Discussion

Veldhuis: This area presents a lot of challenges to me. One of the difficulties I'm having as an endocrinologist with the testosterone theory, is that I don't see this syndrome X (metabolic syndrome) appearing across puberty in boys. At this stage their testosterone goes up 10-30-fold, but they get just mild insulin resistance. This makes me wonder whether insulin resistance is a marker for some other activity in the system. Polycystic ovary syndrome (PCOS) patients (bearing in mind that this is a diverse category) appear to have primary insulin resistance. If PCOS patients who are not particularly obese but who are hyperandrogenaemic are given drugs or other interventions to lower their insulin levels, this also lowers androgen levels. If androgens were the only thing one measured and one knew nothing about insulin action through its tyrosine kinase pathways, one would say that it is the androgen that is the prime cause here.

Bjorntorp: I didn't have time to show that in the stressed men. Particularly in the small subset of 'burned out' men I referred to, testosterone levels are lowered. The hyperandrogenicity problem is probably a separate female issue. There is a sort of chicken and egg discussion about which comes first, the changes in the androgens or the changes in the oestrogens. But when we give androgens in moderate amounts to female rats, they become highly insulin resistant. When investigators have given androgens to women — there is one US study (Lovejoy et al 1996) and one Dutch study on transsexuals (Elbers et al 1997) — they also become insulin resistant. I believe that when you give testosterone, these things happen.

Veldhuis: There are a few exceptions. One data set from John Nestler showed that, when he reduced insulin with diazoxide, androgen levels also fell (Nestler et al 1989,1990). Most experiments show the converse, but it is hard to give long-term androgens. When we monitor androgens, we may be looking at a marker of another underlying event that is driving syndrome X. We certainly see syndrome X all the time without any hint of hyperandrogenism. Could you clarify your thinking on the relationship between this group of women who are stressed and hyperandrogenaemic and the PCOS patients? Is PCOS simply an extended subgroup of this type of woman, or is PCOS a separate disease? It is such a tough area.

Bjorntorp: Yes. PCOS is a mess. First of all, I think we have to separate out PCOS and polycystic ovaries. There are reports now of polycystic ovaries in up to 20% of women. We have found around 25% of women to be hyperandrogenic. We are going to look at their ovaries. On the other hand, I have recently seen hints in the literature that stress might be involved in polycystic ovaries.

Veldhuis: There are all kinds of mild hints of HPA axis dysregulation in PCOS. Almost any mild degree ofdysregulation feature that you wish to propose will have been reported, but not consistently. This is one of the problems that I have.

Prior: I'd like to expand the concepts a little more. Some time ago Kaplan and Adams showed that stressed, non-dominant premenopausal cyclic female monkeys continued to have regular cycles but had disturbed ovulation (Kaplan et al 1986, Adams et al 1985). Disturbed ovulation was associated with obliteration of the normal female protection against atherosclerosis. In those early studies, androgens weren't reported.

Bjorntorp: I know Carol Shively very well; we have a close contact. I asked her if she had looked at androgens. She tells me that they are elevated in females.

Prior: There are two types of non-ovulation that differ remarkably in many of their outcomes, especially in terms of what happens to bone. A simplistic way of looking at non-ovulation is as 'turned on' (meaning high luteinizing hormone [LH], ovaries enlarged and increased androgen manifestations) or 'turned off" (low gonadotropins, normal or low-ish oestrogen levels). But these two types of non-ovulation have a common morphology with polycystic ovaries. I think we should hone our terminology and stop defining a state that means androgen excess by the same non-specific morphological feature that also characterizes the very different hypothalamic non-ovulation (Prior 1997).

Burger: PCOS is a very difficult model or analogy to use in the present discussion. I have been quite taken by the sort of analysis that has come from Bart Fauser's group in Rotterdam, who has adopted a much more pragmatic approach to the whole concept of what we call PCOS (Imani et al 2000). He looks at the characteristics of women presenting because of infertility or coming to the gynaecological endocrine clinic. He takes a number of the classic features that we associate and then looks at their prevalence in individual women. He sees overlapping Venn diagrams of a group who have insulin resistance, a group who have hyperandrogenaemia, a group who have clinical hirsutism and a group with obesity. They overlap, but it is only a small proportion who have the full complement of all these features that were originally associated with the Stein— Leventhal description of PCOS. It is this sort of analysis that will help us to clarify what sort of terminology we should use. He uses it as a much more pragmatic approach to say, 'What is the prognosis of this individual and how should they be managed? Let's forget about trying to make a diagnosis of a category to which only very few will actually belong.' This is an illuminating perspective.

