Testosterone and the cardiovascular system

Hugh Jones, MD interviewed by Hugo Verhoeven, MD

Hugo Verhoeven, MD: Good afternoon, ladies and gentlemen. My name is Hugo Verhoeven from the Centre for Reproductive Medicine and Endocrinology in Düsseldorf, Germany. I am reporting from the Fourth World Congress on the Aging Male in Prague and it is my exceptional honour to talk this afternoon to Dr. Jones, who is working at the Centre for Diabetes and Endocrinology at the Barnsley District General Hospital and also at the Academic Unit of Endocrinology at the University of Sheffield. We are going to discuss a quite important topic: the benefits of testosterone therapy on the cardiovascular system. Dr. Jones, thank you very much for giving me the honour of talking to you. How long have we known that there is an immediate, positive effect of testosterone on the cardiovascular system?

Hugh Jones, MD: Thank you. Historically, back in the 1940s, there were several publications throughout the world, many from America and the United Kingdom, where patients with angina, males, were given testosterone and it did show an improvement in their symptoms of angina. However, those studies were not properly controlled scientifically. What then happened was not a lot until 1977, when there was a proper study done that did show benefit but, again, a long gap before things were taken further. Over the last six to eight years, there have been several publications looking at the benefits of testosterone in heart disease.

For many, many years, testosterone has been contraindicated in heart disease and a lot of the licenses for drugs in their details show it should not be given or given with caution to men with coronary artery disease and also not to be given to men with heart failure. Now, the actual basis for that, there does not seem to be any clear basis. Men are known to be more prone to dying from heart disease than women. This is a relationship which occurs throughout the world. What does happen is that if you remove the differences between smoking and obesity between the sexes, males are still more than two-to-one more likely to develop heart disease.

Why is that? Is it something to do with the male sex hormone? We undertook studies to look at what the incidence or prevalence of low testosterone levels were in men with heart disease. Several studies have been done in the past, but they used different assays and not used a control group and what we showed was that men who have got proven coronary disease on angiography, narrowing of their coronary arteries, up to 70% of their arteries, have lower testosterone when compared to a group of men who have normal coronary arteries, they just attended because they have had chest pain or valve heart disease for further investigation. It was clear that men do have lower testosterone if they have heart disease. But which is the chicken, which is the egg?

Hugo Verhoeven, MD: Exactly.

Hugh Jones, MD: Is it that you have a low testosterone and that makes you more likely to develop heart disease or is the fact that you have heart disease lowering the testosterone? We need long-term studies of giving testosterone to men to see whether it improves their outlook in the long term. But what we have done is shorter-term studies. We have looked at men with angina and treated them with testosterone because there is evidence now that testosterone actually makes blood vessels larger, it vasodilates the blood vessels and enhances the blood flow to not only the heart, but to other tissues, as well. We have been looking mainly at the heart and we did a study of three-month therapy to men with chronic stable angina and monitored the improvement by treadmill testing and looking at the heart’s electrophysiology and we showed that men were actually walking after three months about 52 seconds further before they got the same degree of lack of blood supply to the heart. But what we did show was that those men who had lower testosterone had more of an improvement and we have done a follow-up study where we just picked men with very low testosterone levels and heart disease and in that group, after a month, they were walking 73 seconds further. So the lower your testosterone, the better the improvement.

Now the question is, where is testosterone acting? There are several anti-anginal drugs and we have managed to identify that testosterone, one of its actions is to block calcium entry into cells, it is a calcium channel blocker. Now we have evidence that it is working at the same site or the same pore of the calcium channel as Nifedipine and other similar drugs which are used commonly as anti-anginals.

So I think we now have evidence to take this further forward and do longer-term studies because at the moment we have only done studies in angina for three months, but we want to see whether this effect is long-term. I have had individual patients who have continued now for two or three years and from anecdotal, if you like, data from following these patients, the benefit is long-term.

Hugo Verhoeven, MD: It is my understanding that this therapy is an experimental therapy and not an alternative to other vasodilatating medication, is that correct?

Hugh Jones, MD: That is correct at this stage. We need longer-term studies to evaluate this to be sure that it is safe in the long-term. So we need multi-centre studies to take this further forward. The testosterone improves angina but the other question is, does it improve the hardening of the arteries? As in medicine, you need five-year outcome studies to look at this further and those studies need large numbers of patients. We need 2,500 patients so to do that sort of study, you need a multi-centre study, you need to be funded by whoever will fund that sort of study.

Hugo Verhoeven, MD: What are your indications at this moment of your experimental work? What kinds of patients are you going to treat?

Hugh Jones, MD: Well, in the United Kingdom, you have to have testosterone levels below the normal range or symptoms, so it is a combination of measuring the blood level of testosterone and assessing the patient clinically. I think European-wide that there is an area of what we call clinical doubt. If the total testosterone is very low, there is no doubt the patient needs treatment. But then there is a grey area, a lot of those patients with low-normal testosterone levels have symptoms and do warrant treatment. So you can still, from the basis of treating those patients if they are hypogonadal, that is an indication in its own right. If they have angina, as well, that may well improve. But I think now the evidence and lots of experts feel that coronary heart disease should not be a contraindication to using testosterone therapy.

