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Effects of the Levonorgestrel-containing Intrauterine Device, Copper Intrauterine Device, and Levonorgestrel-Containing Oral Contraceptive on the Endometrial and Cervical Transcriptomes Offer Insights into Mechanisms of Action of Intrauterine Devices

ABSTRACT: The contraceptive effectiveness of intrauterine devices has been attributed in part to effects of a foreign body reaction on the endometrium. We performed this study to identify compare the effects on the endometrial transcriptome of intrauterine devices and combined oral contraceptives, to better understand their mechanisms of action. We collected endometrial and cervical biopsies from women using the levonorgestrel-intrauterine device, copper intrauterine device or levonorgestrel-containing combined oral contraceptives, and from women not using contraceptives (control group). Transcriptional profiling was performed with Affymetrix arrays, Principal Component Analysis and the bioconductor package limma. Pathway analysis was performed using EnrichR and Reactome 2016. In endometrial samples from copper intrauterine device users (n=13), there were no genes with statistically significant differential expression compared to controls (n=11), whereas in levonorgestrel-intrauterine device users (n=11), 2509 genes were significantly dysregulated and mapped onto several immune and inflammatory pathways. In combined oral contraceptive users (n=12), 133 genes were significantly dysregulated and mapped predominantly onto pathways involving regulation of metal ions. Both levonorgestrel-intrauterine device and combined oral contraceptive use were associated with significant downregulation of members of the metallothionein gene family. In cervical samples, none of the groups showed statistically significant differential gene expression compared to controls. In conclusion, hormonal and copper intrauterine devices differ significantly in their effects on the endometrial transcriptome, with endometrium from copper intrauterine device users being indistinguishable from luteal phase endometrium. These results suggest that the contraceptive mechanisms of intrauterine devices are unlikely to rely on a common pathway involving a foreign body reaction in the endometrium.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137765 | GEO | 2020/04/29

REPOSITORIES: GEO

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Project description:Purpouse: Aims of this study were (1) to characterize the endometrial transcriptome, (2) to identify functional pathways, and (3) to molecularly characterize selected pathways overrepresented in the endometrium of day 7 post-ovulation induction of cows treated to ovulate larger versus smaller follicles Methods: Seventy-four multiparous, nonlactating, presynchronized Nelore cows received a progesterone-releasing device and estradiol benzoate on Day–10 (D?10). Animals received cloprostenol (large follicle-large CL group; LF-LCL; N = 35) or not (small follicle-small CL group; SF-SCL; N = 39) on D?10. Progesterone devices were withdrawn and cloprostenol administered 42 to 54 hours (LF-LCL) or 30 to 36 hours (SF-SCL) before GnRH treatment (D0). Tissues were collected at slaughter on D7. Transcriptional profiling of the endometrial tissue was performed by RNA-seq and protein markers for proliferation and apoptosis were identified by immunohistochemistry. Results: Functional enrichment data indicated that LF-LCL endometrium expressed greater abundance of genes associated with biosynthetic and metabolic processes, whereas SF-SCL endometrium .gene expression profile was biased towards cell proliferation. Extracellular matrix-related genes were also upregulated in the SF-SCL endometrium suggesting reorganization of the ECM towards a proliferation permissive phenotype. Immunohistochemistry data confirmed the greater proliferative activity observed in SF-SCL endometrium I comparison to LF-LCL counterparts, and indicated a time-related transition within experimental group. In conclusion, the periovulatory endocrine milieu regulates bovine endometrial gene expression. Furthermore, timing and amplitude of ovarian steroid secretion pattern seem to determine the transition from a proliferation permissive to a biosynthetic and metabolically active endometrial phenotype, which may be associated with the preparation of an optimally receptive uterine environment. Conclusion: the periovulatory endocrine milieu affected D7 endometrial molecular signature. Main pathways affected were related to cell proliferation, ECM composition and remodeling, biosynthetic and metabolic processes. Reported data further suggest that the endometrial tissue from LF-LCL cows experienced an early proliferative phase (D4), whereas the SF-SCL endometrium, exposed to a distinct periovulatory endocrine environment, expressed a delayed onset of the proliferative activity (D7). endometrial mRNA profiles of endocrine manipulated cows were generated by deep sequencing using Illumina HiScanSQ platform

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Effects of the Levonorgestrel-containing Intrauterine Device, Copper Intrauterine Device, and Levonorgestrel-Containing Oral Contraceptive on the Endometrial and Cervical Transcriptomes Offer Insights into Mechanisms of Action of Intrauterine Devices

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