Endometrial Preparation for Implantation After IVF Embryo Transfer

Endometrial preparation or priming plays a main role in IVF treatments, especially with donor eggs or in Frozen Embryo Transfers (FETs) where donated or own embryos are used. This step involves the administration of hormonal medications to favor embryo implantation. In other words, to increase the chances of getting pregnant.

The protocol followed to prepare the endometrial lining (endometrium) is based on the use of progesterone and estrogen. Depending on the medication type, it can be administered via oral, transdermal, or vaginal route.

The different sections of this article have been assembled into the following table of contents.

Why is endometrial preparation so important?

The endometrial or uterine lining, i.e. the endometrium, is the inner layer of the womb (uterus). In short, it is responsible for embryo implantation, which is the beginning of a new pregnancy. The uterine lining is a vascularized layer, given that it requires a considerable amount of blood to circulate to the womb during pregnancy.

In natural pregnancies, endometrial thickness changes throughout the menstrual cycle. It has two growth phases in accordance with their function:

Proliferative phase

From the beginning of the cycle until day 14, when ovulation occurs. Due to the secretion of estrogen, it increases its thickness, with two layers clearly differentiated (an inner one and another more superficial). The endometrium can measure up to 10 mm at this stage.

Secretory or luteal phase

This second phase begins on day 15 of the cycle until the end, and is dependent on progesterone. Due to the effect of progesterone, the number and size of endometrial glands increase. These glands synthesize a substance that makes implantation easier, in case there was an embryo ready to do it.

If no embryo attaches to the endometrium, it sheds and is expelled in the form of menstrual flow, which means that a new cycle begins.

These phases are perfectly regulated, and implantation can take place in a particular time interval of the cycle. This time interval of endometrial receptivity is known as implantation window. In general, it occurs between days 19 and 21.

Phases of endometrial growth

The fact that endometrial receptivity is such a short phase of the cycle makes it a fundamental step in IVF cycles, and forces the embryo transfer to be scheduled beforehand, on the day when the endometrial lining is prepared for embryo implantation.

What does endometrial preparation involve?

In IVF cycles, the goal is to simulate what would happen if pregnancy occurred naturally, but optimizing it to its maximum in order to boost the chances of pregnancy. To this end, patients take a series of medications, generally progesterone pessaries.

This is a key step in all fertility treatment cycles. However, based on the treatment chosen, the type of medication administered may differ:

• Intrauterine insemination and IVF with fresh eggs: progesterone is administered only during the second phase of the cycle, after egg retrieval or insemination.
• Egg donation, cycles with frozen eggs/embryos, and reciprocal IVF: endometrial priming is key to success in all these three treatments. Estrogens are administered in the first days of the menstrual cycle, and progesterone on the day of fertilization or the equivalent day in case of FET.

In case the recipient has the ovarian function, oral contraceptives, or GnRH analogs (for example, Decapeptyl) may be used to stop the function of endogenous hormones in order for it not to be involved in the cycle. In some cases, a natural cycle may be enough, that is, without artificial preparation, just with the hormones produced naturally.

Medications for endometrial preparation

As one shall see, there exists a wide range of protocols. The administration times vary on a case-by-case basis as well, as your OB/GYN will adjust the duration of each treatment option, and the medication used to each patient.

Endometrial growth is monitored via an ultrasound scan. Thanks to this, the specialist can see when the endometrial lining is in an optimal state to receive the embryos after the ET. Progesterone administration, however, must be continued until day 12-20 of pregnancy approximately.

How's the ideal endometrium for pregnancy?

As we have just seen, the endometrium plays a major role when it comes to succeeding after undergoing a fertility treatment cycle. Simply put, both embryo quality and endometrial thickness are key factors.

A number of studies on the ideal endometrial thickness have been conducted to date. In general, 7-10 mm are considered good for embryo implantation. Conversely, an endometrial thickness below 6 mm indicates a bad prognosis and is associated with implantation failure.

The pattern observed in ultrasounds is examined as well. Only in those cases where a triple line pattern is visible, we can consider there is a good chance of achieving pregnancy.

Ideal endometrial thickness to get pregnant

In any case, a triple line endometrium that is 8 mm thick does not translate into embryo implantation by default. Also, in some cases of patients with a uterine lining of 6 mm, implantation may occur. In short, each case should be examined individually.

Other factors influencing embryo implantation

Aside from thickness and appearance, there are other factors that determine embryo implantation. For instance, the following:

Embryo quality

High quality embryos are more likely to attach to the endometrium. Learn more: Embryo Quality and Grading.

Endometrial receptivity

Endometrial receptivity is not present every day during the cycle, but just during the implantation window. In some cases, this time frame may occur earlier or later than expected, or not fit into the findings from the ultrasound scan. If so, the transfer would be scheduled incorrectly, thereby causing the pregnancy success rates to drop substantially.

Embryo-endometrial synchrony

In addition to the factors listed above, fluid communication between the endometrium and the embryo is essential. Moreover, there must be synchronized, which means that the endometrial development and endometrial receptivity days occur at the same time.

