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Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis

OBJECTIVE: Bromocriptine treatment has been shown to reduce menstrual bleeding and pain in women with adenomyosis in a pilot clinical trial. The underlying mechanism contributing to the treatment effect is however unknown. The purpose of this study was to explore the effect of bromocriptine on the p...

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Autores principales: Tang, Yiqun, Ponandai-srinivasan, Sakthivignesh, Frisendahl, Caroline, Andersson, Johanna K., Pavone, Dora, Stewart, Elizabeth A., Lalitkumar, Parameswaran Grace Luther, Korsching, Eberhard, Bogavarappu, Nageswara Rao, Gemzell-Danielsson, Kristina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10034369/
https://www.ncbi.nlm.nih.gov/pubmed/36967761
http://dx.doi.org/10.3389/fendo.2023.1026168
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author Tang, Yiqun
Ponandai-srinivasan, Sakthivignesh
Frisendahl, Caroline
Andersson, Johanna K.
Pavone, Dora
Stewart, Elizabeth A.
Lalitkumar, Parameswaran Grace Luther
Korsching, Eberhard
Bogavarappu, Nageswara Rao
Gemzell-Danielsson, Kristina
author_facet Tang, Yiqun
Ponandai-srinivasan, Sakthivignesh
Frisendahl, Caroline
Andersson, Johanna K.
Pavone, Dora
Stewart, Elizabeth A.
Lalitkumar, Parameswaran Grace Luther
Korsching, Eberhard
Bogavarappu, Nageswara Rao
Gemzell-Danielsson, Kristina
author_sort Tang, Yiqun
collection PubMed
description OBJECTIVE: Bromocriptine treatment has been shown to reduce menstrual bleeding and pain in women with adenomyosis in a pilot clinical trial. The underlying mechanism contributing to the treatment effect is however unknown. The purpose of this study was to explore the effect of bromocriptine on the proliferation and migration properties of the endometrium in women with adenomyosis, by assessing cellular and molecular changes after six months of vaginal bromocriptine treatment. METHODS: Endometrial specimens were collected during the proliferative phase from women with adenomyosis (n=6) before (baseline) and after six months of treatment with vaginal bromocriptine. Immunohistochemistry was used to determine changes in the protein expression of Ki67 in the endometrium of women with adenomyosis. Primary endometrial stromal cells isolated at baseline were expanded in vitro and exposed to different doses of bromocriptine to determine the optimal half-maximum inhibitory concentration (IC50) using CellTiter-Blue(®) Cell Viability Assay. Cell proliferation was assessed by bromodeoxyuridine ELISA assay and Ki67 gene expression was checked by real-time PCR. The migratory ability of endometrial stromal cells was determined by wound healing and transwell migration assays. Small RNA sequencing was applied on tissues collected from women with adenomyosis before and after bromocriptine treatment to identify differentially expressed microRNAs (miRNAs) after bromocriptine treatment. Bioinformatic methods were used for target gene prediction and the identification of biological pathways by enrichment procedures. RESULTS: Vaginal bromocriptine treatment reduced the Ki67 protein expression in the endometrium of women with adenomyosis and did not change the prolactin mRNA expression and protein concentration of prolactin in endometrial tissues. Bromocriptine significantly inhibited the proliferative and migrative abilities of endometrial stromal cells derived from women with adenomyosis in vitro. Moreover, small RNA sequencing revealed 27 differentially expressed miRNAs between the endometrium of women with adenomyosis before and after six months of vaginal bromocriptine treatment. KEGG pathway analysis on targeted genes of 27 miRNAs showed that several signaling pathways associated with cell proliferation and apoptosis were enriched after bromocriptine treatment. CONCLUSION: Bromocriptine treatment exhibits an anti-proliferative effect in the endometrium of women with adenomyosis in vivo and in vitro. Bromocriptine might inhibit the proliferation of endometrial tissue in adenomyosis in part through the regulation of dysregulated microRNAs and proliferation-associated signaling pathways.
