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DISCUSSION

Veldhuis: One of the things I am struggling with is this relationship between stress and depression: which comes first? These both aggravate each other. Can you separate this a little bit further for us? In a sense, just being alive and producing cortisol must be a chronic stressor.

Carroll: That's what Selye meant when he talked about the 'stress of life'. As far as the relationship with depression is concerned it doesn't matter whether it's the chicken or the egg — there are probably several paths to it. One of these paths is genetic. A small number of individuals have the genes for bipolar disorder or familial unipolar depression. They often become depressed in the first instance through some kind of precipitating life stress, but after that the illness seems to run a course of its own and the recurrences often come independently of stress. By the time we get to study them they've been depressed for a month or two and, as I said, that in itself constitutes a new chronic stress for the individual. The state of being depressed is about the most painful existential condition that humans can endure.

Veldhuis: Are there data on glucocorticoid receptor-deficient mice that would help in establishing this hypothesis? Right now the challenge I see, although it is extremely attractive from an associative viewpoint, is causal connectivity. Maybe you could demonstrate that a mouse with a constitutively activated glucocorticoid receptor system, independently of peripheral steroid levels, tended to develop all these diseases and die early and that the resistant receptor genotype had the converse experience. Are people gathering such information?

Carroll:: It's a very good idea; I don't know of any data on this.

Veldhuis: In humans we don't think of the type I receptor as connected to the metabolic features of cortisol activity except at the level of sodium retention and potassium excretion. However, the ratio of these receptors changes in ageing. What is your assessment of the role of the type I mineralocorticoid receptor (MR) in the rodent during the ageing process? This is sort of a black box to me as an endocrinologist.

Carroll: The best answer I can give to that is to say that MRs are concerned with the amplitude of the rhythms, there is down regulation of MRs as I pointed out in the stressed animal and in the depressed patient and that may well be the mechanism by which the nadir cortisol values are elevated. It's the MR that raises the nadir of the values, but the elevated occupancy of glucocorticoid receptor round the clock is what causes the tissue damage.

Burger: I wondered if you could say a little bit more about the direction of the changes you've described in the male reproductive axis. You mentioned in the rat the loss ofcycling, which is probably also true ofthe human female. What about the effects of chronic stress and depression on the male reproductive axis and on testosterone levels?

Carroll: Acute stress clearly leads to a decrease in testosterone production. In chronic stress this may come back a little, but it still remains suppressed. We have to be careful about which chronic stresses we are discussing, because if it's a social stress where a male rat is defeated by a stronger male, in that context the testosterone stays very low. That's the way the animal hierarchies of dominance work.

Burger: Do they also have a shorter lifespan?

Carroll: Yes, if you put these animals in the visible burrow system where you can observe their interactions, you can see that the ones that are pushed to the periphery get less of everything: less food, less shelter and less access to the opposite sex. They develop stress-related pathologies.

Burger: Has any attempt been made to actually replace or increase the testosterone levels of animals in that situation?

Carroll: There have been a few experiments along these lines. The studies that I am aware of look at male animals that have been through a social defeat. Their testosterone is greatly reduced. If they are put back into a group of rats they already knew, their stress parameters come back pretty rapidly, but if they are kept in isolation then their stress parameters stay low. There are social interactions with the rate of recovery from a severe stress.

Burger: Is that true for exogenous replacement as well?

Carroll: I am not aware that anyone has looked at exogenous replacement.

Veldhuis: That would be very interesting.

Handelsman: I've been quite struck by the number of depressed people on selective serotonin reuptake inhibitors (SSRIs) who have relatively low testosterone levels. Against that, in placebo-controlled studies there seems little change in healthy young men in testosterone. The depression in testosterone seems unrelated to whether they get better or not.

Laron: Do SSRIs reduce growth hormone (GH) as well?

Veldhuis: No, they stimulate GH slightly.

Handelsman: This may be a naive question, but what is the effect on life expectancy of adrenalectomy, with or without maintenance of glucocorti-coids?

Carroll: I don't know.

Veldhuis: This could be interesting. Giving glucocorticoids back according to the rhythmic hypothesis would be necessary, or giving a modern anti-glucocorticoid that's fairly selective to an intact animal could work as well.

