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Testicular mosaicism in non-mosaic postpubertal Klinefelter patients with focal spermatogenesis and in non-mosaic prepubertal Klinefelter boys. 有局灶性精子生成的非嵌合型青春期后 Klinefelter 患者和非嵌合型青春期前 Klinefelter 男孩的睾丸嵌合。
IF 6 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2024-10-01 DOI: 10.1093/humrep/deae192
Semir Gül, Veerle Vloeberghs, Inge Gies, Ellen Goossens
<p><strong>Study question: </strong>Do testis-specific cells have a normal karyotype in non-mosaic postpubertal Klinefelter syndrome (KS) patients with focal spermatogenesis and in non-mosaic prepubertal KS boys?</p><p><strong>Summary answer: </strong>Spermatogonia have a 46, XY karyotype, and Sertoli cells surrounding these spermatogonia in postpubertal patients also have a 46, XY karyotype, whereas, in prepubertal KS boys, Sertoli cells surrounding the spermatogonia still have a 47, XXY karyotype.</p><p><strong>What is known already: </strong>A significant proportion of patients with non-mosaic KS can have children by using assisted reproductive techniques thanks to focal spermatogenesis. However, the karyotype of the cells that are able to support focal spermatogenesis has not been revealed.</p><p><strong>Study design, size, duration: </strong>Testicular biopsy samples from non-mosaic KS patients were included in the study. Karyotyping for sex chromosomes in testis-specific cells was performed by immunohistochemical analysis of inactive X (Xi) chromosome and/or fluorescent in situ hybridization (FISH) analysis of chromosomes 18, X, and Y.</p><p><strong>Participants/materials, setting, methods: </strong>A total of 22 KS patients (17 postpubertal and 5 prepubertal) who were non-mosaic according to lymphocyte karyotype analysis, were included in the study. After tissue processing, paraffin embedding, and sectioning, the following primary antibodies were used for cell-specific analysis and Xi detection; one section was stained with MAGE A4 for spermatogonia, SOX9 for Sertoli cells, and H3K27me3 for Xi; the other one was stained with CYP17A1 for Leydig cells, ACTA2 for peritubular myoid cells, and H3K27me3 for Xi. Xi negative (Xi-) somatic cells (i.e. Sertoli cells, Leydig cells, and peritubular myoid cells) were evaluated as having the 46, XY karyotype; Xi positive (Xi+) somatic cells were evaluated as having the 47, XXY. FISH stain for chromosomes 18, X, and Y was performed on the same sections to investigate the karyotype of spermatogonia and to validate the immunohistochemistry results for somatic cells.</p><p><strong>Main results and the role of chance: </strong>According to our data, all spermatogonia in both postpubertal and prepubertal non-mosaic KS patients seem to have 46, XY karyotype. However, while the Sertoli cells surrounding spermatogonia in postpubertal samples also had a 46, XY karyotype, the Sertoli cells surrounding spermatogonia in prepubertal samples had a 47, XXY karyotype. In addition, while the Sertoli cells in some of the Sertoli cell-only tubules had 46, XY karyotype, the Sertoli cells in some of the other Sertoli cell-only tubules had 47, XXY karyotype in postpubertal samples. In contrast to the postpubertal samples, Sertoli cells in all tubules in the prepubertal samples had the 47, XXY karyotype. Our data also suggest that germ cells lose the extra X chromosome during embryonic, fetal, or neonatal life, while Sertoli c
研究问题:在有局灶性精子生成的非嵌合型青春期后克氏综合征(KS)患者和非嵌合型青春期前克氏综合征男孩中,睾丸特异性细胞的核型是否正常?青春期后患者精原细胞的核型为46,XY,围绕这些精原细胞的Sertoli细胞的核型也为46,XY,而在青春期前的KS男孩中,围绕精原细胞的Sertoli细胞的核型仍为47,XXY:已经知道的是:相当一部分非马赛克 KS 患者可以通过辅助生殖技术,利用局灶性精子发生技术生儿育女。然而,能够支持局灶性精子发生的细胞的核型尚未揭示:研究包括非马赛克 KS 患者的睾丸活检样本。通过免疫组化分析非活性X(Xi)染色体和/或荧光原位杂交(FISH)分析18、X和Y染色体,对睾丸特异性细胞中的性染色体进行核型分析:研究共纳入了 22 名 KS 患者(17 名青春期后,5 名青春期前),根据淋巴细胞核型分析,这些患者均为非马赛克患者。组织处理、石蜡包埋和切片后,使用以下一抗进行细胞特异性分析和Xi检测:一张切片用MAGE A4染色以检测精原细胞,用SOX9染色以检测Sertoli细胞,用H3K27me3染色以检测Xi;另一张切片用CYP17A1染色以检测Leydig细胞,用ACTA2染色以检测管周肌细胞,用H3K27me3染色以检测Xi。Xi阴性(Xi-)体细胞(即Sertoli细胞、Leydig细胞和管周肌细胞)被评估为具有46, XY核型;Xi阳性(Xi+)体细胞被评估为具有47, XXY核型。对同一切片进行了 18、X 和 Y 染色体的 FISH 染色,以研究精原细胞的核型,并验证体细胞的免疫组化结果:根据我们的数据,青春期后和青春期前非嵌合型KS患者的所有精原细胞似乎都是46, XY核型。然而,在青春期后的样本中,精原细胞周围的 Sertoli 细胞也是 46 XY 核型,而在青春期前的样本中,精原细胞周围的 Sertoli 细胞却是 47 XXY 核型。此外,在青春期后样本中,部分仅有 Sertoli 细胞的小管中的 Sertoli 细胞核型为 46 XY,而其他一些仅有 Sertoli 细胞的小管中的 Sertoli 细胞核型为 47 XXY。与青春期后样本相反,青春期前样本中所有小管中的 Sertoli 细胞都是 47, XXY 核型。我们的数据还表明,生殖细胞在胚胎期、胎儿期或新生儿期会失去额外的X染色体,而Sertoli细胞在青春期前后会失去额外的X染色体。在青春期后的患者和青春期前的男孩中,管周肌细胞和雷迪格细胞也可能是马赛克的,但这还需要进一步研究:含有精原细胞的青春期前睾丸样本数量有限,因此需要更多样本才能得出明确结论。并非所有细胞核都与切片平面重合,这限制了通过免疫组化和 FISH 在某些细胞中准确检测 X 染色体。为克服这一限制,可采用不同技术对从新鲜组织中分离出来的完整细胞进行 X 染色体分析。此外,没有证据表明胚胎发育过程中生殖细胞迁移过程中 Xi 激活后 X 染色体失活会再次发生,这限制了通过 H3K27me3 预测生殖细胞中 X 染色体含量:我们的发现将为开展新的临床重要研究奠定基础,这些研究将探讨精原细胞和Sertoli细胞中额外的X染色体究竟何时以及通过何种机制丢失:本研究得到了土耳其科学技术研究理事会(TUBITAK)(2219--土耳其公民国际博士后研究奖学金计划)和布鲁塞尔自由大学战略研究计划(SRP89)的资助。作者声明不存在利益冲突:不适用。
