I have been asked by many how and why I decided to write this book and my response has always been that it “hit me like a bolt of lightning one day” and that’s the truth. I remember the moment in 2014, sitting on an airplane, deciding that it would be fun to write about testosterone. I didn’t think so much at the time that this was going to be some sort of clinical memoir, however, I merely thought that this was going to write a series of quirky chapters about the many ways that one molecule affects the world, along the lines of the book “Cod: A Biography of the Fish that Changed the World” by Mark Kurlansky about the importance of codfish on world history, economics and trade; or the book “Gulp” by Mary Roach, a tome of quirky fascination about the human digestive tract – with the reader being taken on a journey, so to speak, from the nose to the anus.
But, I could not avoid, and more importantly, came to embrace, the unique perspective on human behavior, evolution and psychology that we take on when we implement hormonal therapy for the treatment of prostate cancer. I’m certainly not going to glorify it, nor am I going to gloss over the many side effects that it causes patients, but rather I chose to intellectualize and contextualize the fact that we manipulate one of humanity’s most important chemicals to manage cancer.
So, having said that, here are the take home messages for clinical care that I learned doing this writing:
1. Subjective responses to ADT arise from many sources: I don’t talk to patients about the side effects of ADT like they are monolithic anymore. I have patients who take it and are miserable, and others who actually feel like it makes them better, less bothered by intrusive thoughts of sex or aggression. I became convinced that this is the result of a triad of factors: fetal testosterone exposure, variations in the reactivity of the androgen receptor, and cumulative levels of testosterone in the blood throughout life. I want to do more research on this, and think that if we dig deeper, we could pre-define who will have the greatest change.
2. Genetics drives drug side effect reporting. I came across some really interesting research on the genetics of the placebo effect, in particular on a gene called carboxy-O-methyltransferase (COMT). This gene affects the metabolism of dopamine and a single nucleotide polymorphism drives levels of this neurotransmitter in response to various stimuli. Subjects with a polymorphism conferring higher COMT activity end up with lower dopamine levels in the prefrontal cortex of their brains. This may result in a more ‘aversive’ personality type ( called the ‘warrior” genotype by psychologists who study this) in contrast to those with a distinct allele, called the “worrier” genotype. This genotype may be associated with a greater subjective response to stimuli and, in my view, this effect of genetics on drug side effects in oncology merits further study. It takes up only one paragraph in the book but is something I intend to follow further under the umbrella of a survivorship research project in prostate cancer patients.
3. Prostate cancer is the most “Evolutionary” Cancer…. and treating it is evolutionary medicine. Thinking about health and disease through an evolutionary framework allows us to think about how and why evolution forced a certain molecular process to develop and what that might mean for patients. The application to prostate cancer is relatively simple. Prostate cancer is driven in part by the chronic stimulation from testosterone over many decades, and the promotion of tumor. More importantly, perhaps, is to think about the development of CRPC from an evolutionary perspective. We and others have studied and published on the role of AR amplification on tumor progression. Why does the cell have a mechanism for amplification of the AR in the first place? This is an evolutionary question. In some systems, in some cells, amplification of the androgen receptor allows for a selective or competitive advantage. I found and wrote about, AR amplification in the brains of fish with low testosterone in response to an aggressive challenge ( a fight with another fish). There’s an evolutionary mechanism in the fish. The Cancer just stole it.
4. Cognitive Effects of Testosterone and ADT need more attention.
The neuroscience world can learn from what we do to our patients. While many patients do just fine with ADT, others have experiences with declines in cognitive performance that they may not be able to express, and we may not be able to detect in a 25-minute clinic visit. When was the last time you measured executive function or short-term memory in a patient? For the patients among this readership, it may be useful to think on these issues and examples that you have of these side effects and discuss them with your treating physician. We need to do more to recognize who is at risk for cognitive effects, and how to evaluate this in the clinic. I have joined a team to study this phenomenon, and look forward to participating in this research.
5. Learning to listen to patients is a lifelong journey. Most importantly, I came to appreciate the power of listening to patients stories, when they want to share them. I want to hear more about the patients and the life they led prior to being diagnosed with prostate cancer and how the diagnosis has affected them, what they have heard about hormonal therapy from others and what their fears are. Some fear intimacy, others fear the loss of sex, others fear fatigue and still others fear to lose their executive ‘edge’ in the boardroom. All are important, and I’ve known that for a long time. This process, however, has given me renewed enthusiasm for listening. Thus, in a way, this detour away from clinical medicine into writing has brought me right back to recognizing the joys in it.
Written by: Charles J. Ryan, MD
Further Related Content:
Watch: The Virility Paradox, A Book Review with Charles Ryan
The Virility Paradox: The Vast Influence of Testosterone on Our Bodies, Minds, and the World We Live In