Journal of Assisted Reproduction and Genetics最新文献

Purpose: To investigate the impact of different frozen embryo transfer regimens on maternal thyroid function during early pregnancy and subsequent thyroid function in the newborns.

Methods: A secondary analysis of a randomized controlled trial including women aged 18-40 years with a body mass index ≤ 35 kg/m² undergoing frozen embryo transfer at Copenhagen University Hospital - Herlev (April 2021-May 2024). Ovulatory participants were randomized to modified natural or programmed cycle, and anovulatory participants to gonadotrophin-stimulated or programmed cycle. Maternal thyroid-stimulating hormone, free thyroxine, total thyroxine, and total triiodothyronine were measured. Neonatal thyroid-stimulating hormone was evaluated through the neonatal screening program.

Results: In total, 251 cycles were analyzed: 94 modified natural and 99 programmed in the ovulatory group, and 29 gonadotrophin-stimulated and 29 programmed in the anovulatory group. Total triiodothyronine and thyroxine levels were significantly higher in programmed cycles during endometrial preparation and early pregnancy. Free thyroxine was elevated at gestational age 4 + 2 in programmed vs. modified natural cycles, but not compared to gonadotrophin-stimulated cycles. Thyroid-stimulating hormone levels were comparable at all time points. Neonatal thyroid-stimulating hormone did not differ between groups.

Conclusions: Although significantly higher maternal levels of total triiodothyronine, thyroxine, and free thyroxine were observed in programmed cycle, both maternal and neonatal thyroid-stimulating hormone levels were unaffected. These findings provide reassuring evidence for the endocrine health of women conceiving through programmed cycle and their newborns. The trial was prospectively registered in EudraCT with identification no. 2020-001218-39, registration date: 17 November 2020. Date of first patient's enrollment: 20 April 2021.

Purpose: To assess gender-based differences in career trajectories among reproductive endocrinology and infertility (REI) physicians in the United States, focusing on leadership, research productivity, and professional involvement.

Methods: This was a cross-sectional comparative study of demographic, professional, and research metrics stratified by gender. Practicing REI physicians were identified through the ASRM directory. Physician gender was evaluated as a variable influencing career outcomes. Main outcome measures included practice setting, geographic distribution, research productivity (h-index, publications, citations), academic leadership, journal editorial board, and society board positions. Mann-Whitney U and Chi-square tests were performed.

Results: Among 767 REI physicians, 55% were male and 45% female. Slightly more females worked in academic settings (33.3% vs. 25.1%), while more males were in private practice (70.4% vs. 66.7%). Leadership representation was comparable between genders. Female physicians had marginally greater representation on editorial (7.8% vs. 7.1%) and society boards (5.8% vs. 4.3%). Males, however, had significantly higher research productivity (mean h-index: 16.44 vs. 10.94; publications: 52.53 vs. 26.72; citations: 2216.69 vs. 1155.28; all p < 0.001).

Conclusion: Despite near parity in leadership representation, gender disparities persist in research productivity among REI physicians. These discrepancies may reflect systemic inequities in academic support, promotion criteria, and institutional culture. Structural barriers such as inequitable research resources, gendered service loads, and family-building or domestic responsibilities may further constrain women's ability to engage in sustained scholarly productivity and advancement. Future efforts can prioritize inclusive data practices, equitable promotion policies, and targeted interventions to support diversity within reproductive medicine.

Purpose: Sixty-five percent of US workers get their health insurance from self-insured employers who are exempt from state insurance coverage mandates. We evaluated if self-insured employers in states with in vitro fertilization coverage mandates offer insurance coverage for in vitro fertilization and other fertility treatments, and if so, we evaluated the details of that coverage.

Methods: We qualitatively analyzed 165 health plan documents from 2019 to 2021 from 45 self-insured employers in seven states with in vitro fertilization coverage mandates (Arkansas, Connecticut, Illinois, Maryland, Massachusetts, New Jersey, New York).

