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

Dr. Richard Paulson delves into the intricacies of endometrial preparation for assisted reproductive technology (ART). He discusses the historical evolution of hormonal induction of endometrial receptivity, from its early applications in egg donation to its current use in frozen embryo transfer. Dr. Paulson also explores the optimal methods of estrogen and progesterone administration, including oral, transdermal, intramuscular, and vaginal routes.

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. One of my areas of interest for a long time has been the question of endometrial receptivity and in particular the hormonal induction of endometrial receptivity.

Now this procedure, if you will, really was first invented in the context of egg donation because remember embryo cryopreservation wasn't very efficient. So it was when IVF first started and people saw that you could have sperm in one dish and egg in another dish that it didn't take a huge leap of the imagination to say, oh gosh, we could be donating eggs from one person to another. And of course the early recipients were all young women with premature ovarian failure.

So they had no ovarian function and the only way to induce receptivity to embryo implantation was with the progesterone. So the world's first pregnancy in an agonadal recipient took place in 1983. The patient took oral estrogen and vaginal progesterone, 50 milligrams twice a day.

Remember that, 50 milligrams twice a day. And one two-cell embryo was transferred on the second day of progesterone. Second day of progesterone, that means the progesterone started when that embryo was at the pre-nuclear stage.

So remember that, that's actually 24 hours after ovulation. The procedure, or if you will, the preparation of the endometrium was then extended to surrogacy. Same kind of idea, eggs being donated from one person to another.

And when embryo cryopreservation became more efficient, we started using it for preparation of the endometrium prior to frozen embryo transfer. And indeed, that is what it's being used for mostly nowadays. In fact, egg donation and gestational surrogacy, as most of you know, has really shifted towards frozen embryo transfer in any event.

So let's talk about how it is we prepare the endometrium. You need estrogen and you need progesterone. You don't need anything else.

People have tried, but estrogen and progesterone is all that has ever been shown to be necessary and nothing added to it has actually been shown to make a difference. So apparently, that's how that works. So how do you give somebody estrogen? So there's lots of options.

Estradiol in the circulation is relatively low quantities, and as a consequence, you don't have to give that much medication. So we can use oral estrogen. Typically, we use two milligram oral doses, maybe twice a day or three times a day.

You can use transdermal, and because transdermal is absorbed much more efficiently, the dose is lower. So estrogen patches that are used are typically 100 microgram doses. 0.1 milligram dose by a patch is equivalent to about two milligrams orally.

So two milligrams twice a day, for example, orally translates into two patches at one time, and that's how it can be used. The patches actually are more physiologic. They provide the right kind of ratio of estrone and estradiol, but I would say that the majority of cycles in the United States still use oral, and that is because we're more comfortable with it.

It's easier for the patients to take it via pill. You can also use intramuscular, or you can use vaginal administration. We won't go into depth on those.

Those do produce actually higher levels. So estrogen has to be given for some period of time to prepare the endometrium, and specifically to prepare the endometrial cells and to allow them to develop progesterone receptors, because it is progesterone that actually causes the luteinization and opens the window of implantation. So most of us give estrogen for about 10-12 days.

We look for an endometrial thickness of seven millimeters, but you should know that no one has ever correlated endometrial thickness with the presence of progesterone receptors and so on. So the thickness is not all there is to it. Let's move on to progesterone.

So progesterone is present in the body in much higher levels. Remember, we measure progesterone in nanogram quantities, nanogram per mil, and therefore the doses that are given are much higher. So intramuscular doses are typically 50 milligrams, 50 milligrams per ml.

That's a dose. Vaginal doses then typically are around 100 or 200 a day. So oral is not really a reality.

Really, we're stuck with intramuscular or vaginal. The transdermal administration for progesterone also doesn't work. First of all, you have to think about how big that patch would have to be.

I often like to joke that you'd have to have a progesterone jacket to wear. And still, of course, there's five alpha reductase in the skin, which metabolizes the progesterone and makes it be inactivated. So we're going to stick with intramuscular and vaginal.

So that's it for the options that we have for progesterone administration. So I've been investigating progesterone administration for a very long time, and I want to tell you more about that and particularly about the uterine first pass effect that was discovered as a consequence of measuring endometrial tissue levels rather than serum levels of progesterone. And we're going to talk about that in the next video.

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.