Aggressive sperm immobilization improves reproductive outcomes in patients with suboptimal semen parameters and previous ICSI fertilization failure.

Intracytoplasmic sperm injection (ICSI) is the most effective procedure to resolve male infertility, enhancing overall fertilization and pregnancy outcomes. However, it is important to note that fertilization failure (FF) can still occur in a few cases after ICSI. This study aims to introduce a specialized technique of aggressive sperm immobilization for ICSI and evaluate its impact on reproductive outcomes in cases involving prior fertilization failure. All infertile couples with male partners having suboptimal semen samples and previous ICSI fertilization failure were evaluated using retrospective data from National Taiwan tertiary university hospital (NTUH) between January 2016 and February 2022. Fertilization failure in our study was defined as less than 30% fertilization rate (FR, the number of normally fertilized oocytes divided by the total number of injected mature oocytes). Data involving both standard (routine procedure) and aggressive sperm immobilization (SI) techniques during different ICSI cycles were included in this study. Standard and aggressive SI methods were performed by compressing the distal half tail of the spermatozoa ≦ 5 and 15 times prior to ICSI respectively. Generalized estimating equations analysis were applied to compare the clinical outcomes between two procedures. Overall, data from 23 infertile couples who had undergone 65 ICSI cycles (31 standard SI with low fertilization rate and 34 aggressive SI) were included in the study. The average FR in the ICSI cycles with standard SI and aggressive SI were 23.6 ± 23.1% and 49.5 ± 31.8 respectively (P = 0.0002). The majority of embryos were transferred at the day 3 stage, with an average number transferred of 2.6 ± 0.9 in the aggressive SI group and 1.9 ± 0.9 in the standard group. The number of embryos transferred per transfer cycle was higher in the aggressive SI (P = 0.015), whereas the number of good-quality embryos was similar between the two procedures (P = 0.44). There were one and seven live births from the standard SI cycles and aggressive SI cycles respectively. In conclusion, aggressive SI was associated with a significantly higher FR, resulting in more available embryos for transfer without compromising embryo quality. Therefore, this specialized technique improved pregnancy outcome among infertile couples with a previous ICSI-FF. It can be a safe, economic, and effective method to improve the assisted reproductive technologies outcomes for infertile patients affected by previous ICSI-FF.

Risk of placenta accreta spectrum following myomectomy: a nationwide cohort study.

BACKGROUND: Whether myomectomy increases the risk of placenta accreta spectrum in the following pregnancies remains controversial. OBJECTIVE: This study aimed to investigate the effect of myomectomy on the risk of placenta accreta spectrum in the following pregnancies. Moreover, different methods of myomectomy on the risk of placenta accreta spectrum were explored. STUDY DESIGN: A nationwide cohort study was conducted using data from the Taiwan National Health Insurance Research Database, including all pregnant patients in Taiwan who gave birth between January 2008 and December 2017. A 1:1 propensity score estimation matching was performed for the analysis of myomectomy on the risk of placenta accreta spectrum. Among pregnant patients who received myomectomy, different methods of myomectomy on the risk of placenta accreta spectrum were compared with the control group. RESULTS: Among the 1,371,458 pregnant patients in this study, 11,255 pregnant patients had a history of myomectomy. The risk of placenta accreta spectrum was higher in pregnant patients with a history of myomectomy than in pregnant patients without a history of myomectomy (incidence: 0.96% vs 0.20%; adjusted odds ratio, 2.28; 95% confidence interval, 1.85-2.81; P<.01). Among pregnant patients with a history of myomectomy, 5045 (46.87%) received laparotomic myomectomy, 3973 (36.93%) received laparoscopic myomectomy, and 1742 (16.20%) received hysteroscopic myomectomy. The incidence of placenta accreta spectrum was higher in the hysteroscopic group than in the laparotomic group or the laparoscopic group (1.89% [hysteroscopic group] vs 0.71% [laparotomic group] and 0.81% [laparoscopic group]; P<.05). Compared with patients without a history of myomectomy, the adjusted odds ratio for placenta accreta spectrum was 3.88 (95% confidence interval, 2.68-5.63; P<.05) in the hysteroscopic group. CONCLUSION: Myomectomy, especially hysteroscopic myomectomy, is associated with an increased risk of placenta accreta spectrum in the subsequent pregnancy.

Association between estradiol levels in early pregnancy and risk of preeclampsia after frozen embryo transfer.

