Controlled Ovarian Stimulation Protocols Research Articles

PREDICTING PROBABILITY OF CUMULATIVE LIVE BIRTH BASED ON BOTH BASELINE INFORMATION AND PROTOCOLS OF CONTROLLED OVARIAN STIMULATION

To develop a prediction model for the probability of cumulative live birth from one initiated assisted reproductive technology (ART) cycle based on couples’ baseline characteristics and controlled ovarian stimulation (COS) protocols. Therefore, we sought to create a clinical prediction model for counseling and COS protocol selection. A retrospective cohort study. From Jan 2012 to Mar 2016, all women at age of 19-39 years old with at least 5 antral follicle count (AFC) underwent just one complete ART cycle with long GnRH-agonist, depot GnRH-agonist, modified long GnRH agonist and GnRH-antagonist protocols in Chengdu Xi’nan Gynecology Hospital were included, and followed up to Mar 2018. Couples with chromosome abnormality were excluded. Cumulative live birth was defined as first live birth resulting from one initiated ART cycle, including cycles in which fresh and/or frozen embryos were transferred, until one delivery with a live birth occurs or until all embryos are used, whichever occurs first. A multivariate stepwise logistic regression model was used to predict the probability of cumulative live birth. The accuracy of the model was then tested using a receiver operating characteristic curve (ROC). 6862 patients with 6862 complete ART cycle were enrolled with a 72.89% overall cumulative live birth rate (CLBR), namely 5002 cycles cumulatively had live birth. Predictors in the model were female’s age (-0.07, 95% CI:-0.09∼-0.05, P<0.001), height (0.06, 95% CI:0.05∼0.08, P<0.001), weight (-0.01, 95% CI:-0.02∼0.00 , P=0.005), duration of infertility (-0.06, 95% CI:-0.08∼-0.04 , P<0.001), number of previous ART cycle (-0.60, 95% CI:-0.79∼-0.41 , P<0.001), basal AFC (0.08, 95% CI:0.07∼0.09, P<0.001), basal FSH (-0.09, 95% CI:-0.12∼-0.06, P<0.001) and COS protocols [long GnRH-agonist (reference category), depot GnRH-agonist (-0.08, 95% CI:-0.64∼0.48, P=0.785), modified long GnRH agonist (-0.69, 95% CI:-0.96∼-0.43 , P<0.001), GnRH-antagonist protocols (-0.12, 95% CI:-0.71∼0.47, P=0.696)]. The area under the curve (AUC) for ROC was 0.708. This model provides a scientific predicting method for probability of cumulative live birth, thus help doctors give patients more accurate counseling and select more suitable COS protocol.

Fertility preservation in borderline ovarian tumor patients and survivors.

Borderline ovarian tumors (BOTs) represent around 15% of all epithelial ovarian cancer. Around one third of those patients is under 40 and has not completed childbearing when the tumor is diagnosed. Cancer survivors are more and more concerned about their future fertility since a large proportion of those with BOTs are young. Whatever the tumor stage, information regarding future fertility after treatment and fertility preservation (FP) options must be delivered to all patients before treatment. A multidisciplinary team will discuss and propose personalized treatment and FP strategies. Nowadays, the FP options offered to patients with BOT are the followings: i) minimal invasive conservative surgery, ii) oocyte cryopreservation after controlled ovarian stimulation (COS) or in vitro maturation (IVM) and iii) ovarian tissue cryopreservation. Generally, the most common strategy to preserve future fertility is represented by minimal invasive conservative surgery. However, with the remarkable success and evolution of assisted reproductive technologies (ART) -notably progress and efficiency in COS and oocyte vitrification -have led to offer another potential approach for FP consisting in oocyte cryopreservation. Several COS protocols, such as random start or dual stimulation associating tamoxifen or aromatase inhibitors with gonadotropins provide similar results when compared to standard protocols while providing safety by minimizing the risk of high estrogen exposure. When COS is contraindicated, oocyte cryopreservation can still be possible throw IVM. Even though, oocyte competence after IVM is lower than that obtained after COS. A less used approach is cryopreservation of ovarian tissue, consisting in freezing ovarian cortex fragments for a future thawing and graft. Some concerns and limitations regard the ovarian cortex graft and the risk of reintroducing malignant cells once performed. Nonetheless, the latter it is the only option in prepubertal patients.

The Ovarian Sensitivity Index (OSI) Significantly Correlates with Ovarian Reserve Biomarkers, Is More Predictive of Clinical Pregnancy than the Total Number of Oocytes, and Is Consistent in Consecutive IVF Cycles.

