Premature formation of nucleolar channel systems indicates advanced endometrial maturation following controlled ovarian hyperstimulation

Abstract

study question: Is there a shift in the timing of nucleolar channel system (NCS) formation following controlled ovarian hyperstimulation (COH)?summary answer: NCSs appear prematurely following COH compared with natural cycles. what is known already: During natural cycles, NCSs of endometrial epithelial cell (EEC) nuclei are exclusively present during the window of implantation and are uniformly distributed throughout the upper endometrial cavity. study design, size, duration: Prospective two-cohort study. Cohorts I and II each consisted of seven volunteers for the duration of three menstrual study cycles that were separated by at least one wash-out or rest cycle, between December 2008 and May 2012. participants/materials, setting, methods: Participants were recruited from a pool of healthy oocyte donors. Consecutive endometrial biopsies were obtained during the same luteal phase on cycle days (CD) 16, 20 and 26 for Cohort I, and on CD14, 22 and 24 for Cohort II, following random assignment to a natural cycle group, a COH cycle group (using a GnRH antagonist), or a COH cycle group receiving luteal phase hormonal supplementation (COH + S). The day of oocyte retrieval was designated CD14 in COH cycles and the day of the LH surge was designated CD13 in natural cycles. Prevalence of NCSs in the nuclei of EECs was quantified using indirect immunofluorescence with an antibody directed against a subset of related nuclear pore complex proteins that are major constituents of NCSs. Progesterone and estradiol levels were measured on the day of each endometrial biopsy.main results and the role of chance: The natural cycle group exhibited peak NCS prevalence on CD20 [53.3%; interquartile range (IQR) 28.5 -55.8], which rapidly declined on CD22 (11.8%; IQR 6.3-17.6), CD24 (2.5%; IQR 0.0-9.2) and CD26 (0.3%; IQR 0.0 -3.5), and no NCSs on CD14 and 16 defining a short NCS window around CD20. In contrast, in COH and COH + S cycles, NCS prevalence was high already on CD16 (40.4%; IQR 22.6 -53.4 and 35.6%; IQR 26.4 -44.5, respectively; P ¼ 0.001 compared with CD16 of the natural cycle group, Mann -Whitney), whereas no significant difference in NCS prevalence was detected on any of the other five CDs between the three groups (P . 0.05).limitations, reasons for caution: The cohort size was small (n ¼ 7) but was offset by the all-or-none presence of NCSs on CD16 in natural versus COH and COH + S cycles and the fact that each subject served as her own control.wider implications of the findings: Premature appearance of NCSs and hence maturation of the endometrium following COH is consistent with previous studies based on histological dating but contradicts studies based on mRNA expression profiling, which reported a lag in endometrial maturation. However, this is the first study of this kind that is based on consecutive endometrial biopsies within the same cycle and that reports such clear-cut differences: no versus robust NCS presence on CD16. Our observation of advanced endometrial maturation following COH may contribute to the reduced i...

Timing the window of implantation by nucleolar channel system prevalence matches the accuracy of the endometrial receptivity array

“…2, #1-24). In contrast, in our previous studies, peak NCS prevalence was closer to 50% (19,21,23). This discrepancy could be caused by fixation with formaldehyde instead of paraformaldehyde and by laboratory-specific differences in tissue processing.…”

“…Therefore, it is possible that NCS prevalence slightly precedes the receptive phase determined by ERA. Perhaps the NCS window is narrower and only marks the opening of the WOI, as supported by our observations on NCS prevalence before and after controlled ovarian hyperstimulation (23).…”

“…Although their appearance is independent of fertility status, it is dependent on a 4-ng/ml progesterone threshold (21,22). Our recent finding that premature formation of NCSs was linked to advanced endometrial maturation after controlled ovarian hyperstimulation further supported an association of NCS presence with the WOI (23). Despite all this information, the function of these curious organelles remains as enigmatic as when they were discovered.…”

“…The NCSs were quantified by an observer-independent method described previously (20) that has since been applied repeatedly (21,23). Briefly, an observer who was blinded regarding the CD of biopsy collection analyzed all samples.…”

Perinatal outcomes after fresh versus vitrified-warmed blastocyst transfer: retrospective analysis

“…The early luteal phase is critical to pregnancy, as it governs embryo implantation and placentation (3,14). The elucidation of the cause and effect relationship between COS and pregnancy outcomes has, therefore, been the key objective of a number of studies, each with a different approach (7,(15)(16)(17)(18)(19)(20).…”