Introduction: The failure of remodeling the spiral arteries is associated with the pathogenesis of preeclampsia. Estradiol (E2) plays a crucial role in placentation and may be involved in the development of preeclampsia. However, there is a lack of data in this area. This study aims to assess the association between serum estradiol levels in early pregnancy and the risk of preeclampsia. Methods: We conducted a retrospective cohort study on patients who conceived after frozen embryo transfer (FET) using data from a database at a university-affiliated in vitro fertilization center. The study period spanned from January 1, 2010, to December 31, 2020. Multivariable logistic regression analyses were performed to determine the adjusted effect of E2 levels on the risk of preeclampsia. We compared the odds ratios of preeclampsia across quartiles of E2 levels and assessed their significance. Results: Serum E2 levels at the fifth gestational week were significantly different between women with and without preeclampsia after FET programmed cycles (607.5 ± 245.4 vs. 545.6 ± 294.4 pg/ml, p=0.009). A multivariable logistic regression model demonstrated that E2 levels in early pregnancy were independent risk factors for preeclampsia. We observed an increased odds ratio of preeclampsia with increasing quartiles of estradiol levels after adjusting for potential confounders in FET programmed cycles. When comparing quartiles 3 and 4 (E2 > 493 pg/ml at the fifth gestational week) to quartiles 1 and 2, the odds ratios of preeclampsia were significantly higher. Conclusion: We found that serum E2 levels in early pregnancy may impact the risk of preeclampsia, particularly following FET programmed cycles. The association between E2 levels in early pregnancy and preeclampsia deserves further investigation.

The value of LH maximum level in predicting optimal oocyte yield following GnRH agonist trigger.

Background: Risk factors associated with a suboptimal response to Gonadotropin-releasing hormone (GnRH) agonists include a high or low body mass index (BMI), prolonged use of oral contraceptive pills, and low luteinizing hormone (LH) levels on either the start or trigger days of controlled ovarian stimulation (COS). However, this approach may increase the need for a dual trigger and may also result in a higher incidence of ovarian hyperstimulation syndrome (OHSS) in hyper-responders. We aimed to investigate whether the maximum LH level during stimulation can serve as a predictive factor for achieving an optimal oocyte yield using the GnRH agonist trigger alone. Methods: We retrospectively reviewed all antagonist protocols or progestin-primed ovarian stimulation (PPOS) protocols triggered with GnRH agonist only between May 2012 and December 2022. Subjects were divided into three groups, depending on basal LH level and LH maximum level. The freeze-all strategy was implemented in all cycles: Group 1, consistently low LH levels throughout COS; Group 2, low basal LH level with high LH max level during COS; Group 3, consistently high LH levels throughout COS. The primary outcome was the oocyte yield rate. The secondary outcome includes the number of collected oocytes, suboptimal response to GnRH agonist trigger, oocyte maturity rate, fertilized rate, clinical pregnancy rate, ongoing pregnancy rate, and live birth rate. The pregnancy outcomes were calculated for the first FET cycle. Results: Following confounder adjustment, multivariable regression analysis showed that Group 1 (cycles with consistently low LH levels throughout COS) remains an independent predictor of suboptimal response (OR: 6.99; 95% CI 1.035-47.274). Group 1 (b = -12.72; 95% CI -20.9 to -4.55) and BMI (b = -0.25; 95% CI -0.5 to -0.004) were negatively associated with oocyte yield rate. Patients with low basal LH but high LH max levels had similar clinical outcomes compared to those with high LH max levels through COS. Conclusions: The maximum LH level during COS may serve as an indicator of LH reserve and could be a more reliable predictor of achieving an optimal oocyte yield when compared to relying solely on the basal LH level. In the case of hyper-responders where trigger agents (agonist-only or dual trigger) are being considered, we propose a novel strategy that incorporates the maximum LH level, rather than just the basal or trigger-day LH level, as a reference for assessing LH reserve. This approach aims to minimize the risk of obtaining suboptimal oocyte yield and improve overall treatment outcomes.

Disordered hypothalamus-pituitary-ovary axis in heterotopic extraovarian sex cord-stromal proliferation: a case report of fallopian tube serous adenofibroma.