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引用次数: 0
Exploring the impact of fertility-preserving treatment on pregnancy: key issues in patients with endometrial cancer and atypical hyperplasia. 探讨保留生育功能的治疗对怀孕的影响:子宫内膜癌和非典型增生患者的关键问题。
IF 6 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2024-10-01 DOI: 10.1093/humrep/deae187
Wei-Zhen Tang, Tai-Hang Liu
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引用次数: 0
Trophectoderm grade is associated with the risk of placenta previa in frozen-thawed single-blastocyst transfer cycles. 在冷冻解冻的单囊胚移植周期中,胎膜等级与前置胎盘的风险有关。
IF 6 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2024-10-01 DOI: 10.1093/humrep/deae172
Jiaan Huang, Yao Lu, Yaqiong He, Yuan Wang, Qinling Zhu, Jia Qi, Ying Ding, Xinyu Li, Ziyin Ding, Steven R Lindheim, Yun Sun
<p><strong>Study question: </strong>Do obstetric and perinatal complications vary according to different blastocyst developmental parameters after frozen-thawed single-blastocyst transfer (SBT) cycles?</p><p><strong>Summary answer: </strong>Pregnancies following the transfer of a blastocyst with a grade C trophectoderm (TE) were associated with an increased risk of placenta previa compared to those with a blastocyst of grade A TE.</p><p><strong>What is known already: </strong>Existing studies investigating the effect of blastocyst morphology grades on birth outcomes have mostly focused on fetal growth and have produced conflicting results, while the risk of obstetric complications has rarely been reported. Additionally, growing evidence has suggested that the appearance of TE cells could serve as the most important parameter for predicting implantation and live birth. Given that the TE ultimately develops into the placenta, it is plausible that this independent predictor may also impact placentation.</p><p><strong>Study design, size, duration: </strong>This retrospective cohort study at a tertiary-care academic medical center included 6018 singleton deliveries after frozen-thawed SBT cycles between January 2017 and December 2021.</p><p><strong>Participants/materials, setting, methods: </strong>Singleton pregnancies were grouped into two groups according to blastocyst developmental stage (Days 5 and 6), four groups according to embryo expansion (Stages 3, 4, 5, and 6), three groups according to inner cell mass (ICM) quality (A, B, and C), and three groups according to TE quality (A, B, and C). The main outcomes included pregnancy-induced hypertension, preeclampsia, gestational diabetes mellitus, preterm premature rupture of membrane, placenta previa, placental abruption, placenta accreta, postpartum hemorrhage, preterm birth, low birth weight, small for gestational age, and birth defects. Multivariate logistic regressions were performed to evaluate the effect of blastocyst developmental stage, embryo expansion stage, ICM grade, and TE grade on measured outcomes adjusting for potential confounders.</p><p><strong>Main results and the role of chance: </strong>No association was found between blastocyst developmental stage and obstetric or perinatal outcomes both before and after adjusting for potential confounders, and similar results were found with regard to embryo expansion stage and ICM grade. Meanwhile, the incidence of placenta previa derived from a blastocyst with TE of grade C was higher compared with those derived from a blastocyst with TE of grade A (1.7%, 2.4%, and 4.0% for A, B, and C, respectively, P = 0.001 for all comparisons). After adjusting for potential covariates, TE grade C blastocysts had 2.81 times the likelihood of resulting in placenta previa compared to TE grade A blastocysts (adjusted odds ratio 2.81, 95% CI 1.11-7.09). No statistically significant differences were detected between any other measured outcomes and TE grades
