Agonist triggering in oocyte donation programs-Mini review.

Oocyte donation programs involve young and healthy women undergoing heavy ovarian stimulation protocols in order to yield good-quality oocytes for their respective recipient couples. These stimulation cycles were for many years beset by a serious and potentially lethal complication known as ovarian hyperstimulation syndrome (OHSS). The use of the short antagonist protocol not only is patient-friendly but also has halved the need for hospitalization due to OHSS sequelae. Moreover, the replacement of beta-human chorionic gonadotropin (b-hCG) with gonadotropin-releasing hormone agonist (GnRH-a) triggering has reduced OHSS occurrence significantly, almost eliminating its moderate to severe presentations. Despite differences in the dosage and type of GnRH-a used across different studies, a comparable number of mature oocytes retrieved, fertilization, blastulation, and pregnancy rates in egg recipients are seen when compared to hCG-triggered cycles. Nowadays, GnRH-a tend to be the triggering agents of choice in oocyte donation cycles, as they are effective and safe and reduce OHSS incidence. However, as GnRH-a triggering does not eliminate OHSS altogether, caution should be practiced in order to avoid unnecessary lengthy and heavy ovarian stimulation that could potentially compromise both the donor's wellbeing and the treatment's efficacy.

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

OBJECTIVE: 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. DESIGN: 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. SETTING: A university-affiliated private in vitro fertilization center. PATIENT(S): 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. INTERVENTION(S): 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. MAIN OUTCOME MEASURE(S): 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. RESULT(S): 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. CONCLUSION(S): 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. CLINICAL TRIAL REGISTRATION NUMBER: NCT03300960.

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

BACKGROUND: 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. OBJECTIVE AND RATIONALE: 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. SEARCH METHODS: 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. OUTCOMES: 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. WIDER IMPLICATIONS: 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.

Women utilizing oocyte donation have a decreased live birth rate if they displayed a low progesterone level in a previous hormonal replacement mock cycle.

PURPOSE: Is serum progesterone(P) level on day 2 of vaginal P administration in a hormonally substituted mock cycle predictive of live birth in oocyte donation(OD)? METHODS: Retrospective analysis of 110 mock cycles from 2008 to 2016 of OD recipients having at least one subsequent embryo transfer (ET). Endometrial preparation consisted of sequential administration of vaginal estradiol, followed by transdermal estradiol and 600 mg/day vaginal micronized P. In mock cycles, serum P was measured 2 days after vaginal P introduction. OD was performed 1 to 3 years later, without P measurement. RESULTS: In mock cycles, mean serum P level on day 2 was 12.8 ± 4.5 ng/mL (range: 4-28 ng/mL). A total of 32% patients had P < 10 ng/mL. At the time of first OD, age of recipients and donors, number of retrieved and attributed oocytes, and number of transferred embryos were comparable between patients with P < 10 ng/mL in their mock cycles compared with P ≥ 10 ng/mL. Pregnancy and live birth rate after first ET were significantly lower for patients with P < 10ng/mL (9% vs. 35 %; P = 0.002 and 9% vs. 32%; P = 0.008, respectively). Considering both fresh and subsequent frozen-thawed ET, cumulative live birth rate per-patient and per-transfer were significantly lower in patients with P < 10 ng/mL in their mock cycle (14% vs. 35%; P = 0.02 and 11% vs. 27%; P = 0.03). CONCLUSION: A low P level in hormonally substituted cycles several years before ET performed with the same endometrial preparation is associated with a significantly lower chance of live birth. This suggests that altered vaginal P absorption is a permanent phenomenon. Monitoring serum P in hormonally substituted cycles appears mandatory to adjust luteal P substitution.

Ovarian stimulation outcomes among transgender men compared with fertile cisgender women.

PURPOSE: To compare assisted reproductive technology (ART) outcomes among transgender men with those of fertile cisgender women. METHODS: This retrospective cohort study included 12 transgender men, six with no testosterone exposure and six after testosterone treatment, and 12 cisgender women (oocyte donors) who underwent ART in our institution between June 2017 and December 2019. Statistical analyses compared ART data and outcomes between three groups: cisgender women, transgender men without testosterone exposure, and transgender men after testosterone exposure. Comparisons were also made between transgender men with and without testosterone exposure. RESULTS: The transgender men with no testosterone exposure (23.3 ± 4 years) were significantly younger than the transgender men who had undergone testosterone treatment (30.3 ± 3.8 years; P = 0.012) and the cisgender women (29.1 ± 3.1 years; P = 0.004). The amount of FSH used for ovulation induction (1999 ± 683 mIU/mL) was significantly lower among transgender men without prior testosterone exposure compared with that among cisgender women (3150 ± 487 mIU/mL; P = 0.007). There were no differences in the peak estradiol levels, the number of oocytes retrieved, the number of MII oocytes, and the oocyte maturity rates between the three groups. Five out of six testosterone-treated transgender men underwent embryo cryopreservation, and they all achieved good-quality embryos. CONCLUSIONS: Transgender men have an excellent response to ovulation stimulation even after long-term exposure to testosterone. Oocyte/embryo cryopreservation is, therefore, a feasible and effective way for them to preserve their fertility for future biological parenting.

