Manipulating Testosterone Levels To Treat Metastatic Prostate Cancer

The treatment for prostate cancer involved lowering the levels of the male hormone testosterone using drugs called luteinising hormone-releasing hormone (LHRH) agonists. This was done because it was thought that testosterone stimulated prostate cancer cells to grow. However, there is no evidence to suggest that testosterone promotes cancer.

It was noted, in earlier research, that high doses of testosterone actually could reduce the growth of and kill cancer cells. The mechanism of this isn't known, but it was noted that increased testosterone interfered with part of the cell division process in cancer cells, called DNA licensing, which seemed to cause prostate cancer cells to make breaks in their DNA and die. What was also noted was a phenomenon known as senescence, which meant that the cancer cells were present but didn’t cause any issues.

The study

In the RESTORE study which is still ongoing, 47 men with prostate cancer that was resistant to castration and that had started to metastasise to other parts of the body, and who showed no symptoms but whose disease had become resistant to treatment with either enzalutamide (in 30 patients) or abiraterone (in 17 patients), received a large dose of testosterone (400 mg) that was injected intramuscularly every 28 days. These patients still continued with their LHRH agonist therapy, to inhibit testosterone that was produced by the testicles, and they stopped taking enzalutamide or abiraterone (androgen receptor signalling inhibitors that cause chemical castration).

The aim of this study was to rapidly expose the cancer cells with very high and then followed by very low levels of testosterone. This form of therapy is known as bipolar androgen therapy (BAT) because of these alternating extremes in testosterone levels. The men that showed declining PSA levels or stable disease continued with BAT after three cycles. If the metastatic disease then started to progress, they were treated again with enzalutamide or abiraterone.

The findings

The aim of the study is to still use 60 men with castration-resistant metastatic prostate cancer, but the following findings have already been made on the 47 men that were used.

• Prostate specific antigen (PSA) levels fell in around 40% of men, and in about 30% of them levels fell by more than 50%.
• Prostatic masses shrank in some men.
• In several test subjects the disease didn't advance. This included men whose disease continued to be stable for more than 12 months.
• One man may appear to have been cured because his PSA levels dropped to 0 after three months and have remained so after 22 cycles of treatment, with no trace of the disease being present.
• Some men reported other positive outcomes including increased energy and muscle strength and decreased fatigue.

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The clinical significance

The study is still in its research phase and needs to be completed before the full results are made available, but the results are unexpected and exciting.

Since the study is in its early stages, the researchers are still trying to figure out how BAT works and how to incorporate it into the treatment paradigm for prostate cancer.

Further research

A randomised trial in the United States using multiple centres, called TRANSFORMER, is comparing BAT to enzalutamide in 111 men (target group is 180) diagnosed with castration-resistant metastatic prostate cancer whose disease had advanced after receiving abiraterone. The researchers state that if they find that testosterone is superior to enzalutamide, they will move onto larger clinical trials.

Testosterone Therapy

As men get older, their testosterone levels gradually decrease. Testosterone is naturally produced by the testicles and these organs begin to decrease in function with advancement of age.

Effects of testosterone

Testosterone is an androgen which is a hormone found in high levels in men. It is also found in women but in extremely low levels. Testosterone helps to maintain the following in men:

• Muscle mass and strength.
• Fat distribution, by keeping it away from the abdomen and hips and distributing it around the arms and legs.
• Body and facial hair.
• Appropriate bone density.
• Red blood cell production.
• Sperm production.
• Sexual drive/libido.

Changes in testosterone levels with age

Testosterone levels peak during the teenage years and early adulthood. The hormone then starts to decrease at about 1% per year from ages 30-40. 

It's important to distinguish between normal decreased levels of testosterone and when the problem is being caused by a condition called hypogonadism. This condition occurs when the body can't produce normal levels of testosterone due to issues with the testicles (primary cause) or with the pituitary gland in the brain (secondary cause). If the cause is due to a mass on the pituitary gland, then this may have to be managed through surgical intervention.

Symptoms of lowered testosterone levels

Not all men experience signs and symptoms of lowered testosterone levels, but if they do they include the following:

• Physical changes - these may include decreased muscle strength and mass, increased body fat on the abdomen and hips, decreased bone density, swelling of the breasts (gynecomastia), body and facial hair loss, fatigue and decreased energy.
• Sexual dysfunction - may include decreased sexual desire, less spontaneous erections, generally weak erections, delayed ejaculation, decreased sensation during orgasm and infertility.
• Emotional changes - can include a depressed mood, decrease in self-confidence and motivation, feeling sad and experiencing problems with memory and concentration.
• Changes in sleep patterns​ - insomnia or other sleep-related problems.

Other conditions that can affect men such as diabetes, cardiovascular diseases, obstructive sleep apnoea, thyroid dysfunction and major depression can also cause these signs and symptoms. It's therefore important that men who do experience these issues consult with their primary care doctors so that they can be examined and investigated further. Only then can they be diagnosed properly and receive the correct management.

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Managing symptomatic low testosterone

The only way low testosterone levels can be diagnosed is by performing blood tests to determine these levels. If the patient does have abnormally low testosterone levels together with symptoms of the condition, and where other causes have been excluded, then the patient's physician will discuss testosterone replacement therapy. This would include giving the hormone orally or intramuscularly, but the latter is the more effective and popular route of administration.

Natural ways of increasing testosterone levels include losing weight and increasing physical exertion through both cardiovascular and strength training exercises.