Originally published 4/21/2018
Less than a year after we posted the original blog on the safety of testosterone replacement therapy (TRT) in the context of prostate cancer (PCa), a team from Baylor College of Medicine (Houston, TX) published the following statement: “The fears of [TRT] causing or worsening prostate cancer do not appear to be well supported by available data.”[i] In fact, starting in 2010, doctors appear to have been more comfortable prescribing TRT for patients after PCa treatment. “Men who received testosterone were younger, more likely to have erectile dysfunction, depressive disorder, and lower pretreatment PSA values compared to men who did not receive.” [ii]
In 2020, Lenfant, et al. published their extensive review of peer-reviewed literature (up to Oct. 2019) on the subject. Noting a “lack of evidence regarding the safety of long-term treatment for the risk of [PCa] progression,” they concluded there was collective agreement that TRT does not increase the risk of subsequent discovery of prostate cancer.[iii] According to Ory & Ramasamy, “Recent evidence has failed to show an increased risk of de novo disease in the general population, or of progression or recurrence in men after definitive therapy or on active surveillance for localized disease.”[iv] Nevertheless, Lenfant, et al. caution against TRT in cases of high risk localized PCa, positive surgical margins, lymph node involvement, and metastatic disease.
Ory & Ramasamy’s position is consistent with that of the Lenfant team. Their hypothesis is that the “testosterone bath” or saturation theory explained in the blog below does not apply to men with dangerous PCa cell mutations. They point to “existing evidence in advanced prostate cancer: increasing testosterone >20 ng/dL in men with metastatic or recurrent prostate cancer is associated with worse outcomes,” and they emphasize “… the importance of involving the patient’s oncologist and thoroughly counseling them as to the risks of pursuing testosterone in this disease state.”[v]
Thus, more research is needed into the association between high-risk PCa cell lines and the risks of TRT. However, for the majority of men treated for low-to-intermediate risk localized PCa but who suffer from symptoms of lab-tested low testosterone, TRT appears to be a safe way to restore quality of life.
I have previously written on the safety of testosterone replacement therapy (TRT) as well as the use of multiparametric MRI to monitor TRT use during active surveillance. Both of those articles are backed up by published research because I believe it’s important for patients to have access to scientifically tested information.
Ever since the 1940s, mainstream medical practice has firmly discouraged TRT for men at risk of prostate cancer, or already diagnosed with it. It was believed that testosterone “fuels” prostate cancer. Yet numerous studies in the past decade have shown that administering TRT to patients with low testosterone (low T) who also had prostate cancer made no difference whatsoever with their cancer! Their testosterone levels increased, but had no detectable effect on their cancer. While these studies concluded that testosterone supplementation does not drive prostate cancer, they don’t answer the question, “Why not?”
Answering the question
I found a 2009 paper by Gat et al.[vi] that offers a credible answer. First, it’s important to understand a few basics. Testosterone is a male hormone produced by the testicles. It is supplied to the body by blood circulation, where “much of it is transported bound to a specific plasma (blood) protein, sex hormone-binding globulin (SHBG).”[vii] Another circulating portion of it is bound to another blood protein called albumin. A third amount, the least, is called free testosterone because it is not bound to anything. Free testosterone is also called bioavailable testosterone, because not being bound to a protein, it easily picked up by tissues. Thus, a blood draw to evaluate total testosterone actually measures the levels of both bound and free testosterone that are circulating in the blood.
Gat et al. discovered a condition – actually, a flaw in Mother Nature’s design – that causes a certain amount of free testosterone to detour directly to the prostate gland instead of dispersing into the bloodstream. They call it a “back-door” entry to the prostate. The flaw has to do with standing upright, which means that venous blood (blood in veins) returning to the heart from the lower part of the body has to fight against gravity. In order to do so, the veins have one-way valves that prevent venous blood from flowing backward and pooling low in the body. According to Gat’s research, those valves tend to wear out as men age. In particular, the vein heading upward from the testicles (Internal Spermatic Vein or ISV) is prone to this.