Results: A minority (41%) of self-insured employers in states with in vitro fertilization coverage mandates cover in vitro fertilization. Most health plans impose lifetime limits on in vitro fertilization use, with those limits split almost evenly between dollar-based and cycle-based limits. Finally, health plans in our sample from the finance and insurance, manufacturing, and educational services industries, and from non-union employers, had more comprehensive coverage for infertility testing and treatments.

Conclusion: While state in vitro fertilization coverage mandates are important policy initiatives to improve access to in vitro fertilization, our findings suggest that state mandates are insufficient to expand access to all patients since a minority of self-insured employers in our sample covered in vitro fertilization. In addition, it is insufficient to label a health plan as simply "covering" or "not covering" in vitro fertilization; instead, the details of that coverage matter since the "coverage" may not be sufficient for the patient to afford even one in vitro fertilization attempt.

Purpose: Ovarian stimulation (OS) is a critical component of assisted reproduction techniques (ART), in which gonadotropins are administered to induce follicular development and maturation to improve the chances of conception. It has been reported that ovarian response to OS can be affected by certain genetic factors. This study explores the relationship among SNVs of AMHR2 (c.-482A > G/rs2002555 and c.1749C > T/rs2071558), basal FSH and estradiol levels, gonadotropin dosage, and ovarian response to identify predictive indicators.

Methods: Oocytes were retrieved from 684 infertile Chinese women treated with ART. All patients were divided into three groups: low (< 6 oocytes), normal (6-14 oocytes), high response (> 14 oocytes). Genotyping of c.-482A > G and c.1749C > T were detected on the Sequenom iPlexMassARRAY platform. Transcriptional function of c.-482A > G variant in AMHR2 promoter was validated by Luciferase Reporter Assay in 293 T cells.

Results: Our results indicated that both c.-482A > G and c.1749C > T SNVs were associated with basal FSH levels (p = 0.047 and 0.023, respectively). Genotype and allele distribution frequencies of AMHR2 c.-482A > G were significantly different among the three ovarian response groups (p = 0.007 and 0.009, respectively). AMHR2 c.-482A > G was associated with the number of total oocytes retrieved (p = 0.011). FSH was associated with the ovarian response (p < 0.001). Validation by Luciferase Assay indicated AMHR2 c.-482A > G mutation in the promoter region affect the promoter activity.

Conclusion: AMHR2 c.-482A > G SNVs may be involved in the mechanism of the ovarian response to OS. AMHR2 c.-482A > G SNVs can interact with basal FSH levels, and jointly serve as predictor of the ovarian response to OS.

Purpose: Fatty acid-supplemented warming solutions have been shown to improve blastocyst development and pregnancy outcomes after single vitrified-warmed cleavage stage embryo transfers. However, the effects of fatty acids, phospholipids, and L-carnitine on oocyte mitochondrial function and blastocyst development remain unexplored. This study aimed to evaluate whether supplementing both vitrification and warming solutions with these compounds enhance oocyte mitochondrial function and embryo development.

Methods: Preclinical study conducted with a C57Bl/6 J mouse strain. The study included five experimental groups. The control group comprised fresh oocytes not subjected to vitrification. The vitrification groups consisted of oocytes vitrified in Tvitri-4 medium supplemented with L-carnitine (T4/LC), L-carnitine and fatty acids (T4/FA), or L-carnitine, fatty acids, and phosphatidylcholine (T4/PC). Total cell number in the trophectoderm and inner cell mass (ICM) was analyzed by differentially labeling the nuclei with polynucleotide-specific fluorochromes. Oocyte mitochondrial activity was assessed by mitochondrial membrane potential (ΔΨm), intracellular oxidant levels, and oxidative metabolism. ΔΨm and the levels of oxidant species were evaluated using JC-1 and carboxy-H2DCFDA, respectively, while redox state was measured by the FAD/NAD(P)H autofluorescence ratio.