Muller: There are data showing that adrenalectomy reduces hippocampal damage (Stein & Sapolsky 1988). In referring to the senile brain, you mentioned impairment in the monoaminergic systems (Gottfries 1992). What about impairment of acetylcholine neurotransmission (Sherman & Friedman 1990, Pepeu et al 1993)? As far as depression is concerned we know that there is a cholinergic theory of depression: typical antidepressant drugs are endowed with anticholinergic activity (Baldessarini 1996).

Carroll: That idea has been around for a long time. In the cholinergic system there are similar changes as in the monoaminergic system in normal ageing, but these changes are very different from the loss of cholinergic cells in the nucleus basalis that occurs in AD. Ageing is not like AD.

Bjorntorp: You are the pioneer in dexamethasone suppression testing. This is useful for Cushing's disease and depression. When we are looking at a functional increase of cortisol in patients with chronic stress, which is the best way to assay the feedback loop and the receptor loop? We have tried a lower dose than the conventional one (0.5 mg rather than 1 mg) but I'm not sure that we really know what we are measuring. It might be useful to look at the escape of the inhibition; you might see something there.

Carroll: Even though I did introduce the dexamethasone suppression test for depression, I would never use dexamethasone again, because a major confound in all of the dexamethasone work in psychiatry has been accelerated metabolism of the steroid. I think we know why that happens now, because we give dexamethasone at 11p.m. and we sample blood the next day. With the hyperthermia there is increased pharmacokinetic clearance, and we know that these escapers very often have lower plasma dexamethasone concentrations when the cortisol samples are drawn. I would use some other paradigm, such as a hydrocortisone infusion in the human, and look for indices of adrenocorticotropic hormone (ACTH) suppression.

Bjorntorp: You say that the metabolism of dexamethasone explains all this, but are you sure that the circulating dexamethasone is mirroring what's happening? Is this a measurement of bound dexamethasone?

Carroll: It depends who you ask. If you ask Ron de Kloet he would say that with dexamethasone the brain is like an adrenalectomized brain because the synthetic dexamethasone doesn't get to the brain, and that the site of action of dexamethasone suppression of the HPA axis is the anterior pituitary. I don't think everyone agrees with that. If you put dexamethasone into the cerebral ventricles it will certainly act on glucocorticoid receptors. Don't forget about the pituitary: it is sitting there, between the brain and the adrenal gland and makes human experiments on direct central nervous system (CNS) feedback difficult because whatever you think you are doing to the brain, at the same time you are also doing it to the anterior pituitary.

Prior: The experience I have as a clinician is that many women who present with ovulatory disturbances of the menstrual cycle often give a story of childhood sexual, psychological or physical abuse. It seems that this sets their hyper-responsiveness to other life stresses for a long time. One of the common threads besides disturbances of ovulation is sleep disturbance. Again, when we talk about sleep we are talking about higher cortisol during the night when it should be at its nadir.

Carroll: That is an emerging story; it certainly happens in a significant number of depressed women. Be careful not to over-generalize from that sample because there are many women with depression where this clearly does not apply. Then there are all the depressed men and it doesn't apply to them either.

Prior: To reflect on the idea that those who have fewer children have less allostatic load, I'll agree with that in terms of the outcomes after pregnancy, but also there is an amplification effect of oestradiol on corticotropin-releasing hormone (CRH). It is further amplified by social stress, as shown by Kirschbaum's group in young men (Kirschbaum et al 1996). The question is one of homeostatic balance. Until you understand why women have fewer children I wouldn't necessarily jump to the conclusion it was related to long life and homeostasis!

Carroll-. Go back and read Westendorp & Kirkwood (1998) and I think you will get the point. Look at those telling data from the English aristocracy. You mostly won't see it in modern times because very few families have 8—12 children, but they used to.

Veldhuis-. Perinatal imprinting is another subtlety that could confound retrospective and even prospective studies. The Plotsky data published on maternal—infant separation producing delayed adult differences in stress responses, tell me there are sparingly plastic changes in CNS feedback that occur early in life. These are a bit frightening to us in clinical research, because we don't know what they all are. They are not always acknowledged even for the elements we know, such as sexual abuse in childhood. They can confound and add heterogeneity to these cross-sectional studies and perhaps add some strange autocorrelation to the prospective studies. The oestrogen issue is complicated — I'd love to have a separate symposium on sex steroid interactions with the stress axis.

