Sponsored by an educational grant from Ipsen
Thank you very much for the invitation to give you an overview about testosterone and cognitive functions.
The brain is the only organ which is able to think about itself which makes it very interesting. During recent years, huge advances have been made concerning imaging of cerebral processes. For example, during spatial cognition, some areas are activated in the back of the brain, the primary vision area and feeling moods can be made visible by functional magnetic resonance imaging, for example. These are areas of the brain which are involved in feeling moods.
There are also differences between the genders. So there are differences between male and female brains and these point toward sex hormones. For example, during mental rotation tasks and images done by functional MRI, you see for example in a male brain, differences to a female brain, other areas are activated and that might be due to testosterone.
In healthy men, you see that the solving of tasks for spatial cognition are strongly associated with testosterone levels, mental rotations and so on, but not with estradiol levels. That means healthy men. So what happens if testosterone is not there, if men are hypogonadal what happens to that spatial cognition abilities?
We did a study in hypogonadal men and they had to solve tasks of this kind. Imagine that this is a glass cube seen from the front and inside the glass cube is a tube. Now the subjects get this picture and then they have to figure out from which side the glass cube is now seen. Someone has a solution for that? What do you think? It is the same thing seen from a different side. (From the audience “from the bottom”) Yes, a man gave the right answer! It is seen from the bottom.
So we treated the hypogonadal men. You see clearly hypogonadal they received testosterone and this is the different score, before and after, they scored higher, higher than controls who learned, you see the controls learned how to do that, but not as much as the patients and that is significantly different.
During these tasks, all the subjects underwent cerebral imaging for positron emission tomography (PET) so we could see what happened in the glucose metabolism in their brains while they were doing these tasks and then you can somehow subtract these images and see what was activated. So these basically look nice, they are raw data, but it all comes down to these areas being activated which belong to the ventral processing stream which is an area which is involved to process spatial data and these areas are activated by testosterone.
Other groups did studies, as well. For example, these people were a group of Bremner from Seattle they had older men receiving either testosterone, which is the blue one, testosterone plus an estrosol which is an aroma-taste inhibitor, so they take out the estradiol effect because they wanted to know if it is just testosterone or maybe its metaboline, estradiol, and they have a placebo group. You can see the placebo group improved over time so that means you can learn. That is also a good thing. But those groups receiving testosterone, improved much more, significantly more and it was not an estradiol effect.
The same holds true for Alzheimer’s disease. You see that compared with placebo, the persons receiving testosterone improved in spatial working memory and when then testosterone was taken away, they dropped back.
There are, of course, other functions of the brain than just processing spatial cognition, for example, feelings; depression seems to be related to testosterone. These are depression scores and depression scores are the highest the lower free testosterone levels are. So that seems to be a threshold somewhere it goes down but at least those men who have very low testosterone levels have the highest scores.
As you may know, testosterone functions are modulated by the androgen receptor polymorphism, CAG repeat polymorphism and testosterone effects in the future will probably have to be judged under this light also. So there are two groups which examined the effects of testosterone and took into account this polymorphism. You can see that the less functional the receptor was the men were feeling depressed, wished to be dead, even arrived at a dead point totally discouraged. That was significantly associated in Finland and also in the Massachusetts Male Aging Study.
So this is a study which was performed by psychiatrists in depressed men who had already their treatment with SSRIs, that means Selective Serotonin Re-uptake Inhibitors, which is the usual treatment for depression, so that means they all have regular anti-depressive medication but they were still hypogonadal and they did not improve by SSRIs. In addition to this classical medication, they received testosterone or placebo and you see the depression scores in the testosterone group significantly dropped compared to the placebo, as well as the clinical appearance of those patients.
This is a study performed in 163 older men receiving testosterone. This is not controlled, but you can see the positive moods increase and negative moods tend to decrease under transdermal treatment with testosterone.
This was also done with Testim® and you see the same results were seen positive moods increased and negative moods decreased.
So what about aggression? Aggression is usually associated with testosterone. What you have to keep in mind is there are several aspects to aggression. Some aspects, some sub-dimensions may be considered maybe beneficial even, and some adverse. For example, tension, anger, exhaustion are parts of aggression which are reduced by testosterone treatment, but these men also felt more vigour, more energy, more strength to tackle problems and this is a good part of aggression. So basically, what we see during treatment with testosterone, there are improvements in sub-dimensions of aggression.
So, in summary, testosterone can improve the spatial cognition abilities in hypogonadal men, it facilitates a favourable shift in mood patterns of hypogonadal men, a decrease in negative and an increase in positive moods. This applies most likely also to clinically overt depressive disorders, as well as to the sub-dimensions of aggression.
Audience Question: Do you have experience with testosterone in psychiatric illness like PMD? We give testosterone to depressive patient and we can give in-adversely to a PMD patient. Is there a risk to cause more aggressiveness in these patients?
Professor Zitzmann: You saw the study concerning depression and they clinically were better. But, of course, what you should consider is that if you have a depressive person lacking energy and then give him testosterone, you have to survey how he behaves of course. Is that what you mean?
Audience Question: A maniacal depressive person. Bipolar disease.
Professor Zitzmann: No, I don’t think that this has any relation to testosterone, this is not known to be, that bipolar diseases can be affected by that, no.
Audience Question: Dr. Zitzmann, Masters and Johnson showed 50 years ago that estrogen relieves major depression in 10% of post-menopausal depression and testosterone another 50%, leaving one-third. That was not compared to anti-depressants. Do you know of any figures comparing testosterone replacement versus anti-depressants, SSRIs and things?
Professor Zitzmann: No, and I think this is not a good way to treat depressive people. I think they should receive their classical anti-depressive medication and then, if they do not improve and are hypogonadal, then you give testosterone. Another thing is, if you have someone coming to your practice and feeling slightly depressed and lacking vigour and he is hypogonadal, such as a person with late onset hypogonadism, that means symptoms and low testosterone but not clinically depressive, then he might benefit from depression. But what you have to keep in mind is that depression and low testosterone levels are in a vicious circle. That means if you have a depression that will cause testosterone to drop, as well as does testosterone foster depression. So it may be that can be broken by external testosterone.
Audience Question: Just one quick question, are there any contraindications in your opinion in any of these psychiatric problems for testosterone? Are you aware of any contraindication?
Professor Zitzmann: It has been tested only in depression, not for bipolar, not in psychosis. I think there is no idea that it might be of benefit, but one could look at the hypogonadal state of these patients and see what happens, but studies are not known. I would still be careful treating a depressive person with testosterone because he might get enough energy, for example, to commit suicide, which could happen so he should be under psychiatric care if he is clinically depressive.
Copyright © 2006 ISSAM