When the valves wear out
If the ISV malfunctions, blood pools in the veins directly above the testicle. The veins begin to bulge with extra blood, and the pressure of the pooled blood is greater than the flow pressure from the prostate. While the majority of ISV blood will still make its way to the rest of the body, some of it is forced upward (backflow) into the prostate gland. The blood that heads to the rest of the body will carry the majority of testosterone produced by the testicles, since it is bound with blood proteins. However, the majority of free testosterone – the kind most readily available for tissue absorption – is not traveling with those proteins. Instead, the blood that backflows to the prostate is saturated with free testosterone, reaching concentrations up to 130 times greater than free testosterone in circulating blood![viii] This means the gland is literally bathing in free testosterone. It also means that free testosterone levels will be lower when a testosterone blood draw is taken.
The effect of the free testosterone “bath”
Now we circle back to the connection between testosterone and prostate cancer. 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 occurs – 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. So yes, there is a causal link between testosterone and prostate cancer – but it’s not found on the path decades of research has followed.
Gat’s work illuminates the problem of two different testosterone effects: total testosterone circulating in the blood vs. a localized saturation of free testosterone affecting the prostate gland. The results of studies showing that testosterone supplementation to treat low T did not affect prostate cancer were puzzling to those who expected the cancer to run wild. However, if Gat is correct, it’s not serum blood levels that are cancer-causing. It’s the pooling and backflow of testicular venous blood saturating the gland that’s the source. No wonder the efforts to find a correlation between serum levels of testosterone and prostate cancer ended up with frustration.
To be clear, Gat et al. are not claiming that every case of prostate cancer is due to the weak ISV valves. There are many factors that can stimulate genetic changes in prostate cells such that they become malignant. However, high serum testosterone is not the culprit, and since TRT is a treatment that affects blood levels, using it therapeutically to benefit low T patients should not be a source of worry
What is needed now is verification of Gat’s (and his colleagues’) work, and that must come from replicating their methodologies. Science is only as good as repeated research results. It is hoped that the will and means will be found to validate this discovery, since TRT can be beneficial to low T patients regardless of their risk or history of prostate cancer.
NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.
[i] Rodriguez KM, Pastuszak AW, Khera M. The Role of Testosterone Therapy in the Setting of Prostate Cancer. Curr Urol Rep. 2018 Jun 30;19(8):67.
[ii] Chen T, Li S, Eisenberg ML. Trends in Testosterone Therapy use in Prostate Cancer Survivors in the United States. J Sex Med. 2021 Aug;18(8):1346-1353.
[iii] Lenfant L, Leon P, Cancel-Tassin G, Audouin M et al. Testosterone replacement therapy (TRT) and prostate cancer: An updated systematic review with a focus on previous or active localized prostate cancer. Urol Oncol. 2020 Aug;38(8):661-670.
[iv] Ory J, Ramasamy R. Testosterone Therapy in Men with Advanced Prostate Cancer: Too Many Unknowns for Safe Use. Androg Clin Res Ther. 2021;2(1):131-132
[v] Ory, Ibid.
[vi] 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.
[vii] https://en.wikipedia.org/wiki/Testosterone
[viii] Gat, Y & Gornish, M. (2009). Reversal of benign prostate hyperplasia by super-selective intraprostatic androgen deprivation therapy. European Urological Review. 4. 10-14.
About Dr. Dan Sperling
Dan Sperling, MD, DABR, is a board certified radiologist who is globally recognized as a leader in multiparametric MRI for the detection and diagnosis of a range of disease conditions. As Medical Director of the Sperling Prostate Center, Sperling Medical Group and Sperling Neurosurgery Associates, he and his team are on the leading edge of significant change in medical practice. He is the co-author of the new patient book Redefining Prostate Cancer, and is a contributing author on over 25 published studies. For more information, contact the Sperling Prostate Center.