研究问题:冷冻解冻单囊胚移植(SBT)周期后,产科和围产期并发症是否因囊胚发育参数的不同而不同?与移植 A 级滋养层(TE)囊胚的孕妇相比,移植 C 级滋养层(TE)囊胚的孕妇发生前置胎盘的风险更高:关于囊胚形态等级对分娩结局影响的现有研究主要集中在胎儿生长方面,结果相互矛盾,而产科并发症风险方面的研究则鲜有报道。此外,越来越多的证据表明,TE 细胞的出现可作为预测植入和活产的最重要参数。鉴于TE最终会发育成胎盘,这一独立的预测因素也可能会影响胎盘:这项回顾性队列研究在一家三级医疗学术医学中心进行,纳入了 2017 年 1 月至 2021 年 12 月间经过冷冻解冻 SBT 周期的 6018 例单胎分娩:根据囊胚发育阶段(第5天和第6天)将单胎妊娠分为两组,根据胚胎扩张情况(第3、4、5和6阶段)分为四组,根据内细胞团(ICM)质量(A、B和C)分为三组,根据TE质量(A、B和C)分为三组。主要结果包括妊娠高血压、子痫前期、妊娠糖尿病、早产胎膜早破、前置胎盘、胎盘早剥、胎盘早剥、产后出血、早产、低出生体重、胎龄小和出生缺陷。通过多变量逻辑回归评估囊胚发育阶段、胚胎扩张阶段、ICM 分级和 TE 分级对测量结果的影响,并对潜在的混杂因素进行调整:主要结果和偶然性的作用:在调整潜在混杂因素之前和之后,均未发现囊胚发育阶段与产科或围产期结果之间存在关联,胚胎膨大期和 ICM 分级也发现了类似的结果。同时,TE 为 C 级的囊胚与 TE 为 A 级的囊胚相比,前置胎盘的发生率更高(A、B 和 C 级分别为 1.7%、2.4% 和 4.0%,所有比较的 P = 0.001)。调整潜在的协变量后,TE C 级囊胚导致前置胎盘的可能性是 TE A 级囊胚的 2.81 倍(调整后的几率比 2.81,95% CI 1.11-7.09)。无论调整前还是调整后,其他测量结果与 TE 等级之间均未发现有统计学意义的差异:该研究的局限性在于其回顾性的单中心设计。此外,虽然研究组的样本量相对较大,但某些亚组的样本量相对较小,缺乏足够的力量,尤其是 ICM C 级组。因此,在解释这些结果时应谨慎:本研究扩展了我们对 TE 分级对胎盘异常的潜在下游影响的认识:本研究得到了国家重点研发计划(2023YFC2705500, 2023YFC2705501, 2023YFC2705505, 2019YFA0802604)、国家自然科学基金(82130046, 82320108009, 82371660, 32300710)、上海市领军人才计划、创新研究团队等的资助;上海市领军人才计划、上海市地方高校高水平创新研究团队(SHSMU-ZLCX20210201、SHSMU-ZLCX20210200、SHSMU-ZLCX20180401)、上海交通大学医学院附属仁济医院临床科研创新培养基金项目(RJPY-DZX-003)、上海市科学技术委员会(23Y11901400)、上海市重中之重研究中心建设项目(2023ZZ02002)、上海市加强公共卫生体系建设三年行动计划(GWVI-11.1-36).作者无利益冲突:不适用。
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引用次数: 0
Clinical pregnancy rates after blastocyst culture at a stable temperature of 36.6°C versus 37.1°C: a prospective randomized controlled trial. 在 36.6°C 与 37.1°C 的稳定温度下进行囊胚培养后的临床妊娠率:一项前瞻性随机对照试验。
IF 6 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2024-10-01 DOI: 10.1093/humrep/deae193
Koen Wouters, Ileana Mateizel, Ingrid Segers, Hilde Van de Velde, Lisbet Van Landuyt, Anick De Vos, Celine Schoemans, Danijel Jankovic, Christophe Blockeel, Panagiotis Drakopoulos, Herman Tournaye, Neelke De Munck
<p><strong>Study question: </strong>Is there a difference in clinical pregnancy rates (CPRs) in good prognosis patients after single embryo transfer (SET) on Day 5, in case of stable culture at 36.6°C or 37.1°C?</p><p><strong>Summary answer: </strong>CPR (with heartbeat at 7 weeks) after blastocyst transfer do not differ after culturing at 36.6°C or 37.1°C.</p><p><strong>What is known already: </strong>Since the beginning of IVF, embryo culture has been performed at 37.0°C; however, the optimal culture temperature remains unknown. Changes in incubator types have led to significant improvements in temperature control. Stable temperature control, i.e. with temperature differences of max. 0.1°C between chambers, is possible in some incubators. A previous prospective pilot study showed that embryo development on Day 5/6 was not affected when embryos were cultured at a stable temperature of 36.6°C or 37.1°C, but culture at 37.1°C resulted in an increased CPR when compared to culture at 36.6°C (74.2% vs 46.4%).</p><p><strong>Study design, size, duration: </strong>A prospective randomized controlled trial was performed in a tertiary fertility centre between February 2017 and November 26, 2022. A sample size of 89/89 patients with fresh single embryo transfer (SET) was required to achieve 80% power to detect a difference of 0.22 between group proportions (0.43-0.65) at a significance level of 0.05 using a two-sided z-test with continuity correction.</p><p><strong>Participants/materials, setting, methods: </strong>Patients were recruited on the day of oocyte retrieval based on inclusion criteria with final randomization after denudation once six mature oocytes were present. The primary endpoint was CPR (heartbeat at 7 weeks); secondary endpoints were fertilization rate, blastocyst development, biochemical pregnancy rate, live birth rate (LBR), and cumulative live birth rate (CLBR).</p><p><strong>Main results and the role of chance: </strong>A total of 304 patients were eligible for the study; of these 268 signed the consent, 234 (intention-to-treat) were randomized and 181 (per-protocol) received a SET on Day 5: 90 received culture at 36.6°C and 91 at 37.1°C. Patients were on average 32.4 ± 3.5 versus 32.5 ± 4.2 years old, respectively. No differences were observed in embryological outcomes per cycle between culture at 36.6°C versus 37.1°C: 12.0 ± 3.8 vs 12.1 ± 3.8 COCs retrieved (P = 0.88), 10.0 ± 3.1 versus 9.9 ± 2.9 mature oocytes inseminated (P = 0.68), with a maturation rate of 84.2% (901/1083) versus 83.5% (898/1104) (P = 0.87); and 8.0 ± 3.1 versus 7.9 ± 2.7 normally fertilized oocytes with a fertilization rate of 79.7% (720/901) vs 80.5% (718/898) (P = 0.96), respectively. On average 1.5 ± 1.7 versus 1.4 ± 1.9 (P = 0.25) and 1.1 ± 1.1 versus 0.9 ± 1.0 (P = 0.45) supernumerary blastocysts were vitrified on Day 5 and Day 6, respectively. The utilization rate per fertilized oocyte was 46.1% vs 41.5% (P = 0.14). A SET was performed for 181 patients, l
