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Gleicher N.,The Center for Human Reproduction | Gleicher N.,Foundation Medicine | Kushnir V.A.,The Center for Human Reproduction | Barad D.H.,The Center for Human Reproduction | Barad D.H.,Foundation Medicine
Reproductive Biology and Endocrinology | Year: 2015

Background: Approximately 10% of women suffer from premature ovarian senescence (POS), ca. 9% as occult primary ovarian insufficiency (OPOI, also called premature ovarian aging, POA) and ca. 1% as primary ovarian insufficiency (POI, also called premature ovarian failure, POF). In a large majority of cases POS is currently only diagnosed at advanced clinical stages when women present with clinical infertility. Methods: We here, based on published evidence, suggest a new diagnostic paradigm, which is based on identifying young women at increased risk for POS at much earlier stages. Results: Risk factors for POS are known from the literature, and can be used to identify a sub-group of young women at increased risk, who then are followed sequentially with serial assessments of functional ovarian reserve (FOR) until a diagnosis of POS is either reached or refuted. At approximately 25% prevalence in general U.S. populations (and somewhat different prevalence rates in more homogenous Asian and African populations), so-called low (CGGn<26) mutations of the fragile X mental retardation 1 (FMR1) gene, likely, represents the most common known risk factor, including history-based risk factors from medical, genetic and family histories. Conclusions: Women so affirmatively diagnosed with POS at relative young ages, then have the opportunity to reconsider their reproductive planning and/or choose fertility preservation via oocyte or ovarian tissue cryopreservation at ages when such procedures are clinically much more effective and, therefore, also more cost-effective. Appropriate validation studies will have to precede widespread utilization of this paradigm. © Gleicher et al.; licensee BioMed Central.


Weghofer A.,The Center for Human Reproduction | Weghofer A.,Medical University of Vienna | Tea M.-K.,Medical University of Vienna | Barad D.H.,The Center for Human Reproduction | And 6 more authors.
PLoS ONE | Year: 2012

BRCA1/2 mutations and recently described constitutional FMR1 genotypes have, independently, been associated with prematurely diminished ovarian reserve. Whether they interrelate in distribution, and whether observed effects of BRCA1/2 and FMR1 on ovaries are independent of each other, is unknown. In a prospective comparative cohort study, we, therefore, investigated the distribution of constitutional FMR1 genotypes, normal (norm), heterozygous (het) and homozygous (hom), and of their respective sub-genotypes (high/low), in 99 BRCA1/2 mutation-positive women and 410 female controls to determine whether distribution patterns differed between study and control patients. In contrast to controls, BRCA1/2 carriers demonstrated almost complete absence of all constitutional FMR1 genotypes except for sub-genotypes with low (CGG n<26) alleles. Cross tabulation between BRCA1/2-positive patients and controls confirmed significant group membership, related to FMR1 distribution (P<0.0001). These results offer as most likely explanation the conclusion that BRCA1/2 mutations are embryo-lethal, unless rescued by low (CGG n<26) FMR1 sub-genotypes, present in approximately one quarter of all women. Women with low FMR1 sub-genotypes, therefore, should reflect increased BRCA1/2-associated cancer risks, while the remaining approximately 75 percent should face almost no such risks. If confirmed, this observation offers opportunities for more efficient and less costly BRCA1/2 cancer screening. The study also suggests that previously reported risk towards prematurely diminished ovarian reserve in association with BRCA mutations is FMR1-mediated, and offers a possible explanation for the so-called "BRCA paradox" by raising the possibility that the widely perceived BRCA1/2-associated tumor risk is actually FMR1-mediated. © 2012 Weghofer et al.


Gleicher N.,The Center for Human Reproduction | Gleicher N.,Foundation Medicine | Kim A.,The Center for Human Reproduction | Weghofer A.,The Center for Human Reproduction | And 3 more authors.
Reproductive Biology and Endocrinology | Year: 2012

