The History of the GnRH Analogue Conferences

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Liselotte Mettler, MD: "Today on February 10, 2001 it is my pleasure to interview Professor Bruno Lunenfeld, the starter of the GnRH Analogue Conferences the sixth of which we are holding at the present time in Geneva. I would like to ask him when these meetings started, what is the intention of the meetings, and what is the future? Let us start with the historical part, please."

Professor Bruno Lunenfeld: "As you know very well, this is the 6th GnRH meeting. We started some fifteen years ago, and in the beginning we were investigating the possibility of the uses of GnRH agonists. We were then investigating the possibility of the use of GnRH agonists in precocious puberty; this was indication number one at that time. We were then already thinking of the possibility of using GnRH in four different situations; in the situation where we would like to intervene or to modulate diseases that are dependent on sex steroids, which could be, endometriosis, uterine fibroids, and you can name many more. The second indication was to stop sex steroid production if it is too early or too modulated like in precocious puberty or in order to prevent an untimely LH peak as we saw often in ART protocols. The third situation was to look at situations where there are hormone dependent cancers and whether we could intervene by these situations. We already knew by that time that castration was one of the main treatment modalities for prostatic cancer and, therefore, we thought we could use GnRH agonists for this kind of purpose. The fourth situation, which we're still debating today, is can we use GnRH agonists or analogues in the modulation of cancer specific areas not directly via the steroid patterns. Now this all became clear of course because we already knew at that time that GnRH agonists were the first and only medication which could do exactly the same that a surgically hormone specific type of vasectomy could do or what a castration, orchiectomy, or a male castration could perform. We could do this reversibly with GnRH analogues; this was the beginning and the rationale of having these GnRH meetings. The meeting was opened at that time by Andrew Schally, the discoverer of GnRH who also received the Nobel Prize for this purpose."

Liselotte Mettler, MD: "Let us go now to the two different sides - agonists and antagonists. At this meeting we have for the first time clinical data on interaction of antagonists so please differentiate the two, and how do you foresee the future interaction of these two lines?"

Professor Bruno Lunenfeld: "The main problem of the GnRH analogues was the flare up effect, and because of the mechanism of action of GnRH analogues, you know that the first situation is a flare up of the hormones (LH and FSH) and then there is a desensitization. This flare up effect, of course, can be detrimental or has a negative effect in hormone dependent diseases like prostate cancer. It can have a negative effect in the uterine fibroid situation, and it can have negative effects in many other situations. Therefore, the moment we had antagonists, which worked by competitive binding, we get a direct inhibition of the gonadotrophins and do not have this flare up effect. This is with of course a major advantage. The big problem with the antagonists was that the first generations had histamine release and we needed a lot of work and many, many years of work until antagonists could be used clinically without side effects."

Liselotte Mettler, MD: "At the present time, which other fields are antagonists already used?"

Professor Bruno Lunenfeld: "In the beginning I forgot to stress one of the most important uses of GnRH agonists namely in assisted reproductive procedures. As you know and have heard in this meeting, 80% or maybe even 90% of assisted reproductive cycles are used together today with GnRH agonists. In this area, the antagonists are playing a very important part as you have heard in this meeting because they can reduce the time of treatment and they reduce the number of ampoules of gonadotrophins. This makes treatment more acceptable by patients. It's a more friendly treatment for the patient and permits a more flexible therapy than with the use of GnRH agonists.

Liselotte Mettler, MD: "So in the area of reproductive medicine it's already an accepted concept. How is it in the area of urology?"

Professor Bruno Lunenfeld: "The main problem was that the GnRH antagonists available today, as you have heard here, were mainly short acting antagonists. Only very recently has a long acting GnRH antagonists been discovered. It is now in Phase II and Phase III clinical trials and it will be on the market very soon, and this is Abarelix which has a very, very long action and, of course, can be used then in diseases which need very long suppressions of sex steroids like prostate cancer, uterine fibroids, and endometriosis."

Liselotte Mettler, MD: "In the gynecological area the antagonists have also been discussed at this meeting in uterine fibroids and endometriosis. How many of these products are available that are not given daily?"

Professor Bruno Lunenfeld: "For the time being the only antagonists which is a long acting antagonist is a product which is not yet on the market which is Abarelix."

Liselotte Mettler, MD: "Cetrorelix has a 3 mg compound from the Serono Company which is used in reproductive medicine. Has it also been used in clinical trials for myomas and endometriosis?"

Professor Bruno Lunenfeld: "Very limited trials in this respect, and very limited material with a very nice potential I am not aware of large scale clinical trials.

Liselotte Mettler, MD: "Professor Lunenfeld, my last question goes to the field of cancer. Cancer is still a threatening disease, how is the future action of antagonists and agonists in the field of cancer?"

Professor Bruno Lunenfeld: "I think we've had a very nice symposium here on this respect. Professor Bartsch has given some very nice data, and I believe OBGYN.net already interviewed him. I think, again, the antagonists don't have the flare up effect and they probably do much more than just decrease testosterone on prostatic cancer. I think they have a nice and big future in prostatic cancer but it's only at the next Congress in two years that we'll be able to tell."

Liselotte Mettler, MD: "May I finally allude to some personal aspects? Your birthday is going to be on Sunday and already OBGYN.net would like to congratulate you for all your achievements in our field and wishes you a very happy birthday."

Professor Bruno Lunenfeld: "Thank you very much."