conditions.

In an attempt to answer the question of whether prostate cancer cell growth is stimulated at all testosterone levels, an experiment was conducted showing that testosterone results in increased prostate cancer cell proliferation at low testosterone concentrations, but that prostate cancer cell growth was inhibited by high ambient testosterone concentrations. Optimal testosterone concentration for growth was found to be < 1ng/mL of testosterone, which corresponds to human serum testosterone levels of <240 ng/mL, which is clearly hypogonadal. Other studies have observed similar result.

What about clinical studies examining the effects of testosterone in men with a history of prostate cancer? To date, no studies have shown an association of testosterone therapy to prostate cancer incidence, recurrence, or progression.

So, what are the effects of testosterone therapy on prostate cancer growth in clinical practice?

In one study of 451 hypogonadal men on testosterone therapy for 12 months, men were divided in two groups based on a baseline testosterone threshold of 8.7 nmol/L (250 ng/dL).6
Only in the group with a starting testosterone level below 8.7 nmol/L had a significant increase in PSA, but this increase was small – 0.3 ng/mL – and stabilized by 12 months.6

After 12 months of testosterone therapy, increase in prostate specific antigen was statistically significant in men with baseline testosterone of 8.7 nmol/L or less (+0.19 ng/ml; final prostate specific antigen 1.26 ng/ml) but not in men with higher baseline testosterone levels The average percent prostate specific antigen increase from baseline was higher in men with low baseline testosterone levels (21.9%) than that seen in men with high baseline testosterone levels (14.1%).6 Thus, in hypogonadal men, it should be expected that testosterone therapy results in a small, temporary increase in PSA levels, rather than a continued increase.

In fact, most studies demonstrate an increased risk of prostate cancer in men with low testosterone.7
Furthermore, there’s an increased risk of higher tumor burden, tumor bilaterality, and more aggressive disease in men with low testosterone than in men with normal testosterone levels.7

Does giving testosterone to men with a history of treated or untreated prostate cancer increase the risk of recurrence / progression?

For both low and high risk prostate cancer, there is little evidence of recurrence and /or progression in men on testosterone therapy. In 2013, Dr. Pastuszak and colleagues published a study examining 103 hypogonadal men with all types of prostate cancer treated with radical prostatectomy, and subsequently with testosterone therapy TTh, and compared these to a group of non-hypogonadal men with prostate cancer treated with radical prostatectomy but not with testosterone therapy.8 There was a small, clinically insignificant increase in PSA levels in both groups of men, with no evidence of recurrence. Interestingly, the recurrence rate in the testosterone treatment group was lower than that in the reference group. It was concluded that testosterone therapy is effective and, while followed by an increase in prostate specific antigen, does not appear to increase cancer recurrence rates, even in men with high risk prostate cancer.8 However, given the retrospective nature of this and prior studies, testosterone therapy in men with history of prostate cancer should be performed with a vigorous surveillance protocol.

To complement this, in 2015, Dr. Pastuszak and colleagues published a study examining 98 hypogonadal men with all types of prostate cancer treated with radiation and subsequent testosterone therapy.9
In non-high risk patients, there were no significant increases in PSA levels. As one may expect, there was a small increase in recurrence in high risk patients, but the biochemical recurrence rate in the high risk patients was only 6%, which is far lower than what’s been published in the literature.9 It was concluded that testosterone therapy in men following radiation therapy for prostate cancer is associated with a minor increase in PSA and a low rate of biochemical recurrence.9

How about men on active surveillance? In the largest study so far of 124 men with prostate cancer on active surveillance, published in 2016, 28 were treated with testosterone therapy for at least 6 months (median 40 months).10 No differences in prostate cancer progression rates were observed between groups. It was concluded that biopsy progression in men on active surveillance appears unaffected by testosterone therapy over 3 years.10

If testosterone does not negatively impact outcomes in men with prostate cancer that has either been treated or UNTREATED, what happens if men with METASTATIC prostate cancer are given testosterone?Intriguingly, cutting edge research from Sam Denmeade’s group at Hopkins suggest it may be beneficial!

In a Memorial Sloan Kettering study on 12 men with metastatic castration-resistant prostate cancer (CRPC) found such treatment was safe, but none achieved an objective response; however, none achieved supraphysiological levels of testosterone either. A group at the University of Chicago treated 15 men with CRPC and no or little metastases with testosterone. Three had decreased PSA while on testosterone treatment.

In laboratory experiments, Denmeade and colleagues found that prostate cancer cells that are not killed by hormonal deprivation treatment can paradoxically be killed if they get the opposite treatment: high levels of testosterone. Based on this, a small pilot clinical trial was performed, showing that men with metastatic CRPC 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. 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. The theory is that rapid cycling between high and low levels of testosterone does not allow time for prostate cancer cells to adapt to the ever-changing environment.

This approach of giving testosterone therapy to men with metastatic CRPC is called bipolar androgen therapy, or BAT. The basis for BAT arose from the knowledge that androgen receptor activation induces apoptosis of prostate cancer cells in vitro and in vivo. Furthermore, high androgen levels can cause lethal DNA breaks, and these can be further potentiated via the use of etoposide. The initial study examining the clinical response to BAT followed 14 men with either castration-resistant prostate cancer or metastatic castration-resistant prostate cancer with a low to moderate metastatic burden. These men were treated with testosterone cypionate 400 mg once monthly + etoposide 100mg daily for 3 months. PSA and imaging were monitored, and men who responded were kept on BAT. Remarkably, 7 of 14 men had a 50% or more PSA decline in response to BAT, and 5 of 10 men with radiographically visible metastases had a reduction in tumor volume. After the BAT treatment, 12 of 13 men subsequently responded to ADT, consistent with theoretical re-sensitization of the tumor to testosterone after BAT. The authors also more recently published the results of a Phase II trial with 29 men, and found similar results, leading them to conclude that BAT shows promise as an effective alternative to therapies that work by inhibiting androgen receptor signaling. If proven effective in larger studies, BAT may offer a treatment strategy that not only controls tumor growth, but also preserves quality of life.

