Aromatase in endometriosis

Professor Serdar Bulun, MD, PhD interviewed by Professor Thomas D'Hooghe, MD, PhD

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Professor Thomas D'Hooghe, MD, PhD:  “I am Professor D’Hooghe from Leuven University and the coordinator of the Leuven University Fertility Centre.  I do half-time research in the area of pathogenesis of endometriosis.” 

Professor Serdar Bulun, MD, PhD:  “I am Dr. Bulun from Northwestern University where I am a Professor and Director of Reproductive Biology, Research Section.  My interests are endometriosis, breast cancer, and oestrogen related diseases.” 

Professor Thomas D'Hooghe, MD, PhD:  “I would like to ask you Dr. Bulun how you got the idea of looking at aromatase in endometrium and endometriosis?  What made you start exploring that area?” 

Professor Serdar Bulun, MD, PhD:  “In the early ‘90s when I started to work in the field of aromatase it was already known that aromatase was present in breast cancer.  Aromatase is the enzyme that makes oestrogen and breast cancer is an oestrogen dependent disease; therefore, the presence of aromatase in breast cancer drew the attention of researchers and clinicians. 

A number of aromatase inhibitors were developed and these were proven to be extremely useful for the treatment of breast cancer.  These drugs are now known to be superior to tamoxifen in the treatment of breast cancer.   

I was in the lab of Evan Simpson, who was conducting some of these pioneering studies, and as a gynaecologist I wanted to explore the role of aromatase in endometriosis.  We found very high levels of aromatase in the endometriotic tissue and to us that explained why a lot of patients did not respond to regimens that stopped oestrogen production in the ovaries, such as GnRH-analogues.  That brought about the following studies.” 

Professor Thomas D'Hooghe, MD, PhD:  “When you say that aromatase is expressed to a large extent in endometriotic lesions, did you see a difference according to the type or size of lesions, or the presence of aromatase quantities?” 

Professor Serdar Bulun, MD, PhD:  “We did not see any difference when we looked at our data, but to be honest with you, we did not design our study to do that.  Part of the reason is, as you know as an endometriosis surgeon, the availability of these tissues is limited and if you get your hands on these frozen tissues that would be a very valuable asset.  Just as a glimpse of this data I could say we haven’t seen it, but we never investigated in that way.” 

Professor Thomas D'Hooghe, MD, PhD:  “You just mentioned that aromatase is not responsive to GnRH-analogues, I mean the endometriosis activity.  Can you explain a little more how exactly that works?  Why do these lesions producing this aromatase activity not respond to LHRH-analogues?  

Professor Serdar Bulun, MD, PhD:  “Oestrogen is made in certain parts of the body.  We now know that it is made in three principle sites: one is the ovary, another site is skin and fat, in fact, that is how post-menopausal women and men make their oestrogen.  For example men need oestrogen because if we do not have any oestrogen production, these individuals have very brittle bones. As bones keep growing forever, oestrogen in men and women stops the bone growth and maintains bone mass.  Testosterone is not effective in men in maintaining bone mass.  We understood this through other studies.  The third site of oestrogen production in a woman with endometriosis is the endometriosis itself. 

In all of these sites, including the ovary, fat and skin and endometriosis, the protein that is responsible for oestrogen production is aromatase, that doesn’t change.  When you give a GnRH-agonist or LHRH-agonist to a woman, this stops oestrogen production only in the ovary, whereas oestrogen production in these two other sites continues.” 

Professor Thomas D'Hooghe, MD, PhD:  “A number of years ago you published your first study on the post-menopausal woman that you treated with the aromatase inhibitor as she had substantial vaginal endometriosis.  Was this the start of further experiments?  Can you elaborate a little bit on what happens afterwards, in the most recent years in terms of the animal research and the clinical research?”  

Professor Serdar Bulun, MD, PhD:  “Since then we have conducted four specific studies.  One of them was conducted on an endometriosis model in mice.  In this model we have shown that aromatase is substantial for the growth of both ectopic and utopic uterine tissues. 

Then we made use of your model, the model that you pioneered in the Primate Research Institute in Kenya.  We worked with the same investigators. We induced endometriosis in baboons and then, to an extent to our surprise, we saw that in this, in a way, artificial model, that aromatase is present in the endometriosis, in the endometriotic lesions.  This was very interesting.  Then we treated these animals using aromatase inhibitors and we showed that aromatase inhibitors were extremely efficacious in the treatment of endometriosis. 

Finally, we conducted two additional human studies in women of reproductive age.  These ages varied from 20 to 46, I believe.  We treated a total of 25 women.  In one study including ten women we used the aromatase inhibitor letrozole, plus a progestin as an add back treatment.  This treatment was very successful in those women, who had severe endometriosis, and who did not respond to existing medical treatments. 

In another group of 15 women, and this is very recent, these studies have not been published yet, we used anastrozole and added a low-dose oral contraceptive.  The majority of these 15 women responded positively to this treatment with decreased pelvic pain.” 

Professor Thomas D'Hooghe, MD, PhD:  “The reason why you added the progestins or oral contraceptives is to block the development of ovarian cysts.  To what extent do you think that one would ever have, or may be able to develop, a treatment that just consists of aromatase inhibitors without other add back therapy; do you think that will be an option in the future with new products or new doses?”  

Professor Serdar Bulun, MD, PhD:  “I’m sure that will be.  It needs to be explored.  We did not investigate it because we had limited resources.  We just added a progestin or oral contraceptives as a caution.  But it is worthwhile to use aromatase inhibitors only by themselves if it’s for short intervals and then look at their effects on the ovaries.  We haven’t done that yet.” 

Professor Thomas D'Hooghe, MD, PhD:  “Thank you very much for all these very interesting answers.  Is there anything else you would like to say or add to what you’ve said in terms of your research in aromatase and aromatase inhibitors in endometriosis?” 

Professor Serdar Bulun, MD, PhD:  “I thank you very much for giving me this opportunity.  I am hoping that these pilot studies will be the first studies and that other clinical investigators will follow by conducting large clinical trials, and compare them to gold standard treatments such as GnRH-analogues in the field.  Then we will get our real answers.  Thank you.” 

Professor Thomas D'Hooghe, MD, PhD:  “Thank you very much.”

See also: Letrozole may help women with endometriosis