Pregnancy after oocyte donation in a patient with NLRP7 gene mutations and recurrent molar hydatidiform pregnancies.

Molar pregnancies are benign trophoblastic diseases associated with a risk of malignant transformation. If aetiology remains mostly unknown, the risk of recurrent molar pregnancy is around 1.5% after one molar pregnancy and around 25% after 2 molar pregnancies. In the later situation, genetic mutations have been described, increasing hugely this risk. In case of mutations, probability to obtain a normal pregnancy is estimated around 1.8%. We report the case of a Caucasian 30-year-old woman whose previous five spontaneous pregnancies had a negative outcome: a spontaneous miscarriage and then 4 complete hydatidiform moles. Genetic testing revealed that the patient carried two heterozygous mutations in the NLRP7 gene (c.2982-2A > G and Y318CfsX7). According to this, counselling was conducted to advocate for oocyte donation in order to obtain a normal pregnancy. This technique enabled a complication-free, singleton pregnancy that resulted in a healthy term live birth of a 2900 g female. Few months after delivery, the patient presented a new complete hydatidiform mole. Women presented with mutations in the NLRP7, KHDC3L or PADI6 genes are unlikely to obtain normal pregnancies, with a major risk of reproductive failure. In such a context, oocyte donation may be the best option. Only 4 normal pregnancies and deliveries have been published in this situation through this technique to our knowledge.

Evaluation of the safety and efficacy of corifollitropin alfa combined with GnRH agonist triggering in oocyte donation cycles. A prospective longitudinal study.

OBJECTIVE: In order to help make the dream of parenthood come true for oocyte acceptors, it is essential that the procedure is not dangerous or unpleasant for oocyte donors. The aim of this study was to identify differences in safety, efficacy and patient acceptability between a traditional stimulation antagonist protocol with recombinant-FSH (rFSH) with hCG-triggering, compared with an innovative antagonist protocol with corifollitropin alfa (Elonva®) plus GnRH agonist triggering in oocyte donors. METHODS: A prospective longitudinal study was conducted at an in vitro fertilization center in Greece. The same eighty donors underwent two consecutive antagonist stimulation schemes. Primary outcomes were patient satisfaction (scored by a questionnaire) and delivery rate per donor. Secondary outcomes were mean number of cumulus-oocyte-complexes, metaphase II (MII) oocytes and ovarian hyperstimulation syndrome (OHSS) rate. RESULTS: Donors reported better adherence and less discomfort with the corifollitropin alpha + GnRH agonist-triggering protocol (p<0.001). No significant differences were identified in the clinical pregnancy rate per donor (p=0.13), the delivery rates, the number of oocytes (p=0.35), the number of MII oocytes (p=0.50) and the number of transferred embryos, between the two protocols. However, the luteal phase duration was significantly shorter (p<0.001) in the corifollitropin alpha + GnRH agonist-triggering protocol. Moreover, three cases of moderate OHSS (3.75%) were identified after hCG triggering, whereas no case of OHSS occurred after GnRH agonist ovulation induction (p=0.25). CONCLUSION: The use of corifollitropin alpha combined with a GnRH agonist for triggering is a safe, effective and acceptable protocol for oocyte donors.

The Role of Macrophages in Oocyte Donation Pregnancy: A Systematic Review.

The embryo of an oocyte donation (OD) pregnancy is completely allogeneic to the mother, which leads to a more serious challenge for the maternal immune system to tolerize the fetus. It is thought that macrophages are essential in maintaining a healthy pregnancy, by acting in immunomodulation and spiral arterial remodeling. OD pregnancies represent an interesting model to study complex immunologic interactions between the fetus and the pregnant woman since the embryo is totally allogeneic compared to the mother. Here, we describe a narrative review on the role of macrophages and pregnancy and a systematic review was performed on the role of macrophages in OD pregnancies. Searches were made in different databases and the titles and abstracts were evaluated by three independent authors. In total, four articles were included on OD pregnancies and macrophages. Among these articles, some findings are conflicting between studies, indicating that more research is needed in this area. From current research, we could identify that there are multiple subtypes of macrophages, having diverse biological effects, and that the ratio between subtypes is altered during gestation and in aberrant pregnancy. The study of macrophages' phenotypes and their functions in OD pregnancies might be beneficial to better understand the maternal-fetal tolerance system.

