Ai

Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles.

OBJECTIVE To explore the feasibility of luteal-phase ovarian stimulation using hMG and letrozole in terms of ovarian response and pregnancy outcome using frozen-thawed embryo transfer. DESIGN A prospective cohort study. SETTING Academic tertiary-care medical center. PATIENT(S) Two hundred forty-two female patients undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment. INTERVENTION(S) Ovarian stimulation was initiated with hMG 225 IU and letrozole 2.5 mg daily after spontaneous ovulation. Letrozole administration was stopped when the dominant follicles reached diameters of 12 mm. Ovulation was induced with a GnRH agonist 100 μg when at least three follicles reached diameters of 18 mm or one dominant follicle reached 20 mm. The highest quality embryos were extracted and cryopreserved for later transfer. MAIN OUTCOME MEASURE(S) The primary outcome measured was the number of oocytes retrieved. Secondary outcomes were the clinical pregnancy rate, ongoing pregnancy rate, and implantation rate after frozen embryo transfer (FET) cycles. RESULT(S) Of the 242 women enrolled in the study, all participants succeeded in producing oocytes and 227 women had highest-quality embryos to cryopreserve. The average number of oocytes retrieved was 13.1, producing an average of 4.8 highest quality embryos. Moreover, no cases experienced a premature LH surge or moderate/severe ovarian hyperstimulation syndrome during the stimulation cycles. In FETs, the clinical pregnancy rate, ongoing pregnancy rate, and implantation rate were 55.46% (127/229), 48.91% (112/229), and 40.37% (174/431), respectively. Of all the pregnancies in the study, 68 resulted in live births and 44 were ongoing. CONCLUSION(S) Luteal-phase ovarian stimulation is feasible for producing competent oocytes/embryos in women undergoing IVF/ICSI treatments, with optimal pregnancy outcomes in FET cycles.

Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol)

Previous studies have shown that existing antral follicles in the luteal phase enable ovarian stimulation. In a pilot study, the efficacy of double stimulations during the follicular and luteal phases in women with poor ovarian response was explored (defined according to the Bologna criteria). Thirty-eight women began with mild ovarian stimulation. After the first oocyte retrieval, human menopausal gonadotrophin and letrozole were administrated to stimulate follicle development, and oocyte retrieval was carried out a second time when dominant follicles had matured. The primary outcome measured was the number of oocytes retrieved: stage one 1.7 ± 1.0; stage two 3.5 ± 3.2. From the double stimulation, 167 oocytes were collected and 26 out of 38 (68.4%) succeeded in producing one to six viable embryos cryopreserved for later transfer. Twenty-one women underwent 23 cryopreserved embryo transfers, resulting in 13 clinical pregnancies. The study shows that double ovarian stimulations in the same menstrual cycle provide more opportunities for retrieving oocytes in poor responders. The stimulation can start in the luteal phase resulting in retrieval of more oocytes in a short period of time. This offers new hope for women with poor ovarian response and newly diagnosed cancer patients needing fertility preservation.

Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization

OBJECTIVE To investigate the use of medroxyprogesterone acetate (MPA) to prevent LH surge during controlled ovarian hyperstimulation (COH) and to compare cycle characteristics and pregnancy outcomes in subsequently frozen-thawed ET (FET) cycles. DESIGN A prospective controlled study. SETTING Tertiary-care academic medical center. PATIENT(S) Three hundred patients undergoing IVF/intracytoplasmic sperm injection treatment. INTERVENTION(S) In the study group, hMG and MPA were administered simultaneously beginning on cycle day 3. Ovulation was induced with a GnRH agonist or cotriggered by a GnRH agonist and hCG when dominant follicles matured. A short protocol was used in the control group. Viable embryos were cryopreserved for later transfer in both protocols. MAIN OUTCOME MEASURE(S) The primary outcome measure was the number of oocytes retrieved. Secondary outcomes included the number of mature oocytes, the incidence of premature LH surge, and clinical pregnancy outcomes from FETs. RESULT(S) The number of oocytes retrieved in the study group was similar to those in the controls (9.9 ± 6.7 vs. 9.0 ± 6.0), and higher doses of hMG were administered. In the study group, LH suppression persisted during ovarian stimulation, and the incidence of premature LH surge was 0.7% (1/150). No statistically significant differences were found in the clinical pregnancy rates (47.8% vs. 43.3%), implantation rates (31.9% vs. 27.7%), and live-birth rates (42.6% vs. 35.5%) in the study group and controls. CONCLUSION(S) The results show that MPA is an effective oral alternative for the prevention of premature LH surge in woman undergoing COH. This finding will help establish a new regimen for ovarian stimulation in combination with embryo cryopreservation. CLINICAL TRIAL REGISTRATION NUMBER ChiCTR-ONRC-14004419.

