Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Zhizaoju Road No. 639, Huangpu District, Shanghai 200011, People's Republic of China.
Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, South Chongqing Road No. 280, Huangpu District, Shanghai 200025, People's Republic of China.
Hum Reprod. 2018 Feb 1;33(2):229-237. doi: 10.1093/humrep/dex367.
Can dydrogesterone (DYG) be used as an alternative progestin in a progesterone primed ovarian stimulation (PPOS) protocol?
DYG can be used as an appropriate alternative progestin in a PPOS protocol.
PPOS is a new ovarian stimulation regimen based on a freeze-all strategy that uses progestin as an alternative to a GnRH analog for suppressing a premature LH surge during the follicular phase. Medroxyprogesterone acetate (MPA) has been successfully used as an adjuvant to gonadotrophin in the PPOS protocol. However, the use of MPA may lead to stronger pituitary suppression and thus may require a higher dosage of hMG and a longer duration of ovarian stimulation than that of conventional ovarian stimulation protocol.
STUDY DESIGN SIZE, DURATION: A prospective RCT including 516 patients was performed between November 2015 and November 2016. Computerized randomization was conducted to assign participants at a 1:1 ratio into two treatment groups: an hMG + DYG group (260 patients) or an hMG + MPA group (256 patients) followed by IVF or ICSI with the freeze-all strategy. One cycle per patient was included. The primary outcome of the trial was the number of oocytes retrieved. The sample size was chosen to detect a difference of two oocytes with a power of 90%.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients under 36 years of age with normal ovarian reserve who were undergoing their first IVF/ICSI procedure due to tubal factor infertility were randomized into two groups based on the oral progestin protocol used: hMG co-treatment with DYG (hMG + DYG) or hMG co-treatment with MPA (hMG + MPA). The different progestin was simultaneously administered at the beginning of menstrual cycle 3 (MC3). Oocyte maturation was co-triggered by administration of a GnRH agonist and hCG. All viable embryos from both protocols were cryopreserved for later transfer. Only the first frozen embryo transfer (FET) cycle was included in our study. The embryological and clinical outcomes were measured.
Basic characteristics, such as age, BMI and infertility duration, in both groups were comparable. There was no significant difference in the number (mean ± SD) of oocytes retrieved [10.8 ± 6.3 for the hMG + DYG group versus 11.1 ± 5.8 for the hMG + MPA group, P = 0.33] or the oocyte retrieval rate [74.3 ± 19.6% for the hMG + DYG group versus 75.0 ± 19.5% for the hMG + MPA group, P = 0.69] between the groups. The viable embryo rate per oocyte retrieved did not differ between the two groups [odds ratio (OR): 1.08, 95% CI: 0.97-1.21, P = 0.16]: 37.4% (1052/2815) for the hMG + DYG group versus 35.6% (1009/2837) for the hMG + MPA group. During the whole process of ovarian stimulation, the mean LH level in the hMG + DYG group was always higher than that in the hMG + MPA group (P < 0.001); however, no patient from either group experienced a premature LH surge. In addition, no patients experienced moderate or severe ovarian hyperstimulation syndrome during the ovarian stimulation. No significant difference was found in the clinical pregnancy rate of the first FET cycle between the two groups (OR: 0.82, 95% CI: 0.56-1.21, P = 0.33): 57.6% for the hMG + DYG group (125/217) versus 62.3% for the hMG + MPA group (132/212).
The patients and physician were not blinded to the study. Further, a large proportion of patients were still pregnant at the end of the clinical trial, therefore live birth rates were not observed in the follow-up period. The dose-effectiveness of DYG administration was not addressed in the trial design.
DYG, which exhibits no or only weak inhibition of ovulation in normal dosage, can serve as an hMG adjuvant during ovarian stimulation. This finding suggests the possibility of a new application of DYG: as an appropriate alternative progestin for a PPOS protocol in IVF.
STUDY FUNDING/COMPETING INTEREST(S): This work was supported by The National Nature Science Foundation of China (Grant no. 81503603), Shanghai Three-year Plan on Promoting TCM Development (Grant no. ZY3-LCPT-2-2006) and the Natural Science Foundation of Shanghai (Grant nos. 15401932700 and 15ZR1424900). None of the authors declare any conflict of interest.