Results: The ICM cell number did not differ between fresh and oocytes vitrified and warmed with L-carnitine and lipids (Tvitri-4/fatty acids and Tvitri-4/phosphatidylcholine) (p > 0.05). Additionally, oleic and linoleic acids with L-carnitine preserved mitochondrial membrane potential and reduced oxidative stress by lowering oxidant levels.

Conclusion: Adding lipids to the vitrification and warming solutions can modulate mitochondrial membrane potential and the production of oxidant species in mouse oocytes.

Purpose: The purpose of this study was to identify genes in the placenta of monosomy X embryos whose methylation abnormalities may be associated with embryonic death.

Methods: Methylation levels were assessed via reduced representation bisulfite sequencing of the chorionic villi of embryos from 8 spontaneous abortions during the first trimester of pregnancy with the 45,X karyotype and 7 embryos from medical abortions with the 46,XX and 46,XY karyotypes. The methylation levels of several identified differentially methylated genes were analyzed in 22 embryos from spontaneous abortions with monosomy X compared with 11 embryos from medical abortions using targeted bisulfite massive parallel sequencing.

Results: Compared with embryos with 46,XX and 46,XY karyotypes, respectively, differentially methylated CpG sites in embryos with monosomy X were located in 831 and 254 differentially methylated genes (DMGs). However, only 74 DMGs were unique for 45,X embryos after subtraction of the DMG of spontaneously aborted embryos with a normal karyotype (n = 4). Compared with embryos of both sexes, 48 genes in embryos with monosomy X were differentially methylated, 21 of which are important in normal placental and embryonic development and whose dysregulation is linked to preeclampsia and embryonic death. Targeted analysis confirmed that the ALCAM gene is hypermethylated and that the BDH1 gene is hypomethylated in embryos with monosomy X.

Conclusion: Aberrant methylation of genes involved in placentation, proliferation, and cell differentiation has been detected in spontaneously aborted embryos with monosomy X. These disorders may be associated with the high lethality of embryos with monosomy X.

The higher incidence of ovarian aging has led to a significant decline in the female fertility rate, raising social concerns about women's health. In recent years, the rapid development of RNA cross-linked proteomics technology has identified the role of RNA-binding proteins (RBPs) in ovarian aging. Ovarian aging disrupts the hypothalamic-pituitary-ovarian axis, resulting in aberrant hormone secretion, irregular menstrual cycles, oocyte apoptosis, and abnormal embryonic development. Given this, we have compiled the role of RNA-binding proteins in ovarian aging and further explored how different ovarian RBPs promote apoptosis and serve as therapeutic targets. We aim to analyze the effects of RNA-binding proteins on ovarian function to provide more explicit ideas for delaying ovarian aging and treating ovarian diseases.

Purpose: Cryptorchidism is one of the most prevalent male congenital abnormalities, affecting 1.6%-9% of newborn males, and it poses substantial risks to male fertility. INSL3 and its receptor RXFP2 play a major role in the first phase of the biphasic testicular descent process. The genetic etiology of cryptorchidism has long remained controversial, and the association between INSL3 gene mutations and cryptorchidism still requires robust evidence to substantiate. This study aims to clarify that the novel homozygous frameshift variants of INSL3 are the genetic cause of cryptorchidism in patients.

Methods: Whole-exome sequencing (WES) and Sanger sequencing were performed on peripheral blood samples collected from two infertile patients with cryptorchidism. The AlphaFold database and PyMOL software were used to predict the 3D structure of INSL3 protein. In vitro analyses were performed to determine the effects of the identified INSL3 variants on protein function.

Results: We identified two novel homozygous frameshift variants (NM_005543:c.176_182delCGACCGG:p.Ala59GlufsTer66 for F1-II-1; c.148dupC:p.Arg50ProfsTer16 for F2-II-1) in INSL3. Both variants were absent or rare from public databases. Prediction of 3D protein structure indicated that INSL3 variants caused alterations in the spatial conformation of the protein. In vitro experiments further confirmed that these variants led to the production of truncated proteins, which potentially disrupt the function of INSL3 and its interaction with RXFP2.

