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Myth: Testosterone Causes Prostate Cancer

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Myth: Testosterone Causes Prostate Cancer

Dr. Abraham Morgentaler, the leading expert on testosterone replacement therapy and its effects on prostate cancer, states in his article published in JAMA that.


"… the limited clinical trials to date have shown risk of prostate cancer in men undergoing TRT of approximately 1%, a rate not different from untreated men not being treated with testosterone."

Opinion Based on Flawed Studies!

One of the biggest myths about testosterone therapy is that it causes prostate cancer. There are a number of "low power studies" based on completely flawed theories around the claim that testosterone causes prostate cancer. This misinformation stems way back to the 1940s when doctors knew very little about prostate cancer. In particular, one study where doctors discovered when castrating people with prostate cancer, they lived a bit longer.

In their hugely flawed study, they noticed that one guy, yes one, lived longer after castrating him. So, of course, they assumed that lowering testosterone by castration was the answer. For generations, after it was, and still is, amazingly accepted that testosterone causes prostate cancer.

The Study that Started the Myth 

The basis of this opinion is all because of one study by (4) Dr. Huggins and Dr. Hodges in 1941. The study looked at treating men who already had prostate cancer by:

1. Castrating them (lowering testosterone)
2. Chemically castrating them (declining testosterone)
3. Giving them estradiol (estrogen)

Importantly this study did not look at men without prostate cancer and did not look at what happens when you GIVE testosterone. There have been several studies since. Two notable ones looked at what happens when you give testosterone to men with advanced prostate cancer. One study used biopsy as a litmus test of whether the disease burden increased or decreased. The other study looked at disease progression.

1. In the Harvard study by Dr. Morgantaler (April 2011), 100% of the 12 patients' biopsies at the beginning of the study had prostate cancer. During this study, the participants received testosterone weekly. Afterward, 50% of the biopsies were negative.
2. In the Johns Hopkins Study (December 2017), 47 men received pulse therapy with testosterone. One man was disease-free by the end of the study, and, in the rest of the men, the disease did not progress.

It's Low Testosterone That Causes Cancer, Not High!

New research (1) (2) now shows that it is not high testosterone levels that can cause prostate cancer; it is low testosterone, which causes the condition to be more aggressive. This shifting paradigm from old school theories to the correct new way of thinking is excellent news for prostate cancer patients and those worried about testosterone replacement therapy.

There are only a certain number of androgen receptors in the human body that bind with testosterone to 'activate it.' That is why testosterone only increases prostate cancer incidence in men who have extremely low testosterone levels of up to 200 ng/dl. After this level, a curious thing happens. The rate of prostate cancer starts to decline over time, and if you achieve high enough levels, you will see the decline drop at or below what is the considered baseline risk for prostate cancer for men who do not take testosterone.

This model describes the saturation effect. It is likened to you pouring water on a sponge. After a while, the sponge can only hold so much water. After that, the water just seeps away from the sponge. Think of the prostate as having a finite number of receptors for testosterone. Up until a level of 200 ng/dl, the testosterone will attach to these receptors and stimulate the prostate. After that, at higher testosterone levels, the testosterone no longer attaches to these receptors to stimulate the prostate.

It doesn't matter how much testosterone is circulating in our blood. Once all the receptors are full, they too can take no more. This saturation point explains why high testosterone levels do not affect prostate cancer risk, but low levels certainly can. In fact, men with low testosterone levels tend to develop a more aggressive form of prostate cancer.

The Importance of Estradiol

Now you may wonder if testosterone doesn't cause prostate cancer at optimal levels and drops the risk of prostate cancer, what causes this drop in prostate cancer? Believe it or not, it is ESTRADIOL (i.e., estrogen). Wait. "I thought estrogen was bad for men." That is a falsehood that was started by weightlifters and then propagated by misinformed doctors to help boost testosterone production. No, estrogen, particularly the form of estrogen called estradiol, which comes directly from testosterone, does not make you cry when you watch kittens on TV or make you have breasts (gynecomastia).

This falsehood was a ploy propagated by the book from the 1980s. called the "Underground Steroid Book" to deceive doctors into prescribing estrogen blockers such as aromatase inhibitors (ie anastrozole) to help increase testosterone by blocking one of the pathways testosterone goes down. If you block one of the pathways, it causes a backup. Therefore, you force testosterone into the more "desirable" path of boosting testosterone levels and DHT (dihydrotestosterone), which men want to build muscle. Incidentally, DHT is 10-100 times more active than testosterone.

So How Does Estradiol Reduce Prostate cancer Risk in Men?

There are two things estradiol does to reduce and even treat prostate cancer. It causes apoptosis (suicide) of the prostate cancer cells and reduces the blood supply to prostate cancer cells. In fact, before the advent of the drugs Casodex and Lupron, which are androgen deprivation drugs, men with prostate cancer were treated with a synthetic estrogen called DES (Diethylstilbestrol). Incidentally, there are two reasons why they stopped using DES. The first is that Casodex and Lupron were the new, more expensive drugs, and thus they were favored to be prescribed. The second is that DES increased the risk of heart disease (by increasing matrix metalloprotease).

The funny thing is Casodex and Lupron (the drugs of choice for treating prostate cancer) cause heart disease, depression, diabetes, sexual dysfunction, gynecomastia, dementia, hot flashes, and osteoporosis. Estradiol does not increase these diseases and symptoms. It decreases the risk of heart disease, osteoporosis, dementia, PROSTATE CANCER, sexual dysfunction, and visceral fat (which causes diabetes, high cholesterol, and high blood pressure).

