Testosterone Replacement Therapy and Prostate Cancer

There has been a long-standing notion in the medical community that testosterone is a driver in the development and progression of prostate cancer. This notion has been reinforced by the development of multiple effective therapies which work by lowering testosterone levels to reduce the cancer and lead patients into remission.¹

Many men are testosterone deficient and contend with multiple symptoms which greatly impact their quality of life.² If diagnosed, deficiency can be treated well by testosterone replacement therapy (TRT), which raises testosterone levels back into the normal range. However, due to concerns that TRT could promote prostate cancer development, clinicians may avoid treating deficient patients, particularly those with a history of prostate cancer.

In light of a building body of evidence, the discussion around the potential role of testosterone and TRT in the development and progression of prostate cancer is now being reopened which may mean a change in perspective for many clinicians. ‍

Prostate Cancer treatment

Prostate cancer is the most common cancer diagnosed in men, but fortunately, there are several treatment options available.¹ The mainstay treatment since the 1940s has been hormone therapy, known as androgen suppression therapy or androgen deprivation therapy.¹

Androgens, or male hormones, are known to stimulate the growth of prostate cancer cells leading to the development and worsening of the disease. As such, hormone-based treatment options aim to reduce androgen levels in the body to prevent their subsequent stimulation of the cancer cells, leading the cancer to shrink. Remarkably, almost all patients treated reach remission.¹ The main androgen targeted by these therapies is testosterone.  

What is Testosterone?

Testosterone is an important hormone in men, driving sperm production, sex drive and the development of male sexual organs as well as regulating characteristics such as voice deepening, development of body and facial hair, growth spurts and muscle growth. It also works to maintain overall health, for instance by promoting red blood cell production and maintaining bone and muscle mass.² With age, testosterone levels begin to slowly decline and for some men, such low levels of testosterone are reached that they are considered clinically deficient in the hormone.³

Low testosterone can lead to the development of a spectrum of clinical symptoms which can greatly impact a man's quality of life. Symptoms can include sexual symptoms such as erectile dysfunction and reduced sexual desire, clinical symptoms such as infertility, obesity and osteoporosis, and cognitive symptoms such as sleep disturbances, anger and irritability.⁴  

Given the evident benefit of androgen deprivation therapy in the treatment of prostate cancer, clinicians may make the fair assumption that if reducing androgen levels leads to cancer regression and remission, then increasing testosterone levels would likely have the opposite effect.  

‍Changing perspectives

‍We are now looking at mounting evidence which contradicts the notion that TRT could cause prostate cancer. By opening up the discussion and unpicking the research to date, we can challenge the original conclusions drawn and help doctors become more comfortable treating patients with testosterone deficiency. While the number of men who are testosterone deficient is expected to be vastly underdiagnosed, around 39% of men over the age of 45 are thought to be deficient.⁵  

Here we take a brief look at some of the key research:

1. Testosterone and Prostate Cancer risk

‍It would stand to reason that should testosterone be a key driver in the development of prostate cancer, high testosterone levels would make the person more likely to develop cancer. This reasoning is reinforced by similar research which found that post-menopausal women prescribed hormone replacement therapy (HRT) have a moderate increase in the risk of developing breast cancer.⁶

However, many large scale analyses, such as one collaborative meta-analysis of 18 studies showed that there was no meaningful difference in the risk of prostate cancer between men with the highest 20% of testosterone levels and those with the lowest 20%. In fact, numerous guidelines, including the European Association of Urology (EAU) and the Endocrine Society (ES) have concluded that there is no compelling evidence that testosterone therapy is associated with increased prostate cancer risk.²

2. Low Testosterone and Prostate Cancer

Building on the long-standing beliefs, it would also be assumed that having low testosterone levels would have somewhat of a protective effect and individuals would have a lower likelihood of developing prostate cancer.  

Current evidence indicates that not only are individuals with low testosterone levels diagnosed with prostate cancer at the same rate as others but that lower levels are associated with poorer outcomes in these men as well, such as aggressive high grade prostate cancer and higher rates of positive biopsy results.²

3. TRT and Prostate Cancer recurrence

Rightfully wary of causing undue harm, healthcare professionals have avoided prescribing TRT to patients who have been treated for prostate cancer, in case this should cause a recurrence of their cancer.  

