Broekmans Frank J, Verweij Pierre J M, Eijkemans Marinus J C, Mannaerts Bernadette M J L, Witjes Han
Division of Female and Baby, Department for Reproductive Medicine and Surgery, University Medical Center, Utrecht 3584 CX, The Netherlands
MSD, Oss 5342CC, The Netherlands.
Hum Reprod. 2014 Aug;29(8):1688-97. doi: 10.1093/humrep/deu090. Epub 2014 Jun 5.
Can predictors of low and high ovarian responses be identified in patients undergoing controlled ovarian stimulation (COS) in a GnRH antagonist protocol?
Common prognostic factors for high and low ovarian responses were female age, antral follicle count (AFC) and basal serum FSH and LH.
Predictors of ovarian response have been identified in GnRH agonist protocols. With the introduction of GnRH antagonists to prevent premature LH rises during COS, and the gradual shift in use of long GnRH agonist to short GnRH antagonist protocols, there is a need for data on the predictability of ovarian response in GnRH antagonist cycles.
STUDY DESIGN, SIZE, DURATION: A retrospective analysis of data from the Engage trial and validation with the Xpect trial. Prognostic models were constructed for high (>18 oocytes retrieved) and low (<6 oocytes retrieved) ovarian response. Model building was based on the recombinant FSH (rFSH) arm (n = 747) of the Engage trial. Multivariable logistic regression models were constructed in a stepwise fashion (P < 0.15 for entry). Validation based on calibration was performed in patients with equivalent treatment (n = 199) in the Xpect trial.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women with an indication for COS prior to IVF. The Engage and Xpect trials included patients of similar ethnic origins from North America and Europe who had regular menstrual cycles. The main causes of infertility were male factor, tubal factor and endometriosis.
In the Engage trial, 18.3% of patients had a high and 12.7% had a low ovarian response. Age, AFC, serum FSH and serum LH at stimulation Day 1 were prognostic for both high and low ovarian responses. Higher AFC and LH were associated with an increased chance of high ovarian response. Older age and higher FSH correlated with an increased chance of low ovarian response. Region (North America/Europe) and BMI were prognostic for high ovarian response, and serum estradiol at stimulation Day 1 was associated with low ovarian response. The area under the receiver operating characteristic (ROC) curve (AUC) for the model for a high ovarian response was 0.82. Sensitivity and specificity were 0.82 and 0.73; positive and negative predictive values were 0.40 and 0.95, respectively. The AUC for the model for a low ovarian response was 0.80. Sensitivity and specificity were 0.77 and 0.73, respectively; positive and negative predictive values were 0.29 and 0.96, respectively. In Xpect, 19.1% of patients were high ovarian responders and 16.1% were low ovarian responders. The slope of the calibration line was 0.81 and 1.35 for high and low ovarian responses, respectively, both not statistically different from 1.0. In summary, common prognostic factors for high and low ovarian responses were female age, AFC and basal serum FSH and LH. Simple multivariable models are presented that are able to predict both a too low or too high ovarian response in patients treated with a GnRH antagonist protocol and daily rFSH.
LIMITATIONS, REASONS FOR CAUTION: Anti-Müllerian hormone was not included in the prediction modelling.
The findings will help with the identification of patients at risk of a too high or too low ovarian response and individualization of COS treatment.
STUDY FUNDING/COMPETING INTERESTS: Financial support for this study and the editorial work was provided by Merck, Sharp & Dohme Corp. (MSD), a subsidiary of Merck & Co. Inc., Whitehouse Station, NJ, USA. F.J.B. received a grant from CVZ to his institution; P.J.M.V. and H.W. are employees of MSD, and B.M.J.L.M. was an employee of MSD at the time of development of this manuscript.
NCT 00696800 and NCT00778999.
在采用GnRH拮抗剂方案进行控制性卵巢刺激（COS）的患者中，能否识别出卵巢低反应和高反应的预测因素？
卵巢高反应和低反应的常见预后因素为女性年龄、窦卵泡计数（AFC）、基础血清促卵泡生成素（FSH）和促黄体生成素（LH）。
在GnRH激动剂方案中已确定了卵巢反应的预测因素。随着GnRH拮抗剂的引入以防止COS期间LH过早升高，以及长效GnRH激动剂使用逐渐转向短效GnRH拮抗剂方案，需要有关GnRH拮抗剂周期中卵巢反应可预测性的数据。
研究设计、规模、持续时间：对ENGAGE试验的数据进行回顾性分析，并通过XPECT试验进行验证。构建了针对高（获卵数>18个）和低（获卵数<6个）卵巢反应的预后模型。模型构建基于ENGAGE试验的重组FSH（rFSH）组（n = 747）。采用逐步法构建多变量逻辑回归模型（纳入标准为P<0.15）。基于校准的验证在XPECT试验中接受等效治疗（n = 199）的患者中进行。
研究对象/材料、地点、方法：体外受精前有COS指征的不孕女性。ENGAGE和XPECT试验纳入了来自北美和欧洲、月经周期规律、种族相似的患者。不孕的主要原因是男性因素、输卵管因素和子宫内膜异位症。
在ENGAGE试验中，18.3%的患者为卵巢高反应，12.7%的患者为卵巢低反应。刺激第1天的年龄、AFC、血清FSH和血清LH对卵巢高反应和低反应均具有预后价值。较高的AFC和LH与卵巢高反应的可能性增加相关。年龄较大和FSH较高与卵巢低反应的可能性增加相关。地区（北美/欧洲）和BMI对卵巢高反应具有预后价值，刺激第1天的血清雌二醇与卵巢低反应相关。卵巢高反应模型的受试者工作特征（ROC）曲线下面积（AUC）为0.82。敏感性和特异性分别为0.82和0.73；阳性预测值和阴性预测值分别为0.40和0.95。卵巢低反应模型的AUC为0.80。敏感性和特异性分别为0.77和0.73；阳性预测值和阴性预测值分别为0.29和0.96。在XPECT试验中，19.1%的患者为卵巢高反应者，16.1%的患者为卵巢低反应者。卵巢高反应和低反应的校准线斜率分别为0.81和1.35，两者与1.0均无统计学差异。总之，卵巢高反应和低反应的常见预后因素为女性年龄、AFC、基础血清FSH和LH。提出了简单的多变量模型，该模型能够预测接受GnRH拮抗剂方案和每日rFSH治疗的患者卵巢反应过低或过高的情况。
局限性、谨慎原因：预测模型中未纳入抗苗勒管激素。
这些结果将有助于识别卵巢反应过高或过低风险的患者，并实现COS治疗的个体化。
研究资金/利益冲突：本研究及编辑工作的资金支持由美国新泽西州怀特霍斯车站默克公司的子公司默克、夏普和多贺美公司（MSD）提供。F.J.B.从CVZ获得了一笔赠款给其所在机构；P.J.M.V.和H.W.是MSD的员工，B.M.J.L.M.在撰写本稿件时是MSD的员工。
NCT 00696800和NCT00778999。
