DHEA and the aging male

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Wiebke Arlt, MD (DFG Senior Clinical Fellow), Dept of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom

It’s a slight change in topic from testosterone to DHEA, which is a crucial testosterone precursor, as most of you will know. 

Why are we interested in replacing testosterone and DHEA in the aging male? Because we all want to go into this box here, at some point on a high level of functioning we just want to drop dead. We don’t want to go for this frailty thing here, and decline and decline. This is why we want to give hormones. But does it make sense?

So you’ve heard a lot now about the andropause and I’m telling you something now about the adrenopause. Cortisol levels stay at the same level through our lifetime but DHEA and DHEAS levels drop.

This is illustrated by this slide which is generated from the Orentreich data, which are ten years old, 20 years old, excuse me, but still definitive, showing that there’s really a drop in circulating serum levels in DHEAS, and this is also true for DHEA, the active form, down to 20% in persons over 70 years of age.

So this has generated all that you can see here, and it’s a huge market, especially in the US and North America in general, where DHEA can be bought over the counter. But does it hold its promise?

First I would like to tell you a bit about how DHEA works. As I’ve told you, DHEA is the crucial precursor of androgens and of all sex steroids. Patients who have mutations in C17 and cannot generate DHEA; do not have any sex steroids at all. We know from the pharmacokinetic studies, together with Bruno Allolio, that in women, if you give them DHEA orally, you will get a significant increase not only in DHEA and DHEAS, but also in androgens. While in men, androgen levels won’t rise but oestrogen levels will significantly rise. So this could mean, ok, can we expect now oestrogen effects only in males? However, what was noted is that if you give DHEA to men, you do not get an increase in circulating testosterone or DHT, but you get an increase in ADG. This is androstanediol glucuronide and this is a main androgen metabolite, which may be a better reflector for what is actually happening within the cells. This is a very important marker. Something we also have to take into account when we talk about DHEA reaction is that from DHEA also other steroids can be generated, which may be important, for example, for androstanediol, which is supposed to have immune modulatory functions, even stronger than those of DHEA.

So, basically what happens in the body with DHEA is always dependent on the expression of steroidogenic enzymes in the respective target cells. So, it depends what the cell has to show if you get androgens, oestrogens, or intermediate steroids in your target cell.

The main action of DHEA is clearly delivered indirectly. It’s an endocrine and intracrine action by the conversion of DHEA to sex steroids, and other intermediate steroids. But what is important to know is that DHEA also has a neurosteroidal function, and it activates the NMDA receptor and it acts anti-GABAergic, which means it may have a potential anti-depressive effect. In addition, we know that there are high-affinity binding sites, very specific for DHEA on both immune cells, and on endothelial cells. So far no DHEA receptor has been identified, but this may well come.

What do we know about the influence of DHEAS and functional level and mortality? These are the data from the Paquid study and they seem to suggest that men, who die two or four years after follow up, start off with a lower DHEAS level. There is also a further follow up to this eight and 10 years after starting this observational study. Again, the men in the lowest quartile for serum DHEAS had the highest odds of dying during observation. This is an odds ratio of 1.9 and this was significant. So is this the amount of all that is likely to die?

What is very interesting is that there is obviously a correlation of the incidence of coronary heart disease and DHEAS levels, but only in men, and not in women. This further underlies that it is important to analyse this in a sex specific way.

And again here, looking at functional status in elderly people you see that the people with the lowest functioning scores have the lowest DHEAS levels. This is significant in men and there’s only a trend for this in women.

However, if you analyse a big cohort like Ravaglia did, 1,000 people, men and women, and you compare the health status in these people, the DHEAS levels are always lower in these subjects who have general problems with health. If you correct for this, there are no significant differences. It just seems as if low DHEAS levels are a rather non-specific marker for low health status than a specific risk indicator for specific diseases. Rather a consequence than a cause.

We have done studies in Würzburg, together with Bruno Allolio looking at the model of pathologic DHEA deficiency. In aging, though we have a drop down to 20% of intra individual maximum levels, this is still only a relative deficiency of DHEA. However, patients with adrenal insufficiency clearly have a nearly total loss of DHEA production. This is why we’ve chosen these patients for the study.

Basically we’ve replaced them with four months of DHEA in a double bind, placebo controlled, randomised cross-over study. As you can see here we could increase the red bars of the DHEA treated women, not only DHEA and DHEAS levels, but also androgen levels. You see in the right-hand corner the ADG is significantly going up even more so than the circulating androgens.

The interesting clinical observation was that the previously impaired well being in these patients significantly improved. Going down is an improvement as shown here. This was mostly due to an anti-depressive and anti-anxiety action of DHEA.

If you say, “hey, what does this mean clinically?” here you can see it as compared to the normal female population. At baseline the patients have an impaired well being and this is reduced down to normal with ongoing treatment in the sense of an improvement. This has been confirmed so far by three other randomised studies, and it has also been confirmed by a UK study, a joint Cambridge/Oxford project in men with adrenal insufficiency. It seems to be a neurosteroidal effect rather than androgen related.