Handelsman. I did some work with David Phillips looking at two separate birth cohorts. In these, low birth weight (which is a well known predictor of cardiovascular disease), was also a strong predictor of lifelong non-married state. This suggests there are a lot of complexities that are not necessarily related to traumatic experiences.

Morley. Clearly when we talk about cortisol we have to look at plasma clearance. In ageing there is a decrease in plasma cortisol clearance time which makes measurements of cortisol very difficult to interpret. The Kirkwood data (Westendorp & Kirkwood 1998) were strongly contested at a meeting in Holland about 14 months ago by data that looked exactly the opposite. You can look at the two sets of data and take whichever set you like. women who have lots of kids learn to adapt and function well if they live in Holland, but if they live in England they can't adapt. The thing that really interested me is that you alluded to dietary restriction as everybody does at an ageing meeting. The real problem with dietary restriction is what you are really doing is taking animals who are living the worlds most gluttonous, although reasonably stressful, life in unusually small cages. We've recently completed a study looking at baboons in Ethiopia and compared them to the average American baboon kept in relatively poor conditions in a farm. Using leptin as a surrogate for fat, it turned out that leptin is almost unmeasurable in the average baboon living in a normal environment. With regard to dietary restriction, nobody will ever get fat levels down to that level. it would be considered too cruel and unacceptable by any animal review board so we have to recognize that dietary restriction isn't going to be valid for humans. Also, in mice and rats restriction really produces premature ageing if you want to look at the hormones. Almost all the hormone changes in rodents look just like the hormone changes you see in old animals and the possible interpretation of this, which makes a lot of sense, is that if you slow down life so that almost nothing happens, you can live a long time. These data also hint that we shouldn't replace hormones because replacing hormones may hurry life up: we may have two great years, but on the other hand we might die 10 years earlier.

Carroll: It depends what you call 'ageing'. This takes us back to Meites, who talked about menopause and somatopause as biomarkers of ageing. It all depends on the biologic context in which it occurs. Your point about food restriction illustrates the same thing: animals in the wild who are existing under high foraging demand for food are very stressed and calorie restricted at the same time. Animals in the lab have it easy, when we cut back their calories by 30% they've still got much more than the high-foraging-demand animals in the wild, so they are not stressed even though they have equivalent calorie intake.

Veldhuis: Are you saying that over-feeding is stressful and conducive to shorter life?

Handelsman: Remember to keep in perspective that people have never lived longer or been better fed than now.

Morley: If you look at the epidemiological studies that show that low cholesterol is good for the heart, the only way they could ever do those is to take out the amount of food eaten because the studies clearly showed that the more food you ate the less likely you were to have a heart attack. In fact the conundrum is easily explainable, because the very heavy eaters are the people who exercise a lot, so the only way they could get rid of the high food intake was to take out the exercise. These things are never easy and the pitfalls we all have to deal with demonstrate that we shouldn't accept that just because we overeat that it is bad for us. Gross overeating is clearly bad, somewhere in between is most probably OK.

Bjorntorp: Having gone through some of the literature on cortisol in ageing, I found a study looking at cortisol turnover with ageing. If you are fat then the adipose tissue transforms cortisol to cortisone by 11 b-hydroxysteroid dehydrogenase.

Veldhuis: I agreed with that review. Our deconvolution methods depend upon an assumption of a stable distribution. I haven't found consistent data reporting altered distributions in ageing.

Riggs: I was particularly interested in your comments that normal ageing is associated with a disproportionate decrease in synaptic connections, with a smaller decrease in the number of neurons. I was reminded of the data in rodents showing that synaptic connections can be related to the degree of stimulus the rodents are exposed to. Is there any evidence in humans that those elderly people that stay busy, that read, and remain active and stimulated have less affected synaptic connections?

Carroll-. The only data I know that touch tangentially on this are those on AD. The risk of AD is clearly related in Snowdon et al's (1996) study of nuns to the complexity of their mental operations at age 18, when they wrote essays about why they wanted to enter the convent. They were later followed through to death and autopsy, and those who developed AD late in life had less complex mental operations in their teenage years. You can interpret that several ways, you can say AD begins at birth, or you can say that the ones who were better educated and stimulated intellectually somehow managed to mitigate their independent risk ofAD.

