Progesterone-primed ovarian stimulation in oocyte donation: a model for elective fertility preservation?

RESEARCH QUESTION: Does type of LH peak suppression (progesterone-primed ovarian stimulation [PPOS] versus gonadotrophin releasing hormone [GnRH] antagonist) affect oocyte competence, embryo development and live birth rates in recipients of vitrified donated oocytes? DESIGN: Retrospective cohort study conducted between 2016 and 2018, involving 187 recipient cycles of donated vitrified oocytes. Oocyte donors were stimulated under LH suppression with desogestrel for PPOS (DSG group) or ganirelix GnRH antagonist (ANT group). Recipients younger than 50 years received vitrified oocytes from DSG donation cycles (DSG-R) or ANT donation cycles (ANT-R). RESULTS: A mean of 10.07 ± 3.54 oocytes per recipient were warmed (survival rate of 80.7%), and 5.90 ± 2.89 were fertilized (fertilization rate 72.6%). Out of 187 recipients, 168 achieved embryo transfers. No significant differences were found in warming survival rates, fertilization rates and embryo development between DSG-R and ANT-R groups. Ninety-four clinical pregnancies and 81 live births were achieved. No statistically significant differences were found in clinical pregnancy rates (47.7% versus 52.5, P = 0.513) and live birth rates (39.5% versus 46.5%, P = 0.336) per recipient cycle between DSG-R and ANT-R, respectively. Multivariable logistic regression was applied to assess the effect of treating oocyte donors. Live birth rate adjusted for associated factors was not statistically different between vitrified oocytes from DSG or ANT (OR 0.74, 95% CI 0.37 to 1.47). CONCLUSION: Reproductive outcomes of recipients of vitrified oocytes are not affected by donor PPOS treatment. PPOS is suitable for suppressing LH peak in elective fertility preservation and in freeze-all strategies.

The effect of late-follicular phase progesterone elevation on embryo ploidy and cumulative live birth rates.

RESEARCH QUESTION: Does late-follicular phase progesterone elevation have a deleterious effect on embryo euploidy, blastocyst formation rate and cumulative live birth rates (CLBR)? DESIGN: A multicentre retrospective cross-sectional study including infertile patients aged 18-40 years who underwent ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol and preimplantation genetic testing for aneuploidies (PGT-A) followed by a freeze-all strategy and euploid embryo transfer between August 2017 and December 2019. The sample was stratified according to the progesterone concentrations on the day of trigger: normal (≤1.50 ng/ml) and high (>1.50 ng/ml). Moreover, sensitivity analyses were performed to determine whether different conclusions would have been drawn if different cut-offs had been adopted. The primary outcome was the embryo euploidy rate. Secondary outcomes were the blastocyst formation rate, the number of euploid blastocysts and CLBR. RESULTS: Overall 1495 intracytoplasmic sperm injection PGT-A cycles were analysed. Late-follicular phase progesterone elevation was associated with significantly higher late-follicular oestradiol concentrations (2847.56 ± 1091.10 versus 2240.94 ± 996.37 pg/ml, P < 0.001) and significantly more oocytes retrieved (17.67 ± 8.86 versus 12.70 ± 7.00, P < 0.001). The number of euploid embryos was significantly higher in the progesterone elevation group (2.32 ± 1.74 versus 1.86 ± 1.42, P = 0.001), whereas the blastocyst formation rate (47.1% [43.7-50.5%] versus 51.0% [49.7-52.4%]), the embryo euploidy rate (48.3% [44.9-51.7%] versus 49.1% [47.7-50.6%], the live birth rate in the first frozen embryo transfer (34.1% versus 31.1%, P = 0.427) and CLBR (38.9% versus 37.0%, P = 0.637) were not significantly different between the two groups. CONCLUSIONS: Euploidy rate and CLBR do not significantly differ among PGT-A cycles with and without late-follicular progesterone elevation in a freeze-all approach.

COH outcomes in breast cancer patients for fertility preservation: a comparison with the expected response by age.

