Dipti Gupta, MD, MPH: Dr. Slovin, are there differences among these agents in how they work? What are the long-term cardiovascular risk profiles with these agents?
Susan Slovin, MD, PhD: Those are great questions, Dr. Gupta. If we take a look here, we are modulating androgens. That’s really where we have the problems. We do know that when we give a GnRH agonist, there is a disconnect between the brain and the gonads. And in doing so, that feedback that we always talk about—the feedback loop of having the testosterone get the signal from the hypothalamus—is completely obliterated. And during that time period, where the gonads just don’t quite know what to do and they don’t get the signal from the brain, what ultimately happens is there is that surge. What you can see here with an agonist is that the testosterone goes up well before it goes down. And, if you happen to have the misfortune of having a very large prostate, or widespread metastatic disease, that sudden flare in testosterone can cause urinary obstruction, for example, or pain.
The difference, however, is that if you use an antagonist, as you can see on the left, you have an immediate decline in serum testosterone, such that you do not have that flare—ergo, you don’t have those side effects that can be seen. It actually can drop the serum testosterone usually within a good 24 to 48 hours. Whereas the agonist, as you see in red, may take as long as 14 to 21 days, and is predicated by the use of bicalutamide or another antiandrogen that will block the androgen receptors and prevent the flare. We think of giving hormonal therapy as something very lightweight, but it is important to remember that you are inducing physiologic changes in the body that really can be long-term. And particularly the longer they’re on treatment, the worse it actually becomes.
Now, we are not only discussing physiologic changes, but we’re also seeing changes in the immune system. While there have never really been prospective trials that look at changes in the immune system, I’ve actually taken this quote from an article that was looking at hypogonadism in men. The article revealed that you do need testosterone for a variety of different things. They found that when you have no testosterone, you actually have an enhancement of cellular and humoral immunity. They looked at this in a preclinical setting, but there was a correlation suggesting that testosterone somehow plays a role in the immune system.
What about the increasing risks that I’ve alluded to? Well, as you can see here, we’re looking at the incident risk of cardiovascular disease, myocardial infarction, sudden cardiac death, and stroke. And, in patients who had no androgen deprivation therapy—unfortunately, I don’t have the numbers on it—if you look at those patients who had treatment with a GnRH agonist or orchiectomy, you can see that the risks are high. The problem with many of these studies, however informative, is they have been observational.
This is a large study of close to 40,000 patients. You can see that 40% of these patients receive some form of androgen deprivation therapy, many of whom have these LHRH agonists. Very few were treated with orchiectomy. Some of them had antiandrogen therapy. The point is, there were data to support our concerns about the role of cardiovascular disease.
There was a move by the FDA, as well as by European agencies, to put a black box warning. This ultimately happened for the use of androgen deprivation therapy—in particular, GnRH agonists. This came as a result of a review of several studies that were very tantalizing in their recommendations that the risk of cardiovascular events was perhaps much higher in patients who underwent androgen deprivation therapy. If one were to go back and sort of look in the retrospective scope of the data, these were all based, again, on retrospective studies. Everybody came to the conclusion that there was definitely an enhanced risk of cardiovascular disease. But at the end of the day, no recommendations were made into how we can bring in a cardiologist, or somebody who’s a primary care specialist, or someone else, to really manage this. And if you read the fine print, they actually say, “We’re not sure of what kind of recommendations to suggest. We recognize that this is something that’s ongoing, but we just don’t know what to do about it.” And, “We’re not so sure that one needs to go through a lipid profile or any other workup before we do anything. We’re not quite sure. Maybe we should wait a year before we really assess anything with cardiovascular risk.”
Transcript Edited for Clarity