Salpingectomy increases peri-implantation endometrial HOXA10 expression in women with hydrosalpinx

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, New Haven, Connecticut, United States
Fertility and sterility (Impact Factor: 4.59). 03/2007; 87(2):367-72. DOI: 10.1016/j.fertnstert.2006.06.041
Source: PubMed


To determine whether women with hydrosalpinx would have diminished endometrial HOXA10 expression and whether salpingectomy would reverse HOXA10 suppression. The homeobox gene HOXA10 is a transcription factor that is necessary for embryo implantation; its expression in human endometrium correlates with receptivity and implantation. Increased endometrial HOXA10 expression may be one mechanism by which salpingectomy results in increased implantation rates in IVF.
Prospective clinical trial.
Academic medical center.
Women with unilateral or bilateral hydrosalpinx.
Expression of HOXA10 was examined prospectively during the midluteal phase in endometrium obtained from infertile women (n = 9) with hydrosalpinges before and after salpingectomy, as well as from fertile controls (n = 6). Quantitative HOXA10 mRNA expression was determined by real-time reverse-transcription polymerase chain reaction, and HOXA10 protein expression was determined by immunohistochemistry.
Expression of HOXA10 mRNA and protein.
Expression of HOXA10 mRNA was significantly lower in infertile women with hydrosalpinges, compared with the case of fertile controls. Salpingectomy resulted in a statistically significant, 15-fold increase in endometrial HOXA10 expression. Immunohistochemical analysis confirmed the quantitative real-time reverse-transcription polymerase chain reaction findings. Increased HOXA10 expression was evident in both glandular epithelial cells and endometrial stroma.
HOXA10 is necessary for implantation. Here, we demonstrate decreased HOXA10 expression in response to hydrosalpinx fluid as a potential molecular mechanism for diminished implantation rates. Salpingectomy restores endometrial HOXA10 expression. This may be one mechanism by which salpingectomy results in augmented implantation rates in IVF.

