Leah Hawkins Bressler1, Marc A Fritz1, San-Pin Wu2, Lingwen Yuan2, Suzanna Kafer2, Tianyuan Wang3, Francesco J DeMayo2, Steven L Young1. 1. Department of Obstetrics & Gynecology, Division of Reproductive Endocrinology & Infertility, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 2. Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. 3. Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Abstract
CONTEXT: Suboptimal endometrial thickening is associated with lower pregnancy rates and occurs in some infertile women treated with clomiphene. OBJECTIVE: To examine cellular and molecular differences in the endometrium of women with suboptimal vs optimal endometrial thickening following clomiphene. METHODS: Translational prospective cohort study from 2018 to 2020 at a university-affiliated clinic. Reproductive age women with unexplained infertility treated with 100 mg of clomiphene on cycle days 3 to 7 who developed optimal (≥8mm; n = 6, controls) or suboptimal (<6mm; n = 7, subjects) endometrial thickness underwent preovulatory blood and endometrial sampling. The main outcome measures were endometrial tissue architecture, abundance and location of specific proteins, RNA expression, and estrogen receptor (ER) α binding. RESULTS: The endometrium of suboptimal subjects compared with optimal controls was characterized by a reduced volume of glandular epithelium (16% vs 24%, P = .01), decreased immunostaining of markers of proliferation (PCNA, ki67) and angiogenesis (PECAM-1), increased immunostaining of pan-leukocyte marker CD45 and ERβ, but decreased ERα immunostaining (all P < .05). RNA-seq identified 398 differentially expressed genes between groups. Pathway analysis of differentially expressed genes indicated reduced proliferation (Z-score = -2.2, P < .01), decreased angiogenesis (Z-score = -2.87, P < .001), increased inflammation (Z-score = +2.2, P < .01), and ERβ activation (Z-score = +1.6, P < .001) in suboptimal subjects. ChIP-seq identified 6 genes bound by ERα that were differentially expressed between groups (P < .01), some of which may play a role in implantation. CONCLUSION: Women with suboptimal endometrial thickness after clomiphene exhibit aberrant ER expression patterns, architectural changes, and altered gene and protein expression suggesting reduced proliferation and angiogenesis in the setting of increased inflammation.
CONTEXT: Suboptimal endometrial thickening is associated with lower pregnancy rates and occurs in some infertile women treated with clomiphene. OBJECTIVE: To examine cellular and molecular differences in the endometrium of women with suboptimal vs optimal endometrial thickening following clomiphene. METHODS: Translational prospective cohort study from 2018 to 2020 at a university-affiliated clinic. Reproductive age women with unexplained infertility treated with 100 mg of clomiphene on cycle days 3 to 7 who developed optimal (≥8mm; n = 6, controls) or suboptimal (<6mm; n = 7, subjects) endometrial thickness underwent preovulatory blood and endometrial sampling. The main outcome measures were endometrial tissue architecture, abundance and location of specific proteins, RNA expression, and estrogen receptor (ER) α binding. RESULTS: The endometrium of suboptimal subjects compared with optimal controls was characterized by a reduced volume of glandular epithelium (16% vs 24%, P = .01), decreased immunostaining of markers of proliferation (PCNA, ki67) and angiogenesis (PECAM-1), increased immunostaining of pan-leukocyte marker CD45 and ERβ, but decreased ERα immunostaining (all P < .05). RNA-seq identified 398 differentially expressed genes between groups. Pathway analysis of differentially expressed genes indicated reduced proliferation (Z-score = -2.2, P < .01), decreased angiogenesis (Z-score = -2.87, P < .001), increased inflammation (Z-score = +2.2, P < .01), and ERβ activation (Z-score = +1.6, P < .001) in suboptimal subjects. ChIP-seq identified 6 genes bound by ERα that were differentially expressed between groups (P < .01), some of which may play a role in implantation. CONCLUSION: Women with suboptimal endometrial thickness after clomiphene exhibit aberrant ER expression patterns, architectural changes, and altered gene and protein expression suggesting reduced proliferation and angiogenesis in the setting of increased inflammation.
Authors: Sylvia C Hewitt; San-Pin Wu; Tianyuan Wang; Madhumita Ray; Marja Brolinson; Steven L Young; Thomas E Spencer; Alan DeCherney; Francesco J DeMayo Journal: Endocrinology Date: 2022-09-01 Impact factor: 5.051
Authors: Zishui Fang; Yao Tian; Cong Sui; Yaxin Guo; Xinyao Hu; Youhua Lai; Zhiqi Liao; Jie Li; Guihai Feng; Lei Jin; Kun Qian Journal: Front Cell Dev Biol Date: 2022-07-22