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Professor Horacio Croxatto interviewed by Professor Thomas D'Hooghe Professor Thomas D'Hooghe: My name is Professor Thomas D’Hooghe from Leuven University Fertility Centre in Belgium. I have as a guest Professor Horacio Croxatto from Chile, who just gave an excellent presentation on the potential role of progesterone receptor modulators in the treatment of endometriosis. Professor Croxatto, may I ask you, you described in your talk, progestins, anti-progestins, and then what you would call I think, mesoprogestins. Can you elaborate a little bit on those different classes of drugs and their potential application in endometriosis? Professor Horacio Croxatto: Yes, until recently there were clearly two groups of steroids that bind to progesterone receptor preferentially over other steroid receptors. The first group, discovered long ago, are progestins. These are steroids showing agonist activity or mimicking progesterone ability either to sustain pregnancy in ovariectomised animals or to induce progestational changes in the endometrium. Then, a few decades ago mifepristone, an antagonist of progestins, became a player in this concert and the term anti-progestins was coined. Until recently we’ve had these two groups that bind to the ligand-binding domain of progesterone receptors. More recently another group of compounds that exhibits both agonist and antagonist activity in the progesterone receptor was described. They behave as agonists in the absence of other progestins and they behave as antagonists in the presence of other progestins. Then, almost at the same time, borrowed from the field of oestrogens, the term progesterone receptor modulator was coined and applied preferentially to this third group of compounds. This became fashionable. The term modulation has been in fashion in biology, and our students use it in every answer to any question. Modulation is in, and this has spread into medicine also. In my view, all three groups of progesterone receptor ligands modulate the receptor. Therefore, I don’t see any reason to restrict this name to those that have dual action. I think we should search for a different name, and I proposed some time ago to use the term mesoprogestins, because they are between the two extremes of agonist and antagonist. Also the basic mechanism through which they interact with the receptor is the same for all three groups, therefore, I don’t think we should reserve or restrict the term progesterone receptor modulators to this third group. Even though the term progesterone receptor modulators is in fashion it’s not very meaningful. Professor Thomas D'Hooghe: Indeed, biologically not really correct. Professor Horacio Croxatto: I think we should use generic terms such as progesterone receptor ligands. Professor Thomas D'Hooghe: Thank you that’s very clarifying. In terms of the effects on endometrial biology and endometriosis development you mentioned that these drugs, mesoprogestins as you call them, have the potential to block the endometrium and still allow ovulation. Can you explain a little bit how this works on the biological, histopathological level of both the endometrium and the ovary? Professor Horacio Croxatto: Anti-progestins and mesoprogestins both have the ability to antagonise the proliferative effect of oestrogen in the primate endometrium, though not necessarily in other species. But in non-human primates, who menstruate, they antagonise the oestrogen proliferative effect. In addition, they act as anti-progestins in the endometrium and by virtue of these two mechanisms, they show a preferential effect on the endometrium as opposed to other oestrogen-dependent tissues like the vagina and the oviduct. I should also add the ovary and probably the hypothalamus and pituitary. In primate studies, as well as in clinical studies, carried out so far, of which I can talk about, it has been shown that mesoprogestins do inhibit ovulation in a small proportion of animals, or women treated. But in all of them, they suppress menstruation, by virtue of these effects that I mentioned. Professor Thomas D'Hooghe: May I just ask, because I think that is important from a biological point of view; if they suppress menstruation is that primarily because the anti-oestrogenic effect that the endometrium is blocked from growing up? Because I can imagine once the endometrium is growing in the late secretory phase and then you have an anti-progestin effect, sooner or later the patient can stop bleeding. Does it occur at the very basic level of endometrial growth? Professor Horacio Croxatto: I think so, that this is at the very basic level so that the endometrium does not mature, does not develop the critical machinery that starts menses when progesterone levels drop. Professor Thomas D'Hooghe: That’s very interesting. I know the information will be limited at this moment, but are there any data you can mention on long term effects, either in primates or in women, in terms of taking for a considerable length of time, let’s say six months or one year, if this effect of non-menstrual bleeding is still on, or does it start sooner or later, so they start to bleed a little bit, or remain in amenorrhea? Professor Horacio Croxatto: No, chronic treatment studies in animals and women are not very long, but at least for three months they sustain the amenorrhea. It is reversible; once you stop treatment the cycles return. Professor Thomas D'Hooghe: What, in your opinion, is the added value of these mesoprogestins compared to the classical long-term continuous progesterone treatment in endometriosis, or combined oral contraceptive continuous treatment in endometriosis woman? What do those drugs have to offer extra on top of the available drugs? Professor Horacio Croxatto: In my view they conserve the steroidal oscillations of the menstrual cycle, so in a way the whole body of the woman sees the normal physiological changes. But because of their selective or preferential effect on the endometrium, the endometrium doesn’t see this. Then it doesn’t grow, it doesn’t bleed, and I assume, or expect, that in endometriosis the endometrial foci at the peritoneal level will not experience cyclic growth and shedding, and therefore there will be less inflammation, less adhesions, less pain. Professor Thomas D'Hooghe: So, there is quite a bit of evidence, if I understand you correctly, that the effect on the endometrium is mimicked by the effect on the endometriosis lesions? Professor Horacio Croxatto: I would expect that, but I cannot say that has been proven yet. Professor Thomas D'Hooghe: One last question is about side effects. The way you present it, it seems like maybe a more natural way, that allows a more natural cycle at the ovarian level and selective inhibition of endometrial growth at the endometrium level; does it also mean that there are many less side effects than with classical hormonal treatments, suppressive treatments of endometriosis? Professor Horacio Croxatto: The clinical tolerance has been very good in our studies. We have found no serious adverse events, and no significant changes in metabolic and safety parameters. Professor Thomas D'Hooghe: Then the last question is probably the most difficult to answer. When do you think we may have these drugs available for clinical research for clinical applications, do you foresee any timeline there? Professor Horacio Croxatto: I would expect that by 2006 the pharmaceutical companies, who are handling these compounds, will open the possibility for more researchers to undertake new clinical trials and I guess phase two and phase three studies will have been finished by then. Professor Thomas D'Hooghe: Thank you very much, Professor. Professor Horacio Croxatto: You are most welcome. Feedback/Questions: Dr. Usha MG Madathilparambil MD Steroid receptors in the uterus: implications in endometriosis.
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