New Concepts Regarding Testosterone and Prostate Cancer: A Breath of Fresh Air

After a quarter of a century struggling to decipher what is true and untrue about prostate cancer (PCa) and androgens, the review by Paul Mathew in this issue of ONCOLOGY comes as a breath of fresh air.[1] What a pleasure to read a new perspective on a problem that has been bedeviled by rigid ideas developed more than 70 years ago, like flies fixed in amber!

When I completed my residency in urology in 1988, the prostate cancer and testosterone story was clear and without controversy. Prostate cancer was explained by what was called the androgen hypothesis:

1) Androgens play a key role in the etiology of PCa,

2) High testosterone is a risk factor for PCa,

3) Low levels of testosterone are protective, and

4) Administering testosterone to men with existing PCa universally causes rapid growth-something every trainee at that time learned was like “pouring gasoline on a fire,” or “feeding a hungry tumor.”

The evidence seemed indisputable. Castration in men with painful bony metastases provided rapid relief, often within hours. Acid phosphatase and the new biomarker, prostate-specific antigen (PSA), both declined rapidly once serum testosterone fell into the castrate range. My chief, the late Reuben Gittes, regaled the residents with tales from his research lab, where prostate cancer tumors could be grown under the skin of the backs of mice, and then transferred to other mice. These grafts “took” in intact male mice, but not in castrated mice. They also failed to take in hormonally intact female mice, but took if females were treated with testosterone. No wonder testosterone therapy was rarely used at that time, reserved exclusively for only the most severe cases of testosterone deficiency, such as men with absent testes, or following pituitary ablation!

Once I started my own practice at Boston’s Beth Israel Hospital (now Beth Israel Deaconess Medical Center), I was curious about testosterone therapy because of undergraduate research I had performed with testosterone in lizards (in which the full range of sexual behavior in castrated males was restored by implanting minute amounts of testosterone within the sexual centers of their brains).[2] I soon found that low testosterone levels were common in men presenting with sexual or reproductive issues, and that treatment produced substantial benefits in them. However, I was very concerned by the possibility that my use of testosterone therapy in these men might precipitate rapid growth of an occult cancer. I therefore began performing prostate biopsies in men with normal PSA levels and normal digital rectal examinations (DREs), solely to rule out the presence of occult PCa prior to initiating treatment with testosterone.

Although the androgen hypothesis predicted that this group would have a very low rate of PCa, 11 of 77 men (14%) had PCa, a rate similar at that time to positive biopsy rates in men with known risks, such as an abnormal DRE or elevated PSA level.[3] Similar results were seen in a larger group of 345 men with PSA levels < 4.0 ng/mL.[4] In fact, men with more severe testosterone deficiency had double the rate of positive prostate biopsies seen in men with milder testosterone deficiency.[3] Clearly, the “low testosterone is protective” portion of the androgen hypothesis was incorrect.

Evidence soon accumulated that none of the basic tenets of the androgen hypothesis were correct.[5] High levels of serum testosterone or dihydrotestosterone are not associated with increased risk of PCa.[6,7] Androgen deprivation does reduce PSA levels, but raising serum testosterone well into the supraphysiologic range for months in otherwise healthy men has been shown to have no effect on mean PSA level or prostate volume.[8] The explanation for this, termed the saturation model, is that the ability of testosterone to stimulate PCa growth is finite,[9] with maximal stimulation occurring at fairly low serum testosterone concentrations, in the range of 250 ng/dL.[10] Thus, the “high testosterone is risky for prostate cancer development” part of the androgen hypothesis also has proved incorrect.

What about the concept that administering androgens to a man with prostate cancer will universally cause rapid growth? In 2011, my colleagues at Baylor College of Medicine and I reported on 13 men with untreated PCa, on active surveillance, who received testosterone therapy for a mean of 2.5 years.[10] There was no increase in mean PSA level, or in prostate volume. No man demonstrated cancer progression-and all men reported subjective improvement in symptoms. Our more recent single-center experience at Men’s Health Boston with a larger group of 33 men was presented at the annual meeting of the American Urological Association in 2013, with similar reassuring results. These results support the validity of the saturation model.[9]

If none of the tenets of androgen hypothesis orthodoxy are correct, then what are we left with? Dr. Mathew takes us several steps down this new path. Whereas the primary thrust of the last 7 decades of research into treatment of advanced prostate cancer has been to find ways to more completely deprive PCa of androgen, Dr. Mathew asks a completely different question: Are there ways in which testosterone administration may be beneficial? Basic science and a number of clinical experiences have suggested for years that steroid hormones may have bifunctional roles, as Dr. Mathew puts it. As the androgen hypothesis finally fades from prominence, now is an excellent time to shake the sleep from our eyes, breathe in the fresh air, and look again at a world of new possibilities.

Financial Disclosure: Dr. Morgentaler has received research grants from Auxilium, Antares, Eli Lilly, and Lipocine. He has received consulting or scientific advisory board compensation from AbbVie, Auxilium. He has received honoraria from Bayer and Merck.

References:

1. Mathew P. The bifunctional role of steroid hormones: implications for therapy in prostate cancer. Oncology (Williston Park). 2014;28:397-404.

2. Morgantaler A, Crews D. Role of the anterior hypothalamus-preoptic area in the regulation of reproductive behavior in the lizard. Anolis carolinensis: implantation studies. Horm Behav. 1978;11:61-73.

3. Morgentaler A, Bruning CO III, DeWolf WC. Incidence of occult prostate cancer among men with low total or free serum testosterone. JAMA. 1996;276:1904-6.

4. Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen of 4.0 ng/ml or less. Urology. 2006;68:1263-7.

5. Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol. 2006;50:935-9.

6. Endogenous Hormones 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;100:170.

7. Muller RL, Gerber L, Moreira DM, et al. Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the reduction by dutasteride of prostate cancer events trial. Eur Urol. 2012;62:757-64.

8. Cooper CS, Perry PJ, Sparks AE, et al. Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men. J Urol. 1998;159:441-3.

9. 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;55:310-20.

10. Rastrelli G, Corona G, Vignozzi L, et al. Serum PSA as a predictor of testosterone deficiency. J Sex Med. 2013;10:2518-28.

11. Morgentaler A, Lipshultz LI, Bennett R, et al. Testosterone therapy in men with untreated prostate cancer. J Urol. 2011;185:1256-60.