Background and Objectives: Some biomarkers of ovarian responsiveness to gonadotropins and the total number of retrieved oocytes are known to affect the success rate after controlled ovarian stimulation (COS) and in vitro fertilization (IVF). The aim of this study was to study another putative marker, the Ovarian Sensitivity Index (OSI: (number of retrieved oocytes/total gonadotropin dose) × 1000), assessing whether (a) it correlates with ovarian responsiveness biomarkers, (b) it is an independent predictor of clinical pregnancy, (c) it predicts clinical pregnancy comparably to the number of retrieved oocytes, and (d) it is consistent in the repeated COS cycles of the same woman. Design: retrospective analysis. Setting: public IVF Unit in University Hospital. Cases and Measurements: 1612 patients submitted to 3353 IVF cycles were included, their OSI was calculated and it was correlated with the ovarian responsiveness biomarkers (age, BMI, anti-Mullerian hormone, antral follicle count). The OSI and the total number of oocytes were compared for their value in predicting clinical pregnancy. The inter-cycle consistency of the OSI was estimated in 209 patients who underwent two consecutive cycles in which the ovarian stimulation regimen was changed from the Gonadotropin-releasing Hormone (GnRH)-agonist long protocol to the GnRH-antagonist protocol or vice-versa. Results: The OSI turned out to be significantly related to age and BMI (inversely), the anti-Mullerian hormone (AMH) and the antral follicle count (AFC) (directly), to be an independent predictor of clinical pregnancy, and to correlate with clinical pregnancy better than the total number of oocytes (p < 0.0001 vs. <0.002). In patients who underwent two consecutive COS cycles changing stimulation regimen, the OSI showed 82% consistency. Conclusion(s): The OSI significantly correlates to the currently used biomarkers of ovarian responsiveness; it is an independent predictor of clinical pregnancy; it is more predictive of clinical pregnancy than the total number of oocytes, and is highly consistent in repeated IVF cycles even when the COS protocol changes. These characteristics make the OSI quite suitable to be incorporated into more complex prediction models of IVF outcome.

Efficacy and safety of controlled ovarian stimulation using GnRH antagonist protocols for emergency fertility preservation in young women with breast cancer-a prospective nationwide Swedish multicenter study.

STUDY QUESTIONHow efficacious and safe are the current approaches to controlled ovarian stimulation (COS) aimed at fertility preservation (FP) in women with breast cancer (BC)?SUMMARY ANSWERIn women with BC undergoing COS aiming at egg/embryo cryopreservation, letrozole-based protocols and those randomly started were equally effective compared with conventional COS, and the overall survival was similar between the women that proceeded to FP and those who did not.WHAT IS KNOWN ALREADYCryopreservation of oocytes and embryos is an established method for FP in women with BC. Recent improvements to COS protocols include concomitant use of letrozole, random-cycle start day of stimulation and the use of GnRHa for the egg maturation trigger. To date, limited sample size of the available studies has not allowed investigation of differences in the efficacy of the different approaches to COS for FP in this patient population.STUDY DESIGN, SIZE, DURATIONA prospective multicenter study with national coverage including 610 women with BC counseled between 1 January 1995 and 30 June 2017 at six Swedish FP regional programs.PARTICIPANTS/MATERIALS, SETTING, METHODSAfter counseling, 401 women elected to undergo COS. Treatments differed in the use or not of concomitant letrozole, a conventional or random-cycle day COS initiation and the use of hCG versus GnRHa trigger for oocyte maturation. Numbers of cryopreserved oocytes and embryos were defined as primary outcome. Pregnancy attempts, reproductive outcomes and long-term survival, investigated by the linking of individuals of the cohort to the total population register of the Swedish Tax Agency (up to 25 November 2018), were evaluated.MAIN RESULTS AND THE ROLE OF CHANCEUsing letrozole or not resulted in similar numbers of oocytes and embryos cryopreserved (meanoocytes = 9.7 versus 10 and meanembryos 4.0 versus 5.3, respectively), similar to COS with random versus conventional start (meanoocytes 9.0 versus 10.6 and meanembryos 4.8 versus 4.8). In COS with letrozole, a GnRHa trigger was associated with a higher number of oocytes retrieved (P < 0.05) and embryos cryopreserved (P < 0.005), compared with conventional hCG trigger. Of 99 women who returned to fertility clinics after cancer treatment, 32 proceeded to thawing of oocytes or embryos and 10 of them had live births. The all-cause survival between the women that underwent COS and those who did not was similar and did not differ between the two groups.LIMITATIONS, REASONS FOR CAUTIONData on tumor characteristics and estrogen receptor (ER) status were not known for all women at the time of FP counseling and planning of COS, thus protocols with letrozole have been used for both estrogen-sensitive and non-estrogen-sensitive BC. For the same reason, subsequent adjustment for ERs in the BC or tumor characteristics as potential confounders were not performed as these parameters were not available and did not influence the provision of FP through COS.WIDER IMPLICATIONS OF THE FINDINGSThe results of our study support the premise that recently introduced potential improvements to COS protocols for FP in women with BC are efficacious and safe.STUDY FUNDING/COMPETING INTEREST(S) This study was supported by research grants from the Swedish Cancer Society, the Stockholm County Council, the Percy Falk Stiftelsen, Radiumhemmets Forskningsfonder, The Swedish Breast Cancer Association and Karolinska Institutet to K.A.R.W. J.B. reports grants from Amgen, AstraZeneca, Pfizer, Roche, Sanofi-Aventis and Merck, outside the submitted work, and payment from UpToDate to Asklepios Medicine HB for a chapter on BC prediction and prognostication. All the other authors have no competing interests to report.

