EndometriosisZONE.org Progesterone resistence in endometriosis

EndometriosisZONE.org
Progesterone resistence in endometriosis
Dr Kristof Chwaliz and Professor Linda Giudice interviewed by Professor Serdar Bulun

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Professor Serdar Bulun, MD: “We are here today to discuss the role of progesterone and specifically progesterone resistance in the pathogenesis of endometriosis. I am Dr. Serdar Bulun. I work at Northwestern University, in the department of OBGYN.”

Professor Linda Giudice, MD, PhD: “Hi, I am Dr. Linda Giudice and I am a Reproductive Endocrinologist and Gynaecologist at Stanford University in California.”

Dr. Kristof Chwalisz, MD, PhD: “I am Kristof Chwalisz. I am a medical doctor currently working for TAP Pharmaceutical Products Inc. in Lake Forest, Illinois, USA. TAP is a joint venture company , which develops products for women’s health, men’s health and gastroenterology. My position is Therapeutic Area Head, Women’s Health.

Professor Serdar Bulun, MD: “We are a group of scientists and physicians and clinicians working on the subject of effects of progesterone on endometriosis and we all started our work independently. What we have found is that our work met at a common pathway, which is progesterone resistance. To this end, Dr. Giudice used a very high-tech approach, which is genomics. She studied tissues from patients to find out how progesterone resistance comes about, and Dr. Giudice will explain her results to us.”

Professor Linda Giudice, MD, PhD: “Thank you. We did a clinical study that involved four centres; at Stanford University, The University of North Carolina at Chapel Hill, The University of California in San Francisco, and also Vanderbilt University. We recruited women with endometriosis, minimal to mild disease, and asked them for their tissue of endometrial biopsy. After informed consent we then looked at global gene profiling, across the entire genome essentially, at genes that are expressed differently in the endometrium of women with endometriosis, just in the time of implantation, compared to women who do not have disease.

We found a number of genes that are deregulated that we believe fall into two categories: One that has to do with the pathogenesis of the disease and the other with the infertility associated with the disease. In the latter category we believe that these genes have provided an inhospitable environment for embryo development, including embryo toxicity, immune disregulations, embryo attachment and an impact on angiogenesis. On the pathogenesis side we have looked at genes and have discovered genes that we think contribute in terms of cell cycling proliferation angiogenesis.

The conclusion is that the endometrium of women with endometriosis is different from the endometrium of women without the disease. Some of the things we have found are likely to be relevant in terms of the underlying infertility as well as pathogenesis. Much of this we believe is related to a progesterone resistance.”

Professor Serdar Bulun, MD: “Thank you very much. I will explain some of the studies conducted in my laboratory, which also agree with what Dr. Giudice just explained. We concentrated on one specific gene in the endometrium and this gene is responsive to progesterone. In other words, during the luteal phase of women, whereby endometrium is exposed to large amounts of progesterone, this gene is expressed and it gives rise to an enzyme, which is named 17 beta-HSD, Type 2.

17 beta-HSD, Type 2 is a very important enzyme for the endometrium. What is does is protect endometrium from very high levels of oestradiol. Oestradiol is biologically active oestrogen and, as we all know, too much oestradiol gives rise to proliferation and abnormal growth of endometrium.

Because endometriosis is also endometrium-like tissue it also responds to oestradiol in the same fashion. What we found was in endometriosis tissue this enzyme is deficient. We could not find any evidence of this enzyme in endometriosis tissue no matter how much progesterone is in the system. Therefore, this is an additional pathway to many others, which gives rise to uncontrolled growths or resistance to apoptosis tissue regression in endometriosis.

To summarise that finding, although there would be a lot of progesterone in the system, endometriotic tissue would not respond to this progesterone by increasing this enzyme, 17 beta-HSD type 2. As a consequence, the active oestrogen in the system in the endometrium would not be inactivated because of the lack of this enzyme and these patients would be exposed to even higher levels of oestradiol. We found this in every patient that we studied. This is a very common mechanism of diease in endometriosis. I believe our findings also agree with the genomics results of Dr. Giudice’s experiments.

I would like to direct a question to Dr. Chwalisz, who developed a compound that would interact with progesterone receptors in a different session than the progesterone hormone. He envisions that this is why this compound is effective in the treatment of endometriosis. Would you tell us about it?”

Dr. Kristof Chwalisz, MD, PhD: “Thank you. First of all, a slight correction, this is a joint project between TAP and Schering AG. The compound was synthesised at Jenapharm and was screened by a group of scientists from EnTec GmbH in Jena, Germany, so this is the effort of a large group of people. We are, indeed, currently evaluating one of these compounds in Phase III studies in women with uterine fibroids, and we have just finalised some of our Phase II studies in endometriosis.