For example, let's imagine we have a blastocyst embryo (day 5-6 of development) of optimal quality that is put into a uterus but the endometrium is not receptive. Implantation would be highly unlikely.

Factors determining embryo implantation

In conclusion, as we shall see, thickness and appearance are factors to consider when it comes to predicting the success rates of any particular fertility treatment. However, in spite of this, predicting whether implantation will occur or not is not easy, as a number of factors are involved. For this reason, the best practice is to individualize each case, basing the protocol to follow on the characteristics of each patient.

Ask the experts

The medications used to improve endometrial thickness in patients undergoing fertility treatment vary on a case-by-case basis.

According to Dr. Miguel Dolz Arroyo, in general, there are various options, but actually, the best of all would be not stimulating the patient at all:

A natural cycle is the most effective of all options. Thus, whenever a natural cycle can be used, the prognosis will be optimal.

Dr. Miguel Dolz Arroyo, gynecologist

Dr. Miguel Dolz states that there exist various strategies to improve endometrial thickness in patients whose receptivity is insufficient. For example, in certain IVF patients, a long protocol with GnRH agonists usually improves endometrial receptivity. One should note that 1-1.5 ml can make a difference.

FAQs from users

How long will I needle during the endometrial preparation?

As Dr. Marina González tells us,

During endometrial preparation, it is not really necessary to administer any medication subcutaneously. We can carry out the preparation in different ways: in a natural cycle, modified natural cycle, or substituted cycle.

Read more

What happens if I miss a day of endometrial priming medication?

Preparation of the endometrium is essential prior to embryo transfer. Generally, the endometrium is prepared by different hormonal drugs. Their purpose is to create an optimal environment in the endometrium for the embryo to implant and grow.

If you forget to take any of the drugs, it is essential to inform your doctor as soon as possible.
Read more

Is it necessary to prepare the endometrium for AI?

In artificial insemination cycles it is not usually necessary to prepare the endometrium separately since, thanks to the secretion of estrogens by the ovaries, they will act on the endometrium causing its gradual growth.

In a small group of patients, it may happen that this synchronous endometrial development does not occur and that, when performing routine ultrasound controls during the cycle, we find that the endometrium is not growing as it should. These patients may benefit from low doses of estrogens during the end of ovarian stimulation to externally support endometrial growth.

In most instances 2 to 4 mg of oral or vaginal estrogens are sufficient to achieve adequate thickness. Also, all patients will use progesterone after insemination to promote implantation.
Read more

Natural vs. stimulated cycle, which is better during the IVF endometrial preparation phase?

During a frozen embryo thaw cycle, natural or medicated endometrial development results in equivalent pregnancy success rates per embryo transfer. Natural cycle does not involve medication so it is less expensive but the day of embryo transfer cannot be scheduled as in a medicated.

What are normal estrogen and progesterone levels before transfer?

Dr. Héctor Izquierdo, gynecologist at IVF-Spain tells us in this video the adequate levels of estrogen and progesterone to carry out an embryo transfer. As the doctor tells us:

We don't have the case for an adequate level of estrogen to carry out the transfer or there are no studies described that tell us that a level must be reached. The important thing is that the endometrial line, the part of the uterus where the embryo is going to be implanted, is adequate, greater than 8 mm. In the case of progesterone, there is clinical data that shows us that a progesterone greater than 10 ng/dL helps the pregnancy to be effective.

What are the symptoms caused by endometrial preparation treatments?

In some cases, the medications used for preparing the endometrium can cause some side effects, mild in most cases. The most common ones are:

• Bloating
• Fatigue
• Increased vaginal discharge

Is endometrial preparation possible with the use of oral pills only?

Yes. Contrary to the medications used for ovarian stimulation, endometrial preparation protocols are possible with just medications taken orally.

In the case of estrogens, they can be administered orally or via transdermal patches.

As for progesterone, it can be administered orally or with vaginal pessaries. Since the side effects of oral pills are more common, the second option is preferable.

However, in those cases where the patient's ovaries work but oral contraceptives are not used, GnRH analogues may be necessary, which are administered intravenously (injections) to stop the endogenous hormonal activity.

What hormone is responsible for preparing the endometrium during the proliferative phase? When is it administered?

The hormones that promote endometrial growth during the first phase of the cycle (proliferative) are estrogens. They are administered in most of the treatments that involve an embryo transfer in an additional cycle, aside from the ovarian stimulation one. In short, estrogen is administered in the following cases:

• IVF-ICSI treatments with donor eggs, with both fresh and frozen eggs/embryos
• Frozen embryo transfers (using embryos that were frozen in previous cycles)
• Embryo donation

Recommended readings

As we have just read, endometrial preparation is key for embryo implantation. To learn more about this process, we recommend that you have a look at this post: What Is Embryo Implantation?

In order to increase the chances of embryo implantation, aside from proper preparation of the endometrium, scheduling the embryo transfer for just the right day is essential, too. Learn more: IVF Embryo Transfer Procedure – Definition, Process & Tips.

References