PURPOSE: Breast cancer is the most common cancer diagnosed during childbearing age, and fertility preservation is becoming increasingly more essential. However, recent studies indicate a possible poorer response to controlled ovarian hyperstimulation (COH) in cancer patients than in non-cancer controls and a negative impact of BRCA mutations on female fertility. This study aims to evaluate ovarian response and the number of mature oocytes (MII) vitrified in women with breast cancer, with or without BRCA mutation, comparing them to the expected response according to an age-related nomogram. METHODS: This is a retrospective observational study involving sixty-one breast cancer patients who underwent COH for oocyte cryopreservation. The age-specific nomogram was built using 3871 patients who underwent COH due to oocyte donation, fertility preservation for non-medical reasons, or FIVET for male factor exclusively. RESULTS: The mean number of oocytes retrieved was 13.03, whereas the mean number of MII oocytes was 10.00. After the application of the z-score, no statistically significant differences were found compared with the expected response in the general population, neither by dividing patients according to the presence or absence of BRCA mutation nor according to the phase in which they initiated stimulation. CONCLUSION: The results obtained do not support the notion of a negative impact of the BRCA mutation on the ovarian response of women with breast cancer. Women with breast cancer undergoing COH for fertility preservation can expect the ovarian response predicted for their age.

What is the clinical impact of the endometrial receptivity array in PGT-A and oocyte donation cycles?

PURPOSE: To evaluate the influence of the endometrial receptivity array (ERA) test on the implantation rate (IR) and pregnancy rate (PR) in patients with previous failed euploid embryo transfers (Euploid-ET) or oocyte donation embryo transfers (Donor-ET). METHODS: Single-center retrospective study of patients with ≥ 1 previous failed Euploi-ET (n = 24) or ≥ 2 failed Donor-ET (n = 32) who underwent an ERA test and a post-ERA Euploid-ET/Donor-ET between 2012 and 2018. Controls were patients with ≥ 1 previously failed Euploid-ET (n = 119) or ≥ 2 failed Donor-ET (n = 158) who underwent Euploid-ET/Donor-ET during the same period without performing an ERA test. Only blastocyst stage embryos were included. IR/PR was compared between the post-ERA ET and the last ET in the control group. RESULTS: There was no statistically significant difference regarding IR [55.6% (34.6-76.5%) vs. 65.0% (56.9-73.1%)] nor PR (58.3% vs.70.6%, p = 0.238) in the Euploid-ET ERA vs. Euploid-ET control groups. In the Donor-ET arm, both IR [26.8% (12.3-41.4%) vs. 57.2% (50.1-64.3%)] and PR (34.4% vs. 65.2%, p = 0.001) were significantly lower in the ERA group. Multivariate analysis confirmed that performing an ERA test did not influence the PR in the Euploid-ET arm and was associated with a diminished PR in the Donor-ET arm. In the ERA group, 41.1% patients were non-receptive (NR). No significant difference was found regarding IR/PR in NR vs. receptive patients in both Euploid-ET/Donor-ET arms. CONCLUSIONS: In our sample, the performance of an ERA test did not improve pregnancy outcomes. Future prospective studies in larger samples are needed to confirm the role of the ERA test in Euploid-ET/Donor-ET.

Inconclusive results in preimplantation genetic testing: go for a second biopsy?

The transition in biopsy timing from blastomere to trophectoderm biopsy has led to a remarkable decrease in the percentage of undiagnosed blastocysts. However, patients with few or no euploid blastocysts can be affected by this residual percentage of diagnosis failure. The aim of this study is to assess whether blastocyst rebiopsy and revitrification is an efficient and safe procedure to be applied in cases of no results after analysis. Fifty-three patients agreed to the warming of 61 blastocysts to perform a second biopsy and PGT-A by aCGH. Only 75.4% of the blastocysts survived, reexpanded, and could be rebiopsied. After the second biopsy and analysis, 95.6% of the blastocysts were successfully diagnosed with an euploidy rate of 65.9%. Eighteen euploid blastocysts were warmed and transferred to 18 patients with a 100% survival and reexpansion rate. Seven clinical pregnancies have been achieved with 4 live births, 1 ongoing pregnancy, and 2 miscarriages. Thus, although few transfers of rebiopsied and revitrified blastocysts have been performed till date, our preliminary results show that this approach is efficient and safe to be applied for undiagnosed blastocysts, as it ultimately allows the transfer of euploid blastocysts and good clinical outcomes.

Cumulative live birth rates and number of oocytes retrieved in women of advanced age. A single centre analysis including 4500 women ≥38 years old.

