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What kind of disease is endometriosis?
Hugo Verhoeven MD and Professor Ivo Brosens Hugo
Verhoeven MD:
My name is Hugo Verhoeven from the Centre for Reproductive Medicine in Düsseldorf.
I am on the Advisory Board of EndoZone and it is my special pleasure talking
this morning to Professor Ivo Brosens from the Life Institute for Fertility and
Embryology in Leuven, Belgium. We are sitting here together at the 12th
meeting of the European Society of Gynaecological Endoscopy in Luxembourg, and
the topic we are going to discuss this morning with Professor Ivo Brosens is a
new theory of why patients develop endometriosis. Professor
Brosens, thank you very much for giving me the pleasure of talking to you once
again. Professor
Ivo Brosens:
I would be pleased to give the answer, but I think I am not able to say
why women get endometriosis. I think though that these days the evolution of our
knowledge of the disease of endometriosis has shown that it is a much more
complex disease than what we used to think. In other words, it is more than a
disease with lesions outside the uterus associated with pain or infertility; and
maybe the organ, which we have neglected in the whole history of endometriosis,
has been the uterus. The uterus
may play a role as well in the pathogenesis of the disease, as also in the
outcome of the pregnancy in patients with endometriosis. So I think these are
two aspects, which these days we have much more data on, and that have been
neglected in the past. Hugo
Verhoeven MD:
About a year ago I heard you for the first time talking about the idea
that endometriosis is a uterine disease with extra uterine lesions. What kind of
uterine disease could be the basis of the formation of endometriosis? Professor
Ivo Brosens:
Well that’s indeed the problem. Up to now, and we are here at the
conference of Gynaecological Endoscopy, we evaluate the disease endometriosis by
the lesions, which by definition are extra-uterine. We know that the uterine
cavity looks normal in patients with endometriosis. The main problem is that we
have, apart from evaluation of the effect of ovarian steroids on the
endometrium, no systems to evaluate uterine function. The main problem is that
to date, there are so many factors, which could be evaluated to see whether the
uterus is dysfunctional and that we have not a really good picture of what’s
happening during the process of implantation and placentation. At the moment
there are many data showing that in patients with endometriosis associated
infertility the uterus is functioning abnormally. And
functioning abnormally involves particularly the inner part of the uterus,
including the endometrium and the junctional zone of the myometrium. This is the
sex steroid hormone-responsive part of the uterus, which may be affected in
patients who have endometriosis, but also in some patients who haven’t got
visible implants. So, the dysfunction of the uterus may be a problem, which is
larger than endometriosis, and may also involve, for example, patients with
unexplained infertility. Hugo
Verhoeven MD:
What you are saying is that all the methods we are using at this moment
to evaluate the morphology of the uterus are not giving the answer to the
question, “what could be the basis of the uterine disease?”.
It’s more a hormonological or molecular biological problem. What
possibilities do we have to clear this problem? How can we evaluate uterine
function? Professor
Ivo Brosens:
Well, I think we can give one example. This involves the study of
cytokines and growth factors in the uterus. An example is the study done by
European Fertility Associates on aromatase expression. It is an interesting
factor, but it’s not that this will be the most important factor. Because you
take one factor and find interesting changes, doesn’t mean that other factors
are not important. The result
of the EFA study on aromatase was that patients who have a high expression of
aromatase mRNA show a significantly decreased implantation rate after IVF. It
shows that the uterine micro-environment is important for implantation. Hugo
Verhoeven MD:
Let’s go back now. What would then be the link between the uterine
dysfunction and the extra uterine lesions? How will they appear there? Professor
Ivo Brosens:
Many studies have shown an indirect link, such a study by Gaetje and
collaborators from Frankfurt, which was published in The Lancet some
years ago. This study showed for example that endometrial cells in patients with
endometriosis are more invasive than endometrial cells from patients without
endometriosis. Hugo
Verhoeven MD:
And why is that? Professor
Ivo Brosens:
Well probably because there is a modulation of the response of the cells
to the sex steroid hormones. And this modulation may be secondary to factors of
cells such as T lymphocytes, which have an influx in the uterine cavity. So
there may be an immune modulation of the hormone response, that may be very
important and make the endometrium behave differently, and is more aggressive. We know that
almost all women will have retrograde menstruation. But in women who have a
defective hormone response the endometrial cells may be more proliferative and
