A direct healthcare cost analysis of recombinant LH versus hMG supplementation on FSH during controlled ovarian hyperstimulation in the GnRH-antagonist protocol.

PURPOSE: We have previously published a retrospective matched-case control study comparing the effect of recombinant LH (r-hLH) versus highly purified human menopausal gonadotropin (hMG) supplementation on the follicle-stimulating hormone (FSH) during controlled ovarian hyperstimulation (COH) in the GnRH-antagonist protocol. The result from that study showed that the cumulative live birth rate (CLBR) was significantly higher in the r-hLH group (53% vs. 64%, p = 0.02). In this study, we aim to do a cost analysis between these two groups based on our previous study. METHODS: The analysis consisted of 425 IVF and ICSI cycles in our previous study. There were 259 cycles in the r-hFSH + hMG group and 166 cycles in the r-hFSH + r-hLH group. The total cost related to the treatment of each patient was recorded. Probabilistic sensitivity analysis (PSA) and a cost-effectiveness acceptability curve (CEAC) were performed and created. RESULTS: The total treatment cost per patient was significantly higher in the r-hFSH + r-hLH group than in the r-hFSH + hMG group ($4550 ± 798.86 vs. $4290 ± 734.6, p = 0.003). However, the mean cost per live birth in the r-hFSH + hMG group was higher at $8052, vs. $7059 in the r-hFSH + r-hLH group. The CEAC showed that treatment with hFSH + r-hLH proved to be more cost-effective than treatment with r-hFSH + hMG. Willingness-to-pay was evident when considering a hypothetical threshold of $18,513, with the r-hFSH + r-hLH group exhibiting a 99% probability of being considered cost-effective. CONCLUSION: The cost analysis showed that recombinant LH is more cost-effective than hMG supplementation on r-hFSH during COH in the GnRH-antagonist protocol.

Impact of adenomyosis and endometriosis on IVF/ICSI pregnancy outcome in patients undergoing gonadotropin-releasing hormone agonist treatment and frozen embryo transfer.

Although numerous studies have attempted to establish the relationship between adenomyosis and infertility, no consensus has emerged. Our aim was to investigate whether adenomyosis and endometriosis affected IVF outcomes in our patients. This was a retrospective study of 1720 patients from January 2016 to December 2019. In total, 1389 cycles were included: 229 cycles in the endometriosis group (group E), 89 cycles in the adenomyosis group (group A), 69 cycles in the endometriosis and adenomyosis group (group EA), and 1002 cycles in the control group (group C). Most patients in groups A and EA received GnRH agonist treatment before FET. The 1st FET live birth rates (LBR) were 39.3%, 32.1%, 25% and 48.1% in groups E, A, EA, and C. The miscarriage rates were 19.9%, 34.7%, 39%, and 17.6%. The per retrieval cycle cumulative live birth rates (cLBRs) in patients < 38 y/o were 56.4%, 58.1%, 44.8%, and 63%. The per retrieval cycle cLBRs in patients ≥ 38 y/o were 25%, 9.8%, 17.2%, and 29.5%. Among groups A and EA, LBRs were 25.58% and 18.89% in patients with a ≥ sevenfold decrease and a < sevenfold decrease in CA-125 level, respectively, after GnRH agonist treatment. Endometriosis was not associated with a poorer pregnancy outcome. Patients with adenomyosis with/without endometriosis had higher miscarriage rates, lower LBRs, and lower cLBRs, especially in patients aged ≥ 38 years, even after GnRH agonist treatment before FET cycles. Patients who have a greater than sevenfold decrease in CA-125 level after GnRH agonist treatment might have better clinical pregnancy outcomes.

Presence of endometrioma decreased blastocyst formation rate but not impair Assisted Reproductive Technology (ART) outcome.

