Impact of dehydroepiandrosterone sulfate and free androgen index on pregnancy and neonatal outcomes in PCOS patients.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder associated with infertility and pregnancy complications. The pathogenesis of PCOS and its impact on reproductive function may be influenced by the source of androgens, including testosterone, free androgen, dehydroepiandrosterone sulfate (DHEAS). However, the differential effects of these androgen on pregnancy and neonatal outcomes and the cut-off value of East Asian population with PCOS remain unclear. METHODS: A retrospective cohort study was conducted at the Reproductive Medicine Center of the First Affiliated Hospital of Sun Yat-sen University from January 2015 to November 2022, involving 636 cycles of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Subgroup analyses were performed using cut-off values of 6.4 for free androgen index (FAI), 9.5 µmol/L for DHEAS. Pregnancy and neonatal outcomes were compared between groups. Restricted cubic spline (RCS) was used to identify significant cut-off values affecting pregnancy. RESULTS: Higher FAI levels (> 6.4) were associated with decrease in clinical pregnancy rate (PR) (50.61% vs. 41.66%, p = 0.024), live birth rate (LBR) (42.42% vs. 32.35%, p = 0.011). When DHEAS levels exceeded 9.5 µmol/L, there was a significant decrease in clinical PR (51.27% vs. 42.73%, P = 0.039), LBR (42.73% vs. 32.73%, P = 0.012). Negative correlations were also observed between DHEAS levels and cumulative pregnancy rate (70.57% vs 56.62% p = 0.002) and cumulative live birth rate (CLBR) (59.35% vs 43.37%, p = 0.0007). Both FAI and DHEAS elevated is associated with the lowest clinical pregnancy rate (37.84%). Conversely, when solely FAI is elevated, the pregnancy rate increases to 52.38%, while an elevation in DHEAS alone is associated with a pregnancy rate of, both of which are lower than when neither FAI nor DHEAS are elevated (60.68%). The live birth rates exhibit a similar trend (30.00% vs 40.00% vs 41.83% vs 44.48%). RCS revealed a significant decrease in CPR and CLBR when DHEA levels exceeded 7.69 umol/L, while the cut-off value of FAI was 6.36 for CPR and CLBR. CONCLUSION: In conclusion, PCOS patients with biochemical hyperandrogenism show unsatisfactory clinical PR and CLBR when undergoing assisted reproductive technology (ART). This may be attributed to the influence of both adrenal-derived DHEAS and ovarian-derived FAI on the unfavorable pregnancy outcomes.

GDF9His209GlnfsTer6/S428T and GDF9Q321X/S428T bi-allelic variants caused female subfertility with defective follicle enlargement.

BACKGROUND: Antral follicles consist of an oocyte cumulus complex surrounding by somatic cells, including mural granulosa cells as the inner layer and theca cells as the outsider layer. The communications between oocytes and granulosa cells have been extensively explored in in vitro studies, however, the role of oocyte-derived factor GDF9 on in vivo antral follicle development remains elusive due to lack of an appropriate animal model. Clinically, the phenotype of GDF9 variants needs to be determined. METHODS: Whole-exome sequencing (WES) was performed on two unrelated infertile women characterized by an early rise of estradiol level and defect in follicle enlargement. Besides, WES data on 1,039 women undergoing ART treatment were collected. A Gdf9Q308X/S415T mouse model was generated based on the variant found in one of the patients. RESULTS: Two probands with bi-allelic GDF9 variants (GDF9His209GlnfsTer6/S428T, GDF9Q321X/S428T) and eight GDF9S428T heterozygotes with normal ovarian response were identified. In vitro experiments confirmed that these variants caused reduction of GDF9 secretion, and/or alleviation in BMP15 binding. Gdf9Q308X/S415T mouse model was constructed, which recapitulated the phenotypes in probands with abnormal estrogen secretion and defected follicle enlargement. Further experiments in mouse model showed an earlier expression of STAR in small antral follicles and decreased proliferative capacity in large antral follicles. In addition, RNA sequencing of granulosa cells revealed the transcriptomic profiles related to defective follicle enlargement in the Gdf9Q308X/S415T group. One of the downregulated genes, P4HA2 (a collagen related gene), was found to be stimulated by GDF9 protein, which partly explained the phenotype of defective follicle enlargement. CONCLUSIONS: GDF9 bi-allelic variants contributed to the defect in antral follicle development. Oocyte itself participated in the regulation of follicle development through GDF9 paracrine effect, highlighting the essential role of oocyte-derived factors on ovarian response.

Higher Cumulative Live Birth Rate but Also Higher Late Miscarriage Risk in Non-Obese Women with Polycystic Ovary Syndrome Undergoing the First IVF/ICSI Cycle.

