Improving Endometrial Receptivity: Tips for Optimising Your IVF Outcome

Speaking of endometrial receptivity, it has indeed been considered a type of last frontier in assisted reproduction. It’s shrouded in mystery about how it works. Part of this is because of the endometrial tissue itself. If we compare it to the ovaries or egg, or sperm cells, it’s very dynamic—it changes with each menstrual cycle. That’s why it’s sometimes hard to gauge how to approach it.

To begin with, a brief introduction of what the endometrium is: we have to think of the ovaries and the uterus as going through two separate processes in parallel—the ovarian cycle and the endometrial cycle.

Over the 28 days of a standard ovarian cycle, a follicle is stimulated and starts producing estrogen. This estrogen acts as a stimulus for the inner cavity of the uterus—what we call the endometrium or the lining. Estrogen causes the endometrium to thicken or grow, but it’s not receptive just yet.

The endometrium becomes receptive when the follicle ovulates, when it releases the egg. That follicle turns into something called a corpus luteum or “yellow body,” which starts producing progesterone instead of estrogen. Once enough progesterone is produced, it helps the endometrium acquire its receptivity.

So, there’s a specific timeframe when that lining is receptive—when it can bond or attach to the embryo.

Yes, I think this is going to be a type of onion we’ll have to go through layer by layer. We just peeled off the initial layer—the basic function of the lining. That’s why most endometrial preparation protocols are just estrogen followed by progesterone. But with progesterone, many changes happen in the endometrium.

With progesterone, different glands start forming within the endometrial tissue. That’s a basic difference between a lining exposed only to estrogen and one exposed to progesterone. Also, blood vessels finish proliferating within the endometrial tissue. Certain types of white cells rush to the place where the embryo is trying to attach, and a process of cross-talk begins between the embryo and the endometrial lining.

There are many adhesion molecules, integrins, and different types of white cells that take part in this cross-talk. Also, a concept that has changed over time: we used to view the endometrial cavity as a sterile compartment. Now we know that’s not true.

There is a microbiome—mainly good bacteria, primarily lactobacilli—but there could also be bad bacteria that cause silent infections and inflammatory processes that interfere with implantation.

Yes, and before we go into these issues, I’d like to make a small disclaimer: this is a huge grey area. Many of these theories or therapies have been proven in some studies. There is evidence in certain populations and conditions, but there are also many studies that disprove it or can’t find enough evidence.

Another important point: endometrial receptivity is often not the primary suspect when something goes wrong. The most important factor is usually the embryo and whether it is genetically competent. That said, many conditions can affect the endometrial environment. Starting with anatomical issues is a good way to move from general to specific.

When the uterus develops during fetal life, certain anatomical abnormalities may arise. One of them is the uterine septum. That’s when the uterus forms, with an inner wall that doesn’t reabsorb and stays. This can be a problem for embryo implantation or pregnancy development. We need to look for that during initial fertility workups. There can also be issues like endometrial polyps or fibroids that affect the cavity. None of these are guaranteed reasons for failure, but we know that removing a polyp or fibroids inside the cavity tends to improve outcomes.

Yes, and in most cases—certainly those that I’ve seen, and I’m sure you’ve had this experience too—we would typically recommend removing a uterine polyp or polyps. With fibroids, it kind of depends on the size and the location whether they’d want to touch it or not, because you don’t want to risk the structural integrity of the uterus. But essentially, what we’re talking about at the moment is anything that would affect that kind of topography. In other words, we’re still talking about things that you can see, as opposed to things that are on the molecular level, which is the toughest.

So that is something that people should have ruled out if they’re looking at issues that would affect receptivity.

You’re always looking for a probable cause, right? There are a few reasons as to why an endometrium may not achieve the desired thickness. One of the reasons why that may happen may be due to the formation of scar tissue—something that we’ve dubbed Asherman’s syndrome. This is something that we might suspect in patients who have had, for example, multiple endometrial procedures, such as multiple D&Cs. That would be something that we could see with a hysteroscopy and that we would be able to treat with that hysteroscopy, in the same way that we could remove a polyp.

I just want to touch on fibroids because I think what you were saying was very important. There are different types of fibroids, and we name these fibroids depending on the sites at which they are growing. Fibroids are uterine muscle cell tumours, benign. The great majority of these so-called tumours are benign, and we need to know that they are also very common. Many women go through fibroids. The reality is that most fibroids are not going to need treatment.

Fibroids can develop inside the endometrial cavity, inside the uterine wall muscle, and essentially outside the uterus, outside that outer layer of the uterus. When talking about infertility, most fibroids that are going to affect the embryo’s implantation process are going to develop inside the cavity or are going to affect the cavity. These are the fibroids that we sometimes need to treat.

