Very low testosterone levels can be linked to a more aggressive prostate cancer, due to the prime prostate cancer driver, Dihydrotestosterone, being produced by systems that by-pass testosterone.
Men with very low testosterone levels appear to have a reduced risk of developing prostate cancer overall, with one large 2018 European Urology study (1) finding a 23% lower risk for those with the lowest levels compared to men with higher levels.
However, there’s a significant ‘But’. This research prompted an immediate response from Christopher JD Wallis and other Canadian scientists in the same journal - an article entitled “Low Testosterone and Prostate Cancer: Is the Protection Real?”
The reason is simple - the protective conclusion is contradicted by a significant association between very low testosterone and more aggressive forms of the disease. Men with the lowest testosterone levels who have been diagnosed with prostate cancer are more likely to have aggressive disease. Indeed, low testosterone levels may indicate disease worsening in men diagnosed with low-risk prostate cancer who are being evaluated during active surveillance, according to a study (2) of men with low-risk prostate cancer undergoing active surveillance which found that those with free testosterone levels below 0.45 ng/dL had a significantly higher risk of disease reclassification to higher risk, with an odds ratio of 4.3.
Another study found that low total serum testosterone levels at diagnosis were strongly associated with aggressive prostate cancer, with men in the low testosterone group having a 2.9-fold increased risk of intermediate-risk, a 5.6-fold increased risk of high-risk, and a 72.4-fold increased risk of metastatic disease compared to men with normal testosterone levels. This association was also linked to a 10.7-fold increased risk of prostate cancer-specific mortality (3).
So, while low testosterone may sometimes reduce the initial risk of prostate cancer, it may also be a marker for more aggressive disease biology. Indeed, research shows it might be more appropriate to measure levels of the enzyme 5-alpha reductase, that can convert nice safe testosterone and other precursors to the more aggressive form of testosterone - Dihydrotestosterone, or DHT. Levels of the latter might also be a better indicator of aggression. Not all DHT is produced from testosterone.
Dihydrotestosterone (DHT) plays a central role in the progression of prostate cancer, particularly in the development of castration-resistant prostate cancer (CRPC), where tumors continue to grow despite low circulating testosterone levels. While androgen deprivation therapy (ADT) aims to reduce testosterone, CRPC often persists due to intratumoral synthesis of DHT from alternative precursors, such as androstenedione and inactive androgen metabolites like 3α-diol, bypassing testosterone as the primary precursor (4). This alternative pathway involves enzymes like steroid 5α-reductase isoenzyme-1 (SRD5A1) and 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), which are upregulated during treatment by ADT and facilitate the conversion of these precursors into active DHT. Findings have suggested that ADT might even by driving a more aggressive cancer - and we have seen this in a few patients at CANCERactive.
We have also covered before how 5-alpha reductase can be reduced by Dutasteride, and even by a number of Natural compounds.
Go to: 5-alpha reductase, Dutasteride and prostate cancer
Go to: Natural compounds that reduce 5-alpha reductase.
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References
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Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies; Eleanor L Watts et al; European Urology, Volume 74, Issue 5, November 2018, Pages 585-594
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Low free testosterone levels predict disease reclassification in men with prostate cancer undergoing active surveillance; Ignacio F. San Francisco et al; BJUI, 21 February 2014
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Low serum testosterone is associated with tumor aggressiveness and poor prognosis in prostate cancer; Huankang Tu et al; Oncol Lett; 2017 Mar;13(3):1949-1957
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Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer; Kai-Hsiung Chang et al; PNAS July 27, 2011, 108 (33) 13728-13733.