Abstract：
OBJECTIVE: Does ovarian stimulation with highly purified (hp)-HMG protect from elevated progesterone in the follicular phase compared to recombinant FSH (r-FSH) cycles through a different regulation of follicular steroidogenesis?
CONCLUSIONS: hp-HMG enhanced the Δ4 pathway from pregnenolone to androstenodione leading to lower serum progesterone at the end of the cycle, while r-FSH promoted the conversion of pregnenolone to progesterone causing higher follicular phase progesterone levels.
BACKGROUND: Elevated progesterone in the follicular phase has been related to lower clinical outcome in fresh IVF cycles. Progesterone levels are positively correlated to ovarian response, and some studies have shown that when r-FSH alone is used for ovarian stimulation serum progesterone levels on the day of triggering are higher than when hp-HMG is given. Whether this is caused by a lower ovarian response in hp-HMG cycles or to a difference in follicular steroidogenesis in the two ovarian stimulation regimens has not been well characterized.
METHODS: A randomized controlled trial including 112 oocyte donors undergoing ovarian stimulation with GnRH antagonists and 225 IU/day of r-FSH (n = 56) or hp-HMG (n = 56) was carried out in a university-affiliated private infertility clinic. Subjects were recruited between October 2016 and June 2018.
METHODS: The women were aged 18-35 years with a regular menstrual cycle (25-35 days) and normal ovarian reserve (serum anti-Müllerian hormone (AMH) = 10-30 pMol/l) undergoing ovarian stimulation for oocyte donation. FSH, LH, estradiol (E2), estrone, progesterone, pregnenolone, 17-OH-progesterone, androstenodione, dehidroepiandrostenodione, and testosterone were determined on stimulation Days 1, 4, 6, and 8 and on day of triggering in serum and in follicular fluid. Samples were frozen at -20°C until assay. Total exposures across the follicular phase were compared by polynomic extrapolation.
RESULTS: Subjects in both groups were comparable in terms of age, BMI, and AMH levels. Ovarian response was also similar: 17.5 ± 7.9 (mean ± SD) versus 16.5 ± 7.5 oocytes with r-FSH and hp-HMG, respectively (P = 0.49). Serum progesterone (ng/ml) on day of trigger was 0.46 ± 0.27 in the hp-HMG group versus 0.68 ± 0.50 in the r-FSH group (P = 0.010). Differences for progesterone were also significant on stimulation days 6 and 8. The pregnenolone: progesterone ratio was significantly increased in the r-FSH group from stimulation day 8 to the day of trigger (P = 0.019). Serum androstenodione (ng/ml) on day of trigger was 3.0 ± 1.4 in the hp-HMG group versus 2.4 ± 1.1 in the r-FSH group (P = 0.015). Differences in adrostenodione were also significant on stimulation Day 8. The pregnenolone:androstenodione ratio was significantly higher in the hp-HMG group (P = 0.012) on Days 6 and 8 and trigger. There were no other significant differences between groups. Follicular fluid E2, FSH, LH, dehidroepioandrostenodione, androstenodione, and testosterone were significantly higher in the hp-HMG than r-FSH group. No differences were observed for progesterone, estrone, 17-OH-progesterone, and pregnenolone in follicular fluid.
CONCLUSIONS: All women included in the study were young, not infertile, and had a normal BMI and a good ovarian reserve. The findings might be different in other patient subpopulations. Hormone analyses with immunoassays are subject to intra-assay variations that may influence the results.
CONCLUSIONS: Stimulation with hp-HMG may prevent progesterone elevation at the end of the follicular phase because of a different follicular steroidogenesis pathway, regardless of ovarian response. This should be considered, particularly in patients at risk of having high progesterone levels at the end of the follicular phase when a fresh embryo transfer is planned.
BACKGROUND: Roche Diagnostics provided unrestricted funding for all serum and follicular fluid hormone determinations. J.L.R., M.M., and A.P. have nothing to declare. E.B. has received consulting fees from Ferring, Merck, Gedeon Richter, and Roche and has participated in a research cooperation with Gedeon-Richter. In addition, the author has participated in speakers\' bureau and received fees from Ferring, Gedeon Richter, Merck, and Roche. P.A. has received consulting fees from MSD and has participated in speakers\' bureau and received fees from Ferring. P.A. also declares travel/meeting support from MSD. E.L. has received consulting fees from Ferring and MSD. In addition, the author has participated in a research cooperation with Gedeon-Richter. Also, the author has participated in speakers\' bureau and received fees from Ferring and IBSA, as well as travel/meeting support from IBSA and Gedeon Richter. E.B., P.A., and E.L. also own stocks in IVIRMA Valencia.