研究问题:在 36.6°C 或 37.1°C 稳定培养的情况下,预后良好的患者在第 5 天进行单胚胎移植(SET)后的临床妊娠率(CPR)是否存在差异?囊胚移植后的 CPR(7 周时有心跳)在 36.6°C 或 37.1°C 温度下培养后没有差异:自体外受精开始以来,胚胎培养一直在 37.0°C 进行;但是,最佳培养温度仍然未知。培养箱类型的变化使温度控制有了显著改善。稳定的温度控制,即培养室之间的温差不超过 0.1°C。0.1°C。之前的一项前瞻性试验研究表明,在 36.6°C 或 37.1°C 的稳定温度下培养胚胎,第 5/6 天的胚胎发育不受影响,但与 36.6°C 的培养温度相比,37.1°C 的培养温度导致 CPR 增加(74.2% 对 46.4%):一项前瞻性随机对照试验于2017年2月至2022年11月26日在一家三级生殖中心进行。样本量为89/89例新鲜单胚胎移植(SET)患者,需要达到80%的功率,才能在0.05的显著性水平下检测到组间比例(0.43-0.65)0.22的差异,采用双侧z检验并进行连续性校正:根据纳入标准在取卵当天招募患者,一旦出现六个成熟卵母细胞,则在去核后进行最终随机化。主要终点是CPR(7周时的心跳);次要终点是受精率、囊胚发育、生化妊娠率、活产率(LBR)和累积活产率(CLBR):共有 304 名患者符合研究条件;其中 268 人签署了同意书,234 人(意向治疗)被随机分配,181 人(按协议)在第 5 天接受了 SET:90 人在 36.6°C 接受了培养,91 人在 37.1°C 接受了培养。患者的平均年龄分别为(32.4 ± 3.5)岁和(32.5 ± 4.2)岁。36.6°C与37.1°C的胚胎培养结果无差异:取回的 COC 为 12.0 ± 3.8 对 12.1 ± 3.8(P = 0.88),授精的成熟卵母细胞为 10.0 ± 3.1 对 9.9 ± 2.9(P = 0.68),成熟率为 84.2%(901/1083)对 83.5%(898/1104)(P = 0.87);正常受精卵细胞数为 8.0 ± 3.1 对 7.9 ± 2.7,受精率分别为 79.7%(720/901)对 80.5%(718/898)(P = 0.96)。第 5 天和第 6 天玻璃化的超数囊胚平均分别为 1.5 ± 1.7 对 1.4 ± 1.9(P = 0.25)和 1.1 ± 1.1 对 0.9 ± 1.0(P = 0.45)。每个受精卵细胞的利用率为 46.1% 对 41.5%(P = 0.14)。181 名患者进行了 SET,生化妊娠率分别为 72.2%(65/90)和 62.7%(57/91)(P = 0.17)。每个新鲜移植周期的 CPR 为 51.1%(46/90)对 48.4%(44/91)[OR (95% CI) 1.11 (0.59-2.08), P = 0.710]。迄今为止,观察到的 CLBR 分别为 73.3%(66/90)和 67.0%(61/91)(P = 0.354)。每组中,都有 7 名没有活产的患者冷冻了剩余的囊胚。意向治疗组的 CPR 分别为 38.3% vs 38.6% [OR (95% CI) 0.98 (0.56-1.73),P = 0.967],培养温度为 36.6°C vs 37.1°C:研究结果的广泛意义:胚胎在培养至囊胚期期间往往能容忍温度偏差的微小变化,这一点从胚胎在两种略有不同的温度下具有相似的植入潜力中可以看出:试验注册号:NCT03548532:NCT03548532.Trial registration date: 23 October 2017.Date of first patient's enrolment:2017年11月10日。
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引用次数: 0
Is AMH a promising predictive biomarker for mTESE success in iNOA patients? AMH 是预测 iNOA 患者 mTESE 成功与否的可靠生物标志物吗?
IF 6 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2024-10-01 DOI: 10.1093/humrep/deae179
Julia Uraji, Juan J Fraire-Zamora, Claudia Massarotti, Sofia Makieva, George Liperis, Kashish Sharma, Sarah Martins da Silva, Raevti Bole, Jackson C Kirkman-Brown, Omar Farhan Ammar
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引用次数: 0
Development of an IVF prediction model for donor oocytes: a retrospective analysis of 10 877 embryo transfers. 开发供体卵母细胞试管婴儿预测模型:对 10 877 例胚胎移植的回顾性分析。
IF 6 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2024-10-01 DOI: 10.1093/humrep/deae174
Oisin Fitzgerald, Jade Newman, Luk Rombauts, Alex Polyakov, Georgina M Chambers
<p><strong>Study question: </strong>Can we develop a prediction model for the chance of a live birth following the transfer of an embryo created using donated oocytes?</p><p><strong>Summary answer: </strong>Three primary models that included patient, past treatment, and cycle characteristics were developed using Australian data to predict the chance of a live birth following the transfer of an embryo created using donated oocytes; these models were well-calibrated to the population studied, achieved reasonable predictive power and generalizability when tested on New Zealand data.</p><p><strong>What is known already: </strong>Nearly 9% of ART embryo transfer cycles performed globally use embryos created using donated oocytes. This percentage rises to one-quarter and one-half in same-sex couples and women aged over 45 years, respectively.</p><p><strong>Study design, size, duration: </strong>This study uses population-based Australian clinical registry data comprising 9384 embryo transfer cycles that occurred between 2015 and 2021 for model development, with an external validation cohort of 1493 New Zealand embryo transfer cycles.</p><p><strong>Participants/materials, setting, methods: </strong>Three prediction models were compared that incorporated patient characteristics, but differed in whether they considered use of prior autologous treatment factors and current treatment parameters. We internally validated the models on Australian data using grouped cross-validation and reported several measures of model discrimination and calibration. Variable importance was measured through calculating the change in predictive performance that resulted from variable permutation. The best-performing model was externally validated on data from New Zealand.