Polycystic Ovary Syndrome: Impact of Lipotoxicity on Metabolic and Reproductive Health.

IMPORTANCE: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of reproductive-aged women. Women with PCOS are at increased risk of developing several metabolic and reproductive abnormalities, including metabolic syndrome. Underlying the combined metabolic and reproductive dysfunction is lipotoxicity, defined as the ectopic deposition of lipid in nonadipose tissue where it induces oxidative stress linked with insulin resistance and inflammation. OBJECTIVE: To examine what metabolic components underlie insulin resistance in PCOS, how lipotoxicity through insulin resistance impairs metabolism and reproduction in these women, and why evidence-based, individualized management is essential for their care. EVIDENCE ACQUISITION: PubMed search was performed using relevant terms to identify journal articles related to the subject. Relevant textbook chapters were also used. RESULTS: Polycystic ovary syndrome by Rotterdam criteria represents a complex syndrome of heterogeneous expression with variable adverse metabolic and reproductive implications. Women with classic PCOS are often insulin resistant and at greatest risk of developing metabolic syndrome with preferential fat accumulation and weight gain. Moreover, PCOS women may also have an altered capacity to properly store fat, causing ectopic lipid accumulation in nonadipose tissue, including the ovaries, where it can perpetuate insulin resistance and inflammation and harm the oocyte. CONCLUSIONS AND RELEVANCE: A personalized approach to managing PCOS is essential to improve the health of all PCOS women through cost-effective prevention and/or treatment, to minimize the risk of pregnancy complications in those individuals wishing to conceive, and to optimize the long-term health of PCOS women and their offspring.

Transfer of embryos with segmental mosaicism is associated with a significant reduction in live-birth rate.

OBJECTIVE: To evaluate the impact of segmental mosaicism on pregnancy outcomes from the transfer of embryos previously designated as euploid. DESIGN: Retrospective cohort analysis. SETTING: Single, private, high-volume fertility center. PATIENT(S): Three hundred and twenty-seven women who underwent 377 frozen single euploid embryo transfers. INTERVENTION(S): Trophectoderm biopsy of embryos cultured to the blastocyst stage, where all transferred embryos were designated euploid by high-density oligonucleotide array comparative genomic hybridization (aCGH); after ascertaining all outcomes, revaluation of aCGH results for evidence of segmental mosaicism (defined as mosaicism on a portion of a chromosome). MAIN OUTCOME MEASURE(S): Live-birth rate and spontaneous abortion rate. RESULT(S): Of the 377 embryos transferred, 357 were euploid with no mosaicism, and 20 embryos had segmental mosaicism. Segmental mosaics had a statistically significantly lower live-birth rate compared with euploid controls (30.0% vs. 53.8%). When controlling for age and day of Trophectoderm biopsy, the odds for live birth after transfer of segmental mosaics were reduced by 66% compared with euploid controls (0.34; 95% confidence interval, 0.13-0.92). The spontaneous abortion rate was statistically significantly higher after transfer of segmental mosaics compared with euploid controls (40.0% vs. 18.2%). CONCLUSION(S): Blastocysts with segmental mosaicism have reduced reproductive potential but retain the ability to result in live birth. These results support reporting segmental mosaicism to optimize selection of a single embryo for transfer that will maximize the chance of life birth.

Earlier day of blastocyst development is predictive of embryonic euploidy across all ages: essential data for physician decision-making and counseling patients.

