Vigorous vs. moderate exercise to improve glucose metabolism in inactive women with polycystic ovary syndrome and insulin resistance: a pilot randomized controlled trial of two home-based exercise routines.

Objective: To study the impact of vigorous vs. moderate exercise on metabolic parameters in polycystic ovary syndrome (PCOS). Design: Randomized controlled trial. Setting: Unsupervised home-based exercise program. Patients: Patients with PCOS on the basis of the Rotterdam criteria with insulin resistance. Interventions: Participants were block randomized to a home-based exercise program of 75 minutes of vigorous exercise or 150 minutes of moderate exercise per week, for 8 weeks total. Main Outcome Measures: Changes in glucose, insulin, and insulin resistance. Results: In total, 36 participants were randomized, of whom 20 completed the study. The percentage changes from baseline at 4 and 8 weeks for fasting glucose, insulin, and homeostatic model assessment for insulin resistance did not significantly differ between the groups, except for the change in the 8-week glucose level, which was more favorable in the moderate arm (8.06% [standard deviation, 6.44%] in the vigorous group compared with -0.32% [standard deviation, 4.91%] in the moderate group). The absolute values of the main outcomes (fasting glucose, insulin, and homeostatic model assessment for insulin resistance) at baseline and 4 and 8 weeks did not significantly differ between trial arms. When assessing the change from baseline at 4 and 8 weeks, overall and within each trial arm, only the 8-week fasting glucose level was significantly greater than the baseline value in the vigorous arm (93.5 [95% confidence interval, 88.7-98.3] vs. 86.8 [95% confidence interval, 81.1-92.4]). Conclusions: Unsupervised short-term exercise programs may not achieve significant metabolic improvements in patients with PCOS, regardless of vigorous vs. moderate intensity. Future studies should investigate this question in larger sample sizes and longer or structured exercise programs. Clinical Trial Registration Number: ClinicalTrials.gov identifier, NCT02303470.

Uterine synechiae after intrauterine device use: a case series.

PURPOSE: The intrauterine device (IUD) is one of the most effective and safe contraceptive methods. Substantial literature suggests an overall return to normal fertility following IUD removal. However, there are no studies to date that evaluate endometrial function specifically in nulliparous women after levonorgestrel IUD use. METHODS: We present three nulliparous women with a history of levonorgestrel IUD use who were evaluated for uterine dysfunction at the University of California, San Francisco Center for Reproductive Health. These patients had no other known risk factors or history of uterine manipulation, including prior uterine surgery, pelvic radiation, intrauterine infection, hypothalamic amenorrhea, or uterine anomaly. RESULTS: Upon evaluation, these patients were found to have uterine synechiae concerning for Asherman syndrome. All three patients were eventually able to conceive through assisted reproductive technology or natural conception. CONCLUSION: This case series is the first to suggest a possible effect of endometrial dysfunction on fertility resumption following levonorgestrel IUD removal in nulliparous patients. It is possible that a small subset of patients may be at risk for Asherman syndrome after IUD use. Larger prospective trials are needed to explore this possible association.

Multi-chorionic pregnancies following single embryo transfer at the blastocyst stage: a case series and review of the literature.

OBJECTIVE: To report cases of in vitro fertilization-frozen embryo transfer (IVF-FET) with single blastocyst transfer resulting in di- or tri-chorionic pregnancies, and to review the literature on monozygotic, multi-chorionic pregnancies originating at the blastocyst stage. DESIGN: Retrospective case series and literature review. MATERIALS AND METHODS: All in vitro fertilization cycles (fresh, frozen, autologous, and donor oocyte) performed between June 2012 and June 2017 at the University of California, San Francisco Center for Reproductive Health, were reviewed retrospectively. Cycles with cleavage-stage embryos or transfer of more than one blastocyst were excluded. Cycles were analyzed to determine if clinical pregnancy occurred with the presence of two or more gestational sacs noted on initial ultrasound. An in-depth chart review was performed with further exclusions applied that would lend credence to dizygosity rather than monozygosity such as fetal/neonatal sex discordance, fresh embryo transfer, and natural cycle FET (in which concomitant spontaneous pregnancy could have occurred). Demographic, clinical and IVF-FET cycle characteristics of the resulting patients were collected. Additionally, a review of the English language literature was performed (PUBMED, PMC) using the search words monozygotic twins, dichorionic diamniotic, in vitro fertilization, and single embryo transfer in order to identify cases of DC-DA monozygotic twinning from 1978 to 2017. Resulting articles were reviewed to eliminate all cases of dizygosity and day 3 embryo transfers. We obtained the following data from the literature search: basic patient demographics, type of fertilization, type and day of embryo transferred, number of embryos transferred, gestational ultrasound details, presence of any genetic testing if performed after delivery, and number of live births. RESULT(S): Two thousand four hundred thirty-four women underwent fresh or frozen single embryo transfer between June 2012 and June 2017 at the University of California, San Francisco Center for Reproductive Health. Of these, 11 women underwent a single blastocyst transfer with subsequent clinical pregnancies identified as multi-chorionic gestations. Four were in downregulated controlled FET cycles, in which concomitant spontaneous pregnancy could not have been possible. We then reviewed all cases of monozygotic dichorionic-diamniotic (DC-DA) splitting in IVF patients reported in the literature from 1978 to 2017. These eight cases demonstrate monozygotic splitting after the blastocyst stage, which challenges the existing dogma that only monochorionic twins can develop after day 3 post-fertilization. CONCLUSION(S): The accepted theory of monozygotic twinning resulting from the splitting of an embryo per a strict post-fertilization timing protocol must be re-examined with the advent of observed multi-chorionic pregnancies resulting from single blastocyst transfer in the context of IVF.

