Progesterone - Preparing the Uterus for an Embryo

by Samantha Wake

Introduction

Inadequate uterine receptivity is responsible for many implantation failures in IVF. In light of this, KARMA IVF has updated the protocol for preparing the uterus for an embryo transfer. Consequently, you may notice some changes to the way medication is administered and you may find you are coming in for additional ultrasound appointments/bloodwork prior to having an embryo transfer; we want you to understand the rationale for this!

Background

At KARMA we predominantly use a ‘Freeze All’ protocol for IVF cycles. This refers to freezing any embryos that have developed into a blastocyst, provided they are of adequate quality, and transferring them at a later date. The main reason for this is that prior to an egg retrieval, the ovaries have been stimulated in order to increase the number of eggs retrieved. The uterine environment may be negatively affected by this and it may hinder the chances of an embryo implanting. It is also dangerous to proceed with a ‘fresh’ transfer when a patient is at risk of ovarian hyperstimulation syndrome (OHSS).

Fresh vs. frozen embryo transfers

We can determine if someone is at risk of OHSS by monitoring their estrogen level; if the estrogen level is high on the day of the hCG trigger (2 days prior to the retrieval), a fresh transfer will not be considered. However, for patients with low levels of estrogen and progesterone, we can consider doing a fresh transfer.

If you are one of these patients, you will be directed to start taking Crinone 2 times a day vaginally, from the day of the retrieval up to the tentatively scheduled fresh transfer date (Day 5) and thereafter. Estrace is not given during a fresh cycle as estrogen is naturally high following a retrieval. You will return to the clinic 4 days after your retrieval for an ultrasound and bloodwork before the final decision to proceed with a fresh transfer is made by the Doctor. If the ultrasound and bloodwork indicate the uterus is not in the best condition to receive an embryo (more on this later!), the cycle will be converted to a “Freeze All’ and the embryo(s) will be stored for future use.

How is the uterus prepared for a frozen embryo transfer (FET)?

It is common practice to prepare the uterine lining in a medicated FET cycle. Estrogen (in the form of estrace) and progesterone (in the form of Crinone and progesterone in oil (PIO)) are administered concurrently to mimic the hormonal conditions that would occur naturally in a cycle. 

Estrace is to be taken 3 times a day orally and 2 times a day vaginally starting on Day 1 of your cycle (first day of full menstrual bleed) until your ultrasound lining check appointment (Day 10-14). At this initial lining check, the sonographer will measure the thickness of your uterine lining. If it is less than 0.7cm, you will continue taking Estrace for a few more days and then repeat the ultrasound. 

Once the nurse confirms the lining has reached a thickness of 0.7cm, you will start taking Crinone 2 times a day vaginally and have your first injection of PIO administered intra-muscularly by the nurse. You will also continue taking estrace. The PIO is administered every other day until the transfer date and once more 9 days later.

You will be asked to come in for another lining check the day before the transfer as a precaution. Following the embryo transfer, you will continue taking Estrace and Crinone for the next 2 weeks until your pregnancy test. It is at the discretion of the medical team whether any more PIO injections are needed following a positive bHCG result.

Why might my transfer be cancelled?

There are many important checks that take place the day before your scheduled fresh or frozen embryo transfer to determine whether the uterine environment is in an optimal state. For example, a uterine lining measuring less than 0.7cm is sub-optimal and will require a repeat lining check the following morning. If it is still not thick enough, the transfer may be cancelled. We use 0.7cm as a cut-off point as we know linings thinner than this are associated with lower pregnancy rates.

The sonographer will be monitoring the uterine muscle contractions during your ultrasound. If there are 3 contractions per minute or more, you will be asked to come in the following morning for a re-check. If the contraction count is still 3/min or higher, the transfer may be cancelled as it indicates high muscular contractile activity of the uterus. This is known to negatively influence implantation and may cause expulsion of the embryo from the uterus.

Your blood will also be drawn on this day to assess your progesterone level. If the progesterone level is above 35ng/mL, the transfer may be cancelled. If your level is below 10ng/mL, your transfer may be pushed back 1 more day to allow for more absorption of progesterone. If it remains too low, the transfer may be cancelled.  We closely monitor your progesterone level because it plays an important role in embryo implantation and maintenance of a pregnancy.

Can ERA improve my chances of a successful FET?

The purpose of ERA (endometrial receptivity assay) is to undergo a mock FET cycle whereby the uterus is prepared with medication in the same way as a FET cycle except, instead of undergoing a transfer on the specified date, a biopsy is taken of the endometrial cells.

These cells are sent off to a genetics lab for analysis to determine on which day the endometrium is most receptive. Patients’ results can range from P+4 to P+7; this denotes how many days of progesterone is needed prior to the embryo transfer date to ensure it takes place during the ‘window of implantation’. Ultimately, this will increase the likelihood of an embryo attaching to the endometrium.

Igenomix™ (the company that analyses the ERA samples) reports that in patients who previously had a regular FET on a non-receptive day and later had an FET on a receptive day (determined by ERA), their pregnancy rate increased from 19.4% to 60%. It is your choice whether you wish to first proceed with this ERA testing cycle before an FET cycle.

Conclusion

Although we are conscious that these extra appointments and injections are time-consuming and make it less convenient for our patients, we are acting based on current recommendations from leading reproductive research with the aim of improving ongoing pregnancy rates across the clinic. If you have any questions about the new protocol or assessments, please ask the nursing staff.