Background: Ovarian aging patterns differ between races, and appear to affect fertility treatment outcomes. What causes these differences is, however, unknown. Variations in ovarian aging patterns have recently been associated with specific ovarian genotypes and sub-genotypes of the FMR1 gene. We, therefore, attempted to determine differences in how functional ovarian reserve (FOR) changes with advancing age between races, and whether changes are associated with differences in distribution of ovarian genotypes and sub-genotypes of the FMR1 gene.Methods: We determined in association with in vitro fertilization (IVF) FOR in 62 young Caucasian, African and Asian oocyte donors and 536 older infertility patients of all three races, based on follicle stimulating hormone (FSH), anti-Müllerian hormone (AMH) and oocyte yields, and investigated whether differences between races are associated with differences in distribution of FMR1 genotypes and sub-genotypes.Results: Changes in distribution of mean FSH, AMH and oocyte yields between young donors and older infertility patients were significant (all P < 0.001). Donors did not demonstrate significant differences between races in AMH and FSH but demonstrated significant differences in oocyte yields [F(2,59) = 4.22, P = 0.019]: Specifically, African donors demonstrated larger oocyte yields than Caucasians (P = 0.008) and Asians (P = 0.022). In patients, AMH levels differed significantly between races [F (2,533) = 4.25, P = 0.015]. Holm-Sidak post-hoc comparisons demonstrated that Caucasians demonstrated lower AMH in comparison to Asians (P = 0.007). Percentages of FMR1 genotypes and sub-genotypes in patients varied significantly between races, with Asians demonstrating fewer het-norm/low sub-genotypes than Caucasians and Africans (P = 0.012).Conclusion: FOR changes in different races at different rates, and appears to parallel ovarian FMR1 genotypes and sub-genotype distributions. Differences in ovarian aging between races may, therefore, be FMR1-associated. © 2012 Gleicher et al.; licensee BioMed Central Ltd.


Gleicher N.,The Center for Human Reproduction | Gleicher N.,Foundation Medicine | Gleicher N.,Yale University | Weghofer A.,The Center for Human Reproduction | And 4 more authors.
Journal of Autoimmunity | Year: 2012

There, likely, is no more controversial issue in reproductive medicine than the effects of autoimmunity on female reproductive success. Published studies are, therefore, often biased. We performed PubMed, Google Scholar and Medline searches for the years 2000-2010 under various key words and phrases, referring to effects of autoimmunity/autoimmune diseases on pregnancy/pregnancy outcomes/pregnancy rates/reproduction/reproductive outcomes/fertility/infertility/fertility treatments/infertility treatments, and a number of similar terms. Reference lists of selected manuscripts were evaluated for additional, potential references. All selected manuscripts were reviewed by at least one author (N.G.). Opinions were reached based on preferential review of only selected studies, which offered data, primarily developed in pursuit of unrelated scientific questions. Data from various medical fields point, surprisingly effectively, toward significant impacts of autoimmunity on female reproductive success. Autoimmunity not only increases miscarriage risks but also reduces female fecundity and infertility treatment success. A, likely, reason why differences of opinion have persisted is that effects are primarily observed in genetically predisposed women, with specific fragile X mental retardation 1 (FMR1) genotypes. This discovery coincides with recently increasing appreciation of the importance of the long arm of the X chromosome (Xq) in control of functional ovarian reserve (reflective of female fertility) and autoimmunity, with FMR1at Xq27.3, located at cross roads of both. Autoimmune effects on female reproductive success deserve recognition. Further investigations must not ignore patient stratification, based on ovarian FMR1 genotypes. Genetic definition of high-risk patients should lead to development of successful therapeutic interventions. © 2011 Elsevier Ltd.


Gleicher N.,The Center for Human Reproduction | Gleicher N.,Foundation Medicine | Kushnir V.A.,The Center for Human Reproduction | Barad D.H.,The Center for Human Reproduction | Barad D.H.,Foundation Medicine
Reproductive Biology and Endocrinology | Year: 2015

Background: Embryo selection has been an integral feature of in vitro fertilization (IVF) almost since its inception. Since the advent of extended blastocyst stage embryo culture, and especially with increasing popularity of elective single embryo transfer (eSET), the concept of embryo selection has increasingly become a mainstay of routine IVF. Discussion: We here, however, argue that embryo selection via blastocyst stage embryo transfer (BSET), as currently practiced, at best improves IVF outcomes only for a small minority of patients undergoing IVF cycles. For a large majority BSET is either ineffective or, indeed, may actually be harmful by decreasing IVF pregnancy chances. Overall, only a small minority of patients, thus, benefit from prolonged embryo culture, while BSET, as a tool to enhance IVF outcomes, is increasingly utilized as routine care in IVF for all patients. Summary: Since newer methods of embryo selection, like preimplantation genetic screening (PGS) and closed system embryo incubation with time-lapse photography are practically dependent on BSET, these concepts of embryo selection, currently increasingly adopted in mainstream IVF, require reconsideration. They, automatically, transfer the downsides of BSET, including decreases in IVF pregnancy chances in some patients, to these new procedures, and in addition raise serious questions about cost-effectiveness. © Gleicher et al.


