- The testosterone therapy (TRT) causes prostate cancer myth is based on a single, very small, study from 1942. Since then, the overwhelming majority of medical evidence has shown this idea to be untrue.
- Newer studies have actually shown that men with low testosterone seem to be at a higher risk of developing prostate cancer. They also appear to be at risk for more aggressive forms of prostate cancer.
- The ‘Prostate Saturation Model’ has shown that only a very small amount of testosterone (230 ng/dL) is needed to fully activate the prostate gland. T levels over the ‘saturation point’ do not appear to increase prostate cancer risk.
- TRT does not appear to worsen BPH (benign prostate hypertrophy). New evidence shows BPH may improve with TRT.
DOES TESTOSTERONE (OR TRT) CAUSE PROSTATE CANCER?
The short Answer:
No, the overwhelming amount of evidence indicates that testosterone or testosterone replacement therapy (TRT) does not cause prostate cancer. In addition, testosterone does not appear to increase the risk of BPH (benign prostate hypertrophy), either. In this article, I will take you through a bit of the history of why it was once thought that T could be associated with prostate cancer. Then we will look at the studies that dispel this myth.
The most recent guidelines from the AUA, summarize the current thinking about TRT and prostate cancer, nicely.
The American Urological Academy (AUA):
“…there are a large percentage of men in need of testosterone therapy who fail to receive it due to clinician concerns, mainly surrounding prostate cancer development and cardiovascular events, although current evidence fails to definitively support these concerns.”
“Clinicians should inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer. (Strong Recommendation; Evidence Level: Grade B)”
a few definitions to know:
DHT –
DHT is derived from testosterone. An enzyme in the prostate (5-alpha-reductase) converts testosterone in the blood to DHT. DHT is responsible for the maturation and maintenance of our sexual organs. It also plays a role in libido.
prostate gland –
The prostate gland is a small walnut sized gland located between the bladder and the penis. It functions to secrete fluid for ejaculation. As men age the prostate slowly grows over time. Doctors have given this growth the name benign prostate hypertrophy. This growth can sometimes restrict urine flow through the bladder, making urination difficult. The prostate converts testosterone in the blood stream to a more powerful type of androgenic hormone called DHT. DHT activates receptors on the cells of the prostate to help maintain their function.
PSA Test –
A PSA test stands for prostate specific antigen. The PSA test is a measure of the amount of PSA in the blood. It has been shown to be helpful screening test for prostate cancer. Other conditions can also cause PSA levels to increase, such as infection of the prostate or a blockage of the prostate ducts. So, an elevated PSA is not necessarily a marker of prostate cancer.
Testosterone was first synthesized in 1935, but it was rarely used until the early 2000’s. Why? Physicians were taught that androgens (testosterone and DHT) caused prostate cancer. They also believed that high testosterone levels, such as those seen with TRT, would drastically increase prostate cancer cancer growth.
Where did this thinking come from?
To answer this question, we have to go back to 1942. Two researchers named Huggins and Hodge conducted a study that showed reducing testosterone levels to zero, caused prostate cancer cells to shrink. When they added testosterone back by injection, they saw that the cancer grew. This led them to the conclusion that prostate cancer is testosterone dependent. They also theorized that prostate cancer could be activated by testosterone injections. The researchers won the Nobel Prize for their work and shortly after androgen deprivation therapy (the elimination of testosterone) became a treatment for prostate cancer. Even today physicians use androgen deprivation therapy (ADT), along side surgery and radiation to help treat aggressive prostate cancer.
Since the elimination of testosterone was an effective treatment, the “testosterone causes prostate cancer” theory became even further entrenched. It was taught in medical schools and became ingrained in the minds of physicians. Over time, numerous studies have shown the contrary, however we tend to hold on to what we first learn. Fortunately, as more information has become available, our understanding of the relationship between T and cancer has evolved.
DO MEN WITH HIGH TESTOSTERONE HAVE A HIGH RISK OF PROSTATE CANCER?
If testosterone were to cause prostate cancer, then it would lead us to believe that men with higher levels should be at a greater risk.
New research has challenged this idea. The majority of studies have failed to show a relationship between high testosterone levels and prostate cancer. In 2004, the Harvard professor Dr. Morgentaler and his colleagues examined all the available studies between 1984 and 2004, regarding testosterone levels and cancer rates. Their review found no evidence that higher testosterone levels were associated with an increased risk of prostate cancer.
A 2008 study reviewed the majority of previous research in this area as well. The researchers found no connection between prostate cancer and blood levels of testosterone, DHEA or DHT. They actually found that older men with lower testosterone levels had the highest risk of prostate cancer.
The REDUCE trial, which involved 3,255 men, also showed no association between testosterone levels and the rate of prostate cancer.
