149 research outputs found

    The utility of all-freeze IVF cycles depends on the composition of study populations

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    Abstract Background Because often introduced without proper validation studies, so-called “add-ons” to IVF have adversely affected in vitro fertilization (IVF) outcomes worldwide. All-freeze cycles (embryo banking, EB) with subsequently deferred thaw cycles are such an “add-on” and, because of greatly diverging reported outcomes, have become increasingly controversial. Based on “modeling” with selected patient populations, we in this study investigated whether reported outcome discrepancies may be the consequence of biased patient selection. Results In four distinct retrospective case control studies, we modeled in four cohort pairings how cryopreservation with subsequent thaw cycles affects outcomes differently in good-, average- and poor-prognosis patients: (i) 127 fresh vs. 193 frozen donor-recipient cycles to model best-prognosis patients; (ii) 741 autologous fresh non-donor IVF cycles vs. 217 autologous frozen non-donor IVF cycles to model average prognosis patients; (iii) 143 favorably selected autologous non-donor IVF cycles vs. the same 217 frozen autologous cycles non-donor to monitor good- vs. average-prognosis patients; and (iv) 598 average and poor-prognosis autologous non-donor cycles vs. the same 217 frozen autologous non-donor cycles to model poor vs. average prognosis patients. In best-prognosis patients, EB marginally improved IVF outcomes. In unselected patients, EB had no effects. In poor-prognosis patients, EB adversely affected IVF outcomes. Unexpectedly, the study also discovered independent-of-age-associated chromosomal abnormalities, a previously unreported effect of recipient age on miscarriage risk in donor-egg recipients. Conclusions In poor-prognosis patients, EB cycles should be considered contraindicated. In intermediate-prognosis patients EB does not appear to change outcomes, not warranting additional cost and time delays. Therefore, only good-prognosis patients are candidates for EB, though they will experience only marginal benefits that may not be cost-effective

    Changing clinical significance of oocyte maturity grades with advancing female age advances precision medicine in IVF

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    Summary: In current IVF practice, metaphase-2 (M2) oocytes are considered most efficient in producing good quality embryos. Maximizing their number at all ages is standard clinical practice, while immature germinal vesicle (GV) oocytes are mostly automatically discarded. We present preliminary evidence that oocyte maturity grades with advancing age significantly change in their abilities to produce good quality embryos, with M2 oocytes significantly declining, GV oocytes improving, and M1 oocytes staying the same. These data contradict the over-40-year-old dogma that oocyte grades functionally do not change with advancing age, supporting potential changes to current IVF practice: (1) Stimulation protocols and timing of oocyte retrieval can be adjusted to a patient’s age and ovarian function. (2) In older and younger women with prematurely aging ovaries, GV oocytes may no longer be automatically discarded. (3) In some infertile women, rescue in vitro maturation of immature oocytes may delay the need for third-party egg donation

    Reconsidering the Polycystic Ovary Syndrome (PCOS)

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    Though likely the most common clinical diagnosis in reproductive medicine, the Polycystic Ovary Syndrome (PCOS) is still only poorly understood. Based on previously published research, and here newly presented supportive evidence, we propose to replace the four current phenotypes of PCOS with only two entities—a hyperandrogenic phenotype (H-PCOS) including current phenotypes A, B, and C, and a hyper-/hypoandrogenic phenotype (HH-PCOS), representing the current phenotype D under the Rotterdam criteria. Reclassifying PCOS in this way likely establishes two distinct genomic entities, H-PCOS, primarily characterized by metabolic abnormalities (i.e., metabolic syndrome) and a hyperandrogenic with advancing age becoming a hypoandrogenic phenotype (HH-PCOS), in approximately 85% characterized by a hyperactive immune system mostly due to autoimmunity and inflammation. We furthermore suggest that because of hypoandrogenism usually developing after age 35, HH-PCOS at that age becomes relatively treatment resistant to in vitro fertilization (IVF) and offer in a case-controlled study evidence that androgen supplementation overcomes this resistance. In view of highly distinct clinical presentations of H-PCOS and HH-PCOS, polygenic risk scores should be able to differentiate between these 2 PCOS phenotypes. At least one clustering analysis in the literature is supportive of this concept