Yes. The most common, typical way those lesions appear is post-procedure. If you suddenly see your period go AWOL and you’re being told, “Oh, you’re perimenopausal”—which is what my client was told because she was 41—just be really mindful of getting to somebody who actually knows what they’re talking about when it comes to the internal environment and micro-instrumentation surgery, who can properly address adhesions. As I’m sure you’ve seen in your practice, it can make a dramatic difference to the odds of success. If you’re talking about the embryo being able to implant, and Asherman syndrome is present, it is going to make things very difficult.

Particularly in those devastating cases with multiple pregnancy losses and multiple procedures, people don’t even realise that what’s often causing the higher risk of miscarriage is the fact that they’ve gone through more procedures. It’s not necessarily a chromosomal abnormality anymore. The rule is: never make assumptions. Always make sure that’s properly checked out.

Yes. PRP is platelet-rich plasma. PRP has a number of uses in medicine. It’s not something we use exclusively in fertility. It’s even used in aesthetic medicine, many branches. That’s where the term “vampire facials” comes from.

There’s a difference between ovarian PRP—also called ovarian rejuvenation—and PRP for the endometrium. Platelet-rich plasma, when injected, may not do much on its own. But when these platelets break down, they release growth factors. Those growth factors can help in cases of refractory endometria—endometria that don’t respond well to medication.

The treatment usually consists of acquiring your PRP from a blood sample. We isolate the platelets and concentrate them more than they would be in normal blood, and then infuse this PRP into the endometrial lining, usually about three or four applications during the endometrial preparation protocol. This can sometimes help with lining thickness. There are multiple studies showing that thicker linings are associated with better implantation and better pregnancy rates.

When we talk about preparing your lining, making sure that it’s receptive, there are three very important hormones that we need to talk about. I will get to TSH, but I’m going to mention that one last because there’s a lot to talk about. I would like to talk about estrogen and progesterone.

You’ll hear me say estrogen a lot. Just so we know, there are different types of estrogen. There are actually 4 types of estrogen that a woman would naturally produce across their lifetime. There’s a certain estrogen that they produce before puberty. There’s another type of estrogen, which is estradiol, which is the one we’re going to focus on that you’ll produce throughout your fertility period, and then another type that will be produced exclusively in pregnancy, and then after menopause.

Estradiol is very important because that’s the estrogen that the follicle produces. In fact, 95% of a woman’s circulating estradiol comes from the developing follicle during the cycle.

When we prepare a woman’s lining, we do so with estrogen. Is it estradiol? No, it’s a different type of estrogen. But we know there’s a certain threshold at which we want that estrogen level to act. It’s something that we don’t usually measure, but it’s a good idea to measure it, because high levels of estrogen before an embryo transfer may not be ideal.

A lot of patients are confused about why and when we measure progesterone. Most clinics will adopt a protocol in which we measure progesterone about a week before the embryo transfer, and then again a day before. Patients are always confused as to when we want progesterone to be low and when we want it to be high.

The endometrium will not become receptive until it’s been exposed to progesterone, ideally for 120 hours, or 5 days. That’s why we measure your progesterone levels a week before the transfer — we want to be sure that the lining has not yet been exposed to progesterone. We want low progesterone levels. Then, a day before the embryo transfer, we measure it again after you’ve been on progesterone for about 3 to 4 days, because we want your lining to have very good levels of progesterone, above 10 nanograms per millilitre, which is over 30 nanomoles for the European version.

TSH is a hormone that controls the thyroid activity. It controls the T3 and T4 hormones, which are the active thyroid hormones. When your body senses that thyroid levels are too high, it’ll try to decrease your TSH levels so that those come down. But if your body senses that T3 and T4 are too low, it will try to increase TSH to raise those hormones.

When we think about doing a preparation protocol and the TSH levels are too high, that means — and it’s kind of counterintuitive — that we may have a hypoactive thyroid. That’s why it’s called hypothyroidism.

The range we want TSH to be in for the general population is between 0.4 and, depending on the country and the lab, about 4.5. There are two populations in which we set different limits — pregnant women and women trying to get pregnant. In these populations, we want the TSH to be below 2.5.

If you get a TSH result that is, say, 3.2 — does that mean you have hypothyroidism? No, not at all. But it means that to achieve pregnancy, we may need to lower that TSH a bit more. TSH levels above that 2.5 threshold may have adverse clinical outcomes in terms of pregnancy and fertility.

There are a lot of caveats to this. This is something that your doctor needs to go through with you, because there are a lot of things that we need to explain. It’s not as simple as “above 2.5, we need to treat” — that’s a gross oversimplification of one of the things that we also need to have a look at 100%.