BACKGROUND: NCT: NCT02738580.
UNASSIGNED: 19 February 2016.
UNASSIGNED: 03 October 2016.
CONCLUSIONS: hp-HMG enhanced the Δ4 pathway from pregnenolone to androstenodione leading to lower serum progesterone at the end of the cycle, while r-FSH promoted the conversion of pregnenolone to progesterone causing higher follicular phase progesterone levels.
BACKGROUND: Elevated progesterone in the follicular phase has been related to lower clinical outcome in fresh IVF cycles. Progesterone levels are positively correlated to ovarian response, and some studies have shown that when r-FSH alone is used for ovarian stimulation serum progesterone levels on the day of triggering are higher than when hp-HMG is given. Whether this is caused by a lower ovarian response in hp-HMG cycles or to a difference in follicular steroidogenesis in the two ovarian stimulation regimens has not been well characterized.
METHODS: A randomized controlled trial including 112 oocyte donors undergoing ovarian stimulation with GnRH antagonists and 225 IU/day of r-FSH (n = 56) or hp-HMG (n = 56) was carried out in a university-affiliated private infertility clinic. Subjects were recruited between October 2016 and June 2018.
METHODS: The women were aged 18-35 years with a regular menstrual cycle (25-35 days) and normal ovarian reserve (serum anti-Müllerian hormone (AMH) = 10-30 pMol/l) undergoing ovarian stimulation for oocyte donation. FSH, LH, estradiol (E2), estrone, progesterone, pregnenolone, 17-OH-progesterone, androstenodione, dehidroepiandrostenodione, and testosterone were determined on stimulation Days 1, 4, 6, and 8 and on day of triggering in serum and in follicular fluid. Samples were frozen at -20°C until assay. Total exposures across the follicular phase were compared by polynomic extrapolation.
RESULTS: Subjects in both groups were comparable in terms of age, BMI, and AMH levels. Ovarian response was also similar: 17.5 ± 7.9 (mean ± SD) versus 16.5 ± 7.5 oocytes with r-FSH and hp-HMG, respectively (P = 0.49). Serum progesterone (ng/ml) on day of trigger was 0.46 ± 0.27 in the hp-HMG group versus 0.68 ± 0.50 in the r-FSH group (P = 0.010). Differences for progesterone were also significant on stimulation days 6 and 8. The pregnenolone: progesterone ratio was significantly increased in the r-FSH group from stimulation day 8 to the day of trigger (P = 0.019). Serum androstenodione (ng/ml) on day of trigger was 3.0 ± 1.4 in the hp-HMG group versus 2.4 ± 1.1 in the r-FSH group (P = 0.015). Differences in adrostenodione were also significant on stimulation Day 8. The pregnenolone:androstenodione ratio was significantly higher in the hp-HMG group (P = 0.012) on Days 6 and 8 and trigger. There were no other significant differences between groups. Follicular fluid E2, FSH, LH, dehidroepioandrostenodione, androstenodione, and testosterone were significantly higher in the hp-HMG than r-FSH group. No differences were observed for progesterone, estrone, 17-OH-progesterone, and pregnenolone in follicular fluid.
CONCLUSIONS: All women included in the study were young, not infertile, and had a normal BMI and a good ovarian reserve. The findings might be different in other patient subpopulations. Hormone analyses with immunoassays are subject to intra-assay variations that may influence the results.
CONCLUSIONS: Stimulation with hp-HMG may prevent progesterone elevation at the end of the follicular phase because of a different follicular steroidogenesis pathway, regardless of ovarian response. This should be considered, particularly in patients at risk of having high progesterone levels at the end of the follicular phase when a fresh embryo transfer is planned.
