By Monica Mollica Iron Mag
The number one concern among clinicians worldwide and reason for not prescribing testosterone is the fear that it will cause prostate cancer and/or worsen benign prostatic hyperplasia (BPH, age-associated prostate gland enlargement that can cause urination difficulty). This article is a summary of a recent presentation by Dr. Khera at The Annual European Association of Urology (EAU) Congress held in March 2015. The EAU is Europe’s largest annual event for medical health care professionals, showcasing the latest medical research findings in the andrology and urology fields. In this presentation, Dr. Khera debunks the popular widespread myth that testosterone supposedly is harmful for the prostate, and presents provocative new testosterone research…
What is the effect of testosterone on normal prostate tissue?
Dr. Khera sets the stage by presenting the notorious case study from 1941, which showed that reducing testosterone to castrate levels caused prostate cancer to regress, and that administration of testosterone caused prostate cancer to grow. However, this was only shown in one single patient. He highlights that since 1941 until today, not even one study has shown that testosterone causes prostate cancer.
Dr. Khera presents the landmark study published 2006 in JAMA, which looked at the effects of testosterone replacement therapy on the prostate, and changes in intra-prostatic and blood levels of testosterone and DHT. Hypogonadal men were randomly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months. As expected, it was found that testosterone treatment significantly elevated blood levels of testosterone and DHT. However, intra-prostatic levels were unchanged. The conclusion was that testosterone replacement therapy normalizes blood levels of androgens, but has little effect on prostate tissue androgen levels and cellular functions. Dr. Khera explains that the prostate acts like a sponge; it takes up a finite amount of testosterone from the blood, and then it doesn’t care how high blood levels of testosterone get because it is saturated with testosterone.
Historically it was believed that that there was a linear relation between blood testosterone levels, prostate growth and PSA. This is not true. As eloquently described by Morgentaler et al. 2008, the prostate saturation model shows the linear relation only occurs at hypogonadal testosterone levels <250 ng/dL. Proof-of-concept for the limit (saturation) of androgen-dependent growth came from another landmark study by Bhasin et al., which demonstrated that supra-physiological testosterone supplementation (weekly 600 mg testosterone enanthate for 10 weeks) – raising blood testosterone levels to almost 2500 ng/dL, did not cause any change in PSA levels. A more recent study by Dr. Khera himself found that men with baseline testosterone below 250 ng/dL are more likely to have an increased PSA after testosterone replacement therapy (percent increase from baseline 21.9%) than those with baseline level above 250 ng/dL (percent increase from baseline 14.1%), supporting the prostate saturation hypothesis. Notably, the greatest PSA elevation was observed after 1 month of treatment and decreased thereafter. Clinicians should be aware that severely hypogonadal patients may experience a temporary increase in PSA levels (but still within normal range) after testosterone replacement therapy.
Looking at the other end of the spectrum, do low testosterone levels protect against development of prostate cancer? To the surprise of many, multiple studies show that low testosterone levels are associated with increased risk of prostate cancer:
Lower testosterone levels correlate with:
– Higher pathological prostate cancer stage 
– Higher biopsy Gleason grade 
– Increased positive surgical margins – 39% in men with low testosterone vs. 14.6% in men with normal testosterone (indicating less chance of complete removal of cancer cells) 
– Higher prostate tumor density 
– Higher Gleason score 
In addition, lower pre-operative testosterone levels increase the risk for prostate cancer recurrence following radical prostatectomy.
Dr. Khera then brings up the interesting speculation “does low testosterone cause prostate cancer, or does prostate cancer cause low testosterone?” He argues that it may be prostate cancer that causes low testosterone, because after radical prostatectomy testosterone levels rise. Seemingly prostate cancer has an inhibitory effect on testosterone levels, and when it is surgically removed, testosterone levels rise.
Testosterone replacement therapy and prostate cancer
An important question is “does giving testosterone to men with a history of prostate cancer increase the risk of recurrent prostate cancer”? Many clinicians refuse giving testosterone treatment to men with a history of prostate cancer, because they believe the prostate cancer will come back. What do the data show?
Prostate cancer rate in multiple testosterone studies has been found to be similar to that seen in screening studies of the general population. A meta-analysis of 19 placebo-controlled testosterone replacement therapy studies in men with low or low-normal testosterone levels reveals no difference in prostate cancer incidence, change in PSA or urinary symptom scores. In a collaborative analysis of worldwide data on endogenous hormones and prostate cancer risk, serum concentrations of sex hormones were not associated with the risk of prostate cancer. In three long-term testosterone replacement therapy (median 5 years, max 16 years) registry studies, the incidence of prostate cancer was found to be 1.5% to 2.3%. This is much lower than that seen in screening studies, where prostate cancer incidence rates have been reported to be 7.35% (US) and 9.6% (EU). Thus, men receiving testosterone treatment actually have lower rates of prostate cancer than the general population.
