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.
For years, testosterone and DHT (dihydrotestosterone) have been cast as villains in the prostate cancer story. But like many things in medicine, the truth isn’t so black-and-white. New genomic research is revealing a much more nuanced relationship—one that could reshape how we understand, diagnose, and treat prostate cancer.


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


Think of luminal tumors like a high-performance car that needs premium fuel (testosterone) to run. Take away the fuel, and the car stalls. Basal tumors, on the other hand, are off-road vehicles—they’ll keep moving no matter what terrain you throw at them.


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.


Dr. Schaeffer emphasizes this: In luminal tumors, the biology is well understood and highly controllable with androgen modulation. Reintroducing testosterone under close medical supervision doesn't necessarily fuel recurrence—and may even support recovery in carefully selected patients.


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/

https://pmc.ncbi.nlm.nih.gov/articles/PMC9983358/

https://pmc.ncbi.nlm.nih.gov/articles/PMC6783279/