Morley. The problem with this is that the more active and higher your education level, the less likely you are to develop AD or dementia quickly because the diagnosis takes time. There was a recent paper that actually looked at plaques in people who did and didn't have AD and there was no difference. You can come to the conclusion that there might be very little difference between normal ageing and AD. Our animal model in the SAMP8 mice clearly suggest that it is just an exaggeration. if everybody and every animal overproduces b-amyloid it's how much you over produce and for how long — if you excessively overproduce you will get AD (Morley et al 2000, Kumar et al 2000). But in bright people the diagnosis will not be made as early. All the educational epidemiological studies show the higher your education the less likely you are to get AD. I don't think this is because your synapses are necessarily better, its just that its harder to diagnose someone who is very bright.

Carroll. I think you have overstated the case here; the data from autopsy confirm the in vivo clinical diagnoses with about 80% agreement

Müller. Although there are data showing that education level is inversely related to the development of AD (Geerlings et al 1999), this may be due to the improved lifestyle of better educated people. Several studies have shown that oestrogen therapy can improve cognitive function or prevent AD in elderly women (Paganini-Hill & Henderson 1994, Jacobs et al 1998, Tang et al 1996), whereas other studies have not found an association (Brenner et al 1994, Shaywitz & Shaywitz 2000). Anyway, women with high serum concentrations of non-protein bound and bioavailable oestradiol are less likely to develop cognitive impairment than women with low concentrations (Yaffe et al 2000). Reportedly, oestrogens induce synapsis formation in the hippocampal pyramidal neurons (McEwen & Alves 1999). I think that we have to consider all these aspects together.

Robertson. In human epidemiology, I wonder whether there are data from agents that affect body temperature, for example non-steroidal anti-inflammatory agents and barbiturates. Is there any evidence that these might be having a favourable impact on ageing?

Carroll: There are data showing that NSAIDs reduce the risk of AD. I do not know of any similar data for ageing in general.

Robertson: You gave the impression that you wished the glucocorticoid receptor in human subjects was a little less active. Do you think a slightly less effective receptor or a slightly less effective adrenal cortex might be beneficial for ageing in human beings?

Carroll: I would rather say let's eliminate that nocturnal secretion of cortisol. There are ways this can be done. For example, one of the current experimental approaches of treating depression is to give metyrapone, or ketoconazole, but this is mostly done with daytime administration. I would prefer to go with a midnight or 10 p.m. administration; there you might have a chance of success because this would truly uncouple the GR from circulating steroids for a certain length of time at the right period of the circadian cycle.

Björntorp: I heard that there is now a CRH inhibitor available for treating depression.

Carroll: Every pharmaceutical corporation that I know is trying to develop CRH antagonists, and to get them into clinical trials as rapidly as possible. The potential indications include depression, but also anxiety states, for example. Any data currently available are very preliminary and so we just have to wait.

Handelsman: Can you comment on the point that Dr Müller made about oestradiol and/or other oestrogens preventing AD? Are there are any studies of testosterone in men having similar effects?

Carroll: The data show that oestrogen is worthless as a treatment of already diagnosed AD patients, but the epidemiologic studies suggest that women who are maintained on oestrogen after menopause have a reduced incidence of AD.

Prior: However, it is wise to remember that these studies are highly biased by the differences between oestrogen-taking women and non-oestrogen taking women (Barrett-Connor 1991).

Handelsman: This may be like the cardiovascular story all over again.

Prior: Are the temperature differences that you are talking about measurable in a practical way? Can you detect the difference between depressed and non-depressed patients?

Carroll: Yes. There have even been studies measuring daytime temperatures in depressed patients when they come in for an outpatient visit. There are clear 0.3— 0.4 °C differences between depressed and control subjects even in the daytime.

Prior: What would be the best time to measure it?

Carroll: I would go for the night time, when the differences will be greatest.

Prior: Could it be measured at the patient's usual bedtime? Or do you have to wake them in the middle of the night?

Carroll: We could give them a capsule to swallow and get telemetric data from it.

Prior: We're not talking epidemiology here! I guess we could get the equipment for small studies.

Veldhuis: Those capsules are about US$80 a piece and the monitoring equipment is a couple of hundred dollars.

Carroll: But the data they produce are wonderful.

Prior: They have been used in the past to show that core temperature rises prior to vasomotor episodes (Freedman & Woodward 1996).

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