Comparison of live-birth defects after luteal-phase ovarian stimulation vs. conventional ovarian stimulation for in vitro fertilization and vitrified embryo transfer cycles

OBJECTIVE To assess live-birth defects after a luteal-phase ovarian-stimulation regimen (LPS) for in vitro fertilization (IVF) and vitrified embryo transfer (ET) cycles. DESIGN Retrospective cohort study. SETTING Tertiary-care academic medical center. PATIENT(S) Infants who were born between January 1, 2013 and May 1, 2014 from IVF with intracytoplasmic sperm injection (ICSI) treatments (n = 2,060) after either LPS (n = 587), the standard gonadotropin-releasing hormone-agonist (GnRH-a) short protocol (n = 1,257), or mild ovarian stimulation (n = 216). INTERVENTION(S) The three ovarian-stimulation protocols described and assisted reproductive technology (ART) treatment (IVF or ICSI, and vitrified ET) in ordinary practice. MAIN OUTCOME MEASURE(S) The main measures were: gestational age, birth weight and length, multiple delivery, early neonatal mortality, and birth defects. Associations were assessed using logistic regression by adjusting for confounding factors. RESULT(S) The final sample included 2,060 live-born infants, corresponding to 1,622 frozen-thawed (FET) cycles, which led to: 587 live-born infants from LPS (458 FET cycles); 1,257 live-born infants from the short protocol (984 FET cycles); and 216 live-born infants from mild ovarian stimulation (180 FET cycles). Birth characteristics regarding gestational age, birth weight and length, multiple delivery, and early neonatal death were comparable in all groups. The incidence of live-birth defects among the LPS group (1.02%) and the short GnRH-a protocol group (0.64%) was slightly higher than in the mild ovarian-stimulation group (0.46%). However, none of these differences reached statistical significance. For congenital malformations, the risk significantly increased for the infertility-duration factor and multiple births; the adjusted odds ratios were 1.161 (95% confidence interval [CI]: 1.009-1.335) and 3.899 (95% CI: 1.179-12.896), respectively. No associations were found between congenital birth defects and various ovarian-stimulation regimens, maternal age, body mass index, parity, insemination method, or infant gender. CONCLUSION(S) To date, the data do not indicate an elevated rate of abnormality at birth after LPS, but further study with larger populations is needed to confirm these results. However, infertility itself poses a risk factor for congenital malformation. A higher likelihood of birth defects in multiple births may lead couples to favor elective, single ET; couples undertaking ART should be made aware of the known increased birth defects associated with a twin birth.

Luteal-phase ovarian stimulation vs conventional ovarian stimulation in patients with normal ovarian reserve treated for IVF: a large retrospective cohort study.

We have previously reported a new luteal‐phase ovarian stimulation (LPS) strategy for infertility treatment. The purpose of this study was to systematically assess the efficiency and safety of this strategy by comparing it with conventional ovarian stimulation protocols.

Elevated progesterone on the trigger day does not impair the outcome of Human Menotrophins Gonadotrophin and Medroxyprogesterone acetate treatment cycles.

To demonstrate the incidence and effects of elevated progesterone (P) on the trigger day on the outcome of in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles using Medroxyprogesterone acetate (MPA) co-treated with Human Menotrophins Gonadotrophin (hMG + MPA), we performed a retrospective analysis including 4106 IVF/ICSI cycles. The cycles were grouped according to the P level on the trigger day: <1 ng/mL, between 1–1.5 ng/ml (including 1), between 1.5–2 ng/mL (including 1.5), and ≥2 ng/mL. The primary outcome measure was live birth rate. The prevalence of P level categories was 12.93% (531/4106), 2.92% (120/4106), and 1.92% (79/4106) in women with P between 1–1.5 ng/mL, between 1.5–2 ng/mL, and ≥2 ng/mL, respectively. The mean stimulation duration, total hMG dose, serum follicle stimulating hormone (FSH), estrogen(E2) on the trigger day and the number of oocytes in patients with elevated P were significantly higher than patients with P < 1 ng/mL (P < 0.05). However, there were no significant differences in the oocyte retrieval rates, fertilization rates, implantation rates, clinical pregnancy rates and live birth rates between the groups based on frozen embryo transfer (FET). We concluded that elevated P on the trigger day had no negative effect on the final outcome of the hMG + MPA treatment cycles based on FET.