STUDY QUESTION: Is there any relationship between the number of oocytes retrieved and cumulative live birth rates (CLBRs) in women of advanced age? SUMMARY ANSWER: CLBRs increase with the number of oocytes retrieved in women of advanced reproductive age up to 41 years old, the added value is minimal in women more than 41 years and futile in women 44 years or older. WHAT IS KNOWN ALREADY: CLBR is actually the most relevant outcome of IVF from patients' perspective. There are several studies that have analysed CLBR's but some of them have included several stimulation cycles, others have not included the frozen embryo transfers (FETs) in their analysis and none has focused on women of advanced reproductive age. We aimed to assess CLBR in women ≥38 years after a single stimulation cycle plus the subsequent frozen embryo transfers. STUDY DESIGN, SIZE, DURATION: This is a retrospective analysis carried out in a University-affiliated tertiary centre between January 2000 and December 2013. Overall, 4570 infertile women aged ≥38 years who underwent their first cycle in our centre were included. PARTICIPANT/MATERIALS, SETTING, METHODS: Patients were categorized in four age-groups: 38-39 years (G1 = 1875 cycles), 40-41 years (G2 = 1380 cycles), 42-43 years (G3 = 833 cycles) and ≥44 years (G4 = 482 cycles). CLBR's were evaluated by adding the pregnancies and live births achieved in the FET's to the ones obtained in the fresh cycle. In order to find out the actual effect of the number of oocytes retrieved in these patients, a predictive model of CLBR according to age and oocyte yield was built. MAIN RESULTS AND THE ROLE OF CHANCE: CLBRs significantly decrease with increasing age among women ≥38 years of age, with the most prominent and clinically relevant decline observed at 42-43 years old, and clear evidence for futility in women aged ≥44 years (25.9% at 38-39 years, 16.4% at 40-41 years, 7% at 42-43 years and 1.2% from 44 years onwards). The higher the number of oocytes retrieved, the higher the CLBR; however, this is more evident up to 41 years old and no clear benefit is observed from 44 years and beyond. LIMITATIONS, REASONS FOR CAUTION: Limitations are related to the retrospective nature of the study; however, no significant differences were observed in the treatment protocols used. Other potential limitations could be the fact that embryo cryopreservation was carried out with slow freezing in 80% of cases and that a small proportion of patients still have frozen embryos; nevertheless, we do not expect a relevant impact of these issues as slow freezing showed excellent results that did not differ significantly compared to vitrification and, on the other hand, the extra benefit coming from the FETs was very limited. WIDER IMPLICATIONS OF THE FINDINGS: The number of oocytes retrieved is significantly associated with CLBR also in women of advanced reproductive age. However, the added benefit appears to be restricted mainly in women up to 41 years old. Women over 43 do not experience any benefit in CLBR irrespective of the number of oocytes retrieved, and thus should be discouraged from doing an IVF cycle with their own oocytes; for the other age-groups, recommendations should be given considering the age and the expected ovarian response. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: NA.

Transition from blastomere to trophectoderm biopsy: comparing two preimplantation genetic testing for aneuploidies strategies.

SummaryShortly after the implementation of comprehensive chromosome screening (CCS) techniques for preimplantation genetic testing for aneuploidies (PGT-A), the discussion about the transition from day 3 to blastocyst stage biopsy was initiated. Trophectoderm biopsy with CCS is meant to overcome the limitations of cleavage-stage biopsy and single-cell analysis. The aim of this study was to assess the results obtained in our PGT-A programme after the implementation of this new strategy. Comparisons between the results obtained in 179 PGT-A cycles with day 3 biopsy (D+3) and fresh embryo transfer, and 204 cycles with trophectoderm biopsy and deferred (frozen-thawed) embryo transfer were established. Fewer embryos were biopsied and a higher euploidy rate was observed in the trophectoderm biopsy group. No differences in implantation (50.3% vs. 61.4%) and clinical pregnancy rate per transfer (56.1% vs. 65.3%) were found. Although the mean number of euploid embryos per cycle did not differ between groups (1.5 ± 1.7 vs. 1.7 ± 1.8), the final number of euploid blastocysts available for transfer per cycle was significantly higher in the trophectoderm biopsy group (1.1 ± 1.3 vs. 1.7 ± 1.8). This factor led to an increased cumulative live birth rate in this last group (34.1% vs. 44.6%). Although both strategies can offer good results, trophectoderm biopsy offers a more robust diagnosis and the intervention is less harmful for the embryos so more euploid blastocysts are finally available for transfer and/or vitrification.

Linking back-to-back stimulation cycles with oral contraceptives or progestins in women undergoing embryo accumulation for preimplantation genetic testing, a retrospective study.

