AUA2022: PLENARY RECAP Testosterone, Science, and Human Dignity
By: Abraham Morgentaler, MD | Posted on: 01 Sep 2022
I have had a set of unique experiences that have impacted my views on the nature of science, and what it means to be human. Those experiences stem directly from my research with testosterone (T) for over 45 years, in particular navigating the previously uncharted waters of testosterone therapy (TTh) in men with prostate cancer (PCa).
My interest in human dignity comes from the experiences and examples of my parents, who were survivors of Auschwitz in World War II. My mother, Chava Rosenfarb, became a widely acclaimed Yiddish author who detailed the indignities of the Holocaust. My father, Dr. Henry Morgentaler, fought to eliminate the indignities suffered by women forced to undergo illegal, risky abortions in Canada by offering safe, legal abortions.
How I Started With T
My involvement with T began in 1975 working in the laboratory of the brilliant evolutionary biologist, David Crews, at Harvard University, where I was able to restore sexual behavior in castrated male lizards by implanting miniature T pellets in specific areas of the brain.1
In medical school I learned almost nothing about T, except that it fueled PCa and was treated with castration. That made a big impression!
In urology residency, I was taught T was like the devil. High levels caused PCa and low levels were protective. And if a physician were foolish enough to give T to a man with PCa, it was like feeding a hungry tumor or pouring gasoline on a fire. The fear of precipitating PCa meant that almost no TTh was prescribed in the U.S., and its use was limited only to rare cases in young men with severe issues, such as absent testes or pituitary tumors.
When I started my urological career in 1988 at Beth Israel Hospital in Boston (now Beth Israel Deaconess Medical Center) and specialized in sexual medicine, there were few treatment options. Viagra® (sildenafil) would not appear for another 10 years. I wondered whether men might be like the lizards I had studied. They were! Sexual symptoms improved with TTh, and men felt more vigorous. Yet senior colleagues advised me to stop.
“You’re going to give these men PCa!” they said.
I persisted. To minimize PCa risk, for many years I performed prostate biopsies prior to initiating TTh. Contrary to expectations, we found low T was not at all protective for PCa.2 And shockingly, our review of the risks of TTh in 2004 revealed no evidence that high endogenous T levels or TTh was associated with anything worrisome regarding PCa.3 Yet the belief that androgens drove PCa was taught around the world to students and residents. Something was very wrong with a foundational medical concept!
A Revolution in Understanding the Relationship of T and PCa
I will never forget the day I descended into the basement of Harvard’s Countway Library to read the landmark 1941 study by Huggins and Hodges,4 which led to androgen deprivation therapy (ADT) as standard treatment for advanced PCa. My palms were sweaty as I read the concluding sentence, “Cancer of the prostate is activated by testosterone injections.”
Yet on second reading I discovered only 3 men had received T, and for no more than 18 days. Of these 3 men, they reported results for 2. One of these had already been castrated. This meant the conclusion that TTh was dangerous for the prostate was based on erratic results in a single, hormonally noncastrated patient!5
In 2006 I developed the Saturation Model5 and expanded it more fully in 2009 with Abdul Traish.6 This solved the mystery as to why androgen deprivation caused cancer regression, yet raising T in a noncastrated individual had little, if any, effect. The explanation is that the ability of androgens to stimulate prostate growth reaches a maximum at a low concentration of T.
Over time I offered TTh to men with progressively riskier PCa situations, eventually to men with biochemical recurrence and even metastatic disease.7 Is TTh like pouring gasoline on a fire? Apparently not. For my entire career I worried that the next patient would be the one who would rapidly develop the terrible outcomes with TTh I’d been taught to expect. It never happened.
Clinical Experience With TTh in Men With Metastatic PCa
I have learned so much about our humanity from my patients with metastatic PCa who sought treatment with TTh. All were told that TTh might kill them. Quickly. Tomorrow or next week. Yet they were willing to risk it. One man on ADT said, “The way I feel now isn’t a life at all. I’d gladly live a shorter time to be able to feel like myself again.”
John was on ADT for metastatic PCa. He had suffered 3 strokes over the past 5 years. John sat expressionless on his chair, and could barely grunt “yes” or “no” when asked a question. He needed assistance to stand.
When I saw John 3 months after initiating TTh I could not believe my eyes. He was charming and talkative. He stood without assistance. When I asked if they were having sex, John and his wife looked at each other and giggled. They were!
At 10 months John’s wife called to tell me he had died following a heart attack. She said, “John was so happy this past year. We’re grateful to you for giving that to us.”
In 2021 we published results of TTh in 20 men with biochemical recurrence or metastatic PCa. None suffered rapid adverse events or death. A modified version of the bipolar androgen therapy protocol has been promising,8 comprised of cycles of 8 weeks of high-dose T injections followed by 4 weeks of antiandrogens.9
- How we choose to die is really a statement about how we choose to live. One patient said, “While I’m alive I’d like to live as well as I can.” Who could disagree?
- There is more to life than mere survival. Where is it written that every man with metastatic PCa must die without T—weak, depressed, and sexless?
- For many of my patients, quality of life was more important than duration of life. This was about dignity for them. “Living well” or “feeling like myself” became more critical as time became more precious.
- Medicine is practiced one patient at a time, each with their own biology, and life story.
- T deficiency is a reduced state of the human condition.
- Challenge assumptions, no matter how well established. Much of what we learn eventually turns out to be incorrect.
- Working in health care is ultimately working to benefit humankind. When faced with uncertainty, let us err on the side of human dignity.
- Morgentaler A. How the rise of testosterone therapy in men was inspired by lizard research with David Crews. J Exp Zool. 2022;337(1):103-106.
- Morgentaler A, Bruning CO, DeWolf WC. Occult prostate cancer in men with low serum testosterone levels. JAMA, 1996;276(23):1904-1906.
- Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. New England Journal of Medicine, 2004;350(5):482-492.
- Huggins C, Hodges CV. Studies on prostatic cancer. Cancer Res, 1941;1(4): 293-297.
- Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. European urology, 2006; 50(5):935-939.
- Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. European urology, 2009;55(2):310-321.
- Morgentaler A, Abello A, Bubley G. Testosterone therapy in men with biochemical recurrence and metastatic prostate cancer: initial observations. Androg Clin Res Ther. 2021;2(1); 121-128.
- Schweizer MT, Antonarakis ES, Wang H, et al. Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study. Sci Transl Med. 2015;7(269):269ra2.
- Morgentaler A. Strategies for testosterone therapy in men with metastatic prostate cancer in clinical practice: introducing modified bipolar androgen therapy. Clinical Research and Therapeutics, 2020;1(1):76-84.