BACKGROUND: Fallopian tube serous adenofibromas are uncommon tumors of the female genital tract, only dozens of cases have ever been reported. Earlier study indicated that they might be derived from embryonic remnants of the Müllerian duct. Clinical presentation of these tumors is usually asymptomatic. Small cysts of 0.5-3 cm in diameter are mostly incidentally found at the fimbriae end, with coarse papillary excrescences lined by epithelial cells and connective tissue stroma without nuclear pleomorphism or mitosis. CASE PRESENTATION: A 23-year-old woman with normal secondary sexual characters and 46, XX karyotype, presented to the gynecology clinic complaining of irregular menstrual cycles. Laboratory studies reported unique discrepancy of hormone levels; anti-Müllerian hormone (AMH): 6.05 ng/mL (The normal range of AMH is 1.70-5.63 ng/mL in women aged under 35 years old), follicle stimulating hormone (FSH): 31.9 mIU/mL (reference range: 3.85-8.78, follicular phase; 4.54-22.51, ovulatory phase; 1.79-5.12, luteal phase; 16.74-113.59, menopause), and luteinizing hormone (LH): 52.0 mIU/mL (reference range: 2.12-10.89, follicular phase; 19.18-103.03, ovulatory phase; 1.20-12.86, luteal phase; 10.87-58.64, menopause), mimicking gonadotropin-resistant ovary syndrome. The ultrasound reported a right adnexal cyst of 10.4 × 7.87 × 6.7 cm. Laparoscopic evaluation was performed; pathology revealed serous adenofibroma of the fallopian tube with ovarian stroma contents. Heterotopic extraovarian sex cord-stromal proliferations was most probable. The patient's hormone levels returned to the reproductive status two weeks after surgery; FSH: 7.9 mIU/mL, LH: 3.59 mIU/mL,and AMH: 4.32 ng/mL. The patient's menstrual cycles have resumed to normal for over two years after removal of the fallopian tube cyst. CONCLUSIONS: This case of fallopian tube serous adenofibromas presented a discrepancy of serum AMH and FSH mimicking gonadotropin-resistant ovary syndrome. The clinical picture derived from heterotopic extraovarian sex cord-stromal proliferation indicated a disordered hypothalamus-pituitary-ovary axis.

Aggressive Cervical Dilation Exploits Potential Weakness in the Septum of Duplicated Cervix during Hysteroscopic Cervix-preserving Metroplasty of Complete Septate Uterus: A Cohort Study.

STUDY OBJECTIVE: To evaluate whether aggressive cervical dilation is effective for creating the initial perforation between noncommunicating cavities of the complete septate uterus (CSU), which serves as the first step of hysteroscopic cervix-preserving metroplasty (CPM). DESIGN: A retrospective cohort. SETTING: A tertiary referral center. PATIENTS: Fifty-three patients with CSU were diagnosed using vaginal examinations, combined two- and three-dimensional vaginal ultrasounds, and office-based hysteroscopies. INTERVENTIONS: Patients who had received hysteroscopic CPM with the initial perforation created by aggressive cervical dilation or by the traditional method of bougie-guided incisions were compared. MEASUREMENTS AND MAIN RESULTS: Of the 53 patients with CSU, 44 patients received hysteroscopic CPM that required the creation of a perforation. Patients who received aggressive cervical dilation for creation of the perforation had nonsignificantly shorter surgical times (33.5 minutes, 95% confidence interval [CI], 28.4-38.6 vs 48.7 minutes, 95% CI, 28.2-71.3, p = .099), used significantly lower volumes of distending media (3.6 liters, 95% CI, 3.1-4.1 vs 6.8 liters, 95% CI, 4.2-9.3, p <.001), and had higher success rates (84.4%, 95% CI, 67.2-94.7 vs 50.0%, 95% CI, 21.1-78.9, p = .019). The sites of perforation all occurred on the endocervical septum and were generally fibrous and avascular. CONCLUSION: We present a novel, effective method for creating the initial perforation in hysteroscopic CPM. The success may be because of the existence of a potential weakness in the septum of the duplicated cervix, which spontaneously tears upon aggressive mechanical dilation. The method forgoes the risks associated with sharp incisions based on potentially unreliable cues and may greatly simplify the procedure.

The role of circulating miRNAs in mechanism of action and prediction of therapeutic responses of metformin in polycystic ovarian syndrome.