PURPOSE: This study aims to assess the impact of endometrioma on patients who undergo ART treatment due to endometriosis. METHODS: A retrospective study was conducted on women ≤ 40 years of age who underwent ART treatment at an academic medical center between January 2014 and December 2020. Two-hundred-and-eight women had received IVF/ICSI treatment due to endometriosis and there were 89 patients presence of endometrioma. Patients were further divided into primary endometrioma, recurrent endometrioma and those having received cystectomy for endometrioma prior to IVF/ICSI. The control group included 624 infertile women without endometriosis. RESULTS: In the endometrioma subgroup (B) the blastocyst formation rate was significantly lower when compared with the endometriosis (A) and control groups (C). The cumulative live birth rates (CLBRs) (60.5% versus 49.4% versus 56.9%, p = 0.194 in A versus B, p = 0.406 in A versus C, p = 0.878 in B versus C) were comparable. Multiple logistic regression analysis revealed that female age, total FSH dose and blastocyst formation rate were the significant variables in predicting CLBR (OR 0.89, CI 0.80-0.99, p < 0.025, OR 0.68 CI 0.53-0.88, p = 0.003 and OR 30.04, CI 9.93-90.9, p < 0.001, respectively). The CLBRs were comparable at 47.1%, 60% and 57.9% in the primary endometrioma, s/p cystectomy and recurrent endometrioma group. CONCLUSION: Although the blastocyst formation rate was lower in the endometrioma group, CLBR was not worse than those who were in the endometriosis or control group. Cystectomy for endometrioma did not alter IVF/ICSI outcomes if the ovarian reserve was comparable. Recurrent endometrioma did not worsen IVF/ICSI outcomes than primary endometrioma.

Development of a Predictive Model for Optimization of Embryo Transfer Timing Using Blood-Based microRNA Expression Profile.

MicroRNAs (miRNAs) can regulate the expression of genes involved in the establishment of the window of implantation (WOI) in the endometrium. Recent studies indicated that cell-free miRNAs in uterine fluid and blood samples could act as alternative and non-invasive sample types for endometrial receptivity analysis. In this study, we attempt to systematically evaluate whether the expression levels of cell-free microRNAs in blood samples could be used as non-invasive biomarkers for assessing endometrial receptivity status. We profiled the miRNA expression levels of 111 blood samples using next-generation sequencing to establish a predictive model for the assessment of endometrial receptivity status. This model was validated with an independent dataset (n = 73). The overall accuracy is 95.9%. Specifically, we achieved accuracies of 95.9%, 95.9%, and 100.0% for the pre-receptive group, the receptive group, and the post-respective group, respectively. Additionally, we identified a set of differentially expressed miRNAs between different endometrial receptivity statuses using the following criteria: p-value < 0.05 and fold change greater than 1.5 or less than -1.5. In conclusion, the expression levels of cell-free miRNAs in blood samples can be utilized in a non-invasive manner to distinguish different endometrial receptivity statuses.

Corrigendum: A retrospective, matched case-control study of recombinant LH versus hMG supplementation on FSH during controlled ovarian hyperstimulation in the GnRH-antagonist protocol.

[This corrects the article DOI: 10.3389/fendo.2022.931756.].

A retrospective, matched case-control study of recombinant LH versus hMG supplementation on FSH during controlled ovarian hyperstimulation in the GnRH-antagonist protocol.

Background: The role of luteinizing hormone (LH) in controlled ovarian hyperstimulation (COH) requires more evidence for its efficacy. Several studies compared recombinant human LH (r-hLH) or human menopausal gonadotropin (hMG) in combination with recombinant human follicle-stimulating hormone (r-hFSH) but lack the results with GnRH-antagonist protocol and in Asians. Methods: This is a retrospective, single-center study inspecting women receiving GnRH antagonist protocol and r-hFSH+hMG or r-hFSH+r-hLH regimen for over five days for COH in the in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle in Taiwan from 2013 to 2018. The outcomes of IVF/ICSI cycles were analyzed after propensity score matching between the two groups. A subgroup analysis was conducted in cycles in which women underwent their first embryo transfer (ET), including fresh ET and frozen ET (FET). Results: With a total of 503 cycles, the results revealed that the r-hFSH+r-hLH group performed better in terms of numbers of oocytes retrieved (r-hFSH+hMG vs. r-hFSH+r-hLH, 11.7 vs. 13.7, p=0.014), mature oocytes (8.7 vs. 10.9, p=0.001), and fertilized oocytes (8.3 vs. 9.8, p=0.022), while other outcomes were comparable. The analysis of first ET cycles also showed similar trends. Although the implantation rate (39% vs. 43%, p=0.37), pregnancy rate (52% vs. 53%, p=0.90), and live birth rate (39% vs. 45%, p=0.19) were not significantly different, the miscarriage rate was higher in the r-hFSH+hMG group than the r-hFSH+r-hLH group (26% vs. 15%, p<0.05) in first ET cycles. The cumulative pregnancy rate was significantly higher in the r-hFSH+r-hLH group (53% vs. 64%, p=0.02). No significant difference in rates of ovarian hyperstimulation syndrome (OHSS) was observed. Conclusion: The results support the hypothesis that the treatment of r-hLH+r-hFSH improves COH clinical outcomes in the IVF/ICSI cycle.

