Optimizing luteal support in frozen embryo transfer cycles


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Volume 109, Issue 2, Pages 242–243


Thomas L. Toth, M.D., Denis A. Vaughan, M.D.


Reflections on "Vitrified blastocyst transfer cycles using only vaginal progesterone replacement with Endometrin have inferior ongoing pregnancy rates: results from the planned interim analysis of a three-armed randomized non-inferiority trial" by Devine et al.

Read the full text here.

Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. 


Go to the profile of Ivan Valencia
almost 4 years ago

Hello.  Not new data. Here is a little example presented at ESHRE 2017 from IVI.group.  https://www.researchgate.net/publication/320505317_Low_serum_progesterone_on_the_day_of_embryo_transfer_is_associated_with_a_diminished_ongoing_pregnancy_rate_in_oocyte_donation_cycles_after_artificial_endometrial_preparation_a_prospective_study

Vaginal route is a good way to deliver drugs but we should not assume and take for granted that it is a perfect and efficient one in every woman.

Not all vaginas are equal..

Best regard from Quito, Ecuador.

Go to the profile of Micah J Hill
almost 4 years ago


I would say this is new data.  There is a great lack of adequately powered RCT data on this topic and observational cohorts, such as you cite,  cannot definitively answer this question.   Im very impressed by this study design and look forward to the final RCT results when all 3 arms are unblinded.

Go to the profile of Kevin S. Richter
almost 4 years ago

We thank Drs. Toth and Vaughan for their thoughtful and constructive commentary on our manuscript in this issue of Fertility and Sterility (1).  We conducted a randomized prospective trial to compare live birth rates among routes of progesterone replacement for vitrified-warmed blastocyst transfer cycles.  We reported the results of our planned interim analysis, due to the somewhat surprising finding of significantly poorer ongoing pregnancy rates among subjects receiving Endometrin vaginal progesterone only versus subjects who received intramuscular (IM) progesterone in oil (either alone or in combination with Endometrin).  The question of the ideal progesterone replacement protocol in programmed endometrial preparation cycles has taken on increasing clinical significance as the number of frozen embryo transfers has continued to rise.

Toth and Vaughan caution against generalization of the finding of inferior ongoing pregnancy rates associated with Endometrin 200 mg twice daily to other vaginal progesterone regimens for progesterone replacement.  It certainly remains possible that other formulations of vaginal progesterone and/or altered dosing regimens are as effective as IM progesterone, and this possibility is acknowledged and discussed extensively in our manuscript.  However, in the absence of evidence from well designed and adequately powered studies comparing other vaginal progesterone regimens to IM progesterone, and in the face of such a large (approximately one-third lower) and statistically significant decrease in ongoing pregnancy, we think it prudent to consider other formulations of vaginal progesterone likely to be similarly disadvantaged.  Therefore, we recommend IM progesterone replacement for vitrified-warmed blastocyst transfer, unless compelling evidence of the non-inferiority of a particular vaginal progesterone regimen becomes available.

We wholeheartedly agree that, ideally, randomized prospective studies would be performed to evaluate other formulations, dosages, frequencies, and durations of vaginal progesterone against IM progesterone replacement.  However, such studies typically take years to complete and cost millions of dollars.  Unfortunately, the investment required may be prohibitive of definitively clarifying more than a minority of the potentially clinically significant variables involved.

Like Toth and Vaughan, we look forward to the live birth analysis.  Subject enrollment in the two remaining treatment arms has now been completed per our original sample size objectives, with the last delivery expected in March of 2018.  We will then be able to report on the more definitive and important live birth outcome that was set as primary in our original study design.  Along with live birth, we will analyze serum progesterone concentration data, which we collected approximately two weeks after embryo transfer.  We are in agreement with Drs. Toth and Vaughan that these data have potential to further our understanding of the poorer ongoing pregnancy rate observed in the Endometrin only arm.

Finally, we await with great anticipation the live birth comparison between subjects receiving twice daily Endometrin plus IM progesterone once every three days versus those receiving daily IM progesterone.  We very much hope that the former regimen proves non-inferior, providing our patients an option that diminishes the discomfort of daily IM injections along with the confidence that we are not compromising treatment outcomes.

  1.  Devine K, Richter KS, Widra EA, McKeeby JL. Vitrified blastocyst transfer cycles using only vaginal progesterone replacement with Endometrin have inferior ongoing pregnancy rates: results from the planned interim analysis of a three-armed randomized non-inferiority trial. Fertil Steril. 2018

Kevin S. Richter, Ph.D., Kate Devine, M.D., Eric A. Widra, M.D., Jeffrey L. McKeeby, M.D.

Shady Grove Fertility, Rockville, Maryland