Combined 17β-Estradiol with TCDD Promotes M2 Polarization of Macrophages in the Endometriotic Milieu with Aid of the Interaction between Endometrial Stromal Cells and Macrophages

The goal of this study is to elucidate the effects of 17β-estradiol and TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) on macrophage phenotypes in the endometriotic milieu. Co-culture of endometrial stromal cells (ESCs) and U937 cells (macrophage cell line) was performed to simulate the endometriotic milieu and to determine the effects of 17β-estradiol and/or TCDD on IL10, IL12 production and HLA-DR, CD86 expression by U937 macrophages. We found that combining 17β-estradiol with TCDD has a synergistic effect on inducing M2 activation when macrophages are co-cultured with ESCs. Moreover, the combination of 17β-estradiol and TCDD significantly enhanced STAT3 and P38 phosphorylation in macrophages. Differentiation of M2 macrophages induced by 17β-estradiol and TCDD were effectively abrogated by STAT3 and P38MAPK inhibitors, but not by ERK1/2 and JNK inhibitors. In conclusion, 17β-estradiol and TCDD in the ectopic milieu may lead to the development of endometriosis by inducing M2 polarization of macrophages through activation of the STAT3 and P38MAPK pathways.

Dual trigger for final oocyte maturation improves the oocyte retrieval rate of suboptimal responders to gonadotropin-releasing hormone agonist

OBJECTIVE To identify the risk factors for suboptimal response to GnRH agonist (GnRH-a) trigger and evaluate the effect of hCG on the outcome of patients with suboptimal response to GnRH-a. DESIGN A retrospective data analysis. SETTING A tertiary-care academic medical center. PATIENT(S) A total of 8,092 women undergoing 8,970 IVF/intracytoplasmic sperm injection (ICSI) treatment cycles. INTERVENTION(S) All women underwent hMG + medroxyprogesterone acetate (MPA)/P treatment cycles during IVF/ICSI, which were triggered using a GnRH-a alone or in combination with hCG (1,000, 2,000, or 5,000 IU). Viable embryos were cryopreserved for later transfer. MAIN OUTCOME MEASURE(S) The rates of oocyte retrieval, mature oocytes, fertilization, and the number of oocytes retrieved, mature oocytes, and embryos frozen. RESULT(S) In total, 2.71% (243/8,970) of patients exhibited a suboptimal response to GnRH-a. The suboptimal responders (LH ≤15 mIU/mL) had a significantly lower oocyte retrieval rate (48.16% vs. 68.26%), fewer mature oocytes (4.10 vs. 8.29), and fewer frozen embryos (2.32 vs. 3.54) than the appropriate responders. Basal LH levels served as the single most valuable marker for differentiating suboptimal responders with the areas under the receiver operating curve of 0.805. Administering dual trigger (GnRH-a and hCG 1,000, 2,000, 5,000 IU) significantly increased oocyte retrieval rates (60.04% vs. 48.16%; 68.13% vs. 48.16%; and 65.76% vs. 48.16%, respectively) in patients with a suboptimal response. CONCLUSION(S) Basal LH level was useful predictor of the suboptimal response to GnRH-a trigger. Administrating dual trigger including 1,000 IU hCG for final oocyte maturation could improve the oocytes retrieval rate of GnRH-a suboptimal responder.

New application of dydrogesterone as a part of a progestin-primed ovarian stimulation protocol for IVF: a randomized controlled trial including 516 first IVF/ICSI cycles