Yes, this is real. The implantation window comes about 6 to 7 days after ovulation. In a 28-day cycle, this would be around day 22 to day 24–25.

What defines this window of implantation is that the lining, after being exposed to progesterone, develops a glandular system and starts expressing certain adhesive molecules—certain integrins—that make it ideal for the embryo to attach.

Some research suggests that around one in five or one in six women may have a displaced window of implantation. That means the lining isn’t expressing those molecules or glands at the same time as expected.

There are different commercial kits that measure whether the lining is receptive after five days of progesterone. There have been studies trying to determine whether this works or not. One large study in the U.S. did a clinical trial where they either transferred the embryo according to the test results or transferred it on the usual day, regardless of the test. They did not find a significant improvement with the endometrial biopsy.

Does that mean it doesn’t work? We can’t say for sure yet. More research is needed. Smaller independent studies may show some benefit. What we do know is that this should not be applied to the general population. It should be reserved for women with recurrent implantation failure—those who have had multiple chromosomally normal embryo transfers without success.

Any medical term ending in ‘itis’ means inflammation of the tissue. So, endometritis is inflammation of the endometrial lining.

One reason for this could be microbial infection—overgrowth of certain bacteria, causing more inflammation than usual. There are now commercial kits that can measure this and identify the specific pathogen. Previously, we would stain endometrial biopsy samples and look for a white cell response, which indicated inflammation, though not the specific bacteria.

Many people assume it’s a standard STI, like chlamydia or gonorrhoea. I thought so, too. But often, the bacteria found are things like streptococci—organisms you wouldn’t expect. Most endometritis cases are silent infections. You may not know you have it. You won’t necessarily have unusual bleeding, pain, or other symptoms, yet the inflammatory process may still be occurring.

This inflammation draws an immunological response, specifically plasma cells. These cells try to fight the infection, but are not ideal in the lining during embryo implantation. That’s why identifying and treating endometritis is important.

Is it 100% proven that it causes implantation failure? Not exactly. It’s a grey area. But studies show women with recurrent implantation failure, and even more so those with recurrent miscarriage, have a higher incidence of endometritis.

Yes, it’s a very important point. When we talk about good and bad bacteria, we don’t mean having no bacteria at all. We want a good amount of beneficial bacteria.

Lactobacilli are considered good bacteria. They may improve implantation chances and help prevent overgrowth of harmful bacteria. Maintaining adequate levels is important.

Yes, absolutely. The clinic’s reproductive immunology unit is wonderful because this area—alloimmunity—can be very confusing, but is incredibly important in tough cases.

Autoimmunity and reproductive immunology can seem confusing, but I think we can break it down. This is also dynamic and changes depending on the specific phase of the cycle. We’ve seen that the white blood cell primarily involved in the “cross-talk” between the embryo and the endometrial lining is the so-called natural killer (NK) cell, although that name is misleading. Initially, we measured these cells in the blood, but now we understand that blood NK levels may not reflect what’s happening in the uterus. We’re now able to measure uterine NK (uNK) cells, which fluctuate throughout the endometrial cycle.

During the window of implantation, these uNK cells surge to help mediate the communication between the embryo and the lining. There are different types of uNK cells—let’s call them “good” and “bad” for simplicity. We want a higher ratio of good to bad uNK cells. Too many uNK cells, or too many of the bad type, can negatively affect embryo implantation.

Let me also touch briefly on HLA-KIR interactions, because I get asked about this a lot. All of us have specific HLA types. The embryo inherits its HLA profile from the parents’ DNA. NK cells in the uterus have receptors called KIR (Killer-cell Immunoglobulin-like Receptors), and there are different types of KIRs, just as there are different types of HLAs.

Some HLA-KIR combinations are more favourable than others. I should say, our immunologist would caution against using the word “compatibility” too loosely, as it’s a complex field. But for simplicity, we can say some combinations are more favourable for implantation and pregnancy outcomes. Poor combinations have been associated with implantation failure, miscarriage, and even complications like preeclampsia.

These are the kinds of things we might explore in more challenging cases—when someone has had repeated failures or losses and is wondering if something has been missed. Immune testing can sometimes reveal that the body is reacting to the embryo in a way that prevents successful implantation, especially when foreign DNA from the sperm is introduced.

Three concepts we should talk about. Let’s start with the embryo.

When we talk about embryo grade, first of all, this was a euploid blastocyst. Now, blastocyst and day five embryo are not synonymous. Blastocyst is a stage that a mature embryo reaches — sometimes on day five, sometimes on day six, and sometimes even later, on day seven.

