Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China.
Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, P. R. China.
Hum Reprod. 2022 Apr 1;37(4):725-733. doi: 10.1093/humrep/deac023.
Does intrauterine infusion of granulocyte colony-stimulating factor (G-CSF) prevent adhesion reformation and promote endometrial growth after hysteroscopic adhesiolysis?
Intrauterine perfusion of G-CSF can increase endometrial thickness but does not prevent the recurrence of intrauterine adhesions (IUAs) in patients with Asherman syndrome (AS) after surgery.
Intrauterine infusion of G-CSF has been used in attempts to treat patients with recurrent miscarriage and an idiopathic thin endometrium for either fresh or frozen-thawed embryo transfer cycles but without uniform efficacy. There have been no reports on the effect of G-CSF on the recurrence of IUAs, endometrial regrowth or pregnancy results in specific populations with AS.
STUDY DESIGN, SIZE, DURATION: This two-center prospective double-blind randomized controlled trial ran between April 2016 and August 2021. In it, 245 patients with moderate to severe AS were randomized to G-CSF and control groups at a 1:1 ratio; 229 women were included in the adhesion recurrence analysis; and 164 patients were analyzed for pregnancy outcomes.
PARTICIPANTS/MATERIALS, SETTING, METHODS: All eligible patients received the first hysteroscopic adhesion separation and balloon placement procedure. Patients who met our inclusion and exclusion criteria were randomized after surgery. These patients returned for balloon removal and underwent intrauterine perfusion with 300 µg (1.8 ml) G-CSF or 1.8 ml normal saline according to randomization at 7 days after surgery. A second-look hysteroscopy was carried out 1-2 months later. The primary outcome was the rate of formation of new adhesions at the second hysteroscopy. The secondary outcomes included endometrial thickness in the periovulatory period after surgery, as well as the clinical pregnancy and live birth rates.
Age, menstrual cycle characteristics, pregnancy history and IUA score before surgery were similar between groups. There were no statistically significant differences in the adhesion reformation rate or median adhesion score reduction. However, G-CSF perfusion significantly improved endometrial thickness (7.91 ± 2.12 mm vs 7.22 ± 2.04 mm; P = 0.019, 95% CI for difference: -1.26 to -0.12), as well as cumulative pregnancy and live birth rate over time (P = 0.017 and P = 0.042). Furthermore, multivariate logistic regression analysis showed that postoperative endometrial thickness was an independent prognostic factor for pregnancy and live birth rates.
LIMITATIONS, REASONS FOR CAUTION: These results cannot be extended to older patients or those without AS, as our subjects had moderate or severe AS and were aged <40 years. The low number of patients included in the fertility analysis could lead to biased results.
Intrauterine perfusion of G-CSF could be an effective adjuvant therapy for patients with AS to increase endometrial thickness.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the National Key Research and Development Program of China (2018YFC1004800), the National Natural Science Foundation of China (82001624 and 81871209), the Natural Science Foundation of Zhejiang Province (LQ20H040004) and the provincial and ministerial construction project of Zhejiang Province (2017 WKJ-ZJ-1721). The authors declare that they have no conflicts of interest regarding this work.
ClinicalTrials.gov (NCT02855632).
4 March 2016.
DATE OF FIRST PATIENT’S ENROLMENT: 13 April 2016.
宫内输注粒细胞集落刺激因子（G-CSF）是否能预防宫腔镜粘连松解术后粘连的再形成并促进子宫内膜生长？
宫内灌注 G-CSF 可以增加子宫内膜厚度，但不能预防中重度宫腔粘连（Asherman 综合征，AS）患者术后宫腔粘连（IUAs）的复发。
宫内输注 G-CSF 已用于尝试治疗反复流产和特发性薄型子宫内膜患者的新鲜或冷冻胚胎移植周期，但疗效不一致。尚无关于 G-CSF 对 IUAs 复发、子宫内膜再生或特定 AS 人群妊娠结果影响的报道。
研究设计、规模、持续时间：这是一项于 2016 年 4 月至 2021 年 8 月进行的、为期 2 年的、以 2 中心前瞻性双盲随机对照试验。其中，245 例中重度 AS 患者以 1:1 的比例随机分为 G-CSF 组和对照组；229 例女性纳入粘连复发分析；164 例患者分析妊娠结局。
参与者/材料、设置、方法：所有符合条件的患者均接受了第一次宫腔镜粘连分离和球囊放置手术。符合纳入和排除标准的患者在手术后进行随机分组。这些患者在手术后 7 天返回进行球囊取出，并根据随机分组进行 300µg（1.8ml）G-CSF 或 1.8ml 生理盐水的宫内灌注。1-2 个月后进行第二次宫腔镜检查。主要结局是第二次宫腔镜检查中新粘连形成的发生率。次要结局包括手术后排卵期间的子宫内膜厚度以及临床妊娠率和活产率。
年龄、月经周期特征、妊娠史和术前 IUAs 评分在组间相似。粘连再形成率或中位粘连评分降低无统计学差异。然而，G-CSF 灌注显著改善了子宫内膜厚度（7.91±2.12mm 与 7.22±2.04mm；P=0.019，95%CI 差值：-1.26 至-0.12），以及随时间推移的累积妊娠和活产率（P=0.017 和 P=0.042）。此外，多变量逻辑回归分析显示，术后子宫内膜厚度是妊娠和活产率的独立预后因素。
局限性、谨慎的原因：这些结果不能推广到年龄较大的患者或没有 AS 的患者，因为我们的研究对象患有中重度 AS，年龄<40 岁。生育分析中纳入的患者数量较少可能导致结果存在偏差。
宫腔内灌注 G-CSF 可能是治疗 AS 患者的一种有效的辅助治疗方法，可增加子宫内膜厚度。
研究资助/利益冲突：本研究得到了国家重点研发计划（2018YFC1004800）、国家自然科学基金（82001624 和 81871209）、浙江省自然科学基金（LQ20H040004）和浙江省省部共建项目（2017 WKJ-ZJ-1721）的资助。作者声明他们对此项工作没有任何利益冲突。
ClinicalTrials.gov（NCT02855632）。
2016 年 3 月 4 日。
2016 年 4 月 13 日。