PURPOSE: The purpose of this study is to evaluate whether day of blastocyst development is associated with embryo chromosomal status as determined by high-density oligonucleotide microarray comparative genomic hybridization (aCGH). METHODS: This is a retrospective cohort analysis, including women who underwent in vitro fertilization (IVF) with trophectoderm biopsy at a single private fertility center from January 2014 to December 2014. Repeat cycles were excluded. Cycles were assessed for percentage of blastocysts biopsied on days 5, 6, or 7 and rate of euploid embryos per cycle. Cycles were stratified by Society for Assisted Reproductive Technology (SART) age groups (< 35, 35-37, 38-40, 41-42, > 42) and by donor status. RESULTS: A total of 388 IVF cycles and 2132 biopsied blastocysts were evaluated. The percentages of blastocysts biopsied on days 5, 6, and 7 were 62.5, 35.8, and 1.7%, respectively. Blastocyst euploid rates on days 5, 6, and 7 were 49.5, 36.5, and 32.9%, respectively. Earlier blastocyst development was associated with a significantly increased euploid rate (p < 0.0001). Younger maternal age (p < 0.0001) and higher number of blastocysts biopsied per patient (p = 0.0063) were both independently associated with greater percentage of euploidy. CONCLUSIONS: Earlier blastocyst development is independently associated with a higher likelihood of embryonic euploidy in both autologous and donor embryos. In non-biopsied embryos, these data support selection of day 5 blastocysts for transfer over later-developing embryos. These results can assist with patient counseling regarding expectations and outcomes. To our knowledge, this is the first study to examine embryonic euploidy as stratified by both day of blastocyst development and SART age group.

Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation.

Pregnancies resulting from fresh in vitro fertilization (IVF) cycles exposed to supraphysiologic estrogen levels have been associated with higher rates of low birth weight and small for gestational age babies. We identified GATA3, a transcription factor selectively expressed in the trophectoderm during the blastocyst stage of embryo development, in an upstream analysis of genes that were differentially methylated in chorionic villus samples between IVF and non-IVF infertility treatment pregnancies. In this study, we investigate the hypothesis that GATA3 is hormonally regulated and plays an important functional role in trophoblast migration, invasion, and placentation. We found that GATA3 expression was hormonally regulated by estradiol in HTR8/SVneo first trimester trophoblast cells; however, no change in expression was seen with progesterone treatment. Furthermore, GATA3 knockdown resulted in decreased HTR8/SVneo cell migration and invasion compared with controls. RNA sequencing of GATA3 knockdown cells demonstrated 96 differentially regulated genes compared with controls. Genes known to play an important role in cell-cell and cell-extracellular matrix interactions, cell invasion, and placentation were identified, including CTGF, CYR61, ADAMTS12, and TIMP3 Our results demonstrate estradiol down-regulates GATA3, and decreased GATA3 expression leads to impaired trophoblast cell migration and invasion, likely through regulation of downstream genes important in placentation. These results are consistent with clinical data suggesting that supraphysiologic estrogen levels seen in IVF pregnancies may play an important role in attenuated trophoblast migration, invasion, and impaired placentation. GATA3 appears to be an important regulator of placentation and may play a role in impaired outcomes associated with fresh IVF cycles.

Increased blastomere number in cleavage-stage embryos is associated with higher aneuploidy.

OBJECTIVE: To evaluate the relationship between blastomere number and aneuploidy. DESIGN: Historical cohort study. SETTING: In vitro fertilization clinic. PATIENT(S): Two hundred fifty-nine patients undergoing in vitro fertilization (IVF) in combination with comprehensive chromosomal screening of embryos. INTERVENTION(S): A total of 1,915 embryos were biopsied on day 3 and underwent comprehensive chromosomal screening with microarray-based comparative genomic hybridization. MAIN OUTCOME MEASURE(S): Relationship between day 3 blastomere number, aneuploidy rate, and progression to the blastocyst stage. RESULT(S): A number of day 3 blastomeres >9 was associated with significantly increased aneuploidy rates. Rapidly developing embryos were significantly more likely to blastulate regardless of their chromosomal status. Number of embryos per patient greater than 13 was independently associated with lower aneuploidy rates after controlling for maternal age. This trend was not significant with the use of a more clinically relevant threshold of greater than six embryos per patient. CONCLUSION(S): Embryos with 6-9 cells at the cleavage stage should be considered for transfer over embryos with >9 cells. Day 3 blastomere number may be used in conjunction with extended culture to improve selection of euploid embryos, especially when supernumerary embryos are available. Further studies are needed to show if these selection criteria improve clinical outcomes.