Euploid rates among oocyte donors: is there an optimal age for donation?

PURPOSE: To examine cycle blastocyst euploid rates among age subgroups of oocyte donors. METHODS: Retrospective cohort analysis of ova donation in vitro fertilization cycles (OD-IVF) for which trophectoderm biopsy for preimplantation genetic testing for aneuploidy (PGT-A) by array comparative genomic hybridization (aCGH) or next generation gene sequencing (NGS) was employed between January 2015 and December 2018 in a single high-volume fertility center. RESULTS: Compared to oocyte donors age 26-30, oocyte donors age ≤ 25 had similar cycle blastocyst euploid rates (80 [66.7, 87.5]%, vs. 75 [62.5, 87.5]%, median [IQR], p = 0.07), blastocyst formation rates (66.7 [50, 75]%, vs. 62.5 [52, 75]%, p = 0.55), and number of retrieved oocytes (29 [23, 37] vs. 27 [20, 35], p = 0.18). Age of oocyte donor from 18 to 34 was not correlated with cycle blastocyst euploid rate. CONCLUSION: Oocyte donors age ≤ 25 had similar cycle blastocyst euploid rates, blastocyst formation rates, and number of retrieved oocytes compared to donors age 26-30. There was no correlation between cycle blastocyst euploid rates and age of the oocyte donor from 18 to 34 years. Given the lack of significant age-related change in cycle blastocyst euploid rates, our data support existing practices which do not favor a specific age subgroup of young oocyte donors.

Ovarian hyperstimulation syndrome following GnRH agonist trigger for final follicular maturation in a patient undergoing random start ovarian stimulation for egg-donation cycle with an inadvertent concomitant early pregnancy.

We report the first case of OHSS following GnRH agonist trigger for final follicular maturation in random start ovarian stimulation for egg-donation cycles during inadvertent concomitant early pregnancy. As an additional note, the sustained activity exerted by the increasing endogenous hCG production seemed to be responsible for the suboptimal performance in terms of oocyte yield in the current case. OHSS can occur in random-start stimulations protocols even after the use of a GnRH agonist for triggering in case of concomitant unnoticed early pregnancy especially if stimulation is commenced in the periovulatory/luteal phase. The present case report introduces a note of extreme caution when proceeding with this protocol in an otherwise fertile population (egg-donors, elective or oncologic oocyte cryopreservation).

Predicting suboptimal oocyte yield following GnRH agonist trigger by measuring serum LH at the start of ovarian stimulation.

STUDY QUESTION: Are the LH levels at the start of ovarian stimulation predictive of suboptimal oocyte yield from GnRH agonist triggering in GnRH antagonist down-regulated cycles? SUMMARY ANSWER: LH levels at the start of ovarian stimulation are an independent predictor of suboptimal oocyte yield following a GnRH agonist trigger. WHAT IS KNOWN ALREADY: A GnRH agonist ovulation trigger may result in an inadequate oocyte yield in a small subset of patients. This failure can range from empty follicle syndrome to the retrieval of much fewer oocytes than expected. Suboptimal response to a GnRH agonist trigger has been defined as the presence of circulating LH levels <15 IU/l 12 h after triggering. It has been shown that patients with immeasurable LH levels on trigger day have an up to 25% risk of suboptimal response. STUDY DESIGN, SIZE, DURATION: In this retrospective cohort study, all patients (n = 3334) who received GnRH agonist triggering (using Triptoreline 0.2 mg) for final oocyte maturation undergoing a GnRH antagonist cycle in our centre from 2011 to 2017 were included. The primary outcome of the study was oocyte yield, defined as the ratio between the total number of collected oocytes and the number of follicles with a mean diameter >10 mm prior to GnRH agonist trigger. PARTICIPANTS/MATERIALS, SETTING, METHODS: The endocrine profile of all patients was studied at initiation as well as at the end of ovarian stimulation. In order to evaluate whether LH levels, not only at the end but also at the start, of ovarian stimulation predicted oocyte yield, we performed multivariable regression analysis adjusting for the following confounding factors: female age, body mass index, oral contraceptives before treatment, basal and trigger day estradiol levels, starting FSH levels, use of highly purified human menopausal gonadotrophin and total gonadotropin dose. Suboptimal response to GnRH agonist trigger was defined as <10th percentile of oocyte yield. MAIN RESULTS AND THE ROLE OF CHANCE: The average age was 31.9 years, and the mean oocyte yield was 89%. The suboptimal response to GnRH agonist trigger cut-off (<10th percentile) was 45%, which was exhibited by 340 patients. Following confounder adjustment, multivariable regression analysis showed that LH levels at the initiation of ovarian stimulation remained an independent predictor of suboptimal response even in the multivariable model (adjusted OR 0.920, 95% CI 0.871-0.971). Patients with immeasurable LH levels at the start of stimulation (<0.1 IU/l) had a 45.2% risk of suboptimal response, while the risk decreased with increasing basal LH levels; baseline circulating LH <0.5 IU/L, <2 IU/L and <5 IU/L were associated with a 39.1%, 25.2% and 13.6% risk, respectively. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the study is its retrospective design. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study of GnRH agonist trigger cycles only, since most of the previous research on the predictive value of basal LH levels was performed in dual trigger cycles. LH values should be measured prior to start of ovarian stimulation. In cases where they are immeasurable, suboptimal response to GnRH agonist trigger can be anticipated, and an individualized approach is warranted. STUDY FUNDING/COMPETING INTEREST(S): There was no funding and no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Medroxyprogesterone acetate versus ganirelix in oocyte donation: a randomized controlled trial.