BACKGROUND: Roche Diagnostics provided unrestricted funding for all serum and follicular fluid hormone determinations. J.L.R., M.M., and A.P. have nothing to declare. E.B. has received consulting fees from Ferring, Merck, Gedeon Richter, and Roche and has participated in a research cooperation with Gedeon-Richter. In addition, the author has participated in speakers\' bureau and received fees from Ferring, Gedeon Richter, Merck, and Roche. P.A. has received consulting fees from MSD and has participated in speakers\' bureau and received fees from Ferring. P.A. also declares travel/meeting support from MSD. E.L. has received consulting fees from Ferring and MSD. In addition, the author has participated in a research cooperation with Gedeon-Richter. Also, the author has participated in speakers\' bureau and received fees from Ferring and IBSA, as well as travel/meeting support from IBSA and Gedeon Richter. E.B., P.A., and E.L. also own stocks in IVIRMA Valencia.
BACKGROUND: NCT: NCT02738580.
UNASSIGNED: 19 February 2016.
UNASSIGNED: 03 October 2016.
摘要：
目的：与重组FSH（r-FSH）周期相比，高度纯化（hp）-HMG刺激卵巢是否通过不同的卵泡类固醇生成调节来保护卵泡期孕酮升高？而r-FSH促进孕烯醇酮向孕酮的转化，导致卵泡期孕酮水平升高。
背景：卵泡期孕酮升高与新鲜IVF周期的临床结局降低有关。孕酮水平与卵巢反应呈正相关,一些研究表明，当r-FSH单独用于卵巢刺激时，触发当天的血清孕酮水平高于给予hp-HMG时。这是由hp-HMG周期中的低卵巢反应还是两种卵巢刺激方案中的卵泡类固醇生成差异引起的，尚未得到很好的表征。
方法：一项随机对照试验，包括112名接受GnRH拮抗剂和225IU/天r-FSH（n=56）或hp-HMG（n=56）的卵巢刺激的卵母细胞捐献者，在一所大学附属的私人不孕诊所进行。受试者在2016年10月至2018年6月之间招募。
方法：女性年龄为18-35岁，月经周期正常（25-35天），卵巢储备正常（血清抗苗勒管激素（AMH）=10-30pMol/l），接受卵巢刺激以进行卵母细胞捐献。FSH,LH,雌二醇（E2），estrone,黄体酮,孕烯醇酮,17-OH-孕酮，雄烯二酮,去氢表雄酮，在刺激第1、4、6和8天以及触发当天测定血清和卵泡液中的睾酮。将样品在-20°C下冷冻直至测定。通过多项式外推法比较整个卵泡期的总暴露量。
结果：两组受试者的年龄相当，BMI,AMH水平。卵巢反应也相似：17.5±7.9（平均值±SD）和16.5±7.5个r-FSH和hp-HMG的卵母细胞，分别为(P=0.49)。hp-HMG组触发日的血清孕酮（ng/ml）为0.46±0.27，r-FSH组为0.68±0.50（P=0.010）。孕酮的差异在刺激第6天和第8天也是显著的。从刺激第8天到触发天，r-FSH组的孕烯醇酮：孕酮比率显着增加（P=0.019）。hp-HMG组触发当天的血清雄烯二酮（ng/ml）为3.0±1.4，r-FSH组为2.4±1.1（P=0.015）。在刺激第8天,adrostoendione的差异也是显著的。在第6天和第8天和触发天，hp-HMG组的孕烯醇酮：雄烯酮比率显着升高（P=0.012）。组间没有其他显著差异。卵泡液E2，FSH，LH,去氢表皮雄酮，雄烯二酮,和睾酮在hp-HMG组明显高于r-FSH组。孕酮没有观察到差异，estrone,17-OH-孕酮，和卵泡液中的孕烯醇酮。