Live birth rate comparison of three controlled ovarian stimulation protocols for in vitro fertilization-embryo transfer in patients with diminished ovarian reserve after endometrioma cystectomy: a retrospective study

BackgroundWomen with endometriosis and previous cystectomy may respond less well to gonadotropin stimulation, which results in fewer oocytes retrieved and poor pregnancy outcomes. Choosing an appropriate protocol for such populations is essential. This study involved an analysis of the effect of different controlled ovarian stimulation (COS) protocols on the clinical outcomes of in vitro fertilization-embryo transfer (IVF-ET) in women with diminished ovarian reserve (DOR) who underwent ovarian endometrioma cystectomy.MethodsA total of 342 patients that underwent IVF-ET treatment at the Beijing Obstetrics and Gynecology Hospital from January 1, 2013 to April 30, 2018 were included in this retrospective study. The patients were distributed into three groups according to the COS protocols, namely prolonged GnRH-agonist (Group A, n = 113), GnRH-antagonist (Group B, n = 121), and long GnRH-agonist (Group C, n = 108). The clinical and laboratory parameters of the three protocols were analyzed and a logistic regression of clinical pregnancy and live births was conducted.ResultsThere were no significant differences in the age, infertility duration, basic follicle stimulation hormone (FSH), luteinizing hormone (LH), or estradiol (E2) levels as well as other baseline characteristics among groups (P > 0.05). The total gonadotrophin (Gn) dosage and duration tended to be less in the GnRH-antagonist group than in the others (P < 0.05). No significant differences were found in the implantation rate and clinical pregnancy rate among the groups, but the prolonged GnRH-agonist group showed the highest rates. In addition, no significant differences were present in the number of retrieved oocytes, oocyte fertilization rate, embryo utilization rate, live birth rate, abortion rate, ectopic pregnancy rate, or multiple pregnancy rate in the three groups (P > 0.05). Age had a significant effect on both clinical pregnancy and live birth.ConclusionFor those DOR patients who had undergone ovarian endometriosis cystectomy, the prolonged GnRH-agonist protocol may achieve better clinical IVF-ET outcomes, but there were no significant differences from the other groups. The GnRH-antagonist protocol may reduce the cost and time of drug treatment. Age should be considered for its influence on pregnancy outcome. However, a larger sample size may be needed for further study.

The role of Letrozole (LE) in controlled ovarian stimulation (COS) in patients at high risk to develop ovarian hyper stimulation syndrome (OHSS). A prospective randomized controlled pilot study

BackgroundRecently, it has been shown that PCOS patients with extremely high anti-Mullerian hormone (AMH) level are more likely to experience OHSS during IVF, compared to PCOS patients with lower AMH level. While recent data questioned the effect of Letrozole (LE) on the occurrence of OHSS in non-PCOS patients, it role in PCOS patients with very high AMH level was never investigated in a prospective manners. Hence, our main objective was to evaluate the clinical outcome of PCOS patients at very high risk for OHSS undergoing two different COS protocols (with or without LE). MethodsA prospective randomized controlled study (RCT) of 51 patients with specifically high levels of AMH undergoing one of two COS protocols. The control group (group A) consisted of 24 PCOS women who received low-dose gonadotropins using the multiple-dose GnRH-antagonist protocol, GnRH agonist-triggered and “freeze all”. The study group (group B) consisted of 24 women with PCOS who received the same protocol combined with LE. High risk criteria for OHSS were: PCOS patients with low BMI, young age, and extremely high level of serum AMH (inclusion criteria for AMH > 50 pmol/L). ResultsCumulative live birth rates per retrieval were similar in both groups. While no single case of severe OHSS was observed in, in the study group (group B), the rate of moderate and mild OHSS was 5 times lower compared to the control group (P < 0.05). ConclusionIn PCOS patients with extremely high AMH levels the LE co-administration to GnRH-Ant protocols results in reduced incidence of OHSS than conventional GnRH-Ant protocols. LE co-administration may prove to be highly effective in preventing OHSS, even in the women who are at high risk to these dangerous complications.

An Observational Retrospective Cohort Trial on 4,828 IVF Cycles Evaluating Different Low Prognosis Patients Following the POSEIDON Criteria.

Objective: To study the actual controlled ovarian stimulation (COS) management in women with suboptimal response, comparing clinical outcomes to the gonadotropins consume, considering potential role of luteinizing hormone (LH) addition to follicle-stimulating hormone (FSH).Design: Monocentric, observational, retrospective, real-world, clinical trial on fresh intra-cytoplasmic sperm injection (ICSI) cycles retrieving from 1 to 9 oocytes, performed at Humanitas Fertility Center from January 1st, 2012 to December 31st, 2015.Methods: COS protocols provided gonadotropin releasing-hormone (GnRH) agonist long, flare-up, short and antagonist. Both recombinant and urinary FSH were used for COS and LH was added according to the clinical practice. ICSI outcomes considered were: gonadotropins dosages; total, mature, injected and frozen oocytes; cumulative, transferred and frozen embryos; implantation rate; pregnancy, delivery and miscarriage rates. Outcomes were compared according to the gonadotropin regimen used during COS.Results: Our cohort showed 20.8% of low responders, defined as 1–3 oocytes retrieved and 79.2% of “suboptimal” responders, defined as 4–9 oocytes retrieved. According to recent POSEIDON stratification, cycles were divided in group 1 (6.9%), 2 (19.8%), 3 (11.7%), and 4 (61.5%). The cohort was divided in 3 groups, according to the gonadotropin's regimen. Women treated with FSH plus LH showed worst prognostic factors, in terms of age, basal FSH, AMH, and AFC. This difference was evident in suboptimal responders, whereas only AMH and AFC were different among treatment groups in low responders. Although a different result, in terms of oocytes and embryos detected, major ICSI outcomes (i.e., pregnancy and delivery rates) were similar among groups of COS treatment. Outcomes were significantly different among Poseidon groups. Implantation, pregnancy and delivery rates were significantly higher in Poseidon group 1 and progressively declined in other POSEIDON groups, reaching the worst percentage in group 4.Conclusions: In clinical practice, women with worst prognosis factors are generally treated with a combination of LH and FSH. Despite low prognosis women showed a reduced number of oocytes retrieved, the final ICSI outcome, in terms of pregnancy, is similarly among treatment group. This result suggests that the LH addition to FSH during COS could improve the quality of oocytes retrieved, balancing those differences that are evident at baseline.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03290911

