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

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 = 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 = 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 implantation rates seen in fresh compared with frozen and donor IVF-embryo transfer cycles. Therefore, the NCS window could serve as a sensitive guide for timing of embryo transfer in frozen and donor cycles. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the March of Dimes Birth Defects foundation (1-FY09-363 to U.T.M.); Ferring Pharmaceuticals, Parsippany, NJ; East Coast Fertility, Plainview, NY and the CMBG Training Program (T32 GM007491 to M.J.S.). We report no competing interests.

Evaluation of ketamine systemic absorption from topical preparations. Short Communication.

The aim of this study was to evaluate the systemic absorption of the topically administered ketamine using different vehicles and additives, in order to develop a transdermal therapeutic system (TTS) of this drug. After the application of different ketamine preparations (1% in hydrogel, o/w cream, or organogel) the ketamine appeared in the blood. The lowest level could be observed with o/w cream, while the highest concentration was achieved by means of the hydrogel system, however this difference was not significant. Further studies are going to be performed with higher drug concentrations for the characterization of the differences in the pharmacodynamics of the drug with different vehicles and to evaluate the correlation between the in vitro and in vivo absorption.

In vitro and in vivo percutaneous absorption of topical dosage forms: case studies.

This article evaluated the influence of vehicle compositions on topical drug availability. In vitro drug release and in vivo experiments were performed in case of the hydrophilic ketamine hydrochloride and the lipophilic piroxicam. Ketamine hydrochloride is a NMDA receptor antagonist that has been useful for anesthesia and analgesia. The study of transdermal ketamine delivery is a novelty, because nobody has investigated the hypnotic effects of ketamine after this administration route. In vitro measurements gave a good basis for screening among the developed products. The physiological changes after ketamine administration showed, that there were significant differences among the parameters tested (breathing rate, duration of sleep) from the developed products (hydrogel, lyotropic liquid crystal and o/w cream) compared to the reference product (Carbopol gel). The in vivo feedback for piroxicam was the measurement of the anti-inflammatory activity by edema inhibition percentage. Significant differences were measured in case of the developed systems compared to the reference.