60 years of Error re Testosterone and Prostate cancer

Dr. Weeks’ Comment: In 1941, one doctor had one theory based on findings in one patient for which he then won a Nobel Prize. The theory is that giving testosterone to a man with prostate cancer is like throwing gasoline on a fire. This was believed for 60 years. It is not true.

GREAT VIDEO interview with Dr. ABRAHAM MORGENTALER

IS TESTOSTERONE DANGEROUS?

Dr. Abraham Morgentaler has spent decades challenging the historical dogma that testosterone therapy (TRT) accelerates prostate cancer growth, arguing that this belief is based on weak, limited evidence from the 1940s rather than modern clinical data. He proposes the saturation model, which posits that androgen receptors in prostate tissue become fully saturated at relatively low testosterone concentrations (approximately 250 ng/dL), meaning that further increases in testosterone do not stimulate additional cancer cell proliferation.

Morgentaler’s research and reviews of large-scale studies, including the TRAVERSE trial and various biopsy cohorts, indicate that there is no significant association between testosterone therapy and increased prostate cancer risk or progression. Recent publications, such as his 2026 Journal of Urology paper, advocate for a new framework of androgen adequacy versus inadequacy, supporting the safe use of TRT in carefully selected men with a history of prostate cancer or biochemical recurrence, particularly when it improves quality of life without compromising survival.

Historical Context: Morgentaler traced the contraindication of TRT to a 1941 study by Charles Huggins, noting it was based on data from only one patient treated for 18 days, yet it prohibited TRT for over 60 years.
Clinical Evidence: Data from over 5,000 men in the TRAVERSE trial showed no difference in prostate cancer diagnosis rates between those receiving testosterone and those on placebo.
Modern Application: Current evidence suggests TRT is safe for men with untreated prostate cancer on active surveillance, those post-radical prostatectomy, and even some with metastatic disease, provided they are monitored for PSA changes.

Here’s a deeper dive into Morgentaler’s work and the evidence base:

The Historical Origin

The contraindication traces to Charles Huggins’s 1941 paper, which reported that testosterone raised acid phosphatase levels in men with metastatic prostate cancer. Morgentaler’s 2008 historical review (“Guilt by Association,” Journal of Sexual Medicine) exposed the weakness: only one untreated patient received testosterone for just 18 days, while another reported patient had been previously castrated and was androgen-deprived — making him an outlier. Morgentaler also noted a fundamental logical flaw: proving that lowering testosterone shrinks cancer does not prove that raising testosterone grows it. Despite this, the conclusion shaped clinical practice for over 60 years.

The Saturation Model (2009)

Formally proposed in European Urology, the model is built on three mechanistic observations:

Testosterone and its derivative 5α-dihydrotestosterone (5α-DHT) exert prostatic effects by binding to the androgen receptor (AR).
There is a finite number of AR binding sites per cell.
Once those sites are fully occupied, additional circulating androgen cannot elicit further biological activity.

The saturation point is estimated at approximately 250 ng/dL (~8 nmol/L) — well below the normal physiologic range of 300–1,000 ng/dL. This explains the apparent paradox: castration (dropping T to near zero) causes dramatic tumor regression, yet giving testosterone to a hormonally intact man produces little to no additional stimulation. The prostate is “exquisitely sensitive” to changes at very low concentrations but largely indifferent above the threshold.

Morgentaler draws an analogy to other essential nutrients: prostate cancer, like all cancers, hijacks the mechanisms of its underlying tissue. It needs androgens, but also calcium, sodium, chloride, and many other substances. Depriving it of any one of these causes cells to suffer. Testosterone is “simply one of those requirements.”

Key Clinical Evidence

TRAVERSE Trial (2023)

The largest randomized RCT of TRT to date — 5,246 men with hypogonadism, median follow-up ~33 months:

Outcome	TRT Group	Placebo Group	P-value
High-grade PCa (Gleason ≥4+3)	5/2,596 (0.19%)	3/2,602 (0.12%)	0.51
Any prostate cancer	12 (0.5%)	11 (0.4%)	0.87
Acute urinary retention	0.77%	0.61%	NS
Invasive surgical procedures	0.89%	0.46%	NS

PSA rose modestly in the TRT group (~0.11 ng/mL at 3 months) but stabilized — consistent with the prostate filling to physiologic androgen levels, not malignant growth. No worsening of lower urinary tract symptoms.

Other Trial Data

PCPT and REDUCE trials (finasteride trials): control-arm biopsy data showed no relationship between naturally higher testosterone levels and prostate cancer risk.
Population-level data: Testosterone use in the U.S. increased sixfold from 2002 to 2013, with no corresponding increase in prostate cancer incidence.
Largest series of TRT in men with existing prostate cancer (reported 2026): Men on active surveillance, post-radiation, or post-radical prostatectomy who received TRT showed no significant differences in recurrence or progression rates compared to historical controls.

