Timing of hCG for Ovulation Triggering

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Hans van der Slikke, MD, PhD: “It is July 2003 and we are in Madrid, Spain, at the ESHRE conference and next to me is Dr. Kolibianakis, welcome!”

Stratis Kolibianakis, MD: “Thank you.”

Hans van der Slikke, MD, PhD: “You are originally from Crete, Greece, and now you are working at the Free University in Brussels, Belgium. You presented at this meeting about timing of hCG in IVF and in ICSI as well?”

Stratis Kolibianakis, MD: “In IVF and ICSI cycles.”

Hans van der Slikke, MD, PhD: “Why did you do this research? Why do you think this is an interesting question, the timing of hCG?”

Stratis Kolibianakis, MD: “There are several reasons. If you look at the literature, first of all, you will see a marked discrepancy in the criteria used for hCG administration. In medicine in general, if you see a disease that has too many treatments, probably you come to the conclusion that there is no effective treatment. 

So, seeing that there are so many criteria for hCG administration probably means that we don’t have a solid basis on which to establish these criteria. If you search the literature you will see that this is true, so that’s one. 

Secondly, if you look more carefully at these criteria, you will see that they are not strict criteria. So in almost all of the criteria used you will see the words “at least when this criterion is met”. This means in fact that you can give hCG when you reach, for example, three follicles of 17 mm, but you don’t have to do that necessarily. You can go for one or two days more. 

I think this is a source of problems. You have to define what are the best criteria to use for hCG administration, and certainly to use strict criteria. That’s one approach to the problem. The other, which is less obvious, comes from our work in the last two or three years on the endometrium. If you look at the histology of the endometrium at oocyte pick-up, you will see a universal picture of advancement of the endometrium, which means secretory changes, in almost all cycles. Either you use analogues (antagonists or agonists) or even in non-analogue cycles. This means that there are events occurring in the follicular phase that lead to this picture. 

We have shown last November in a paper published in Fertility & Sterility that this endometrium advancement, if it goes to the extreme -- so more than three days compared to the expected chronological date -- leads to a significantly lower ongoing pregnancy rate. The next thing to consider is what can we do to alter this picture? So you have to think how secretory changes occur. In the natural cycle it is well established that this occurs through progesterone action. Progesterone acts on progesterone receptors, which are induced by oestradiol, and this is established knowledge. In the hyperstimulated cycle unfortunately, there are no receptor kinetics but you have to assume because of the several times higher oestradiol levels much earlier in the follicular phase that probably these phenomena occur much earlier and by the time of oocyte pick-up they lead to advancement.”

Hans van der Slikke, MD, PhD: “So you made clear that the timing may be an important factor. Which protocols did you use in your research”

Stratis Kolibianakis, MD: “We decided to go for recombinant FSH and administration of the antagonist on day 6 of stimulation. We used Puregon and Orgalutran.”

Hans van der Slikke, MD, PhD: “How did you make your two groups?”

Stratis Kolibianakis, MD: “The idea is that you have to reach certain criteria for follicular development. In this study we decided to go for three follicles of 17 mm, which is arbitrary on the one hand. On the other hand, it is the criterion used in almost all comparative studies between agonist and antagonist, so phase three studies. We thought it was a good starting point. 

As soon as the patient, which means of course that you have to do several ultrasounds to confirm that, has three follicles of 17 mm, hCG is administered in the one arm and in the other arm, as soon as this criterion is met, you prolong the follicular phase for two days later. Without considering at all oestradiol levels which, however, you measure.”

Hans van der Slikke, MD, PhD: “Without measuring oestradiol levels…”

Stratis Kolibianakis, MD: “You measure oestradiol levels but do not consider them in your decision.”

Hans van der Slikke, MD, PhD: “Oh, I see, yes. How big were your two arms?”

Stratis Kolibianakis, MD: “The study is now finished and in each arm there was 208 and 205 patients randomised.”

Hans van der Slikke, MD, PhD: “So that’s a rather big group. And the results?”

Stratis Kolibianakis, MD: “The result is that there is a difference between the early and the late group of hCG administration in ongoing pregnancy rate and implantation rate, and this means that there is a significantly higher ongoing pregnancy rate in the early hCG group. The difference is about 10% if we talk about ongoing pregnancy rate per oocyte pick-up. It’s also about 8% in implantation rate.”

Hans van der Slikke, MD, PhD: “And what were the ages of these women?”

Stratis Kolibianakis, MD: “The criteria we used for selection of the population were broad criteria. So this really is an unselected population. This poses some problems in that your randomisation may fail, which was not the case as I presented, but on the other hand the results are much more applicable. So you should expect that if you repeat the study, again in a broad population, your results will be the same. So we are not talking about a certain group of patients.”

Hans van der Slikke, MD, PhD: “I see.”

Stratis Kolibianakis, MD: “So, less than 39 years of age was the answer to your question.”

Hans van der Slikke, MD, PhD: “So, the results are better in the early group in terms of pregnancy rate. Were there any differences in women you had to cancel the cycle because of hyperstimulation?”

Stratis Kolibianakis, MD: “No, there were two patients in each group that we had to give the agonist instead of hCG because we thought it was unethical to continue with hCG. But it was the same, two patients is a very small number in both groups. But you would expect theoretically that you may have a little bit more hyperstimulation in the late hCG group, and this was indeed the case, it was about 3 to 5%. Three percent in the early group and 5% in the late. Not so many cases.”

Hans van der Slikke, MD, PhD: “So, concluding it seems better not to wait too long after you have three follicles of 17 mm.”

Stratis Kolibianakis, MD: “I think what is really an important message for this study is that whatever study you do, you have to use strict criteria. Otherwise your conclusion, and you have seen a lot of papers in this congress talking about relationships of LH to outcome that if you use loose criteria all your results are in doubt. So whatever criteria you use should be strict. Now this study suggests that by taking an arbitrary, from our point of view again, arbitrary criterion of three follicles of 17 mm, if you prolong the follicular phase you will have worse results. This is in contrast to the popular belief that bigger follicles and more follicles are associated with a better outcome.”

Hans van der Slikke, MD, PhD: “Did you have any difference in the quality of the eggs you harvested?”

Stratis Kolibianakis, MD: “The quality of the transferred embryos and eggs according to the established criteria using in vitro fertilisation did not differ. This suggests that the difference may not be due to an embryonic factor. Fertilisation rate was the same…”

Hans van der Slikke, MD, PhD: “But the endometrium, yes.”

Stratis Kolibianakis, MD: “…but of course there are more sophisticated criteria, but I’m talking about the established criteria that we use in the everyday practice to distinguish between the embryos to be transferred and those that are not going to be transferred. With this evaluation, no suggestion of an embryonic factor is present. So we think and we try actually to assess that now by a prospective randomised study on endometrium quality that is really an effect mainly due to an endometrial factor.” 

Hans van der Slikke, MD, PhD: “Thank you very much.”

Stratis Kolibianakis, MD: “Thank you, it was a pleasure.”