Introducing the Virility Triad

I have spent the better part of the last 20 years thinking about testosterone and the androgen receptor (AR) and its effect on prostate cancer. I started by applying synthetic testosterone to cancer cells in the laboratory at the University of Wisconsin, progressed to studying the effect of retained androgen receptor signaling in human prostate tumors at Memorial Sloan Kettering and finally studied the clinical effects of abiraterone, apalutamide, ketoconazole and other drugs as therapies for prostate cancer here at UCSF. One of the best pieces of career advice that I ever got was a very simple: Follow the AR.

What I have come to appreciate most, especially in the last few years, is that the AR and testosterone activation is so powerful in driving prostate cancer because it is the result of the activity of a “selfish gene”. By calling it this I am playing off the very important book of the same name, written by Richard Dawkins in 1976. He asserted that evolution occurs because there are certain genes the expression of which drives the ‘inclusive fitness’ of the cell or the organism as a whole. He basically said we evolve because the effect of certain genes is so powerful that their survival controls the survival of the whole organism.

In prostate cancer the selfishness of the AR leads to the survival of the cell despite all the therapies we administer to it – Lupron, Abiraterone, Enzalutamide etc. Despite all this, remarkably, most patients, when they develop metastatic CRPC, have retained AR signaling and expression. Put another way, despite our best efforts, the AR usually wins.

But cancer has really just adopted the AR from physiology. That’s the point. The AR is a selfish gene because it is essential to both human survival and reproduction. Survival of the human species comes from its virilizing effects – the might that comes from  brawn; reproductive effects come from its ability to drive mental processes like libido and nurturing reproductive organs such as, say, the prostate. 

Thus, prostate cancer, as strange as this may seem, is a disease that is the consequence of our evolutionary progress. It is thus possible to reverse engineer the mechanism and appreciate that the mechanisms we associate with AR adaptation in prostate cancer really come from basic biology, and are not necessarily cancer specific. 

Consider the example of the Mangrove Rivulus, a fish. They are a particularly aggressive species that live in rivers in North and South America and are a good experimental model for the study of animal aggression. They look like a cross between the minnows I used to catch in a net off our dock in Wisconsin and a drab-colored aquarium fish. If placed in proximity to one another, male rivulus fish will inevitably fight. When fights are induced experimentally in the lab, a few interesting observations emerge. One, high testosterone fish win more fights. That’s not surprising. But, repeated loss of fights reduced androgen receptor expression in their brains, while repeated victories increased AR expression. This is an example of the self- perpetuating feed-forward nature of testosterone and its receptor. But perhaps the most interesting phenomena was that fish with low testosterone levels at the outset increased their brain AR levels the most—almost as if compensating for low levels of testosterone by increasing receptor expression.  

So here is an example of a physiologic mechanism by which a low androgen environment leads to an induction of the Androgen receptor, which enhances survival. Sound familiar? Yes, that is exactly what prostate cancer does! This is like CRPC, but in the brain of a tiny fishWe have known for some time now that as we study prostate cancer it has been necessary to focus not only on testosterone levels, but also the shape, expression and integrity of the AR. Many laboratories, including here at UCSF, have shown that CRPC tumors amplify the AR….just like these fish.  I find this fascinating.

But what is really interesting ( to me at least) is that these principles apply to our study of the role of testosterone and behavior. Like the Mangrove Rivulus fish, our brains are stuffed with androgen receptors and our brains are literally shaped by testosterone even before we’re born. In my forthcoming book Virility and its Perils, I delve into the concept that testosterone is part of both a feed-forward and a feed-back system. Most of the time, its feed-back, which means that high levels will shut down production, like heat and a thermostat. But some of the time, especially in the brain high levels induce an addiction-like need for itself. Understanding the interrelatedness of these concepts that apply to all of us requires appreciation of the interaction of three scientific concepts, which I have dubbed the “Virility Triad” (VT): 

  1. Testosterone levels in the blood (which correlate to testosterone levels in the brain or any other organ). 
  2. The genetics of the AR. Genetics determine whether we have fast or slow androgen receptors—more testosterone on a fast androgen receptor has a magnifying effect compared to the same amount on a slow receptor. This can manifest itself in the poly-glutamine (CAG) repeats in the promoter region, which is a germline genetic process that determines if the AR is under active ( with long CAG repeats) or hyper active ( with few CAG repeats). Short CAG repeats have been associated with aggressive behavior, for example, and long CAG repeats are associated with decreased masculinization.
  3. Life-long behaviors and health are influenced by how much testosterone our brains were exposed to before birth—our fetal testosterone. When fetal testosterone levels spike in the uterus at about week fifteen of pregnancy, key parts of the baby’s brain are stimulated to develop, and the extent to which they develop, and respond to testosterone later in life, is proportional to this spike. Fetal testosterone exposure can actually be measured throughout life by the ratio of the index finger to the ring finger. A greater difference between these two lengths ( a low 2d :4d ratio – eg 0.9 because the index finger is 0.9x the length of the ring) is a marker of a HIGH fetal testosterone and has been associated with behavioral issues such as risk taking, and health issues, including an increased risk of prostate cancer. 
Interestingly, behavioral psychologists have been studying the relationship of CAG repeats and fetal testosterone through the 2d:4d for a long time. Ironically, those of us who treat a deadly disease that is driven by this selfish AR gene and targeted with AR directed therapies have yet to fully consider the implications of both of these on the prognosis and therapeutic choice of our patients, let alone whether these factors are associated with side effects of these new drugs. We are beginning to do some of these studies so stay tuned.

Written by: Charles Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, Director and Professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota

Published Date: March 14th, 2017

1. Li, Cheng-Yu, Ryan L. Earley, Shu-Ping Huang, and Yuying Hsu. "Fighting experience alters brain androgen receptor expression dependent on testosterone status." Proceedings of the Royal Society B: Biological Sciences 281, no. 1796 (2014): 20141532.