Advanced / Metastatic Disease

Morgentaler’s own clinical series of men with biochemical recurrence or metastatic prostate cancer on TRT showed:

No unexpected or rapid disease progression in most patients
Overall mortality 13.6%, prostate cancer–specific mortality 4.5%
In the metastatic group, 7 of 10 men with follow-up imaging showed no disease progression
Notable case: a 94-year-old man on androgen deprivation who was too fatigued to enjoy daily activities improved markedly on TRT

The 2026 Journal of Urology Paper

Morgentaler and Abdulmaged Traish published “Testosterone Does Not Drive Prostate Cancer: Presenting the New Framework of Androgen Adequacy vs Inadequacy” (J Urol 2026;215(6):688–701). Key points:

Systematically reviews the entire literature and finds no convincing evidence that testosterone drives prostate cancer development or progression.
Proposes replacing the old “androgen hypothesis” with a framework of adequacy vs. inadequacy — the prostate suffers from deprivation, not from adequate supply.
Argues that the field has relied on an “unchallenged historical narrative rather than evidence-based medicine.”
The paper generated editorial comment and letters in the journal, indicating active engagement from the urologic community.

Current Clinical Implications

Morgentaler’s position, supported by the evidence, is that TRT is safe in:

Men with untreated low-risk prostate cancer on active surveillance
Men post-radical prostatectomy
Men post-radiation therapy
Selected men with biochemical recurrence or even metastatic disease who prioritize quality of life

He has called for prospective RCTs comparing TRT with placebo before and after radical prostatectomy (for erectile function outcomes) and is exploring whether high-dose TRT or bipolar androgen therapy could be useful in treating biochemical recurrence or metastatic prostate cancer.

The broader message: testosterone is “unique among factors required for prostate cell function because it can be reduced to very low levels therapeutically without compromising survival” — but the reverse (that raising it is dangerous) has never been proven.

MORE INFO TO CONSIDER

Kill Prostate Cancer Without Killing Your Sex Drive by Dr. Frank Shallenberger, MD

October 12, 2026

Wouldn’t it be great if you could have your cake and eat it too? That’s not something that usually happens. But when it comes to treating prostate cancer, that’s exactly what a new study says.

The study shows that men being treated for prostate cancer by being deprived of testosterone can also have testosterone.

In fact, the results show that this revolutionary method of treatment might even be better than what is currently done, especially for your sex drive.

Prostate cancers are stimulated by the hormone testosterone. So, one of the most common ways to treat it is to deprive a man with prostate cancer of the hormone. The name of this approach is androgen deprivation therapy or ADT. ADT can be done with surgery, but is usually done with drugs that either decrease the levels of testosterone or render the testosterone unable to work by blocking its receptors. No matter how the man’s testosterone levels are dealt with, the end results of ADT are three: (1) The prostate cancer will initially stop growing and then shrink. (2) The man will have all of the undesirable and unhealthy results of not having any testosterone. (3) The prostate cancer will eventually learn how to grow with even very low levels of testosterone and the therapy will no longer work.

The reason why ADT stops working after a while has to do with the testosterone receptors on the cancer cells. Testosterone receptors consist of molecules on the surface of the cancer cells that testosterone can react with to stimulate the cells to grow. The more receptors a prostate cancer cell has, the more testosterone will stimulate its growth. And here’s the problem. When doctors give men ADT and knock out their testosterone, the cancer cells respond by increasing their receptors. In fact, they can increase the receptors so much that no matter how much ADT is given, the cells will still be able to get enough testosterone to grow. And this is why ADT eventually fails. But what if there was a way to stop the increase in receptors? Well, there is.

When doctors give a man with prostate cancer a very high dose of testosterone, the cancer cells respond by decreasing their receptors. It’s easy to understand why this would happen. When the cancer cells see how high the testosterone levels have become, they decrease the number of their receptors because with these high levels they need only a few receptors. So, with this in mind, it might make sense to alternate between giving a man with prostate cancer a very high dose of testosterone to decrease the receptors and then giving him a course of ADT once the receptors are low. In this scenario two things could happen. One, when the receptors are low the testosterone-lowering effects of the ADT will be more effective. Two, since the man is getting some testosterone, he will be much less likely to suffer from all of the significant side effects of ADT and will have a much better quality of life. All of these effects are beneficial. But that’s not all that can happen.