EVEN SUPRAPHYSIOLOGIC TESTOSTERONE LEVELS DIDN’T INCREASE PSA OR PROSTATE CANCER RISK
Remember that PSA is our best screening test for prostate cancer. A study posted in the New England Journal of Medicine by Bhasin et al. examined the effects of high doses of testosterone (600 mg), for 10 weeks. The researchers measured various blood markers including PSA levels. They found that even high doses of testosterone, that boosted levels twice the normal physiologic limit, had no effect on PSA levels.
So the elimination, of testosterone causes prostate cancer to shrink, but high levels of testosterone do not seem to affect the prostate at all? How can this be?
The ‘prostate saturation model’ explains this phenomenon:
THE PROSTATE SATURATION MODEL
The graph above illustrates the prostate saturation model. The latest research has proven this is how the prostate behaves. The model show us that the increase in PSA (a marker of cancer growth) is dependent on testosterone up to a point. This point is called the saturation point. Any further increase in testosterone beyond this level, does not increase PSA or the risk tumor growth!
So what testosterone level represents the saturation point?
Studies from Rastrelli et al., Khera et al. and Mogentaler et al. showed that only a small amount of testosterone is needed to stimulate the prostate. The researchers found that a testosterone level around 230 ng/dL is all that is needed to cause PSA levels to increase to the “saturation point”. Any increase in testosterone above the saturation point results in no increase in PSA levels. So if you want to cut your cancer risk, just reduce your testosterone to under 230 ng/dL. I am kidding!
A study by Marks et al. gives us an idea about what is happening inside the prostate at different testosterone levels. The researchers performed a biopsy (taking a surgical sample of tissue) of the prostate before and after giving testosterone replacement therapy. They found that as levels of testosterone and DHT in the blood increased with TRT, the levels of testosterone and DHT in the prostate remained the same. Remember DHT is like the “fuel” for the prostate. They also found no change in other indicators of prostate cancer or incidence of prostate cancer.
So, elevating testosterone levels does not appear to increase levels of DHT in the prostate itself.
THE PROSTATE IS LIKE A SPONGE
The best analogy I have come across is to think of the prostate as a sponge. A sponge can only hold a certain amount of water before it is completely saturated. If you put a dry sponge in a sink it will only be able to absorb so much before it can hold no more. Adding more water to the sink does not cause the sponge to absorb more.
The prostate acts, in a similar way. The prostate appears to be saturated at very low T levels (somewhere around 230 ng/dL). Increases in testosterone above this level is like adding water to the sink. The prostate cannot absorb any more testosterone and higher T levels do not increase risk.
So, at very low levels of testosterone the risk of prostate cancer drops. This is why androgen deprivation therapy works, since testosterone levels are at zero. When T levels get into the normal physiologic range the risk of cancer is no greater than that of the general population with normal testosterone levels.
DOES LOW TESTOSTERONE INCREASE THE RISK OF PROSTATE CANCER?
While it is a common belief that high testosterone levels increase prostate cancer risk, newer research is showing the opposite. Research that became available over the last 20 years, has shown a correlation between low testosterone and higher prostate cancer risk, according to a recent talk given by Dr. Mohit Khera, a leading researcher at Baylor College of Medicine.
A quote from a 2016 review article, on testosterone and prostate cancer, summarizes our current understanding well: “The link between low endogenous testosterone levels and prostate cancer has been extensively studied. Men with low endogenous testosterone levels have increased rates and severity of prostate cancer at diagnosis.”
Here are a few of the groundbreaking studies done in this area:
1. 2001 – High-Grade Prostate Cancer is Associated with Low Serum Testosterone Levels
This study examined 156 men with prostate cancer. The researchers used something called a Gleason score, which is a way to score how prostate cancer cells look under a microscope. A higher Gleason score essentially means a higher grade (more severe) of cancer is present. In this study they found that men with high Gleason scores had lower testosterone and estrogen levels in their blood.
This was the first study to show this relationship. In recent years, more information has become available.
2. 2006 – Prevalence of Prostate Cancer Among Hypogonadal Men with a PSA Under 4.0,
The researchers examined prostate cancer rates among men whose PSA was below 4.0 ng/mL (normal <4.0 ng/mL) . The study involved 345 men with low testosterone and these men underwent a prostate biopsy. Prostate cancer was detected in 21% of men with a total testosterone under 250 ng/dL, compared to a 12% detection rate in men with testosterone over 250 ng/dL. Similar results were seen when the researchers examined free (unbound) testosterone. Men with a free testosterone under 1.0 ng/dL had nearly double the rate of prostate cancer compared to men over 1.0.
3. 2012 – Low Testosterone is Related to Poor Prognosis Factors in Men with Prostate Cancer
The researchers in this study biopsied the prostates of 137 men with prostate cancer. They found that men with higher testosterone levels had lower PSA levels and smaller prostate size on examination. They also found that men with lower T levels were more likely to have higher risk of cancer progression and an overall poor prognosis.
