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Abstract：
OBJECTIVE: Is B-cell CLL/lymphoma 6 (BCL6) endometrial expression, a surrogate biomarker of endometriosis, elevated in women with unexplained recurrent pregnancy loss (uRPL) and unexplained infertility (UI) compared to fertile subjects?
CONCLUSIONS: Endometrial BCL6 expression is elevated to a similar degree in women with uRPL and UI compared to fertile controls.
BACKGROUND: Endometriosis has been linked to the genesis of endometrial progesterone resistance and to specific nuclear proteins, including endometrial BCL6. BCL6 overexpression (immune histologic score > 1.4) has been strongly associated with poor reproductive outcomes in IVF cycles in women with UI. Our previous data have demonstrated an accuracy of 94% for diagnosing endometriosis, and BCL6 protein is elevated in the decidua of women with uRPL.
UNASSIGNED: In this case-control study, at a tertiary university teaching hospital, 110 samples (control n = 28; uRPL n = 29; UI n = 53) from pathological archives were analyzed. Timed endometrial biopsies were obtained between 2 January 2002 and 31 December 2016.
UNASSIGNED: LH-timed endometrial biopsies were obtained from women with UI, uRPL (two or more consecutive losses) and normal fertile subjects during the mid-secretory phase of the menstrual cycle. Endometrial BCL6 protein levels were compared in women with UI and uRPL and fertile controls using western blot analysis and immunohistochemistry (HSCORE).
RESULTS: The mean age of the uRPL group was significantly higher than the others [mean (SD)] control = 32.7 (2.6); uRPL = 35.8 (3.7); UI = 32.7 (4.4); P = 0.002, ANOVA]. Seventy-nine percent of women in both subfertile groups (uRPL and UI, 65 out of 82) displayed elevated BCL6 protein levels. From these, a subset of cases with abnormal BCL6 went to laparoscopy and endometriosis was found in 9 out of 11 cases of uRPL and in 20 out of 21 cases of UI. Median BCL6 HSCORE for controls versus uRPL and UI was significantly different [median (interquartile); control = 0.3 (0.02 to 0.5); uRPL = 3 (1.9 to 3.6); UI = 2.9 (1.6 to 3.1); P < 0.0001, Kruskal-Wallis]. A significant trend in the association between the degree of infertility (fertile, uRPL and UI) and the HSCORE level (negative, medium and high) was found (P < 0.001; x 2 for trend). Western blot of representative samples from each group demonstrated similar findings based on protein levels in the whole endometrium. After running ANCOVA analysis for age difference, the BCL6 difference among groups was still significant (P-value < 0.0001).
CONCLUSIONS: We studied subjects with two consecutive pregnancy losses rather than the definition adopted in Europe of three losses. The findings may lack external validity in other clinical settings (e.g. low prevalence of endometriosis).
CONCLUSIONS: Based on the data presented here, we postulate that the degree of BCL6 expression may represent a continuum of progesterone resistance and response to inflammation that occurs in women with endometriosis, yielding different degrees of infertility, from uRPL to UI.
BACKGROUND: This study was supported by NICHD/NIH R01 HD067721 (SLY and BAL), by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior: Grant 99999.003035/2015-08 (BAL) and by CAPES/PROAP (RFS). Two authors (BAL, SLY) have licensed intellectual property for the detection of endometriosis. Dr Bruce Lessey is an unpaid scientific Advisor for CiceroDx. The other authors report no conflict of interest.
CONCLUSIONS: Endometrial BCL6 expression is elevated to a similar degree in women with uRPL and UI compared to fertile controls.
BACKGROUND: Endometriosis has been linked to the genesis of endometrial progesterone resistance and to specific nuclear proteins, including endometrial BCL6. BCL6 overexpression (immune histologic score > 1.4) has been strongly associated with poor reproductive outcomes in IVF cycles in women with UI. Our previous data have demonstrated an accuracy of 94% for diagnosing endometriosis, and BCL6 protein is elevated in the decidua of women with uRPL.
UNASSIGNED: In this case-control study, at a tertiary university teaching hospital, 110 samples (control n = 28; uRPL n = 29; UI n = 53) from pathological archives were analyzed. Timed endometrial biopsies were obtained between 2 January 2002 and 31 December 2016.