PIH33 COST MINIMIZATION ANALYSIS OF HIGH PURITY URINARY HUMAN FOLLICLE-STIMULATING HORMONE FOR THE CONTROLLED OVARIAN STIMULATION IN IN-VITRO FERTILIZATION IN CHINA

In China, about 50 million women in reproductive age are estimated to be infertile. The economic burden due to infertility was as high as 230 billion RMB in 2008. Controlled ovarian stimulation (COS) via gonadotrophin-releasing hormone agonist (GnRH-a) long protocol is the most commonly used method in in-vitro fertilization (IVF). Clinical research to date shows no significant difference between the two COS protocols using high-purity urinary human follicle-stimulating hormone (HP-FSH) or genetically recombined follicle-stimulating hormone (rFSH) with respect to pregnancy outcomes. This study aims to compare the costs between HP-FSH and rFSH regimens for COS in treatment of infertility in China. Cost minimization analysis was conducted to compare the mean direct costs per treatment cycle with IVF from perspective of payers. Two scenarios were considered; one cycle or the first two treatment cycles. Total costs associated with GnRH-a long protocol, including drugs, medical expenses, and treatment emergent adverse events were estimated and compared between HP-FSH and rFSH regimens. Detailed medical costs were obtained through key opinion leader surveys. One-way sensitivity analyses were conducted with key parameters varying by ±10%. The total cost for the first cycle with HP-FSH was estimated to be ¥24,886, which was ¥3,106 (11.1%) lower than the cost of treatment with rFSH due to reduced cost of FSH (¥3,885 vs. ¥6,804). Sensitivity analyses showed that the cost-savings by using HP-FSH ranged from ¥2,425 to ¥3,786. In scenario of the two treatment cycles, the cumulative cost of COS using HP-FSH was estimated to be ¥33,079, which remained lower than the cost of treatment with rFSH by ¥2,987 (9.9%). HP-FSH is a cost-saving option compared with rFSH in COS for the treatment of patients with infertility from the payers’ perspective.

Abstract P4-16-02: Fertility preservation before neoadjuvant or adjuvant chemotherapy for breast cancer: Final results of PRESAGE trial

Abstract Background: Breast cancer is the most frequent form of cancer in young women. For these patients, breast cancer is generally more aggressive and chemotherapy is more often needed. Chemotherapy is commonly associated with amenorrhea and a decrease of ovarian reserve depending on the patient's age, agents and dose. Embryo, oocyte and ovarian tissue cryopreservation are the three options to preserve fertility. Embryo and oocyte cryopreservation require controlled ovarian stimulation (COS). The use of COS is associated with an increase of estradiol levels. It led to develop protocols using Tamoxifen or Letrozole combined with FSH to protect patients of the potential deleterious effects of the COS. PRESAGE is the first French prospective multicenter feasibility study about fertility preservation by COS combined with Tamoxifen and oocyte +/- embryo cryopreservation before neoadjuvant (NAC) or adjuvant (AC) chemotherapy for breast cancer. Material and method: Prospective multicenter study for patients of less than 40 years, with a breast cancer, for whom a treatment of NAC or AC is indicated and who wish to preserve their fertility. The main objective was to evaluate the feasibility of a COS associating Tamoxifen with FSH followed by an oocyte+/- embryo cryopreservation. The secondary objectives were to evaluate the average deadline prior to the beginning of the chemotherapy and the impact of the type of COS (depending on the phase of the menstrual cycle, conventional-start or random-start COS protocol) on the number and the quality of oocytes harvested. Statistical analysis was performed using SAS statistical software version 9.4 (SAS Institute, Cary, NC). Results: 101 patients were included between February 2014 and July 2017 and 97 patients were eligible for statistical analysis. Mean age of the patients was 31,5 +/- 4 years, the half of them was nulliparous (53/97) and 23,7 % (23/97) were single. They presented mainly SBR II or III (91/96, 94,8 %) lesions, ER + (66/96, 68,7 %). 38 patients benefited from a NAC and 59 of an AC. We have found a significant shorter care (time between the first oncologist's consultation and the beginning of the chemotherapy) according to the type of chemotherapy: 29,7 +/- 15,6 days in NAC group vs 45,2 +/- 21,5 days in AC group (p=0,003) with the same duration of ovarian stimulation in the two groups (10,5 +/-2 days). The success rate of the COS procedure was 90,7 % (88/97) with no significant difference between the groups according to the type of COS (p = 0.06) or the type of chemotherapy (AC vs. NAC p= 0,3). In the 88 patients who had oocyte retrieval, the number of oocytes harvested per patient was 12,8 +/- 7,8 , the number of oocytes preserved was 9,7 +/- 6,1 and an IVF was performed in 12,5% of patients (11/88) with 5,1 +/- 3,1 embryos obtained. We have found no impact of the type of chemotherapy or the type of COS on the number of oocytes or embryos preserved. Conclusion: with a high success rate (90,7%), our study suggests that COS with Tamoxifen and FSH is feasible before adjuvant or neoadjuvant chemotherapy in breast cancer patients. We also show that COS procedure before neoadjuvant chemotherapy can be realized without increasing the time before introducing chemotherapy. Citation Format: Bordes V, Palpacuer C, FRICK C, Leperlier F, Dezellus A, De Blay P, Delay F, Sauterey B, Augereau P, Duros S, Lefeuvre-Plesse C, Lavau S, Durand LM, Mouret MA, Gremeau AS, Campone M, Mirallie S. Fertility preservation before neoadjuvant or adjuvant chemotherapy for breast cancer: Final results of PRESAGE trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-02.

