黄体期使用促性腺激素释放激素激动剂的效果评价

由于控制性超促排卵(COH)过程中超剂量雌、孕激素的生成以及垂体降调节药物的使用,经常出现黄体功能不全,需要常规进行黄体支持,常见的黄体支持方案包括使用人绒毛膜促性激素(hCG)及补充雌孕激素等。在近些年,多项研究表明促性腺激素释放激素激动剂(GnRH-a)在黄体支持中有很多积极方面,可以改善临床结局。其主要机制尚不清楚,可能与刺激黄体分泌雌、孕激素,提高子宫内膜容受性,提高胚胎发育潜能,促进滋养细胞分泌hCG相关。GnRHa进行黄体支持的机制及用法用量还有待进一步探究。     

The addition of single dose GnRH agonist to luteal phase support in artificial cycle frozen embryo transfer: a randomized clinical trial

This prospective randomized clinical trial (RCT) was to evaluate the effect of single-dose gonadotrophin-releasing hormone agonist (GnRHa) in artificial cycle frozen-embryo transfer (AC-FET). A total of 868 FET cycles were included and randomized into two groups: Group A (n?=?434) received GnRHa 0.1?mg subcutaneous injection on day 3 after embryo transfer (ET); Group B (n?=?434) did not receive GnRHa. The demographic characteristics, primary endpoint (implantation rate) and secondary endpoints (chemical pregnancy rate, clinical pregnancy rate, ongoing pregnancy rate) were compared between two groups and subgroups (aged <35?years and 35-37?years). There were no significant differences in terms of the rates of implantation, clinical pregnancy, ongoing pregnancy, and miscarriage between two groups. While, the subgroups analysis showed the implantation rate was significantly increased in advanced age women (35–37?years) in GnRHa group compared with control group (45.3% vs. 27.8%, p?=?.03). In conclusion, single dose of GnRHa (0.1?mg triptorelin acetate) supplementation 3?days after ET in AC-FET cycles did not show significant benefit on pregnancy outcomes as a whole. However, in ageing women subgroup, the implantation rate was increasing by adding up GnRHa in peri-implantation periods, and this tendency needs to be further demonstrated by RCT with larger sample size.     

Efficiency of follicle-stimulating hormone, commenced in the luteal phase, for overcoming a poor response in assisted reproduction

Aim:  The efficacy of commencement of recombinant follicle-stimulating hormone (recFSH) during the luteal phase in the long-protocol gonadotropin-releasing hormone (GnRH) agonist regimen in poor responders was compared with the conventional protocol in a prospective, randomized, controlled study.
Methods:  Forty-two women who responded poorly to previous conventional controlled ovarian hyperstimulation were included in the study. Recombinant FSH (150 IU) was started simultaneously with the GnRH agonist long protocol in the study group. The control group was started recFSH on Day 2 of menstruation in the long-protocol GnRH agonist regimen. The number of metaphase (M) II oocytes, the number of embryos transferred, and the pregnancy rate were analyzed as main outcome measures.
Results:  Patients in the study group had a higher number of MII oocytes compared with the control group (6.8 vs 3.2, respectively; P  < 0.005), received a higher number of embryos (2.7 vs 1.2, respectively; P  < 0.05), and had higher pregnancy rates (38% vs 15%, respectively; P  < 0.005).
Conclusions:  Commencement of recFSH during the luteal phase simultaneously with the long-protocol GnRH agonist regiment in poor responder women produces better results compared with the conventional long-protocol GnRH agonist plus high-dose recFSH regimen.     