OBJECTIVE: To study the involvement of microribonucleic acids (miRNAs) in the pathogenesis of chronic anovulation and mechanism of metformin treatment in polycystic ovary syndrome (PCOS). DESIGN: Case-control and prospective validation cohort study. SETTING: Tertiary university hospital. PATIENT(S): A total of 146 patients with PCOS and chronic anovulation and 20 non-PCOS controls were enrolled. Patients who resumed ovulation after metformin treatment (MET-OV) and remained anovulatory after metformin treatment (MET-AO) were assigned to MET-OV and MET-AO groups, respectively. INTERVENTION(S): All patients with PCOS received metformin treatment for 6 months. MAIN OUTCOME MEASURE(S): Baseline and chronological changes in the plasma levels of 14 miRNAs (miR-21, 93, 132, 193b, 221, 222, 223, 27a, 125b, 200b, 212, 320a, 429, and 483) selected by literature review, anthropometric data, and hormonal as well as metabolic profiles were measured. Predictive modeling based on baseline circulatory miRNA levels and clinical parameters was performed to predict ovulation recovery after metformin treatment. RESULT(S): No significant differences were observed in the baseline hormonal and metabolic profiles between the MET-OV and MET-AO groups. However, the expression of miR-27a, miR-93, and miR-222 was significantly higher in the MET-OV group than that for the MET-AO and control groups. After 6 months of metformin treatment, the levels of insulin, luteinizing hormone, and 6 circulating miRNAs (miR-21, 27a, 93, 221, 222, and 223) and homeostatic model assessment for insulin resistance decreased significantly in the MET-OV group, but remained unchanged in the MET-AO group. The area under curve, sensitivity, and specificity of the adjusted prediction model, based on miRNA levels and clinical parameters using logistic regression analysis for predicting ovulatory response after metformin treatment, were 0.807, 0.892, and 0.632, respectively. CONCLUSION(S): The present study demonstrated a distinct pattern of baseline expression and chronological changes in the levels of several circulatory miRNAs between the MET-OV and MET-AO groups, suggesting that aberrantly overexpressed diabetogenic miRNAs are involved in the pathophysiology of chronic anovulation in PCOS, and their down-regulation might contribute toward the therapeutic effects of metformin. This could provide new insights into the mechanism of action and applicability of individualized metformin therapy in women with PCOS.

Progestin-primed ovarian stimulation versus GnRH antagonist protocol in poor responders: Risk of premature LH surge and outcome of oocyte retrieval.

PURPOSE: For poor ovarian responders (PORs), gonadotropin-releasing hormone (GnRH) antagonist was commonly used for prevention of premature LH surge during controlled ovarian stimulation (COS) over the past two decades. The application of progestin-primed ovarian stimulation (PPOS) recently increased, but the role of PPOS for PORs was uncertain. We aimed to analyze the incidence of premature luteinizing hormone (LH) surge and the outcome of oocyte retrieval among PPOS and GnRH antagonist protocol for PORs. METHODS: This was a single-center retrospective study, which enrolled the PORs (defined by the Bologna criteria) undergoing COS with PPOS or flexible GnRH antagonist protocol during January 2018 to December 2021. We compared the incidence of premature LH surge (LH > 10 mIU/mL) and the outcome of oocyte retrieval between the PPOS group and the GnRH antagonist group. RESULTS: A total of 314 women were recruited, with 54 in the PPOS group and 260 in the GnRH antagonist group. The PPOS group had lower incidence of premature LH surges compared with the GnRH antagonist protocol group (5.6% vs 16.9%, P value 0.035). There was no significant difference between the two groups regarding the number of oocytes retrieved (3.4 vs 3.8, P value 0.066) and oocyte retrieval rates (88.9% vs 88.0%, P value 0.711). CONCLUSION: Compared with PPOS, GnRH antagonist protocol had higher risk of premature LH surges for PORs but may not affect pregnancy rates. PPOS is suitable for oocyte or embryo cryopreservation, but should not totally replace GnRH antagonist protocol for patients undergoing in vitro fertilization (IVF).

Clinical use of aqueous subcutaneous progesterone compared with vaginal progesterone as luteal support in in vitro fertilization: A randomized controlled study in Taiwan.

