By Dr. Emilia A. Ripoll, M.D.
“The eye sees only what the mind is prepared to comprehend.” — Henri Bergson, French Philosopher (1859-1941)
In 1847, Hungarian-born physician Dr. Ignaz Semmelweiss shocked the European medical community by publishing his findings that when doctors washed their hands before delivering babies, it dramatically reduced the risk of death for the mothers.
Semmelweiss’ observations were simple: When doctors at Vienna General Hospital washed their hands with a chlorinated lime solution before delivery, it reduced the mothers’ mortality rate from Puerperal fever. The mortality rate dropped from almost 16 percent to well below 4 percent (a four-fold decrease). Women in Vienna literally begged to deliver their children in Semmelweiss’ clinic.
Word of Semmelweiss’ work spread quickly throughout Europe; however, his ideas were widely discredited by the medical establishment because he couldn’t prove what caused Puerperal fever. Keep in mind that the data from Semmelweiss’ hand-washing protocol was published 13 year before Louis Pasteur popularized the “germ theory of disease.”
Although Semmelweiss could not prove what caused Puerperal fever, he did demonstrate what prevented it.
Testosterone & Prostate Cancer
Fast-forward about 100 years and let’s use the example of Semmelweiss’s discovery and its subsequent rejection as a lens to examine our understanding of the relationship between testosterone and prostate cancer.
Since the middle of the 20th century, several studies have demonstrated that androgen (testosterone) deprivation in men with advanced (metastatic) prostate cancer creates a rapid decrease in PSA. More specifically, the use of LR-RH antagonists (androgen deprivation therapy) in men with advanced prostate cancer reduces PSA by 90 percent.
Even normal males who receive testosterone deprivation for six months have a drop in testosterone from an average of 435 to 50 ng/ml, and a PSA decrease from 2.95 to 0.5 ng/ml. Their prostate volume also declines from 55 cc to 37 cc.
So reducing testosterone in men (both healthy men and those with metastatic prostate cancer) shrinks prostate tissue size (volume) and lowers the amount of PSA circulating in the blood. All of which makes a perfectly good case for reducing testosterone levels for men with prostate cancer — and by corollary that lowering testosterone levels in healthy men is a reasonable way to prevent (or at the very least limit) prostate cancer.
Despite this research, three facts undermine this simple model of the interaction between testosterone and prostate cancer:
- Twenty-year-old men have the highest testosterone levels and yet the lowest incidence of prostate cancer.
- Prostate cancer prevalence increases as testosterone levels decline.
- The most aggressive forms of prostate cancer routinely occur in men with the lowest levels of testosterone.
In the 1990s, Dr. Abraham Morgentaler, an associate clinical professor of urology at Harvard Medical School and the founder of Men’s Health Boston, began questioning the accepted medical gospel that testosterone encourages the growth of prostate cancer. Morgentaler investigated the early castration studies done by Drs. Charles Huggins and Clarence Hodge in the 1940s, ‘50s, and 60s (Huggins received the Nobel prize for Medicine in 1966 for his work on the connection between testosterone and prostate cancer), as well as the work of Drs. Willet Whitmore and Jackson Fowler on testosterone administration to men with metastatic prostate cancer.
In 2004, Morgentaler uncovered that Huggins and Hodge had based their 1941 findings, which would be considered medical dogma for almost 60 years, on only three patients — and the results were only given for two men, one of which had already been castrated. Essentially, the medical axiom that testosterone replacement therapy is like throwing gasoline on the fire of prostate cancer was based upon the response of one patient!
“I sat there in the basement of the library reading the same line over and over to make sure I hadn’t misread it,” Morgentaler writes in his book, Testosterone for Life.”
Similarly, when reviewing the seminal paper written in 1981 by Whitmore and Fowler about testosterone treatment in men with metastatic prostate cancer, Morgentaler realized that of the 52 men studied over 18 years, all but four of them had been castrated or treated with estrogen to drastically lower their testosterone levels. Of the four who were untreated, one had a negative reaction to testosterone injections, but the other three received daily testosterone injections for 52, 55, and 310 days without any apparent negative effects. One patient actually demonstrated a “favorable response” to receiving testosterone injections.
The Testosterone Saturation Model
The resolution of the seeming paradox that testosterone defines masculinity in 20 years olds and yet stimulates prostate cancer as men age lies in a new understanding of the relationship between testosterone and the prostate.
Morgentaler writes in his editorial “Turning Conventional Wisdom Upside Down”: “The androgen-prostate relation has been formalized as The Saturation Model. It describes an exquisite sensitivity of prostate cancer to androgens at very low concentrations, followed by indifference of prostate cancer to androgens at higher concentrations. A likely mechanism is provided by the finite ability of the androgen receptor to bind androgens, with maximal binding (ie, saturation) occurring at approximately 120 ng/dl in human prostate tissue [healthy testosterone levels in men range between 500-1200 ng/dl]. The Saturation Model explains why manipulation of serum testosterone into and out of the castrate range produces large changes in PSA, whereas variations in serum testosterone within the naturally occurring range do not.”