Luteal phase support with estradiol and progesterone versus progesterone alone in GnRH antagonist ICSI cycles: a randomized controlled study

In vitro fertilization (IVF) cycles are associated with a defective luteal phase. Although progesterone supplementation to treat this problem is standard practice, estrogen addition is debatable. Our aim was to compare pregnancy outcomes in 220 patients undergoing antagonist intracytoplasmic sperm injection (ICSI) cycles protocol. The patients were randomly assigned into two equal groups to receive either vaginal progesterone alone (90?mg once daily) starting on the day of oocyte retrieval for up to 12 weeks if pregnancy occurred or estradiol addition (2?mg twice daily) starting on the same day and continuing up to seven weeks (foetal viability scan). Primary outcomes were pregnancy and ongoing pregnancy rates per embryo transfer. Secondary outcomes were implantation and early pregnancy loss rates. Pregnancy rates showed no significant difference between group 1 (39.09%) and 2 (43.63%) (p value?=?0.3). Similarly, both groups were comparable regarding ongoing pregnancy rate (32.7% group 1 and 36.3% group 2, p value?=?0.1). Implantation rates showed no difference between group 1 (19.25%) and group 2 (23.44%) (p value?=?0.2). Early pregnancy loss rates were comparable, with 6.3% and 7.2% in groups 1 and 2, respectively, (p value?=?0.4). In conclusion, the addition of 4?mg estrogen daily to progesterone for luteal support in antagonist ICSI cycles is not beneficial for pregnancy outcome.     

卵巢正常反应不孕症患者体外受精不同长方案促排卵效果的研究

目的探讨卵巢正常反应不孕症患者体外受精/卵胞质内单精子显微注射(IVF/ICSI)促排卵时应用口服避孕药(OC)长方案和黄体中期长方案的促排卵效果及临床结局。方法选择接受长方案IVF/ICSI助孕的卵巢正常反应患者共4 677个周期;根据年龄分为≤35岁组和35岁组,不方便超声监测排卵或自然周期超声监测卵泡不破裂的患者共2 762个周期,应用OC长方案(OC组);自然周期超声监测正常排卵的患者共1 915个周期,应用黄体中期长方案(黄体中期组);常规行IVF/ICSI,比较上述不同年龄人群2种促排卵方案的临床和实验室相关指标。结果 (1)OC组促性腺激素(Gn)启动日雌二醇(E2)[≤35岁组:(24.63±10.62)ng/L,35岁组:(24.24±10.40)ng/L]和促黄体生成素(LH)水平[≤35岁组:(0.92±0.59)IU/L,35岁组:(0.82±0.66)IU/L]均明显低于黄体中期组[≤35岁组:(25.89±12.80)ng/L,35岁组:(25.71±10.93)ng/L;≤35岁组:(1.37±0.59)IU/L,35岁组:(1.01±0.70)IU/L](P0.05);(2)OC组人绒毛膜促性腺激素(h CG)注射日E2水平[≤35岁组:(4 143.8±2 769.9)ng/L,35岁组:(3 597.5±2 160.4)ng/L]和因卵巢过度刺激综合征(OHSS)行全胚冷冻率(≤35岁组:9.1%,35岁组:10.2%)均明显高于黄体中期组[≤35岁组:(3 850.8±2 092.4)ng/L,35岁组:(3 213.4±1 804.5)ng/L;≤35岁组:4.9%,35岁组:5.9%](P0.05),但h CG注射日的内膜厚度[≤35岁组:(10.75±2.25)mm,35岁组:(10.47±2.38)mm]却明显小于后者[≤35岁组:(11.62±2.43)mm,35岁组:(11.09±2.68)mm](P0.05);(3)在年龄35岁的OC组Gn总用量[(3 775.4±1 200.0)IU]和使用时间[(13.5±2.2)d]明显高于黄体中期组[(3 516.9±1 156.1)IU,(12.4±2.2)d](P0.05);(4)2种降调节方案患者的获卵数、ICSI成熟卵数、双原核(2PN)受精率、平均移植胚胎数、优质胚胎率和早期流产率均无明显差异(P0.05),但OC组的着床率(≤35岁组:41.4%,35岁组:25.5%)和临床妊娠率(≤35岁组:55.7%,35岁组:37.5%)明显小于黄体中期组(≤35岁组:46.7%,35岁组:31.4%;≤35岁组:65.6%,35岁组:46.9%)(P0.05)。结论 (1)OC长方案可加深垂体抑制,尤其是35岁的高龄患者需增加Gn用量才能达到与黄体中期长方案相似的促排卵效果;(2)OC长方案可能通过影响子宫内膜厚度及容受性而降低着床率和临床妊娠率;(3)OC长方案使h CG注射日E2水平更高,易诱发OHSS的发生。故对卵巢功能正常的不孕患者,IVF/ICSI助孕时尽量选择黄体中期长方案。     

Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction

The pharmacological and physiological profiles of progestogens used for luteal phase support during assisted reproductive technology are likely to be important in guiding clinical choice towards the most appropriate treatment option. Various micronized progesterone formulations with differing pharmacological profiles have been investigated for several purposes. Dydrogesterone, a stereoisomer of progesterone, is available in an oral form with high oral bioavailability; it has been used to treat a variety of conditions related to progesterone deficiency since the 1960s and has recently been approved for luteal phase support as part of an assisted reproductive technology treatment. The primary objective of this review is to critically analyse the clinical implications of the pharmacological and physiological properties of dydrogesterone for its uses in luteal phase support and in early pregnancy.     

A Phase III randomized controlled trial of oral dydrogesterone versus intravaginal progesterone gel for luteal phase support in in vitro fertilization (Lotus II): results from the Chinese mainland subpopulation

Abstract

Lotus II, a randomized, open-label, multicenter, international study compared the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) gel for luteal support in IVF. A prespecified subgroup analysis was performed on 239 Chinese mainland subjects from the overall study population (n?=?1034), who were randomized to oral dydrogesterone 30?mg or 8% MVP gel 90?mg daily from the day of oocyte retrieval until 12?weeks of gestation. The aim was to demonstrate non-inferiority of oral dydrogesterone to MVP gel, assessed by the presence of a fetal heartbeat at 12?weeks of gestation. In the Chinese mainland subpopulation, there was a numerical difference of 9.4% in favor of oral dydrogesterone, with ongoing pregnancy rates at 12?weeks of gestation of 61.4% and 51.9% in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 9.4%; 95% CI: ?3.4 to 22.1); in the overall population, these were 38.7% and 35%, respectively (adjusted difference, 3.7%; 95% CI: ?2.3 to 9.7). In both the Chinese mainland subpopulation and the overall population, dydrogesterone had similar efficacy and safety to MVP gel. With convenient oral administration, dydrogesterone has potential to transform luteal support treatment.     

Repeated GnRH agonist doses for luteal support: a proof of concept

Research questionWhat are the safety and feasibility of repeated subcutaneous doses of gonadotrophin-releasing hormone (GnRH) agonist for luteal support in IVF cycles triggered by a GnRH agonist?DesignIn this prospective trial, patients exhibiting oestradiol concentrations of over 2500 pg/ml after use of a GnRH agonist for triggering ovulation were initially randomized to GnRH agonist luteal support (0.1 mg subcutaneously every other day, starting on day 3 after embryo transfer) or to a control group supported by 80 µg of recombinant human chorionic gonadotrophin (HCG) on day 3 after embryo transfer. All patients underwent a day 5 blastocyst transfer. Randomization to the HCG luteal support was stopped owing to two cases of ovarian hyperstimulation syndrome (OHSS) and the study was continued solely with GnRH agonist luteal support.ResultsThe study included 39 women in the repeated GnRH agonist luteal support group and seven in the HCG micro dose group. There were no cases of OHSS among patients supported by a GnRH agonist, and no other adverse events were recorded. There were no cases of bleeding before the pregnancy test, and hence no cases of an insufficient luteal phase. A clinical pregnancy rate of 43.6% was achieved with GnRH agonist luteal support. Hormone dynamics during the stimulation cycle reflected rising LH and progesterone concentrations after the introduction of GnRH agonist support.ConclusionsRepeated doses of GnRH agonist every other day as a method of luteal support provided safe and effective luteal support for women who underwent GnRH agonist triggering in a GnRH antagonist IVF cycle.     