Contamination of ART culture Media-The role of semen and strategies for prevention.

OBJECTIVE: Microbial contamination of ART culture media is rare but serious. We examined our own experience and conducted a review of the literature with a view to preventing its occurrence and recurrence. CASE REPORT: A total of 12 cases were recorded during January 2006 to March 2019. The contaminations were caused by semen and were shown to be bacteria that were resistant to the prophylactic antibiotics used in the medium. After the procedures were cancelled due to contaminations, nine husbands received antibiotic treatment, while nine couples changed over to the ICSI program. Eventually, eight couples concluded the study with live birth deliveries, and there was no recurrence of contamination. CONCLUSION: ART laboratories should preserve all sperm suspension samples until embryo transfer has been completed for the purpose of checking whether contamination has occurred. In addition to antibiotic treatment, implementation of the ICSI procedure during the next ART cycle has already been proven to be effective. In the future, the zona-removal technique may be considered as another potential option.

Cost-effectiveness of freeze-all policy - A retrospective study based upon the outcome of cumulative live births.

OBJECT: We have previously reported that cumulative live birth rates (CLBRs) are higher in the freeze-all group compared with controls (64.3% vs. 45.8%, p = 0.001). Here, we aim to determine if the freeze-all policy is more cost-effective than fresh embryo transfer followed by frozen-thawed embryo transfer (FET). MATERIALS AND METHODS: The analysis consisted of 704 ART (Assisted reproductive technology) cycles, which included in IVF (In vitro fertilisation) and ICSI (Intra Cytoplasmic Sperm Injection) cycles performed in Taichung Veterans General Hospital, Taiwan between January 2012 and June 2014. The freeze-all group involved 84 patients and the fresh Group 625 patients. Patients were followed up until all embryos obtained from a single controlled ovarian hyper-stimulation cycle were used up, or a live birth had been achieved. The total cost related to treatment of each patient was recorded. The incremental cost-effectiveness ratio (ICER) was based on the incremental cost per couple and the incremental live birth rate of the freeze-all strategy compared with the fresh ET strategy. Probabilistic sensitivity analysis (PSA) and a cost-effectiveness acceptability curve (CEAC) were performed. RESULTS: The total treatment cost per patient was significantly higher for the freeze-all group than in the fresh group (USD 3419.93 ± 638.13 vs. $2920.59 ± 711.08 p < 0.001). However, the total treatment cost per live birth in the freeze-all group was US $5319.89, vs. US $6382.42 in the fresh group. CEAC show that the freeze-all policy was a cost-effective treatment at a threshold of US $2703.57 for one additional live birth. Considering the Willingness-to-pay threshold per live birth, the probability was 60.1% at the threshold of US $2896.5, with the freeze-all group being more cost-effective than the fresh-ET group; or 90.1% at the threshold of $4183.8. CONCLUSION: The freeze-all policy is a cost-effective treatment, as long as the additional cost of US $2703.57 per additional live birth is financially acceptable for the subjects.

Does the "freeze-all" policy allow for a better outcome in assisted reproductive techniques than the use of fresh embryo transfers? - A retrospective study on cumulative live birth rates.

OBJECTIVE: There are increasing concerns regarding the adverse effects associated with control ovarian hyperstimulation (COH) in both endometrial and uterine environments. With the "segmentation treatment policy" of assisted reproductive techniques (ART), endometrial problems may be obviated through embryo cryopreservation. However, it remains unclear if the "freeze-all policy" offers a better outcome when compared with fresh embryo transfer (ET). To clarify this, we compared the cumulative live birth rates (CLBRs) between these two patient populations. MATERIALS AND METHODS: This is a retrospective study on 853 patients undergoing ovarian stimulation and ART (including IVF/ICSI) during the period from January 2012 to June 2014 in Taichung Veterans General Hospital, Taiwan, ROC. We followed up with these patients through to November 2016. Patients whose embryos were not completely transferred back were excluded. The study group ('freeze-all') included 84 patients whose cycles were performed initially without fresh ET, but were later given frozen-thawed ET. The control group ('fresh ET') had 625 patients whose cycles were performed with fresh ET, followed by frozen-thawed ET. Basic parameters and CLBRs were statistically compared between these two groups. RESULTS: The CLBRs in the study group were significantly higher than those in the control group (64.3% vs. 45.8%, p = 0.001). Subgroup analysis revealed that when the number of oocyte pick up (OPU) is between 4 and 15, the CLBRs in the study group were significantly better (58.3% vs. 40.9%, p = 0.042). For those with OPU <4 or OPU >15 the CLBRs were similar in these two groups (OPU < 4: study vs. control 23.1% vs. 18.8% respectively, p = 0.713; OPU>15: study vs. control 85.7% vs. 80.8% respectively, p = 0.625) CONCLUSION: The Freeze-all policy improved the ART outcome for normal responders.

