Ovarian stimulation for oocyte donation: a systematic review and meta-analysis.

Since its introduction in the 1980s, oocyte donation (OD) has been largely integrated into ART. Lately, both demand and the indications for OD have increased greatly. Oocyte donors are healthy and potentially fertile women undergoing voluntarily ovarian stimulation (OS). Selection of the optimal type of stimulation is of paramount importance in order to achieve the most favourable outcomes for the oocyte recipients, but most importantly for the safety of the oocyte donors. This is the first systematic review (SR) with the objective to summarize the current evidence on OS in oocyte donors. The scope of this SR was to evaluate the OD programme by assessing four different aspects: how to assess the ovarian response prior to stimulation; how to plan the OS (gonadotrophins; LH suppression; ovulation trigger; when to start OS); how to control for the risk of ovarian hyperstimulation syndrome (OHSS) and other complications; and the differences between the use of fresh versus vitrified donated oocytes. A systematic literature search was conducted in May 2020, according to PRISMA guidelines in the databases PubMed and Embase, using a string that combined synonyms for oocytes, donation, banking, freezing, complications and reproductive outcomes. Studies reporting on the safety and/or efficacy of OS in oocyte donors were identified. The quality of the included studies was assessed using ROBINS-I and ROB2. Meta-analysis was performed where appropriate. Data were combined to calculate mean differences (MD) for continuous variables and odd ratios (OR) for binary data with their corresponding 95% CIs. Heterogeneity between the included studies was assessed using I2 and tau statistics. In total, 57 manuscripts were selected for the review, out of 191 citations identified. Antral follicle count and anti-Müllerian hormone levels correlate with ovarian response to OS in OD but have limited value to discriminate donors who are likely to show either impaired or excessive response. Five randomized controlled trials compared different type of gonadotrophins as part of OS in oocyte donors; owing to high heterogeneity, meta-analysis was precluded. When comparing different types of LH control, namely GnRH antagonist versus agonist, the studies showed no differences in ovarian response. Use of progesterone primed ovarian stimulation protocols has been evaluated in seven studies: the evidence has shown little or no difference, compared to GnRH antagonist protocols, in mean number of retrieved oocytes (MD 0.23, [95% CI 0.58-1.05], n = 2147; 6 studies; I2 = 13%, P = 0.33) and in clinical pregnancy rates among recipients (OR 0.87 [95% CI 0.60-1.26], n = 2260, I2 = 72%, P < 0.01). There is insufficient evidence on long-term safety for babies born. GnRH agonist triggering is the gold standard and should be used in all oocyte donors, given the excellent oocyte retrieval rates, the practical elimination of OHSS and no differences in pregnancy rates in recipients (four studies, OR 0.86, 95%CI 0.58-1.26; I2 = 0%). OS in OD is a safe procedure with a low rate of hospitalization after oocyte retrieval. The use of a levonorgestrel intrauterine device or a progestin contraceptive pill during OS does not impact the number of oocytes retrieved or the clinical pregnancy rate in recipients. Ultrasound monitoring seems enough for an adequate follow up of the stimulation cycle in OD. Use of fresh versus vitrified donated oocytes yielded similar pregnancy outcomes. This update will be helpful in the clinical management of OS in OD based on the most recent knowledge and recommendations, and possibly in the management of women under 35 years undergoing oocyte vitrification for social freezing, owing to the population similarities. More clinical research is needed on OS protocols that are specifically designed for OD, especially in term of the long-term safety for newborns, effective contraception during OS, and treatment satisfaction.

Martinez F ，Racca A ，Rodríguez I ，Polyzos NP ... -  《-》

Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles.

Youssef MA ，Van der Veen F ，Al-Inany HG ，Griesinger G ，Mochtar MH ，Aboulfoutouh I ，Khattab SM ，van Wely M ... -  《Cochrane Database of Systematic Reviews》

GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis.

Griesinger G ，Diedrich K ，Devroey P ，Kolibianakis EM ... -  《HUMAN REPRODUCTION UPDATE》

Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol: RCT including 1050 first IVF/ICSI cycles.