Conclusion: In this study, two novel homozygous frameshift variants in INSL3 were detected in two patients with cryptorchidism. These findings strengthen the link between INSL3 mutations and male infertility caused by cryptorchidism.

Purpose: To investigate whether the magnitude of estradiol (E₂) decline from hCG trigger day to post-retrieval day 2 impacts clinical outcomes of fresh embryo transfers in high responders undergoing GnRH antagonist ovarian stimulation cycles.

Methods: This retrospective cohort study analyzed 1859 fresh embryo transfer cycles (high responders, January 2018-December 2021) under antagonist protocols. Final oocyte maturation was triggered with GnRHa, hCG, or dual trigger. Serum E₂ was measured on trigger day and 48 h post-retrieval. Patients were stratified by E₂ ratio (post-retrieval day 2/hCG day): low (≤ 0.2, n = 202) vs. high (> 0.2, n = 1657). Multivariate logistic regression compared clinical pregnancy rates (CPR) and live birth rates (LBR) between groups. Given the substantial sample size imbalance between groups (1:8 ratio), we implemented bootstrap adjustment with 1000 replicates to address potential estimation bias.

Results: Mean patient age was 31.0 years; 82.0% involved day 3 transfers. Overall CPR and LBR were 56.2% and 45.2%, respectively. The low E₂ ratio group (≤ 0.2) showed significantly reduced CPR (46.5% vs. 57.3%; aOR = 1.38, 95% BCa CI = (0.04, 0.67), bootstrap "p" = 0.031) and LBR (35.6% vs. 46.3%; aOR = 1.42, 95% BCa CI = (0.04, 0.64), bootstrap "p" = 0.028) compared to the high-ratio group (> 0.2).

Conclusion: A post-retrieval E₂ ratio ≤ 0.2 predicts significantly decreased CPR and LBR in fresh embryo transfers under GnRH antagonist protocols. This ratio may serve as a clinical criterion for outcome prediction.

Purpose: To determine the optimal hCG dose in a dual hCG/GnRH agonist trigger for comparable pregnancy outcomes to hCG, while maintaining low OHSS rates in good-prognosis patients.

Subjects: This retrospective cohort study included patients aged 18-41 years undergoing IVF or IVF/ICSI with fresh embryo transfer from 2013 to 2024. Patients received either hCG-only (5,000-10,000 IU hCG/250-500 mcg Ovidrel) or dual trigger (1,500-2,000 IU hCG + 2 mg GnRH agonist).

Results: A total of 2641 cycles were analyzed (1,939 hCG-only, 616 1,500 IU hCG dual trigger, and 86 2,000 IU hCG dual trigger). The 2,000 IU hCG dual trigger group yielded more mature oocytes (16.0 vs. 11.6, aRR 1.29), fertilized embryos (12.9 vs. 8.8, aRR 1.43), and blastocysts (8.0 vs. 4.9, aRR 1.55) than hCG-only. Implantation rates were higher with 2,000 IU hCG dual trigger than hCG-only (50.0% vs. 32.0%, RR 1.56), with a dose-dependent improvement within the dual trigger groups (50.0% at 2,000 IU vs. 36.4% at 1,500 IU, RR 1.37). Ongoing pregnancy rates were similar between 2,000 IU hCG dual trigger and hCG-only (46.8% vs. 39.5%, aRR 1.12), but lower with 1,500 IU hCG dual trigger (46.8% vs. 37.6%, aRR 1.37). OHSS rates were low across all groups.

Conclusion: 2,000 IU hCG appears to be the optimal dose in a dual hCG/GnRH agonist trigger, resulting in similar pregnancy outcomes to an hCG trigger and low rates of OHSS among good-responder patients. Ongoing pregnancy rates were significantly lower with hCG doses under 2,000 IU in the dual trigger protocol.