    Expected advances in human fertility treatments and their likely translational consequences

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    Abstract Background Due to rapid research progress in reproductive biology and reproductive clinical endocrinology, many human infertility treatments are close to potential breakthroughs and translational applications. We here review current barriers, where such breakthroughs will likely come from, what they will entail, and their potential clinical applications. Main text The radical nature of change will primarily benefit older women, reduce fertility treatment costs and thereby expand access to treatment. A still widely overlooked prerequisite for implantation and normal pregnancy maintenance is timely development of maternal immunological tolerance toward an implanting paternal semi-allograft, if malfunctioning associated with implantation failure and pregnancy loss, while premature termination of tolerance appears associated with premature labor, pre-eclampsia/eclampsia and gestoses of pregnancy. Common denominators between pregnancy and invasive malignancies have again been attracting attention, suggesting that, like in malignant tumors, degrees of embryo aneuploidy may affect invasiveness and ability to “disarm” the immune system’s innate response against implanting embryos. Linking tolerance to implantation, we offer evidence that the so-called “implantation window” is likely immunological rather than hormonally defined. Conclusions Because many here outlined treatment changes will disproportionally benefit older women, they will exert a pronounced effect on society, as increasing numbers of women at grandparental ages will become mothers

    Reduced RNA expression of the FMR1 gene in women with low (CGGn<26) repeats.

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    Low FMR1 variants (CGGn<26) have been associated with premature ovarian aging, female infertility and poor IVF treatment success. Until now, there is little published information concerning possible molecular mechanisms for this effect. We wished to examine whether relative expression of RNA and the FMR1 gene's fragile X mental retardation protein (FMRP) RNA isoforms differ in women with various FMR1 sub-genotypes (normal, low CGGn<26 and/or high CGGn≥34). This prospective cohort study was conducted between 2014 and 2017 in a clinical research unit of the Center for Human Reproduction in New York City. The study involved a total of 98 study subjects, including 18 young oocyte donors and 80 older infertility patients undergoing routine in vitro fertilization (IVF) cycles. The main outcome measure was RNA expression in human luteinized granulosa cells of 5 groups of FMRP isoforms. The relative expression of FMR1 RNA in human luteinized granulosa cells was measured by real-time PCR and a possible association with CGGn was explored. All 5 groups of FMRP RNA isoforms examined were found to be differentially expressed in human luteinized granulosa cells. The relative expression of four FMR1 RNA isoforms showed significant differences among 6 FMR1 sub-genotypes. Women with at least one low allele expressed significantly lower levels of all 5 sets of FRMP isoforms in comparison to the non-low group. While it would be of interest to see whether FMRP is also decreased in the low-group we recognize that in recent years it has been increasingly documented that information flow of genetics may be regulated by non-coding RNA, that is, without translation to a protein product. We, thus, conclude that various CGG expansions of FMR1 allele may lead to changes of RNA levels and ratios of distinct FMRP RNA isoforms, which could regulate the translation and/or cellular localization of FMRP, affect the expression of steroidogenic enzymes and hormonal receptors, or act in some other epigenetic process and therefore result in the ovarian dysfunction in infertility

    New national outcome data on fresh versus cryopreserved donor oocytes

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    Abstract Background Improvements in oocyte cryopreservation techniques and establishment of cryopreserved donor oocyte banks have led to improved access to and lower cost of donor oocytes, upending the traditional practice of fresh oocyte donation. The objective of this study was to examine national trends in utilization and live birth rates with fresh versus cryopreserved donor oocytes. Methods A retrospective analysis of 2013 through 2015 aggregate U.S. national data reported by the Society for Assisted Reproductive Technology which included 30,160 IVF cycles with either fresh or cryopreserved donor oocytes was performed. Results During the study period utilization of fresh oocyte donations rapidly declined by 32.9%, while cryopreserved oocyte donation increased by 44.4%. Fresh donor oocytes produced significantly higher live birth rates per recipient cycle start than cryopreserved donor oocytes (51.1% vs. 39.7%). Over the three-year study period fresh donor oocytes produced stable live birth rates per recipient cycle start while those with cryopreserved oocytes significantly declined year-by-year. Conclusion Despite rising popularity of cryopreserved donor oocytes, prospective patients should be counselled that fresh donor oocytes still represent standard of care due to higher live birth rates