Hugo Verhoeven, MD: But it is a wrong position to say, here is a patient who has cardiovascular problems and the testosterone levels are normal, to bring the testosterone in supraphysiological levels for having a bettering of their cardiovascular problems.

Hugh Jones, MD: That is not the case at the moment, no. Clearly, you would have to do longer-term studies on that. But the ethos of an endocrinologist or anyone giving testosterone is to return testosterone to the normal physiological range. We know that if you use anabolic steroids in the supraphysiological ranges, because on the stacking regimes you can get levels one hundred and one thousand fold greater than normal physiological range. That is linked to heart disease. You can increase the risk of myocardial infarction. But the anabolic steroids are totally different from++ natural, physiological testosterone because they are not metabolizing the same way.

Hugo Verhoeven, MD: It is perhaps a repeat of what we said already, but is it your impression that most of the patients with cardiovascular problems are hypogonadal?

Hugh Jones, MD: We have done a survey of over one thousand men who went in for coronary angiography in South Yorkshire, the area we come from, and we measured the testosterone levels using various parameters and we showed that 23.9% of the men who have significant coronary disease were profoundly hypogonadal. A further quarter were in that borderline range. So about 50% of men with coronary heart disease with significant narrowing of the coronary vessels may warrant treatment.

Hugo Verhoeven, MD: What about women? Could there also be an indication for prevention or treating cardiovascular disease in women with androgens?

Hugh Jones, MD: I would believe not. The evidence in the literature states heavily that testosterone is not good for the heart in women. I think it is the total reverse in men. Testosterone is good for the heart in men, estrogen is bad, and in women, testosterone is bad and estrogen may be good. This is all complicated by this recent publication of the Women’s Health Initiative Study in the United States. I think polycystic ovaries syndrome is associated with high testosterone. That is associated with insulin resistance which is associated with vascular disease. So men are a separate issue to women. All my comments really relate to men.

Hugo Verhoeven, MD: Why do men have more cardiovascular problems and why are they dying more frequently from that compared to women?

Hugh Jones, MD: Well, this is why we need longer-term studies and it does look as if with vascular disease it is multi-factorial and you have to take everything into consideration: diabetes, obesity, smoking, all the risk factors, lack of exercise. But it may well be that a lower testosterone is a contributory factor but really we need long-term studies. We are in the early days of investigation, even though testosterone is used for heart disease in the 1940s, it is only now I think that the interest and research is coming out to increase the interest in doing much bigger studies.

Hugo Verhoeven, MD: Because what you are saying now is, it is something completely new.

Hugh Jones, MD: Well, yes. There are studies done by other people which suggest the same. There was a study that was done in London where they instilled testosterone directly into coronary arteries and it dilated and increased the flow of arteries within two minutes. What we know is that testosterone is working through a different mechanism rather than the classical androgen receptor which works through the chromosomes and that takes at least forty minutes to see any effect anyway. So this is through a different mechanism to dilate arteries but the testosterone effect on atheroma may be through this receptor and the classic androgen receptors, so it is very difficult at the moment to dissect out which is which.

Hugo Verhoeven, MD: Maybe it’s also, again, a little bit provocative, does a man with a very high free testosterone have lower risk of cardiovascular disease?

Hugh Jones, MD: I doubt that very much. I do not know. I think you get to a set level of testosterone and that may be 12 nanomils per litre, 13, and that is okay. We do not know. We cannot answer that question.

Hugo Verhoeven, MD: If you are treating patients with testosterone, different methods of applications can be used: one can use injections, tablets, patches and gel. What is your choice at this time?

Hugh Jones, MD: The most common method in the United Kingdom is still injections using testosterone intramuscular injections, either on a weekly or fortnightly basis and some of our studies have been based on that. We have also used the patches in our study but there are, as you know, a lot of problems with testosterone patches. However, patients with coronary heart disease seem to persist longer than patients who are just hypogonadal because they feel the benefit. I think most of my patients now have been changed to the Testogel because that is much more acceptable to the patient. It is easily applied every morning and does not have any irritation or application problems and is well-tolerated and, more than anything, it keeps the testosterone level within the normal physiological range, so potentially much safer than the intramuscular injections which can, in some instances, go above the normal range to the supraphysiological range and gradually fall before the next injection is due. Patients do not feel as good just before an injection is due and can feel a bit more moody and a bit tired and depressed in that phase if you do not get the balance correct.

Hugo Verhoeven, MD: My last question. Is there any correlation between blood pressure and testosterone?

Hugh Jones, MD: That is not easy. Some studies show that . . . People with hypertension, one thing is clear: people with hypertension have got lower testosterone levels and that is treated or untreated. So there is some link in there that we do not understand. If you treat men with testosterone, statistically we cannot show a significant lowering of blood pressure. However, there are one or two studies which might say that it lowers blood pressure by two or three millimeters of mercury, but they would have to be high-powered studies. But in the size of studies that we have done, we have not been able to show any treatment effect.

Hugo Verhoeven, MD: Thank you very much for this very interesting information.

Hugh Jones, MD: Thank you.