UNASSIGNED: LH-timed endometrial biopsies were obtained from women with UI, uRPL (two or more consecutive losses) and normal fertile subjects during the mid-secretory phase of the menstrual cycle. Endometrial BCL6 protein levels were compared in women with UI and uRPL and fertile controls using western blot analysis and immunohistochemistry (HSCORE).
RESULTS: The mean age of the uRPL group was significantly higher than the others [mean (SD)] control = 32.7 (2.6); uRPL = 35.8 (3.7); UI = 32.7 (4.4); P = 0.002, ANOVA]. Seventy-nine percent of women in both subfertile groups (uRPL and UI, 65 out of 82) displayed elevated BCL6 protein levels. From these, a subset of cases with abnormal BCL6 went to laparoscopy and endometriosis was found in 9 out of 11 cases of uRPL and in 20 out of 21 cases of UI. Median BCL6 HSCORE for controls versus uRPL and UI was significantly different [median (interquartile); control = 0.3 (0.02 to 0.5); uRPL = 3 (1.9 to 3.6); UI = 2.9 (1.6 to 3.1); P < 0.0001, Kruskal-Wallis]. A significant trend in the association between the degree of infertility (fertile, uRPL and UI) and the HSCORE level (negative, medium and high) was found (P < 0.001; x 2 for trend). Western blot of representative samples from each group demonstrated similar findings based on protein levels in the whole endometrium. After running ANCOVA analysis for age difference, the BCL6 difference among groups was still significant (P-value < 0.0001).
CONCLUSIONS: We studied subjects with two consecutive pregnancy losses rather than the definition adopted in Europe of three losses. The findings may lack external validity in other clinical settings (e.g. low prevalence of endometriosis).
CONCLUSIONS: Based on the data presented here, we postulate that the degree of BCL6 expression may represent a continuum of progesterone resistance and response to inflammation that occurs in women with endometriosis, yielding different degrees of infertility, from uRPL to UI.
BACKGROUND: This study was supported by NICHD/NIH R01 HD067721 (SLY and BAL), by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior: Grant 99999.003035/2015-08 (BAL) and by CAPES/PROAP (RFS). Two authors (BAL, SLY) have licensed intellectual property for the detection of endometriosis. Dr Bruce Lessey is an unpaid scientific Advisor for CiceroDx. The other authors report no conflict of interest.
摘要：
目的：是B细胞CLL/淋巴瘤6（BCL6）子宫内膜表达，子宫内膜异位症的替代生物标志物，
结论：与育龄对照组相比，患有原因不明的复发性妊娠丢失(uRPL)和原因不明的不孕症(UI)的女性子宫内膜BCL6表达升高的程度相似。
背景：子宫内膜异位症与子宫内膜孕酮抵抗的发生和特定的核蛋白有关，包括子宫内膜BCL6。BCL6过表达（免疫组织学评分>1.4）与UI女性的IVF周期不良生殖结局密切相关。我们以前的数据显示诊断子宫内膜异位症的准确率为94%。并且BCL6蛋白在患有uRPL的女性蜕膜中升高。
未经评估：在本病例对照研究中，在一所大学教学医院，分析了来自病理档案的110个样品(对照n=28;uRPLn=29;UIn=53)。在2002年1月2日至2016年12月31日期间进行子宫内膜活检。
未经证实：LH定时子宫内膜活检取自有UI的女性，在月经周期的分泌中期，uRPL（两个或多个连续损失）和正常的可育受试者。使用蛋白质印迹分析和免疫组织化学（HSCORE）比较了患有UI和uRPL的女性和可育对照的子宫内膜BCL6蛋白水平。
结果：uRPL组的平均年龄显着高于其他对照组[平均值（SD）]=32.7（2.6）；uRPL=35.8（3.7）；UI=32.7（4.4）；P=0.002，方差分析]。在这两个低生育能力组(uRPL和UI，82个中的65个）显示BCL6蛋白水平升高。从这些,一部分BCL6异常病例进入腹腔镜检查，11例uRPL中有9例发现子宫内膜异位症，21例UI中有20例发现子宫内膜异位症。对照的BCL6HSCORE中位数与uRPL和UI存在显着差异[中位数（四分位数间）；对照=0.3（0.02至0.5）；uRPL=3（1.9至3.6）；UI=2.9（1.6至3.1）；P<0.0001，Kruskal-Wallis]。不孕症程度(肥沃，uRPL和UI)和HSCORE级别(负，发现中等和高)(P<0.001；x2表示趋势)。来自每组的代表性样品的Western印迹显示基于整个子宫内膜中的蛋白质水平的相似发现。在对年龄差异进行ANCOVA分析后，组间BCL6差异仍有统计学意义(P值<0.0001).