STUDY QUESTION: Is oral medroxiprogesterone acetate (MPA) non-inferior compared to ganirelix with respect to the number of mature oocytes (MII) retrieved at ovum pick-up (OPU) in oocyte donation cycles? SUMMARY ANSWER: MPA is comparable to ganirelix in terms of number of MII retrieved at OPU in oocyte donation cycles. WHAT IS KNOWN ALREADY: Oral treatment with MPA inhibits the pituitary LH surge during ovarian stimulation in infertile patients. Because of its negative effect on the endometrium, MPA suppression is combined with freeze-all. Published reports indicate that both the number of MII retrieved and pregnancy rates from these oocytes are comparable to short protocol of GnRH agonists during IVF cycles with freeze-all. MPA might allow for more comfortable and cost-effective ovarian stimulation. STUDY DESIGN, SIZE, DURATION: Randomized clinical trial, open-label, single center, to assess the non-inferiority of MPA (10 mg/day) versus ganirelix (0.25 mg/day) from Day 7, in ovarian stimulation cycles triggered with triptoreline acetate. Trigger criterion was ≥3 follicles of diameter >18 mm. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 252 oocyte donors were selected (eligible), 216 were randomized and 173 reached OPU: 86 under MPA and 87 under ganirelix. The main outcome was the number of MII retrieved at OPU. Secondary outcomes were embryological laboratory outcomes and reproductive outcomes in recipients. The study was powered to test that the lower limit of the 95% confidence interval of the difference in retrieved MII between groups will be above the non-inferiority limit of -3. Differences were tested using a two-sided Student's t-test or a Pearson's Chi2 test, as appropriate. MAIN RESULTS AND THE ROLE OF CHANCE: All participants were in their first cycle of oocyte donation. On average, donors were 24 (SD 4.5) years old and with a BMI of 23 (SD 2.9) kg/m2. Duration of stimulation was similar in both groups (11.2 days), as well as the total gonadotropin dose up to trigger (2162 IU in MPA and 2163 IU in ganirelix). The number of MII retrieved was no different: 15.1 (SD 8.3) with MPA and 14.6 (SD 7.0), 95% CI of the difference -2.78, -1.83 excluding the pre-defined non-inferiority limit (-3). Recipients and embryo transfer (ET) characteristics were also similar between groups. The average age of recipients was 42 (SD 4.8) years and the BMI was 24 (SD 4.4) kg/m2. The mean number of MII assigned to each recipients was 6.7 (SD 1.2) in MPA and 6.6 (SD 1.2) in ganirelix (P = 0.58). MII were fertilized with partner sperm in 84% cycles overall and fertilization rate was 76% in MPA versus 74% in ganirelix (P = 0.34). Overall, there was 54% of double ET and 46% of single ET, with 40% of ETs were performed in D5. In spite of similar recipients and cycle characteristics, reproductive outcomes were unexpectedly lower with MPA. Biochemical pregnancy rate was 44 versus 57% (P = 0.023); clinical pregnancy rate 31 versus 46% (P = 0.006); ongoing pregnancy rate 27 versus 40%, (P = 0.015) and live birth rate 22 versus 31%, (P = 0.10). LIMITATIONS, REASONS FOR CAUTION: Although oocyte recipient and ET characteristics are similar among groups, this RCT has been designed under a hypothesis of non-inferiority in the number of MII obtained and recipients were not randomized; therefore, the reproductive outcomes in recipients should be evaluated with extreme caution. WIDER IMPLICATION OF THE FINDINGS: Ovarian stimulation using MPA for prevention of LH surge yields comparable number of MII oocytes compared to ganirelix in oocyte donation cycles. The unexpected finding in reproductive outcomes should be further investigated. STUDY FUNDING/COMPETING INTEREST(S): None to report. TRIAL REGISTRATION NUMBER: EudraCT number: 2015-004328-73; ClinicalTrials.gov Identifier: NCT02796105. TRIAL REGISTRATION DATE: 29 September 2015 (EudraCT); 9 June 2016 (ClinicalTrials.gov). DATE OF FIRST PATIENT'S ENROLLMENT: The date of enrollment of the first participant was 07 July 2016, and the last participant last visit in the study was on 10 July 2017.