OBJECTIVE: This study aims to compare the efficacy, tolerability and patient satisfaction between aqueous subcutaneous progesterone (Prolutex, 25 mg/vial; IBSA) and vaginal progesterone (Crinone, 90 mg/tube; Merck) as luteal support for fresh embryo transfers in in-vitro fertilization (IVF). MATERIALS & METHODS: In this prospective randomized study, 65 patients who underwent IVF were recruited and randomly assigned to either the Prolutex (25 mg daily, n = 33) or Crinone (90 mg daily, n = 32) group. The luteal support regimens were given daily, starting from two days after oocyte pickup. If the serum pregnancy test was positive, luteal support was continued until 7 weeks of gestation. Primary outcomes were clinical pregnancy rate and serum progesterone level at the mid-luteal phase and at 4 weeks of gestation. Secondary outcomes were drug tolerability and patient satisfaction assessed by questionnaire. RESULTS: There were no significant differences in clinical pregnancy rates (Prolutex 25.0% versus Crinone 33.3%, p = 0.699), serum progesterone levels and patient satisfaction between Prolutex and Crinone group. Although the patients that had received Prolutex complained of more local pain at the injection sites, they also had less annoying vaginal discharges and vulvar discomforts. CONCLUSION: Prolutex is of comparable efficacy and patient satisfaction to Crinone, and its availability means patients have more options in regards to the routes of progesterone administration as luteal phase support during IVF.

Usage and cost-effectiveness of elective oocyte freezing: a retrospective observational study.

BACKGROUND: The previous model-based cost-effectiveness analyses regarding elective oocyte cryopreservation remained debatable, while the usage rate may influence the cost per live birth. The aim of this study is to disclose the usage and cost-effectiveness of the planned cryopreserved oocytes after oocyte thawing in real-world situations. METHODS: This was a retrospective single-center observational study. Women who electively cryopreserved oocytes and returned to thaw the oocytes were categorized as thawed group. The oocytes were fertilized at our center and the sperm samples for each individual was retrieved from their respective husbands. Clinical outcomes were traced and the cumulative live birth rate per thawed case was calculated. The costs from oocyte freezing cycles to oocyte thawing, and embryo transfer cycles were accordingly estimated. The cumulative cost per live birth was defined by the cumulative cost divided by the live births per thawed case. RESULTS: We recruited 645 women with 840 oocyte retrieval cycles for elective oocyte freezing from November 2002 to December 2020. The overall usage rate was 8.4% (54/645). After the storage duration exceeded ten years, the probabilities of thawing oocytes were 10.6%, 26.6%, and 12.7% from women who cryopreserved their oocytes at the age ≤ 35 years, 36-39 years, and ≥ 40 years, respectively (P = 0.304). Among women who thawed their oocytes, 31.5% (17/54) of women achieved at least one live birth. For the age groups of ≤ 35 years, 36-39 years, and ≥ 40 years, the cumulative live birth rates per thawed case were 63.6%, 42.3%, and 17.6%, respectively (P = 0.045), and the cumulative costs for one live birth were $11,704, $17,189, and $35,642, respectively (P < 0.001). CONCLUSIONS: The overall usage rate was 8.4% in our cohort. The cumulative live birth rate was greatest in the youngest group and the cumulative cost per live birth was highest in the oldest group, which was threefold greater than that in the group aged ≤ 35 years. The findings added to the limited evidence of the usage rate in real-world situations, which could hopefully aid future analysis and decision-making in public health policy and for women willing to preserve fertility. TRIAL REGISTRATION: None.

First report of a successful pregnancy by preimplantation genetic testing for Beckwith-Wiedemann syndrome.

OBJECTIVE: Beckwith-Wiedemann syndrome (BWS) is a rare imprinting gene disorder. Maternal CDKN1C mutation comprises 5% of etiologies of BWS. There is no successful report of preventing BWS by preimplantation genetic testing for monogenic disease (PGT-M) in the literature. Is PGT-M applicable for preventing BWS ? CASE REPORT: This 39-year-old woman conceived naturally and delivered a boy who was diagnosed of BWS. The genetic testing of her son revealed CDKN1C gene mutation, and of the mother showed a carrier of the same mutation. She underwent controlled ovarian stimulation, oocyte pickup, and intracytoplasmic sperm injection. Trophectoderm biopsies were performed and samples were checked for PGT. Two wild-type and euploid embryos were thawed and transferred. One intrauterine pregnancy was achieved. The patient delivered a healthy female baby at 37 weeks of gestation. CONCLUSION: In this case, we first report a successful pregnancy with a wild-type CDKN1C gene baby achieved by PGT-M.

Reduced mitochondrial DNA content correlate with poor clinical outcomes in cryotransfers with day 6 single euploid embryos.