</p><p><strong>Main results and the role of chance: </strong>The best-performing model had an internal validation AUC-ROC of 0.60 and Brier score of 0.20, and external validation AUC-ROC of 0.61 and Brier score of 0.23. While these results indicate ∼15% less discriminatory ability compared to models assessed on an autologous cohort from the same population the performance of the models was clearly statistically significantly better than random, demonstrated generalizability, and was well-calibrated to the population studied. The most important variables for predicting the chance of a live birth were the oocyte donor age, the number of prior oocyte recipient embryo transfer cycles, whether the transferred embryo was cleavage or blastocyst stage and oocyte recipient age. Of lesser importance were the oocyte-recipient parity, whether donor or partner sperm was used, the number of prior autologous embryo transfer cycles and the number of embryos transferred.</p><p><strong>Limitations, reasons for caution: </strong>The models had relatively weak discrimination suggesting further features need to be added to improve their predictive power. Variation in donor oocyte cohorts across countries due to differences such as
研究问题:我们能否建立一个预测模型,预测使用捐赠卵母细胞制作的胚胎移植后的活产几率?利用澳大利亚的数据建立了三个主要模型,其中包括患者、既往治疗和周期特征,用于预测使用捐赠卵母细胞进行胚胎移植后的活产几率;这些模型与所研究的人群进行了很好的校准,在新西兰的数据上进行测试时达到了合理的预测能力和可推广性:全球近 9% 的 ART 胚胎移植周期使用捐赠卵母细胞制作的胚胎。在同性伴侣和 45 岁以上女性中,这一比例分别上升到四分之一和二分之一:本研究使用基于人口的澳大利亚临床登记数据,包括 2015 年至 2021 年间发生的 9384 个胚胎移植周期,用于开发模型,并使用 1493 个新西兰胚胎移植周期作为外部验证队列:我们比较了三种预测模型,它们都包含患者特征,但在是否考虑使用先前的自体治疗因素和当前治疗参数方面有所不同。我们在澳大利亚的数据上使用分组交叉验证对模型进行了内部验证,并报告了模型辨别度和校准度的几种测量方法。变量重要性是通过计算变量排列导致的预测性能变化来衡量的。在新西兰的数据上对表现最佳的模型进行了外部验证:表现最好的模型的内部验证 AUC-ROC 为 0.60,Brier 得分为 0.20,外部验证 AUC-ROC 为 0.61,Brier 得分为 0.23。虽然这些结果表明,与在同一人群的自体队列中评估的模型相比,判别能力降低了 15%,但这些模型的性能在统计学上明显优于随机模型,具有普适性,并能很好地校准所研究的人群。预测活产几率最重要的变量是卵细胞捐献者的年龄、卵细胞受体胚胎移植周期的次数、移植的胚胎是卵裂期还是囊胚期以及卵细胞受体的年龄。卵细胞受体的奇偶性、使用的是供体精子还是伴侣精子、之前自体胚胎移植周期的次数以及移植胚胎的数量则不那么重要:这些模型的辨别能力相对较弱,这表明需要添加更多特征来提高其预测能力。由于是否允许匿名捐献和有偿捐献等原因,各国捐献卵母细胞队列存在差异,因此有必要对模型进行重新校准,然后再应用于非澳大利亚队列:这些结果证实了卵细胞年龄和抗逆转录病毒疗法治疗史作为预测治疗结果的关键预后因素的重要性。其中一个开发的模型已被纳入一个面向消费者的网站(YourIVFSuccess.com.au/Estimator),使患者能够获得使用捐赠卵母细胞成功几率的个性化估算:本研究由澳大利亚政府资助,是未来医学研究基金(MRFF)新兴优先事项和消费者驱动研究计划的一部分:EPCD000007。L.R.申报了雅培公司和默克公司的个人咨询费、雅培公司的讲课费、默克公司的教育补助金、澳大利亚和新西兰生育协会以及世界子宫内膜异位症协会的前任主席,以及莫纳什试管婴儿集团(ASX:MVF)的小股东。G.M.C.声明接受了澳大利亚政府为研究以及开发和维护YourIVFSuccess网站提供的资助。O.F.、J.N.和A.P.声明没有利益冲突:不适用。
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引用次数: 0
Biallelic RXFP2 variants lead to congenital bilateral cryptorchidism and male infertility, supporting a role of RXFP2 in spermatogenesis. RXFP2 双倍拷贝变体会导致先天性双侧隐睾症和男性不育,支持 RXFP2 在精子发生中的作用。
IF 6 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2024-10-01 DOI: 10.1093/humrep/deae195
Hannes Syryn, Julie Van de Velde, Griet De Clercq, Hannah Verdin, Annelies Dheedene, Frank Peelman, Andrew Sinclair, Katie L Ayers, Ross A D Bathgate, Martine Cools, Elfride De Baere
<p><strong>Study question: </strong>Does RXFP2 disruption impair male fertility?</p><p><strong>Summary answer: </strong>We identified biallelic variants in RXFP2 in patients with male infertility due to spermatogenic arrest at the spermatid stage, supporting a role of RXFP2 in human spermatogenesis, specifically in germ cell maturation.</p><p><strong>What is known already: </strong>Since RXFP2, the receptor for INSL3, plays a crucial role in testicular descent during prenatal development, biallelic variants lead to bilateral cryptorchidism, as described in four families to date. While animal models have also suggested a function in spermatogenesis, the postnatal functions of RXFP2 and its ligand INSL3, produced in large amounts by the testes from puberty throughout adulthood, are largely unknown.</p><p><strong>Study design, size, duration: </strong>A family with two male members affected by impaired fertility due to spermatogenic maturation arrest and a history of bilateral cryptorchidism underwent clinical, endocrinological, histological, genomic, in vitro cellular, and in silico investigations.