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Summary:

  • Testosterone is safe, indicated, and efficacious in prostate cancer survivors that have been treated and cured
  • Testosterone administration does not increase the risk or incidence of prostate cancer in the general population or prostate cancer survivors
  • Low levels of testosterone are associated with increased risk and higher Gleason scores
  • Higher testosterone levels portend a decreased risk of cancer
  • The "Saturation Model" explains this discrepancy where maximal stimulation of prostate cancer occurs at a very low level of testosterone
  • Estradiol produces an effective tumor response along with improvement in function and symptomatic quality of life indices
  • Estradiol has a direct apoptotic effect in addition to an androgen suppressive effect
  • Estradiol provides androgen deprivation without estrogen deprivation

(1) 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. doi:10.1093/jnci/djm323
(2) Morgentaler A, Lipshultz LI, Bennett R, Sweeney M, Avila D Jr, Khera M. Testosterone therapy in men with untreated prostate cancer. J Urol. 2011;185(4):1256-1260. doi:10.1016/j.juro.2010.11.084
(3) Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol. 2006;50(5):935-939. doi:10.1016/j.eururo.2006.06.034
(4) Studies on Prostatic Cancer. I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate
Charles Huggins and Clarence V. Hodges
Cancer Res April 1 1941 (1) (4) 293-297;

Other relevant studies 

5) Morgentaler A. Testosterone therapy for men at risk for or with history of prostate cancer. Curr Treat Options Oncol. 2006 Sep;7(5): 363-9

"Since the early 1940s, Huggins showed that … estrogen therapy and castration caused regression of prostate cancer."
"The fear has been that higher testosterone levels would "awaken" dormant cells and cause a recurrence of cancer."

6) Abraham Morgentaler, Emani Luis Rhoden. Prevalence of Prostate Cancer Among Hypogonadal Men with Prostate-Specific Antigen Levels of 4.0 ng/ml or Less. Urology. Vol. 68, Issue 6, p1263-1267

"Prostate cancer was present in more than 1 of 7 hypogonadal men with PSA of 4.0 ng/ml or less."
"An increased risk of prostate cancer was associated with more severe reductions in testosterone."

7) Mark R. Feneley, Malcolm Carruthers. Is testosterone treatment good for the prostate? Study of safety during long-term treatment. The Journal of Sexual Medicine, Volume 9, Issue 8, pgs 2138-2149 August 2012

"An updated audit of prostate safety from the UK Androgen Study was carried out to analyse the incidences of prostate cancer during long term testosterone replacement therapy."
"The incidence of prostate cancer during long-term testosterone replacement therapy was equivalent to that expected in the general population."
"This study adds to the considerable weight of the evidence that with proper clinical monitoring, testosterone treatment is safe for the prostate."


8) Abraham Morgentaler. Testosterone Deficiency and Prostate Cancer: Emerging Recognition of an important and troubling relationship. European Urology. Volume 52, Issue 3, September 2007, Pages 623-625

"It turns out his assertion (Huggins) was based on only a single patient. Yet multiple testosterone trials of up to 36 months in duration have failed to demonstrate any dramatic acute increase in prostate cancer, and at least 16 longitudinal studies, involving several hundred thousand men, have consistently failed to show any long-term risk on prostate cancer development from higher levels of endogenous testosterone."

"A critical shortcoming of the focus on high testosterone is that utterly fails to account for the high prevalence of prostate cancer at an age when men are older and their testosterone levels have declined, and the absence of clinical prostate cancer when men are young and have their highest lifetime testosterone levels."

"The accelerating accumulation of new studies demonstrating a worrisome association between low testosterone and prostate cancer can no longer be ignored."

"The probability of cancer was more than double when men in the lowest tertile of testosterone were compared to men in the highest tertile."

"Results showed that low testosterone raises the risk of prostate cancer to the level of men who are a decade older."

"Raising testosterone levels in men with metastatic prostate cancer who already have castrate testosterone levels does indeed cause prostate cancer. But it has been nearly impossible to show that raising testosterone causes any incremental increases in prostate cancer growth beyond the near-castrate range of testosterone (>200 ng/dL)."

"A recently published landmark study in which hypogonadal men receiving testosterone therapy for 6 months failed to demonstrate an increase in prostatic concentrations of testosterone and dihydrotestosterone, nor in markers of cellular proliferation, despite a substantial increase in serum testosterone and dihydrotestosterone levels."

"Nishiyama et al also found no correlation between serum testosterone or dihydrotestosterone and prostate tissue concentrations of dihydrotestosterone."

"I therefore believe we should discard the old analogy that "Testosterone acts like food for a hungry tumor" because higher testosterone does not appear to cause greater prostate cancer growth."

"" Testosterone is like water for a thirsty tumor," because once the tumor is no longer "thirsty," additional amounts are treated as excess."

9) Hsing AW. Hormones and prostate cancer: What's next? Epidemiol Rev. 2001;23(1):42-58

"Five of the nine prospective studies evaluated the role of estradiol, and in the study of Gann et al., after adjustment for sex hormone-binding globulin and androgens, serum levels of estradiol were inversely associated with prostate cancer risk."

10) Severi G, Morris HA, MacInnis RJ, et al. Circulating steroid hormones and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006 Jan; 15(1):86-91

"risk of prostate cancer was approximately 30% lower for a doubling of the concentration of estradiol."

"High levels of testosterone and adrenal androgens (and estradiol) are thus associated with reduced risk of aggressive prostate cancer."