Effect of premature serum progesterone rise on embryo transfer outcomes and the role of blastocyst culture and transfer in assisted reproductive technology cycles with premature progesterone rise.

OBJECTIVE: In 1991, researchers reported that a modest preovulatory increase in serum progesterone levels is associated with lower pregnancy rates and higher incidence of pregnancy loss in in vitro fertilization (IVF). We wonder whether embryo transfer (ET) in assisted reproductive technology (ART) cycles in patients with premature progesterone rise (PPR) have a negative impact on the clinical pregnancy rates (CPRs) and/or live birth rates (LBRs) in our series. Consequently, will blastocyst transfer reverse the negative impact? MATERIALS AND METHODS: This noninterventional, retrospective, observational tertiary center study was conducted between January 2010 and December 2012. All fresh ET cycles with serum progesterone levels measured (n = 599) on the day of hCG administration were analyzed. RESULTS: Sera lutenizing hormone (LH), E2, and progesterone (P) were measured and analyzed. The CPRs of cycles in patients with p ≤ 1.5 ng/mL (low) versus those with p > 1.5 ng/mL (high) were 37.04% versus 41.03% [odds ratio (OR) = 1.18, 95% confidence interval (CI): 0.728-1.920; p = 0.50). The LBRs of cycles in patients with low progesterone level versus those with PPR were 30.52% versus 34.62% (OR = 1.21, 95% CI: 0.729-1.992; p = 0.47). No statistically significant association was detected. We further analyzed the outcomes according to different stages of ET and found that blastocyst (D5) ET significantly increase the LBRs as compared with cleavage stage (D2/D3) ET in the PPR group (44.44% versus 21.43%; p = 0.043). CONCLUSION: PPR did not significantly compromise the clinical outcomes in this series. However, shifting to blastocyst transfer probably could increase the live birth in cycles with PPR.

Characterization of embryonic stem cell lines derived from New Zealand white rabbit embryos.

The purposes of this study were to examine technical details in deriving and maintaining rabbit embryonic stem (rES) cell lines and to analyze their characteristics. When STO cells were used as feeder cells, no rES cell lines were established using either intact blastocysts or inner cell masses (ICMs). On the mouse embryonic fibroblasts (MEF) feeder, rES cell lines were efficiently (24%) derived. Addition of leukemia inhibitory factor (LIF) to the cells cultured on the MEF feeders further increased the derivation efficiency (57%) of rES cells. The fact that LIF induced serine-phosphorylation of STAT3 suggested LIF-dependent maintenance of rES cells. Most of the rES cell lines expressed AP, SSEA-4, Oct4, TRA-1-60, and TRA-1-81. Western blot or RT-PCR analysis also confirmed the expression of Oct4, Nanog, and Sox2. When induced to form EBs in vitro or injected to the severe combined immunodeficiency (SCID) mice, the rES cells generated embryoid bodies (EBs) and teratomas with three germ layers expressing the marker genes including MAP2, Desmin, and GATA4, respectively. In conclusion, rabbit ES cell lines can be efficiently established using our current protocols with LIF supplement. These ES cells express pluripotent stem cell markers and retain their capability to differentiate into different tissue cells. Furthermore, rES cells depend on LIF for self-renewal, likely via the JAK-STAT pathway.

Mitochondria transfer can enhance the murine embryo development.

PURPOSE: To evaluate the effect of mitochondrial transfer on embryonic development. MATERIALS AND METHODS: Mitochondria concentrates were collected from murine hepatocytes and fertilized murine zygotes from young and older mice in the 2PN stage were subjected to mitochondrial transfer and cultured in vitro to evaluate the embryonic development. RESULTS: After extended in vitro culture, 37.65% and 20.91% embryos from the young mice developed to the blastocyst stage in the injected and control groups respectively, which is statistically significant. There was no difference in terms of hatching rates (1.76% and 1.82% respectively). Zygotes from the older mice (>20 weeks old) that received mitochondrial transfer also had a better developmental outcome than the control group (54.35% and 18.92% developed to morula stage, 43.48% and 8.11% developed to the blastocyst stage respectively), which is statistically significant. CONCLUSIONS: Our results for the murine model provide direct scientific evidence that mitochondrial transfer improves embryonic development. However, potential risks such as mitochondrial heteroplasmy, nuclear-mitochondrial interaction and epigenetic aspects all deserve further evaluation before mitochondrial transfer is applied clinically.

Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women.

BACKGROUND: Recent studies have revealed that HRT may increase the risk for atherosclerotic vascular disease (ASVD). METHODS: We investigated the effects of HRT via different administration routes on the markers for ASVD and endothelial function in healthy postmenopausal women. The oral HRT group (n=18) received conjugated equine estrogen 0.625 mg/day; the transdermal HRT group (n=18) received 17beta-estradiol (E2) gel 0.6 mg/day for 6 months. The control group (n=30) had no treatment for 6 months. RESULTS: The C-reactive protein (CRP) rose from 0.129+/-0.116 to 0.752+/-0.794 mg/dl (P<0.01) in the oral HRT group but remained unchanged in the transdermal HRT and control groups. The flow-mediated vasodilation (FMD) in the brachial artery was increased significantly by HRT from 6.0% before oral HRT to 14.7% after oral HRT (P<0.001) and from 5.9% before transdermal HRT to 13.9% after transdermal HRT (P=0.001). CONCLUSIONS: These data suggest that oral estrogen induces ASVD risk by increasing acute inflammation; however, transdermal estrogen avoids this untoward effect. Additionally, transdermal estrogen exerts a positive effect on endothelial function similar to that of oral estrogen. Therefore, the transdermal route might be favourable in terms of ASVD risks.

The serum follicle-stimulating hormone-to-luteinizing hormone ratio at the start of stimulation with gonadotropins after pituitary down-regulation is inversely correlated with a mature oocyte yield and can predict "low responders".

OBJECTIVE: The aim of this study was to investigate the relationship of serum FSH and LH levels at the commencement of stimulation to ovarian follicular development in women undergoing pituitary down-regulation and controlled ovarian hyperstimulation with gonadotropins in IVF or intracytoplasmic sperm injection (ICSI) cycles. DESIGN: Retrospective analysis. SETTING: An IVF program in a tertiary medical center. PATIENT(S): A total of 245 women proven to be pituitary down-regulated by their serum E(2) levels. INTERVENTION(S): Patients treated with a GnRH agonist and FSH and hMG underwent assisted reproductive technique (ART). MAIN OUTCOME MEASURE(S): Mature oocyte yield, pregnancy rate (PR), and live birth rate. RESULT(S): The serum FSH levels and the FSH-to-LH ratio at the commencement of gonadotropin stimulation were inversely correlated to the number of mature oocytes (r = -0.193 and r = -0.224, respectively). When assessed with receiver-operating characteristic (ROC) analysis, there was statistically significant ability for the FSH/LH ratio to differentiate between the "poor response" cycles (with mature oocyte yield < or =4) and the normal response cycles. Using the cutoff value derived from ROC analysis, cycles with the FSH-to-LH ratio > or =3 produced less mature oocytes (8.25 vs. 11.74), lower peak E(2) levels (1,975.3 pg/mL vs. 3,324.8 pg/mL), and higher percentage of poor ovarian response cycles (32.5% vs. 14.3%). CONCLUSION(S): The serum FSH-to-LH ratio at the start of gonadotropin stimulation after pituitary down-regulation provided a practical method for early prediction of mature oocyte yield.

The effect of preincubation period of oocytes on nuclear maturity, fertilization rate, embryo quality, and pregnancy outcome in IVF and ICSI.

PURPOSE: To clarify the effect of preincubation of oocytes on the results of IVF and ICSI. METHODS: A total of 176 IVF and 64 ICSI cycles received long protocol ovarian stimulation. The oocytes were incubated for 1-8 h before insemination or sperm injection. Metaphase II (MII) percentage was evaluated in the ICSI arm; fertilization rates, embryo quality, and pregnancy outcomes were analyzed in both IVF and ICSI arms according to the preincubation period duration of oocytes. RESULTS: The MII percentage of the ICSI arm was significantly lower (P < 0.05) in the group with preincubation period of < 2.5 h. The fertilization rates in groups with preincubation for 2.5-5.5 h were significantly higher (P < 0.001) for IVF. Embryo quality and pregnancy outcomes were not significantly different between the IVF or ICSI arm. CONCLUSIONS: The preincubation of oocytes for at least 2.5 h is beneficial to both IVF and ICSI outcomes by increasing the nuclear maturity of oocytes.