“Premature luteinization” in the era of GnRH analogue protocols: time to reconsider

Abstract

Traditionally, premature luteinization in the pre-GnRH analogue era has been defined as P level > 0.9 ng/mL on the day of hCG administration [4]. During the GnRH analogue era the term of premature luteinization was non-intentionally dragged from the previous period with the same definition. Although most investigators still apply an absolute P level on hCG day as an indication for elevated P level, the cut-off point has differed considerably between one study and another ranging from 0.9 to 2.0 ng/mL [1, 10]. Most recent studies have suggested that a cut-off point of 1.25 [16] or 1.5 ng/mL [2], may differentiate more properly in their detrimental effect on endometrial receptivity, however this should be investigated further taking into account the type of gonadotropin and GnRH analogue (agonist or antagonist) employed. Since P elevation is linked to the COH itself, driven by high FSH dosage, it is clear that P elevation is positively correlated to estradiol (E2) level on the day of hCG administration as well as number of retrieved oocytes, as has been recently demonstrated [1, 2]. Moreover, defining a single threshold for a detrimental serum P level on endometrial receptivity and clinical pregnancy achievement has been suggested to be imprecise [23], since other confounding variables including maximal E2 level could affect the end result. Therefore, to take into consideration the increase in the late follicular P level and to control for the ovarian response of each patient undergoing COH, the P/E2 ratio was introduced by our group [10, 24]. Calculation of the P/E2 ratio was performed as follows: P (ng/mL) X 1,000/ E2 (pg/mL). Accordingly, in a GnRH analogue ART setting, a P/E2 ratio of >1 may define more properly infertile patients developing elevated P before hCG administration or ENLOP as suggested. Prospective targeted studies are needed to evaluate the most appropriate way of definition taking into account the effect of this phenomenon on endometrial receptivity and pregnancy achievement. Progesterone assays in the past were targeted to assess ovulation during the luteal phase. In a non-luteinized environment elevated P is 5–10 folds lower than the luteal phase level. It is therefore crucial that only validated precise assays for moderate P elevation [25] in the follicular phase should be employed when planning any future study targeting this topic.