Objective: To investigate whether the mitochondrial DNA (mtDNA) content of a single biopsy at trophoblast correlates with the developmental potential and reproductive outcomes of blastocyst. Methods: A retrospective analysis applied the dataset of 1,675 embryos with preimplantation genetic testing for aneuploidy (PGT-A) from 1,305 individuals, and 1,383 embryos involved cryotransfers of single euploid embryo between January 2015 and December 2019. The studied cohort was divided for algorithm establishment on the NGS platform (n=40), correlation of biological features (n=1,635), and correlation of reproductive outcomes (n=1,340). Of the algorithm derived from the NGS platform, the reliability and repeatability were validated via qPCR assay and inter-run controls, respectively. Of the correlation across biological features, stratification analyses were applied to evaluate the effect from a single contributor. Eventually, the correlation between the mtDNA ratios and reproductive outcomes was adjusted according to the significant effector(s). Results: The mtDNA ratios showed statistically different between embryos with different days of blastocyst formation ([Day 5]: 1.06 vs. [Day 6]: 0.66, p=0.021), and between embryos with different expansion stages ([Expansion 5]: 1.05 vs. [Expansion 6]: 0.49, p=0.012). None or weakly correlated with the maternal age, morphology, ploidy, and gender. Analyzed by the different days of blastocyst formation with fixed expansion score as 5 in the euploid single embryo transfers (eSET), the day 6 eSET showed significantly lower reduced mtDNA ratio (n=139) in failure groups of fetal heartbeat (p=0.004), ongoing pregnancy (p=0.007), and live birth (p=0.01); however, no correlation between mtDNA ratios and pregnancy outcomes was observed in the day 5 eSET (n=1,201). Conclusions: The study first demonstrated that mtDNA ratio was dependent on the days of blastocyst formation while expansion stage was fixed. Lower mtDNA ratios were observed in the day 6 eSET with adverse outcomes. The present stratification analyses reveal that the timeline of embryo is an important covariate to the mtDNA content.

Progestin primed ovarian stimulation using corifollitropin alfa in PCOS women effectively prevents LH surge and reduces injection burden compared to GnRH antagonist protocol.

Utilizing corifollitropin alfa in GnRH antagonist (GnRHant) protocol in conjunction with GnRH agonist trigger/freeze-all strategy (corifollitropin alfa/GnRHant protocol) was reported to have satisfactory outcomes in women with polycystic ovary syndrome (PCOS). Although lessening in gonadotropin injections, GnRHant were still needed. In addition to using corifollitropin alfa, GnRHant was replaced with an oral progestin as in progestin primed ovarian stimulation (PPOS) to further reduce the injection burden in this study. We try to investigate whether this regimen (corifollitropin alfa/PPOS protocol) could effectively reduce GnRHant injections and prevent premature LH surge in PCOS patients undergoing IVF/ICSI cycles. This is a retrospective cohort study recruiting 333 women with PCOS, with body weight between 50 and 70 kg, undergoing first IVF/ICSI cycle between August 2015 and July 2018. We used corifollitropin alfa/GnRHant protocol prior to Jan 2017 (n = 160), then changed to corifollitropin alfa/PPOS protocol (n = 173). All patients received corifollitropin alfa 100 µg on menstruation day 2/3 (S1). Additional rFSH was administered daily from S8. In corifollitropin alfa/GnRHant group, cetrorelix 0.25 mg/day was administered from S5 till the trigger day. In corifollitropin alfa/PPOS group, dydrogesterone 20 mg/day was given from S1 till the trigger day. GnRH agonist was used to trigger maturation of oocyte. All good quality day 5/6 embryos were frozen, and frozen-thawed embryo transfer (FET) was performed on subsequent cycle. A comparison of clinical outcomes was made between the two protocols. The primary endpoint was the incidence of premature LH surge and none of the patients occurred. Dydrogesterone successfully replace GnRHant to block LH surge while an average of 6.8 days of GnRHant injections were needed in the corifollitropin alfa/GnRHant group. No patients suffered from ovarian hyperstimulation syndrome (OHSS). The other clinical outcomes including additional duration/dose of daily gonadotropin administration, number of oocytes retrieved, and fertilization rate were similar between the two groups. The implantation rate, clinical pregnancy rate, and live birth rate in the first FET cycle were also similar between the two groups. In women with PCOS undergoing IVF/ICSI treatment, corifollitropin alfa/PPOS protocol could minimize the injections burden with comparable outcomes to corifollitropin alfa/GnRHant protocol.

High concordance in preimplantation genetic testing for aneuploidy between automatic identification via Ion S5 and manual identification via Miseq.