Kushnir V.A.,The Center for Human Reproduction | Khanna P.,Mount Sinai School of Medicine | Barad D.H.,The Center for Human Reproduction | Barad D.H.,Foundation Medicine | And 2 more authors.
Reproductive Biology and Endocrinology | Year: 2014

Background: To assess whether an objective performance criterion for in vitro fertilization (IVF) centers can be established. Methods: A retrospective analysis of 2011 National ART Surveillance System data for 451 U.S. IVF centers, 137 of which were included in the analysis since they performed >20 fresh embryo transfers per age group and >20 fresh oocyte donor transfers. The analysis of autologous cycles was restricted to women under age 40. The main outcome measure was correlation between center-specific live birth rates (LBR) in autologous and donor oocyte cycles. Results: 55.6% donor and 46.7%, 39.1% and 28.7% (for ages <35, 35-37 and 38-40 years) autologous cycles resulted in live births per fresh embryo transfer. Donor LBR predicted autologous LBR (< 35 years, P < 0.001; 35 - 38 years, P < 0.001; 38 - 40 years, P = 0.015). Clinics with high prevalence of patients with diminished ovarian reserve had lower autologous LBR per age group (P = 0.015). Every 10% increase in donor LBR increased odds of autologous LBR above the age-adjusted national average by 68% (OR 1.68; 95% CI 1.36 - 2.07; P < 0.001). Conclusions: Since center-specific donor and autologous IVF cycle outcomes correlate, and as donor cycles reflect fewer patient covariates, they represent a first comparable performance measure between centers, allowing for internal as well as external quality control. © Kushnir et al.; licensee BioMed Central Ltd.


Gleicher N.,The Center for Human Reproduction | Gleicher N.,Foundation Medicine | Kushnir V.A.,The Center for Human Reproduction | Barad D.H.,The Center for Human Reproduction | Barad D.H.,Foundation Medicine
Reproductive Biology and Endocrinology | Year: 2014

Only a few years ago the American Society of Assisted Reproductive Medicine (ASRM), the European Society for Human Reproduction and Embryology (ESHRE) and the British Fertility Society declared preimplantation genetic screening (PGS#1) ineffective in improving in vitro fertilization (IVF) pregnancy rates and in reducing miscarriage rates. A presumably upgraded form of the procedure (PGS#2) has recently been reintroduced, and is here assessed in a systematic review. PGS#2 in comparison to PGS#1 is characterized by: (i) trophectoderm biopsy on day 5/6 embryos in place of day-3 embryo biopsy; and (ii) fluorescence in-situ hybridization (FISH) of limited chromosome numbers is replaced by techniques, allowing aneuploidy assessments of all 24 chromosome pairs. Reviewing the literature, we were unable to identify properly conducted prospective clinical trials in which IVF outcomes were assessed based on " intent to treat" Whether PGS#2 improves IVF outcomes can, therefore, not be determined. Reassessments of data, alleged to support the efficacy of PGS#2, indeed, suggest the opposite. Like with PGS#1, the introduction of PGS#2 into unrestricted IVF practice again appears premature, and threatens to repeat the PGS#1 experience, when thousands of women experienced reductions in IVF pregnancy chances, while expecting improvements. PGS#2 is an unproven and still experimental procedure, which, until evidence suggests otherwise, should only be offered under study conditions, and with appropriate informed consents. © 2014 Gleicher et al.; licensee BioMed Central Ltd.


Sen A.,The Center for Human Reproduction | Kushnir V.A.,The Center for Human Reproduction | Barad D.H.,The Center for Human Reproduction | Gleicher N.,The Center for Human Reproduction
Nature Reviews Endocrinology | Year: 2013

An increasing body of evidence suggests that immune-mediated processes affect female reproductive success at multiple levels. Crosstalk between endocrine and immune systems regulates a large number of biological processes that affect target tissues, and this crosstalk involves gene expression, cytokine and/or lymphokine release and hormone action. In addition, endocrine-immune interactions have a major role in the implantation process of the fetal (paternally derived) semi-allograft, which requires a reprogramming process of the maternal immune system from rejection to temporary tolerance for the length of gestation. Usually, the female immune system is supportive of all of these processes and, therefore, facilitates reproductive success. Abnormalities of the female immune system, including autoimmunity, potentially interfere at multiple levels. The relevance of the immune system to female infertility is increasingly recognized by investigators, but clinically is often not adequately considered and is, therefore, underestimated. This Review summarizes the effect of individual autoimmune endocrine diseases on female fertility, and points towards selected developments expected in the near future.


