Discussion

Veldhuis: One of the distinctions I see between your work and Henry Burger's is that you propose that oestradial elevations occur before FSH. Therefore, you have the task of accounting for an isolated oestradiol increase. Is that right?

Prior: Yes. My hypothesis would be that FSH isn't measurably higher (Burger 1994), but this doesn't mean that it isn't occasionally higher and at a level sufficient to recruit a larger cohort of follicles.

Veldhuis: We do come to a distinction that will probably need more careful study, as to whether the antral follicle cohort is increased or not. High quality ultrasonogrophy prospectively could be marvellous.

Is it your view that the luteal phase defects are a marker of the primary ovarian disease associated with follicle attrition, or is this a neuroendrocrine disorder reflected in due course in an abnormal cytodifferentiation?

Prior: I would guess that it is the organization of the stimuli to the follicle, but I don't know the answer.

Burger: I don't know the answer either, but I have normally interpreted luteal phase defects as related to a defect in follicular function. However, it is very hard to diagnose them in young reproductive-age women. It is a woolly area.

Veldhuis: I don't know whether iNOS is in the ovary, but the NOergic pathway is clearly there — it is partly driven by FSH. Can you think of a mechanism that would drive inappropriate oestradiol episodically leading to some defect in follicle growth, which is a mixture of oestradiol, FSH, insulin-like growth factor (IGF)1 and also negative regulators producing orderly follicle growth, yet enough oestradiol to drive a surge, and then complex organizaton of that follicle into a corpus luteum? Could the ovarian ageing seen in the human be the analogue of the CNS ageing seen in the rat? In the female rat there is strong evidence for CNS-dependent ageing, rather than primary ovarian ageing, based on the ovarian transplantation studies (Evans et al 1992). Is there a possible model for iNOS being involved in the early changes in the ovary? The species difference is not the basic issue to me, but rather the site where the defect first emerges.

Prior: I don't know, but this is a useful thing to start thinking about.

Handelsman: The point that Jerilynn Prior made was that all the flushing episodes seem to start through sleep. It has always struck me that there are clearly oestrogen-dependent symptoms and then there are the rest. I have always assumed that some of these are due to sleep disturbance from flushing during the night. If this was so, it should be oestrogen sensitive. It appears that this is not the case. Is sleep disturbance important?

Prior: I would say that it is very important. Something happens to sleep physiology, because there is sleep disturbance in women who have never reported hot £ushes. There is some neuroendrocrine change that occurs at that stage of life.

Veldhuis: There aren't many data. We wrote one paper showing this LH—FSH synchrony loss in the monotrophic FSH elevation stage of the premenopause (Matt et al 1998a) and in ageing men (Pincus et al 1997). It is clearly abnormal, but I don't know that it can't be explained by a downstream problem in variable oestrogen overproduction and then withdrawal, leading sometimes to high FSH. In the men it seems clear that there is some central nervous system (CNS) dysregulation of the outflow control of several factors, some neurogenic, some hormonal, and some across axes (Pincus et al 1996, Veldhuis et al 1999a,b, 2000). But whether these derangements are in any sense primary is unclear. The sleep disorder raises the question of whether CNS alterations are precursory.

Müller: Referring to this argument, in addition to their genomic actions, steroids can have non-genomic effects that occur with a shorter time lapse. They can act directly at the level of hormone-sensitive neurotransmitter receptors present on cellular membranes of neuronal cells, and can also be synthesized in the CNS, independently from their peripheral sources (Baulieu 1997). For instance, precursors (pregnenolone sulfate, dehydroepiandrosterone) or metabolites (allopregnanolone) of progesterone, act respectively as antagonists and agonists of the GABAa receptor, thus influencing neuronal activity within large parts of the CNS (Genazzani et al 1996). If they can modulate GABAergic or glutaminergic function, we should not be surprised that they can induce behavioural alterations.

For instance, insomnia may be an expression of latent depression. Many of the symptoms such as irritability and depressed mood can be interpreted as the action of these steroids directly on the brain.

It is interesting that in rats, also, before the complete arrest of the oestrus cyclicity there is a phase called constant oestrus, involving continuous activation of oestrogen production (Kalra et al 1993). This is reminiscent of the high variability of circulating oestradiol levels of women in the late perimenopause (Burger 1999).

Veldhuis: In the rat there is a blunting of LH surge in middle-aged females, well before their oestrus cyclicity changes, pointing to a CNS component (Matt et al 1998b). This may be a feature of the rodent (Evans et al 1992). Others would say it is also a feature of the human.

Burger: I have debated this issue at some length with Phyllis Wise. I challenged her about the relevance of the rodent model to an understanding of the human endocrinology. I must say that she has persuaded me that there are similarities that warrant the continued exploration of that model.

Laron: Coming back to the issue of sleep disturbance, we know that in puberty children love to sleep for a long time. Would this mean that they have much more of what the menopausal women lack?

Veldhuis: GH secretagogues are thought to be somnogenic (Giustina & Veldhuis 1998). There are data showing that the actions of GH secretagogues favour sleep (Thorner et al 1990).

