Premature progesterone and freeze all cycles: do we really need randomized controlled trials?
Micah J. Hill, D.O., Mae Wu Healy, D.O.
Over the past 6 years, evidence has increased that premature progesterone elevation decreases live birth in IVF cycles. The putative mechanism is advancing the endometrium, leading to endometrial-embryo asynchrony. This is supported by evidence suggesting that the premature progesterone elevation affects the endometrium at several detectable levels: gene expression, siRNA, implantation markers, histologic features, and ultrasonographic characteristics (1). This negative effect is summarized in a meta-analysis of observational data including over 60,000 IVF cycles and should be considered incontrovertible (2). It has further been observed that this negative effect does not occur in oocyte donor-recipient cycles, suggesting that removing the endometrium from the negative hormonal milieu resolves the problem of premature progesterone elevation. This is further supported by data showing no association of premature progesterone elevation with oocyte or embryo quality. This leads to the logical postulation that freezing all embryos and performing a subsequent frozen embryo transfer (FET) cycle is the appropriate management of premature progesterone elevation. We have published observational data supporting this hypothesis, clearly showing a negative effect of premature progesterone elevation in fresh but not subsequent frozen cycles (3). However, only one small randomized controlled trial (RCT) has examined this hypothesis and it was underpowered to detect a difference between fresh and frozen transfer strategies (4). A study powered to detect a difference in live birth of 50% in FET cycles versus 25% fresh cycles in patients with premature progesterone elevation would only require 110 subjects to be randomized. The question is do we really need a large RCT to explore this hypothesis?
The principle of equipoise states that clinical trials should only be undertaken if there is reasonable uncertainty that the intervention may be of benefit. In the context of this debate, there is strong evidence that premature progesterone elevation negatively impacts fresh IVF cycles. There is strong evidence that this effect does not carry over into subsequent FET cycles. The combined evidence and biologic plausibility suggest with great likelihood that the negative effect of premature progesterone elevation can be ameliorated by freezing embryos and subsequent FET. So do we need a RCT to demonstrate this before we implement that strategy into our practices? Is it ethical based on the principal of equipoise to even perform such an RCT? Our group has published several studies investigating the effect of premature progesterone elevation, so such a RCT was the logical next step for us. However, we recently decided that it would be unethical to conduct an RCT to investigate fresh versus frozen transfer in the presence of premature progesterone elevation. The evidence against fresh embryo transfer in these patients is overwhelming and there was great certainty that half of the subjects would be exposed to unnecessary harm.
We know prematurely elevated progesterone is bad in fresh cycles. We know this effect does not carry over to frozen cycles. Do we need an RCT to tell us that a freeze all strategy is the best way to manage cycles with premature progesterone elevation? I believe the answer is no. As recently stated by Braakhekke et al. in their review of equipoise applied to reproductive medicine “If it is evident that a treatment ‘works’ based on insight into the underlying pathophysiologic processes and a few clinical observations, it is unnecessary and even unethical to perform an RCT” (5).
- Labarta E, Martinex-Conejero JA, Alama P, Horcajadas JA, Pellicer A, Simon C, Bosch E. Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod 2011;26:1813-25
- Venetis CA, Kolibianakis EM, Bosdou JK, Tartlatizis BC. Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60,000 cycles.
- Healy MW, Patounakis G, Connell MT, Devine K, DeCherney AH, Levy MJ, Hill MJ. Does a frozen embryo transfer ameliorate the effect of elevated progesterone seen in fresh transfer cycles? Fertil Steril 2016;105:93-9.
- Yang S, Pang T, Li R, Yang R, Zhen X, Chen X,, et al. The individualized choice of embryo transfer timing for patients with elevated serum progesterone level on te HCG day in IVF/ICSI cycles: a prospective randomized clinical study. Gynecol Endocrinol 2015;31:355-8.
- Braakhekke M, Mol F, Mastenbroek S, Mol BW, van der Veen F. Equipoise and the RCT. Hum Reprod in press