Institute of Reproductive Health, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
Hum Reprod. 2021 Jul 19;36(8):2134-2147. doi: 10.1093/humrep/deab143.
Is it possible to establish a new in-vitro activation (IVA) protocol for infertility treatment?
A new IVA procedure is an efficient and easily performed approach for infertility treatment of patients with diminished ovarian reserve (DOR).
IVA of primordial follicles with or without stimulators has been developed to treat patients with primary ovarian insufficiency (POI) successfully. However, the efficiency of the procedure is still very low. There is a requirement to optimize the protocol with increased efficiency for clinical application.
STUDY DESIGN, SIZE, DURATION: Newborn mouse ovaries were used to establish a new 1-h IVA protocol with the mechanistic target of rapamycin (mTOR) stimulator phosphatidic acid (PA, 200 µM) and the phosphatidylinositol-3-kinase (PI3K) stimulator 740Y-P (250 µg/ml); a prospective observational cohort study in POI patients was performed on 15 POI patients and 3 poor ovarian response (POR) patients in three different centers of reproductive medicine in China.
PARTICIPANTS/MATERIALS, SETTING, METHODS: One-third of ovarian cortex was removed and processed into bigger strips (1 × 1 cm2, 1-2 mm thickness). Strips were then sutured back after treatment. The new approach only requires one laparoscopic surgery.
Follicular activation and development increased in cultured mouse and human ovarian tissues after 1 h of stimulator treatment. Compared with tiny ovarian cortex pieces (1 × 1 mm2), large ovarian strips (1 × 1 cm2) showed the lowest apoptotic signals after incubation. We applied the orthotropic transplantation procedure with large strips in the clinic, and 9 of 15 POI patients showed at least one-wave follicular growth during the monitoring period. One patient was reported with one healthy delivery after natural conception and another patient with a healthy singleton delivery after IVF. All the contacted patients (n = 13) responded with no side effects on their health 2-4 years after IVA procedure.
LIMITATIONS, REASONS FOR CAUTION: Further clinical trials with a large number of well-defined patients are required to compare different IVA protocols. A long-term follow-up system should be set up to monitor patient's health in the future cohort study.
By using stimulators, the findings in the study provide a more efficient IVA protocol for the treatment of patients with DOR. It requires only one laparoscopic surgery and thus minimizes patients' discomfort and costs. This strategy could be useful for patients diagnosed with POI and desire pregnancy as soon as possible after the operation.
STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key Research and Development Program of China (2018YFC1003703 and 2018YFC1004203); the National Natural Science Foundation of China (81871221); Co-construction of Provincial Department (201601006). The authors have no conflict of interest to disclose.
ChiCTR2000030872.
是否有可能为不孕症治疗建立新的体外激活（IVA）方案？
对于卵巢储备功能减退（DOR）患者的不孕症治疗，新的 IVA 程序是一种高效且易于实施的方法。
已经开发了使用有或没有刺激剂的原始卵泡的 IVA 来成功治疗原发性卵巢功能不全（POI）患者。然而，该程序的效率仍然非常低。需要优化该方案以提高效率，以便临床应用。
研究设计、大小、持续时间：使用新生小鼠卵巢建立了一个新的 1 小时 IVA 方案，该方案使用雷帕霉素（mTOR）刺激剂磷脂酸（PA，200μM）和磷脂酰肌醇-3-激酶（PI3K）刺激剂 740Y-P（250μg/ml）；在中国三个生殖医学中心进行了前瞻性观察性队列研究，纳入了 15 名 POI 患者和 3 名卵巢反应不良（POR）患者。
参与者/材料、设置、方法：切除三分之一的卵巢皮质并加工成较大的条带（1×1cm2，1-2mm 厚）。治疗后，将条带缝合回原处。新方法仅需要一次腹腔镜手术。
在经过 1 小时的刺激剂处理后，培养的小鼠和人卵巢组织中的卵泡激活和发育增加。与微小的卵巢皮质片（1×1mm2）相比，孵育后大的卵巢条带（1×1cm2）显示出最低的凋亡信号。我们在临床上应用了同种异体移植程序，并在监测期间，15 名 POI 患者中的 9 名至少有一波卵泡生长。一名患者报告自然受孕后成功分娩，另一名患者接受试管婴儿后成功分娩一名健康的单胎。所有联系到的患者（n=13）在 IVA 手术后 2-4 年均未出现健康相关的副作用。
局限性、谨慎的原因：需要进行更多数量的、明确定义的患者的临床试验来比较不同的 IVA 方案。应该建立一个长期的随访系统，以便在未来的队列研究中监测患者的健康状况。
通过使用刺激剂，该研究中的发现为 DOR 患者的治疗提供了一种更有效的 IVA 方案。它仅需要一次腹腔镜手术，因此最大限度地减少了患者的不适和成本。对于诊断为 POI 并希望在手术后尽快怀孕的患者，这种策略可能很有用。
研究资金/利益冲突：本研究得到了中国国家重点研发计划（2018YFC1003703 和 2018YFC1004203）；国家自然科学基金（81871221）；省级共建（201601006）的支持。作者没有利益冲突需要披露。
ChiCTR2000030872。