</p><p><strong>Participants/materials, setting, methods: </strong>The endocrinological and histological findings were correlated with publicly available single-cell RNA sequencing (scRNA-seq) data. The genomic defects have been characterized using long-read sequencing and validated with in silico modeling and an in vitro cyclic AMP reporter gene assay.</p><p><strong>Main results and the role of chance: </strong>An intragenic deletion of exon 1-5 of RXFP2 (NM_130806.5) was detected in trans with a hemizygous missense variant c.229G>A, p.(Glu77Lys). The p.(Glu77Lys) variant caused no clear change in cell surface expression or ability to bind INSL3, but displayed absence of a cAMP signal in response to INSL3, indicating a loss-of-function. Testicular biopsy in the proband showed a maturation arrest at the spermatid stage, corresponding to the highest level of RXFP2 expression in scRNA-seq data, thereby providing a potential explanation for the impaired fertility.</p><p><strong>Limitations, reasons for caution: </strong>Although this is so far the only study of human cases that supports the role of RXFP2 in spermatogenic maturation, this is corroborated by several animal studies that have already demonstrated a postnatal function of INSL3 and RXFP2 in spermatogenesis.</p><p><strong>Wider implications of the findings: </strong>This study corroborates RXFP2 as gene implicated in autosomal recessive congenital bilateral cryptorchidism due to biallelic variants, rather than autosomal-dominant cryptorchidism due to monoallelic RXFP2 variants. Our findings also support that RXFP2 is essential in human spermatogenesis, specifically in germ cell maturation, and that biallelic disruption can cause male infertility through spermatogenic arrest at the spermatid stage.</p><p><strong>Study funding/competing interest(s): </strong>Funding was provided by the Bellux Society
研究问题:RXFP2 干扰是否会损害男性生育能力?我们在精原细胞阶段精子发生停滞的男性不育症患者中发现了RXFP2的双侧变体,这支持了RXFP2在人类精子发生过程中的作用,特别是在生殖细胞成熟过程中的作用:由于 RXFP2(INSL3 的受体)在产前发育过程中的睾丸下降过程中起着至关重要的作用,因此双倍拷贝变体会导致双侧隐睾症,迄今已有四个家庭出现了这种情况。虽然动物模型也显示了RXFP2在精子发生过程中的功能,但RXFP2及其配体INSL3(睾丸从青春期到整个成年期都会产生大量RXFP2)在产后的功能在很大程度上还不为人所知:研究设计、规模和持续时间:对一个有两名男性成员的家族进行了临床、内分泌学、组织学、基因组学、体外细胞学和硅学研究:内分泌学和组织学检查结果与公开的单细胞 RNA 测序(scRNA-seq)数据相关联。利用长线程测序对基因组缺陷进行了表征,并通过硅学建模和体外环磷酸腺苷报告基因检测进行了验证:RXFP2 (NM_130806.5)外显子1-5的基因内缺失与半杂合错义变异c.229G>A,p.(Glu77Lys)被检测到。p.(Glu77Lys)变异体在细胞表面表达或结合 INSL3 的能力方面没有明显变化,但在 INSL3 的作用下没有 cAMP 信号,表明其功能缺失。疑似患者的睾丸活检结果显示,精子阶段的成熟停滞,与scRNA-seq数据中RXFP2的最高表达水平相对应,从而为生育能力受损提供了可能的解释:尽管这是迄今为止唯一一项支持RXFP2在精子发生成熟过程中发挥作用的人类病例研究,但多项动物研究已经证实了INSL3和RXFP2在精子发生过程中的产后功能:这项研究证实,RXFP2是双倍拷贝变体导致的常染色体隐性先天性双侧隐睾症的相关基因,而不是单倍拷贝RXFP2变体导致的常染色体显性隐睾症的相关基因。我们的研究结果还证明,RXFP2在人类精子发生过程中,特别是在生殖细胞成熟过程中是必不可少的,而双倍拷贝干扰可通过精子阶段的生精停滞导致男性不育:研究经费由贝鲁克斯儿科内分泌学和糖尿病学会(BELSPEED)提供,并得到佛兰德斯研究基金会(FWO)高级临床研究员基金(E.D.B.,1802220N)和根特大学医院特别研究基金(M.C.,FIKO-IV机构基金)的支持。作者声明无利益冲突:不适用。
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引用次数: 0
Challenges ahead: catalyzing research for the 2% prevalence of repeated implantation failure. 未来的挑战:针对 2% 的反复植入失败率开展研究。
IF 6 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2024-10-01 DOI: 10.1093/humrep/deae184
Hossam Elzeiny
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引用次数: 0
Exposure of antral follicles to medroxyprogesterone acetate during stimulation does not cause molecular perturbations in gonadotropin-responsiveness and steroidogenic function of granulosa cells in progestin-primed cycles. 在孕激素刺激周期中,前卵泡暴露于醋酸甲羟孕酮不会对促性腺激素反应性和颗粒细胞的类固醇生成功能造成分子扰动。
IF 6 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2024-10-01 DOI: 10.1093/humrep/deae189
Ozgur Oktem, Yashar Esmaeilian, Ece İltumur, Sevgi Yusufoglu, Deniz Uğurlu Çimen, Said Incir, Kayhan Yakin, Baris Ata, Bulent Urman
<p><strong>Study question: </strong>Does medroxyprogesterone acetate (MPA) exposure in progestin-primed ovarian stimulation (PPOS) cycles cause molecular perturbations in the steroidogenic function and gonadotropin responsiveness of the granulosa cells?</p><p><strong>Summary answer: </strong>PPOS cycles are identical to traditional GnRH antagonist cycles not only for clinical IVF characteristics but also for gonadotropin receptor expression, response to gonadotropins, and steroidogenic function at the molecular level.