Antagonist or Agonist – Which to prefer?

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Hugo Verhoeven, MD: “Good morning, my name is Hugo Verhoeven from the Centre for Reproductive Medicine in Dsseldorf in Germany. I am on the editorial board of OBGYN.net, and am reporting this morning from the fourth COGI meeting, Controversies in Obstetrics and Gynaecology, in Berlin, Germany. It is a real pleasure for me to talk this morning with Dr. Cohen from Paris, France, who is a very well known person in the scenery of infertility treatment here in Europe and all over the world.”

Jean Cohen, MD: “Thank you.”

Hugo Verhoeven, MD: “Thank you for being with me.”

Jean Cohen, MD: “I am Jean Cohen, there is also Jacques Cohen, who is a very well-known biologist, so it is Jean.”

Hugo Verhoeven, MD: “So we’ll say then, Jean, welcome and thank you for being here. The topic that we are going to talk about is the use of GnRH analogues in the treatment of infertility. We are going to compare the use of agonists with the use of antagonists. So let’s start with a very short overview of what is an agonist, and what is an antagonist?”

Jean Cohen, MD: “Well, they are both analogues of GnRH. That means that GnRH is a hormone that comes from the hypothalamus to the pituitary gland in order to promote the secretion of FSH and LH, and that gave the Nobel Prize years ago to Guilleman and Schally. It’s a composition of ten amino acids. If you change them, you get either agonists that will act exactly the same way as GnRH, or antagonists, if you change other amino acids, and the antagonists will have the opposite action.

That means that concerning the agonist, at the beginning of the action of the agonist, you will promote the secretion of FSH and then you will completely cover and invade the receptors and then you block the receptors, that is called de-sensitisation, and then, after a few days, you get normal secretions with analogues. So with the analogues you need a certain phase of what is called flare-up that is a promotion of FSH and then after a few days, there is no more secretion. The antagonist analogues are contrary, they block immediately at the beginning of the action. So both of them will reduce secretion of gonadotrophins, FSH and LH.

At the beginning, this project was proposed in order to treat, for instance, prostate cancer and it’s the idea of some people who said, in IVF, when there is premature LH peak, we know that the result of IVF will not be good, so in order to reduce the premature LH peak in the IVF cycles, it was a proposition, at that time we only were having analogues, to give analogues, agonists, in order to get the flare-up for a few days but then to have the sensitisation and normal LH.

So the use of agonists necessitates a few days of promoting, then you get the desensitisation, and then you have no more LH. After a certain number of years, because it was hard to obtain a product that was accepted without any allergic reaction, then we got the antagonist, which does not necessitate the first phase and get the immediate banishment of secretion of LH. So they are both used in IVF in order to avoid the premature LH peak, which is detrimental for the results of IVF.”

Hugo Verhoeven, MD: “Good. The analogues, the agonists, we have had them for a long time. We are using them in ovulation induction and in IVF for I think 10 or 15 years now, and we are still quite happy with them. So what is the reason now for switching to antagonists? What are the advantages and maybe also the disadvantages?”

Jean Cohen, MD: “So, as I told you, when you use agonists, you have to have a long period before you get the desensitisation. You can use the agonists for the initial flare-up period, which is called a short protocol; let us not speak of that because it has been abandoned by most of the centres.

But when you want to use the long protocol, that means obtain desensitisation of the LH receptors, then when you do that, you need approximately 15 to 20 days of agonist administration before starting the stimulation of the ovaries. So, the period is long then as you get desensitisation, you will need more ampoules of gonadotrophins in order to get the same number of follicles that will be natural. So it’s long, more ampoules, that means more costly, and for the woman the comfort is not so good because she has to wait for a long period.

The antagonist brought some benefit, that means you start immediately the gonadotrophin secretion, then with antagonists you will use less ampoules and you will have a much more comfortable stimulation. When the women have got both types of protocol, they all prefer antagonists, so you are going to tell me why is there still a controversy?

The only reason is that the pregnancy rate is a little less with antagonists than with agonists. You get approximately 2-3% less pregnancy rate per cycle with antagonists than with agonists and this, of course, makes the doctors prefer to have the more important pregnancy rate as does the patients, so most of them continue to use, or at least some of them, continue to use agonists.

The promoters of antagonists said at the beginning of agonists, also, there was some difficulty of use and the pregnancy rate was not as good immediately, so maybe we need some period of experiment and adaptation with the antagonists until we get the same pregnancy rates. I’m not sure because it has been shown that antagonists have a direct effect on the endometrium and the ovary and so this may be the reason for having less pregnancies.”

Hugo Verhoeven, MD: “Is there a chance to overcome this detrimental, this negative effect on the endometrium?”

Jean Cohen, MD: “Well, there have been proposals on different protocols. For instance waiting some time for the right diameter of the follicle, for instance, not starting antagonists before you reach 12mm diameter in a way not to make an obstacle to the growth. There have been proposals to give more FSH at the moment you start giving antagonists. There have been proposals to start at a different moment of the cycle. There are new ways of clinical experiments that may turn up, I’m not sure.”

Hugo Verhoeven, MD: “I have two more questions. Question one: we have the antagonists available as a depot, so it is a single injection for the patient, and as daily injections. What are the advantages and disadvantages of the two methods?”

Jean Cohen, MD: “Well, one, the depot is called the French protocol and the daily is called the German protocol because it has been started in those difference places. I think, being French, I think that the daily protocol is easier to use than the depo one. But anyway, they get both the same results.”

Hugo Verhoeven, MD: “And the last question: there are some people in the world arguing with the use of the agonists because it’s easier to schedule the cycle. So, let’s say, as soon as you give the agonist, you can start with FSH whenever you want, if you go on vacation or your centre is closed, you can then schedule the patient. Of course, we have alternatives for that and I would like you to comment on that.”

Jean Cohen, MD: “Well, certainly, it is easier for the doctor and for the centre with agonists than with antagonists because antagonists will drive you to necessarily have to puncture some day. For instance, in the centres where, like, you know, the social lulls in Europe now, you don’t work on Sunday, you don’t work on Saturday, etcetera, etcetera, if you want to avoid those days where it is difficult to open the centre, etcetera, then it’s better with an agonist than with an antagonist.”

Hugo Verhoeven, MD: “Of course, you can also schedule your next cycle with giving a contraceptive pill?”

Jean Cohen, MD: “Exactly.”

Hugo Verhoeven, MD: “Okay, well, I think this was very informative, Monsieur Cohen. Merci beaucoup.”

Jean Cohen, MD: “Enchant. C’est mon plaisir.”

Hugo Verhoeven, MD: “Merci beaucoup.”