Testosterone deficiency increases prostate cancer risk

Low value for free testosterone is an independent PCa risk factor

Since 1941, testosterone has continued to fuel prostate cancer (PCa) and therefore testosterone administration is contraindicated in PCa patients even after radical prostatectomy. But more recent findings in hypogonadal men hint at a slow rehabilitation of testosterone substitution. Perhaps this is a paradigm shift?

The procedure recommended by international and national guidelines for patients with hypogonadism includes classic testosterone substitution. Although according to AUA and EAU guidelines, there is currently no evidence that such an approach would increase the PCa risk of hypogonadal men, fears of testosterone substitution persist in public opinion. However, these are unfounded, as the following study shows.

Testosterone replacement in hypogonadal men

For a registry study started in 2004, 428 hypogonadal men received testosterone substitution with 1000 mg hormone every three months for a period of 13 years. In addition, 395 men decided against hormone replacement therapy and thus formed the control group. For all participating men, initially suspicious lesions or an active PCa were excluded using transrectal ultrasound. A re-evaluation took place between one and four times a year. Biopsies on suspected PCa were performed according to the EAU guidelines.

Testosterone administration reduces PCa risk in hypogonadism

The results showed that 12 men (= 2.8%) in the testosterone group suffered from prostate cancer. In the control group, on the other hand, there were 44 patients (= 11.1%).  Of the men with PCa from the testosterone group, the positive biopsy occurred within the first 14.2 months. None of the patients with hormone replacement tested positive for PCa for the first time after 18 months.

All affected men underwent radical prostatectomy after diagnosis of PCa. Histologic evaluation showed Gleason Score (GS) ≤ 6 in three patients, GS 3 in all others. 10 of the 12 PCa patients continued testosterone replacement approximately 25 months after successful prostatectomy. In comparison, GS ≤ 6 was found in two cases among the men in the control group, GS 7 among seven men, GS 8 among 21 participants and GS 9 among 14 men. 

In the control group, 14 patients (= 32%) also suffered biochemical progress under Androgen deprivation therapy (ADT) and 12 men (= 27%) died. In the testosterone group, however, there was neither biochemical progress nor death.

In summary, it can be concluded from this work that hypogonadal men with testosterone administration have a lower incidence of PCa, and in the cases that form a tumor, these lesions have significantly lower tumor degrees than the untreated hypogonadal control group.

The result is very surprising, especially before the dogma that PCa and testosterone do not go together, which has been a predominant belief since 1941. However, these results have now been supported in another independent retrospective study.

For men in the lower testosterone reference range, the EAU guidelines routinely recommend free testosterone testing. If this is also clearly lowered, hypogonadism is present. As previously explained, low testosterone levels are associated with significantly higher grade prostate tumors. However, equally low free testosterone levels seem to increase the risk of an aggressive PCa.

Reduced free testosterone as a risk factor in PCa

In total, the researchers retrospectively evaluated the data of 830 PCa patients. The men all received radical prostatectomy and both free testosterone and Gleason score and cancer stage were determined.

The results of this work showed that low levels of free testosterone were a good predictor for high-risk tumors (GS 9-10). To what extent these findings will ultimately lead to a shift in the treatment of testosterone substitution in hypogonadal patients without PCa or after radical prostatectomy remains to be seen.

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