This retrospective study was carried out to determine which strategy is associated with improved outcomes in two back-to-back cycles when undergoing embryo accumulation. Eighty patients with two stimulation cycles performed with <45 days between retrievals between Jan'16-Mar'17 were included. Patients were segregated according to the strategy used to link stimulations: spontaneous menses (SM), vaginal micronized progesterone (VMP) or oral contraceptive pills (OCP). Main outcome measure was oocytes retrieved. The oocytes retrieved difference between cycles was -0.9 in SM, -1.5 in VMP and +0.4 in OCPs. Although not statistically significant, more oocytes retrieved were observed in the 2ndcycle when OCPs were used (9.0 ± 3.7 vs. 9.4 ± 4.1)? whereas fewer oocytes retrieved were observed when SM (9.4 ± 3.9 vs. 8.5 ± .0) or VMP (9.8 ± 5.7 vs. 8.2 ± 4.4) were used. After adjusting for age, gonadotropins and stimulation days (2nd cycle) and treatment group in an ANCOVA model, no treatment was associated with a higher average number of oocytes retrieved (power: 14.9%) or a higher difference of oocytes retrieved (power: 22.3%). Although no statistical significance was reached, OCPs were observed to achieve higher average and positive difference of oocytes retrieved in the 2nd cycle.

Should progesterone on the human chorionic gonadotropin day still be measured?

OBJECTIVE: To evaluate in our setting whether there is currently a level of P on the hCG day (P-hCG) predictive of no pregnancy. DESIGN: Observational study of prospectively collected data of the P-hCG levels of stimulated IVF cycles. SETTING: In vitro fertilization unit. PATIENT(S): All cycles of IVF/intracytoplasmic sperm injection with fresh embryo transfer performed between January 2009 and March 2014. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Pregnancy rate. RESULT(S): Clinical pregnancy rate per ET was 38.7% and live birth rate was 29.1%. The P-hCG concentration was positively correlated to E2 on the hCG day, and the number of oocytes was negatively correlated to age. Progesterone on hCG day was higher among agonist- compared with antagonist-treated patients (mean ± SD: 1.13 ± 0.69 ng/mL vs. 0.97 ± 0.50 ng/mL) and among recombinant FSH compared with recombinant FSH + hMG stimulation (mean ± SD: 1.11 ± 0.58 ng/mL vs. 0.94 ± 0.50 ng/mL). Pregnancy rate was positively associated with the number of oocytes. There was no correlation between P-hCG value and pregnancy rate, overall or according to the type of treatment. CONCLUSION(S): In our setting there is no P-hCG value differentiating a good from a poor cycle success rate. CLINICAL TRIAL REGISTRATION NUMBER: NCT02323347.

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.

Live birth using vitrified--warmed oocytes in invasive ovarian cancer: case report and literature review.

This article reports the live birth of a healthy newborn using vitrified-warmed oocytes in a young patient with invasive mucinous ovarian carcinoma (stage Ic). Diagnosis was performed after a laparoscopic left adnexectomy. She underwent two cycles of ovarian stimulation, and 14 oocytes were vitrified before fertility-sparing surgery with uterus preservation went ahead. One year later, a transfer of two embryos was performed after insemination of warmed oocytes. Eighteen days after the transfer, she underwent a laparotomy because of abdominal pain, vaginal bleeding and haemoperitoneum. A right cornual ectopic pregnancy in the uterus was diagnosed and a wedge resection was performed to resolve it. One week later, a viable intrauterine pregnancy was confirmed under ultrasound. An elective Caesarean section was performed at week 38 of gestation, resulting in the birth of a healthy boy weighing 2650 g. As far as is known, this is the first live birth reported through vitrified-warmed oocytes in a patient with invasive ovarian cancer. Although oocyte vitrification is an alternative to be considered for fertility preservation in highly selected cases of ovarian cancer, controversial issues are discussed. Fertility preservation is a proven possibility in some cancer patients according to their age, disease and time available until the beginning of their oncological treatment. Although oocyte vitrification is an alternative to be considered for fertility preservation in highly selected cases of ovarian cancer, no live birth has been reported. We report the live birth of a healthy newborn through vitrified-warmed oocytes in a young patient with invasive mucinous ovarian carcinoma (stage Ic). Diagnosis was performed after a laparoscopic left adnexectomy. She underwent two cycles of ovarian stimulation, and 14 oocytes were vitrified before fertility-sparing surgery with uterus preservation went ahead. One year later, a transfer of two embryos was performed after the insemination of the warmed oocytes. Eighteen days after the transfer she underwent a laparotomy because of abdominal pain, vaginal bleeding and haemoperitoneum. A right cornual ectopic pregnancy in the uterus was diagnosed and a wedge resection was performed to resolve it. One week later, a viable intrauterine pregnancy was confirmed under ultrasound. An elective Caesarean section was performed at week 38 of gestation, resulting in the birth of a healthy boy weighing 2650 g. To our knowledge, this is the first live birth reported using vitrified-warmed oocytes in invasive ovarian cancer. Controversial issues are reviewed and discussed.

