A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial.
A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial.
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DOI：
10.1093/humrep/dex253
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发表时间：
2017-09-01
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通讯作者：
Dhillo WS
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作者：
Abbara A;Clarke S;Islam R;Prague JK;Comninos AN;Narayanaswamy S;Papadopoulou D;Roberts R;Izzi-Engbeaya C;Ratnasabapathy R;Nesbitt A;Vimalesvaran S;Salim R;Lavery SA;Bloom SR;Huson L;Trew GH;Dhillo WS
在卵巢过度刺激综合征（OHSS）高危女性中，使用第二剂Kisspeptin-54延长LH暴露时间是否能改善卵母细胞成熟？第二剂量的kisspeptin-54在10小时后，第一次提高卵母细胞产量的妇女在OHSS的高风险。Kisspeptin作用于下丘脑，刺激下丘脑释放内源性GnRH库。我们以前报道过，单剂量kisspeptin-54导致LH峰持续约12-14小时，这安全地触发OHSS高危女性的卵母细胞成熟。在2015年8月至2016年5月期间招募的62名OHSS高风险女性中进行的II期随机安慰剂对照试验。在控制性卵巢刺激后，所有患者（n = 62）在取卵前36 h接受皮下注射Kisspeptin-54（9.6 nmol/kg）。患者以1：1的比例随机接受第二剂kisspeptin-54（D;双倍，n = 31）或生理盐水（S;单次，n = 31），10小时后。患者、胚胎学家和IVF临床医生对剂量分配保持盲态。 研究参与者：62名18-34岁的OHSS高风险女性（窦卵泡计数≥23或抗苗勒管激素水平≥40 pmol/L）。 设置：在英国伦敦Hammersmith医院IVF单位进行的单中心研究。 主要结局：达到至少60%的卵母细胞产率（首次kisspeptin-54触发剂给药早晨从≥14 mm卵泡中回收的成熟卵母细胞百分比）的患者比例。 次要结局：生殖激素水平、种植率和OHSS发生率。第二剂量的kisspeptin-54在10小时后，第一诱导进一步LH分泌后4小时给药。在第二剂kisspeptin-54后，较高比例的患者达到卵母细胞产率≥60%（单次：14/31，45%，双次：21/31，71%;绝对差异+26%，CI 2- 50%，P = 0.042）。接受两次kisspeptin-54给药的患者在第二次kisspeptin给药后有可变的LH反应，这似乎取决于第一次kisspeptin注射后的LH反应。在第一剂kisspeptin后LH升高较低的患者在第二剂kisspeptin后有更实质性的“补救”LH反应。Kisspeptin第二次给药后的可变LH反应导致更大比例的患者达到卵母细胞产率≥ 60%，但也未增加卵巢过度反应和中度OHSS的频率（单次给药：1/31，3.2%，双次给药：0/31，0%）。进一步的研究是必要的，直接比较kisspeptin-54卵母细胞成熟的更确定的触发器。用Kisspeptin触发最终卵母细胞成熟是一种新的治疗选择，即使在OHSS高风险的女性中也可以使用新鲜胚胎移植。这项研究完全由作者设计、执行、分析和报告。医学研究理事会（MRC）、威康信托基金会和国家卫生研究所（NIHR）为开展研究提供了研究资金。没有竞争利益需要申报。Clinicaltrial.gov标识符NCT 01667406 2012年8月8日。2015年8月10日。
Can increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)? A second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS. Kisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12–14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS. Phase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation. Study participants: Sixty-two women aged 18–34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L). Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK. Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%. Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence. A second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspeptin-54 (Single: 14/31, 45%, Double: 21/31, 71%; absolute difference +26%, CI 2–50%, P = 0.042). Patients receiving two doses of kisspeptin-54 had a variable LH-response following the second kisspeptin dose, which appeared to be dependent on the LH-response following the first kisspeptin injection. Patients who had a lower LH-rise following the first dose of kisspeptin had a more substantial ‘rescue’ LH-response following the second dose of kisspeptin. The variable LH-response following the second dose of kisspeptin resulted in a greater proportion of patients achieving an oocyte yield ≥60%, but without also increasing the frequency of ovarian over-response and moderate OHSS (Single: 1/31, 3.2%, Double: 0/31, 0%). Further studies are warranted to directly compare kisspeptin-54 to more established triggers of oocyte maturation. Triggering final oocyte maturation with kisspeptin is a novel therapeutic option to enable the use of fresh embryo transfer even in the woman at high risk of OHSS. The study was designed, conducted, analysed and reported entirely by the authors. The Medical Research Council (MRC), Wellcome Trust & National Institute of Health Research (NIHR) provided research funding to carry out the studies. There are no competing interests to declare. Clinicaltrial.gov identifier NCT01667406 8 August 2012. 10 August 2015.