The impact of intentional endometrial injury on reproductive outcomes: a systematic review and meta-analysis.

BACKGROUND: Endometrial injury is an intentional damage made to the endometrium, usually produced by a Pipelle catheter. Over the last two decades, endometrial injury has been studied to improve implantation rates and decrease the incidence of implantation failure in invitro fertilization (IVF) cycles. Recently, additional studies of endometrial injury, performed not only in patients with implantation failure but also in intrauterine insemination cycles, have been conducted, and the endometrial injury made by hysteroscopy has been researched. The evidence describing the impact of endometrial injury is controversial; therefore, we conducted a systematic review and meta-analysis to examine the issue. OBJECTIVE AND RATIONALE: Our objective is to review the research that has been done until now and perform a meta-analysis regarding endometrial injury and its influence on implantation success and pregnancy rates in patients with at least one failed IVF cycle. In particular, we aim to study the efficacy of the procedure and look for confounding factors, such as maternal age, in assessing the efficacy of endometrial injury. SEARCH METHODS: The systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Study protocol can be assessed at PROSPERO International prospective register of systematic reviews (registration number CRD42018092773). Searches were conducted by an experienced research librarian in the following databases: MEDLINE(R) using the OvidSP interface and PUBMED, Embase, Web of Science and Cochrane Library. This review considered for inclusion randomized-controlled trials examining the success of performing local endometrial injury on IVF outcomes in women with previous failed IVF cycles. OUTCOMES: Ten studies, comprising a total of 1260 patients, were selected. Overall, when studying the effect of endometrial injury on clinical pregnancy rates (CPRs) and live birth rates (LBRs), higher rates were shown in the endometrial injury group. However, endometrial injury did not significantly improve CPRs and LBRs, when considering sub-group analyses of studies including patients with two or more failed IVF cycles, studies examining older patients or studies which did not include hysteroscopy. There was no significant difference found regarding multiple pregnancy rates, while a handful of studies showed an improvement in miscarriage rates. WIDER IMPLICATIONS: Endometrial injury should be used restrictively and not routinely in clinics. Maternal age and number of previous failed treatment cycles may be contributing factors which can influence the results when studying the effect of endometrial local injury. It is possible that the relative contribution of endometrial receptivity to the chances of implantation decreases with any additional failed cycle. The optimal study to prove the efficacy of local endometrial injury on implantation and pregnancy rates, should be a random-controlled trial studying the effect of local endometrial injury in oocyte donation cycles, in recipients with repeated implantation failure. This kind of study will conclude whether local endometrial injury is an efficient procedure with minimum confounding factors, and may assist in defining the population, even outside of donation cycles, that will benefit from the procedure.

Oocyte donation: insights gleaned and future challenges.

With the first successful report of an IVF pregnancy achieved via donor oocytes in 1984, the applications of assisted reproductive technology (ART) were further expanded to include women unable to conceive with their own oocytes. Today, oocyte donation makes up an increasingly large percentage of all ART cycles worldwide. Oocyte donation presents several unique challenges to clinicians as two separate interests, those of the donor and those of the recipient, must be represented. These challenges include successful preparation of the endometrium in donor oocyte recipients, the synchronization of donor/recipient cycles, and the optimization of ovarian stimulation while maximizing donor safety. Facing these challenges has not only allowed for the creation of successful donor egg programs but has also provided insights into many aspects of ART. Much of what we know about the window of implantation, frozen ET procedures, triggering of oocyte maturation, and fertility preservation has been learned through experience and investigations with donor egg cycles. Not only has oocyte donation, through its optimization and wide use, provided new treatment opportunities for patients, it has also become a critical scientific tool to study many aspects of menstrual cycle dynamics and implantation. Concomitantly, with its increased efficiency, it has also raised several clinical and ethical challenges.