Effects of controlled ovarian stimulation on thyroid stimulating hormone in infertile women

ObjectiveTo study the effects of long-acting gonadotropin-releasing hormone agonist (GnRH-a) on thyroid function in euthyroid patients of in vitro fertilization (IVF)/ intracytoplasmic sperm injection of embryo transfer (ICSI-ET) and to investigate the timing and alteration of thyroid stimulating hormone (TSH) during controlled ovarian stimulation(COS). Materials and methodsEuthyroid patients scheduled for IVF/ICSI were enrolled. Euthyroidism was defined as having no history of hypothyroidism with normal TSH before IVF. Long GnRH-a protocol was chosen as COS protocol. 207 patients were divided into two groups based on basal serum TSH level: group A with 0.35mIU/L＜TSH＜2.5mIU/L (n = 137) and group B with 2.5mIU/L ≤ TSH＜4.5mIU/L (n = 70). Serum TSH was tested on 6 time points: before COS (2–5days in menstrual cycle, before GnRH-a injection), Gn injection day 1, Gn injection day 5, human chorionic gonadotropin (HCG) day, 14 and 28 days after transplantation. The serum TSH, clinical pregnancy and abortion rate were investigated. ResultThe serum TSH value was significantly (P < 0.05) increased after injection of long-acting GnRH-a in all patients. Both groups had significant (P < 0.05) increases in serum TSH level after long-acting GnRH-a injection. The TSH level was increased in 131(63.3%) patients after GnRH-a injection, of which twenty (9.7%) had subclinical hypothyroidism with TSH level over 4.5 mIU/L. The other 76 (36.7%) patients had decreased TSH. In group A, 79 (57.7%) patients showed an increase of TSH, including three patients (2.2%) with simultaneous rise of TPOAb and four (2.9%) diagnosed of subclinical hypothyroidism with TSH level over 4.5 mIU/L, and the rest fifty-eight (42.3%) patients had decreased TSH with one patient with elevated TPOAb who was diagnosed with subclinical hyperthyroidism. In group B, fifty-two (74.3%) patients showed an increase of TSH, including thirteen (18.6%) patients with elevated TPOAb and sixteen (22.9%) patients diagnosed of subclinical hypothyroidism with TSH level over 4.5 mIU/L, and the rest eighteen (25.7%) patients had decreased TSH with one patient diagnosed with subclinical hyperthyroidism. Group B had a significant higher proportion of patients with elevated serum TSH than group A (P ＜ 0.05). Compared to the baseline level, serum TSH ascended distinctly and reached peak level on HCG day in all patients. Group A and B had similar trends of alteration. Patients in group A had significantly (P＜0.05) higher clinical pregnancy rate than in group B. No significant (P＞0.05) difference in abortion rate were observed between the two groups. ConclusionGnRH-a can significantly increase serum TSH levels with possible development of subclinical thyroid dysfunction. Infertile patients with serum TSH > 2.5 mIU/L are more susceptible to GnRH-a while patients with basal TSH less than 2.5 mIU/L may get a higher clinical pregnancy rate when receiving IVF/ICSI.

Treatment of female rhesus macaques with a somatostatin receptor antagonist that increases oocyte fertilization rates without affecting post-fertilization development outcomes.

To determine the effects of PGL1001, a somatostatin receptor isoform-2 (SSTR-2) antagonist, on ovarian follicle development, oocyte fertilization, and subsequent embryo developmental potential in the rhesus macaque. Cycling female rhesus macaques (N= 8) received vehicle through one menstrual (control) cycle, followed by daily injections of PGL1001, a SSTR-2 antagonist, for three menstrual (treatment) cycles. Main endpoints include overall animal health and ovarian hormones (e.g., estradiol [E2], progesterone [P4], and anti-Müllerian hormone [AMH]), ovarian circumference, numbers of oocytes and their maturation status following controlled ovarian stimulation (COS), as well as oocyte fertilization and subsequent blastocyst rates that were assessed in control and PGL1001 treatment cycles. Circulating PGL1001 levels were assessed at baseline as well as 6, 60, and 90days during treatment. PGL1001 treatment did not impact overall animal health, menstrual cycle length, or circulating levels of ovarian hormones (E2, P4, and AMH) in comparison to vehicle treatment during natural cycles. PGL1001 treatment increased (p˂0.05) ovarian circumference and the day 8 to day 1 ratio of AMH levels (p˂0.05) during a COS protocol, as well as oocyte fertilization rates compared to the vehicle treatment interval. Blastocyst development rates were not significantly different between vehicle and PGL1001 treatment groups. Prolonged treatment with PGL1001 appears to be safe and does not affect rhesus macaque general health, menstrual cycle length, or ovarian hormone production. Interestingly, PGL1001 treatment increased the fertilization rate of rhesus macaque oocytes collected following ovarian stimulation.

Elective and Onco-fertility preservation: factors related to IVF outcomes.