</p><p><strong>What is known already: </strong>PPOS is increasingly used as an alternative to GnRH antagonists due to the inhibitory effect of progesterone on LH release by reducing GnRH pulsatility at the hypothalamic level. Although a growing body of evidence from clinical studies did not indicate significant differences between PPOS and antagonist protocols for IVF cycle characteristics and obstetrical outcomes, it is still unknown whether exposure of the antral follicle cohort to progesterone or its synthetic derivatives during ovarian stimulation causes any subtle molecular aberrations in terms of steroidogenesis and gonadotropin responsiveness. To address this issue, detailed comparative molecular analyses were conducted in the luteinized mural granulosa cells (GCs) obtained from normal responding IVF patients undergoing PPOS and antagonist cycles.</p><p><strong>Study design, size, duration: </strong>A clinical translational research study was conducted with IVF patients.</p><p><strong>Participants/materials, setting, methods: </strong>This study included 55 normal responding IVF patients who underwent ovarian stimulation with either PPOS using MPA (5 mg twice daily) or GnRH antagonist cetrorelix acetate. Recombinant forms of FSH and hCG were used for ovarian stimulation and ovulation triggering, respectively. Luteinized mural GCs obtained during the oocyte retrieval procedure were used for the experiments. Cell culture, quantitative real-time PCR, immunoblotting, confocal time-lapse live cell imaging, and hormone assays were used.</p><p><strong>Main results and the role of chance: </strong>Demographic and IVF cycle characteristics of the patients undergoing ovarian stimulation with PPOS and GnRH antagonist were similar, including ovarian response, mature oocyte yield, and fertilization rates. Molecular analyses revealed that the expression of the enzymes involved in sex-steroid synthesis (StAR, SCC, 3β-HSD, 17β-HSD, aromatase) and the uptake/storage/utilization of cholesterol (LDL receptor, Hormone-sensitive lipase, hydroxy-methyl glutaryl Co-enzyme-A reductase, and Sterol O-acyltransferase1) in the GCs of the PPOS cycles were comparable to those of the antagonist cycles. The expression of the receptors for gonadotropins, estrogen, and progesterone hormones was also similar. Basal and hCG-induced increases in 3β-HSD expression and progesterone production and basal and FSH-induced increases in aromatase expression and E2 output
研究问题:醋酸甲羟孕酮(MPA)在孕激素刺激卵巢(PPOS)周期中的暴露是否会对颗粒细胞的类固醇生成功能和促性腺激素反应能力造成分子扰动?PPOS周期与传统的GnRH拮抗剂周期不仅在临床IVF特征上相同,而且在促性腺激素受体表达、对促性腺激素的反应和类固醇生成功能的分子水平上也相同:PPOS 通过降低下丘脑水平的 GnRH 脉冲性,对 LH 的释放具有抑制作用,因此 PPOS 越来越多地被用作 GnRH 拮抗剂的替代品。尽管越来越多的临床研究证据表明,PPOS 和拮抗剂方案在试管婴儿周期特征和产科结果方面没有显著差异,但在卵巢刺激过程中,前卵泡群暴露于黄体酮或其合成衍生物是否会在类固醇生成和促性腺激素反应性方面导致微妙的分子畸变,目前仍是未知数。为了解决这个问题,我们对接受 PPOS 和拮抗剂周期治疗的正常反应试管婴儿患者的黄体化壁颗粒细胞(GCs)进行了详细的分子比较分析:研究设计、规模、持续时间:对试管婴儿患者进行临床转化研究:这项研究包括55名正常反应的试管婴儿患者,他们接受了使用MPA(5毫克,每天两次)的PPOS或GnRH拮抗剂醋酸西曲瑞克的卵巢刺激。重组 FSH 和 hCG 分别用于卵巢刺激和促排卵。在卵母细胞提取过程中获得的黄体化壁层 GC 被用于实验。实验采用了细胞培养、定量实时 PCR、免疫印迹、共聚焦延时活细胞成像和激素测定等方法:接受 PPOS 和 GnRH 拮抗剂卵巢刺激的患者的人口统计学和 IVF 周期特征相似,包括卵巢反应、成熟卵母细胞产量和受精率。分子分析表明,参与性类固醇合成的酶(StAR、SCC、3β-HSD、17β-HSD、芳香化酶)和胆固醇的吸收/储存/利用(低密度脂蛋白受体、激素敏感性脂肪酶、羟甲基戊二酰辅酶-A还原酶和甾醇O-酰基转移酶1)在PPOS周期的GC中的表达与拮抗剂周期的相当。促性腺激素、雌激素和孕激素受体的表达也相似。与拮抗剂周期的 GC 相比,PPOS 患者的 GC 在基础和 hCG 诱导的 3β-HSD 表达和孕酮分泌增加,以及基础和 FSH 诱导的芳香化酶表达和 E2 产出增加方面没有表现出任何有意义的差异。此外,基础和 hCG 诱导的低密度脂蛋白受体表达和胆固醇摄取上调在各组之间也没有差异。共聚焦成像还显示了类固醇生成酶的相似表达模式及其与线粒体的共定位。最后,在 PPOS 和拮抗剂周期的 GC 中,其他调节积腺扩张、排卵和黄体功能的重要基因 [松弛素、ADAMTS-1 和表皮生长因子(EGF)样生长因子 amphiregulin] 的表达也相似:局限性、需谨慎的原因:我们的数据来自正常反应的患者,他们的排卵是用hCG诱发的,因此在解释这些数据时应谨慎。目前还不清楚评估的分子参数是否会因不孕病因、卵巢反应程度、触发方式以及任何其他潜在卵巢病变或全身性疾病而有所不同。MPA是用于PPOS的孕激素,这些发现是否可推广到其他孕激素尚不清楚:这项研究提供了令人欣慰的分子证据,即与GnRH拮抗剂周期相比,在卵泡生长期将前卵泡群暴露于MPA不会对类固醇生成、排卵和黄体功能产生任何不利影响:本研究由科茨大学医学院、健康科学研究生院和科茨大学转化医学研究中心(KUTTAM)资助,并由土耳其共和国发展部研究基础设施支持计划提供同等资助。所有作者声明无利益冲突:不适用。
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引用次数: 0
Neurodevelopmental outcomes of school-age children conceived after hysterosalpingography with oil-based or water-based iodinated contrast: long-term follow-up of a nationwide randomized controlled trial. 使用油基或水基碘化造影剂进行子宫输卵管造影术后受孕的学龄儿童的神经发育结果:一项全国性随机对照试验的长期随访。
IF 6 1区 医学 Q1 OBSTETRICS & GYNECOLOGY Pub Date : 2024-10-01 DOI: 10.1093/humrep/deae183
Sarai M Keestra, Nienke Van Welie, Kim Dreyer, Rik Van Eekelen, Tessa J Roseboom, Jaap Oosterlaan, Ben W Mol, Martijn J J Finken, Velja Mijatovic, Marsh Königs