The quicker it gets to that stage, ideally on day five, the better. A day five embryo is already telling us that there’s good quality — grade A is top quality. Usually, we have a separate grade for the inner cell mass and another for the outer cells, or the trophoblast. I’m going to assume it was a double A grade embryo.

Now, in terms of quality — quality doesn’t mean that a grade A embryo is necessarily euploid. In this case, it was a euploid embryo, so we have a reason to believe everything was fine with the embryo. The transfer was six days after a late night trigger. This is either a fresh embryo transfer or a transfer made with a natural modified cycle. I think it’s the latter.

When we think about how to calculate timing: once you apply the trigger, we count 36 hours, and then after those 36 hours, we add the other five days. So, for example, if you had a trigger injection on a Monday evening at 8:00 PM, then day zero is Wednesday 8:00 AM. From there, we count five days — 0, 1, 2, 3, 4, 5. That’s the appropriate way to calculate the embryo transfer. Now, what if it’s a day six embryo? It doesn’t matter. Again, it’s a blastocyst. It doesn’t mean that because it’s a day six embryo, we need to prepare the uterine lining for an extra day. You would transfer it just as you would a day five embryo.

That’s where we have to balance things. Even a euploid, grade AA embryo won’t implant 100% of the time. That’s what the evidence shows us.

So there’s always a possibility that even when everything is tightly measured and seems fine, we could still end up with a negative result. That’s not always a reason to do further studies or modify the whole treatment protocol.

That’s a conversation to have with your doctor regarding the hours of progesterone exposure. And also, whether there’s any reason to go into a more in-depth analysis. If this is the first embryo transfer, it may not be a reason for further testing, but it’s something to discuss with your care provider. It should definitely always be individualised.

When we use Ovitrelle, especially in the context of a modified natural cycle, there are two reasons why we would choose to use it. The first reason is that the growing follicle we’re following needs to ovulate so that it starts producing progesterone. That’s why we use Ovitrelle — to induce ovulation and support the body’s own progesterone production.

Now, that’s not the only reason to use Ovitrelle. Some clinicians might also decide to use Ovitrelle three days after the embryo transfer. This has two purposes: to boost the amount of progesterone you’re producing, and because the embryo naturally produces hCG. It’s a way to trigger the lining to be more receptive to that embryo.

So, to answer your question: Ovitrelle is used to induce ovulation so that the follicle starts producing progesterone, which is necessary for endometrial activation. From your question, it’s not fully clear whether Ovitrelle was used only before transfer or also after, but both uses are valid and serve different functions depending on the protocol.

Sometimes, and this can be very frustrating, there are things that we might miss on a standard ultrasound. The reason for that is the lining is not static. Our ability to see inside the lining sometimes depends on the point in your cycle.

If we suspect that something might be going on, or if there have been a few negative results, it’s a good idea to do a hysteroscopy. There might be something we’re missing on the 2D scan.

I understand that by “3D hysteroscopy,” you mean a 3D ultrasound scan, or possibly comparing it to a regular hysteroscopy. A 3D scan is a non-invasive way to get more information than a 2D scan. This is especially useful if we suspect issues with the shape of the cavity — for example, a T-shaped uterus or an anatomical malformation. In those cases, a 3D scan is a great way to assess the cavity without using a hysteroscopy.

However, for anything more subtle, it’s very hard to replace a hysteroscopy. With a hysteroscopy, you get a firsthand view of the endometrial cavity. That makes a big difference.

Asherman syndrome has to be treated surgically through a hysteroscopy. It doesn’t necessarily have to be a surgical hysteroscopy in the sense that it doesn’t have to be under anaesthesia, but that’s going to depend on the amount of scar tissue. It’ll be super individualized depending on what’s going on internally. So speak to your gynaecologist and see what they say.

Yes. In those cases, the set limit of 2.5 is going to be very similar. But there are other things we’re going to look at. It’s not just the TSH. It’s TSH, T3, T4, and the thyroid antibodies. We kind of have to group them together and then decide what we need to treat and what we don’t need to treat.

Your TSH can be under 2.5 — but if you’ve got TPO or TG antibodies going on in the background, that can still impact the odds of success.

Not that common. Recurrent implantation failure itself is not that common. There was a recent study that looked at doing five embryo transfers. I can’t remember right now if there were 5 euploid or 5 blastocysts, but they found that 96% or 99% of patients achieved pregnancy after 5 transfers. The paper cited something like “recurrent implantation failure mirage” or “statistical anomalies.”

One of the most important factors is the embryo’s genetic content, so with euploid embryos, that makes this situation even less common. It’s not that it can’t happen. When someone is living it, it doesn’t matter what the numbers say — it’s their lived experience, and it’s very difficult going through unsuccessful euploid transfers.