PubMed | The Center for Human Reproduction
Type: Journal Article | Journal: Reproductive biology and endocrinology : RB&E | Year: 2016

A published review of the literature by Dutch investigators in 2004 suggested significant outcome differences between spontaneously - and in vitro fertilization (IVF) - conceived singleton and twin pregnancies. Here we review whether later studies between 2004-2015 confirmed these findings. Though methodologies of here reviewed studies varied, and all were retrospective, they overall confirmed results of the 2004 review, and supported significant outcome variances between spontaneously- and IVF-conceived pregnancies: IVF singletons demonstrate significantly poorer and IVF twins significantly better perinatal outcomes than spontaneously conceived singletons and twins, with differences stable over time, and with overall obstetrical outcomes significantly improved. Exaggerations of severe IVF twin risks are likely in the 50% range, while exaggerations of milder perinatal risks are approximately in 25 % range. Though elective single embryo transfers (eSET) have been confirmed to reduce pregnancy chances, they are, nevertheless, increasingly utilized. eSET, equally unquestionably, however, reduces twin pregnancies. Because twin pregnancies have been alleged to increase outcome risks in comparison to singleton pregnancies, here reported findings should affect the ongoing discussion whether increased twin risks are factual. With no risk excess, eSET significantly reduces IVF pregnancy chances without compensatory benefits and, therefore, is not advisable in IVF, unless patients do not wish to conceive twins or have medical contraindications to conceiving twins.


PubMed | The Center for Human Reproduction
Type: Review | Journal: Reproductive biology and endocrinology : RB&E | Year: 2017

Assisted Reproductive Technology (ART) has undergone considerable changes over the last decade, with consequences on ART outcomes in different regions of the world being unknown.We conducted a systematic review of published national and regional ART registry data to assess how changes in clinical practice between 2004 and 2013 have impacted outcomes in Australia and New Zealand, Canada, Continental Europe, the United Kingdom (U.K.), Japan, Latin America, and the United States (U.S.). The data reflect 7,079,145 total ART cycles utilizing both fresh and previously cryopreserved embryos from autologous oocytes that resulted in 1,454,724 live births. This review focused on the following measures: ART cycle volume, use of cryopreserved embryos, single embryo transfer (SET), live birth rates in fresh and frozen-thawed cycles, and perinatal outcomes in recent years.SETs and utilization of frozen-thawed embryos increased worldwide over the study period. In 2012 SET utilization in all ART cycles was highest in Japan and Australia/New Zealand (82.6% and 76.3% respectively) and lowest in Latin America (16.0%). While gradual improvements in live birth rates were observed in most regions, some demonstrated declines. By 2012-2013, fresh cycle live birth rates were highest in the U.S. (29%) and lowest in Japan (5%). In Japan, the observed decline in fresh cycle live birth rate coincided with transition to minimal stimulation protocols, transfer of frozen-thawed rather than fresh embryos, and implementation of an SET policy. Similarly, implementation of an SET policy in parts of Canada was followed by a decline in fresh cycle live birth rate. Increasing live birth rates in frozen-thawed embryo cycles, seen all over the world, partially compensated for declines in fresh ART cycles. During 2012-2013 Australia/New Zealand and Japan reported the lowest multiple delivery rates of 5.6 and 4% respectively while the US had the highest of 27%. In recent years, preterm delivery rates in all regions ranged between 9.0 to 16.6% for singletons, 53.9 to 67.3% for twins, and 91.4 to 100% for triplets and higher order multiples. Inconsistencies in the way perinatal outcome data are presented by various registries, made comparison between regions difficult.ART practices are characterized by outcome differences between regions. International consensus on the definition of ART success, which accounts for perinatal outcomes, may help to standardize worldwide ART practice and improve outcomes.PROSPERO ( CRD42016033011 ).

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