Is the risk of severe ovarian hyperstimulation syndrome (OHSS) similar in a short GnRH antagonist and long GnRH agonist protocol in first cycle IVF/ICSI patients less than 40 years of age?. There is an increased risk of severe OHSS in the long GnRH agonist group compared with the short GnRH antagonist protocol. WHAT IS KNOWN ALREADY?: In the most recent Cochrane review, the GnRH antagonist protocol was associated with a similar live birth rate (LBR), a similar on-going pregnancy rate (OPR), and a lower incidence of OHSS (odds ratio (OR) = 0.43 95% confidence interval (CI): 0.33-0.57) compared with the traditional GnRH agonist protocol. Previous trials comparing the two protocols mainly included selected patient populations, a limited number of patients and the applied OHSS criteria differed, making direct comparisons difficult. In two recent large meta-analyses, no significant differences in LBR (OR = 0.86; 95% CI: 0.72-1.02) or in the incidence of severe OHSS were reported, while others found a lower LBR (OR = 0.82; 95% CI: 0.68-0.97) and a reduced risk of severe OHSS using the GnRH antagonist protocol (OR = 0.60; 95% CI: 0.40-0.88). Phase IV, dual-centre, open-label, RCT including 1050 women allocated to either short GnRH antagonist or long GnRH agonist protocol in a 1:1 ratio and enrolled over a 5-year period using a web-based concealed randomization code. This is a superiority study designed to detect a difference in severe OHSS, the primary outcome, between the two groups with a power of 80% and stratified for age, assisted reproductive technology (ART) clinic and planned fertilization procedure (IVF/ICSI). The secondary aims were to compare rates of mild and moderate OHSS, positive plasma (p)-hCG, on-going pregnancy and live birth between the two arms. None of the women had undergone previous ART treatment. All infertile women referred for their first IVF/ICSI at two public fertility clinics, less than 40 years of age and with no uterine malformations were asked to participate. A total of 1099 subjects were randomized, including women with poor ovarian reserve, polycystic ovary syndrome and irregular cycles. A total of 49 women withdrew their consent, thus 1050 subjects were allocated to the GnRH antagonist (n = 534) and agonist protocol (n = 516), respectively. In total 1023 women started recombinant human follitropin-β (rFSH) stimulation, 528 in the GnRH antagonist group and 495 in the GnRH agonist group. All subjects were given a fixed rFSH dose of 150 IU or 225 IU according to age ≤36 years or >36 years, with the option to adjust dose at stimulation day 6. Clinical OHSS parameters were collected at oocyte retrieval, and Days 3 and 14 post-transfer. On-going pregnancy was determined by transvaginal ultrasonography at gestational weeks 7-9. In the intention-to-treat (ITT) analysis for reproductive outcomes, 1050 subjects were included. For the ITT analyses on OHSS 1023 subjects who started gonadotrophin stimulation were included. The incidence of severe OHSS [5.1% (27/528) versus 8.9% (44/495) (difference in proportion percentage point (Δpp) = -3.8pp; 95% CI: -7.1 to -0.4; P = 0.02)] and moderate OHSS [10.2% (54/528) versus 15.6% (77/495) (Δpp = -5.3pp; 95% CI: -9.6 to -1.0; P = 0.01) ] was significantly lower in the GnRH antagonist group compared with the agonist group, respectively. In the GnRH antagonist and agonist group, respectively, 4.7% (25/528) versus 8.5% (42/495) women were seen by a physician due to OHSS (P = 0.01), and 1.7% (9/528) versus 3.6% (18/495) were admitted to hospital due to OHSS (P = 0.06). No women had ascites-puncture in the GnRH antagonist group versus 2.0% (10/495) in the GnRH agonist group (P < 0.01). LBRs were 22.8% (122/534) versus 23.8% (123/516) (Δpp = -1.0pp; 95% CI: -6.3 to 4.3; P = 0.70) and OPRs were 24.9% (133/528) versus 26.2% (135/516) (Δpp = -1.3pp; 95% CI: -6.7 to 4.2; P = 0.64) per randomized subject in the GnRH antagonist versus agonist group, with a mean number of 1.1 versus 1.2 embryos transferred in the two groups. Pregnancy rates (PR) per randomized subject, per started gonadotrophin stimulation and per embryo transfer were all similar in the two groups. A possible limitation is the duration of the trial, with new methods, such as 'freeze all' and 'GnRH agonist triggering', being developed during the trial, the new methods were sought avoided, however a total number of 32 women had 'freeze all' and 'GnRH agonist triggering' was performed in three cases. Ultrasonic measurements were performed by different physicians and inter-observer bias may be present. Measures of anti-Mullerian hormone and antral follicle count, to estimate ovarian reserve and thus predict risk of OHSS, were not performed. Finally, the physicians were not blinded to GnRH treatment group after randomization. The short GnRH antagonist protocol should be the protocol of choice for patients undergoing their first ART cycle in females <40 years of age including both low and high responders when an age-dependent initially fixed gonadotrophin dose is used, as an increased risk of severe OHSS and the associated complications is seen in the long GnRH agonist group and as PRs and LBRs are similar in the two groups. Patients at risk of OHSS particularly benefit from the short GnRH antagonist treatment as GnRH agonist triggering can be used. An unrestricted research grant is funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD). The funders had no influence on the data collection, analyses or conclusions of the study. No conflict of interests to declare. EudraCT #: 2008-005452-24. ClinicalTrial.gov: NCT00756028. Trial registration date: 18 September 2008. Date of first patient's enrolment: 14 January 2009.

