Testosterone, DHT, and Prostate Cancer: Unraveling the Complex Connection
Testosterone, DHT, and Prostate Cancer: Unraveling the Complex Connection
Key takeaways
- Testosterone doesn't cause prostate cancer but may influence long-term risk through epigenetics.
- Luminal tumors respond well to hormone suppression and rarely spread; basal tumors are more aggressive.
- Low testosterone levels can be linked to higher-grade prostate cancers.
- Genomic testing helps personalize treatment—especially in choosing whether testosterone therapy is safe.
Let’s break down the real story behind hormones and prostate cancer risk, and why not all prostate cancers are created equal.
Why High Testosterone Doesn’t Always Mean High Risk
Men in their 20s have the highest levels of testosterone and DHT in their lifetime. Yet prostate cancer in this age group is extremely rare. This paradox has puzzled researchers for years. If testosterone were a direct fuel for prostate cancer, we’d expect young men to be diagnosed more frequently—but the opposite is true.
Similarly, women rarely develop breast cancer when estrogen levels are at their peak. This observation suggests that hormones alone don’t ignite cancer; instead, they may shape the environment in which cancer develops over time.
The Epigenetic Imprint of Testosterone
It turns out, testosterone plays a role in "programming" the prostate at the epigenetic level—how genes are expressed rather than what genes are present. During adolescence and early adulthood, surges of testosterone shape prostate cell behavior for the decades to come. This hormonal environment can set the stage for future cancer development, depending on other factors like inflammation, DNA repair capability, and metabolic stress.
So while testosterone itself doesn’t cause cancer, it may influence who's at risk—especially as men age and accumulate additional mutations or stressors in prostate tissue.
Low Testosterone and Aggressive Cancers: Another Paradox
Here’s where things get even more interesting. A widely cited study published in The New England Journal of Medicine found that men with lower testosterone levels were more likely to develop high-grade, aggressive prostate cancers. That finding has since been reinforced by genomic data.
Why? One theory is that if cancer develops in a low-androgen environment, it means the tumor is highly sensitive to even minimal hormonal signals. These cancers are often more aggressive because they’ve adapted to survive in what should be an unfriendly environment.
This leads to a surprising conclusion: The most lethal tumors may not be fueled by testosterone—but instead, may arise in spite of low levels.
Luminal vs. Basal Tumors: Two Very Different Beasts
Recent transcriptomic research (analyzing over 140,000 prostate cancer samples) has helped classify prostate cancers into two major biological types:
1. Luminal Tumors
- Dependent on testosterone and DHT for growth
- More likely to be bulky, proliferative, and localized
- Highly responsive to androgen deprivation therapy (ADT)
- Less likely to metastasize
2. Basal Tumors
- Can thrive with little or no testosterone
- Use alternative growth pathways
- More likely to metastasize and resist hormonal treatment
- Represent the deadliest form of prostate cancer
Why This Matters for Treatment
If a man develops prostate cancer and his tumor is luminal-type, androgen deprivation therapy (ADT)—which lowers testosterone and DHT—is often extremely effective. But if the tumor is basal-type, ADT may do very little.
That distinction isn’t visible through PSA levels or Gleason scores alone. It takes molecular profiling to know which category a tumor falls into. Genomic testing, like transcriptome analysis, is helping physicians personalize treatment strategies with greater precision.
The Case for Testosterone Replacement—Even After Diagnosis
This all leads to a controversial but evidence-informed viewpoint: Testosterone replacement therapy (TRT) may not be universally dangerous for men with prostate cancer. In fact, if a man is recovering from a low-risk, luminal-type cancer and has clinically low testosterone, there may be a case for supporting his hormonal health.
What This Means for the Future of Prostate Cancer Care
The days of one-size-fits-all treatment are numbered. Understanding a tumor’s transcriptomic profile—its “biological fingerprint”—can reveal:
- Likelihood of recurrence or spread
- Responsiveness to hormone therapies
- Suitability for testosterone replacement
- Need for more aggressive interventions
This is precision medicine in action. And as research grows, men may soon be offered more personalized, biologically driven care instead of broad-brush strategies that don't reflect tumor diversity.
Citations:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10164147/