4. 2013 – Low Bioavailable Testosterone and High SHBG is Related to Prostate Cancer Detection on Biopsy
This study involved 279 men who were suspected of having prostate cancer. These men then underwent a prostate biopsy to confirm the diagnosis. The researchers found that men with low levels of bioavailable testosterone (T that is not tightly bound) had a 4.9 times higher risk of having prostate cancer compared to men with normal levels.
5. 2014 – Low Free T Predicts Prostate Cancer Progression
This study examined whether testosterone levels had any effect on the progression of prostate cancer in men whose cancer was being observed (many prostate cancers don’t require surgery). They found that the men whose cancer progressed (higher Gleason score) had lower free testosterone levels compared to men who did not progress. In addition, the researchers found that free testosterone levels were actually more predictive of prostate cancer progression than PSA testing.
Reviewing all of the studies in this area would surely bore you. Here is a table from a review article in the Translational Adrology and Urology journal, that nicely summarizes the studies showing a relationship between low testosterone and prostate cancer. The abbreviation “CaP” stands for prostate cancer.
DOES TESTOSTERONE REPLACEMENT THERAPY INCREASE PROSTATE CANCER RISK?
Many studies have examined whether testosterone replacement therapy increases the risk for prostate cancer. These studies have shown either no risk or a lowered risk. A review article published in the NEJM, examined all of the studies between 1985 and 2004, that examined the risk of prostate cancer with TRT. The review failed to find even one study that showed a concerning relationship. While this is encouraging, no randomized placebo control trials (the best kind of study) have been performed in this area. Here are a few of the more significant studies that have been done in this area:
1. The TRT and Prostate Cancer Meta-Analysis
This analysis used data from 22 different studies involving 2,351 men. The men were observed for prostate cancer for up to 3 years. They found no association between testosterone replacement therapy and the rate of prostate cancer compared to a placebo. They also found that the method of administration (injection or gel) made no difference in cancer rates.
2. The SEER – TRT and High Grade Prostate Cancer Study
The researchers examined a Medicare database and identified 52,975 men diagnosed with prostate cancer. They found that testosterone therapy was not associated with an increased risk of high grade prostate cancer. They also found that the risk of high grade cancer did not increase with the number of testosterone injections.
3. TRT in Men with Untreated Prostate Cancer
This study involved 13 men who had been diagnosed with prostate cancer. The men were given testosterone therapy and observed for 2.5 years. The researchers found no association between testosterone therapy and cancer progression. While this study was small, other studies have shown similar results. A study by Kacker et al. compared prostate cancer progression rates between men receiving testosterone therapy and those who were not. They found no increase in cancer progression rates or PSA levels between the two groups.
DOES TRT MAKE BPH WORSE?
BPH stands for benign prostate hypertrophy. It refers to the noncancerous growth of the prostate that occurs over time. This growth is completely normal but if the prostate grows too much it can block the flow of urine out of the bladder. For many years doctors believed since testosterone is converted to DHT by the prostate, that higher testosterone levels (or TRT) could worsen BPH.
Recent research has dispelled this myth. The graph above is from a study done by Haider et al. This study found that prostate symptoms improved and prostate volume did not change after 12 months of testosterone replacement. Looking at the graph you will see IPS score on the left, which stands for International Prostate Symptom score. A higher IPS score means the men had more difficulty with urination. You can see when the men began TRT their symptoms gradually improved over the first 3 months. After 3 months the symptoms improved even more, and by 12 months the symptoms were drastically improved.
On a side note, it’s interesting to note that C-reactive protein also improved with TRT. C-reactive protein is a maker of inflammation and higher levels cardiovascular disease. A lower C-reactive protein is better.
Similar results were also seen in a study by Shighehara et al. They compared urinary symptoms in men receiving testosterone therapy vs. men who were not. They found that men on TRT saw a significant improvement in prostate symptom scores. They also found that the men on TRT showed improvement in maximum urine flow rate and a decrease in the amount of urine that remained in the bladder after urination (called post void volume). The control group saw no improvement.
SummarY
Our understanding of testosterone therapy and its effects continues to evolve. While it is difficult to say anything definitively in medicine, the evidence to this point indicates TRT does not cause prostate cancer. New studies have even examined using testosterone as a possible treatment for prostate cancer. It is important to mention that while TRT does not cause prostate cancer, testosterone therapy can stimulate prostate cancer cells to grow, if cancer were to develop. It is important for men to have regular prostate exams and PSA checks. Any reputable clinic should be checking your PSA at least once per year, and before you start therapy.
Dr. Morgentaler’s Talk on TRT and Prostate Cancer:
If you get a chance, check out this amazing talk from Dr. Morgentaler, (the Harvard researcher) one of the leading researchers in testosterone therapy. He was one of the first researchers to begin looking at how TRT effects the prostate. He also discusses how his opinion of testosterone therapy changed as new research became available.
If you are pressed for time, his summary is at the 23:45 mark.
© Copyright The Veritas Clinic