Purpose: To determine the impact of polycystic ovary syndrome on in vitro fertilization/intracytoplasmic sperm injection and embryo transfer outcomes while analyzing the influencing factors. Patients and Methods: A retrospective cohort study comprised 4839 patients who underwent their first cycle of IVF/ICSI treatment from January 2016 to December 2021. Cumulative pregnancy rates, cumulative live birth rates, and late miscarriage rates compared between the PCOS group and control group. Subgroup analysis and binary regression were used to analyze the influence of BMI on clinical outcomes among individuals diagnosed with PCOS. Results: Non-obese PCOS patients exhibited higher cumulative pregnancy rates, cumulative live birth rates, and late miscarriage rates compared to the control group with the normal BMI population (84.7% vs71.2%, P < 0.001; 74.1% vs 61.6%, P < 0.001; 4.1% vs 2.0%, P = 0.002), but there was no significant difference in early miscarriage rates between the two groups. Conclusion: Non-obese PCOS patients demonstrated a notably higher cumulative live birth rate but also a higher risk of late miscarriage compared to non-PCOS females with a normal BMI.

An Incidental Detection of a Rare UPD in SNP-Array Based PGT-SR: A Case Report.

Uniparental disomies (UPD) refers to the inheritance of both homologs of a chromosome from only one parent with no representative copy from the other parent. UPD was with an estimated prevalence of 0.15‰ in population. Current understanding of UPD was limited to subjects for which UPD was associated with clinical manifestation due to imprinting disorders or recessive diseases. Segmental UPD was rare, especially for a segmental UPD with a combination of hetero- and isodisomy. This paper presents a couple with reciprocal translocation 46,XY, t(14;22)(q32.3;q12.2) for PGT-SR. Among 8 biopsied blastocysts, one euploid blastocyst (No.4) with segmental loss of heterozygosity (LOH)(22) [arr[hg19] q12.1q22.3 (28,160,407 - 35,407,682)] was detected by B allele frequency. We found the chromosome contained both UPiD(22) [arr[hg19] q12.1q22.3 (28,160,407 - 35,407,682) ×2 hmz mat] and UPhD(22) [arr[hg19] q22.3qter(35,407,682 - 51,169,045) ×2 htz mat] by haplotype analysis. UPDtool software confirmed the result. What's more, the segmental UPD and reciprocal translocation shared the same breakpoint, chr22q12.1 (28,160,407), while the breakpoint between iso- and heterodisomy was chr22q22.3 (35,407,682). We reported the first segmental UPD with a combination of hetero- and isodisomy, which may result from aneuploidy rescue. This case emphasizes the importance of the combination of comprehensive chromosome screening and haplotype analysis to reduce the risk of misdiagnosis.

Causal relationships exist between polycystic ovary syndrome and adverse pregnancy and perinatal outcomes: a Mendelian randomization study.

Introduction: Previous observational studies have shown that polycystic ovary syndrome (PCOS) was associated with adverse pregnancy and perinatal outcomes. However, it remains controversial whether PCOS is an essential risk factor for these adverse pregnancy and perinatal outcomes. We aimed to use instrumental variables in a two-sample Mendelian randomization (MR) study to determine causality between PCOS and adverse pregnancy and perinatal outcomes. Materials and methods: Summary statistics were extracted from a recent genome-wide association study (GWAS) meta-analysis conducted in PCOS, which included 10,074 cases and 103,164 controls of European ancestry. Data on Adverse pregnancy and perinatal outcomes were summarized from the FinnGen database of European ancestry, which included more than 180,000 samples. The inverse variance weighted (IVW) method of MR was applied for the main outcome. To assess heterogeneity and pleiotropy, we conducted sensitivity analyses, including leave-one-out analysis, weighted median, MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier), and MR-Egger regression. Results: Two-sample MR analysis with the IVW method suggested that PCOS exerted causal effects on the risk of hypertensive disorders of pregnancy [odds ratio (OR) 1.170, 95% confidence interval (CI) 1.051-1.302, p = 0.004], in particular gestational hypertension (OR 1.083, 95% CI 1.007-1.164, p = 0.031), but not other pregnancy and perinatal diseases (all p > 0.05). Sensitivity analyses demonstrated pleiotropy only in pre-eclampsia or eclampsia (p = 0.0004), but not in other pregnancy and perinatal diseases (all p > 0.05). The results remained consistent after excluding two outliers (all p > 0.05). Conclusions: We confirmed a causal relationship between PCOS and hypertensive disorders of pregnancy, in particular gestational hypertension, but no association with any other adverse pregnancy or perinatal outcome. Therefore, we suggest that women with PCOS who are pregnant should have their blood pressure closely monitored.