How can I thicken my uterine lining for FET?

Well, for frozen embryo transfer we can do two different types of preparation: we can go for a natural cycle (if the patients have regular periods), we let the ovary with her own stretching prepare the endometrium or we can add medication. Actually we do the ovarian part of the preparation of the endometrium by adding estrogens and we’ll do an ultrasound about 10 to 12 days after starting the estrogen pills to see if we got the correct lining and the correct thickness. On the other hand, on a natural cycle, we expect for the patient to prepare the endometrium, so we start doing ultrasounds on day seven or eight and start monitoring the development of the follicle that is going to produce the estrogen that will get our endometrium thick. So we start doing ultrasound at day 7, 8, 9, 10 and we can do it a full natural cycle when we wait for a spontaneous ovulation or we can do the trigger to produce the ovulation and then proceed to the act of progesterone and calculate the takes for embryo transfer.

With regard to this, there were a lot of scientific advances that have tackled this question. Basically, because we had cases in which we noticed that endometrial thickness is not thickening.

So the first question to answer is: how thick is thick? Is 6 mm ok? Is 7 mm ok? Is 5 mm ok? We have two things to consider: thickness and quality. The quality of the uterus is good when we have a triple lining. So is it the quality or the actual quantity, meaning thickness? This is one thing to address. I don’t think that anyone would argue that 7 mm are arbitrary – that it is the aim for us. Like, if we have anything 7 mm or more, that’s what we aim for. However, any 6-6,5 mm that we see with good quality endometrium is as good as just thick endometrium.

So to have cancellation of an embryo transfer just because it is a little thinner than the arbitrary line of 7 mm is not common. I haven’t seen it a lot. We go for it and then we have pregnancies out of it. And there are a lot of papers to prove that the evidence is there and yes, we go ahead with the transfer.

If it is a frozen-thawed embryo transfer – especially in egg donation – and there is travel involved and so on, we are guided by two things. First,  the blood test – we can do estrogen level to see if it matches with the actual figure. Don’t forget that there is some inter-sonographic difference between one doctor and the other. However, usually, it shouldn’t be statistically significant. So that’s one thing to consider. The second is whether we have to discuss cancelling this cycle and then repeating it again. It is easier to do it on frozen-thawed cycle because you are going to be just on tablets which are thickening. Why? Because this is easy to increase, manipulate, modulate, and to give you more oestrogen. From your experience you know that a lot of people are having just tablets 2 or 3 times a day, we can increase it up to 4 times a day or we can add a vaginal form of supplementation. And we’ll be guided also by the blood test. If we are heading to the slow increase of thickness, then we are in the right direction and we go ahead.

However, if despite these simple measures to increase the estrogen level in a frozen-thawed embryo transfer it doesn’t work, we might need to cancel this cycle and then restart it again. It is different than the fresh cycle. The fresh one is a little bit peculiar because you don’t have the possibility to increase your lining by giving like more estrogen. So what do we do then?

We have to see the background. Is there the background of Asherman’s syndrome, were there problems all through the follicular monitoring? Don’t forget that with egg collection, we do a lot of scans and we do reporting on the endometrial thickness. Obviously, with the egg collection, your oestrogen level goes sky high. And having a sky-high level of estrogen, it should lead to thick endometrium. However, any past history of adhesions, Asherman’s, D&Cs and stuff that has had an impact on the endometrial thickness, should be investigated separately before going ahead with an embryo transfer.

Now: are there any things to help to improve thickness? Yes. Some people try sildenafil which is Viagra, given vaginally to increase the vascularity of the endometrium. There are lots of papers on the use of sildenafil to increase the endometrial thickness successfully. Also, there is Neupogen or this granulocyte-colony stimulating factor (G-CSF) that has been used recently by a few clinics as a way to improve endometrial thickness. There are studies but obviously, it is not openly recommended. We cannot use it as a routine, only in some very special circumstances.

There is also some research based on using the platelet-rich plasma (PRP) directly into the cavity of the lining in order to help to increase endometrial thickness. We are still waiting for approval and to see if this is something that we can recommend in the future. So there are a lot of scientific advances in this kind of category, we are waiting for all the evidence. There is hope to make this kind of a problem a problem of the past. Hopefully, by all these advances, we are trying to achieve a better understanding of what works and what does not work.

There are two possibilities: stimulated endometrium and natural endometrium. When it is possible to have a natural endometrium, a natural cycle – I think it’s better. There some studies that there is a higher risk of preeclampsia if you do a transfer in artificially prepared endometrium. So usually, if a patient has a regular cycle, we prefer a natural cycle. We like endometrium over seven millimeters. An endometrium of 9 mm is not better than the one of 7 mm. There is a range, between 7-14 mm, and if the thickness of the endometrium is in this range, we are satisfied. There are no better chances if you have 10 mm, for example. So it’s not necessary to improve the endometrium with some drugs.

If the patient has an irregular cycle, it’s necessary to use estradiol for the preparation of endometrium. There are several types of taking it. You can take it orally or vaginally or in patches, and it’s very individual. The probabilities of success are the same, whether it is an artificial or natural cycle. The natural one is better because you don’t use medication, there are no side effects. There’s also a lower risk of preeclampsia in later pregnancy.

