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Mesoprogestins (Asoprisnil) in the treatment of endometriosis
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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