By Rebeca Reus BSc, MSc (embryologist), Mark P. Trolice MD, FACOG, FACS, FACE (reproductive endocrinologist) and Miguel Dolz Arroyo MD, PhD (gynecologist).
Last Update: 10/11/2018

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.

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 layers, given that it requires a considerable amount of blood to circulate to the womb during pregnancy.

In natural pregnancies, endometrial thickness varies 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.

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 vary:

  • 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 in the day of fertilization or the equivalent day in case of FET.

In case the recipient has ovarian function, oral contraceptives or GnRH analogues (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.

As one shall see, there exist 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 ultrasound scan. Thanks to this, the specialist can see when the endometrial lining is in optimal state to receive the embryos after the ET. Progesterone administration, however, must be continued until day 12-20 of pregnancy approximately.

IVF with donor eggs is probably the most confusing of all fertility treatments, and oftentimes, a misleading one. Transparency is one of our strict selection criteria when it comes to recommending fertility clinics to our readers. You can use "The Calculator" to filter clinics based on our selection criteria and get an individual report based on your preferences with answers to your queries and most importantly, to prevent potential frauds.

Last but not least, the report will inform you about promotions and special prices from the fertility clinics selected, if any.

Medications used

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

According to Dr. Miguel Dolz Arroyo, in general there exist 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 the optimal.

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.

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.

In any case, an 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 a synchrony between them, which means that the endometrial development and endometrial receptivity days occur at the same time.

For example, 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.

In conclusion, as we shall see, thickness and appearance are factors to consider when it comes to predicting the success rates of a 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.

FAQs from users

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

By Mark P. Trolice MD, FACOG, FACS, FACE (reproductive endocrinologist).

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 the symptoms caused by endometrial preparation treatments?

By Rebeca Reus BSc, MSc (embryologist).

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?

By Rebeca Reus BSc, MSc (embryologist).

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?

By Rebeca Reus BSc, MSc (embryologist).

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

Suggested for you

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 a 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.

Sharing is caring

Our editors have made great efforts to create this content for you. By sharing this post, you are helping us to keep ourselves motivated to work even harder.

Follow us on social media

Find the latest news on assisted reproduction in our channels.

References

Bourgain C, Devroey P. The endometrium in stimulated cycles for IVF. Hum Reprod Update 2003;9:515 – 522.

Glujovsky D, Pesce R, Fiszbajn, G, Sueldo C, Hart RJ, Ciapponi A. Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes. Cochrane Gynaecology and Fertility Group 2010.

Groenewoud ER, Cantineau AE, Kollen BJ, Macklon NS, Cohlen BJ. What is the optimal means of preparing the endometrium in frozen-thawed embryo transfer cycles? A systematic review and meta-analysis. Hum Reprod Update 2013;19:458–70.

Paulson RJ, Sauer MV, Lobo RA. Embryo implantation after human in vitro fertilization: importance of endometrial receptivity. Fertil Steril 1990;53:870–4.

Psychoyos A. Uterine receptivity for nidation. Ann N Y Acad Sci 1986; 476:36– 42.

Robert F, Casper MD, Elena H, Yanushpolsky MD. Optimal endometrial preparation for frozen embryo transfer cycles: window of implantation and progesterone support. Fertil Steril 2016;105:867–72.

Simon C, Domínguez F, Valbuena D, Pellicer A. The role of estrogen in uterine receptivity and blastocyst implantation. Trends Endocrinol Metab 2003;14:197 – 199.

Read more

Authors and contributors

 Rebeca Reus
BSc, MSc
Embryologist
Degree in Human Biology (Biochemistry) from the Pompeu Fabra University (UPF). Official Master's Degree in Clinical Analysis Laboratory from the UPF and Master’s Degree about the Theoretical Basis and Laboratory Procedures in Assisted Reproduction from the University of Valencia (UV). More information
 Mark P. Trolice
MD, FACOG, FACS, FACE
Reproductive Endocrinologist
Mark P. Trolice is the Director of Fertility CARE – The IVF Center and Clinical Associate Professor in the Department of Obstetrics & Gynecology (OB/GYN) at the University of Central Florida College of Medicine. He is Board-certified in REI and OB/GYN, and maintains annual recertification. His colleagues select him as Top Doctor in America® annually, one among the top 5% of doctors in the U.S. More information
License: ME 78893
 Miguel Dolz Arroyo
MD, PhD
Gynecologist
Bachelor's Degree in Medicine and Surgery from the Medicine Faculty of the University of Valencia (UV) and Doctor in Medicine, finished in 1988 and 1995, respectively. Physician specialized in Obstetrics & Gynecology. Expert in Reproductive Medicine, with more than 20 years' experience in the field. He is the Medical Director and founder of FIV Valencia. More information
License: 464614458

One comment

    1. Chandrasekhar

      This is not a comment but a question, any expert could answer. We couple are waiting for FET preparing endometrium, past 4 months. Nothing is working, with Progynova Max, my endometrium is 6 mm and with a low dose of hMG it reached 7.5 mm, but developed a cyst of 26 mm, not ruptured with Ovitrelle even after 48 hours. Moreover, by 12th day endometrium is going into secretory phase losing its triple line. My wife’s age is 42 years.