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spelling pubmed-100343692023-03-24 Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis Tang, Yiqun Ponandai-srinivasan, Sakthivignesh Frisendahl, Caroline Andersson, Johanna K. Pavone, Dora Stewart, Elizabeth A. Lalitkumar, Parameswaran Grace Luther Korsching, Eberhard Bogavarappu, Nageswara Rao Gemzell-Danielsson, Kristina Front Endocrinol (Lausanne) Endocrinology OBJECTIVE: Bromocriptine treatment has been shown to reduce menstrual bleeding and pain in women with adenomyosis in a pilot clinical trial. The underlying mechanism contributing to the treatment effect is however unknown. The purpose of this study was to explore the effect of bromocriptine on the proliferation and migration properties of the endometrium in women with adenomyosis, by assessing cellular and molecular changes after six months of vaginal bromocriptine treatment. METHODS: Endometrial specimens were collected during the proliferative phase from women with adenomyosis (n=6) before (baseline) and after six months of treatment with vaginal bromocriptine. Immunohistochemistry was used to determine changes in the protein expression of Ki67 in the endometrium of women with adenomyosis. Primary endometrial stromal cells isolated at baseline were expanded in vitro and exposed to different doses of bromocriptine to determine the optimal half-maximum inhibitory concentration (IC50) using CellTiter-Blue(®) Cell Viability Assay. Cell proliferation was assessed by bromodeoxyuridine ELISA assay and Ki67 gene expression was checked by real-time PCR. The migratory ability of endometrial stromal cells was determined by wound healing and transwell migration assays. Small RNA sequencing was applied on tissues collected from women with adenomyosis before and after bromocriptine treatment to identify differentially expressed microRNAs (miRNAs) after bromocriptine treatment. Bioinformatic methods were used for target gene prediction and the identification of biological pathways by enrichment procedures. RESULTS: Vaginal bromocriptine treatment reduced the Ki67 protein expression in the endometrium of women with adenomyosis and did not change the prolactin mRNA expression and protein concentration of prolactin in endometrial tissues. Bromocriptine significantly inhibited the proliferative and migrative abilities of endometrial stromal cells derived from women with adenomyosis in vitro. Moreover, small RNA sequencing revealed 27 differentially expressed miRNAs between the endometrium of women with adenomyosis before and after six months of vaginal bromocriptine treatment. KEGG pathway analysis on targeted genes of 27 miRNAs showed that several signaling pathways associated with cell proliferation and apoptosis were enriched after bromocriptine treatment. CONCLUSION: Bromocriptine treatment exhibits an anti-proliferative effect in the endometrium of women with adenomyosis in vivo and in vitro. Bromocriptine might inhibit the proliferation of endometrial tissue in adenomyosis in part through the regulation of dysregulated microRNAs and proliferation-associated signaling pathways. Frontiers Media S.A. 2023-03-09 /pmc/articles/PMC10034369/ /pubmed/36967761 http://dx.doi.org/10.3389/fendo.2023.1026168 Text en Copyright © 2023 Tang, Ponandai-srinivasan, Frisendahl, Andersson, Pavone, Stewart, Lalitkumar, Korsching, Bogavarappu and Gemzell-Danielsson https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Tang, Yiqun
Ponandai-srinivasan, Sakthivignesh
Frisendahl, Caroline
Andersson, Johanna K.
Pavone, Dora
Stewart, Elizabeth A.
Lalitkumar, Parameswaran Grace Luther
Korsching, Eberhard
Bogavarappu, Nageswara Rao
Gemzell-Danielsson, Kristina
Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis
title Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis
title_full Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis
title_fullStr Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis
title_full_unstemmed Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis
title_short Bromocriptine inhibits proliferation in the endometrium from women with adenomyosis
title_sort bromocriptine inhibits proliferation in the endometrium from women with adenomyosis
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10034369/
https://www.ncbi.nlm.nih.gov/pubmed/36967761
http://dx.doi.org/10.3389/fendo.2023.1026168
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