Outcomes from a university-based low-cost in vitro fertilization program providing access to care for a low-resource socioculturally diverse urban community.

OBJECTIVE: To report on outcomes from a university-based low-cost and low-complexity IVF program using mild stimulation approaches and simplified protocols to provide basic access to ART to a socioculturally diverse low-income urban population. DESIGN: Retrospective cohort study. SETTING: Academic infertility center. PATIENT(S): Sixty-five infertile couples were enrolled from a county hospital serving a low-resource largely immigrant population. INTERVENTIONS(S): Patients were nonrandomly allocated to one of four mild stimulation protocols: clomiphene/letrozole alone, two clomiphene/letrozole-based protocols involving sequential or flare addition of low-dose gonadotropins, and low-dose gonadotropins alone. Clinical fellows managed all aspects of cycle preparation, monitoring, oocyte retrieval, and embryo transfer under an attending preceptor. Retrieval was undertaken without administration of deep anesthesia, and laboratory interventions were minimized. All embryo transfers were performed at the cleavage stage. MAIN OUTCOME MEASURE(S): Sociomedical demographics, treatment response, and pregnancy outcomes were recorded. RESULT(S): From August 2010 to June 2016, 65 patients initiated 161 stimulation IVF cycles, which resulted in 107 retrievals, 91 fresh embryo transfers, and 40 frozen embryo transfer cycles. The mean age of patients was 33.3 years, and mean reported duration of infertility was 5.3 years; 33.5% (54/161) of cycles were cancelled before oocyte retrieval, with 13% due to premature ovulation. Overall, cumulative live birth rates per retrieval including subsequent use of frozen embryos was 29.0%; 44.6% (29/65) of patients enrolled in the program achieved pregnancy. CONCLUSION(S): Use of mild stimulation protocols, simplified monitoring, and minimized laboratory handling procedures enabled access to care in a low-resource socioculturally diverse infertile population.

Vigorous exercise is associated with superior metabolic profiles in polycystic ovary syndrome independent of total exercise expenditure.

OBJECTIVE: To characterize metabolic features of women with polycystic ovary syndrome (PCOS) by exercise behavior and determine relative health benefits of different exercise intensities. DESIGN: Cross-sectional study. SETTING: Tertiary academic institution. PATIENT(S): Three hundred and twenty-six women aged 14-52 years-old with PCOS by Rotterdam criteria examined between 2006 and 2013. INTERVENTION(S): International Physical Activity Questionnaire (IPAQ) administered to classify patients into three groups based on Department of Health and Human Services (DHHS) Guidelines of vigorous, moderate, and inactive, along with physical examination and serum testing. MAIN OUTCOME MEASURE(S): Blood pressure, body mass index (BMI), waist circumference, fasting lipids, fasting glucose and insulin, 2-hour 75-gram oral glucose tolerance, homeostatic model assessment of insulin resistance (HOMA-IR). RESULT(S): The DHHS guidelines for adequate physical activity were met by 182 (56%) women. Compared with moderate exercisers and inactive women, the vigorous exercisers had lower BMI and lower HOMA-IR; higher levels of high-density lipoprotein cholesterol and sex hormone-binding globulin; and a reduced prevalence of the metabolic syndrome. In a multivariate logistic regression analysis controlling for age, BMI, and total energy expenditure, every hour of vigorous exercise reduced a patient's odds of metabolic syndrome by 22% (odds ratio 0.78; 95% confidence interval, 0.62, 0.99). CONCLUSION(S): Women with PCOS who met DHHS guidelines for exercise demonstrated superior metabolic health parameters. Vigorous but not moderate activity is associated with reduced odds of the metabolic syndrome, independent of age, BMI, and total energy expenditure. PCOS patients should be encouraged to meet activity guidelines via vigorous physical activity.

Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae.

It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining >/=5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment.

Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.

UNLABELLED: Background- Variation in LDL-cholesterol (LDL-C) among individuals is a complex genetic trait involving multiple genes and gene-environment interactions. METHODS AND RESULTS: In a genome-wide association study (GWAS) to identify genetic variants influencing LDL-C in an isolated population from Kosrae, we observed associations for SNPs in the gene encoding 3hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR). Three of these SNPs (rs7703051, rs12654264, and rs3846663) met the statistical threshold of genome-wide significance when combined with data from the Diabetes Genetics Initiative GWAS. We followed up the association results and identified a functional SNP in intron13 (rs3846662), which was in linkage disequilibrium with the SNPs of genome-wide significance and affected alternative splicing of HMGCR mRNA. In vitro studies in human lymphoblastoid cells demonstrated that homozygosity for the rs3846662 minor allele was associated with up to 2.2-fold lower expression of alternatively spliced HMGCR mRNA lacking exon13, and minigene transfection assays confirmed that allele status at rs3846662 directly modulated alternative splicing of HMGCR exon13 (42.9+/-3.9 versus 63.7+/-1.0%Deltaexon13/total HMGCR mRNA, P=0.02). Further, the alternative splice variant could not restore HMGCR activity when expressed in HMGCR deficient UT-2 cells. CONCLUSIONS: We identified variants in HMGCR that are associated with LDL-C across populations and affect alternative splicing of HMGCR exon13.

Monocytes form a vascular barrier and participate in vessel repair after brain injury.

Subpopulations of bone marrow-derived cells can be induced to assume a number of endothelial properties in vitro. However, their ability to form a functional vascular barrier has not been demonstrated. We report that human CD14+ peripheral blood monocytes cultured under angiogenic conditions develop a number of phenotypic and functional properties similar to brain microvascular endothelial cells. These cells express the tight junction proteins zonula occludens 1 (ZO-1) and occludin and form a barrier with a transcellular electrical resistance (TCER) greater than 100 ohm cm2 and low permeability to 4 kDa and 20 kDa dextrans. The TCER of the cellular barrier is decreased by bradykinin and histamine. We also demonstrate that these cells associate with repairing vasculature in areas of brain and skin injury. Our data suggest that CD14+ peripheral blood monocytes participate in the repair of the vascular barrier after brain injury.

Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation.

The Notch family of proteins plays an integral role in determining cell fates, such as proliferation, differentiation, and apoptosis. We show that Notch-1 and its ligands, Delta-like-1 and Jagged-1, are overexpressed in many glioma cell lines and primary human gliomas. Immunohistochemistry of a primary human glioma tissue array shows the presence in the nucleus of the Notch-1 intracellular domain, indicating Notch-1 activation in situ. Down-regulation of Notch-1, Delta-like-1, or Jagged-1 by RNA interference induces apoptosis and inhibits proliferation in multiple glioma cell lines. In addition, pretreatment of glioma cells with Notch-1 or Delta-like-1 small interfering RNA significantly prolongs survival in a murine orthotopic brain tumor model. These results show, for the first time, the dependence of cancer cells on a single Notch ligand; they also suggest a potential Notch juxtacrine/autocrine loop in gliomas. Notch-1 and its ligands may present novel therapeutic targets in the treatment of glioma.

Noninvasive MR imaging of magnetically labeled stem cells to directly identify neovasculature in a glioma model.

Bone marrow-derived endothelial precursor cells incorporate into neovasculature and have been successfully used as vehicles for gene delivery to brain tumors. To determine whether systemically administered Sca1+ bone marrow cells labeled with superparamagnetic iron oxide nanoparticles can be detected by in vivo magnetic resonance imaging in a mouse brain tumor model, mouse Sca1+ cells were labeled in vitro with ferumoxides-poly-L-lysine complexes. Labeled or control cells were administered intravenously to glioma-bearing severe combined immunodeficient (SCID) mice. Magnetic resonance imaging (MRI) was performed during tumor growth. Mice that received labeled cells demonstrated hypointense regions within the tumor that evolved over time and developed a continuous dark hypointense ring at a consistent time point. This effect was not cleared by administration of a gadolinium contrast agent. Histology showed iron-labeled cells around the tumor rim in labeled mice, which expressed CD31 and von Willebrand factor, indicating the transplanted cells detected in the tumor have differentiated into endothelial-like cells. These results demonstrate that MRI can detect the incorporation of magnetically labeled bone marrow-derived precursor cells into tumor vasculature as part of ongoing angiogenesis and neovascularization. This technique can be used to directly identify neovasculature in vivo and to facilitate gene therapy by noninvasively monitoring these cells as gene delivery vectors.