Ovarian response to controlled ovarian hyperstimulation in women with cancer is as expected according to an age-specific nomogram.

PURPOSE: To evaluate the ovarian response to controlled ovarian hyperstimulation (COH) in cancer patients according to an age-specific nomogram for the number of retrieved oocytes. METHODS: Retrospective observational study carried out in a University affiliated fertility clinic. Forty-eight patients with cancer underwent ovarian stimulation for oocyte cryopreservation. An age - specific nomogram for the number of retrieved oocytes was built with 1536 IVF cycles due to male factor exclusively, oocyte donation and age related fertility preservation. The number of oocytes retrieved in cancer patients was compared to the expected response according to the nomogram using the Z-score. RESULTS: The mean number of total retrieved oocytes in patients with cancer was 14.04 ± 8.83. After applying the Z-score to compare the number of retrieved oocytes between women with cancer and the expected response according to the age-specific nomogram, we did not observe a statistically significant difference (Z-score 0.23; 95 % CI [-0.13-0.60]). CONCLUSION(S): According to our results, patients with cancer exhibit an ovarian response as expected by age. Despite the limitation of the sample size, the obtained results should encourage oncologists for early referral of women with cancer to fertility specialists.

Cancer and fertility preservation: Barcelona consensus meeting.

Improvements in early diagnosis and treatment strategies in cancer patients have enabled younger women with cancer to survive. In addition to the stressful event of the diagnosis, patients with malignant diseases face the potential loss of the opportunity to have children. Preservation of fertility has become a challenging issue and it is still surrounded by controversies. On the basis of available evidence, a group of experts reached a consensus regarding the options for trying to preserve fertility in women with cancer: among established methods, in postpubertal women, oocyte cryopreservation is the preferred option, whereas ovarian tissue cryopreservation is the only possibility for prepubertal girls. Combining several strategies on an individual basis may improve the chances of success. Realistic information should be provided before any intervention is initiated. Counseling should offer support for patients and provide better care by understanding emotional needs, psychological predictors of distress and methods of coping. Early referral to the fertility specialist is essential as fertility preservation (FP) may improve quality of life in these patients. The information summarized here is intended to help specialists involved in the treatment of cancer and reproductive medicine to improve their understanding of procedures available for FP in young cancer patients.

Concise review: fertility preservation: an update.

Fertility preservation is an emerging field in medicine that enables men, women, and children to maintain reproductive health when it is threatened by gonadotoxic treatment. Patients affected by other nononcologic malignancies that can impair spermatogenesis and ovogenesis can also benefit from fertility preservation treatments. Age-related infertility can also be overcome by cryopreserving gametes or embryos. The only established methods for fertility preservation in male patients are sperm cryopreservation in postpubertal age and experimental testicular tissue cryopreservation in prepubertal age. In adult women, oocyte cryopreservation is the preferred option, whereas ovarian tissue cryopreservation is the only possibility for prepubertal girls. Fertility preservation treatments must be addressed through a multidisciplinary approach that involves gynecologists, urologists, oncologists, pediatricians, and professionals in the field of medically assisted reproduction to work in coordination to provide patients with counseling and comprehensive information about fertility issues.

Poor prognosis for ovarian response to stimulation: results of a randomised trial comparing the flare-up GnRH agonist protocol vs. the antagonist protocol.

OBJECTIVE: To determine the efficacy of the flare-up agonist and the antagonist protocols in patients with poor prognosis for ovarian response. METHODS: A randomised trial was conducted on two hundred and twenty-one women considered as having poor prognosis for ovarian response to stimulation, based on previous cycles or clinical criteria. All women were prospectively randomised into two groups of treatment (flare-up group and antagonist group) by computer-assisted randomisation in a 1:1 ratio. The main outcome measure was clinical pregnancy rate. RESULTS: Groups were homogeneous in age and baseline characteristics. Duration of stimulation, gonadotropin consumption, number of oocytes retrieved and number and quality of embryos transferred did not differ significantly between the groups. E(2) level the day of hCG administration was significantly higher in the flare-up group. Pregnancy rates per started cycle were 15% in the flare-up group and 14.1% in the antagonist group. Cancellation rates were 12.5% in the flare-up group and 16.3% in the antagonist group. None of these differences reached statistical significance. CONCLUSIONS: No statistically significant differences were observed between the two protocols regarding clinical pregnancy rates. In patients with poor prognosis for ovarian response, the flare-up agonist and the antagonist protocols were comparable regarding clinical pregnancy rates.