The Endometrial Response to Chorionic Gonadotropin Is Blunted in a Baboon Model of Endometriosis

J R A Sherwin,J M Hastings,K S Jackson,A T Fazleabas,A M Sharkey,P A Mavrogianis

doi:10.1210/en.2010-0275

Abstract

Endometriosis-associated infertility has a multifactorial etiology. We tested the hypothesis that the endometrial response to the early embryonic signal, human chorionic gonadotropin (hCG), alters over time in a nonhuman primate model of endometriosis. Animals with experimental or spontaneous endometriosis were treated with hCG (30 IU/d), from d 6 after ovulation for 5 d, via an oviductal cannula. Microarray analysis of endometrial transcripts from baboons treated with hCG at 3 and 6 months of disease (n=6) identified 22 and 165 genes, respectively, whose levels differed more than 2-fold compared with disease-free (DF) animals treated with hCG (P<0.01). Quantitative RT-PCR confirmed abnormal responses of known hCG-regulated genes. APOA1, SFRP4, and PAPPA, which are normally down-regulated by hCG were up-regulated by hCG in animals with endometriosis. In contrast, the ability of hCG to induce SERPINA3 was lost. Immunohistochemistry demonstrated dysregulation of C3 and superoxide dismutase 2 proteins. We demonstrate that this abnormal response to hCG persists for up to 15 months after disease induction and that the nature of the abnormal response changes as the disease progresses. Immunohistochemistry showed that this aberrant gene expression was not a consequence of altered LH/choriogonadotropin receptor distribution in the endometrium of animals with endometriosis. We have shown that endometriosis induces complex changes in the response of eutopic endometrium to hCG, which may prevent the acquisition of the full endometrial molecular repertoire necessary for decidualization and tolerance of the fetal allograft. This may in part explain endometriosis-associated implantation failure.

Highlights

We have shown that the infusion of a low dose of human chorionic gonadotropin (hCG) to mimic the early preimplantation embryo, in DF animals, results in formation of a luminal epithelial plaque, the induction of against ␣-smooth muscle actin (ASMA) in stromal fibroblasts and up-regulation of progestogen-associated endometrium protein in glandular epithelial cells
HCG infusion progressively up-regulated endometrial secreted frizzledrelated protein 4 (SFRP4) mRNA levels throughout progression of disease compared with DFϩhCG (Fig. 6B), this did not quite reach statistical significance (Kruskal-Wallis ANOVA, P ϭ 0.06)
There was a striking loss in the ability of hCG to induce the expression of SERPINA3 throughout the progression of endometriosis from 6 through 15 months of disease (Fig. 6C; Kruskal-Wallis ANOVA, P ϭ 0.05)

Summary

Introduction

We demonstrate that this abnormal response to hCG persists for up to 15 months after disease induction and that the nature of the abnormal response changes as the disease progresses Immunohistochemistry showed that this aberrant gene expression was not a consequence of altered LH/choriogonadotropin receptor distribution in the endometrium of animals with endometriosis. Templeton et al [11], reviewing outcome data from the Human Fertilization and Embryology Authority database, concluded that the presence of endometriosis was not associated with a reduction in in vitro fertilization (IVF) pregnancy rates In these data from the early 1990s, the overall live-birth rate per cycle of treatment was only 13.9 and 8% of the patients who had two or more causes of infertility. The genes regulated by hCG modulate embryo attachment, extracellular matrix remodeling, and the immune response around the implanting blastocyst

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Conclusion