结论：纳入研究的所有女性都是年轻的，不是不育,BMI正常，卵巢储备良好。其他患者亚群的发现可能有所不同。使用免疫测定的激素分析经受可能影响结果的测定内变化。
结论：用hp-HMG刺激可以防止卵泡期结束时孕酮升高，因为卵泡类固醇生成途径不同，无论卵巢反应如何。这应该被考虑,特别是在计划进行新鲜胚胎移植的卵泡期结束时，有高孕酮水平风险的患者。
背景：罗氏诊断学为所有血清和卵泡液激素测定提供了不受限制的资金。J.L.R.,M.M.,A.P.没有什么可声明的.E.B.收到了Ferring的咨询费,默克,GedeonRichter,和罗氏，并参与了与Gedeon-Richter的研究合作。此外,提交人参加了演讲者\'局，并收到了费林的费用，GedeonRichter,默克,还有罗氏.P.A.已收到MSD的咨询费，并参加了演讲者局，并收到了Ferring的费用。P.A.还声明MSD的旅行/会议支持。E.L.已收到Ferring和MSD的咨询费。此外,作者参与了与Gedeon-Richter的研究合作。此外，作者曾参加过演讲者的办公室，并收到了Ferring和IBSA的费用，以及IBSA和GedeonRichter的旅行/会议支持。E.B.,P.A.,和E.L.也拥有IVIRMAValencia的股票。
背景：NCT：NCT02738580。
■2016年2月19日。
■2016年10月3日。
背景：卵泡期孕酮升高与新鲜IVF周期的临床结局降低有关。孕酮水平与卵巢反应呈正相关,一些研究表明，当r-FSH单独用于卵巢刺激时，触发当天的血清孕酮水平高于给予hp-HMG时。这是由hp-HMG周期中的低卵巢反应还是两种卵巢刺激方案中的卵泡类固醇生成差异引起的，尚未得到很好的表征。
方法：一项随机对照试验，包括112名接受GnRH拮抗剂和225IU/天r-FSH（n=56）或hp-HMG（n=56）的卵巢刺激的卵母细胞捐献者，在一所大学附属的私人不孕诊所进行。受试者在2016年10月至2018年6月之间招募。
方法：女性年龄为18-35岁，月经周期正常（25-35天），卵巢储备正常（血清抗苗勒管激素（AMH）=10-30pMol/l），接受卵巢刺激以进行卵母细胞捐献。FSH,LH,雌二醇（E2），estrone,黄体酮,孕烯醇酮,17-OH-孕酮，雄烯二酮,去氢表雄酮，在刺激第1、4、6和8天以及触发当天测定血清和卵泡液中的睾酮。将样品在-20°C下冷冻直至测定。通过多项式外推法比较整个卵泡期的总暴露量。
结果：两组受试者的年龄相当，BMI,AMH水平。卵巢反应也相似：17.5±7.9（平均值±SD）和16.5±7.5个r-FSH和hp-HMG的卵母细胞，分别为(P=0.49)。hp-HMG组触发日的血清孕酮（ng/ml）为0.46±0.27，r-FSH组为0.68±0.50（P=0.010）。孕酮的差异在刺激第6天和第8天也是显著的。从刺激第8天到触发天，r-FSH组的孕烯醇酮：孕酮比率显着增加（P=0.019）。hp-HMG组触发当天的血清雄烯二酮（ng/ml）为3.0±1.4，r-FSH组为2.4±1.1（P=0.015）。在刺激第8天,adrostoendione的差异也是显著的。在第6天和第8天和触发天，hp-HMG组的孕烯醇酮：雄烯酮比率显着升高（P=0.012）。组间没有其他显著差异。卵泡液E2，FSH，LH,去氢表皮雄酮，雄烯二酮,和睾酮在hp-HMG组明显高于r-FSH组。孕酮没有观察到差异，estrone,17-OH-孕酮，和卵泡液中的孕烯醇酮。
结论：纳入研究的所有女性都是年轻的，不是不育,BMI正常，卵巢储备良好。其他患者亚群的发现可能有所不同。使用免疫测定的激素分析经受可能影响结果的测定内变化。
结论：用hp-HMG刺激可以防止卵泡期结束时孕酮升高，因为卵泡类固醇生成途径不同，无论卵巢反应如何。这应该被考虑,特别是在计划进行新鲜胚胎移植的卵泡期结束时，有高孕酮水平风险的患者。
背景：罗氏诊断学为所有血清和卵泡液激素测定提供了不受限制的资金。J.L.R.,M.M.,A.P.没有什么可声明的.E.B.收到了Ferring的咨询费,默克,GedeonRichter,和罗氏，并参与了与Gedeon-Richter的研究合作。此外,提交人参加了演讲者\'局，并收到了费林的费用，GedeonRichter,默克,还有罗氏.P.A.已收到MSD的咨询费，并参加了演讲者局，并收到了Ferring的费用。P.A.还声明MSD的旅行/会议支持。E.L.已收到Ferring和MSD的咨询费。此外,作者参与了与Gedeon-Richter的研究合作。此外，作者曾参加过演讲者的办公室，并收到了Ferring和IBSA的费用，以及IBSA和GedeonRichter的旅行/会议支持。E.B.,P.A.,和E.L.也拥有IVIRMAValencia的股票。
背景：NCT：NCT02738580。
■2016年2月19日。
■2016年10月3日。