    With low ovarian reserve, Highly Individualized Egg Retrieval (HIER) improves IVF results by avoiding premature luteinization

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    Abstract Background Highly Individualized Egg Retrieval (HIER), defined as age-specific early oocyte retrieval (ER), has been demonstrated to avoid premature luteinization in women ≥43. We here investigated whether HIER also applies to younger women with premature ovarian aging (POA), and what best lead follicle size should be for administration of ovulation-triggers. Methods Fifty-six women ≥43, and 37 POA patients underwent IVF cycles. Granulosa cells (GCs) were isolated, cultures were established, RNA was extracted and real-time PCR analyses performed, with gene expressions at mRNA level investigated for FSH receptor (FSHR), luteinizing hormone receptor (LHCPR), P450 aromatase (CYP19a1) and progesterone receptor (PGR). POA was defined by age < 40, FSH above 95%CI and/or AMH below 95%CI for age. Women ≥43 years were divided into very early retrieval (VER), with human chorionic gonadotropin (hCG) trigger at 13.5–15.5 mm, ER at 16.0–18.0 mm or standard retrievel (SR) at 18.5–20.5 mm; POA patients were divided into ER and SR. Pregnancy rates and and molecular markers of premature luteinization (PL) were main outcome measures. Results ER resulted in a significantly higher clinical pregnancy rate (16.7%) than VER (5.9%) or SR (6.7%; both P < 0.05). Molecular markers of PL were highest with SR and lowest with VER. In POA, ER improved pregnancy chances even more than in women ≥43 (7.7% with SR vs. 41.7% with ER), while also reducing molecular markers of PL. With low ovarian reserve (LOR), by avoiding PL, ER with hCG trigger at 16.0–18.0 mm, thus, improves clinical pregnancy rates at all ages. As VER demonstrated lowest molecular PL marker but equally poor pregnancy rates as SR, too early ovulation triggers, likely, result in cytoplasmatic immaturity. Conclusions HIER is even more effective in POA patients than women above age 43, demonstrating that HIER should be further investigated going into even more advanced ages

    Degree of mosaicism in trophectoderm does not predict pregnancy potential: a corrected analysis of pregnancy outcomes following transfer of mosaic embryos

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    Abstract Background Preimplantation genetic screening (PGS) is increasingly utilized as an adjunct procedure to IVF. Recently healthy euploid live birth were reported following transfer of mosaic embryos. Several recent publications have surmised that the degree of trophectoderm (TE) mosaicism in transferred embryos is predictive of ongoing pregnancy and miscarriage rates. Methods This is a corrected analysis of previously published retrospective data on vitro fertilization (IVF) cycle outcomes involving replacement of 143 mosaic and 1045 euploid embryos tested by PGS, utilizing high-resolution next-generation sequencing (NGS) of TE and determination of percentages of mosaicism. Receiver operating curves (ROCs) and measurement of area under the curve (AUC) were used to evaluated the accuracy of the predictor variable, proportion of aneuploid cells in a TE biopsy specimen, with IVF outcomes, ongoing pregnancy and miscarriage rates. Results Confirming findings of the previously published report we also found higher ongoing pregnancy rates (63.3% vs. 39.2%) and lower miscarriage rates (10.2% vs. 24.3%) with euploid embryo transfers than with mosaic embryo transfer. There, however, were no significant differences in ongoing pregnancy or miscarriage rates among mosaic embryo transfers at any threshold of aneuploidy. Based on AUC, TE biopsies predicted ongoing pregnancy for euploid, as well as mosaic embryos, in a range of 0.50 to 0.59 and miscarriage in a range from 0.50 to 0.66 Conclusions Degree of TE mosaicism was a poor predictor of ongoing pregnancy and miscarriage
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