Carroll: With regard to Dr Müller's point about the neurosteroids, they tend to have GABAergic and somewhat sedative properties. As I was preparing my review

I came across another reference to yet another alleged explanation for the night sweats and vasomotor instability of menopausal women. This is increased cell number and enlarged cell size of neurokinin B neurons in the infundibular nucleus of the hyothalamus. This is another theory as to why they develop vasomotor instability.

I agree that the menopausal period is one of stress. In general, in the epidemiological studies of depression that I talked about yesterday, an important point to make is that depressive symptoms seem to count, rather than a formal psychiatric diagnosis of major depression. The traditional clinical psychiatric distinction between minor depression and major depression appears to be unimportant in these longitudinal studies.

Müller: There are data showing that the latest antidepressants are effective in blocking some of these postmenopausal symptoms. This has been shown for instance with inhibition of hot flushes by venlafaxine, a specific blocker of noradrenergic re-uptake (Loprinzi et al 2000).

Veldhuis: Does it affect the sleep disturbance?

Haus: We have been talking about sleep disturbances, but nobody has mentioned melatonin. In the USA, melatonin can be purchased over the counter and many people who develop sleep disturbances take it, some under medical direction, many others without. What role might melatonin play in the treatment of sleep disturbances in the elderly? Some publications on this topic have previously appeared (e.g. Dagan et al 1998).

Prior: I haven't seen any data on this.

Riggs: I want to ask about the important studies you did in 1990 on the relationship between decreased luteal phase duration and bone loss. The limitation ofthese studies is that it takes so long to get an accurate estimate of bone loss by bone densitometry. What has changed since then is that we now have the biochemical markers, so it is possible to see changes in bone turnover within a single cycle. Have you had a chance to look at this, to follow up on the earlier studies?

Prior: Progesterone works on bone formation and not on bone resorption. The markers that we have for bone formation are influenced by bone resorption. This means that we don't have a specific marker that we could use to document the progesterone effect on bone.

Riggs: I disagree with that. Formation and resorption are linked together, so the markers for each will be linked together. If you measured resorption and formation, and looked at the gap between them, you ought to be able to see a difference, if there is a difference, within the individual cycle. This might be worth doing.

Prior: There have been several attempts to look at changes in bone resorption across normal ovulatory menstrual cycles. The data are wild. There is obviously a lag of a few days between a time of change in oestrogen and a change in those markers. It is complicated to do this study; I haven't yet got sufficient funding to do it. I have applied to do a study in which I will control resorption in perimenopause, give progesterone cyclically or daily, and see what happens to bone.

Robertson: The vasomotor symptoms of menopause are so dramatic and so discrete. I am amazed we don't have a better handle on them. What is the current understanding of the kindling features: the things that are occurring in the minute or two before the onset of these? What are the mediators of the vasomotor symptoms?

Prior: That's a good question. It is clear that there is an adrenergic activation prior to any temperature change. The women will describe that they woke up suddenly and they felt anxious or angry, and then they felt hot. The better studies of the temperature change suggest that there is a tiny increase in core temperature which the hypothalamus then decides is not OK. It begins the process of vasodilitation that leads to heat dissipation. The core temperature then drops. Some women will get quite chilled afterwards and will describe 'cold sweats'. Hot flushes are increased by social stress (Swartzman et al 1990). For example, people who are having a number of hot flushes will sometimes get a flush if they hear an argument in the next office. Early on in some women flushes are triggered by even a small sip of alcohol. We have used a diary system so that each day a person integrates their assessment of the intensity of the hot flush on a 0—4 scale, the number of discrete episodes during the waking day, and the number and intensity during sleep. We have those data tracked longitudinally in quite a large number of women. I think we are getting a better descriptive idea about it, but the endocrinology and neurobiochemistry are complex.

Burger: There are so many things about hot flushes that are not understood. One ofthe curiosities is that in population surveys ofwomen there seems to be a baseline hot flush frequency reporting rate of about 10% in the normal community under the age of 40. If you ask women whether they have had hot flushes in the last two weeks, about 10% will say they have. I see a lot of patients referred for hot flushes for which I can find no cause whatsoever.

Prior: To put a different perspective on it, I would think that many of those women are in the earliest phases of perimenopause (Prior 1998). If you were to follow them over time, they will begin to show short follicular phases and ovulation disturbances.

Ruiz-Torres:Have you any data on leptin interactions?

Prior: No, but that's an interesting question.

Handelsman: One of the purposes of this meeting is to identify things that we don't understand. The most striking thing for me is watching those log linear declines in primordial follicles, which are disappearing at a phenomenal rate.

What controls this atresia? With the time decay in a log linear fashion, menopause could be delayed by years. Yet we have no idea what controls this atresia that dictates age at menopause.

Veldhuis: First, the ovarian physiologists are going to have to teach us what local factors are produced by the granulosa cell that talk to the theca cell and egg, and vice versa.

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