Is the indication for fertility preservation (FP) related to success in IVF cycles after elective-FP (EFP) for age-related fertility decline and FP before cancer treatment (Onco-FP)? Although success rates were lower in cancer patients, there was no statistically significant association between malignant disease and reproductive outcome after correction for age and controlled-ovarian stimulation (COS) regime. FP is increasingly applied in assisted reproduction, but little is known about the outcome of IVF cycles with vitrified oocytes in FP patients. Retrospective, observational multicenter study of vitrification cycles for FP and of the warming cycles of women who returned to attempt pregnancy from January 2007 to May 2018. In all, 6362 women (EFP = 5289 patients; 7044 cycles + Onco-FP = 1073 patients; 1172 cycles) had their oocytes vitrified for FP. A logistic regression analysis was performed to examine the impact of indication for FP corrected for age at vitrification. The protocol used for COS was also included as a possible confounder. The main outcome measures were oocyte survival and live birth. A detailed description of the baseline and clinical data is provided, with comparisons between EFP and Onco-FP. The cumulative live birth rate (CLBR) per utilized oocyte according to age at vitrification was analyzed in those patients returning to use their oocytes. Age at vitrification was significantly older in EFP patients (37.2 ± 4.9 vs. 32.3 ± 3.5 year; P < 0.0001). Fewer oocytes were retrieved and vitrified per cycle in EFP (9.6 ± 8.4 vs. 11.4 ± 3.5 and 7.3 ± 11.3 vs. 8.7 ± 2.1, respectively; P < 0.05), but numbers became comparable when analyzed per patient (12.8 ± 7.4 vs. 12.5 ± 3.2 and 9.8 ± 6.4 vs. 9.5 ± 2.6). Storage time was shorter in EFP (2.1 ± 1.6 vs. 4.1 ± 0.9 years; P < 0.0001). In all, 641 (12.1%) EFP and 80 (7.4%) Onco-FP patients returned to attempt pregnancy (P < 0.05). Overall oocyte survival was comparable (83.9% vs. 81.8%; NS), but lower for onco-FP patients among younger (≤35 year) subjects (81.2% vs. 91.4%; P > 0.05). Fewer EFP cycles finished in embryo transfer (50.2% vs. 72.5%) (P < 0.05). The implantation rate was 42.6% and 32.5% in EFP versus Onco-FP (P < 0.05). Ongoing pregnancy (57.7% vs. 35.7%) and live birth rates (68.8% vs. 41.1%) were higher in EFP patients aged ≤35 than the Onco-FP matching age patients (P < 0.05). The reason for FP per se had no effect on oocyte survival (OR = 1.484 [95%CI = 0.876-2.252]; P = 0.202) or the CLBR (OR = 1.275 [95%CI = 0.711-2.284]; P = 0.414). Conversely, age (<36 vs. ≥36 y) impacted oocyte survival (adj.OR = 1.922 [95%CI = 1.274-2.900]; P = 0.025) and the CLBR (adj.OR= 3.106 [95%CI = 2.039-4.733]; P < 0.0001). The Kaplan-Meier analysis showed a significantly higher cumulative probability of live birth in patients <36 versus >36 in EFP (P < 0.0001), with improved outcomes when more oocytes were available for IVF. Statistical power to compare IVF outcomes is limited by the few women who came to use their oocytes in the Onco-FP group. The patients' ages and the COS protocols used were significantly different between the EFP and ONCO-PP groups. Although the implantation rate was significantly lower in the Onco-FP patients the impact of cancer disease per se was not proven'. EFP patients should be counseled according to their age and number of available oocytes. No external funding was used for this study. The authors have no conflicts of interest. N/A.

Abstract P3-14-03: PRESAGE : Prospective multicenter feasibility study of fertility preservation before neoadjuvant or adjuvant chemotherapy for breast cancer: Preliminary results

Abstract Background: Breast cancer is the most frequent form of cancer for young women. For these patients, breast cancer is generally more aggressive and chemotherapy is more often needed. Chemotherapy is commonly associated with amenorrhea and a decrease of ovarian reserve depending on the patient's age, agents and dose. There are no guidelines to prevent subfertility for young women on cytotoxic treatments. Embryo, oocyte and ovarian tissue cryopreservation are the three options to preserve fertility. Embryo and oocyte cryopreservation require controlled ovarian stimulation (COS). The use of COS is associated with an increase of estradiol levels. It led to develop protocols using Tamoxifene or Letrozole combined with FSH to protect patients of the potential deleterious effects of the COS. We are currently conducting a study: PRESAGE, the first French prospective multicenter feasibility study of fertility preservation by COS combined with Tamoxifene and oocyte +/- embryo cryopreservation before neoadjuvant (NAC) or adjuvant (AC) chemotherapy for breast cancer. Material and method: Prospective multicenter study for patients of less than 40 years, with a breast cancer for whom a treatment of NAC or AC is indicated and who wish to preserve their fertility. The main objective: To evaluate the feasibility of a COS associating Tamoxifène with FSH followed by an oocyte more and less embryo cryopreservation. The secondary objectives: evaluation of the average deadline prior to the beginning of the chemotherapy, the impact of the type of COS (depending on the phase of the menstrual cycle, conventional-start or random-start COS protocol) on the number and the quality of oocytes harvested. Statistical analysis was performed using BiostaTGV software. Results: The 50 first patients were included between February 2014 and May 2016. Mean age of the patients was 31 years, half of it was nulliparous (25/50) and 20 % (10/50) were single. They presented mainly SBR II (23/50, 46 %) or III (25/50, 50 %) lesions, ER + (34/50, 68 %). 13 patients benefited from a NAC and 37 of an AC. In the NAC group, the time between the first oncologist's consultation and the fertility specialist's consultation was 3,5 +/- 3,9 days and the time between the first oncologist's consultation and the beginning of the chemotherapy was 24,5 +/- 6 days. The success rate of the COS procedure was 88 % (44/50) with no significant difference between the groups according to the type of COS (conventional-start vs. random-start p = 0.61) but there was a significant difference according to the type of chemotherapy (AC vs. NAC p= 0,03). In the 44 patients who had oocyte retrieval, the number of oocytes was 11,6 +/- 6,3 and an IVF was performed with 11,3% of patients (5/44) with 5,4 +/- 4,6 embryos obtained. We have found no impact of the type of chemotherapy or the type of COS on the number of oocytes or embryos preserved. Conclusion: with an 88% success rate, our study suggests that COS with Tamoxifene and FSH is feasible before adjuvant or neoadjuvant chemotherapy with less success in this context but without any impact on the number of oocytes collected. We hope that these preliminary results will be confirmed at the end of the study. Citation Format: Bordes V, Frick C, Leperlier F, Dezellus A, De Blay P, Maigne F, Sauterey B, Augereau P, Lefeuvre-Plesse C, Campone M, Mirallie S. PRESAGE : Prospective multicenter feasibility study of fertility preservation before neoadjuvant or adjuvant chemotherapy for breast cancer: Preliminary results [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-03.