Shared oocyte donation: ideas and expectations in a bioethical context based on a qualitative survey of brazilian women / Doação compartilhada de oócitos: ideias e expectativas em um contexto bioético com base em um levantamento qualitativo de mulheres brasileiras

Abstract Objective Assisted reproduction combines innovative technologies and new forms of procreation through gamete donation; however, it also leads to moral and ethical issues and to the wide application of referential bioethics. The objective of the present study was to understand the bioethical context of shared oocyte donation. Methods The present qualitative study used the Collective Subject Discourse methodology to interview donors and recipients in Brazil. Results Donors suffer from infertility, and in vitro fertilization opens the possibility of having a child; however, the cost is high, and helping the recipient is more important than the financial cost. The recipients regret delaying motherhood; adopting a child is their last option, and they desire to feel the physical stages of pregnancy. The recipients find the rules unfair regarding the lack of an oocyte bank and the fact that the treatment must be performed in shared cycles; however, oocyte donation makes it possible to realize the common dream of motherhood. Conclusion The obtained data showed that the patients are suffering and frustrated due to infertility, and they realize that in vitro fertilization may be the treatment they need. These women believe that children are essential in the constitution of the family, and scientific advances bring about innovative technologies and new forms of family constitution, with repercussions in the social, economic, political, and family contexts that lead to bioethical questions in Postmodernity.

Resumo Objetivo A reprodução assistida agrega tecnologias inovadoras e novas formas de procriação pormeio da doação de gametas; no entanto, também leva a questões éticas e morais e à ampla aplicação da bioética referencial. O objetivo deste estudo foi compreender o contexto bioético da doação compartilhada de oócitos. Métodos Este estudo qualitativo utilizou a metodologia do Discurso do Sujeito Coletivo para entrevistar doadoras e receptoras no Brasil. Resultados As doadoras sofrem de infertilidade, e a fertilização in vitro abre a possibilidade de ter um filho; no entanto, o custo é alto, e ajudar a receptora é mais importante do que o custo financeiro. As receptoras se arrependem de retardar a maternidade; adotar uma criança é sua última opção, e elas desejam sentir os estágios físicos da gravidez. As receptoras consideramas regras injustas emrelação à falta de um banco de oócitos e ao fato de que o tratamento deve ocorrer emciclos compartilhados; no entanto, a doação de oócitos possibilita a realização do sonho comum da maternidade. Conclusão Os dados obtidosmostraram que as pacientes estão sofrendo e frustradas devido à infertilidade, e percebem que a fertilização in vitro pode ser o tratamento de que necessitam. Essas mulheres acreditam que as crianças são essenciais na constituição da família, e os avanços científicos agregam tecnologias inovadoras e novas formas de constituição familiar com repercussões nos contextos sociais, econômicos, políticos e familiares que levam a questões bioéticas na Pós-modernidade.

Low estradiol responses in oocyte donors undergoing gonadotropin stimulation do not influence clinical outcomes.

PURPOSE: To examine the effect of low and very low estradiol responses in oocyte donors receiving gonadotropins on clinical outcomes of donor in vitro fertilization (IVF) cycles and to identify possible mechanisms responsible for low estradiol response. METHODS: This is a retrospective cohort study of oocyte donors undergoing antagonist IVF cycles with progression to oocyte retrieval between January 2010 and December 2016 at a single urban academic fertility center. Oocyte yield, fertilization rate, blastocyst rate, percentage of normal embryos on preimplantation genetic screening (PGS), pregnancy outcomes, and follicular fluid steroid profiles were compared between donors with normal estradiol response and those with low estradiol response. RESULTS: Three hundred sixty-six antagonist oocyte donor IVF cycles were identified: 42 cycles had a normal estradiol response (NE2), defined as peak serum estradiol (E2) of over 200 pg/mL per retrieved oocyte; 140 cycles had an intermediate estradiol response (iE2), defined as peak serum E2 between 100 and 200 pg/mL per retrieved oocyte; 110 cycles had a low estradiol response (LE2), defined as peak serum E2 between 50 and 100 pg/mL per retrieved oocyte; and 74 cycles had a very low estradiol response (vLE2), defined as peak serum E2 less than 50 pg/mL per retrieved oocyte. LE2 cycles resulted in a greater number of mature oocytes (22.4 vs. 13.6, p < 0.017), and fertilizations versus NE2 donors (18.5 vs. 10.7, p < 0.017), although the number of transferred or cryopreserved blastocysts were similar between groups (8.6, 6.9 vs. 4.8, p = 0.095, p = 1). The percentage of chromosomally normal embryos after PGS was similar between LE2, vLE2, and NE2 cycles (66.4, 71.8 vs. 63.1%, p = 0.99, p = 1). Pregnancy outcomes were similar between LE2, vLE2, and NE2 cycles. Serum AMH obtained on the day of peak E2 was similar to baseline serum AMH and did not differ between LE2 versus NE2 cycles. Follicular fluid E2 levels paralleled serum E2 levels and were lower in LE2 cycles versus NE2 cycles. CONCLUSION: The prevalence of very low E2 responses in donors appears to be high (20.2%). In contrast to autologous IVF cycles, LE2 does not portend poor outcomes in oocyte donors.