Take home messages with regards to testosterone treatment initiation and monitoring in men with prostate cancer:

  • Start testosterone therapy based on the same biochemical and symptom characteristics as men without prostate cancer; in other words, first make the diagnosis of hypogonadism.
  • Get a written informed consent from the patient, specific for the setting of testosterone therapy in men with prostate cancer.
  • Make sure there are no medical contraindications to testosterone therapy (i.e. erythrocytosis) and that the PSA level is stable or undetectable.
  • In cases of rising PSA, Dr. Pastuszak does often not discontinue testosterone therapy, but discusses the treatment rationale with the patient and ensures a shared decision making, and closely monitors for potential recurrence or progression.

In answering the questions:

  • Does testosterone result in prostate cancer cell growth?
    • No, only in a narrow range of low testosterone concentrations.
  • Does giving testosterone to men with metastatic castrate-resistant prostate cancer worsen prostate cancer outcomes?
    • No, it may improve outcomes and quality of life.
  • Does giving testosterone to men with a history of prostate cancer treated with radiation increase risk of progression / recurrence?
    • No.

Based on clinical data which are further supported by strong basic science findings, Dr. Pastuszak argues that testosterone therapy can be safely used in men with a history of prostate cancer.

Testosterone therapy and benign prostatic hyperplasia (BPH)

Again, the FDA urges caution in giving men with BPH testosterone therapy, indicating that these men are at increased risk for worsening of signs and symptoms of BPH. But what do the data show?

In a 2016 review of many studies, either no change or even improvement in LUTS with testosterone therapy was observed in virtually all the studies. Notably, this review did not exclude men who had severe LUTS.

A 2016 meta-analysis of 14 trials, including over 2000 men, assessed LUTS in men on testosterone therapy. Results showed no significant difference in change in IPSS scores in men on either testosterone therapy or placebo. Therefore, the data overall support the conclusion that testosterone therapy in the setting of BPH is safe and does not worsen associated symptoms.

There are some legit and well documented side effects of testosterone therapy:

  • Erythrocytosis
  • Sleep apnea
  • Gynecomastia
  • Edema
  • Acne
  • Infertility
  • Testicular atrophy
  • Hepatotoxicity with methylated oral therapies

Most of these are either readily addressed or avoidable with appropriate therapy. These are important for the clinician to be aware of and to discuss with patients.

In summary:

  • Low testosterone likely increases cardiovascular risk.
  • Current data support a low cardiovascular risk in men on testosterone therapy.
  • Testosterone does not stimulate prostate cancer cell growth under all conditions.
  • Testosterone therapy may not increase the risk of prostate cancer, and BAT can improve outcomes in men with metastatic castrate-resistant prostate cancer.
  • Testosterone therapy may not worsen the symptoms of BPH and LUTS, but risk assessment and patient counseling are essential.
  • There are numerous common risks of testosterone therapy, all of which are readily mitigated in the monitored patient.

 

Speakers

Alexander W. Pastuszak, MD, PhD

Alexander W. Pastuszak, MD, PhD
Assistant Professor
Center for Reproductive Medicine
Division of Male Reproductive Medicine and Surgery
Scott Department of Urology
Baylor College of Medicine

References

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  • Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc. 2015;90(2):224-251. Return to content
  • Miner M, Morgentaler A, Khera M, Traish AM. The state of testosterone therapy since the FDA's 2015 labelling changes: Indications and cardiovascular risk. Clin Endocrinol (Oxf). 2018;89(1):3-10. Return to content
  • Pastuszak AW, Kohn TP, Estis J, Lipshultz LI. Low Plasma Testosterone Is Associated With Elevated Cardiovascular Disease Biomarkers. The journal of sexual medicine. 2017;14(9):1095-1103. Return to content
  • Morgunov LY, Denisova IA, Rozhkova TI, Stakhovskaya LV, Skvortsova VI. Hypogonadism and its treatment following ischaemic stroke in men with type 2 diabetes mellitus. The aging male : the official journal of the International Society for the Study of the Aging Male. 2018:1-10. Return to content
  • Khera M, Bhattacharya RK, Blick G, Kushner H, Nguyen D, Miner MM. Changes in prostate specific antigen in hypogonadal men after 12 months of testosterone replacement therapy: support for the prostate saturation theory. J Urol. 2011;186(3):1005-1011. Return to content
  • Pastuszak AW, Rodriguez KM, Nguyen TM, Khera M. Testosterone therapy and prostate cancer. Transl Androl Urol. 2016;5(6):909-920. Return to content
  • Pastuszak AW, Pearlman AM, Lai WS, et al. Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy. J Urol. 2013;190(2):639-644. Return to content
  • Pastuszak AW, Khanna A, Badhiwala N, et al. Testosterone Therapy after Radiation Therapy for Low, Intermediate and High Risk Prostate Cancer. J Urol. 2015;194(5):1271-1276. Return to content
  • Kacker R, Hult M, San Francisco IF, et al. Can testosterone therapy be offered to men on active surveillance for prostate cancer? Preliminary results. Asian journal of andrology. 2016;18(1):16-20. Return to content