Chictr.org.cn: ChiCTR-IPR-15007251.
Chictr.org.cn: 22 October 2015.
DATE OF FIRST PATIENT’S ENROLLMENT: 1 November 2015.
地屈孕酮（DYG）可否替代孕激素用于孕激素预刺激卵巢刺激（PPOS）方案？
DYG 可作为 PPOS 方案中合适的孕激素替代物。
PPOS 是一种新的卵巢刺激方案，基于冻存所有策略，使用孕激素替代 GnRH 类似物抑制卵泡期过早的 LH 激增。醋酸甲羟孕酮（MPA）已成功用作 PPOS 方案中促性腺激素的辅助药物。然而，使用 MPA 可能导致更强的垂体抑制，因此可能需要更高剂量的 hMG 和更长的卵巢刺激时间，比传统的卵巢刺激方案长。
研究设计/大小/持续时间：2015 年 11 月至 2016 年 11 月进行了一项前瞻性随机对照试验，纳入 516 例患者。采用计算机随机化将参与者以 1:1 的比例分为两组：hMG+DYG 组（260 例）或 hMG+MPA 组（256 例），随后采用 IVF 或 ICSI 联合冻存所有策略。每位患者纳入一个周期。试验的主要结局是获卵数。选择样本量以检测出两卵的差异，效能为 90%。
参与者/材料/地点/方法：因输卵管因素不孕而接受首次 IVF/ICSI 治疗的年龄<36 岁、卵巢储备正常的患者，根据使用的口服孕激素方案随机分为两组：hMG 联合 DYG 治疗（hMG+DYG）或 hMG 联合 MPA 治疗（hMG+MPA）。两种孕激素同时在月经周期 3（MC3）开始时给药。当 GnRH 激动剂和 hCG 共同触发卵母细胞成熟时，所有有活力的胚胎均被冷冻保存以备后续移植。仅纳入我们研究的首次冷冻胚胎移植（FET）周期。测量胚胎学和临床结局。
两组的基本特征，如年龄、BMI 和不孕持续时间，均无显著差异。hMG+DYG 组和 hMG+MPA 组的获卵数（均数±标准差）[10.8±6.3 比 11.1±5.8，P=0.33]或获卵率[74.3±19.6%比 75.0±19.5%，P=0.69]均无显著差异。两组的每枚卵获得的可利用胚胎率也无差异[比值比（OR）：1.08，95%置信区间（CI）：0.97-1.21，P=0.16]：hMG+DYG 组为 37.4%（1052/2815），hMG+MPA 组为 35.6%（1009/2837）。在整个卵巢刺激过程中，hMG+DYG 组的平均 LH 水平始终高于 hMG+MPA 组（P<0.001）；然而，两组均无患者发生过早的 LH 激增。此外，两组患者在卵巢刺激期间均未发生中重度卵巢过度刺激综合征。两组首次 FET 周期的临床妊娠率无显著差异（OR：0.82，95%CI：0.56-1.21，P=0.33）：hMG+DYG 组为 57.6%（125/217），hMG+MPA 组为 62.3%（132/212）。
局限性/谨慎原因：患者和医生对研究不知情。此外，由于大量患者在临床试验结束时仍处于妊娠状态，因此在随访期间未观察到活产率。试验设计未解决 DYG 给药的剂量-效应关系。
地屈孕酮在正常剂量下不会抑制排卵或仅轻微抑制排卵，可作为卵巢刺激过程中 hMG 的辅助药物。这一发现表明 DYG 可能有新的应用：作为 IVF 中 PPOS 方案的合适孕激素替代物。
研究资金/利益冲突：本研究由国家自然科学基金（81503603）、上海市中医药三年行动计划（ZY3-LCPT-2-2006）和上海市自然科学基金（15401932700 和 15ZR1424900）资助。作者均无任何利益冲突。
Chictr.org.cn：ChiCTR-IPR-15007251。
Chictr.org.cn：2015 年 10 月 22 日。
2015 年 11 月 1 日。