Comparison of two different dosage of GnRH agonist as ovulation trigger in oocyte donors: a randomized controled trial.

OBJECTIVE: To compare the results obtained with two different GnRH agonist dosages: 0.3mg versus 0.4mg to trigger ovulation in oocyte donor cycles. METHODS: Experimental controlled randomized trial including 40 patients from a private practice center. The patients were randomized into two groups. Group A received a single dose of Triptorelin 0.3mg (Decapeptyl®) 36hours before pick-up. Group B patients received Triptorelin 0.4mg (Decapeptyl®) before pick-up to final oocyte maturation. We evaluated the total number of oocytes collected, the number of mature oocytes and total days of ovarian stimulation. RESULTS: The average of total collected oocytes were 16 (Group A) versus 15 (Group B), and the mean number of mature oocytes were 13 versus 12 respectively. The only variable showing a difference was the percentage of mature oocytes, which was greater in Group A, resulting in 84.6%, in contrast with those treated with 0.4mg of Triptorelin (78.6%), although these differences were not statistical significant (p=0.35). Days of stimulation did not differ between groups. No cases of empty follicle syndrome were reported. CONCLUSIONS: We found that an increase from 0.3 to 0.4mg of triptorelin in an oocyte donation program might not improve outcomes. Nevertheless, more studies might be necessary, not only in oocyte donors but in sterile women as well, to evaluate how GnRH agonist dosage could affect the results among other factors.

Major drawbacks and additional benefits of agonist trigger--not ovarian hyperstimulation syndrome related.

The GnRH agonist trigger alters traditional IVF paradigms when compared with hCG-only triggers. The agonist trigger induces rapid luteolysis and therefore separates the oocyte maturation aspect of LH from the luteal support previously afforded by lingering hCG. This might allow customized and more optimal luteal support. The agonist trigger option also allows continued stimulation and subsequent trigger of high responders with reasonable safety, potentially leading to retrievals of larger cohorts of mature oocytes. It may also reduce the number of retrievals needed to achieve a large family. The agonist trigger might alter other paradigms as well, such as making oocyte donation more efficient per stimulation by virtually eliminating follicular-phase cycle cancellation, coasting, and premature triggering. There are both corresponding potential benefits and drawbacks of using the agonist trigger and the shifting paradigms it allows.

