Article Title: A flexible protocol for artificial preparation of the endometrium without prior gonadotropin-releasing hormone agonist suppression in women with functioning ovaries undergoing frozen-thawed embryo transfer cycles.

Authors and Affiliations: Alex Simon, Arye Hurwitz, Murshid Pharhat, Ariel Revel, Bat-Sheva Zentner, and Neri Laufer; Department of Obstetrics and Gynecology, Hassadah University Hospital, Mount Scopus (Jerusalem, Israel).

Journal: Fertility and Sterility, Volume 71, Number 4, pp. 609-613.

Summarized by Christine M. Schroeder, Ph.D.

Advances in IVF technology and success rates have lead to increasing numbers of patients who have surplus embryos after a fresh IVF cycle. Most commonly, these embryos are cryopreserved for future use.

Patients who undergo transfer of frozen embryos are confronted by several protocol options. Regularly ovulating patients may choose to simply undergo spontaneous ovulation and then have the embryos transferred during the appropriate post-ovulatory time period. Patients with irregular cycles or anovulation, however, must often rely on a medicated frozen embryo transfer (FET) cycle. In these cases, several options are available, including the use Clomid or injectibles to bring about ovulation in the patients, after which appropriately-timed embryo transfer takes place. Like spontaneous unmedicated cycles, however, this protocol can be somewhat unpredictable and patients may have to skip cycles because the timing of ovulation was not as expected.

In an attempt to increase the predictability of FET cycles, many programs have experimented with using a GnRH agonist (e.g., Lupron) in their protocol, as patients using a GnRH agonist are far less likely to experience a spontaneous LH surge. Because of its increased predictability, medicated protocols using GnRH have increased in popularity. The cost and additional effort required by adding a GnRH agonist, as well as several studies questioning its necessity, however, have raise the question of whether it is possible to increase the predictability of a medicated FET cycle without using a GnRH agonist. The purpose of the current study was to investigate one such protocol.

Participants in the study were 140 patients undergoing a total of 185 FET cycles. The mean age of the patients was 30 years. Sixty-six percent of the patients were spontaneously ovulatory, but all had functioning ovaries that were capable of responding to stimulation. Embryos had been frozen between 42 and 72 hours after retrieval in the fresh IVF cycle, and ranged in size from two to eight cells.

All patients underwent a similar protocol:

• Two milligrams of oral estrogen, three times per day, beginning on cycle day one and continuing for between 12 and 20 days (average=15 days).
• The addition of oral micronized progesterone and vaginal progesterone when the endometrial thickness was eight mm or greater.
• Transfer of embryos 48 to 72 hours after onset of progesterone supplementation.
• Cancellation of the cycle if: (1) the endometrium failed to reach eight mm after 20 days of estrogen, (2) if serum progesterone was six nmol/L or greater on the seventh day of estrogen, or (3) if serum progesterone was six nmol/L or greater on the day that progesterone supplementation was to have begun.

Participants transferred an average of three embryos. Of the 185 cycles reviewed, eight were canceled – two because of premature elevation of progesterone levels and six because of inadequate endometrial thicknesses.

Analysis of the cycle results showed:

• A pregnancy rate of 21.7 percent
• A multiple (twins and triplets) pregnancy rate of 21 percent
• An ongoing (second trimester) pregnancy rate of 17.7 percent
• A per-embryo implantation rate of nine percent.

Based on these results, the authors concluded that, among patients with functioning ovaries, an FET protocol that does not use a GnRH agonist may be appropriate and effective.