STUDY QUESTION Can dydrogesterone (DYG) be used as an alternative progestin in a progesterone primed ovarian stimulation (PPOS) protocol? SUMMARY ANSWER DYG can be used as an appropriate alternative progestin in a PPOS protocol. WHAT IS KNOWN ALREADY PPOS is a new ovarian stimulation regimen based on a freeze-all strategy that uses progestin as an alternative to a GnRH analog for suppressing a premature LH surge during the follicular phase. Medroxyprogesterone acetate (MPA) has been successfully used as an adjuvant to gonadotrophin in the PPOS protocol. However, the use of MPA may lead to stronger pituitary suppression and thus may require a higher dosage of hMG and a longer duration of ovarian stimulation than that of conventional ovarian stimulation protocol. STUDY DESIGN SIZE, DURATION A prospective RCT including 516 patients was performed between November 2015 and November 2016. Computerized randomization was conducted to assign participants at a 1:1 ratio into two treatment groups: an hMG + DYG group (260 patients) or an hMG + MPA group (256 patients) followed by IVF or ICSI with the freeze-all strategy. One cycle per patient was included. The primary outcome of the trial was the number of oocytes retrieved. The sample size was chosen to detect a difference of two oocytes with a power of 90%. PARTICIPANTS/MATERIALS, SETTING, METHODS Patients under 36 years of age with normal ovarian reserve who were undergoing their first IVF/ICSI procedure due to tubal factor infertility were randomized into two groups based on the oral progestin protocol used: hMG co-treatment with DYG (hMG + DYG) or hMG co-treatment with MPA (hMG + MPA). The different progestin was simultaneously administered at the beginning of menstrual cycle 3 (MC3). Oocyte maturation was co-triggered by administration of a GnRH agonist and hCG. All viable embryos from both protocols were cryopreserved for later transfer. Only the first frozen embryo transfer (FET) cycle was included in our study. The embryological and clinical outcomes were measured. MAIN RESULTS AND THE ROLE OF CHANCE Basic characteristics, such as age, BMI and infertility duration, in both groups were comparable. There was no significant difference in the number (mean ± SD) of oocytes retrieved [10.8 ± 6.3 for the hMG + DYG group versus 11.1 ± 5.8 for the hMG + MPA group, P = 0.33] or the oocyte retrieval rate [74.3 ± 19.6% for the hMG + DYG group versus 75.0 ± 19.5% for the hMG + MPA group, P = 0.69] between the groups. The viable embryo rate per oocyte retrieved did not differ between the two groups [odds ratio (OR): 1.08, 95% CI: 0.97-1.21, P = 0.16]: 37.4% (1052/2815) for the hMG + DYG group versus 35.6% (1009/2837) for the hMG + MPA group. During the whole process of ovarian stimulation, the mean LH level in the hMG + DYG group was always higher than that in the hMG + MPA group (P < 0.001); however, no patient from either group experienced a premature LH surge. In addition, no patients experienced moderate or severe ovarian hyperstimulation syndrome during the ovarian stimulation. No significant difference was found in the clinical pregnancy rate of the first FET cycle between the two groups (OR: 0.82, 95% CI: 0.56-1.21, P = 0.33): 57.6% for the hMG + DYG group (125/217) versus 62.3% for the hMG + MPA group (132/212). LIMITATIONS REASONS FOR CAUTION The patients and physician were not blinded to the study. Further, a large proportion of patients were still pregnant at the end of the clinical trial, therefore live birth rates were not observed in the follow-up period. The dose-effectiveness of DYG administration was not addressed in the trial design. WIDER IMPLICATIONS OF THE FINDINGS DYG, which exhibits no or only weak inhibition of ovulation in normal dosage, can serve as an hMG adjuvant during ovarian stimulation. This finding suggests the possibility of a new application of DYG: as an appropriate alternative progestin for a PPOS protocol in IVF. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by The National Nature Science Foundation of China (Grant no. 81503603), Shanghai Three-year Plan on Promoting TCM Development (Grant no. ZY3-LCPT-2-2006) and the Natural Science Foundation of Shanghai (Grant nos. 15401932700 and 15ZR1424900). None of the authors declare any conflict of interest. TRIAL REGISTRATION NUMBER Chictr.org.cn: ChiCTR-IPR-15007251. TRIAL REGISTRATION DATE Chictr.org.cn: 22 October 2015. DATE OF FIRST PATIENT’S ENROLLMENT 1 November 2015.

Progestin-primed ovarian stimulation with or without clomiphene citrate supplementation in normal ovulatory women undergoing in vitro fertilization/intracytoplasmic sperm injection: A prospective randomized controlled trial

To compare the endocrinological profiles, cycle characteristics and pregnancy outcomes of progestin‐primed ovarian stimulation (PPOS) with or without clomiphene citrate (CC) supplementation in normal ovulatory women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).