Veldhuis: To me, this is a more honest treatment of the heterogeneity that exists. This may help reduce some of the confusion caused by the clumping of patients in reports. I'm personally intrigued that insulin is driving androgen secretion. When we do in vitro studies with porcine theca cells, and transfect these with cDNA encoding the 17a-hydroxylase promoter, if we add minute amounts of insulin gene transcription goes up within 30—60 minutes. It is gorgeous! If you add a tiny bit of LH with the insulin, there is synergy. Most clinicians find that there are patients who are overly responsive to either insulin, or LH, or both. I want to be careful not to attribute something downstream, such as androgens, to events that are proximal or upstream. The theory of the serine phosphorylation defect has not actually been extended, but this is the kind of thinking that may eventually help us aggregate where appropriate and separate where appropriate. A particular patient might have a polymorphism for the androgen receptor, because a slight decrease in androgen feedback due to a slightly defective receptor based on a polymorphism for the receptor causes her to oversecrete androgen. This may not be the same as another patient who is also anovulatory and hyperandrogenaemic with say a glutamine/alanine substitution in the promoter of the 17a-hydroxylase gene. She in turn is different from an obese syndrome X patient who has a primary defect in the insulin signalling pathway or in MAP kinase. I am struggling with the looseness of the biological endpoints that all of us depend on, and I am trying to drive some further precision in our focus ofwhere the defects are, which would help us find out why the Venn diagrams that Henry Burger referred to are potentially separable.

Burger: Per Bjorntorp, how solidly established and how reproducible is the evidence of dehydroepiandrosterone sulfate (DHEAS) hypersecretion in chronic stress? My impression from having looked at the literature a while back is that it is not very consistent. Is this how we can explain some patients with hirsutism who otherwise have regular cycles and don't seem to fit in the PCOS grouping?

Bjorntorp: I can't answer that question.

Veldhuis: What might the notion of 'burn-out' better be defined to mean? Are you describing the chronically stressed animal without a novel stressor being introduced? Even a chronically stressed animal with a novel stressor will show a new stress response.

Bjorntorp: This is a confusing finding. This kind of burned-out HPA axis is seen in Vietnam veterans and Holocaust victims, for example, along with depression. People who are experts in the field believe that this is because the HPA axis is just worn out. In this situation there is apparently an increased activity of the sympathetic nervous system as a compensatory event. In the burned out men I showed here, which is about 9% of the population, we find background factors which we interpret as causing stress, but not dramatically more than in the less damaged men. My guess is that there is something else involved here.

Veldhuis: There are three clinical situations I can think of where the axis looks fairly flat. In the post-op Cushing's disease patients, the axis has been suppressed and is fairly flat, unless you infuse CRH and then the whole axis wakes up. Postpartum, there is a flat, monotonic, minimally pulsatile output. And there is a flat HPA axis in some cases of chronic fatigue syndrome (which is a bit like PCOS in that it is a poorly defined syndrome). Those three conditions involve inferential CRH deficiency states. If you model it on this basis, then you have to introduce something that I think is important in discussing these axes, and that is to view them as joint feedback and feed forward ensembles. For example, it would be inappropriate to talk only about feedforward, because this is irrelevant unless you can tell me the feedback state concurrently. If you give me any feedback state, I can make it irrelevant by driving feedforward appropriately. Neither feedback nor feedforward can be viewed in isolation. One of the things we may need is a way to describe burn out profiles more formally. On the basis of all the known data on feedback, are there some conditions that would never produce that output in any sensible, easy manner? And are there other conditions that might? If you give me this information and I have the laboratory funds, I might then do the research to clarify some of the plausible options, and not immediately spend precious sponsorship funds on the least likely theories. One of the challenges we have clinically is that we have never assembled a clear, well defined, mapped network based on reasonable, sensible, minimal feedback connections.

Carroll: It is a very difficult area to nail down in humans for the reason that I mentioned before: the pituitary is sitting right in there interposed between your sampling zone and your zone of physiological interest — the brain. As long as that is the case, it is difficult to interpret. Most of the literature says that if you use ACTH and cortisol as your dependent variables for response to a stress, then in the context of chronic stress, acute stress challenges lead to impairment of the expected response. The same is true when CRH is administered. It is clear from the depression literature that if you provoke insulin hypoglycaemia, the ACTH and cortisol responses are blunted, and if you give CRH their response is blunted both in cortisol and ACTH. But you can't interpret that with reference to the brain because the pituitary is sitting right there. If what I was saying earlier today is correct, the pituitary is a prime site of GR action, and this may be the answer. We have to come up with alternative experimental strategies. Johannes Veldhuis and I have been looking at a low feedback strategy, but we don't have data analysed yet for that. This would be the approach: knockout the feedback signal with metyrapone, use ACTH as the dependent variable and then do things to the brain and see what happens. Plasma CRH is not a worthwhile measure in this context, for short-term studies, because it gets diluted in the general circulation.

