Low Testosterone Is Linked to Higher Risk of Prostate Cancer Becoming More Aggressive

The appointment goes something like this. A man has been diagnosed with early-stage prostate cancer. His doctor explains, with genuine reassurance, that the cancer is slow-growing, low-risk, confined. The recommended approach is not surgery, not radiation, but watchful waiting: regular biopsies, PSA blood tests, careful monitoring. The name for this strategy is active surveillance, and for many men it is the right call. The tumour may never require treatment at all.

What the doctor needs to know, however, is whether this particular man is likely to stay in that comfortable zone or whether his cancer will quietly upgrade into something that requires urgent action.

That risk-stratification problem is one of the more stubborn challenges in prostate cancer management. Doctors already use PSA levels, tumour density, and biopsy grading to estimate trajectory, but these markers leave real uncertainty. A new finding from MD Anderson Cancer Center now suggests that a routine hormone measurement, the kind already taken for dozens of other reasons, might sharpen those predictions considerably. The culprit, or rather the signal, is testosterone, and the direction of the association is not what anyone expected.

For decades, the dominant assumption in prostate oncology was that high testosterone feeds prostate cancer growth. This logic drove the development of androgen-deprivation therapy, which remains a mainstay of treatment for advanced disease. Charles Huggins won a Nobel Prize in 1941 partly for demonstrating that surgically lowering testosterone caused prostate tumours to regress. The hormone, in the popular framing, is fuel.

Justin Gregg and colleagues at MD Anderson examined a cohort of 924 men enrolled in an active surveillance programme between 2001 and 2024. Their average age was around 64. The average baseline testosterone was 394 ng/dL, but nearly 30 percent of the group had levels at or below 300 ng/dL, the clinical threshold for hypogonadism. Median follow-up for the non-progressors was just under four years.

The key outcome of interest was not simple progression but what the researchers called “extreme” progression: advancement to Grade Group 3 or higher, representing a meaningful shift toward more aggressive disease. This is the clinical red line.

Men with low testosterone were significantly more likely to cross it. After adjusting for age, BMI, PSA density, and biopsy tumour volume, the hazard ratio for extreme progression in the low-testosterone group was 1.61, roughly a 60 percent higher likelihood of their cancer making that unwelcome jump. The association held up when the researchers tried alternative testosterone cut-points and tested additional potential confounders. Interestingly, low testosterone was not meaningfully associated with moderate progression to Grade Group 2, only with the more severe outcome. “Active surveillance is a safe and effective option for many men with early-stage prostate cancer,” says Gregg, who is an associate professor of Urology and Health Disparities Research at MD Anderson. “However, identifying which patients may be more likely to experience progression remains a key challenge.”

Why would low testosterone be associated with a more aggressive cancer trajectory? The biology here is genuinely murky, and the paper is careful not to overstate its hand. One hypothesis involves androgen receptor sensitivity: when testosterone levels are low for extended periods, prostate cells may upregulate their receptors or develop alternative activation pathways, making them paradoxically more responsive to whatever androgen does remain. Another possibility is that hypogonadism is a marker of broader metabolic dysfunction, obesity-related inflammation, or altered steroid hormone metabolism, and that these co-occurring conditions are the actual drivers. The retrospective design cannot distinguish between these possibilities, and the authors are explicit about that. What the study establishes is an association; the causal mechanism requires prospective investigation with better tools.

There are limits worth noting. The study was conducted before MRI-based risk stratification became routine, which means initial grading may have been less precise than current standards. Blood samples were not uniformly collected in the morning (when testosterone peaks) or repeated to confirm hypogonadal levels, as guidelines technically recommend. The cohort had limited racial and ethnic diversity, and there was no data on whether men were taking 5-alpha reductase inhibitors, which lower both PSA and androgen metabolism. Future work will need to address all of this in prospective settings.

The clinical implication being floated, carefully and appropriately, is that baseline testosterone could serve as an additional stratification marker for men entering surveillance programmes. Men with low testosterone might warrant more intensive monitoring or earlier discussion of definitive treatment. This does not mean every man with low testosterone should rush to treat his prostate cancer, and it certainly does not mean that testosterone therapy would be protective (an intervention with a complicated history and unresolved questions of its own). “Understanding how hormonal factors influence prostate cancer biology may help us refine surveillance strategies,” Gregg notes.

The broader point is that testosterone measurement is cheap, routine, and already done for a dozen other clinical reasons. If it turns out to carry prognostic weight in the surveillance setting, incorporating it into risk models costs almost nothing. Whether it will survive prospective validation, with contemporary MRI grading and properly standardised sampling, remains to be seen. But the field now has a specific, testable hypothesis about a hormone it long assumed was only dangerous in excess.

DOI / Source: https://doi.org/10.1097/JU.0000000000004986

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