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    • "Endometrial epithelial HOXA10 expression is driven by both stromal paracrine factors and also HOXA10 auto-regulation; HOXA10 also regulates its own expression in endometrial epithelium (21-22). The expression of HOXA10 and HOXA11 genes were decreased during the secretory phase of endometrium in some nonoptimal conditions such as in adenomyosis, endometriosis, myoma idiopatic infertility (23). "
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    ABSTRACT: Background: HOXA11 and HOXA10 are expressed in endometrium throughout the menstrual cycle and show a dramatic increase during the mid-luteal phase at the time of implantation. The expression of these genes is decreased in women with myomas. Objective: To determine whether myomectomy would reverse HOXA11 and HOXA10 expression, we evaluated the transcript levels of these genes in the endometria of patients before and after myomectomy. Materials and Methods: Expression of HOXA11 and HOXA10 were examined prospectively during the midluteal phase in endometrium obtained from infertile women (n=12) with myoma before and three months after myomectomy. Endometrial HOXA11 and HOXA10 expression were evaluated using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Results: Endometrial HOXA11 and HOXA10 mRNAs expression levels (normalized to 18SrRNA) were increased insignificantly in endometrium of patients after myomectomy (p=0.7 and p=0.15 respectively). Conclusion: The results suggest that the alteration in expression pattern of these genes could not account for some aspects of fertility after myomectomy.This article extracted from M.Sc. thesis. (Shamila Faramarzi)
    Full-text · Article · Dec 2013 · International Journal of Reproductive BioMedicine
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    • "To further explore the potential effects of intrauterine fluid infusion on uterine gene expression, we examined gene expression profiles relating to uterine receptivity including Lif, Hoxa10, Integrin α(v) and Integrin β(3) [23–27], because these molecules have shown changed expression in the endometrium of hydrosalpinx patients. We also examined Muc1, a barrier glycoprotein expressed at apical surface of uterine epithelial lining [28] and has been proposed as a potential marker to be distinguished for hydrosalpinx [29]. "
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    ABSTRACT: The normal intrauterine fluid environment is essential for embryo implantation. In hydrosalpinx patients, the implantation and pregnancy rates are markedly decreased after IVF-embryo transfer, while salpingectomy could significantly improve the pregnancy rates. The leakage of hydrosalpinx fluid into the endometrial cavity was supposed to be the major cause for impaired fertility. However, the underlying mechanisms of hydrosalpinx fluids on implantation and ongoing pregnancy were not fully understood and remain controversial regarding its toxicity. In present study, by infusing different volume of non-toxic fluid (0.9% saline) into uterine lumen before embryo implantation in mice (Day4 08:30), we found that while the embryos were not "flushed out" from the uteri, the timing of implantation was deferred and normal intrauterine distribution (embryo spacing) was disrupted. The abnormal implantation at early pregnancy further lead to embryo growth retardation, miscarriage and increased pregnancy loss, which is similar to the adverse effects observed in hydrosalpinx patients undergoing IVF-ET. We further examined uterine receptivity related gene expression reported to be involved in human hydrosalpinx (Lif, Hoxa10, Integrin α(v) and β(3)). The results showed that expression of integrin α(v) and β(3) were increased in the fluid infused mouse uteri, implicating a compensatory effect to cope with the excessive fluid environment. Our data suggested that the adverse effects of excessive non-toxic luminal fluid on pregnancy are primarily due to the mechanical interference for normal timing and location of embryo apposition, which might be the major cause of decreased implantation rate in IVF-ET patients with hydrosalpinx.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "The mRNA transcripts of four proteins, progestagen-associated endometrial protein/glycodelin (PAEP), homeobox A10 (HOXA10), leukemia inhibitory factor (LIF) and chemokine ligand 14 (CXCL14) are up-regulated significantly during the MSP (Talbi et al., 2006). Three are strongly implicated in various etiologies of infertility, including endometriosis (PAEP, HOXA10 and LIF; Kao et al., 2003; Dimitriadis et al., 2006), hydrosalpinges (HOXA10; Daftary et al., 2007) or idiopathic infertility (LIF and PAEP; Laird et al., 1997; Skrzypczak et al., 2005; Mikolajczyk et al., 2007). Three additional proteins, calcitonin (CALCA; Diao et al., 2002; Kumar et al., 2003), progesterone receptor-B (PGR-B; Franco et al., 2008) and heparin-binding epidermal growth factor-like growth factor (HBEGF; Das et al., 1994; Yoo et al., 1997; Lessey et al., 2002), are implicated in uterine receptivity for implantation. "
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    ABSTRACT: Although histological dating of endometrial biopsies provides little help for prediction or diagnosis of infertility, analysis of individual endometrial proteins, proteomic profiling and transcriptome analysis have suggested several biomarkers with altered expression arising from intrinsic abnormalities, inadequate stimulation by or in response to gonadal steroids or altered function due to systemic disorders. The objective of this study was to delineate the developmental dynamics of potentially important proteins in the secretory phase of the menstrual cycle, utilizing a collection of endometrial biopsies from women of fertile (n = 89) and infertile (n = 89) couples. Progesterone receptor-B (PGR-B), leukemia inhibitory factor, glycodelin/progestagen-associated endometrial protein (PAEP), homeobox A10, heparin-binding EGF-like growth factor, calcitonin and chemokine ligand 14 (CXCL14) were measured using a high-throughput, quantitative immunohistochemical method. Significant cyclic and tissue-specific regulation was documented for each protein, as well as their dysregulation in women of infertile couples. Infertile patients demonstrated a delay early in the secretory phase in the decline of PGR-B (P < 0.05) and premature mid-secretory increases in PAEP (P < 0.05) and CXCL14 (P < 0.05), suggesting that the implantation interval could be closing early. Correlation analysis identified potential interactions among certain proteins that were disrupted by infertility. This approach overcomes the limitations of a small sample number. Protein expression and localization provided important insights into the potential roles of these proteins in normal and pathological development of the endometrium that is not attainable from transcriptome analysis, establishing a basis for biomarker, diagnostic and targeted drug development for women with infertility.
    Full-text · Article · Jan 2012 · Human Reproduction
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