The Ion S5 (Thermo Fisher Scientific) and Miseq (Illumina) NGS systems are both widely used in the clinical laboratories conducting PGT-A. Each system employs discrepant library preparation steps, sequencing principles, and data processing algorithms. The automatic interpretation via Ion Reporter software (Thermo Fisher Scientific) and the manual interpretation via BlueFuse Multi software (Illumina) for chromosomal copy number variation (CNV) represent very different reporting approaches. Thus, it is intriguing to compare their ability of ploidy detection as PGT-A/NGS system. In the present study, four aneuploid cell lines were individually mixed with a diploid cell line at different aneuploid ratios of 0% (0:5), 10% (1:9), 20% (1:4), 40% (2:3), 50% (3:3), 60% (3:2), 80% (4:1) and 100% (5:0) to assess the sensitivity and specificity for whole chromosomal and segmental aneuploidy detection. The clinical biopsies of 107 blastocysts from 46 IVF/PGT-A cycles recruited between December 2019 and February 2020 were used to calculate the concordance. Initially, the pre-amplified products were divided into two aliquots for different library preparation procedures of each system. Applying the same calling criteria, automatic identification was achieved through the Ion Reporter, while well-trained technicians manually identified each sample through the BlueFuse Multi. The results displayed that both systems reliably distinguished chromosomal CNV of the mixtures with at least 10% aneuploidy from karyotypically normal samples ([Ion S5] whole-chromosomal duplication: 2.14 vs. 2.05, p value = 0.009, segmental deletion: 1.88 vs. 2.05, p value = 0.003; [Miseq] whole-chromosomal duplication: 2.12 vs. 2.03, p value = 0.047, segmental deletion: 1.82 vs. 2.03, p value = 0.002). The sensitivity and specificity were comparable between the Ion S5 and Miseq ([sensitivity] 93% vs. 90%, p = 0.78; [specificity] 100% vs. 100%, p value = 1.0). In the 107 clinical biopsies, three displayed chaotic patterns (2.8%), which could not be interpreted for the ploidy. The ploidy concordance was 99.04% (103/104) per embryo and 99.47% (2265/2277) per chromosome pair. Since their ability of detection were proven to be similar, the automatic identification in Ion S5 system presents comparatively faster and more standardized performance.

Intentional endometrial injury enhances angiogenesis through increased production and activation of MMP-9 by TNF-α and MMP-3 in a mouse model.

There have been reports of improved pregnancy rates after performing intentional endometrial injuries, also known as endometrial scratching, in patients with recurrent implantation failure. In our previous study on intentional endometrial injury, we found an increased expression of matrix metalloproteinase (MMP)-3 following induced injuries to the mice endometrium. In the current study, we further examine whether the rise in MMP-3 could contribute to increased angiogenesis. Female C57B1/6 mice were obtained at 12 weeks of age, and intentional endometrial injuries were induced mechanically in the left uterine horns. Using the appropriate media, uterine-washes were performed on the injured and uninjured (control) horns of the harvested uteri. The uterine tissues were further processed for tissue lysates, histopathology and immunohistochemistry. The results show that intentional endometrial injuries caused an increase in secreted LPA in the injured horns, which were detected in the uterine-washes. In addition, LPA induced increased production of TNF-α in human endometrial epithelial cells (hEEpCs). Furthermore, TNF-α appeared to induce differential and cell-specific upregulation of the MMPs: MMP-3 was upregulated in the epithelial (hEEpCs), while MMP-9 was upregulated in the endothelial cells (human endometrial endothelial cells; hEEnCs). The upregulation of MMP-3 appeared to be necessary for the activation of MMP-9, whose active form stimulated the formation of vessel-like structure by the hEEnCs. The results of this study suggest that there may be enhanced angiogenesis following intentional endometrial injuries, which is mediated in part by TNF-α-induced and MMP-3-activated MMP-9 production.

Metformin: a novel promising option for fertility preservation during cyclophosphamide-based chemotherapy.