Gonadotropin-releasing hormone agonist trigger increases the number of oocytes and embryos available for cryopreservation in cancer patients undergoing ovarian stimulation for fertility preservation

To compare the oocyte and embryo yield associated with GnRH-agonist triggers vs. hCG triggers in cancer patients undergoing controlled ovarian stimulation (COS) for fertilization preservation. Retrospective cohort study. Academic center. Cancer patients undergoing COS with letrozole and gonadotropins or gonadotropin-only protocols for oocyte or embryo cryopreservation. Gonadotropin-releasing hormone agonist or hCG trigger. Number of metaphase II (MII) oocytes or two-pronuclei (2PN) embryos available for cryopreservation were primary outcomes. Separate multivariate linear regression models were used to assess the effect of trigger type on the primary outcomes, after controlling for confounders of interest. A total of 341 patients were included, 99 (29.0%) in the GnRH-agonist group and 242 (71%) in the hCG group. There was no difference in the baseline demographics of patients receiving GnRH-agonist or hCG triggers. Within the letrozole and gonadotropins group (n = 269), the number (mean ± SD, 11.8 ± 5.8 vs. 9.9 ± 6.0) and percentage of MII oocytes (89.6% vs. 73.0%) available for cryopreservation was higher with GnRH-agonist triggers compared with hCG triggers. Similar results were noted with GnRH-agonist triggers in the gonadotropin-only group (n = 72) (i.e., a higher number [13.3 ± 7.9 vs. 9.3 ± 6.0] and percentage of MII oocytes [85.7% vs. 72.8%] available for cryopreservation). Multivariate linear regression demonstrated approximately three more MII oocytes and 2PN embryos available for cryopreservation in the GnRH-agonist trigger group, irrespective of cancer and COS protocol type. Utilization of a GnRH-agonist trigger increases the number of MII oocytes and 2PN embryos available for cryopreservation in cancer patients undergoing COS for fertility preservation.

Dual ovarian stimulation and random start in assisted reproductive technologies: from ovarian biology to clinical application.

The opportunity to use gonadotropins to stimulate the growth of antral follicles coming from different follicular waves available in different moment of the menstrual cycle allowed the implementation of innovative protocols in assisted reproductive technologies. The purpose of this review is to explore the possible advantages related to these new controlled ovarian stimulation (COS) strategies. Women exhibit major and minor wave patterns of ovarian follicular development during the menstrual cycle, as it is in animal species. These observations led to the introduction of two new strategies for COS: the random start and the double ovarian stimulation within a single menstrual cycle. The use of gonadotropin-releasing hormone antagonist COS protocols, started randomly at any day of the menstrual cycle, is today a standard procedure in those cases where obtaining oocytes is an urgent task, such as in case of fertility preservation for malignant diseases or other medical indications.On the other hand, in poor prognosis patients, double ovarian stimulation has been suggested with the aim of maximizing the number of oocytes retrieved within a single menstrual cycle and, in turn increasing the chance to obtain a reproductively competent embryo. Randomized control trials are necessary to confirm these preliminary findings.

Concomitant use of FSH and low-dose recombinant hCG during the late follicular phase versus conventional controlled ovarian stimulation for intracytoplasmic sperm injection cycles

The objective of this study was to investigate the effects of low-dose hCG supplementation on ICSI outcomes and controlled ovarian stimulation (COS) cost. Three hundred and thirty patients undergoing ICSI were split into groups according to the COS protocol: (i) control group (n = 178), including patients undergoing conventional COS treatment; and (ii) low-dose hCG group (n = 152), including patients undergoing COS with low-dose hCG supplementation. Lower mean total doses of FSH administered and higher mean oestradiol level and mature oocyte rates were observed in the low-dose hCG group. A significantly higher fertilization rate, high-quality embryo rate and blastocyst formation rate were observed in the low-dose hCG group as compared to the control group. The miscarriage rate was significantly higher in the control group compared to the low-dose hCG group. A significantly lower incidence of OHSS was observed in the low-dose hCG group. There was also a significantly lower gonadotropin cost in the low-dose hCG group as compared to the control group ($1235.0 ± 239.0×$1763.0 ± 405.3, p < 0.001). The concomitant use of low-dose hCG and FSH results in a lower abortion rate and increased number of mature oocytes retrieved, as well as improved oocyte quality, embryo quality and blastocyst formation and reduced FSH requirements.

