Endometrial receptivity and regeneration in health and disease : molecular, cellular and clinical perspectives

Each month, the endometrium regenerates under the influence of the ovarian hormones and builds up to a receptive state in preparation for embryo implantation. In the absence of pregnancy, it sheds during menses and the regenerative cycle starts again. The mechanisms that regulate endometrial physiology are still poorly understood as are the clinical problems of impaired endometrial function. The aim of this thesis was to gain new molecular, cellular and clinical knowledge on endometrial receptivity, infertility and regeneration.

In Study I we found that 200 mg of mifepristone given to healthy fertile women on day two after the luteinizing hormone peak, rendered the endometrium non-receptive and significantly altered the endometrial receptivity transcriptome. The results contribute to the knowledge about the molecular events of endometrial receptivity and support that mifepristone in the tested dose and regimen could be used as a contraceptive agent by disrupting endometrial receptivity.

In Study II we could identify several species of small RNAs in uterine fluid and found 61 deregulated microRNAs (miRNAs) in uterine fluid from patients with recurrent implantation failure (RIF) compared to healthy women. The deregulated miRNAs were present in endometrial tissue and extracellular vesicles and their predicted target genes were involved in endometrial receptivity and implantation. Our results contribute with new potential mechanisms behind the pathogenesis of RIF and proposes points of investigation for future biomarker and treatment studies. We also show the feasibility of analyzing small RNAs in uterine fluid, supporting potential future use in clinical diagnostics.

In Study III we could not find any deregulated miRNAs in eutopic endometrium from women with endometriosis during the receptive phase, compared to healthy women. We found 11 differentially expressed genes, but could not link them to endometrial receptivity. Our results indicate that impaired endometrial receptivity cannot explain subfertility in endometriosis.

In Study IV we found several different cell subtypes in the stromal and perivascular cell compartments in the proliferative endometrium. Gene expression profiles suggested different roles for these subtypes in the regenerative process. By validation in external data, we could confirm that some of the identified subtypes persist into early pregnancy. The subtypes could represent distinct cell types, functional states or spatial locations. This should be further investigated, along with how cell type distribution might be altered in conditions with impaired endometrial regeneration such as Asherman’s syndrome.

In conclusion, this thesis provides new knowledge on the molecular and cellular mechanisms of endometrial receptivity and endometrial regeneration, with clinical relevance for contraception, endometrial diagnostics and management of infertility.

List of scientific papers

I. von Grothusen C, Lalitkumar PG, Ruiz-Alonso M, Boggavarapu NR, Navarro R, Miravet-Valenciano J, Gemzell-Danielsson K, Simon C. Effect of mifepristone on the transcriptomic signature of endometrial receptivity. Human Reproduction. 2018;33(10): 1889-1897.
https://doi.org/10.1093/humrep/dey272

II. von Grothusen C*, Frisendahl C*, Modhukur V, Lalitkumar PG, Peters M, Faridani OR, et al. Uterine fluid microRNAs are dysregulated in women with recurrent implantation failure. Human Reproduction. 2022. * Shared first author.
https://doi.org/10.1093/humrep/deac019

III. von Grothusen C, Boggavarapu NR, Frisendahl C, Andersson Di Claudio K, Lalitkumar PG, Gemzell-Danielsson K. Effect of endometriosis on the transcriptomic profile of endometrial receptivity. 2022. [Manuscript]

IV. Queckbörner S, von Grothusen C, Boggavarapu NR, Francis RM, Davies LC, Gemzell-Danielsson K. Stromal Heterogeneity in the Human Proliferative Endometrium-A Single-Cell RNA Sequencing Study. Journal of Personalized Medicine. 2021;11(6).
https://doi.org/10.3390/jpm11060448