Toftager M ，Bogstad J ，Bryndorf T ，Løssl K ，Roskær J ，Holland T ，Prætorius L ，Zedeler A ，Nilas L ，Pinborg A ... -  《-》

Medroxyprogesterone acetate is a useful alternative to a gonadotropin-releasing hormone antagonist in oocyte donation: a randomized, controlled trial.

To compare ovarian response and reproductive outcomes in oocyte donors undergoing pituitary suppression with medroxyprogesterone acetate (MPA) versus those undergoing conventional treatment with a gonadotropin-releasing hormone (GnRH) antagonist. A prospective, randomized, controlled trial of cycles was conducted from October 2017 to June 2019 to evaluate ovarian response in terms of the number of oocytes. The reproductive outcomes of the recipients were retrospectively analyzed later. A university-affiliated private in vitro fertilization center. We randomly divided 318 donors into 2 groups in a 1:1 ratio. The oocytes obtained were assigned to 364 recipients. One hundred sixty-one donors were treated with a daily dose of 10 mg of MPA administered orally from the beginning of ovarian stimulation (OS), and 156 were treated with a GnRH antagonist (initiated once the leading follicle reached a diameter of 13 mm). Transvaginal ultrasound was performed, and serum estradiol, luteinizing hormone, and progesterone levels were recorded during monitoring. The following additional parameters were analyzed: endocrine profile (in follicular fluid), number of metaphase II oocytes, and pregnancy outcome. The donors included in the study group were stimulated using recombinant follicle-stimulating hormone and MPA at 10 mg/day, simultaneously begun on cycle day 2 or 3. Ovulation was induced using a GnRH agonist when dominant follicles matured. A short protocol with ganirelix at 0.25 mg/day was used for the control group. Oocytes were assigned to the recipients, followed by routine in vitro fertilization procedures in which 1 embryo was usually transferred. The primary outcome measure was the numbers of oocytes and metaphase II oocytes retrieved. The secondary outcomes were the incidence of premature luteinizing hormone surge, serum and follicular fluid hormone profiles, and clinical pregnancy outcomes in the recipient group. The number of oocytes retrieved was 21.4 ± 11.7 in the MPA group and 21.2 ± 9.2 in the antagonist group (mean difference 0.14; 95% confidence interval -2.233, 2.517). The total dose of recombinant follicle-stimulating hormone, duration of OS, and endocrine profiles of the serum and follicular fluids were comparable in the 2 groups. No early ovulation was observed in either group. No statistically significant differences with respect to implantation rate (68.1% in the MPA group vs. 62% in the antagonist group), clinical pregnancy rate (64.5% in the MPA group vs. 57.8 in the antagonist group), ongoing pregnancy rate (55.4% in the MPA group vs. 48.5% in the antagonist group), live birth rate (55.1% in the MPA group vs. 48.5% in the antagonist group), or cumulative live birth rate (73.8% in the MPA group vs. 70.7% in the antagonist group) were observed between the groups. The administration of MPA resulted in oocyte retrieval rates, endocrine profiles, viable embryo numbers, and pregnancy outcomes similar to those achieved with the GnRH antagonist. Therefore, MPA can be recommended for OS in oocyte donation because it permits a more patient-friendly approach. NCT03300960.

Giles J ，Alama P ，Gamiz P ，Vidal C ，Badia P ，Pellicer A ，Bosch E ... -  《-》