A provocative study by Morgentaler et al. evaluated prostatic changes in hypogonadal men with and without high grade prostatic intraepithelial neoplasia – which is considered a prostatic precancerous lesion – after 1 year of testosterone replacement therapy. It was found that men with prostatic intraepithelial neoplasia do not have a greater increase in PSA or any significantly increased risk of cancer than men without prostatic intraepithelial neoplasia. Therefore, testosterone replacement therapy is not contraindicated in men at high risk for prostate cancer.
Several studies on testosterone replacement therapy in men with a history of prostate cancer treated with radiation [17-20] or radical prostatectomy [21-24], also show no significant increases in recurrences. Notably, prostate cancer recurrence rate is less (1.5%) in men who receive testosterone replacement therapy  than recurrence rates in men who do not get testosterone treatment (10%). Does this indicate that testosterone replacement therapy may even be protective against prostate cancer recurrence? Possibly…. mechanistic studies suggest this may be the case. For examples, membrane androgen receptor activation induces apoptotic regression of human prostate cancer cells in vitro and in vivo , and androgens are able to trigger an inhibition of cell proliferation (shutoff effect) at levels higher than those that affected maximal cell yields. Androgens also may cause growth suppression and reversion of androgen-independent prostate cancer to an androgen-dependent variant.
Surprising new medical research on testosterone and prostate cancer
Dr. Khera continues by presenting an even more provocative approach “A New Way to Treat Recurrent Prostate Cancer: More Testosterone?” developed by Samuel Denmeade, M.D., who treats castrate resistant metastatic prostate cancer with temporary high doses of testosterone. This makes castrate resistant prostate cancer castrate sensitive. When testosterone treatment is then stopped, one sees regression of the metastatic prostate cancer.
Another new strategy is “bipolar androgen therapy (BAT)”, in which high doses of testosterone is added to castrating therapy in order to create rapid cycling of supra-physiological to near-castrate blood testosterone levels. This has been shown to restore prostate cancer sensitivity to androgen deprivation therapy, and shows promise as treatment for castration-resistant prostate cancer.
Dr. Khera presents results from his own research, showing that at lower androgen concentrations than the optimal level, increasing androgen concentration promotes proliferation of prostate cancer cells. However, at the higher concentrations, further increasing androgen concentration results in a dose-dependent inhibition of proliferation. He introduces an RCT currently in progress that his team got FDA approved (NCT00848479), which will investigate the safety of testosterone replacement therapy starting 3 months after radical prostatectomy.
A retrospective study by Dr. Khera and Morgentaler investigated the effect of testosterone therapy (mean duration 23.5 months, range 9-43 months) in 13 men with active untreated prostate cancer. There were no significant changes in PSA nor prostate volume, and no cancer progression was seen in any man. These results are consistent with the saturation model, i.e. maximal prostate cancer growth is reached at low androgen concentrations.
Erectile function and BPH/LUTS
When it comes to efficacy, one may wonder if there is any benefit of giving a man testosterone after radical prostatectomy. Dr. Khera says “absolutely”! A man after radical prostatectomy is at a disadvantage of recovering his erectile function compared to a eugonadal man. While the relationship between testosterone replacement therapy and improvement in erectile function has been well established, the role of testosterone in men following radical prostatectomy may be of even greater significance.
Dr. Khera ends his presentation summarizing the latest research on BPH. He notes, the first line on the testosterone product package insert states “Monitor patients with BPH for worsening of sign and symptoms of BPH”. Is there any evidence for this? Does testosterone treatment really worsen BPH and lower urinary tract symptoms (LUTS)? A randomized controlled study investigating the effects of testosterone replacement therapy on LUTS in hypogonadal men with benign prostate hypertrophy found an improvement in LUTS in hypogonadal men with mild BPH.
Notably, the International Prostate Symptom Score (IPSS) tends to increase within the first 3-4 months of testosterone treatment, as the prostate gets saturated with testosterone. After this initial and temporary small worsening of BPH symptoms, BPH symptoms will improve. This is why patients need to be treated with testosterone for at least 12 months to notice theBPH benefits. Most recently, a EUA Abstract 2015 by Haider et al. demonstrated that long-term testosterone therapy for up to 84 months in hypogonadal men results in a significant reduction in both IPSS scores as well as post-voiding residual bladder volume.
* In hypogonadal men, testosterone replacement therapy will temporarily increase (within the normal range) PSA to a new baseline.
* While significantly increasing blood levels of testosterone and DHT, testosterone replacement therapy does not appear to affect intra-prostatic testosterone and DHT levels, nor prostate size. These findings are likely due to the saturation of androgen receptors within the prostate at low androgen levels
* There is currently no evidence that testosterone replacement therapy promotes the initiation of prostate cancer in hypogonadal men.
* Hypogonadal men receiving testosterone replacement therapy after history of prostate cancer appear to have low recurrence rates of prostate cancer.
* Androgens may play a key role in recovery of erectile function following radical prostatectomy.
* Testosterone replacement therapy does not appear to worsen LUTS. In fact, long-term testosterone treatment may potentially improve LUTS.
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