more invasive and maybe these women will develop lesions or tend to develop
lesions under certain circumstances. Hugo
Verhoeven
MD:
But this could be true for peritoneal lesions. But still, what could be the link
to endometriomas, for instance, and recto-vaginal endometriosis? Professor
Ivo Brosens:
Well, this is interesting because there is probably no disease that masks
so much its identity as endometriosis. In other words, the phenotype of the
lesions depends very much on the location, the peritoneum, the ovary or the
recto-vaginal cavity. The cells that are implanting apparently also change the
environment as much as the micro-environment changes the cells. So it’s a very
complex interaction between the ectopic endometrium cells and the environment
resulting in either dominantly haemorrhagic lesions, such as on the peritoneum
or ovary or metaplastic adenomyotic lesions such as in the retro-cervical or
recto-vaginal space. Hugo
Verhoeven MD:
If the endometrium is reacting differently to hormones, this different
reaction could also be the reason why we see differences or changes in
implantation, and maybe also in embryo development. Could you elaborate on that? Professor
Ivo Brosens:
I think we have also very much neglected the outcome of pregnancy in
patients with endometriosis. If the uterine micro-environment is aberrant in
these patients, then it’s not unlikely that not only the process of
implantation, but also the placentation is going to be affected. Today we
know that one of the main features of endometriosis is the progesterone
resistance. In other words the high expression of aromatase activity can be
explained as progesterone resistance. And progesterone resistance, being a
feature of endometriosis, is also what we see in patients, who develop pregnancy
complications such as pre-eclampsia, small for gestation infants and preterm
premature rupture of the membranes. These conditions are associated by defective
deep decidualisation and placentation. So in the patients with endometriosis the
infertility, may be part of spectrum of reproductive failure. We will need
to expand our follow up beyond the time of ongoing pregnancy because there may
be an increased risk of abnormal obstetrical outcome, including foetal growth. Hugo
Verhoeven MD:
Do we already have an idea of therapeutic consequences of this view? Professor
Ivo Brosens:
Well, there are papers that are suggesting a link between endometriosis
and preeclampsia. Patients with unexplained or endometriosis associated
infertility have a higher risk of preeclampsia and other pregnancy complications
such as small for gestational age infants. Preeclampsia is considered as a disease of the first
pregnancy. But recently it has been shown that the protection of a pregnancy
against preeclampsia is transient. If there is an interval of many years the
risk of preeclampsia increases and by ten years the risk is the same degree as
for a first pregnancy. The risk of preeclampsia may also be decreased, for
example, when there has been a miscarriage, which means after a pregnancy of a
few months. This raises the question whether we can, by inducing an amenorrhea
of three months, also decrease the risk of preeclampsia and small for
gestational age infants. In other words, an induced period of amenorrhea may be
beneficial, one way or the other, for the restoration of the uterine
micro-environment. The recent
study of Schieve, which appeared in the New England Journal of Medicine [1]
last year was very interesting in this respect. It showed a significant increase
of small and very small for gestational age infants after in vitro
fertilisation, In the normal population the risk was about 2.5%, but after IVF
it was 6.5%; so it’s more than doubled. These infants are likely to be as
adults at higher risk for major diseases, like cardiovascular disease and
osteoporosis. In the analysis of the subgroups Schieve found that the risk was
increased in “healthy” women with no specific cause of infertility. He
interpreted that the risk was therefore likely to be caused by the treatment.
However, the risk was not increased in the 180 surrogate mothers and in the
subgroup with severe male infertility treated by ICSI. My interpretation is that
the “healthy” women are likely to represent to a large extent women with
unexplained or endometriosis associated infertility and that the risk in
increased in this group in comparison with the women with normal fertility
represented by the subgroups of surrogate mothers and ICSI treated women. So, to come
back to the question, it will be very important if we can establish the link
between endometriosis, or unexplained infertility, and pregnancy complications
such as small for gestation age infants. The therapy of both major diseases in
women could be linked . Hugo
Verhoeven MD:
That’s a lot of stuff! The answer to the question why do women develop
endometriosis is still unclear, but I think we learned quite a lot today. And
it’s certainly a basis for further research and further data collection. I
would like to thank you very much for this interview. Professor
Ivo Brosens:
Thank you! 1. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med. 2002;346(10):731-7
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