Suboptimal mid-luteal progesterone concentrations are associated with aberrant endometrial gene expression, potentially resulting in implantation failure.

RESEARCH QUESTION: What is the difference in endometrial transcriptomics between women with normal and with low mid-luteal progesterone during the implantation window? DESIGN: An endometrial biopsy and serum progesterone concentration were taken from participants during the mid-luteal phase (LH+7 to LH+9). A total of 12 participants were recruited and categorized into two groups based on their progesterone concentrations: normal progesterone (>15 ng/ml, n = 6) and low progesterone (<15 ng/ml, n = 6). Global endometrial gene expression between the two groups was compared by microarray techniques. Principal component analysis was used to display the gene's expression pattern. Pathway and gene ontology enrichment analysis were performed to determine the biological mechanism of progesterone on the endometrium. RESULTS: Several key genes related to endometrial receptivity were found to be regulated by progesterone. With regard to gene ontology and pathway analysis, progesterone was shown to be mainly involved in structure morphogenesis predominantly during a process of decidualization, extracellular matrix-receptor interaction and cell adhesion. Distinct differences were observed in the transcriptomic profiles between the two groups, indicating potential impairment of endometrial receptivity in women with suboptimal progesterone concentrations. There was a relatively similar pattern of gene expression between endometrial samples with progesterone concentrations approximately 10 ng/ml and >15 ng/ml. Thus, a progesterone concentration of between 10 and 15 ng/ml appears to be sufficient to induce endometrial receptivity. CONCLUSIONS: Abnormally low progesterone below the threshold of 10-15 ng/ml during the implantation window results in aberrant endometrial gene expression that may affect implantation potential.

Evaluating the influence of progesterone concentration and time of exposure on in vitro endometrial decidualisation.

This study aimed to evaluate the influence of progesterone (concentration and time of exposure) on endometrial decidualisation using an in vitro model cell line: Human Endometrial Stromal Cells (HESCs). HESCs exposed to progesterone (1 and 10 µM) had higher percentages of decidualised cells and higher expression of the decidual marker (Insulin Like Growth Factor Binding Protein 1 (IGFBP1)) compared with those exposed to (0.1 µM). Among those HESCs cultured with 1 µM progesterone for 11 days, the highest rate of morphological differentiation (40-50%) occurred between days 7-9 and IGFBP1 peaked on day 7. The cell-cycle pathway was significantly down-regulated in HESCs exposed to at least 1 µM progesterone regardless of the incubation period. We conclude that exposure to high progesterone concentration for 7-9 days is essential to maximise the process of decidualisation.

The strength of evidence supporting luteal phase progestogen after assisted reproduction: A systematic review with reference to trial registration and pre-specified endpoints.

OBJECTIVE: To measure the potential for outcome switching and selective reporting, in trials of luteal phase progestogen in assisted reproduction. STUDY DESIGN: Trials identified through Medline and Embase in August 2017 using the MeSH term "assisted reproductive technology, luteal phase support" and associated text words. Randomised controlled trials (RCTs) comparing progestogen of any type, dose, and route of administration, with placebo or no treatment as luteal phase support in subfertile women undergoing in vitro fertilization (IVF) or intrauterine insemination (IUI). Eight trials after IVF and eleven after IUI, involving 1040 and 2764 participants respectively, were included. RESULTS: None of the eight trials of progestogen therapy after IVF had been registered. Only 5/11 trials of progestogen after IUI had been registered, and only two of these prospectively. One of these had a registered primary outcome of "pregnancy sac plus heartbeat", but reported "pregnancy sac alone"; we judged this as an altered primary outcome. Three other trial had a registered primary outcome of "clinical pregnancy undefined" and reported "intra or extra-uterine pregnancy with a heartbeat"; we judged this alteration as minimal. That trial was negative. Overall, 26 different outcomes had been reported by the various trials. The three outcomes reported most often were pregnancy undefined (9/19), miscarriage (11/19) and clinical pregnancy (9/19). This suggests considerable potential for selective outcome reporting or outcome switching. CONCLUSION: Apart from one negative trial, none of the evidence on luteal phase progestogen after assisted reproduction comes from prospectively registered trials: a slender reed indeed.