Handelsman: Isn't it better for that experiment to use adrenalectomy rather than using drugs?

Carroll: That's not so easy to do in humans!

Velduis: This opens the question of stressing the axis, trying to pin-point responses and residual elements without watching the whole system change simultaneously. Even this is difficult, because of the triple nodes.

Carroll: Paul Plotsky and Paul Sovchenko refer to this as pharmacological adrenalectomy. You have to be very careful about timing and dosage to make it work.

Laron: The aetiology of so-called PCOS is more complicated. We have data that shows insulin-like growth factor (IGF)1 over-dosage causes a PCOS-like syndrome in females (Klinger et al 1998), and in males it increases LH (Laron & Klinger 1998). I don't think there are enough data showing whether insulin competes on the IGF1 receptor in the patients with so-called PCOS. There may be interplay, but it seems that the synergism of IGF1 with androgens is stronger than that between insulin and androgens.

Veldhuis: When you say it produces a PCOS-like syndrome, given what we have heard about the Venn diagram multiplicity, what kinds of features are you referring to?

Laron: It causes hyperandrogenaemia, acne and interrupted menstruation, which are all reversible when the dose is reduced.

Veldhuis: Have the ovaries in these patients been examined by ultrasound?

Laron: Some have, but they did not show the typical changes of PCOS, namely the fibrosis.

Veldhuis: This highlights the complexity of watching an endproduct when you don't know which receptor pathways are triggered.

Prior: I was going to make the clinical observation that when women become overweight, they tend towards increased androgenicity; when men become overweight they tend towards decreased androgenicity. There are some fascinating epidemiological data taking the reported weight and height at age 18, and showing anovulatory infertility in those who have a body mass index higher than 24.5 (Rich-Edwards et al 1994). The relationship between body weight, LH and androgenicity is a key here, somehow.

Veldhuis: I would add insulin to this.

Björntorp: I know what you are saying. The problem with these studies as I see them is that people lump obesity into one pot. You have to separate central obesity and peripheral obesity.

Prior: That is the way I thought of it. Also, we must consider muscularity causing higher weight but not obesity.

Morley: Besides the paper on resistance, there is also a paper by Brüning et al (2000), in which the insulin receptor was specifically knocked out in the brain. These mice are very clearly hypogonadal. Females basically become fat, whereas males don't. This was used as an argument for insulin affecting feeding. In fact, if you knock out oestrogen you actually get fat females.

Brabant: It is unclear whether this is an effect mediated by insulin on body fat or simply via insulin acting on the gonadotroph.

Morley: The other thing in the recent literature that is going to change all of this is a paper showing that fat cells produce a PPARg-related compound called resistin (Steppan et al 2001). If that is hormonal-dependent or changes hormone it will totally change the way we think of this. Most probably this is what is going to happen.

Haus: We studied over 750 24 h profiles (6—8 samples/24 h) of hormonal and biochemical variables in clinically healthy diurnally active subjects between 9 and > 90 years of age. In comparison to young adult subjects (21 1.5 years of age), the elderly (77 7 years of age) showed a drop in their circadian mean of serum

ACTH levels (44.6 6.4pg/ml vs. 25.0 1.6pg/ml) while serum b-endorphin showed in the same subjects a statistically significant increase (3.9 0.2 pmol/l vs. 5.3 0.3 pmol/l) (Haus et al 1989, Nicolau et al 1991). This raises the question of a possible difference with ageing in the splitting of the parent molecule of proopiomelanocortin from which both ACTH and b-endorphin are derived.

Plasma cortisol 24 h mean values varied very little between the same age groups (10.5 0.3 mg/dl vs. 9.5 0.2 mg/dl) (Haus et al 1989, Lakatua et al 1992). However, in the plasma ACTH:plasma cortisol ratio there was a very marked age difference, which was strictly time dependent. In the morning, the ratio was comparable between the young and old subjects. However, during the afternoon and evening there was a substantial difference between the age groups. The younger subjects showed a high amplitude circadian rhythm with rising values of the ACTH:cortisol ratio in the afternoon reaching a peak at 00:00. With increasing age the amplitude of this rhythm became less and the rhythm almost disappeared in subjects above 80 (Lakatua et al 1992). This observation suggests in the elderly a higher sensitivity of the adrenal to ACTH during the evening and early night hours when the adrenal in the young subjects becomes less responsive to ACTH.

Veldhuis: This is the feedforward concept that I want to visualize.

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