STUDY QUESTION How are germ cell numbers and initiation of folliculogenesis affected in fetal Turner syndrome (TS) ovaries? SUMMARY ANSWER Germ cell development was severely affected already in early second trimester pregnancies, including accelerated oogonia loss and impaired initiation of primordial follicle formation in TS ovaries, while the phenotype in TS mosaic ovaries was less severe. WHAT IS KNOWN ALREADY Females with TS are characterized by premature ovarian insufficiency (POI). This phenotype is proposed to be a consequence of germ cell loss during development, but the timing and mechanisms behind this are not characterized in detail. Only few studies have evaluated germ cell development in fetal TS and TS mosaic ovaries, and with a sparse number of specimens included per study. STUDY DESIGN, SIZE, DURATION This study included a total of 102 formalin-fixed and paraffin-embedded fetal ovarian tissue specimens. Specimens included were from fetuses with 45,X (N = 42 aged gestational week (GW) 12–20, except one GW 40 sample), 45,X/46,XX (N = 7, aged GW 12–20), and from controls (N = 53, aged GW 12–42) from a biobank (ethics approval # H-2-2014-103). PARTICIPANTS/MATERIALS, SETTING, METHODS The number of OCT4 positive germ cells/mm2, follicles (primordial and primary)/mm2 and cPARP positive cells/mm2 were quantified in fetal ovarian tissue from TS, TS mosaic and controls following morphological and immunohistochemical analysis. MAIN RESULTS AND THE ROLE OF CHANCE After adjusting for gestational age, the number of OCT4+ oogonia was significantly higher in control ovaries (N = 53) versus 45,X ovaries (N = 40, P < 0.001), as well as in control ovaries versus 45,X/46,XX mosaic ovaries (N = 7, P < 0.043). Accordingly, the numbers of follicles were significantly higher in control ovaries versus 45,X and 45,X/46,XX ovaries from GW 16–20 with a median range of 154 (N = 11) versus 0 (N = 24) versus 3 (N = 5) (P < 0.001 and P < 0.015, respectively). The number of follicles was also significantly higher in 45,X/46,XX mosaic ovaries from GW 16–20 compared with 45,X ovaries (P < 0.005). Additionally, the numbers of apoptotic cells determined as cPARP+ cells/mm2 were significantly higher in ovaries 45,X (n = 39) versus controls (n = 15, P = 0.001) from GW 12–20 after adjusting for GW. LIMITATIONS, REASONS FOR CAUTION The analysis of OCT4+ cells/mm2, cPARP+ cells/mm2 and follicles (primordial and primary)/mm2 should be considered semi-quantitative as it was not possible to use quantification by stereology. The heterogeneous distribution of follicles in the ovarian cortex warrants a cautious interpretation of the exact quantitative numbers reported. Moreover, only one 45,X specimen and no 45,X/46,XX specimens aged above GW 20 were available for this study, which unfortunately made it impossible to assess whether the ovarian folliculogenesis was delayed or absent in the TS and TS mosaic specimens. WIDER IMPLICATIONS OF THE FINDINGS This human study provides insights about the timing of accelerated fetal germ cell loss in TS. Knowledge about the biological mechanism of POI in girls with TS is clinically useful when counseling patients about expected ovarian function and fertility preservation strategies. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC). TRIAL REGISTRATION NUMBER N/A.

中文翻译：

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特纳综合征女性卵原细胞加速丧失和卵泡发育受损始于胎儿早期发育

研究问题 胎儿特纳综合征 (TS) 卵巢中的生殖细胞数量和卵泡发生的起始如何受到影响？总结 答案 生殖细胞发育在妊娠中期早期就已经受到严重影响，包括 TS 卵巢中卵原细胞丢失加速和原始卵泡形成受损，而 TS 嵌合卵巢中的表型不太严重。已知情况 患有 TS 的女性的特征是卵巢早衰 (POI)。这种表型被认为是发育过程中生殖细胞损失的结果，但其背后的时间和机制并未详细描述。只有少数研究评估了胎儿 TS 和 TS 嵌合卵巢中的生殖细胞发育，并且每项研究包含的样本数量很少。研究设计，尺寸，持续时间 本研究共包括 102 个福尔马林固定和石蜡包埋的胎儿卵巢组织标本。包括的样本来自 45,X（N = 42 孕周 (GW) 12-20，除了一个 GW 40 样本）、45,X/46,XX（N = 7，GW 12-20 岁）的胎儿，和来自生物库的对照（N = 53，年龄 12-42 岁）（伦理批准编号 H-2-2014-103）。参与者/材料、设置、方法 在形态学和免疫组织化学分析后，对来自 TS、TS 嵌合体和对照的胎儿卵巢组织中 OCT4 阳性生殖细胞/mm2、卵泡（原始和初级）/mm2 和 cPARP 阳性细胞/mm2 的数量进行量化。主要结果和机会的作用在调整胎龄后，对照卵巢（N = 53）的 OCT4+ 卵原细胞数量显着高于 45,X 卵巢（N = 40，P < 0.001），以及对照卵巢与 45,X/46,XX 镶嵌卵巢 (N = 7, P < 0.043)。因此，对照卵巢中的卵泡数量显着高于 GW 16-20 的 45,X 和 45,X/46,XX 卵巢，中位数范围为 154 (N = 11) 对 0 (N = 24) 对 3 (N = 5) (分别为 P < 0.001 和 P < 0.015)。与 45,X 卵巢相比，GW 16-20 的 45,X/46,XX 镶嵌卵巢中的卵泡数量也显着增加（P < 0.005）。此外，在调整 GW 后，从 GW 12-20 的卵巢 45,X (n = 39) 与对照组 (n = 15, P = 0.001) 相比，确定为 cPARP+ 细胞/mm2 的凋亡细胞数量显着更高。限制、注意原因 OCT4+ 细胞/mm2 的分析，cPARP+ 细胞/mm2 和卵泡（原始和初级）/mm2 应被视为半定量，因为不可能通过体视学进行量化。卵巢皮质中卵泡的不均匀分布需要对报告的确切数量数字进行谨慎解释。此外，本研究仅提供 1 个 45,X 样本，没有 45,X/46,XX 样本年龄在 20 GW 以上，遗憾的是无法评估 TS 和 TS 马赛克样本中卵巢卵泡发生是否延迟或缺失. 研究结果的更广泛意义 这项人体研究提供了有关 TS 中胎儿生殖细胞加速丢失时间的见解。在向患者咨询预期的卵巢功能和生育力保留策略时，了解 TS 女孩 POI 的生物学机制在临床上很有用。研究资助/竞争兴趣 这项工作得到了国际男性生殖内分泌紊乱和儿童健康研究和研究培训中心 (EDMaRC) 的支持。试用注册号 不适用。