Overcoming the dangers of ovarian hyperstimulation

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Hans van der Slikke, MD, PhD: It’s July 2003, we are in Madrid at the ESHRE Conference and next to me is Dr. Garcia Velasco, from Valencia. Very welcome!

Juan Garcia Velasco, MD: Thank you.

Hans van der Slikke, MD, PhD: You are a rising star in the field of ovarian hyperstimulation and at this conference your group had a beautiful presentation about vascular components in hyperstimulation. I want to talk with you about this very serious problem in ART. Could you first give me a summary of the causes as they are known now?

Juan Garcia Velasco, MD: First, I’d like to say that ovarian hyperstimulation is one of the two major complications in the ovarian stimulation treatments. One is the multiple pregnancy rate, which we’re fighting against, and the second one is hyperstimulation, which is an iatrogenic complication in a non-vital treatment: it’s a young lady with no previous disease and suddenly she may end up in hospital, so it makes no sense to have such a high rate of complications in this field. Between 0.5% and 10% of the cycles have a moderate or severe rate of hyperstimulation.

Hans van der Slikke, MD, PhD: And there is a relation between the two of them?

Juan Garcia Velasco, MD: Yes, there’s a high relation because both of them are dependent on the hCG and going to hyperstimulation, which is one of our main research areas in the unit where I work. hCG is going to liberate the mediators that are going to start the syndrome, namely the VEGF (vascular endothelial growth factor). This cytokine is going to produce a vasodilatation, it’s going to permit the liquid to go out the vessels and start the process of losing albumin and ending up in ascites and pulmonary oedema.

So we have to find, I think, two things: first of all, markers of women who may end up in a severe level of hyperstimulation; and second, a clinical study to prevent these women already at risk undergoing such a complication.

Hans van der Slikke, MD, PhD: So first, those factors, those markers, are there already factors or markers known?

Juan Garcia Velasco, MD: Well, there are a few known, but their usefulness is not so clear. Like I mentioned before, VEGF is one of the key molecules regulating this process, but as absolute value in serum or in follicular fluid, they have been shown to be useless.

So at this meeting, we showed some results on the new marker, which is vascular endothelial cadherin, which is a protein that is split when the cells of the endothelium separate, when they start to vasodilate. We found a correlation between the levels of endothelial cadherin and the risk of hyperstimulation and maybe (I will have to continue with this research), women with a high level of endothelial cadherin are those who are going to suffer this syndrome.

Hans van der Slikke, MD, PhD: Do you think there could be an answer in proteomics in this field?

Juan Garcia Velasco, MD: Definitely, I think we cannot look at single pieces of the puzzle. At the end, once we have a clear idea of what is happening, we have to look at the broader image and it’s not only VEGF or endothelial cadherin that will be covered in priority, we will have to look at the whole broad image and, of course, the function of proteomics which are going to give us the answer.

Hans van der Slikke, MD, PhD: The second thing is the clinical prevention measures. Well, as we saw already, the single embryo transfer could be one of the best prevention methods?

Juan Garcia Velasco, MD: Of course. This syndrome is, as I’ve said before, dependent on hCG. Then we have two types of ovarian stimulation: early ovarian hyperstimulation, which depends on how much hCG you give to retrieve the oocytes and then the later ovarian hyperstimulation, which depends on the hCG that is produced by the gestational sac So if you have a multiple pregnancy, let’s say twins or triplets, you are going to double or triple your amount of hCG, so it’s going to make matters worse.

Single embryo transfer is going to reduce, of course, the hCG for the late ovarian hyperstimulation and the risk of ovarian hyperstimulation. Also, because we are aiming to transfer just one embryo, we don’t need to hyperstimulate the women that much and, with a smaller number of oocytes, we will have a good embryo and thus attack both fronts.

Hans van der Slikke, MD, PhD: But first, for the earlier ovarian hyperstimulation, what other measures, apart from what you told us, could be taken?

Juan Garcia Velasco, MD: Well, first of all, to reduce the hCG dose. You can use not 10,000 international units, you can 5,000 or 3,500. In this new approach, which is very effective in those patients undergoing GnRH antagonist treatment, you can use the GnRH antagonist to trigger the ovulation and this will dramatically reduce your ovarian hyperstimulation incidents. If it’s not possible to use it because these patients have a long protocol, then you can coast the patient, you can use the coasting approach, which is nothing new.

It was described about ten years ago, but now because there are more people working in IVF, it’s becoming popular again because it’s a good approach not to cancel the cycle and you can have excellent IVF outcomes without risking the health of the women.

Hans van der Slikke, MD, PhD: Are there other measures except the single embryo transfer to reduce the late complications?

Juan Garcia Velasco, MD: Well, that’s a difficult prevention measure because the risk is already started if you gave hCG and obviously for prevention we are already late, but we even have to sometimes freeze the embryos. If the woman is very high risk, we can cancel the cycle or we can retrieve the eggs and cancel the transfer just to avoid this risk of late ovarian hyperstimulation, which is as serious as the other one.

Hans van der Slikke, MD, PhD: So, I guess in conclusion that the most important measure or milestone would be if we could find a marker by which this woman is at risk and, until then, to be cautious and not to stimulate too much.

Juan Garcia Velasco, MD: Absolutely. Those are the two main messages.

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

Juan Garcia Velasco, MD: Thank you.