Oral oestradiol supplementation as luteal support in IVF/ICSI cycles: a prospective,randomized controlled study

Objective

To explore whether oral oestradiol (E2) supplementation (6 mg) in the luteal phase is beneficial to the outcome of patients undergoing gonadotrophin-releasing hormone agonist (GnRHa) long protocol in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles.

Study design

Prospective, randomized, controlled study at the IVF Clinic, Sun Yat-sen Memorial Hospital. In total, 402 patients with an indication for IVF or ICSI were recruited. Patients were prospectively randomized to receive either progesterone injection plus oral E2 supplementation (Group A, n = 202) or progesterone injection alone (Group B, n = 200) as luteal support after oocyte retrieval. The main outcome measure was the clinical pregnancy rate.

Results

No significant difference in the clinical pregnancy rate or miscarriage rate was observed between Group A and Group B (50.9% vs 58.0%, 14.6% vs 11.2%; p > 0.05). In different age subgroups (≤35 years and >35 years) all measurements were comparable in patients with or without E2 supplementation, as well as in subgroups with different E2 levels on the day of human chorionic gonadotrophin injection (E2 ≥ 3000 pg/ml and E2 < 3000 pg/ml).

Conclusion

Adding E2 as luteal support did not increase the clinical pregnancy rate or reduce the miscarriage rate. Routine use of a combination of E2 and progesterone as luteal support in GnRHa long protocol IVF/ICSI cycles is not recommended.     

Efficacy of luteal phase support with vaginal progesterone in intrauterine insemination: a systematic review and meta-analysis

Purpose

To evaluate the efficacy of luteal phase support with vaginal progesterone in women undergoing intrauterine insemination (IUI).

Methods

Systematic review and meta-analysis. Randomized controlled trials (RCT) comparing supplementation of luteal phase with vaginal progesterone among women undergoing IUI versus a control group were included. The main outcome assessed was live birth rate.

Results

Five RCT met the inclusion criteria. In all 1,271 patients were included (951 IUI cycles in the progesterone group, 935 in the control group). Women treated with vaginal progesterone achieved significantly higher live birth rate (risk ratio [RR] 1.94, 95 % confidence interval [CI] 1.36 to 2.77,), and clinical pregnancy rate (RR 1.41, 95 % CI 1.14 to 1.76) as compared with controls. In the subgroup analysis per stimulation protocol, this beneficial effect of receiving progesterone was only observed in the group stimulated with gonadotropins (RR 2.28, 95 % CI 1.49 to 3.51), compared to the group stimulated with clomiphene citrate (CC) (RR 1.30, 95 % CI 0.68 to 2.50). No differences were observed in the miscarriage and multiple pregnancy rates.

Conclusions

The supplementation of luteal phase with vaginal progesterone significantly increases live birth among women undergoing IUI when receiving gonadotropins for ovulation induction. Women receiving CC to induce ovulation do not seem to benefit from this treatment.     

The role of luteal support during IVF: a qualitative systematic review

Abstract

The aim of this review is to provide qualitative evidence-based synthesis regarding efficacy of luteal-phase support on fertility outcome in women undergoing in vitro fertilization (IVF) with respect to clinical or live birth rates and pregnancy loss rates. Although the need of luteal phase support in IVF/ICSI cycles is well-known, the optimal start, dosage, route and the duration of the luteal phase support is still subject of debate. Data suggest that the optimal period to start with the luteal phase support would be between 24–72?hours after oocyte-retrieval and should continue at least until a positive pregnancy test is achieved. However, the majority of IVF-centers worldwide provide progesterone support up to 8?weeks of pregnancy. Among the well-established routes of luteal support, oral dydrogesterone and subcutaneous progesterone represent new and interesting routes of progesterone administration. The current studies support these routes of progesterone administration use in terms of comparable pregnancy rates and pregnancy loss rates to vaginal and intramuscular progesterone. Furthermore, the acceptance and tolerability among patients seems to be even better. In the frozen-thawed embryo transfer, dydrogesterone and vaginal progesterone are not effective as monotherapy treatments; however, when combined there is no reason to avoid one or the other in this setting.