310 - The relationship between testosterone and prostate cancer, TRT, and more

KEYPOINTS

• 01

  TRAVERSE found no increase in prostate cancer with testosterone, but its limits matter.

  TRAVERSE was designed mainly to test whether testosterone replacement raises cardiovascular risk, and it found it did not. Urologist Ted Schaeffer walks through its pre-specified prostate analysis. The roughly 5,300 men were symptomatic and hypogonadal, averaged in their 60s, and had a low median PSA of about 0.9, making them a low-risk group. Treatment raised testosterone only modestly, about 140 ng/dL, and more than 60% had dropped out by five years. Only about 23 prostate cancers were diagnosed, with no difference between testosterone and placebo. Peter notes the incidence curves diverged slightly, and both agree the trial was likely too small and short to rule out a small effect.

• 02

  In the trial, PSA kept working as a warning signal on testosterone.

  Most men's PSA changed by less than half a point during the trial. The men diagnosed with cancer had higher PSAs at entry and larger rises over time. Ted's takeaways: men with low PSA have low prostate cancer risk, and PSA changes can be interpreted much as usual in men taking exogenous testosterone.

• 03

  The saturation model: prostate androgen receptors max out at low testosterone levels.

  Androgens bind the androgen receptor, which moves to the nucleus and switches on androgen-responsive genes. Once a tissue's receptors are saturated, extra hormone does little more. Saturation thresholds vary by organ. Modeling by former Drive guest Abraham Morgentaler put prostate saturation at a serum testosterone of roughly 200–250 ng/dL, about the 10th percentile for adult men, according to Peter. Prostate and hair follicles are rich in 5-alpha reductase, which converts testosterone to DHT, about 10 times more potent, amplifying the effect. Muscle needs much higher levels for anabolic benefit. That's why raising a man from 300 to 800 ng/dL can visibly build muscle while barely moving PSA.

• 04

  Benign prostate cells are more sensitive to testosterone than cancer cells.

  Benign prostate cells carry higher densities of androgen receptors. Ted says studies of testosterone supplementation more often show mild worsening of BPH (enlarged prostate) and urinary symptoms than any effect on cancer. He describes this as consistent with TRAVERSE and several smaller studies over two to three decades.

• 05

  Aggressive prostate cancers tend to rely less on androgen signaling.

  An early-2000s New England Journal paper Peter and Ted discussed on Ted's first appearance linked lower testosterone to higher-grade cancer. Ted's lab built a nine-gene androgen receptor activity (ARA) signature from mRNA in tumor tissue. Larger signatures of 250 or 600 genes tell the same story: tumors with low androgen receptor output are more aggressive, spread more and resist standard therapy, using other pathways such as PTEN loss or MYC. Ted's garden analogy: high-AR tumors are big weeds with thin roots, while low-AR tumors look nothing like normal gland and are the dangerous ones.

• 06

  Genomic testing can sharpen treatment for higher-grade disease.

  Ted collaborated on Decipher, a clinically certified mRNA test from biopsy or surgical tissue that scores aggressiveness from about 22 genes. A broader genomic panel from the same test reports the ARA score and tumor subtype. In low-grade (Gleason 3+3) cancer, Decipher flags an aggressive outlier only about 7% of the time, and surveillance usually catches those anyway. In phase 3 trial analyses, low-ARA tumors responded especially well when standard hormone therapy was intensified with drugs like enzalutamide, apalutamide or darolutamide. NRG radiation trials, fully enrolled, are testing this, with results expected in about two years.

• 07

  Ted rarely advises against testosterone replacement for symptomatic low testosterone.

  For a cancer-free, symptomatic, hypogonadal man, Ted can't think of a case where he'd advise against it, because low testosterone threatens cardiovascular, bone, muscle and cognitive health. Strikingly, if a man on replacement at about 800 ng/dL is diagnosed with low-grade cancer on surveillance, Ted keeps him on it. He says there's no evidence it accelerates prostate cancer, and about 30% of men naturally run that high. He wouldn't encourage going above that, and he monitors both men the same way.

• 08

  Low-AR, intermediate-risk tumors may favor surgery over radiation.

  Radiation for higher-grade cancer is paired with androgen deprivation, which takes testosterone to near zero, sensitizes cells and adds DNA damage. Ted calls that deprivation 'incredibly morbid.' Only about 50–60% of men recover normal testosterone after two years of it. Because benign tissue remains after radiation, restarting testosterone can create false-positive PSA rises. After surgery with favorable pathology, Ted can keep men on testosterone, perhaps around 400 ng/dL.