Defining thresholds for abnormal premature progesterone levels during ovarian stimulation for assisted reproduction technologies
Thresholds for progesterone can be demonstrated as low as 0.4 ng/mL but result in large numbers needed to treat. Cost-effectiveness and clinically relevant thresholds cluster between 1.5 and 2.0 ng/mL.
Volume 110, Issue 4, Pages 671–679.e2
Authors:
Micah J. Hill, D.O., Mae Wu Healy, D.O., Kevin S. Richter, Ph.D., Toral Parikh, M.D., Kate Devine, M.D., Alan H. DeCherney, M.D., Michael Levy, M.D., Eric Widra, M.D., George Patounakis, M.D., Ph.D.
Abstract:
Objective
To evaluate methodologies to establish abnormal progesterone (P) levels on the day of trigger for recommending freeze only cycles.
Design
Threshold analysis and cost analysis.
Setting
Private ART practice.
Patient(s)
Fresh autologous ART.
Interventions(s)
None.
Main Outcome Measure(s)
Live birth.
Result(s)
Fourteen established statistical methodologies for generating clinical thresholds were evaluated. These methods were applied to 7,608 fresh ART transfer cycles to generate various P thresholds which ranged widely from 0.4 to 3.0 ng/mL. Lower thresholds ranged from 0.4 to 1 ng/mL and classified the majority of cycles as abnormal as well as required very large number needed to treat (NNT) to increase one live birth. Frozen embryo transfer was cost-effective when P was ≥1.5 ng/mL, with 12% of the population having an abnormal test result and an NNT of 13. Statistical and cost-effective thresholds clustered between 1.5 and 2.0 ng/mL.
Conclusion(s)
Statistically significant thresholds for P were demonstrated as low as 0.4 ng/mL but resulted in a very large NNT to increase one live birth. A clinical benefit to a freeze-only approach was demonstrated above P thresholds ranging from 1.5 to 2.0 ng/dL. At these thresholds, elevated P has a demonstrable and clinically significant negative effect and captures a smaller percentage of the patient population at higher risk for fresh transfer failure, thus making freeze-only a cost-effective option.
Comments
One of the most common questions reviewers and readers ask us is "at what P threshold do you recommend a freeze only cycle?". This turned out to be a more complex question than can be answered without a dedicated study. In this paper, we address this specific question and offer a range of data that we hope provides the clinician and the patient with information to make an informed and individualized decision. We welcome any questions and critiques from the readers of F&S.
Dear Micah
Do not you think that after ovarian stimulation putting a relatively "out of phase" endometrium (2 to 3 days in advance), there is reason to wonder about the value of progesterone before HcG?
We have treated this subject with Pr Frydman and R.Fanchin more than 10 years ago. We had the same conclusions as you, but the recent notions acquired in terms of endometrial transformation in the course of an ovarian stimulation make us think, at the time of "Freeze All" , that the problem is other than the progesterone level.
Best regards
Thank you for the comment Andre! As you point out, your group and others have been looking at this question for over 10 years and the preponderance of data now clearly points to a negative effect of elevated P on the day of hCG. I agree that if a program is a "freeze all" program, then there is little utility in regularly measuring progesterone levels. I don't believe the current evidence suggests that elevated P levels effect oocyte quality. We have demonstrated this be showing that FET cycles are not effected by the P level in the initial fresh cycles, donor oocyte cycles are also not effected, and the paper currently in F&S that shows that donors on progestins do not have their oocytes negatively affected.
Thank you Micah for your prompt answer
I do not think that high progesterone level may affect the oocyte quality. I was only referring to the immuno-inflammatory state of a stimulated endometrium.
Congratulations for your paper
Warmest regards