Progesterone Elevation and Preventive Strategies to Avoid Implantation Failure

Despite the wide utilization of gonadotropin-releasing hormone analogs, progesterone elevation (P4E) in the late follicular phase occurs in 5 to 30% of all ovarian stimulation (OS) cycles. Although the detrimental effect of P4E on pregnancy rates in fresh in vitro fertilization cycles is valid in all subsets of cases, higher levels of P4 and a longer duration of P4E may be needed in patients with a hyper-ovarian response in order for a negative impact on pregnancy rates to occur. Available preclinical and clinical data suggest that aggressive OS with high doses of follicle-stimulating hormone might increase 3β-hydroxy steroid dehydrogenase and 17β-hydroxy steroid dehydrogenase enzyme activity in human granulosa cells, which leads to high P4 production and hence a higher amount of leakage to the systemic circulation due to a lack of 17α-hydroxylase enzyme expression in human species. High P4 concentrations appear to alter gene expression in the endometrium; however, caution is necessary regarding its potential effect on oocyte/embryo quality with respect to the role of inherent follicular disruption in some women. In terms of the mechanism of overproduction in P4 synthesis, the main preventive strategy should be avoiding aggressive stimulation. Unfortunately, there is lack of large-scale randomized controlled trials for other approaches, including deferred embryo transfer in the thaw cycle. Since there is a significant inter-assay variability for P4 measurement, it may be wise to recommend that every center should define their own P4E and the level needed for harm to occur based on their own assays and datasets before deciding the best approach.