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Hormonal Induction of Endometrial Receptivity for Fresh or Frozen Embryo Transfer​ Part II

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Video

Title:  Hormonal Induction of Endometrial Receptivity for Fresh or Frozen Embryo Transfer​ Part II

Runtime: 6 min 27 sec

Speaker: Richard J. Paulson MD

Transcript

This transcript was automatically generated.

In this video, Dr. Richard Paulson delves into the complexities of progesterone administration in assisted reproductive technology (ART), discussing the debate between intramuscular and vaginal progesterone and exploring the evidence behind each method. 

Hello, I'm Dr. Richard Paulson from the University of Southern California. I've been doing IVF and egg donation and all of these other things that we all do for a very long time. We've been talking about the options for progesterone administration and we discussed the fact that the intramuscular and vaginal roots really are the two ways that we have of administering progesterone to someone.

The question is which route actually gives you the higher levels that you care about, meaning in the endometrium. And that is what we're going to start talking about. I always was in favor of the vaginal administration because the injections of the progesterone and oil are so painful and so unpleasant to patients.

And it always bothered me that we were measuring progesterone levels in the circulation. Or as I like to say, why are we measuring it in the antecubital fossa when what we really care about is what the levels are at the level of the endometrium. And I remember, this was about 30 years ago, we had a journal club at my house and we talked about it and I went on one of my rants and Frank Stanczyk, who's a PhD biochemist in our division, said, we can do that.

And so that's what we did. We gave the patient's vaginal progesterone, did endometrial biopsies, homogenized the tissue and showed that the endometrial tissue levels were much higher after vaginal administration than after intramuscular. So even though the serum levels appear to be lower, you get more tissue penetration, more tissue action, and measuring the serum progesterone levels is probably not productive.

There were many meta-analyses after that that basically demonstrated clinical equivalence between vaginal and intramuscular progesterone. And that is because even though perhaps you're getting more than you need via the vaginal route, there does not appear to be such a thing as too much progesterone. So it doesn't matter, as long as you deliver enough progesterone, everything should be fine.

This was all, of course, turned on its head in 2021 when a randomized clinical trial came from an East Coast program, which showed in a randomized clinical trial that the women that were only taking vaginal progesterone had much lower live birth rates than those whose regimen included intramuscular progesterone. So very difficult to know why this would be. The implantation rate was the same.

Miscarriage rate was very, very high. The miscarriage rate was really much higher than anything that had previously been reported. So that study is an outlier.

In addition to that, it really makes one wonder whether those patients were taking the vaginal medication correctly because, of course, if it is not administered and it is not absorbing, then this would be a problem. But jury is still out. And yes, most of us continue to use intramuscular in addition to vaginal progesterone.

But I want to go on record as saying I think that's going to disappear and we're all going to understand that vaginal is really just as good as intramuscular. So the last question, of course, is what about timing of progesterone administration? And again, I will tell you that I thought that this question had been resolved. Remember, I told you that first egg-on-adult pregnancy, they started progesterone one day after ovulation.

Most of us start progesterone on the day of ovulation. Long time ago, maybe we used to do it a day prior to because in a fresh IVF cycle, progesterone actually rises about 24 hours before egg retrieval. But all of those are OK and all of those probably produce the same results, particularly then if it's on the day of ovulation or the day after.

And that, I think, is the correct timing. So there is a number of endometrial tests that are now available that have not been shown to be useful. The endometrial receptivity array in particular was a very promising way of evaluating the endometrium.

Prior to that, all we had was histology and people would do a biopsy and look at it. The problem with histology is that it's subjective and it seems to vary in different parts of the uterus. So the endometrial receptivity array looks at a variety of genes that are expressed in the endometrium in the luteal phase.

And in this manner, they were able to find what they thought was the optimal time for embryo transfer. The problem is, is that even though it's very good to describe the luteal progression, it did not actually demonstrate clinical superiority. There's now at least two randomized clinical trials which have shown that using the ERA does not increase the implantation rate.

So I think you should start progesterone on the evening of the day of ovulation. That's what we do. You can wait till the next morning.

If the patient forgets, not a problem. Or even if you start on the morning of the day of ovulation, all of those are going to be okay. In summary, third-party parenting really is what started us down the path towards these artificial cycles.

And now, of course, they're used for frozen embryo transfer. We didn't have time to talk about the natural cycle today. It is being used increasingly.

I will only tease the concept by telling you that in a natural cycle, there's a lot less progesterone than the amount that we're administering, and that it starts a lot later than we normally start exogenous progesterone. But they work equally well. There's nothing wrong with the medicated cycle the way that we have described it.

Remember, estrogen and progesterone is all that is needed. Nothing else has ever been shown to actually increase it. We have a bunch of options for estradiol administration, whether it's oral or transdermal, or you can use intramuscular or vaginal.

But the first two are probably the most common. For progesterone in the United States, we're really stuck with intramuscular and vaginal because a sub-Q format has not yet arrived. I hope it does soon.

That would make the injection certainly a lot more pleasant. The timing of progesterone administration should be on the day of ovulation, perhaps in the evening, or okay to wait till the following morning. So that's it.

Endometrial preparation is really quite simple. I think it was solved 20 years ago. We've got some recent controversies, but I don't believe that they will pan out.

I believe that the artificial cycle, the way that we were doing it 20 years ago, continues to be the right way to do it and will produce the best results that you want for your patients.

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