Treatment with TRT has been shown to have no significant increase in cancer recurrence risk, or cancer-related mortality.^7,8 In fact, one study assessed 57 men treated for testosterone deficiency after radical prostatectomy for a period of 36 months and found no recurrences of prostate cancer.⁹ Further research with a longer follow up duration is needed to confirm these findings.

4. TRT and Cancer progression

Prostate cancer is often a slow-growing cancer. As some treatment options are invasive and often have significant side effects, clinicians may opt to hold off on beginning treatment if the cancer is deemed to be low-risk. Instead, the cancer can be monitored closely (active surveillance) until a time that the cancer begins to progress and treatment may then begin.  

Patients may develop low testosterone as a result of age, other diseases, or because of the cancer itself.¹⁰ In these cases it’s unlikely a patient would be offered TRT due to concern it may promote cancer growth and lead to the patient needing further treatment.  

the end, the use of TRT in prostate cancer patients is still considered experimental and should only be offered after well-informed shared decision making and with close monitoring.

There is a growing evidence suggesting the use of TRT during this time would not increase mortality risk or worsen clinical outcomes.¹¹ Though the use of TRT in prostate cancer patients is still considered experiemental, and should therefore only be offered after well-informed decision making and close monitoring from a specialist.

Driving the conversation forward

With prostate cancer therapies working primarily to reduce testosterone levels and yielding such positive results, a reasonable question would be: How is it possible that TRT does not cause prostate cancer development, progression or worse outcomes?  

While more research is needed, a simple but validated conclusion is proposed. Testosterone does indeed influence prostate cancer tissues and can promote growth. However, once testosterone levels rise above a certain threshold, the receptors which testosterone binds to on the cancer cells become saturated and at that point no further testosterone can bind and no further stimulation can take place.²  

This conclusion (the saturation model) is supported by research which shows that testosterone levels in the prostate do not change during TRT while concentrations in the blood serum become significantly higher. TRT was then shown to cause no change in the prostate gene expression and cause no change in cancer incidence in those individuals.¹² Importantly, guidelines recommend careful assessment of the prostate before commencing TRT, as well as regular monitoring for prostate disease following the initiation of TRT.  

Moving forward

There is mounting evidence to support the notion that testosterone and TRT does not cause or increase the risk of prostate cancer development, worsen mortality and increase rates of recurrence. This is echoed by numerous guidelines and while further research is needed, the decision to give any testosterone treatment should be carefully considered by a specialist.

Take home points

• Testosterone has long been thought to increase prostate cancer risk
• Mounting evidence now suggests that testosterone does not in fact increase prostate cancer risk, with studies showing no change in risk after increasing levels of testosterone in men
• Numerous guidelines have echoed the changing perspective, pushing the conversation forwards to ensure doctors and specialists are aware of the latest evidence

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Continue the conversation on the TRTed Community!

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References

1. Komura et al. Int J Urol. 2018 Mar; 25(3): 220–231.

2. Hacket G, et al. J Sex Med 2017;14:1504–1523.

3. Harman SM, et al. J Clin Endocrinol Metab 2001;86:724–31.  

4. Dohle G, et al. EAU Guidelines on Male Hypogonadism 2018. Available at: http://uroweb.org/guideline/male-hypogonadism/.

5. Mulligan T et al. Int J Clin Pract 2006 Jul 1; 60(7): 762–769.

6. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 2019.394: 1159-1168.

7. Khera et al. Eur Urol 2014 Jan;65(1):115-23.

8. . Bell et al. World J Mens Health 2018 May;36(2): 103–109.

9. Khera M, et al. J Sex Med. 2009;6(4):1165–1170.  

10. Burney J. Cachexia Sarcopenia Muscle 2012 Sep;3(3): 149–155. 

10. Golla & Kaplan. Curr Urol Rep 2017; 18(7): 49.  

11. Kaplan et al. Eur Urol 2016 May; 69(5): 894–903.