<p><strong>Study question: </strong>Does preconceptional exposure to oil-based iodinated contrast media during hysterosalpingography (HSG) impact children's neurodevelopment compared with exposure to water-based alternatives?</p><p><strong>Summary answer: </strong>Our study found no large-sized effects for neurodevelopment in children with preconceptional exposure to oil-based iodinated contrast media during HSG compared with water-based alternatives.</p><p><strong>What is known already: </strong>HSG is widely used as a diagnostic tool in the female fertility work-up. Tubal flushing with oil-based iodinated contrast has been shown to enhance fertility outcomes in couples with unexplained infertility, increasing the chances of pregnancy and live birth compared with water-based alternatives. However, oil-based contrast contains higher doses of iodine and has a longer half-life, and concerns exist that iodinated contrast media can affect women's iodine status and cause temporary (sub)clinical hypothyroidism in mothers and/or foetuses. Considering that thyroid hormones are vital to embryonal and foetal brain development, oil-based contrast media use could increase the risk of impaired neurodevelopment in children conceived shortly after HSG. Here we examine neurodevelopmental outcomes in school-aged children conceived after HSG.</p><p><strong>Study design, size, duration: </strong>This is a long-term follow-up of the H2Oil trial in which oil-based or water-based contrast was used during HSG (Netherlands; 2012-2014; NTR3270). Of 369 children born <6 months after HSG in the study, we contacted the mothers of 140 children who gave consent to be contacted for follow-up. The follow-up study took place from January to July 2022 (NCT05168228).</p><p><strong>Participants/materials, settings, methods: </strong>The study included 69 children aged 6-9 years who were conceived after HSG with oil-based (n = 42) or water-based contrast (n = 27). The assessments targeted intelligence (Wechsler Intelligence Scale for Children), neurocognitive outcomes (computerized neurocognitive tests), behavioural functioning (parent and teacher questionnaires), and academic performance. Linear regression models, adjusted for age, sex, and parental educational attainment were employed to compare groups.</p><p><strong>Main results and the role of chance: </strong>School-aged children born to mothers after oil-based contrast HSG did not significantly differ from children born to mothers after water-based contrast HSG, in regards to intelligence, neurocognitive functioning, behavioural functioning, or academic performance, with the exception of better performance for visuomotor integration functions in children exposed to oil-based contrast preconception. After exploratory correction for multiple comparisons, none of the group differences was statistically significant.</p><p><strong>Limitations, reasons for caution: </strong>The small sample size of this follow-up study limited stati
研究问题在子宫输卵管造影术(HSG)中,与接触水基替代品相比,孕前接触油基碘化造影剂是否会影响儿童的神经发育?我们的研究发现,与水基造影剂相比,在子宫输卵管造影术(HSG)中孕前接触油基碘化造影剂不会对儿童的神经发育造成大的影响:HSG是女性生育检查中广泛使用的诊断工具。事实证明,与水基造影剂相比,使用油基碘造影剂进行输卵管冲洗可提高不明原因不孕夫妇的生育率,增加怀孕和活产的机会。然而,油基造影剂含有较高剂量的碘,且半衰期较长,人们担心碘化造影剂会影响妇女的碘状况,并导致母亲和/或胎儿出现暂时性(亚)临床甲状腺功能减退。考虑到甲状腺激素对胚胎和胎儿的大脑发育至关重要,使用油基造影剂可能会增加在 HSG 术后不久受孕的儿童神经发育受损的风险。在此,我们对 HSG 后受孕的学龄儿童的神经发育结果进行了研究:这是H2Oil试验的长期随访,在该试验中,HSG期间使用了油基或水基对比剂(荷兰;2012-2014;NTR3270)。在 369 名出生儿童中,参与者/材料、环境、方法:该研究包括 69 名 6-9 岁的儿童,他们都是在使用油基造影剂(42 人)或水基造影剂(27 人)进行 HSG 后受孕的。评估针对智力(韦氏儿童智力量表)、神经认知结果(计算机化神经认知测试)、行为功能(家长和教师问卷)和学习成绩。采用线性回归模型对各组进行比较,并对年龄、性别和父母受教育程度进行调整:在智力、神经认知功能、行为功能或学业成绩方面,母亲接受油基对比剂 HSG 后所生的学龄儿童与母亲接受水基对比剂 HSG 后所生的学龄儿童没有显著差异,但孕前接受油基对比剂的儿童在视觉运动整合功能方面表现更好。在对多重比较进行探索性校正后,各组差异均无统计学意义:本随访研究的样本量较小,限制了统计能力。本研究提供的证据表明,孕前接触两种对比度媒体类型之间不存在大的差异,但与没有孕前接触 HSG 的自然受孕儿童相比,不排除对神经发育产生更微妙的影响:本研究有助于我们了解生育检查中使用的不同类型碘造影剂的长期影响,表明选择油性碘造影剂而非水性碘造影剂不太可能对 HSG 后不久受孕的儿童的长期神经发育结果产生重大影响。不过,由于两种造影剂都含有大量碘,因此进一步的研究应关注造影过程中碘暴露的整体安全性,并将造影后受孕的儿童与自然受孕的儿童进行比较:最初的 H2Oil 随机对照试验是一项由研究者发起的研究,由现已合并为阿姆斯特丹大学医学中心的两家学术医院资助。目前的后续研究(Neuro-H2Oil)由阿姆斯特丹生殖与发展研究所(AR&D)授予作者的研究基金资助。S.K.获得了阿姆斯特丹大学医学中心的AMC医学博士/博士奖学金。S.K. 在民间社会组织 "大学基本药物联盟 "和 "人民健康运动 "中担任志愿职务。V.M. 报告接受了加柏公司、默克公司和菲林公司提供的差旅费、演讲费和研究补助金。K.D. 报告从加柏公司领取了差旅费、演讲费和研究补助金。BWM 获得了 NHMRC Investigator grant (GNT1176437)的资助,并从默克公司获得了顾问费、差旅费和研究经费,还为 Organon 和 Norgine 提供了顾问服务,并持有 ObsEva 公司的股票。其他作者不存在利益冲突:NCT05168228.
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Human reproduction
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