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Meta-Analysis
. 2021 Dec;304(6):1587-1597.
doi: 10.1007/s00404-021-06031-9. Epub 2021 Apr 26.

Intrauterine hCG application increases expression of endothelial cell-cell adhesion molecules in human

Michaela Bienert  1   2 , Pardes Habib  3 , Volker Buck  1 , Irmgard Classen-Linke  1 , Roman Skoblo  2 , Benjamin Rösing  4
Affiliations
Meta-Analysis

Intrauterine hCG application increases expression of endothelial cell-cell adhesion molecules in human

Michaela Bienert et al. Arch Gynecol Obstet. 2021 Dec.

Abstract

Endometrial receptivity is a decisive factor in human reproduction. Human chorionic gonadotropin (hCG) is one of the first embryonic signals that precedes the implantation by trophoblast invasion into the endometrium. Meta-analysis of randomized controlled trials reports a moderate-quality evidence for improved live birth rate for an intrauterine hCG dose ≥ 500 IU. Nevertheless, all hCG endometrial effects are not completely understood. We, therefore, utilized endometrial tissue from 12 patients after estradiol and progesterone treatment with or without intrauterine hCG flushing at the window of implantation (WOI) to analyze cellular composition by measuring marker proteins for stromal, endothelial, epithelial and immune cells. Flow cytometry analysis revealed that significantly more cells expressed the endothelial adhesion molecules VE-cadherin (CD144) and S-Endo-1 (CD146) after intrauterine hCG administration. In contrast, the endothelial marker CD31 and markers involved in vessel formation (VEGFR1 and VEGFR2) remained unchanged in their expression. Similarly, stroma markers (CD73, CD90 and CD105), epithelial markers (Desmocollin-2 and E-Cadherin) and immune cell markers (CD11b, CD45, CD79a and HLA-DR) displayed no alterations in their expression. This finding directs the focus on endothelial adhesion molecules as a potential mechanistically explanation of hCG conveyed increase of embryo implantation and pregnancy rates in women undergoing ART.

Keywords: ART; Embryo implantation; HCG; Mesenchymal stroma cells; Reproduction; Vascularization; Window of implantation.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Protein expression in different cell clusters with and without hCG in human endometrium biopsies. Three patients per group were treated with hormonal replacement therapy (HRT) without hCG (HRT; P1–P3) and with hCG (HRT + hCG; P4–P6). The protein expression of the respective markers is shown with colors from light green (0% protein expression) to light red (100% protein expression). Here 100% corresponds to 20,000 cells. Cluster 1 corresponds to the marker set for MSC according to ISCT. Cluster 2 includes markers which are expressed on the stem and stromal cells and cluster 3 describes markers expressed on immune cells. Cluster 4 describes markers expressed on endothelial cells and cluster 5 markers expressed on epithelial cells
Fig. 2
Fig. 2
Flow cytometric characterization of the endothelial cell population in human endometrium with and without hCG treatment. Patients were treated with hormonal replacement therapy without hCG (HRT) and HRT with hCG (HRT + hCG). Protein expression of the respective markers is shown here in percent positive events, where 100% corresponds to 20,000 cells. Endothelial cell population is described by cell–cell adhesion molecules CD31, CD144, CD146 and the VEGFR-receptors VEGFR1 and VEGFR2 with n = 12
Fig. 3
Fig. 3
Flow cytometric characterization of the epithelial cell population in human endometrium with and without hCG treatment. Patients were treated with hormonal replacement therapy without hCG (HRT) and HRT with hCG (HRT + hCG). Protein expression of the respective markers is shown here in percent positive events, where 100% corresponds to 20,000 cells. Epithelial cell population is described by desmocollin 2 and E-cadherin with n = 7
Fig. 4
Fig. 4
Flow cytometric characterization of the stroma/stem cell population in human endometrium with and without hCG treatment. Patients were treated with hormonal replacement therapy without hCG (HRT) and HRT with hCG (HRT + hCG). Protein expression of the respective markers is shown here in percent positive events, where 100% corresponds to 20,000 cells. Stroma/stem cell cluster described by the ISCT markers CD34, CD73, CD90 and CD105 with n = 12
Fig. 5
Fig. 5
Flow cytometric characterization of the immune cell population in human endometrium with and without hCG treatment. Patients were treated with hormonal replacement therapy without hCG (HRT) and HRT with hCG (HRT + hCG). Protein expression of the respective markers is shown here in percent positive events, where 100% corresponds to 20,000 cells. Immune cell population is described by the ISCT markers described by CD11b, CD45, CD79a and HLA-DR with n = 12
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