Premature progesterone elevation in controlled ovarian stimulation: to make a long story short

Abstract

Over the past decades many of us have contributed to the controversy surrounding the origins and consequences of premature progesterone elevation during controlled ovarian stimulation. In this article, we attempt to retrace the progression of information on this complex subject which required reviewing a number of publications that often contradicted one another. The definition of premature progesterone elevation, the pathophysiological mechanisms underlying the high peripheral progesterone levels, and the debated consequences of this event on in vitro fertilixation-embryo transfer outcome will be addressed from a historical perspective.

Influence of human chorionic gonadotrophin during ovarian stimulation: an overview

“…Initially, it was hypothesised that the LH bioactivity of hMG preparations may cause elevations in circulating progesterone in the context of premature LH surges. Contrary to expectations, studies comparing circulating progesterone levels following the administration of FSH or hMG revealed that FSH was associated with a similar or an increased elevation in progesterone compared with hMG (progesterone levels increased from 0.37 ± 0.12 ng/ mL before FSH administration to 0.86 ± 0.12 ng/mL approximately 15 h post-administration, P < 0.01 [93,99]). These data suggest that FSH stimulation alone could be associated with elevated circulatory progesterone levels at the end of stimulation, but did not distinguish between the individual influences of hCG and LH.…”

“…This may result in asynchrony between the embryo development and endometrium receptivity through advanced secretory transformations of the endometrium, thus shifting the implantation window so that it occurs earlier than normal in fresh cycles. A shifted implantation window could have subsequent detrimental effects on implantation and explain the poorer pregnancy outcomes that have been observed in clinical trials [87][88][89][90][91][92][93].…”

“…Several reviews have recently discussed the controversy surrounding the origin of premature progesterone elevation in OS based on evidence to date [90,93,98]. Initially, it was hypothesised that the LH bioactivity of hMG preparations may cause elevations in circulating progesterone in the context of premature LH surges.…”

“…It has been suggested that patients with a good ovarian response produce oocytes/embryos of increased quality, and so may be better equipped to overcome the challenges presented by an impaired endometrial receptivity brought about by high progesterone levels. In contrast, patients with a poor ovarian response are more likely to produce oocytes of lower quality, which are less likely to be able to compensate for the impaired endometrial receptivity, thus resulting in a lower OPR [93,98]. Data from multiple clinical trials have indicated that a progesterone level > 0.9 ng/mL on the day of hCG administration is associated with lower pregnancy rates in patients with a weak ovarian response.…”

“…Data from multiple clinical trials have indicated that a progesterone level > 0.9 ng/mL on the day of hCG administration is associated with lower pregnancy rates in patients with a weak ovarian response. Therefore, it has been speculated that previous trials not reporting a link between premature elevated progesterone levels and reduced pregnancy outcomes may have unknowingly included in their analyses a majority of normal or high ovarian responders, with resulting good-quality embryos being capable of compensating for impaired endometrial receptivity [93]. Taken together, these findings indicate that OS could potentially be adapted to prevent progesterone elevation by individualisation according to a patient's predicted ovarian response and embryo quality [101].…”