Interestingly, we could also observe a significant effect on DHEA on sexual thoughts, sexual interest, and most importantly, sexual satisfaction in these women who often complained about an impaired libido at baseline.

But what now about the healthy, elderly males and also the women? This is a landmark study in this respect, the Morales study from 1994, and this study reported that after three months of DHEA replacement the sense of well being was highly significantly improved in both men and women. Unfortunately this was not assessed by validated questionnaires, and this is why we got the idea to repeat this, in the exact same setting and conditions we used for the women with adrenal insufficiency. So we selected men who were in the lowest quartile of the age-related serum DHEAS and replaced it with DHEA for four months worth of placebo, again in randomised cross-over trial.

And what you can see here is the result, so there is absolutely no change, no influence if you use validated questionnaires.

Also here is illustrated the effects on sexuality. You see this high increase in the women with pathologic DHEA deficiency due to adrenal insufficiency. The normal men with a relative DHEA deficiency do not increase.

There is one study though from Vienna from Werner Reiter, which shows effects of DHEA on erectile dysfunction. He selected a sub-cohort of men who had low DHEAS levels, but no other signs of hypogonadism, and no other somatic causes of erectile dysfunction.

He replaced them with DHEA for 24 weeks, and found a very impressive effect on erectile function and sexual desire. He repeated this in a larger cohort of patients with somatic reasons for erectile dysfunction, and he could not find any effect. So possibly we are looking here at a neurosteroidal effect again.

DHEA was also used in patients with mid-life dysthymia, and patients with major depression, both men and women, and there were significant anti-depressive effects of DHEA. However, these effects are much smaller than the ones you would achieve with anti-depressants like serotonin reuptake inhibitors.

If you just take the average peri-menopausal woman, like done in this study by Barnhart, unselected peri-menopausal women selected for various complaints, then you do not see any increase in well being after treatment with DHEA for three months. That’s very important, but I think further research is also warranted here because the key issue is always you have to select your target population. If they are not impaired at baseline as measured with your validated tools, you of course won’t pick up any change.

The definitive study in this area is the DHEAge study. The DHEA study from Etienne Baulieu, and this is the largest study to date. The first part has been published in 2000 in PNAS, and now last year, several other publications based on this study came out. He replaced 140 men, and 140 women, age groups 60 – 79 years of age, for 12 months with 50 mgs of DHEA or placebo in a parallel group trial. The effects were quite disappointing. There was no significant change in well being or mood. There was a slightly significant increase in libido in women older than 70 years of age. Sebum secretion as an androgenic effect increased in women, and skin hydration went up in men. This was in collaboration with L’Oreal. There was a slight increase in bone mineral density in women but absolutely no effect in men, and there was no change in body composition.

Also, muscle strength was assessed repeatedly and as you can see here there is definitely, absolutely no difference between placebo and DHEA 50 mgs before and after 12 months of treatment, though there was no related exercise program.

One thing which was of interest, especially for the DHEAge study, is the potential effects of DHEA on the immune system. DHEA is known to stimulate the interleukin-2 release, subsequently the natural killer cell activity. It has been shown that DHEA in vitro inhibits the interleukin-6 secretion. Of course we know that aging conversely is associated with a decrease in interleukin-2, and an increase in interleukin-6, and the question is, does this correlate with the drop in DHEAS we observe also in normal aging?

But however disappointingly the immune function in the 280 patients, 140 with DHEA and 140 with placebo, it did not change significantly irrespective of treatment arm. This included natural killer cell cytotoxicity. The effects of aging on the immune system cannot be reversed by DHEA.

However, you have to take into account, and possibly the down stream conversion of DHEA to androgens, and to immune modulatory steroids are altered with age, as we saw when we compared the expression of activity of steroidogenic enzymes in terms of blood mononuclear cells. It clearly shows that in elderly men, and this is the pink bar here, as compared to healthy young men, aging is associated with an increased conversion of DHEA to androstanediol into active androgens in the immune cells, which may compensate for the relative drop in circulating DHEA and DHEAS levels. If we look back at our model of pathologic total DHEA deficiency, these are patients with adrenal insufficiency.

Then you can see that there is really a huge difference between the circulating serum levels with adrenal insufficiency patients having much lower, even than old people.

If we look at immune function in these patients, then we can clearly see that the natural killer cell activity is dramatically reduced in adrenal insufficiency. These are just recent results and we are currently carrying out a replacement study in these patients.

So, what is important for you to take away is that studies in adrenal insufficiency clearly helped to define a therapeutic role of DHEA. However, I do not think that an age-related relative decline in DHEA is necessarily an indication for DHEA replacement. However, in selected patients, fatigue, impaired mood and sexuality may become a target for DHEA replacement therapy. This is awaiting further studies.

DHEA is clearly not the fountain of youth; however, there is no reason for despair.

Getting older shouldn’t stop you from doing your favourite things, irrespective of your hormone levels.

Thank you for your attention. These are the groups back in the UK and Germany who helped to do all these studies.