The PSA/biopsy puzzle
Did you ever work on a 1,000 piece jigsaw puzzle? If so, you probably found yourself in a situation where one section has come together nicely, but a piece is still missing. 600 loose pieces are lying all around the unfinished puzzle on the table. You know EXACTLY what the missing piece should look like, and you have scanned over those 600 pieces at least 10 or 12 times, but you are looking for is not to be found. It’s maddening, so you move to another area of the puzzle and start working there. Several hours later (in jigsaw puzzle time) you stumble on the previously missing piece. It doesn’t look like what you were expecting, but somehow you now recognize it instantly. Aha! Triumphantly, you put it where it goes and you think, “It was right there in front of me all the time. How come I didn’t see it sooner?
A big prostate cancer puzzle is the search for a reliable, inexpensive way to know if a newly diagnosed prostate cancer (PCa) patient is harboring a dangerously aggressive tumor. Of course, his clinical factors (age, PSA, Gleason score and tumor stage) provide significant information. But maybe there’s a puzzle piece lying right in front of us, but we don’t recognize it because it doesn’t look like what we are picturing in our heads.
Looking for testosterone in a biopsy needle
A Japanese research team may have found a missing piece of the big picture.[i] Their starting point was the fact that there was no consensus on a possible connection between testosterone levels in the prostate gland itself, and the aggressiveness of prostate cancer. But there hasn’t been a good way to measure testosterone in prostate tissue.
Generally, testosterone is measured by a blood draw to evaluate the amount of this male hormone circulating in the blood. Until the work of this team, there wasn’t really an accurate or efficient way to measure testosterone in the very small tissue samples that are obtained using biopsy needles. Previous efforts to measure androgen levels in tissue using radioimmunoassay had problems. Not only were large tissue specimens needed (e.g. prostatectomy specimens) but there were concerns with tissue-handling issues, confounding factors, and problems with methodological accuracy.[ii] However, due to advances in a chemical analysis technology called liquid-chromatography tandem mass spectrometry (LC-MS/MS), the team was able to overcome the challenge of reliably and specifically assessing testosterone levels in a very small thread of prostate tissue from a biopsy.
For the study, the researchers used blood and biopsy samples from 196 patients diagnosed with PCa. What they found was that clinical factors such as high Gleason score and percent of positive biopsy needles were strongly correlated with high concentrations of testosterone in the prostate gland. The hormone concentration was consistently high throughout the gland, whether in healthy tissue or tumor tissue.
Thus, at the time of biopsy, if there are high androgen (male hormone) concentrations in the prostate tissue “snips” as well as PCa cells, it would indicate a need for aggressive treatment since such patients would be at risk for advanced PCa. The authors conclude, “Tissues T levels determined from biopsy specimens, in combination with pathological features, may be one of several useful diagnostic tools for predicting the prognosis and determining a suitable therapeutic program for patients with prostate cancer.”[iii]
How did all that testosterone get there?
This leads us to a different section of the puzzle: what is all that testosterone doing there, and how is it connected with PCa? One recent theory as presented in a 2009 paper by Gat et al.[iv] suggests that free testosterone – the kind most readily available to be taken up by prostate cells – gets saturated in the prostate gland due to a plumbing problem (backflow of blood containing free testosterone into the prostate). I have previously written about that theory. At that time I wrote:
According to Gat’s publication, when the abnormal valves lead to a concentration of free testosterone in the prostate, this hormone places constant stress on the genes that respond to it. (Remember: hormones are chemical messengers.) This stress pushes cell mutations, as an increasing number of genetic errors occur – and the cell’s mechanism for detecting copy errors is increasingly damaged. The authors theorize that rapid proliferation of prostate cells results, leading to the condition known as benign prostatic hyperplasia (BPH), and eventually to prostate cancer in many cases.
If you are interested, you may want to get caught up by reading my blog post on the subject.
For now, I believe that the Japanese study is the piece that completes the section of the prostate puzzle on the true relationship between testosterone and prostate cancer. It indirectly supports the Gat hypothesis that high male hormone concentrations trapped in the prostate gland eventually cause trouble.
Gat’s work is out there for all to see, but perhaps it is being overlooked because it’s not the answer science imagines it’s looking for.
[i] Miyoshi Y, Uemura H, Umemoto S, Sakamaki K et al. High testosterone levels in prostate tissue obtained by needle biopsy correlate with poor-prognosis factors in prostate cancer patients. BMC Cancer. 2014; 14: 717.
[iv] Gat Y, Joshua S, Gornish MG. Prostate cancer: a newly discovered route for testosterone to reach the prostate : Treatment by super-selective intraprostatic androgen deprivation. Andrologia. 2009 Oct;41(5):305-15.