These new compounds are called Selective Progesterone Receptor Modulators. These are novel progesterone receptor ligands, ie, molecules, which bind to progesterone receptors but produce different effects compared to progesterone. They are different from progestins and different from anti-progestins. They exhibit a so-called partial agonist/antagonist activity in vivo, so they may have progesterone-like effects or progesterone antagonistic effects depending upon the presence or absence of progesterone, and on the target tissue. In the uterus, they suppress endometrial growth and menstruation at the endometrium level.

We recently conducted a study in women with endometriosis. This was a placebo-controlled study with three doses of other asoprisnil, J867, (this is the chemical code for this compound). We observed beneficial effects on pain. Pain was substantially reduced in women treated with asoprisnil, and all treatment groups significantly improved compared to placebo.

We also observed that a dose-dependent suppression of menstruation. An important aspect of this study was patient safety and treatment tolerability. All the current endometriosis treatments are associated with side effects. For example, the GnRH-agonist or -antagonist produce hot flashes because they dramatically reduce the oestrogen secretion from the ovaries. They also cannot be used longer than six months because there is a substantial bone loss.

Progestagenic compounds, which are similar to progesterone, but have some androgenic activity, produce other side effects. All of these treatments are, however, similarly effective in endometriosis with regard to pain relief. Our goal was to develop a molecule that will suppress pain similarly to GnRH-agonists, but which will have a substantially better safety profile, and will be much better tolerated by the patients. Our preliminary studies show a favourable safety profile, and also good efficacy.

We are hoping that we will be able to confirm this data in larger studies. As you know drug development is a long process. We still have to perform Phase III studies, which will include many patients and will probably take much longer compared to our phase 2 study. Our preliminary data is very promising, so they are encouraging us to do further long-term studies.”

Professor Serdar Bulun, MD: “So far we have concentrated on endometriosis and treating pain-related endometriosis, as well as applying some of these findings in that direction. I would like to ask Dr. Giudice, who has worked for many years on the mechanism of implantation, how changes in these genes, in patients with endometriosis, affect these patients? Can anything be done for these patients? What are the future directions for some of the treatments to improve implantation?”

Professor Linda Giudice, MD, PhD: “One of the genes that we found that was abnormally regulated was a gene that’s an enzyme. This enzyme is important in making a molecule, which in turn is important in attaching to the blastocyst, or the embryo, when it first attaches to the lining of the uterus. There were several other key genes that would give us some understanding of the mechanisms. Before getting into therapy we think that this set of genes, and probably genes culled from other data sets as they become available in endometrium of women with endometriosis, could provide a diagnostic tool to diagnose endometriosis.

That may actually obviate the need for surgical evaluation. If endometriosis is present, the treatment of that would depend on whether the patient has pain or whether she is interested in fertility. With regard to therapies in fertility we are now working on the mechanisms of what regulates particular genes in the endometrium. Once that is better understood I think we can then begin to target therapies, especially for fertility.”

Professor Serdar Bulun, MD: “Thank you. Dr. Chwalisz, obviously J867 that you are working on is extremely promising. Do you think the pharmaceutical industry should stop here; is this the perfect compound or can it be improved? Should there be further studies to develop more selective progesterone receptor modulators? What are your opinions about that?”

Dr. Kristof Chwalisz, MD, PhD: “First of all, I have to state that our data is still very preliminary. We just started our studies on endometriosis and we have some encouraging results, but we are far away from showing that this compound is really effective. We will need more studies to do this.

The whole session today was about progesterone resistance and one could ask why are we developing a progesterone receptor modulator for a disease, which is progesterone resistant? What may happen in endometriosis is that the progesterone receptor in the ectopic endometrium may be different, or may respond differently to progesterone, which was shown by both Dr. Giudice and Dr. Bulun. So, a compound, which modulates the progesterone receptor function and its structure, and is different than progesterone, may be effective in the treatment of endometriosis-associated pain and may even suppress its growth. We have some preliminary data that indicate SPRMs effects on pain; however, we still don’t know how this compound acts on the ectopic endometrium. There is definitely much more work to be done. We need to continue our clinical studies.

With regard to other approaches, of course, there are some other possibilities for the treatment of endometriosis mentioned in today’s presentations such as a tissue selective, endometriosis specific, aromatase inhibitor, or a tissue selective angiogenesis inhibitor. These are potential new concepts, which may arise from the studies done by Dr. Giudice and her colleagues using micro array technology.

We are just at the beginning of the journey and the tremendous technology of micro arrays will probably show us in future where the targets are and what drugs need to be developed. I think that this disease, which is very difficult to treat, will focus our attention for a couple of more years.”

Professor Serdar Bulun, MD: “Thank you very much. I would like to thank both of our participants for such an intriguing discussion session.”



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