结论：我们研究了连续两次流产的受试者，而不是欧洲采用的三次流产的定义。这些发现在其他临床环境中可能缺乏外部有效性（例如子宫内膜异位症的低患病率）。
结论：根据此处提供的数据，我们推测BCL6的表达程度可能代表了子宫内膜异位症女性中孕激素抵抗和对炎症反应的连续性，产生不同程度的不孕症，从uRPL到UI。
背景：这项研究得到了NICHD/NIHR01HD067721（SLY和BAL）的支持，作者：CoordenaçãodeAperfeiçoamentodePessoaldeNívelSuperior：Grant99999.003035/2015-08（BAL）和CAPES/PROAP（RFS）。两位作者（BAL，SLY）具有用于检测子宫内膜异位症的许可知识产权。布鲁斯·莱西博士是CiceroDx的无偿科学顾问。其他作者报告没有利益冲突。
结论：与育龄对照组相比，患有原因不明的复发性妊娠丢失(uRPL)和原因不明的不孕症(UI)的女性子宫内膜BCL6表达升高的程度相似。
背景：子宫内膜异位症与子宫内膜孕酮抵抗的发生和特定的核蛋白有关，包括子宫内膜BCL6。BCL6过表达（免疫组织学评分>1.4）与UI女性的IVF周期不良生殖结局密切相关。我们以前的数据显示诊断子宫内膜异位症的准确率为94%。并且BCL6蛋白在患有uRPL的女性蜕膜中升高。
未经评估：在本病例对照研究中，在一所大学教学医院，分析了来自病理档案的110个样品(对照n=28;uRPLn=29;UIn=53)。在2002年1月2日至2016年12月31日期间进行子宫内膜活检。
未经证实：LH定时子宫内膜活检取自有UI的女性，在月经周期的分泌中期，uRPL（两个或多个连续损失）和正常的可育受试者。使用蛋白质印迹分析和免疫组织化学（HSCORE）比较了患有UI和uRPL的女性和可育对照的子宫内膜BCL6蛋白水平。
结果：uRPL组的平均年龄显着高于其他对照组[平均值（SD）]=32.7（2.6）；uRPL=35.8（3.7）；UI=32.7（4.4）；P=0.002，方差分析]。在这两个低生育能力组(uRPL和UI，82个中的65个）显示BCL6蛋白水平升高。从这些,一部分BCL6异常病例进入腹腔镜检查，11例uRPL中有9例发现子宫内膜异位症，21例UI中有20例发现子宫内膜异位症。对照的BCL6HSCORE中位数与uRPL和UI存在显着差异[中位数（四分位数间）；对照=0.3（0.02至0.5）；uRPL=3（1.9至3.6）；UI=2.9（1.6至3.1）；P<0.0001，Kruskal-Wallis]。不孕症程度(肥沃，uRPL和UI)和HSCORE级别(负，发现中等和高)(P<0.001；x2表示趋势)。来自每组的代表性样品的Western印迹显示基于整个子宫内膜中的蛋白质水平的相似发现。在对年龄差异进行ANCOVA分析后，组间BCL6差异仍有统计学意义(P值<0.0001).
结论：我们研究了连续两次流产的受试者，而不是欧洲采用的三次流产的定义。这些发现在其他临床环境中可能缺乏外部有效性（例如子宫内膜异位症的低患病率）。
结论：根据此处提供的数据，我们推测BCL6的表达程度可能代表了子宫内膜异位症女性中孕激素抵抗和对炎症反应的连续性，产生不同程度的不孕症，从uRPL到UI。
背景：这项研究得到了NICHD/NIHR01HD067721（SLY和BAL）的支持，作者：CoordenaçãodeAperfeiçoamentodePessoaldeNívelSuperior：Grant99999.003035/2015-08（BAL）和CAPES/PROAP（RFS）。两位作者（BAL，SLY）具有用于检测子宫内膜异位症的许可知识产权。布鲁斯·莱西博士是CiceroDx的无偿科学顾问。其他作者报告没有利益冲突。