Cyclophosphamide (CP) could cause severe gonadotoxicity via imbalanced activation of primordial follicles through PI3K/AKT/mTOR activation. Whether metformin, a widely prescribed anti-diabetes agent with mTOR inhibitory effect, could preserve ovarian function against CP toxicity is unknown. Female C57BL/6 mice were randomized into seven groups (n = 11), including control, CP-alone, CP + metformin, CP + sirolimus or everolimus, metformin-alone and sirolimus-alone groups. The duration of pharmaceutical treatment was 4 weeks. CP treatment significantly impaired ovarian function and fertility in mice. CP + metformin treatment significantly attenuated the gonadotoxicity comparing to CP-alone treatment (primordial follicle count: 17.6 ± 4.2 versus 10.3 ± 2.7 follicles/high-power field; P = 0.027). CP + metformin treatment also tended to increase antral follicular count (5.4 ± 1.1 versus 2.5 ± 1.6 follicles/section), serum AMH levels (4.6 ± 1.2 versus 2.0 ± 0.8 ng/ml) and the litter size (4.2 ± 1.3 versus 1.5 ± 1.0 mice per pregnancy), compared with CP-alone group. Expression of phospho-mTOR and the number of TUNEL-positive granulosa cells increased after CP treatment and decreased in the CP + metformin groups, suggesting the mTOR inhibitory and anti-apoptotic effects of metformin. In in-vitro granulosa cell experiments, the anti-apoptotic effect of metformin was blocked after inhibiting p53 or p21 function, and the expression of p53 mRNA was blocked with AMPK inhibitor, suggesting that the anti-apoptotic effect was AMPK/p53/p21-mediated. In conclusion, concurrent metformin treatment during CP therapy could significantly preserve ovarian function and fertility and could be a promising novel fertility preserving agent during chemotherapy. The relatively acceptable cost and well-established long-term safety profiles of this old drug might prompt its further clinical application at a faster pace.

Optimal time interval between hysteroscopic polypectomy and frozen-thawed blastocyst transfer: A retrospective study.

The optimal timing of frozen-thawed blastocyst transfer following hysteroscopic polypectomy is an important and unanswered clinical question. In this study, we conducted a retrospective survey of cases from an infertility center at an academic hospital. We reviewed the charts of all patients who received in-vitro fertilization and frozen-thawed blastocyst transfers (FBT) at the center from January 2009 to November 2019. One hundred and two patients with prior diagnosis of endometrial polyp that were treated with hysteroscopic polypectomy before received their first FBT at the center were identified as cases. Patients without prior diagnosis of endometrial polyp, and who received their first FBT at the center were defined as controls. Controls were enrolled at a 1-to-1 ratio to the cases. The cases and controls did not show differences in baseline characteristics, endometrial thickness, or the number of good blastocysts transferred. The clinical pregnancy rates and live birth rates were similar. Regarding the optimal interval between polypectomy and FBT, a cut-off of 120 days was identified from the ROC curve. A stratified analysis showed that when FBT was performed within an interval of 120 days after polypectomy, there were higher biochemical pregnancy rates (73.2%, 45.2%; OR 3.3; P = .007) and clinical pregnancy rates (64.8%, 41.9%; OR 2.54; P = .032), when compared with intervals greater than 120 days. There were no significant differences in implantation and live birth rates. In conclusion, pregnancy rates following FBT in patients who had received prior endometrial polypectomy were comparable to pregnancy rates after FBT in patients without endometrial polyp. Subgroup analysis showed that an interval greater than 120 days between hysteroscopic polypectomy and FBT was associated with decreased pregnancy rates. Patients who wish to receive embryo transfer after polypectomy should wait no longer than 120 days.

Changes in peripheral mitochondrial DNA copy number in metformin-treated women with polycystic ovary syndrome: a longitudinal study.

BACKGROUND: Patients with polycystic ovarian syndrome (PCOS) are associated with known alterations in mitochondria DNA copy number (mtDNA-CN). The aim of this study is to study the change in mtDNA-CN in patients with PCOS who were treated with metformin. METHODS: This is a prospective cohort of patients with PCOS, who received metformin for one year. From 2009 to 2015, 88 women diagnosed with PCOS, based on the Rotterdam criteria, were enrolled. Serial measurements of mtDNA-CN, 8-hydroxydeoxyguanosine (8-OHdG), anthropometric, metabolic, endocrine, and inflammatory markers were obtained before and after 3, 6, and 12 months of treatment. RESULTS: A significant decrease in mtDNA-CN was seen over the course of one year. Other markers, including 8-OHdG, testosterone, free androgen index, blood pressure and liver enzymes, also decreased in the same interval. On regression analysis, there was a significant association between the change in mtDNA-CN and serum total testosterone, and no association between mtDNA-CN and metabolic factors. CONCLUSIONS: Treatment with metformin is associated with a time-dependent decrease in mtDNA-CN in patients with PCOS who are treated over the course of one year. This may signify a reduction in mitochondria dysfunction. The change in mtDNA-CN corresponds to a similar change in serum total testosterone, and suggests a possible relationship between mtDNA-CN and testosterone. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00172523 . Registered September 15, 2005.