A specific controlled ovarian stimulation (COS) protocol for fertility preservation in women with breast cancer undergoing neoadjuvant chemotherapy.

Aim of the studyThe authors present a novel and specific controlled ovarian stimulation protocol for fertility preservation in women with estrogen-positive receptor breast cancer undergoing neoadjuvant chemotherapy. The protocol foresees random start ovarian stimulation and the use of letrozole associated to tamoxifen.Material and methodsForty breast cancer patients were included in the study. COS was performed either with recombinant FSH or hMG. Concomitantly with COS, letrozole in a dose of 5 mg and tamoxifen in a dose of 20 mg were given orally on a daily basis. The trigger was performed with 0.2 mg of triptorelin, in the presence of follicles ≥ 19 mm. Oocyte retrieval was scheduled 35–36 hours after triptorelin injection. Our main outcome measures were the number of oocytes collected and number of oocytes vitrified, the length of ovarian stimulation, total dose of gonadotropins administered, and levels of estradiol on the day of the trigger.ResultsThe mean age of patients was 30.43 ±4.25 years. Nineteen women commenced COS in the luteal phase, eleven in the early follicular phase and ten in the late follicular phase. The mean number of collected oocytes was 11.78 ±9.12 and the mean number of vitrified oocytes was 9.72 ±7.36. The mean duration of COS was 10.03 ±1.33 days. The mean estradiol concentrations on the triggering day was 623.10 ±441.27, and the mean dose of gonadotropins administered was 2540 ±713.10.ConclusionsThe authors suggest that the protocol is efficient and may be a safe option for oocyte vitrification in these patients.

Methods of controlled ovarian stimulation for embryo/oocyte cryopreservation in breast cancer patients

ABSTRACTIntroduction: Controlled ovarian stimulation (COS) is a crucial step before oocyte collection and subsequent embryo/oocyte cryopreservation. However, in young breast cancer patients, the need for COS raises specific issues that should be taken into account during oncofertility counseling.Areas covered: We aim to perform an overview of COS protocols with a specific focus on the current knowledge and clinical challenges related to their use in young breast cancer patients.Expert commentary: Many protocols for COS are currently available to induce multiple follicular recruitment and maximize oocyte retrieval in women undergoing in vitro fertilization treatment. In cancer patients, to avoid the need to wait for a spontaneous menstruation, emergency protocols are also available so that COS can be started at any time during the menstrual cycle. COS protocols with the addition of tamoxifen or letrozole have been specifically designed for breast cancer patients to limit the potential negative impact of th...

Timing should no longer be an obstacle to oocyte cryopreservation in patients with cancer.

Anticancer treatment-related infertility is preventable with oocyte cryopreservation, but this is often not considered a relevant issue, due to lack of knowledge and time. The aim of this study is to prove that adequate organization of an Oncofertility Unit and the use of new protocols for controlled ovarian stimulation (COS) can reduce the time required by the procedure, encouraging consultants and patients to preserve fertility before gonadotoxic treatments. A total of 125 patients diagnosed with malignant tumors were referred to the Oncofertility Unit of San Raffaele Hospital: 52 patients between April 2011 and October 2013 and 73 patients between October 2013 and November 2015. The 2 periods differ in office organization and type of COS protocol used. Between the 2 periods, a reduction in the mean number of days required from first counseling to the initiation (6.45 ± 1.058 vs 1.61 ± 0.228) and the end of the COS (17.83 ± 1.227 vs 13.70 ± 0.393) was observed (p<0.0001). No differences exist in the groups between the mean time required to complete COS (11.38 ± 0.360 vs 12.17 ± 0.309; p = 0.11) and mean number of frozen oocytes (8.458 ± 1.060 vs 10.30 ± 0.919; p = 0.22). Furthermore, in the second period, the number of patients who accepted fertility preservation increased (46.15% vs 64.38%; p<0.05). Renewed organization of the Oncofertility Unit and the newest random-start COS protocol allowed us to shorten the time for oocyte cryopreservation and start anticancer treatment on time.

Individualization of controlled ovarian stimulation in vitro fertilization using markers of ovarian reserve: a systematic review

IntroductionThe main objective of individualization of treatment in IVF is to offer every single woman the best treatment tailored to her own unique characteristics, thus maximizing the chances of pregnancy and eliminating the iatrogenic and avoidable risks resulting from ovarian stimulation. Personalization of treatment in IVF should be based on the prediction of ovarian response. ObjectiveTo summarize the predictive ability of ovarian reserve markers, and the therapeutic strategies that have been proposed in IVF after this prediction. MethodsA systematic review of the existing literature was performed by searching Medline, LILACS, SciELO and Pubmed, for publications related to ovarian reserve markers and their incorporation into controlled ovarian stimulation (COS) protocols in IVF. Results251 articles were found. Ten articles published between 2010 and 2015 were selected. ConclusionAntral follicle count (AFC) and anti-Mullerian hormone (AMH), the most sensitive markers of ovarian reserve, are ideal in planning personalized COS protocols. These markers permit prediction of the ovarian response with reliable accuracy. Following the categorization of expected ovarian response clinicians can adopt tailored therapeutic strategies for each patient.