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

BACKGROUND: Human chorionic gonadotropin (HCG) is routinely used for final oocyte maturation triggering in in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles, but the use of HCG for this purpose may have drawbacks. Gonadotropin-releasing hormone (GnRH) agonists present an alternative to HCG in controlled ovarian hyperstimulation (COH) treatment regimens in which the cycle has been down-regulated with a GnRH antagonist. This is an update of a review first published in 2010. OBJECTIVES: To evaluate the effectiveness and safety of GnRH agonists in comparison with HCG for triggering final oocyte maturation in IVF and ICSI for women undergoing COH in a GnRH antagonist protocol. SEARCH METHODS: We searched databases including the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of Controlled Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and trial registers for published and unpublished articles (in any language) on randomised controlled trials (RCTs) of gonadotropin-releasing hormone agonists versus HCG for oocyte triggering in GnRH antagonist IVF/ICSI treatment cycles. The search is current to 8 September 2014. SELECTION CRITERIA: RCTs that compared the clinical outcomes of GnRH agonist triggers versus HCG for final oocyte maturation triggering in women undergoing GnRH antagonist IVF/ICSI treatment cycles were included. DATA COLLECTION AND ANALYSIS: Two or more review authors independently selected studies, extracted data and assessed study risk of bias. Treatment effects were summarised using a fixed-effect model, and subgroup analyses were conducted to explore potential sources of heterogeneity. Treatment effects were expressed as mean differences (MDs) for continuous outcomes and as odds ratios (ORs) for dichotomous outcomes, together with 95% confidence intervals (CIs). Primary outcomes were live birth and rate of ovarian hyperstimulation syndrome (OHSS) per women randomised. Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods were used to assess the quality of the evidence for each comparison. MAIN RESULTS: We included 17 RCTs (n = 1847), of which 13 studies assessed fresh autologous cycles and four studies assessed donor-recipient cycles. In fresh autologous cycles, GnRH agonists were associated with a lower live birth rate than was seen with HCG (OR 0.47, 95% CI 0.31 to 0.70; five RCTs, 532 women, I(2) = 56%, moderate-quality evidence). This suggests that for a woman with a 31% chance of achieving live birth with the use of HCG, the chance of a live birth with the use of an GnRH agonist would be between 12% and 24%.In women undergoing fresh autologous cycles, GnRH agonists were associated with a lower incidence of mild, moderate or severe OHSS than was HCG (OR 0.15, 95% CI 0.05 to 0.47; eight RCTs, 989 women, I² = 42%, moderate-quality evidence). This suggests that for a woman with a 5% risk of mild, moderate or severe OHSS with the use of HCG, the risk of OHSS with the use of a GnRH agonist would be between nil and 2%.In women undergoing fresh autologous cycles, GnRH agonists were associated with a lower ongoing pregnancy rate than was seen with HCG (OR 0.70, 95% CI 0.54 to 0.91; 11 studies, 1198 women, I(2) = 59%, low-quality evidence) and a higher early miscarriage rate (OR 1.74, 95% CI 1.10 to 2.75; 11 RCTs, 1198 women, I² = 1%, moderate-quality evidence). However, the effect was dependent on the type of luteal phase support provided (with or without luteinising hormone (LH) activity); the higher rate of pregnancies in the HCG group applied only to the group that received luteal phase support without LH activity (OR 0.36, 95% CI 0.21 to 0.62; I(2) = 73%, five RCTs, 370 women). No evidence was found of a difference between groups in risk of multiple pregnancy (OR 3.00, 95% CI 0.30 to 30.47; two RCTs, 62 women, I(2) = 0%, low-quality evidence).In women with donor-recipient cycles, no evidence suggested a difference between groups in live birth rate (OR 0.92, 95% CI 0.53 to 1.61; one RCT, 212 women) or ongoing pregnancy rate (OR 0.88, 95% CI 0.58 to 1.32; three RCTs, 372 women, I² = 0%). We found evidence of a lower incidence of OHSS in the GnRH agonist group than in the HCG group (OR 0.05, 95% CI 0.01 to 0.28; three RCTs, 374 women, I² = 0%).The main limitation in the quality of the evidence was risk of bias associated with poor reporting of methods in the included studies. AUTHORS' CONCLUSIONS: Final oocyte maturation triggering with GnRH agonist instead of HCG in fresh autologous GnRH antagonist IVF/ICSI treatment cycles prevents OHSS to the detriment of the live birth rate. In donor-recipient cycles, use of GnRH agonists instead of HCG resulted in a lower incidence of OHSS, with no evidence of a difference in live birth rate.Evidence suggests that GnRH agonist as a final oocyte maturation trigger in fresh autologous cycles is associated with a lower live birth rate, a lower ongoing pregnancy rate (pregnancy beyond 12 weeks) and a higher rate of early miscarriage (less than 12 weeks). GnRH agonist as an oocyte maturation trigger could be useful for women who choose to avoid fresh transfers (for whatever reason), women who donate oocytes to recipients or women who wish to freeze their eggs for later use in the context of fertility preservation.

Comparison of starting ovarian stimulation on day 2 versus day 15 of the menstrual cycle in the same oocyte donor and pregnancy rates among the corresponding recipients of vitrified oocytes.

OBJECTIVE: To assess the clinical pregnancy rate per transfer in recipients of embryos from donor oocytes obtained after ovarian stimulation initiated on day 2 (D2) or day 15 (D15) of the menstrual cycle with a secondary end point of comparing the response to stimulation. DESIGN: Prospective observational comparative study. SETTING: Private in vitro fertilization (IVF) program. PATIENT(S): Oocyte donors (OD) and recipients. INTERVENTION(S): Donors stimulated within 3 months, starting on day 2 or day 15 after bleeding, with recombinant follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH) antagonist, and GnRH agonist trigger, and oocytes vitrified and later assigned to recipients, followed by routine IVF procedures one to two embryos transferred. MAIN OUTCOME MEASURE(S): Primary outcome pregnancy rate, and secondary outcome number of mature oocytes retrieved. RESULT(S): Nine D2 and nine D15 cycles were performed in nine donors. There were no differences between D2 and D15 in the number of mature oocytes obtained (14.0±6.96 vs. 16.89±7.52). To date, 20 recipients have received vitrified oocytes (8 recipients received D2 oocytes and 12 recipients received D15 oocytes). There were no differences between the groups of recipients in fertilization rate (77.3% vs. 76.5%) or number of embryos transferred (1.50±0.53 vs. 1.67±0.65). Twelve clinical pregnancies were obtained. No differences were noted in pregnancy rates (62.5% vs. 58.3%) or implantation rates (41.67% vs. 45%) between recipients of D2 oocytes and recipients of D15 oocytes. CONCLUSION(S): Donor oocytes obtained after ovarian stimulation initiated on day 15 of the cycle achieve good pregnancy rates. This information is useful for patients with cancer undergoing fertility preservation. CLINICAL TRIAL REGISTRATION NUMBER: NCT 01645241.