Endometrial thickness is very important. Sometimes it’s a problem because in patients, after some operation in the uterine cavity or after some complicated abortion, for example, it can be problematic. If it doesn’t grow well, there are not many ways how to improve it, because the endometrium is damaged. So if you have damaged endometrium, we can’t stimulate it. It’s a problem, and in some cases in which is not possible to have more than six millimeters, for example, we recommend surrogacy.

We call the patient during a normal cycle, first of all, just after the ovulation to see her uterus and how the uterus responds to her ovulation. First of all, we have to evaluate the uterus of the patient with an ultrasound, without any hormonal effects. Secondly, if we see any problem, any distortion on the uterine lining, or if there is any mass like fibroid, or if she has any liquid inside, in this case, we have to evaluate the uterus and the tubes before the embryo transfer, before we start to prepare the patients. A standard exam in this case is the HSG field (hysterosalpingography). This is a radiological exam, we put the patient on the table in a gynecological position, put a catheter inside of the uterus, give a radio-opaque liquid, and take some pictures with the radiological machine. With this, the liquid fills the inside of the uterus and we can see if there is something wrong like a polyp, or any myoma, any adhesion, or any congenital problems in the inside of the uterus.

Secondly, we keep giving this liquid, the liquid from the uterine cavity goes in through the tubes and like this, we can see if the tubes are opened or obstructed. According to the findings, sometimes the patient may need some surgery before the embryo transfer like hysteroscopy or laparoscopy, so we prepare the patient for the embryo transfer before we start the medication, this is very important.

First of all, as a gynecologist, you have to evaluate the patient’s uterus during their normal life. If you don’t see any problem or if in the medical history of the patient there are no suspicious things like too many abortions, uterus surgery,  in this case, you can start.

We start to do the preparation on the 2nd day of the menstruation and it takes 13 days with the medication. 13 days after we start the medication we call the patient back, and first of all, we do the ultrasound. In the ultrasound, two things are important: the endometrial lining shape that we call “three-line”, is the best picture and the second thing is the endometrial thickness which traditionally must be more than seven millimeters. If you see good shape and thickening that’s more than seven millimeters, it means that the patient is ready and these are the two objective criteria for us. Most of the time, if the patient has had surgeries, some adhesions, some infections before, they might have a problem in the thickening of the uterus even with the medication, vaginal medication, or even with the surgery. In this case, according to the ultrasound findings, sometimes we let the patients go until the transfer, otherwise, if the ultrasound result it’s not satisfying, we stop the medication, we go back to see the patient’s file if needed we repeat all tests like hysteroscopy, laparoscopy, and then we restart.

Thickening of the lining of the womb is a challenge. Some patients, I would say, the majority of the patients respond very well to the treatment. And the treatment involves using HRT, hormone replacement treatment, in the form of hormonal tablets, or patches. But some women, unfortunately, do not seem to respond to HRT. Sometimes they don’t absorb it or don’t have the receptors, that is the little link inside the uterus, to respond, and to react to the hormones. It’s difficult to say. In the case of women who don’t have a good lining we feel that by transferring the embryo, we might not give the embryo the best chance to implant. So the thickening of the lining of the womb is one of the parameters that we look at when we plan an embryo transfer, either refresh or frozen.

That applies also to the fresh transfer, because if we’re not satisfied that the lining is of good measurement, of good thickness, and that usually is around anything above 7-8 mm, we would freeze the embryos. We would plan those embryos to be transferred on a cycle where we can hopefully achieve a better lining. If we are already on a frozen cycle, and the lining is not satisfactory, then again it’s a matter of having this conversation with the patient, what we’re going to do.

In my experience, we suggest not to defrost the embryos, and to retry again maybe different medications. Or sometimes the natural cycle, where the patient actually produces her own hormones, might work a little bit better. Then there are lots of potential add-ons that we could put, some specialists suggest using Viagra or Aspirin. Using different drugs that might improve the thickening of the lining.

Again, none of this has been shown to be evidence-based effective. But in some cases, we do try different things. Now it is important to have a good endometrium, and a part of making the endometrium thick and capable for the embryo to implant is the progesterone. The progesterone is usually given by either vaginal pessaries, or rectal pessaries, or injectable progesterone. It is very important that these medications are continued all through the implantation phase until the doctor suggests stopping. Both HRT and progesterone are essential for the implantation, and for the establishment and the continuation of the pregnancy.

First of all, we have to exclude chronic endometritis and adhesions in the lining. If we observe thin lining, that is why we have to first perform hysteroscopy to exclude these 2 main factors of the endometrium. If we treat chronic endometritis after it grows better than before and usually will prescribe estrogen. There is also a granulocyte colony-stimulating factor which has been shown to be an effective defense to pathogenic microbes. We use sometimes granulocyte colony-stimulating factor but most often we now use growth hormone Gonadotropin because it has been shown in numerous studies that growth hormone induces production of insulin in the liver for growth factor 1, and these are factors which activate vascular endothelial growth factor gene. So, it helps to proliferate, it helps to make better blood support and the lining becomes better. But during the administration of growth hormone, we check in the blood for insulin-like growth factor 1 because there are patients that are at risk of having this factor normally elevated, so to avoid some side effects it is better to determine it before the prescription of growth hormones.