In other words, when testosterone levels are very low, it is readily absorbed by prostate tissue (including prostate cancer), which causes a pulse of PSA. Once saturation occurs (at low levels), additional testosterone does not affect prostate tissue growth. A similar saturation curve has been found in multiple animal studies.
Multiple Sources Come to the Same Conclusion
Although Morgentaler is a medical pioneer, he is far from alone. A wave of new research (from thought leaders such as Drs. Leonard Marks, Emani Rhoden, Joel Kaufman, Shinya Yamamoto, Christopher Cooper, Shalender Bhasin, and others) has been sweeping through the international medical community’s understanding of the relationship between testosterone and prostate cancer. Here are some additional bullets of information about how testosterone nourishes and protects the prostate that you may find interesting.
- In 21 longitudinal studies that looked at the relationship of serum androgens (testosterone) to prostate development, the majority revealed no significant association.
- In pooled data from 18 different studies that had a combined 3,896 men with prostate cancer and 6,438 without prostate cancer, there was no correlation between serum androgen levels and prostate cancer.
- In 19 controlled testosterone replacement therapy (TRT) studies, the data showed no greater proportion of adverse prostate outcomes (increased PSA or prostate cancer), when comparing the TRT group to the placebo group.
- In 1,576 individual cases, no correlation was found between testosterone and PSA.
- In multiple studies of men previously treated for localized prostate cancer, only 2 out of 111(1.8%) who receive testosterone replacement therapy afterwards had a recurrence.
- Weekly intramuscular injections of testosterone (250 – 500 mg) that created abnormally high blood levels of testosterone (1138 – 1994 ng/ml) did NOT change either PSA or prostate volume.
- Weekly intramuscular injections of 600 mg of testosterone showed no changes in mean PSA — despite serum testosterone levels of 2800 ng/ml (more than twice the high end of normal).
- Men with prostate cancer do NOT have higher androgen levels than men without.
- Men with higher testosterone levels are NOT at greater risk for prostate cancer
- Variations in normal serum testosterone levels have no impact on prostate cancer.
Who Benefits from Testosterone Replacement Therapy and Who Does Not?
Hippocrates’ dictums of Primum non nocere (First do no harm) and Salus aegroti suprema lex (Do what is best for the patient first) absolutely apply to testosterone replacement therapy in men. Virtually all men benefit from healthy testosterone levels; however, in some men, balancing the risks and rewards requires great skill.
1. Men with the lowest levels of testosterone (hypogonadism) are at the greatest risk for developing the most lethal forms of prostate cancer — so they have the greatest need to raise their testosterone levels. Unless there are extenuating circumstances, TRT is a smart idea for this group.
2. Men who are at high risk for developing prostate cancer benefit tremendously from the protective effects of testosterone.
3. Hypogonadal men who have undergone definitive treatment for prostate cancer (surgery, radiation, brachytherapy, or cryotherapy), have stable PSA levels, and are considered “successfully treated” would definitely benefit from testosterone’s many life-enhancing benefits including enhanced cognition, heart health, bone density, feeling passionate about life, sexual desire and performance… and remembering where they put their keys.
4. Hypogonadal men who have chosen “active surveillance” as a prostate cancer strategy should be evaluated for TRT on an individual basis by an expert urologist/urologic oncologist. Because the decision about testosterone replacement therapy for this group of men is less clear cut, urological supervision that includes quarterly PSA tests, digital rectal exams, and other tests (as needed) is a wise first choice.
5. As with hypogonadal men on “active surveillance,” men with advanced (metastatic) prostate cancer should be evaluated on an individual basis by an expert urologist/urologic oncologist to see if testosterone replacement therapy is the right quality of life decision.
Looking Back/Looking Forward
Sadly, after repeated attempts to have his hygienic protocols accepted by the European medical community, Ignaz Semmelweiss became despondent, began drinking heavily, spent increasingly more time with a prostitute, and started behaving erratically. In 1865, he was tricked into entering a mental institution. When he realized what was happening, he fought with the security guards, who beat him into submission and put him in a straightjacket. Less than two weeks later, he died from a gangrenous wound suffered during that beating. He was 47 years old.
Fortunately, times have changed. A new school of physicians such as Morgentaler and his colleagues have emerged as the leading edge of medical research about the relationship between testosterone and prostate cancer. Yes, they have suffered the early condemnation of vocal critics of their work, but they have not been locked up in asylums. Quite the opposite — their work has spawned a whole new area of medical research. In time, their work will constitute a constantly changing “new normal.”
Key Points to Remember about Testosterone
- Testosterone replacement therapy can prevent prostate cancer, especially in hypogonadal men.
- Low testosterone does NOT protect you against prostate cancer
- High levels of testosterone do NOT increase your risk of prostate cancer
- Low testosterone is more likely to predispose men to prostate cancer
- Prostate cancer in men with low testosterone is typically higher grade, higher stage, and presents a worse prognosis.
- It is safe for men who have undergone definitive treatment for prostate cancer to receive testosterone replacement therapy.