It turns out that although prostate cancer cells are stimulated by normal levels of testosterone, extremely high levels of testosterone have a totally different effect. Extremely high levels of testosterone actually cause prostate cancer cells to go into apoptosis. That means that they die! This is especially true when they have very high levels of receptors. That’s because the more receptors there are, the more sensitive the cancer cells are to the hormone. And that’s the secret behind this new form of prostate cancer therapy. When a man is given ADT, the result is that the prostate cancer cells dramatically increase the number of receptors. And it’s at that point that the cancer is extra vulnerable to super high doses of testosterone. So, when the doctor follows a course of ADT by a course of high-dose testosterone, the result could be a better cancer die off. But does it really work? That’s what one group of researchers set out to discover. They call the therapy Bipolar Androgen Therapy.

The researchers looked at 26 men with prostate cancer, many of whom had serious disease. Almost all of them had cancers that were a Gleeson score of 7 or higher. Cancers with scores higher than 7 are the most aggressive forms of prostate cancer. The average PSA level was 27, and some of the men had levels over 250. And in most of these men, the cancer had already spread to the bones. They gave the men ADT for the next 18 months. At the six-month point, their PSA tests were all less than 4 – indicating a very positive response to ADT.

Then at the six-month point, the researchers gave each of the men an injection of 400 mg of testosterone. This was a high enough dose to bring their blood testosterone levels way over the normal range. They repeated the injections two more times spaced 28 days apart. After these initial three injections, the next three months the men received only the ADT. And then they had another three-month series of treatments with the testosterone injections. Here’s what happened at the end of the 18 months of treatment.

Most of the men (59%) had a PSA less than 4, indicating complete control of their cancers. This includes some of the men who had PSA levels over 100 at the beginning of the study. And 10% had a PSA level that was undetectable. One man appeared to have been completely cured by the treatments because even after three months of stopping all therapy, his PSA level was still undetectable. These results are much better than what’s typically seen with ADT. And here’s something really important. ADT usually causes men to be weak, have little to no sex drive, become impotent, and have low energy. This was the case with these men also in the first six months of ADT only. But all that changed when they started getting the testosterone. Once they had the testosterone, the quality of life scores went up in all of the men.

Because of the significant difference in results in each of the men in this study, it’s hard to predict who will have the best results with this new method. But two points stand out. One, considering the fact that many of the men in this study had very advanced disease, the fact that 59% had PSA levels less than 4 after 18 months is remarkable. Two, the most undesirable aspects of ADT are the side effects and quality of life issues. And every one of the men improved in that area once they started having the testosterone injections.

So, if you have prostate cancer and are about to start ADT, make sure you have a conversation with your doctor about this new study. Especially if your quality of life is going down. At the same time, as I have reported to you in the past, it’s critically important that men on ADT engage in resistance training at least three hours each week. That, combined with the testosterone injections, will do a lot to prevent muscle and lean body tissue loss.

Yours for better health,

Frank Shallenberger, MD

REF: Schweizer MT, Wang H, t al. Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer: Results From the Phase II BATMAN Study. Prostate. 2016 Sep;76(13):1218-26.

Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer: Results From the Phase II BATMAN Study

Michael T. Schweizer, Hao Wang, Brandon Luber, Rosa Nadal, Avery Spitz, D. Marc Rosen, Haiyi Cao, Emmanuel S. Antonarakis, Mario A. Eisenberger, Michael A. Carducci, Channing Paller, Samuel R. Denmeade

First published: 24 June 2016

https://doi.org/10.1002/pros.23209Digital Object Identifier (DOI)

Read the full text

Abstract

BACKGROUND

We have previously documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e., Bipolar Androgen Therapy; BAT). Because, an adaptive increase in androgen receptor expression following chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with hormone-sensitive (HS) prostate cancer (PC) would also respond to BAT if given following a 6-month ADT lead-in.

METHODS

Asymptomatic HS PC patients with low metastatic burden or non-metastatic biochemically recurrent disease were enrolled. Following 6-month of ADT, those with a PSA <4 ng/ml went on to receive alternating 3-month cycles of BAT and ADT. BAT was administered as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29, and 57. ADT was continued throughout the study to allow rapid cycling from near castrate to supraphysiologic range T following T injections. The primary endpoint was the percent of patients with a PSA <4 ng/ml after 18 months. Secondary endpoints included radiographic response and quality of life (QoL).

RESULTS

Twenty-nine of 33 patients received BAT following the ADT lead-in. The primary endpoint was met, with 17/29 men (59%, 90% confidence interval: 42–74%) having a PSA <4 ng/ml at 18 months. Ten patients receiving BAT had RECIST evaluable disease, and eight (80%) objective responses were observed (four complete; four partial). Three patients progressed per RECIST criteria and three had unconfirmed progression on bone scan. Men treated with 6-month of ADT had improved QoL following the first cycle of BAT as measured by the SF-36, FACT-P, and IIEF surveys.

CONCLUSIONS