Testosterone therapy and the prostate: myths and facts

"Testosterone feeds prostate cancer" is one of the most persistent medical dogmas of the 20th century. It is because of it that many men are afraid of substitution therapy, and some doctors refuse to prescribe it. The editors analyze where this idea came from, what has changed in the understanding of the biology of the prostate, and what myths still prevent a rational decision.

Where did fear come from?

In 1941, Charles Huggins and Clarence Hodges showed that castration or administration of oestrogens caused regression of metastatic prostate cancer. Huggins later received the Nobel Prize for these works. The conclusion seemed logical: if a decrease in androgens inhibits cancer, then their increase should accelerate it.

This logic defined clinical practice for decades. Testosterone began to be seen as "fuel" for prostate cancer, and any replacement therapy as potentially dangerous. However, the evidence base for the reverse claim—that elevated testosterone triggers or accelerates cancer—has been extremely limited.

Androgen deprivation remains the standard of care for advanced prostate cancer. However, the fact that androgen deprivation inhibits an existing tumor does not automatically mean that normalizing the hormone levels in a deficient man causes cancer.

The rethinking began with clinical observations: in men with low testosterone, prostate cancer was not less often, and sometimes more often, detected by biopsy, and an increase in testosterone within the normal range was not accompanied by the expected "explosion" of the disease.

The Saturation Model: Why "More" Doesn't Mean "Worse"

In 2009, Abraham Morgenthaler and Abdulmaged Treish formulated the so-called saturation model. Its essence: androgen receptors of the prostate are saturated already at relatively low concentrations of androgens. Below the saturation threshold, the prostate tissue is sensitive to changes in the testosterone level, above it, a further increase almost does not increase stimulation.

The model explains several paradoxes. First, in castrated men, even a small increase in testosterone significantly increases PSA — they are in the sensitive zone. Secondly, in men with normal testosterone, additional administration of the hormone has little effect on the prostate — they are already at a plateau.

This is consistent with the results of a large pooled analysis of 18 prospective studies (Endogenous Hormones and Prostate Cancer Collaborative Group, 2008): the concentration of endogenous testosterone in the blood was not associated with the risk of future prostate cancer.

The saturation model does not mean that testosterone is "safe for the prostate under all conditions." It merely explains why normalizing the hormone in a deficient patient should not automatically increase risk as the old dogma suggested.

What modern research says

The most important data were obtained within the framework of the TRAVERSE study. A separate prostate safety analysis (Bhasin et al., JAMA Network Open, 2023) in more than 5,000 men with hypogonadism showed that the incidence of high-grade prostate cancer and prostate cancer overall with testosterone gel was not significantly different from placebo. There was also no significant difference in acute urinary retention, invasive prostate procedures, or severity of lower urinary tract symptoms.

At the same time, PSA increased slightly more in the testosterone group than in the placebo group. This is the expected effect: when moving from deficiency to normal, the prostate "leaves" the sensitivity zone of the saturation model. A small increase in PSA in the first months of therapy is not in itself a sign of cancer.

It is important to understand the limitations: TRAVERSE did not include men with high PSA, prostate nodules, or severe symptoms, and follow-up was limited to several years. The data refer to carefully selected patients under monitoring.

For benign prostatic hyperplasia, in controlled trials, TRT did not cause clinically significant worsening of symptoms in most men. However, severe untreated lower urinary tract symptoms are still classified by the Endocrine Society guidelines as requiring urologic evaluation before initiation.

Five common myths

The last myth is especially important for sports readers. The saturation model describes the behaviour of prostate tissue, but supraphysiological doses of androgens have other risks—cardiovascular, hematologic, endocrine—that no TTT study has refuted.

It is also worth remembering: diagnosed prostate cancer remains a contraindication to TRT according to the basic guidelines. Individual urologists in carefully selected patients after radical treatment of low-risk cancer consider therapy individually, but this is an expert-level decision, not a general rule.

Prostate monitoring during TRT

The Endocrine Society guidelines offer a specific prostate monitoring scheme that allows early detection of the problem without giving up sound treatment.

• Before starting - prostate cancer risk assessment: PSA and digital rectal examination in men aged 55–69 years and in high-risk groups from 40 years after discussion with the patient.
• TRT is not started with a palpable node or PSA over 4 ng/ml (over 3 ng/ml in high-risk groups) without a urological examination.
• Re-evaluation 3–12 months after initiation of therapy, then according to standard age screening.
• Urological consultation in case of an increase in PSA above 1.4 ng/ml within 12 months, PSA above 4 ng/ml, changes detected during rectal examination or worsening of urinary symptoms.

Men of African descent and those with first-degree relatives with prostate cancer are at increased risk. For them, the alertness threshold is lower.

Monitoring is a trade-off: it does not eliminate risk completely, but it makes it manageable. Lack of control, such as when using testosterone on your own, deprives a person of this very defense mechanism.

Editorial conclusions

The “testosterone feeds prostate cancer” dogma comes from a valid observation about androgen deprivation, but has been overextended to replacement therapy. The saturation model and current data, including TRAVERSE, do not support an increase in cancer risk when testosterone is normalized in deficient men.

At the same time, diagnosed prostate cancer remains a contraindication, and PSA control and urological evaluation are a mandatory part of treatment. The findings do not apply to supraphysiological doses of anabolic steroids.

We recommend also reading "TRT and cardiovascular risk: current data", "Testosterone replacement therapy: indications and contraindications" and "Diagnosis of hypogonadism in men".

List of used literature

1. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293–297.
2. Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol. 2009;55(2):310–320.
3. Endogenous Hormones and Prostate Cancer Collaborative Group, Roddam AW, Allen NE, Appleby P, Key TJ. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst. 2008;100(3):170–183.
4. Bhasin S, Travison TG, Pencina KM, et al. Prostate safety events during testosterone replacement therapy in men with hypogonadism: a randomized clinical trial. JAMA Netw Open. 2023;6(12):e2348692.
5. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744.
6. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;389(2):107–117.